Tutoria de Urologia 2

CATEDRA DE UROLOGIA
TRABAJO DE TUTORIA
INTEGRANTES:
Andadre Ivanna
Cargua Melanie
Delgado Miguel
Jimenez Ricardo
Tema:
Covid e Infertilidad Masculina
Docente:
Dr.Victor Sanchez
Curso:
7mo C
Semestre A-2022
Rev Int Androl. 2020;18(3):117---123
www.elsevier.es/andrologia
ARTÍCULO ESPECIAL
Infección por SARS-CoV-2: implicaciones para la salud

sexual y reproductiva. Una declaración de posición de
la Asociación Española de Andrología, Medicina Sexual
y Reproductiva (ASESA)
Ferran García José a,∗ , Juan G. Álvarez González b , Juan Manuel Corral Molina c ,
Lluis Bassas Arnau d , Ignacio Moncada Iribarren e ,
José Maria Martínez Jabaloyas f , Fernando Meijide Rico g ,
Rodrigo García-Baquero h , Mariano Rosselló Gayá i , Enrique Lledó García j ,
Carmen Luque López k , Rafael Prieto Castro l y Juan Ignacio Martinez Salamanca m
a
Unidad de Andrología. Instituto Marqués. Barcelona, España
b
Centro Androgen, La Coruña, España. Harvard Medical School, Boston, EE.UU
c
Servicio de Urología, Hospital Clínico de Barcelona. Barcelona, España
d
Fundación Puigvert, Servicio de Andrologia, Universidad Autónoma de Barcelona, Barcelona, España
e
Servicio de Urología, Hospital Universitario La Zarzuela, Madrid, España
f
Servicio de Urología, Hospital Clínico Universitario de Valencia. Valencia, España
g
Servicio de Urología, Hospital Povisa, Vigo, Pontevedra, España
h
Servicio de Urología, Hospital Universitario Puerta del Mar. Cádiz, España
i
Instituto Médico Rosselló --- Centro Asoc. Quirón Palma-Planas Palma de Mallorca
j
Servicio de Urología, Hospital General Universitario Gregorio Marañón, Madrid
k
Centro Salud Albarizas. Marbella, Málaga, España
l
Unidad de Andrología, Medicina Sexual y Reproductiva, Unidad Clínica de Urología, Hospital Regional Universitario Reina Sofía,
Córdoba, España
m
Servicio de Urología, Hospital Universitario Puerta de Hierro Majadahonda, Universidad Autónoma de Madrid, Majadahonda,
Madrid, España
Recibido el 15 de junio de 2020; aceptado el 26 de junio de 2020
PALABRAS CLAVE Resumen

SARS-CoV-2; Objetivo: El objetivo de esta revisión es resumir la evidencia disponible sobre los posibles efec-
COVID-19; tos adversos del SARS-CoV-2 en el sistema reproductor masculino y proporcionar una declaración
Orquitis; de posición oficial de la Asociación Española de Andrología, Medicina Sexual y Reproductiva
Semen; (ASESA).
Fertilidad masculina Métodos: Se realizó una búsqueda exhaustiva en las bibliotecas Pubmed, Web of Science,
Embase, Medline, Cochrane y MedRxiv.
∗ Autor para correspondencia. Unidad de Andrología. Instituto Marqués. Avinguda Diagonal, 662-664, 08034, Barcelona, España. Tel.: +34
932 197 696.

Correo electrónico: ferrangarcia@asesa.org (F.G. José).
https://doi.org/10.1016/j.androl.2020.06.001
1698-031X/© 2020 Publicado por Elsevier España, S.L.U. en nombre de Asociación Española de Andrología, Medicina Sexual y Reproductiva.
Este es un artículo Open Access bajo la licencia CC BY-NC-ND (http://creativecommons.org/licenses/by-nc-nd/4.0/).
118 F.G. José et al.
Resultados: No se ha confirmado la orquitis como una posible complicación de la infección

por SARS-CoV-2. Un estudio informó que el 19% de los hombres con COVID-19 presentaban
molestias escrotales sugestivas de orquitis viral, que no se pudo confirmar. Es posible que el
virus no infecte los testículos directamente, si no que desencadene una respuesta autoinmune
secundaria y que cause una orquitis autoinmune. COVID-19 se ha asociado con anormalidades
en la coagulación por lo que la orquitis podría ser el resultado de una vasculitis segmentaria.
Los datos disponibles sobre la presencia del virus en semen son contradictorios. Sólo un estudio
informó de la presencia de ARN en el 15,8% de enfermos de COVID-19. La presencia de ácido
nucleico o antígeno en el semen no implica la existencia de virus con capacidad de replicación
o infección.
En hombres con COVID-19 se ha observado un incremento significativo de LH en suero y una
drástica disminución de la ratio T/LH y FSH/LH, congruente con un hipogonadismo subclínico.
Conclusiones: Los datos disponibles y los hallazgos de los estudios recientes se basan en tamaños
de muestra pequeños y proporcionan informaciones contradictorias. Existe la posibilidad teórica
de que pueda producirse daño testicular y posterior infertilidad después de la infección por
COVID-19, por lo que especialmente para aquellos hombres en edad reproductiva, se debe
sugerir consulta y evaluación de la función gonadal y análisis de semen. En cuanto a la posibilidad
de transmisión sexual, no hay evidencia suficiente para respaldar la necesidad de que las parejas
asintomáticas eviten las relaciones sexuales para protegerse contra la transmisión del virus.
Se necesita más investigación para comprender los impactos a largo plazo del SARS-CoV-2 en
la función reproductiva masculina, incluidos sus posibles efectos sobre la fertilidad y la función
endocrina testicular.
© 2020 Publicado por Elsevier España, S.L.U. en nombre de Asociación Española de Andrología,
Medicina Sexual y Reproductiva. Este es un artículo Open Access bajo la licencia CC BY-NC-ND
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
KEYWORDS SARS-CoV-2 infection: implications for sexual and reproductive health. A position
SARS-CoV-2; statement of the Asociación Española de Andrología, Medicina Sexual y Reproductiva
COVID-19; (ASESA)
Orchitis; Abstract
Semen; Objective: The main objective of this revision is to summarize the current existing evidence
Male fertility of the potential adverse effects of SARS-CoV-2 on the male reproductive system and provide
the recommendations of the Asociación Española de Andrología, Medicina Sexual y Reproductiva
(ASESA) concerning the implications of COVID-19 infection in the management of male infertilty
patients and testicular endocrine dysfunction.
Methods: A comprehensive systematic literature search of the databases of PubMed, Web of
Science, Embase, Medline, Cochrane and MedRxiv, was carried out.
Results: The presence of orchitis as a potential complication of the infection by SARS-CoV-2
has not yet been confirmed. One study reported that 19% of males with COVID-19 infection had
scrotal symptoms suggestive of viral orchitis which could not be confirmed. It is possible that
the virus, rather than infecting the testes directly, may induce a secondary autoimmune res-
ponse leading to autoimmune orchitis. COVID-19 has been associated with coagulation disorders
and thus the orchitis could be the result of segmental vasculitis. Existing data concerning the
presence of the virus in semen are contradictory. Only one study reported the presence of RNA
in 15.8% of patients with COVID-19. However, the presence of nucleic acid or antigen in semen
is not synonyms of viral replication capacity and infectivity.
It has been reported an increase in serum levels of LH in males with COVID-19 and a significant
reduction in the T/LH and FSH/LH ratios, consistent with subclinical hypogonadism.
Conclusions: The findings of recent reports related to the potential effects of COVID-19 infec-
tion on the male reproductive system are based on poorly designed, small sample size studies
that provide inconclusive, contradictory results. Since there still exists a theoretical possibility
of testicular damage and male infertilty as a result of the infection by COVID-19, males of repro-
ductive age should be evaluated for gonadal function and semen analysis. With regard to the
sexual transmission of the virus, there is not sufficient evidence to recommend asymptomatic
couples to abstein from having sex in order to protect themselves from being infected by the
virus.
Additional studies are needed to understand the long-term effects of SARS-CoV-2 on male
reproductive function, including male fertility potential and endocrine testicular function.
© 2020 Published by Elsevier España, S.L.U. on behalf of Asociación Española de Andrología,
Medicina Sexual y Reproductiva. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
Infección por SARS-CoV-2: implicaciones para la salud sexual y reproductiva. Una declaración de posición de la Asociación119
Introducción [Términos MeSH] O ‘‘testis’’ [Todos los campos]) AND (‘‘virus

SARS’’ [Términos MeSH] O (‘‘SARS’’ [Todos los campos],
En diciembre de 2019 hubo un brote epidémico de neumo- (‘‘semen’’ [Términos MeSH] O ‘‘semen’’ [Todos los cam-
nía de etiología desconocida en Wuhan (provincia de Hubei, pos]) AND (‘‘virus SARS’’ [Términos MeSH] O (‘‘SARS’’ [Todos
China)1 . El 7 de enero de 2020, las autoridades chinas iden- los campos] y (‘‘virus’’ [Todos los campos]) O ‘‘virus SARS’’
tificaron como agente causante del brote un nuevo tipo de [Todos los campos] O (‘‘SARS’’ [Todos los campos] Y ‘‘CoV’’
virus de la familia Coronaviridae, que posteriormente ha sido [Todos los campos]) O ‘‘SARSCoV’’ [Todos los campos]).
denominado Coronavirus 2 del Síndrome Respiratorio Agudo
Severo (SARS-CoV-2, por sus siglas en inglés) y cuya secuen- SARS-CoV-2: Origen y características de los
cia genética fue compartida por las autoridades chinas el 12 coronavirus
de enero2 .
La rápida propagación de la enfermedad por coronavi- SARS-CoV-2 es un beta-coronavirus de origen zoonótico, al
rus 2019 (COVID-19) por todo el mundo, llevó a la OMS a igual que SARS-CoV y MERS-CoV, perteneciente a la familia
declararla pandemia mundial el 11 de marzo3 . Coronaviridae. Algunos estudios filogenéticos han sugerido
Aunque COVID-19 afecta predominantemente el sistema que provendría del murciélago de herradura de donde habría
respiratorio, la evidencia indica que se trata de una enfer- pasado al ser humano a través de mutaciones o recombina-
medad multisistémica que con frecuencia es grave y a ciones sufridas en un huésped intermedio, probablemente
menudo resulta en la muerte. algún animal vivo del mercado de Wuhan, como el pangolín,
El mundo se enfrenta a una emergencia de salud pública aunque este extremo no ha podido ser confirmado.
sin precedentes, que ha superado los 8 millones de casos Los coronavirus son virus ARN monocatenarios con una
en todo el mundo con más de 440.000 fallecidos. En España envoltura lipídica rodeada de una corona de proteínas en
el número de casos diagnosticados supera los 245.000 y una forma de espícula (proteína S). Se dividen en cuatro géneros:
cifra oficial de fallecidos superior a 28.000 (datos del 19 de alfa, beta, gamma y delta-coronavirus. Hasta la fecha se han
junio de 2020). identificado siete coronavirus humanos (HCoV) que pueden
La rápida expansión geográfica, junto con la elevada producir cuadros clínicos que van desde el resfriado común
transmisibilidad y las graves manifestaciones clínicas de la con patrón estacional en invierno, como los alfa-coronavirus
enfermedad, llevaron a los gobiernos y a las autoridades HCoV-NL63 y HCoV-229E y los beta-coronavirus HCoV-OC43 y
sanitarias a tomar medidas de confinamiento para tratar de HCoV-HKU1, al Síndrome Respiratorio Agudo Severo (SARS,
contener la pandemia. En las fases iniciales, tanto la Socie- por sus siglas en inglés), como los beta-coronavirus SARS-CoV
dad Americana de Medicina Reproductiva (ASRM) como la y SARS-CoV-2 o el Síndrome Respiratorio de Oriente Próximo
Sociedad Europea de Reproducción Humana y Embriología producido por el beta-coronavirus MERS-CoV.
(ESHRE) recomendaron la interrupción de los tratamientos SARS-CoV-2 comparte una homología de secuencia del
reproductivos, excepto en los casos más urgentes. Recien- 80% con el virus SARS-CoV responsable del brote de SARS
temente, gracias a la mitigación del primer brote de la en 20035 .
pandemia en algunos países como consecuencia de las
diferentes estrategias aplicadas por los gobiernos y conside-
rando las evidencias científicas existentes, estas sociedades SARS-CoV-2: Mecanismo de acción
han recomendado la reanudación gradual y juiciosa de los
tratamientos de reproducción asistida. En nuestro país, la El genoma de SARS-CoV-2 codifica 4 proteínas estructurales:
Sociedad Española de Fertilidad (SEF) y la Asociación para S (espícula), E (envoltura), M (membrana) y N (nucleocáp-
el estudio de la biología de la reproducción (ASEBIR) han side). La proteína N está en el interior del virión asociada al
publicado un documento sobre las medidas que se deberían RNA viral, y el resto están asociadas a la envoltura viral.
tomar en los centros de reproducción asistida, tanto en rela- Como SARS-CoV, el mecanismo de infección de SARS-CoV-
ción con la atención y asistencia a pacientes, como en los 2 depende de su anclaje a las células humanas a través de
procedimientos de laboratorio4 . la interacción entre la proteína S del virus y el receptor de
A pesar de la abrumadora magnitud de la pandemia, la la célula huésped, la enzima convertidora de angiotensina 2
información existente sobre los efectos adversos del SARS- (ACE-2 por sus siglas en inglés) 6 y de la posterior endocitosis
CoV-2 sobre la salud sexual y reproductiva masculina es del genoma viral en el citoplasma por la acción de una serin-
limitada y las posibles repercusiones a largo plazo sobre la proteasa transmembrana (TMPRSS2)7 .
fertilidad a nivel global y la potencial transmisión por vía ACE-2 se expresa ampliamente en diferentes tejidos
sexual no se han dilucidado. humanos como el intestino, testículo, riñón, cerebro,
El objetivo de este trabajo es resumir la evidencia dis- hígado, pulmón o endotelio vascular. Siendo el intestino del-
ponible en este momento, y proporcionar una declaración gado y el testículo donde se encuentra un mayor nivel de
de posición oficial de la Asociación Española de Andrología, expresión.
Medicina Sexual y Reproductiva (ASESA). En el testículo se ha documentado su presencia en células
de los túbulos seminíferos, en las espermatogonias y en las
células de Sertoli y de Leydig8 .
Método TMPRSS2 se expresa altamente en las células epiteliales
de la próstata, incluida la membrana plasmática apical de
Se realizó una búsqueda exhaustiva en las bibliotecas las células luminales de la próstata. Su expresión está regu-
Pubmed, Web of Science, Embase, Medline, Cochrane y lada por los andrógenos y también se libera en el semen
MedRxiv con base en las siguientes palabras clave: (‘‘testis’’ como un componente de los prostasomas, vesículas similares
a los orgánulos que pueden facilitar la función del esperma momento del diagnóstico de COVID-19, no se completó el
y mejorar la reproducción masculina9 . estudio genitourinario debido a la pandemia 16 .
Hay evidencia de la presencia de ARN del SARS-CoV-2 en Un ‘‘preprint’’ disponible online en el repositorio
varias matrices biológicas, como muestras de heces, sangre www.medRxiv.org y en consecuencia no evaluado por pares,
y orina. informó de la ausencia de SARS-CoV-2 en la biopsia testicular
Basándonos en estas consideraciones previas, la posibi- de un paciente de 67 años fallecido por COVID-1917 .
lidad de que el virus SARS-CoV-2 pueda identificarse en el Otro estudio realizó el análisis post mortem de los testí-
tejido testicular o en el líquido seminal tendría importantes culos de 12 pacientes con COVID-19 utilizando microscopía
implicaciones, especialmente en lo que respecta a la repro- óptica y microscopía electrónica, e inmunohistoquímica
ducción asistida, a la criopreservación de gametos y a la para marcadores linfocíticos e histiocíticos. Para la detec-
posibilidad de transmisión sexual de la enfermedad. ción del virus en el tejido testicular se usó la reacción
en cadena de la polimerasa de transcripción inversa (RT-
PCR). La edad media fue de 65 años (rango 42-87). La
SARS-CoV-2 y testículo duración media de la enfermedad (desde el inicio hasta
la muerte) fue de 42 días (rango 23-75 días). La fiebre
El testículo presenta un estado de privilegio inmunológico estaba presente en diez pacientes. Diez pacientes recibie-
que tolera los alo y autoantígenos. Múltiples mecanis- ron dosis bajas de esteroides. Los testículos de pacientes con
mos intervienen en el mantenimiento de este privilegio COVID-19 exhibieron lesiones tubulares seminíferas signifi-
inmune, empezando por la estructura especial de los tes- cativas, células de Leydig reducidas e inflamación linfocítica
tículos, en la que la barrera hematotesticular desempeña leve. Se observó espermatogénesis normal en tres casos.
un papel central en el secuestro de antígenos y anticuerpos Los otros casos mostraron grados variables de alteración
del sistema inmune. Siguiendo con las células testiculares espermatogénica que en general fue consistente con la edad
de Sertoli, Leydig, células mioides peritubulares y célu- del paciente. Por RT-PCR sólo en un paciente se encon-
las germinales meióticas y post meióticas que expresan tró evidencia de SARS-CoV-2 y en ninguno por microscopía
abundantemente el ligando FAS. Y finalizando con las célu- electrónica18 .
las inmunes, especialmente los macrófagos y las citocinas Uno de los fenómenos notables en el testículo del SARS-
paracrinas y endocrinas. Estos mecanismos generan en el CoV es la infiltración de leucocitos, que podrían afectar la
testículo un sistema inmune innato eficiente contra los pató- función de las células de Leydig y por ende la producción de
genos, cuya interrupción puede provocar orquitis y afectar testosterona, dañar la barrera hematotesticular y destruir
la fertilidad10 . el epitelio seminífero directamente. Más importante aún,
Es conocido que virus como el VIH, el VHB o el mixovirus estas células y sus productos, las citocinas inflamatorias,
parotiditis, pueden ser causa de orquitis viral y en algu- pueden activar la respuesta autoinmune y el desarrollo de
nos casos de infertilidad. Existe evidencia sobre la relación autoanticuerpos dentro de los túbulos. En un modelo murino
entre los miembros de la familia del coronavirus y la orquitis de orquitis autoinmune experimental se ha demostrado la
tanto en humanos (SARS-CoV)11 como en gatos (coronavirus existencia de depósitos de IgG en el epitelio germinal,
felino)12 . Los conocimientos adquiridos con SARS-CoV nos la membrana basal, el intersticio, el endotelio vascular y
deben hacer considerar el riesgo potencial de que SARS-CoV- las células germinales degeneradas19 . Se observó que los
2 pueda provocar orquitis, ya que ambos utilizan el mismo pacientes con SARS-CoV tienen aumentada la IgG en suero y
mecanismo de infección, el anclaje a las células humanas un estudio en testículos de pacientes con SARS-CoV informó
a través de la interacción entre la proteína S del virus y el de la presencia de una extensa precipitación de IgG en
receptor de la célula huésped ACE2 en células de los con- el epitelio seminífero, incluso en algunas células germina-
ductos seminíferos, en las espermatogonias y en las células les degeneradas y células de Sertoli12 . En consecuencia,
de Sertoli y de Leydig. No obstante, la presencia de SARS- cabe la posibilidad de que el virus no infecte los testículos
CoV en el epitelio testicular sigue siendo un tema de debate directamente, si no que desencadene una respuesta auto-
debido a la existencia de informes contradictorios sobre la inmune secundaria y que, como otras orquitis virales, sea
infección directa de los testículos por el virus. Un estudio una orquitis autoinmune. Alternativamente, COVID-19 oca-
identificó su presencia en células epiteliales testiculares y siona una intensa afectación endotelial que sería el principal
células de Leydig mediante microscopía electrónica com- determinante de disfunción microvascular y vasoconstric-
binada con FISH13 . Sin embargo, en otro estudio que utilizó ción, estado procoagulante con formación de microtrombos
hibridación in situ, microscopía electrónica y PCR en tiempo capilares e isquemia. Por lo que un síndrome similar a la
real, la presencia del virus en testículo fue negativa14 . En orquitis podría ser el resultado de la disfunción endotelial20 .
necropsias realizadas a ocho pacientes fallecidos se descri-
bió que la infección por SARS-CoV induce atrofia focal en el
tejido testicular pero no se detectó RNA viral15 . SARS-COV-2 Y función endocrina testicular
Son pocos los estudios enfocados al sistema reproductivo
masculino en pacientes con SARS-CoV-2 por lo que falta evi- Otro ‘‘preprint’’ evaluó la influencia de la infección por
dencia de los efectos del virus sobre el testículo humano, SARS-CoV-2 en la función gonadal masculina. Comparando
lo que es hasta cierto punto comprensible considerando la los resultados hormonales de 81 hombres en edad reproduc-
magnitud y gravedad de la pandemia y el poco tiempo trans- tiva (20-54 años) y COVID-19 con 100 hombres sanos de la
currido desde la aparición del virus en humanos. misma edad. Los resultados mostraron un incremento signifi-
Un estudio en 34 hombres informó que el 19% de ellos cativo de la LH en suero, pero la ratio T/LH y la ratio FSH/LH
tenían molestias escrotales sugestivas de orquitis viral en el se redujo drásticamente en los hombres con COVID-19. Estos
resultados serían congruentes con un hipogonadismo sub- la uretra y ser arrastrado por el semen en el momento de
clínico. El análisis de regresión multivariable mostró que la eyaculación. Tratándose de pacientes graves de COVID-
los niveles de proteína C reactiva se asociaban significati- 19 no puede descartarse una contaminación del semen en
vamente con la relación T/LH en suero en los pacientes con el momento de la obtención. Por otro lado, la presencia de
COVID-1921 . Sin embargo, el estudio presenta algunas limi- ácido nucleico o antígeno en el semen no implica necesa-
taciones, por ejemplo, no se realizó ningún análisis de los riamente la presencia de virus con capacidad de replicación
parámetros seminales ni se determinó la presencia del virus o infección, lo que generalmente solo puede demostrarse
en el semen, que serían pruebas más directas de una posi- mediante aislamiento y cultivo del virus.
ble afectación testicular por el SARS-CoV-2. Sólo 11 casos se
incluyeron para el análisis estadístico, lo que disminuye el SARS-COV-2 Y próstata
poder estadístico del análisis. Además, el eje hipotálamo-
hipófiso-gonadal podría afectarse por la misma condición de
Solo un pequeño estudio retrospectivo evaluó la presencia
la enfermedad, el estrés o la terapia con corticoides que
de SARS-CoV-2 en la secreción prostática de 18 hombres
recibieron algunos pacientes.
diagnosticados con COVID-19 y cinco casos sospechosos. Nin-
guna de las muestras tuvo evidencia de la expresión de ARN
SARS-COV-2 Y Semen del SARS-CoV-225 .
Probablemente la presencia de virus en el semen esté más Conclusiones

extendida de lo que se aprecia y no debe suponerse que los
virus tradicionalmente no transmitidos sexualmente están A pesar de que la información de la que disponemos hasta el
ausentes en las secreciones genitales. Aunque se han iden- momento se basa en tamaños de muestra pequeños que ofre-
tificado hasta 27 virus que pueden aparecer en el semen cen informaciones contradictorias, la posibilidad teórica de
humano, entre los más conocidos el virus de las paperas, que SARS-CoV-2 pueda producir daño testicular y sus posibles
VIH, VHB, VHC, HPV, citomegalovirus, VHS, Zika, Ébola, virus efectos sobre la fertilidad y la función endocrina testicu-
de la fiebre de Lassa, virus de la fiebre del Valle del Rift y lar, así como la posibilidad de transmisión sexual, no debe
los virus Chikunguña, para la mayoría de ellos faltan datos minimizarse.
sobre su posible transmisión sexual22 . Cabe la posibilidad de que el virus pueda atacar el tejido
La eliminación del virus en el semen depende de varios testicular inicialmente, pero se elimine de los testículos
factores entre los que se encuentran la respuesta inmune más tarde, durante el curso de la enfermedad. Alternativa-
del tracto reproductivo, los mediadores inflamatorios que mente, y merced al privilegio inmune del testículo, podría
alteran la barrera hematotesticular, la inmunosupresión sis- ser que el virus no infecte los testículos directamente y que
témica, la estabilidad estructural del virus y la intensidad se trate de una orquitis autoinmune o bien, relacionado con
de la carga viral. los trastornos de coagulación asociados con COVID-19, que la
Es obvio que la presencia de SARS-CoV-2 en el líquido sintomatología de orquitis sea consecuencia de una endote-
seminal tendría implicaciones sexuales y reproductivas por litis. Por otro lado, la hipertermia, la infección secundaria,
el riesgo de transmisión de la infección, pero nuestro conoci- la hipoxia y los esteroides pueden desempeñar un papel en
miento está limitado por la escasez de informes que abordan el daño tisular observado en los testículos de pacientes con
este tema y por sus resultados contradictorios. Dos publica- COVID-19. Todo ello podría conducir al daño de los conductos
ciones han informado de la ausencia del virus en el líquido seminíferos y a la anormalidad endocrina y eventual reduc-
seminal. La primera informó de la ausencia de ARN viral ción o ausencia de espermatogénesis en pacientes que se
tanto en semen como en orina, en un hombre ocho días han recuperado de COVID-19.
después del diagnóstico de COVID-1923 . Esta observación La evidencia actual sobre la presencia del virus en semen
fue confirmada posteriormente en una pequeña cohorte de es insuficiente y contradictoria. Los datos disponibles sugie-
treinta y cuatro varones chinos adultos, después de un mes ren la posibilidad de un aclaramiento viral con el transcurso
desde el diagnóstico de COVID-19 no se encontró ARN viral en del tiempo. Con independencia de ello, la presencia de ácido
semen16 . Ninguno de estos informes evaluó los parámetros nucleico o antígeno en el semen no implica necesariamente
seminales. la presencia de virus con capacidad de replicación o infec-
Una última investigación llamó la atención al informar ción. Se requieren estudios en cohortes más grandes para
que un 15,8% (6 de 38) de pacientes con COVID-19 grave, confirmar o no su presencia en el plasma seminal y la posi-
resultaron positivos para la presencia de SARS-CoV-2 en bilidad de transmisión sexual.
semen24 . De estos pacientes 4 estaban en la fase aguda de La evidencia disponible es insuficiente para respaldar la
la enfermedad (6-11 días desde el inicio de los síntomas) y necesidad de que las parejas asintomáticas eviten las rela-
2 en la fase de recuperación (12-16 días desde el inicio de ciones sexuales para protegerse contra la transmisión del
los síntomas). Sin embargo, se plantearon varias preocupa- virus, especialmente si consideramos que entre personas
ciones por cuestiones metodológicas. El artículo es parco en se transmite principalmente a través del contacto y de las
información sobre metodología y contexto y no informa del gotitas de Flügge.
método utilizado para detectar el virus en el semen, ni eva- La presencia de SARS-CoV-2 en tejido testicular o
luó la presencia del virus en orina, considerando que ésta es muestras de semen es de especial relevancia para la crio-
una de las matrices biológicas en las que se ha informado de preservación de gametos, porque los virus almacenados en
la presencia de ARN viral. Éste, más que de la vía seminal, nitrógeno líquido conservan sus propiedades patogénicas, y
podría provenir de la orina y encontrarse en la próstata o en en el caso del semen por la posibilidad de transmisión sexual.
Por lo que, durante la pandemia de COVID-19, cabrá distin- 3. WHO Director-General’s opening remarks at the media briefing
guir si las muestras proceden de pacientes confirmados o on COVID-19. Apr 11, 2020. [Accessed April 12, 2020]. Available
dudosos de padecer COVID-19 o libres de ella. at: https://www.who.int/dg/speeches/detail/who-director-
El mayor problema se presenta con los pacientes asin- general-s-opening-remarks-at-the-media-briefing-on-covid-
19—11-march-2020.
tomáticos de COVID-19, que se estiman entre 20-40%. Con
4. Recomendaciones para la seguridad y reducción de riesgos
el conocimiento actual, la realización de una RT-PCR para
ante la infección por coronavirus (SARS-CoV-2) en las clínicas
SARS-CoV-2 en varones asintomáticos que vayan a congelar de reproducción asistida. Actualización a 01/06/202 Available
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Research Letter | Infectious Diseases
Clinical Characteristics and Results of Semen Tests

Among Men With Coronavirus Disease 2019
Diangeng Li, PhD; Meiling Jin, MD; Pengtao Bao, PhD; Weiguo Zhao, MD; Shixi Zhang, MD
Introduction
In December 2019, an outbreak of pneumonia associated with coronavirus disease 2019 (COVID-19) Author affiliations and article information are
occurred in Wuhan, China, and rapidly spread to other parts of China and overseas.1 It has been con- listed at the end of this article.
firmed that COVID-19 has the characteristic of human-to-human transmission, mainly through respira-
tory droplets and contact. Other routes require further verification. The virus responsible for COVID-19,
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been detected in stool, gastrointes-
tinal tract, saliva, and urine samples.2 However, little is known about SARS-CoV-2 in semen.
Methods
This cohort study was performed after patients gave written informed consent for research
purposes, and in compliance with the Helsinki Declaration3 with the approval of the ethics
committee of Shangqiu Municipal Hospital, Shangqiu, China. This study is reported following the
Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
We identified all male patients with laboratory-confirmed COVID-19 aged 15 years and older
between January 26, 2020, and February 16, 2020, in Shangqiu Municipal Hospital, which is the only
designated hospital for the treatment of COVID-19 in Shangqiu, in the east of Henan province.
Following guidance from the World Health Organization,4 laboratory confirmation for COVID-19 was
defined as positive result for SARS-CoV-2 in real-time reverse transcriptase–polymerase chain
reaction (RT-PCR) assay of nasal and pharyngeal swabs.1 Enrolled patients were asked to provide a
semen sample for SARS-CoV-2 testing via RT-PCR.
Groups were compared using the t test, χ2 test, or Mann-Whitney or Kruskal-Wallis test. All
statistical analyses were performed using SPSS statistical software version 19 (IBM). P values were
2-tailed, and P < .05 was considered to indicate significant differences.
Results
Among 50 patients identified, 12 patients were unable to provide a semen specimen because of
erectile dysfunction, being in a comatose state, or dying prior to recruitment; therefore, a total of 38
Table. Clinical Characteristics of Patients With Positive Test Results for Severe Acute Respiratory Syndrome Coronavirus 2 in Semen
Time since onset of Time since clinical Presence of
Patienta Approximate age, ya symptoms, d Time since hospitalization, d recovery, d urogenital disease Other comorbidity
1 20s 6 2 NAb No Coronary heart disease,
hypertension
2 20s 10 6 NAb No Coronary heart disease
3 30s 11 5 NAb No No
4 40s 9 8 NAb No No
5 50s 12 10 2 Yes No
6 30s 16 13 3 No Chronic bronchitis
b
Abbreviation: NA, not applicable. Patient was still in the acute stage of infection.
a
For the purpose of anonymity, patients are identified by number and their ages are
given as approximates.
Open Access. This is an open access article distributed under the terms of the CC-BY License.
JAMA Network Open. 2020;3(5):e208292. doi:10.1001/jamanetworkopen.2020.8292 (Reprinted) May 7, 2020 1/3
Downloaded From: https://jamanetwork.com/ on 06/18/2022

JAMA Network Open | Infectious Diseases Clinical Characteristics and Results of Semen Tests Among Men With Coronavirus Disease 2019
patients were enrolled for semen testing. Of these 38 participants who provided a semen specimen,
23 participants (60.5%) had achieved clinical recovery and 15 participants (39.5%) were at the acute
stage of infection. Results of semen testing found that 6 patients (15.8%) had results positive for
SARS-CoV-2, including 4 of 15 patients (26.7%) who were at the acute stage of infection and 2 of 23
patients (8.7%) who were recovering, which is particularly noteworthy. But there was no significant
difference between negative and positive test results for patients by age, urogenital disease history,
days since onset, days since hospitalization, or days since clinical recovery. The clinical characteristics
of patients with positive test results for SARS-CoV-2 in semen are shown in the Table.
Discussion
In this cohort study, we found that SARS-CoV-2 can be present in the semen of patients with COVID-19,
and SARS-CoV-2 may still be detected in the semen of recovering patients. Owing to the imperfect
blood-testes/deferens/epididymis barriers, SARS-CoV-2 might be seeded to the male reproductive
tract, especially in the presence of systemic local inflammation. Even if the virus cannot replicate in the
male reproductive system, it may persist, possibly resulting from the privileged immunity of testes. So
far, researchers have found 27 viruses associated with viremia in human semen. But the presence of
viruses in semen may be more common than currently understood, and traditional non–sexually trans-
mitted viruses should not be assumed to be totally absent in genital secretions.5,6 Studies on viral de-
tection and semen persistence are beneficial to clinical practice and public health, especially concerning
viruses that could cause high mortality or morbidity, such as SARS-CoV-2.
This study is limited by the small sample size and the short subsequent follow-up. Therefore,
further studies are required with respect to the detailed information about virus shedding, survival
time, and concentration in semen.
If it could be proved that SARS-CoV-2 can be transmitted sexually in future studies, sexual
transmission might be a critical part of the prevention of transmission, especially considering the fact
that SARS-CoV-2 was detected in the semen of recovering patients. Abstinence or condom use might
be considered as preventive means for these patients. In addition, it is worth noting that there is a
need for studies monitoring fetal development. Therefore, to avoid contact with the patient’s saliva
and blood may not be enough, since the survival of SARS-CoV-2 in a recovering patient’s semen
maintains the likelihood to infect others. Our study might contribute by providing new information
to the current discourse regarding COVID-19 prevention and control.
ARTICLE INFORMATION
Accepted for Publication: April 13, 2020.
Published: May 7, 2020. doi:10.1001/jamanetworkopen.2020.8292
Correction: This article was corrected on June 1, 2020, to fix an omission in the Methods.
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Li D et al. JAMA
Network Open.
Corresponding Authors: Weiguo Zhao, MD, Department of Respiratory Medicine, The Eighth Medical Center of
Chinese People’s Liberation Army General Hospital, 17th Heishanhu Road, Beijing, 100093, China
(zhaowg309@163.com); Shixi Zhang, MD, Shangqiu Municipal Hospital, Shangqiu, No. 1 Yingbin Road, Shangqiu
City, Henan Province, China, 476100, China (Shixizhang1977@163.com).
Author Affiliations: Nanlou Respiratory Diseases Department, Chinese People’s Liberation Army General
Hospital, Beijing, China (Li); Department of Nephrology, Chinese People’s Liberation Army General Hospital,
Chinese People’s Liberation Army Institute of Nephrology, State Key Laboratory of Kidney Diseases, National
Clinical Research Center for Kidney Diseases, Chinese People’s Liberation Army Postgraduate Medical School,
Beijing, China (Li, Jin); Department of Nephrology, Beijing-Chaoyang Hospital, Beijing, China (Jin); Department of
Respiratory Medicine, The Eighth Medical Center of Chinese People’s Liberation Army General Hospital, Beijing,
China (Bao, Zhao); Shangqiu Municipal Hospital, Shangqiu, China (Zhang).

JAMA Network Open | Infectious Diseases Clinical Characteristics and Results of Semen Tests Among Men With Coronavirus Disease 2019
Author Contributions: Drs Zhao and Zhang had full access to all the data in the study and take responsibility for
the integrity of the data and the accuracy of the data analysis. Drs Li, Jin, and Bao contributed equally to this work.
Concept and design: Li, Jin, Zhao, Zhang.
Acquisition, analysis, or interpretation of data: Li, Jin, Bao.
Drafting of the manuscript: Li, Jin.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Li, Jin, Bao.
Obtained funding: Li, Jin.
Administrative, technical, or material support: Li, Zhao, Zhang.
Conflict of Interest Disclosures: None reported.
Funding/Support: This study was partially supported by grant KF2018-06 from the Open Project Program of the
State Key Laboratory of Kidney Diseases in People’s Liberation Army General Hospital.
Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection,
management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and
decision to submit the manuscript for publication.
REFERENCES
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3. World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical
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1056/NEJMe1803212

medRxiv preprint doi: https://doi.org/10.1101/2020.03.21.20037267; this version posted March 30, 2020. The copyright holder for this
preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in
perpetuity.
It is made available under a CC-BY-NC-ND 4.0 International license .
NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.
ARTÍCULO ESPECIAL
Gac Med Bilbao. 2020;117(2):118-119
Impacto de la pandemia SARS-CoV-2 (COVID-19) en el

ámbito de la medicina reproductiva y sus tratamientos
SARS-CoV-2 (COVID-19) pandemiaren eragina ugalketa-medikuntzaren eta haren
tratamenduen eremuan
Impact of the SARS-CoV-2 (COVID-19) pandemic in the field of reproductive
medicine and its treatments
La esterilidad está catalogada por la OMS como una en- rica posean este tipo de receptores, lo que implicaría la
fermedad y aunque no es de riesgo vital, sí afecta a la ca- imposibilidad de transmisión del virus por estas células.
lidad de vida y a la salud emocional de los que la padecen. Respecto a la gestación, la Organización Mundial de
En España sufrimos, como en gran parte de Europa, la Salud ha manifestado en un comunicado que, las mu-
un importante problema demográ!ico por la disminu- jeres embarazadas e infectadas por el virus no parecen
ción de nacimientos y el envejecimiento de la población, tener más riesgos de gravedad que la población afectada
agravados por una importante tendencia al retraso de la por la COVID-19 no gestante, y las manifestaciones clí-
maternidad. Este hecho, junto con otros factores sociales nicas tampoco varían, siendo similares en los dos grupos
y epidemiológicos, hacen que la infertilidad sea una poblacionales y de edades similares.
cuestión de salud pública ya que afecta a un 20% de la La literatura actual también aclara que la transmisión
población en edad reproductiva. vertical del virus (materno-fetal), no se ha demostrado
Por otro lado, es de sobra conocido que la vida fun- cuando la infección se ha producido en el tercer trimes-
cional de los ovarios es limitada y está condicionada por tre de gestación. Si la infección se produce en el primer
la edad de la mujer; por lo tanto, cuanto más se demoren o segundo trimestre, no hay todavía estudios su!icientes
los tratamientos, peor van a ser los resultados, en térmi- para conocer el impacto en la salud materno-fetal.
nos de recién nacidos sanos.
Impacto de la pandemia en las unidades de repro
SARSCoV2 y aparato reproductor ducción asistida (URA)
Con los conocimientos actuales, que por su puesto no Cuando se decretó por parte del Gobierno central, el es-
son de!initivos, sabemos que el virus COVID-19 afecta tado de alarma y el estado de alerta sanitaria por el Go-
especialmente a las células del epitelio alveolar, puesto bierno de Euskadi y se tomaron medidas de
que posee el receptor que permite la entrada del virus con!inamiento de la población, la actividad asistencial
en la célula, enzima convertidora de la angiotensina 2 en los centros de reproducción asistida fue paralizada,
(ACE2) y que en los casos severos produce una neumo- exceptuando la preservación de la fertilidad por motivos
nía acompañada de una reacción in!lamatoria masiva y oncológicos. Se pudieron !inalizar los ciclos iniciados de
trastornos en la coagulación, que pueden desencadenar FIVTE/ICSI pero se procedió a vitri!icar los embriones
la muerte del paciente. resultantes de los mismos.
Sin embargo no se ha demostrado que los espermato- Esta paralización de actividad fue motivada funda-
zoides, los óvulos, y las células de la teca y granulosa ová- mentalmente porque se priorizaba el tener todos los re-
Autor para correspondencia: gacetamedica@acmbilbao.org (Gaceta Médica de Bilbao).

© 2020 Academia de Ciencias Médicas de Bilbao. Todos los derechos reservados.
Impacto de la pandemia SARS-CoV-2 (COVID-19) en el ámbito de la medicina reproductiva y sus tratamientos 119
cursos sanitarios, públicos y privados, disponibles para zando la seguridad del personal sanitario y de los pa-
luchar contra la pandemia y por no disponer de conoci- cientes.
mientos su!icientes sobre el virus y sus efectos sobre el Por todo ello, a partir de mayo 2020 las sociedades
aparato reproductor humano. cientí!icas españolas (SEGO, ASEBIR, SEF) y la europea
(ESRHE), tras publicar respectivos documentos, aconse-
Reactivación de la actividad en las URA jaron la puesta en marcha de la actividad asistencial en
Cuando los datos epidemiológicos de la pandemia em- los centros reproductivos sin restricciones, pero estable-
pezaron a ser favorables y se comenzó con modi!icacio- ciendo protocolos de seguridad especí!icos, encamina-
nes en el estado de alarma, las sociedades cientí!icas dos a evitar contagios del virus, que implican tanto al
españolas y europeas relacionadas con la medicina re- personal como a los pacientes.
productiva, tras un análisis profundo de los estudios pu- Estos protocolos son dinámicos y se actualizan en
blicados sobre la COVID-19 decidieron publicar función de los nuevos conocimientos sobre la COVID-19.
documentos con recomendaciones para reactivar las
unidades de reproducción asistida.
El Coronavirus es un agente biológico de tipo 2 y los
laboratorios de reproducción humana han mantenido Koldo Carbonero Martínez
siempre medidas de contención biológica nivel 2, para 25 de mayo de 2020
el cultivo y almacenamiento de gametos y embriones. Donostia/San Sebastián. Basque Country. España
Por otra parte, todos los hospitales y centros sanita- Presidente. Sección de Reproducción Asistida de la ACMB
rios establecieron protocolos de seguridad muy estrictos Jefe de Servicio de Ginecología y Obstetricia
que permitían desarrollar actividad asistencial garanti- Hospital de día Quirónsalud Donostia
BIOLOGY OF REPRODUCTION 74, 410–416 (2006)
Published online before print 19 October 2005.
DOI 10.1095/biolreprod.105.044776
Orchitis: A Complication of Severe Acute Respiratory Syndrome (SARS)1

Jian Xu,3 Lihua Qi,3 Xiaochun Chi,3 Jingjing Yang,3 Xiaohong Wei,3 Encong Gong,4 Suatcheng Peh,4
and Jiang Gu2,4
Departments of Anatomy, Histology, and Embryology3 and Pathology,4 School of Basic Medical Sciences,
Peking University, Beijing 100083, China
ABSTRACT Pathological studies revealed that the lungs of SARS

patients had the most dramatic changes, with severe de-
Severe acute respiratory syndrome (SARS) coronavirus has generation of the epithelium, hyaline membrane formation,
Downloaded from https://academic.oup.com/biolreprod/article/74/2/410/2667029 by guest on 19 June 2022

been known to damage multiple organs; however, little is known
exudation of fibrin fluid, and vasculitis, with many alveoli
about its impact on the reproductive system. In the present
study, we analyzed the pathological changes of testes from six collapsed [5, 6]. In addition, other organs were also infected
patients who died of SARS. Results suggested that SARS caused and damaged by the SARS virus. The targets included the
orchitis. All SARS testes displayed widespread germ cell lymphocytes, the epithelium of the distal tubules of the kidney,
destruction, few or no spermatozoon in the seminiferous tubule, and the submucosal lymphoid complex of the gut, the spleen,
thickened basement membrane, and leukocyte infiltration. The and the lymph nodes [7, 8]. However, only sporadic
numbers of CD3 þ T lymphocytes and CD68 þ macrophages information is available regarding the involvement of re-
increased significantly in the interstitial tissue compared with productive organs in SARS patients [9, 10]. Because it is
the control group (P , 0.05). SARS viral genomic sequences known that viruses such as HIV, HBV, and mumps can enter
were not detected in the testes by in situ hybridization. the testis and cause viral orchitis and, in some instances, result
Immunohistochemistry demonstrated abundant IgG precipita- in male infertility and testicular tumor [11], we investigated the
tion in the seminiferous epithelium of SARS testes, indicating possible damage of the testis in SARS patients and the effects
possible immune response as the cause for the damage. Our of SARS on spermatogenesis.
findings indicated that orchitis is a complication of SARS. It
further suggests that the reproductive functions should be
followed and evaluated in recovered male SARS patients. MATERIALS AND METHODS
immunohistochemistry, in situ hybridization, orchitis, SARS, Materials
spermatogenesis, testis
Autopsy specimens of testis were obtained from six patients (cases S01,
S03, S05, S08, S11, and S15) who died of SARS in Ditan Hospital, Beijing,
INTRODUCTION China. The case numbers were derived from the Department of Pathology,
Since the first appearance in Guangdong province, China, Peking University, and the gaps in numbers were female patients who were not
included in this study. The patients’ ages ranged from 20 to 58 yr old (average
in November 2002, the global outbreak of severe acute
39 yr). All six patients met the diagnostic criteria for SARS defined by the
respiratory syndrome (SARS) had spread to more than 28 World Health Organization (WHO) [12]. The average course of disease was 43
countries in three continents, and resulted in more than 8000 days, ranging from 21 to 62 days. Five of these patients were treated with
infections and close to 800 deaths within the following 9 mo steroids, except case S05. More clinical data are presented in Table 1.
[1]. For what appeared initially as a mere infection of the Four non-SARS specimens of testis were taken as controls (C01–C04).
respiratory tract like a common cold, the death toll was Cases C01 and C02 died of accidents (aged 30 and 42 yr). Case C03 died of
alarming, and many lives of health-care workers were claimed. a disease with high fever and was treated with steroids before death (aged 38
With vigilant public health controls and strict preventive yr). The specimens of case C04 were collected from a person during his/her
transsexual operation (aged 28 years and the patient was routinely treated with
measures on further spread within the hospital environment, estrogen before operation). All tissues were fixed in 10% formaldehyde and
the epidemic was brought under control. The concern over this embedded in paraffin.
global outbreak brought together scientists from all over the The use of the specimens and related ethical issues were reviewed and
world, and with their joint effort, the SARS virus, a novel approved by the Research Administration Committee of the Peking University.
coronavirus, was isolated, and subsequently the full genomic
sequences of the SARS virus were determined [2–4].
Morphological Analysis
Although a lot had been learned about the epidemiology,
mode of spread, and certain aspects of the pathogenesis, Six-micrometer paraffin sections were cut and stained with hematoxylin–
a number of SARS-related complications are still waiting to be eosin. Apoptotic cells were detected by TUNEL assay using TdT-Frag EL
studied. DNA Fragmentation Detection Kit, according to the instructions provided by
the supplier (Calbiochem, San Diego, CA). In brief, after dewaxing and
1
rehydration, the sections were covered with 13 TdT balance buffer and
Supported by National 863 project (2003AA208107). incubated at room temperature for 15–30 min, followed by addition of TdT-
2
Correspondence: Jiang Gu, Department of Pathology , School of Basic labeled reaction mixture with enzyme, and incubated at 378C for 1 h. TBS was
Medical Sciences, Peking University, 38 Xueyuan Road, Haidian applied instead of TdT enzyme for negative control. These sections were rinsed
District, Beijing 100083, China. FAX: 86 10 82801237; with TBS between incubations at room temperature with stop solution for 5
e-mail: jgu@privatedoctor.org min, 3% H2O2 for 5 min, and blocking buffer for 10 min. Finally, peroxidase-
streptavidin conjugate was added at room temperature for 30 min. After another
Received: 21 June 2005. rinse with TBS, the sections were incubated for color reaction with DAB
First decision: 5 July 2005. solution at room temperature for 10–15 min. All slides were counterstained
Accepted: 18 October 2005. with Mayer hematoxylin for 30 sec.
! 2006 by the Society for the Study of Reproduction, Inc. Slide evaluation and image analysis were performed under a light
ISSN: 0006-3363. http://www.biolreprod.org microscope (Nikon, E800) at 2003 magnification.
410
SARS ORCHITIS 411
TABLE 1. Clinical data for the 6 SARS cases.

Course SARS pathogen
Cases Age (yr) Fever (initial temp. [8C]) Steroid treatmenta Fathered childrenc
of disease (days) (real-time PCR or ISH)b
S01 51 38 45 þ þ þ
S03 50 39 33 þ þ þ
S05 31 38.5 35 – þ NA
S08 24 39 21 þ þ –
S11 20 38 62 þ þ –
S15 58 38 62 þ þ þ
a
Treatment with ( þ) or without (") steroids.
b
Positive for SARS pathogen indicated by þ.
c
Child indicated by þ; no child indicated by "; NA, information not available.
Immunohistochemistry designed based on SARS coronavirus genome sequence (GenBank, Accession

AY274119). The sequences of the primers were: A: 5 0 -GCGCAAGTAT-

Sections were dewaxed and rehydrated and then heated in glycine buffer TAAGTGAGATG-3 0 (15348–15368 nt); B: 5 0 -GAAGTGCATTTA-
(glycine 3.75 g, EDTA 0.1 g, in 1 L distilled water, pH: 3.6) in a microwave CATTGGC-3 0 (15 473–14 492 nt). Total RNA was extracted from
oven for 10 min 3 2, cooled to room temperature before washing with distilled peripheral blood of a SARS patient with TRIZOL reagent (Roche). The RT-
water. The sections were then treated with 1% H2O2/methanol for 10 min, PCR products were purified and confirmed by sequencing. Then the RNA
washed with PBS, and then incubated with blocking solution for 1 h at 48C in probe was prepared by in vitro transcription with the label of digoxigenin. The
a humidified chamber. Specific mouse monoclonal antibodies against CD3 and concentration of probes was estimated at about 50 lg/ml.
CD68 (Zymed Lab, San Francisco, CA) diluted in blocking solution to 5lg/ml, In situ hybridization staining The paraffin-embedded sections were
and HRP (horseradish peroxidase)-conjugated goat anti-human IgG (Jackson dewaxed, rehydrated, and then immersed in 0.1 N HCl for 10 min before
ImmunoResearch Lab, West Grove, PA) diluted in blocking solution to 3lg/ml digestion with proteinase K (50 lg/ml) at 378C for 20 min. They were then
were applied to the sections and incubated overnight at 48C. Slides for CD3 and postfixed in 4% paraformamidehyde-PBS at room temperature for 10 min, and
CD68 were washed with PBS and biotinylated anti-mouse IgG antibody then dehydrated in a series of increasing concentrations of ethanol and air dried.
(Vector Labs, Burlingame, CA) in 1:200 was applied for 1 h, then washed in Then 20 ll of hybridization solution, consisting of 50 ng labeled probe, 50%
PBS, followed by avidin-biotin complex (Vector Labs) for 30 min at 48C. After formamid, 100 lg/ml yeast tRNA, 0.1 M DTT, 53 Denhardt, 10% dextran
washing with PBS, the sections were incubated with DAB solution (Zymed sulfate, and 23 SSC, was added to the sections and incubated at 558C for 16 h.
Lab) for 5–10 min. Slides for IgG were incubated in 3-Amino-9-ethylcarbazole The washes for posthybridization were carried out in 50% formamid/23 SSC at
(Sigma, St. Louis, MO) for 5–10 min. 558C for 30 min, three times in 23 SSC at 558C, and 0.13 SSC for 20 min at
For negative control, the CD3 or CD68 antibody was replaced with the room temperature. After blocking with horse serum (1:100) for 60 min, AP-
blocking solution. To avoid the possible unspecific reaction between the goat labeled anti-Dig antibody (1:500) was added for 60 min at room temperature.
IgG and human tissue, an additional control (isotype control) was performed in Color reaction was achieved with NBT/BCIP and counterstained with methyl-
which HRP-conjugated goat anti-human IgG was replaced with HRP- green. The negative control was performed without any probe, and the sections
conjugated goat IgG (isotype control antibody, Jackson ImmunoResearch of SARS lungs were stained as positive controls.
Lab, West Grove, PA).
All slides were counterstained with Mayer hematoxylin for 30 sec. The
positive reaction for CD3 or CD68 was brown and IgG was red. Histomorphological Evaluation
Each experiment for every specimen was repeated at least three times. Five
In Situ Hybridization random fields were picked per section using the 203 objective on a light
microscope (E800; Nikon). Tubules that contained positively stained cells were
Probe preparation Sense and antisense digoxigenin-labeled RNA probes recorded as positive tubules. The total numbers of positively and negatively
were kindly provided by Dr. Bo Zhang [13]. Briefly, a pair of primers were stained cells in tubules and interstitial tissue in the fields captured were
FIG. 1. Hematoxylin-eosin stain. A) Testis

from the control case C01, showing normal
morphology. B) Testis from the control case
C03, who died of a disease with high fever
and was treated with steroids, showing mild
basement membrane thickening and vas-
cular congestion. C) Testis from SARS
patient S01, showing loss of germ cells,
leukocytes infiltration (arrows), and vascular
congestion. D) Testis from SARS patient
S05, showing basement membrane thick-
ening, peritubular fibrosis, and vascular
congestion. Bar ¼ 50 lm.
412 XU ET AL.
FIG. 2. TUNEL stain. A) Testis from the

control case C02, showing a few apoptotic
spermatogenetic cells in the tubules (ar-
rows). B) Testis from SARS patient S08,
showing increased apoptotic spermatoge-
netic cells and a few positive Leydig cells
(arrows). C) Negative control stain of SARS
sample S08 without TdT in the staining
process, no positive stain was seen. Bar ¼
50 lm.

counted, and the percentage of positive cells was derived from total cell counts. Leukocyte Infiltration and Autoimmune Antibody
The difference between mean values of SARS and control groups was analyzed
by Student t-test (SAS software), and the level of significance was determined With immunohistochemistry (IHC), the quantities of CD3 þ
as P , 0.05. All assessments were made in a double-blinded fashion. T lymphocytes and CD68 þ macrophages found in the control
testes were 0.65% and 2.11%, respectively (Table 3). These
RESULTS cells were absent in the tubules (Fig. 3, A and B). In SARS
Histomorphology testes, the numbers of both cell types were increased, with
4.49% of T lymphocytes and 11.72% of macrophages (Table
In the control group, testes of cases C01, C02, and C04 3). The difference between the SARS group and the control
displayed normal morphology (Fig. 1A). Testis of case C03 group was significant (P , 0.05). Both cell types were
showed no significant germ cell loss. There was minimal observed to be present in the seminiferous tubules in the SARS
peritubular fibrosis and vascular congestion in the interstitial cases (Fig. 3, C and D, arrowhead) and 5.43% and 7.03% of
tissue (Fig. 1B). All SARS testes demonstrated extensive germ tubules were found to contain T lymphocytes and macro-
cell destruction, with few or no spermatozoon in the phages, respectively (Table 3).
seminiferous epithelium and the lumen. The basement We examined the expression and distribution of IgG in the
membrane was thickened, and there was peritubular fibrosis. testes. In the control group, IgG was localized in the lumen of
Leukocyte infiltration and vascular congestions were present in some of the blood vessels (Fig. 4A, arrow). However, in the
the interstitial tissue (Fig. 1, C and D). SARS testes, deposits of extensive IgG immunoreaction were
detected in the seminiferous epithelium, interstitium, some
Pattern of Apoptosis degenerated germ cells, and Sertoli cells (Fig. 4B). Isotype
control showed negative staining (Fig. 4C).
TUNEL assay showed increased apoptotic spermatogenetic
cells in SARS (Fig. 2B), and this was found to be statistically
different when compared with the control group (Table 2), with SARS Virus Detection
P-value , 0.05. Apoptosis was also demonstrated in a few To determine if the SARS virus infected the testis directly,
Leydig cells (Fig. 2B, arrows) in SARS testes, but this is not we performed in situ hybridization (ISH) using both sense and
statistically different when compared with the control group antisense RNA probes. There was no positive staining
(0.8% of control group and 1.5% of SARS, respectively; P . observed in any of the SARS testis sections (Fig. 5). Specific
0.05). positive signals were obtained in the sections of SARS lungs,
which were stained as positive control (Fig. 5A, insert; full
report of the lung in SARS patients will be published
separately).
TABLE 2. Analysis of TUNEL staining of SARS and control cases.
DISCUSSION
SARS (n ¼ 6) Control (n ¼ 4)
The most well-known and extensively studied viruses that
S01 S03 S05 S08 S11 S15 C01 C02 C03 C04 cause human testicular disorder are HIV and mumps virus.
Autoimmune deficiency syndrome (AIDS) patients often suffer
Positive cells (%) 1.5 5.5 12.6 2.7 3.9 9.5 1.7 2.9 1.9 2.8 from orchitis, hypogonadism, oligospermia, and, in some
Mean value (%) 5.95 6 3.23a 2.33 6 0.661a
cases, testicular germ cell tumor [14–18]. Spermatogenesis
a
Percentage of positive cells, SARS compared to control (P , 0.05). dysfunction in male AIDS patients is invariably reported. The
SARS ORCHITIS 413
FIG. 3. IHC stain with CD68 (A and C)

and CD3 (B and D). A) Testis from the
control case C01, showing a few CD68þ
macrophages in the interstitial tissue (ar-
rows) and no macrophage in the tubule. B)
Testis from the control case C02, showing
a few CD3þ T lymphocytes in the in-
terstitial tissue (arrows), and no positive cell
in the tubule. C) Testis from SARS patient
S08, showing CD68þ macrophages in the
seminiferous tubules (arrow heads) and the
interstitial tissue (arrows). D) Testis from
SARS patient S11, showing CD3þ T lym-
phocytes in the seminiferous tubules (arrow
head) and the interstitial tissue (arrows). E)
Negative control without primary antibody
on the case C01. Bar ¼ 50 lm.

major changes include germ cell depletion, presence of Sertoli cause viral orchitis [9]. SARS is a new disease caused by
cell-only pattern, interstitial inflammation, leukocyte infiltra- a novel coronavirus. We report here that the SARS virus causes
tion, peritubular fibrosis associated with tubular hyalinization, orchitis.
and thickening of the tubular wall [19–21]. Orchitis caused by Germ cells must develop at a temperature lower than 378C.
mumps virus mainly develops in adult patients [22]. The virus Persistent high fever leads to changes in testicular temperature,
attacks the testis directly, destroying the testicular parenchyma, contributing to germ cell degeneration and destruction.
causing degeneration of germ cells, exudation of leukocytes, Previous studies reported that high temperature resulted in
and deposition of collagen [23, 24]. Apart from HIV and meiotic germ cell apoptosis [25]. High fever was also thought
mumps virus, other viruses, such as Hepatitis B and C viruses, to play an important role in mumps orchitis [26]. High fever in
Epstein-Barr virus, and Papilloma virus, were also reported to SARS might have an indirect effect on testicular dysfunction.
TABLE 3. Analysis of CD3 and CD68 positivities in SARS and control cases.
SARS (n ¼ 6) Control (n ¼ 4)
S01 S03 S05 S08 S11 S15 C01 C02 C03 C04
CD3
Positive tubule (%) 9.3 9.3 3.7 2.3 5.9 2.1 0 0 0 0
Mean value (%) 5.43 6 3.2 0
Positive cell (%)a,b 3.95 3.77 6.73 6.61 2.67 3.21 0.15 0.31 0.21 1.94
Mean value (%) 4.49 6 2.68 0.65 6 0.23
CD68
Positive tubule (%) 5.9 13.5 5.4 9.5 4.2 3.7 0 0 0 0
Mean value (%) 7.03 6 3.4 0
Positive cell (%)a,b 4.88 6.65 44.61 3.89 4.36 5.93 1.25 2.94 2.11 2.12
Mean value (%) 11.72 6 2.35 2.11 6 1.69
a
Percentage of positive cells, SARS compared to control (P , 0.05).
b
In the control cases, the positive cells were all in the interstitial tissue.
414 XU ET AL.
FIG. 4. IHC stain with IgG. A) Testis from the control case C01, showing IgG signals in the lumen of blood vessel (arrow). B) Testis from SARS patient S08,

showing extensive IgG signals in the seminiferous epithelium, a few positive germ cells (arrow heads) and Sertoli cells (arrows). C) Negative control with
isotype control antibody on the serial section of B, no positive signal was seen. Bar ¼ 50 lm.
However, temperature might not be the only reason. In the FSH in these SARS patients precludes the possibility of
control group, there was a case (C03) with lasting high fever, a meaningful clinicopathological correlation.
and this testis demonstrated mild fibrosis and congestion with Viruses are known to be capable of infecting the testis
no obvious germ cell loss or leukocyte infiltration. In addition, directly. For example, mumps viruses were found in human
the treatment of SARS with steroids could also have affected Leydig cells and HIV infects human germ cells. HIV, HBV,
spermatogenesis. Glucocorticoid had been used in five cases HSV, and adenoviruses can also be detected in semen [11].
(except S05) and it had been reported to induce rat Leydig cell ACE-2 (angiotensin-converting enzyme 2) was reported as
apoptosis [27]. In this study, we did not find an obvious a functional receptor for the SARS virus [30], and three
increase of apoptotic Leydig cell in the six SARS cases (P . independent groups all identified that ACE-2 was highly
0.05 compared with control). Instead, we found mild Leydig expressed in human testis [31–33], which suggested that the
cell hyperplasia in some cases. The testis of case S05, who did testis has the potential to be infected by the SARS virus. We
not take steroids, also displayed changes of orchitis, as did investigated the possibility of direct SARS virus infection in
another five SARS cases. Glucocorticoid should not induce the testis in all six cases by using the ISH method. None
leukocyte infiltration and is routinely used to treat orchitis to showed positive staining. Conflicting reports exist concerning
suppress inflammation. This indicates that steroid treatment direct infection of testes by the SARS virus. In the study of
might not be the cause for orchitis in SARS, at least not for Zhao et al. [9], it was reported that SARS coronaviruses were
case S05. detected in testicular epithelial cells and Leydig cells by
Reports on testicular endocrine function in viral orchitis are electron microscopy combined with ISH. However, in another
rare. Previous studies observed a drop in testosterone level study by Ding et al. [10], testis was negative for the SARS
together with an increase in LH and FSH levels in patients virus, and infections of the heart, the spleen, and the lymph
suffering from mumps orchitis [28]. Similarly, in some male nodes were not established either, yet the spleen and the lymph
AIDS cases, low serum testosterone levels associated with high nodes were reported as being main targets by other groups [7].
serum LH and FSH levels were also reported [29]. These Hence, it appears that the SARS virus can infect and damage
findings suggest that viruses might act indirectly via changes in multiple organs, but direct infection of the testis could not be
the hypothalamic-pituitary-testis axis. However, there were ascertained at this time.
other studies that found no significant abnormality in sex Leukocytes, especially macrophages, are found within the
hormone in male patients with HIV orchitis [14]. The absence interstitial tissue of most mammal testes. They may be involved
of clinical information on the levels of testosterone, LH, or in Leydig cell development, steroidogenesis, and immune
FIG. 5. ISH detection of SARS virus. A) Testis from SARS patient S08 with antisense digoxigenin-labeled RNA probe, showing no positive signals. Insert:
SARS lungs stained with the same protocol and probe as a positive control, showing positive type II alveolar cell (arrow) and lymphocytes (arrow head)
(will publish separately). B) Testis from SARS patient S08 with sense digoxigenin-labeled RNA probe, showing no positive signals. C) Negative control
stain without probe on the same case. Bar ¼ 50 lm.
SARS ORCHITIS 415
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perpetuity.
perpetuity.
Angiotensin-
converting enzyme 2 (ACE2) is considered as the receptor for binding and entry into
host cells by . Theoretically, any cells expressing ACE2 may be
susceptible to SARS-CoV-2 infection.
. All the findings suggest the potential risk of male gonad to be vulnerable
to SARS-CoV-2 attack.
perpetuity.
written informed consent was waived.

perpetuity.
perpetuity.
perpetuity.
viral reproduction and

transmission were positively enriched in ACE2-positive spermatogonia [9]. SARS, the
similar virus of SARS-CoV-2, has been reported to cause orchitis [13]. Taken together,
we suppose that testes may also run high risk of damage and dysregulation under
.
SARS-CoV-2 infection on male reproductive function,

perpetuity.
perpetuity.
[1] Li, Q, Guan X, Wu P, et al. Early Transmission Dynamics in Wuhan, China, of

Novel Coronavirus-Infected Pneumonia. N Engl J Med, 2020. Jan 29. doi:
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[2] Gralinski, LE, Menachery VD. Return of the Coronavirus: 2019-nCoV. Viruses,
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[3] Xiaoqiang Chai, Longfei Hu, Yan Zhang, et al. Specific ACE2 Expression in
Cholangiocytes May Cause Liver Damage After 2019-nCoV Infection. bioRxiv,
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[4] Hao Zhang, Zijian Kang, Haiyi Gong, et al. The digestive system is a potential
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[5] Xin Zou, Ke Chen, Jiawei Zou, et al. (2020) The single cell RNA seq data analysis
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[6] Markus Hoffmann, Hannah Kleine-Weber, Nadine Krüger, et al. The novel
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cellular protease TMPRSS2 for entry into target cells. bioRxiv, 2020,
[7] Yu Zhao, Zixian Zhao, Yujia Wang, et al. (2020) Single-cell RNA expression
profiling of ACE2, the putative receptor of Wuhan 2019-nCov. bioRxiv, 2020,
[8] Cabin Fan, Kai Li, Yanhong Ding, et al. ACE2 Expression in Kidney and Testis
May Cause Kidney and Testis Damage After 2019-nCoV Infection. MedRxiv,
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[9]
[10] Li N, Wang T, Han D. Structural, cellular and molecular aspects of immune

privilege in the testis. Front Immunol, 2012, 3:152. http://dx.doi.org/10.3389/
fimmu. 2012.00152
[11] Salam AP, Horby PW. The Breadth of Viruses in Human Semen. Send to Emerg
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perpetuity.
[12] Liu W Han R, Wu H, Han D. Viral threat to male fertility. Andrologia, 2018,
50(11): e13140. doi: 10.1111/and.13140.
[13] Xu J, Qi L, Chi X, et al. Orchitis: a complication of severe acute respiratory
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[14]
[15]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
COVID-19 may affect male fertility but
is not sexually transmitted: a
systematic review
Ilan Tur-Kaspa, M.D.,a Tomer Tur-Kaspa,a,b Grace Hildebrand, B.A.,a and David Cohen, M.D.a
a b
Institute for Human Reproduction (IHR), Chicago and Oak Brook, Illinois, and Valparaiso, Indiana, and Wesleyan
University, Middletown, Connecticut
Objective: To determine if SARS-CoV-2, which has led to the rapidly spreading COVID-19 global pandemic, is sexually transmitted.
Since the putative receptor for the virus is identified in reproductive organs, it is also important to examine if COVID-19 may affect
human fertility.
Evidence Review: A systematic review of English publications was conducted up to December 11, 2020 in PubMed, NIH iCite COVID-
19 portfolio, Cochrane Library, and Google Scholar databases, searching for SARS-CoV-2 in the testes; seminal, prostatic, and vaginal
fluids; and cervical smears. A total of 1,997 records were identified, duplicates were removed, and 1,490 records were reviewed for
eligibility by examining titles and abstracts. Subsequently, 202 full-text relevant articles were reviewed by 2 independent reviewers.
Forty-seven studies (literature reviews, editorials, and guidelines) were assessed qualitatively, and 23 studies that tested the male
and female reproductive tracts of patients with COVID-19 for SARS-CoV-2 were quantitatively analyzed.
Results: No epidemiological investigations to date have described evidence suggesting that COVID-19 is an STD. While angiotensin-
converting enzyme 2 receptor is found in the reproductive organs, the lack of co-expression of the TMPRSS2 modulatory protein,
required for SARS-CoV-2 cell entry, in testicular cells, sperm, or oocytes, argues against the hypothesis that gametes transmit
SARS-CoV-2. Molecular detection studies of SARS-CoV-2 RNA in the male and female reproductive tracts were summarized: 98.0%
(293/299) of the seminal fluids, 16/17 testicular biopsies, all 89 prostatic fluids, 98.3% (57/58) of the vaginal fluids, all 35 cervical
smears, and all 16 oocyte samples tested negative for SARS-CoV-2. None of the studies confirmed sexual transmission of SARS-
CoV-2. Nonetheless, COVID-19 may have detrimental effects on male reproduction by inducing orchitis and/or decreasing
testosterone levels, sperm counts, and motility.
Conclusion: On the basis of the current worldwide published information, COVID-19 is not an STD. This information is important for
clinicians, proposed guidelines for public health, U.S. Food and Drug Administration guidelines for gamete and tissue donor eligibility,
and fertility treatments. Universal precautions, currently practiced worldwide, are adequate and sufficient at this time to prevent the
transmission of known or unknown viral infections. We suggest that recovered patients of COVID-19, especially those with
infertility, should be evaluated for their ovarian and testicular function. (Fertil Steril Rev! 2021;2:140–9. "2021 by American
Society for Reproductive Medicine.)
Key Words: COVID-19, infertility, IVF, SARS-CoV-2, sexual transmission
Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/xfnr-d-20-00033
ESSENTIAL POINTS
! SARS-CoV-2 has led to a fast-spreading global pandemic of COVID-19. By December 11, 2020, it has infected more than 71
million people worldwide and caused over 1.5 million deaths globally, with over 15 million infected and almost 300,000
deaths in the United States alone.
! From a public health perspective, it is important to determine if SARS-CoV-2 is sexually transmitted. To cause a sexually
transmitted disease (STD), a virus has to be detected in seminal or vaginal fluids from asymptomatic or symptomatic people
and transmitted through intercourse or insemination.
Received September 1, 2020; revised January 23, 2021; accepted January 25, 2021.
All authors have nothing to disclose.
Supported in part by the Institute for Human Reproduction (IHR).
Presented in part at The American Society for Reproductive Medicine (ASRM) 2020 Virtual Scientific Congress & Expo, October 17-21, 2020 (Late Breaking
News Session). Fertil Steril 2020;114(3) (suppl): E522-523.
Reprint requests: Ilan Tur-Kaspa, M.D., Institute for Human Reproduction (IHR), 409 W. Huron St, Suite 500, Chicago, Illinois 60654 (E-mail: DrTK@
infertilityIHR.com).
Fertil Steril Rev® Vol. 2, No. 2, April 2021 2666-5719/$36.00

© 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.xfnr.2021.01.002
140 VOL. 2 NO. 2 / APRIL 2021

Fertil Steril Rev®
! No epidemiological investigations to date have suggested that COVID-19 is an STD. The lack of co-expression of viral
angiotensin-converting enzyme 2 receptors and the TMPRSS2 modulatory protein in testicular cells, sperm, and oocytes
further rejects the hypothesis that gametes transmit SARS-CoV-2.
! This systematic review of available global clinical data up to December 11, 2020 regarding SARS-CoV-2 in the testes; seminal,
prostatic, and vaginal fluids; cervical smears; and oocytes concludes that the virus is not sexually transmitted. This informa-
tion is important for public health guidelines, U.S. Food and Drug Administration guidelines on gamete donor eligibility, and
fertility treatments.
! COVID-19 may affect male fertility. Further prospective and longitudinal controlled studies are needed to investigate the po-
tential effects of COVID-19 on human fertility.
S
ARS-CoV-2 has led to a large-scale global pandemic of Editorial request, the search was extended to December 11,
COVID-19. As of December 11, 2020, it has infected 2020. This updated comprehensive search found no data
more than 71 million people worldwide and caused that changed any of the conclusions.
over 1.5 million deaths globally, with over 15 million infected Sexual transmission of SARS-CoV-2 was considered if it
and almost 300,000 deaths in the United States alone. occurred through vaginal intercourse, vaginal penetration, or
Coronaviruses are endemic in humans and responsible for insemination. Other forms of possible viral transmission or
15%–30% of respiratory tract infections yearly. The SARS shedding, such as by blood, oral-fecal, and urine, have been
outbreak in 2002–2003 infected approximately 8,000 people discussed by others (16–23). No study documenting the
worldwide, with a 9% mortality rate (1). The 2012 Middle transmission of SARS-CoV-2 through homosexual sexual re-
East respiratory syndrome coronavirus outbreak infected lationships was found in our search. Articles were included if
only approximately 2,500 people but had a 35% mortality original data on SARS-CoV-2 RNA in the male or female
rate (2). COVID-19 clinical manifestations have been summa- reproductive tracts were presented, if there was a discussion
rized by others (3–6). of such possible sexual transmission, or if commentary
While no previous coronavirus infection was reported to regarding any COVID-19 effect on human reproduction was
be a sexually transmitted disease (STD) (1, 2, 7, 8), a May 2020 included.
scientific publication (9) reported the finding of SARS-CoV-2 The quality of the included studies was rated according to
RNA in the semen of 6 out of 38 patients with COVID-19, the Oxford Centre for Evidence-Based Medicine levels of
heightening concern for its potential sexual transmission evidence by 2 investigators independently, with discrepancies
(9). Furthermore, since the putative angiotensin-converting resolved after joint article review and discussion (24).
enzyme 2 (ACE2) receptor for SARS-CoV-2 was found in
reproductive organs (7, 10–14), it was important to examine
RESULTS
if the virus targets and infects the human reproductive tract
and affects fertility and to resolve if it is sexually The search produced a total of 1,997 records. After duplicates
transmitted or not. It is clear that COVID-19 can be trans- were removed, 1,490 records were screened and assessed for
mitted with intimate sexual contact through droplets and fo- eligibility by examining titles and abstracts (by investigators
mites, but from a clinical and public health perspective, it is T.T. and G.H.). Next, 202 full-text relevant articles were re-
imperative to determine if sexual transmission occurs as well. viewed and evaluated by 2 independent reviewers (I.T. and
To determine if COVID-19 is an STD or not and clarify its D.C.) for inclusion in the study. After applying inclusion
possible effect on fertility, we conducted a systematic review and exclusion criteria, 47 qualitative studies (literature re-
of global epidemiological investigations, molecular receptor views, editorials, and guidelines) remained, and 23 quantita-
identification, and detection studies of SARS-CoV-2 in the tive studies that tested the male and female reproductive
male and female reproductive tracts. tracts of 404 adult patients with COVID-19 for SARS-CoV-2
RNA were selected for inclusion.
The results of the literature search are detailed in the on-
MATERIALS AND METHODS line supplement with a PRISMA-style flow diagram
A systematic review of the literature was conducted in accor- (Supplemental Fig. 1, available online). In total, 70 reports
dance with the Preferred Reporting Items for Systematic Re- formed the basis of this review.
views and Meta-Analyses (PRISMA) guidelines (15) on
English literature available through PubMed, NIH iCite
COVID-19 portfolio, Cochrane Library, and Google Scholar Evidence from epidemiological investigations
databases. Briefly, the search terms included the following: For a viral infection to be labeled as an STD, virus infectivity
SARS-CoV-2 and/or COVID-19 with STD, STD, sperm, semi- via sexual intercourse or insemination and not just the pres-
nal fluid, semen fluid, semen, prostatic fluid, orchitis, testes, ence of its viral particles is required (25). Classifying a viral
oocyte, ovary, vaginal fluid, cervical smear, follicular fluid, infection as an STD requires observational epidemiological
embryo, and implantation. The exact search terms are listed studies. The transmission of SARS-CoV-2 through respiratory
in the online supplement (Supplemental Table 1, available on- droplets and aerosol has been documented, but no epidemio-
line). While the initial literature search ended on July 15, logical investigation to date has implicated, or even sus-
2020, following the special pandemic circumstances and the pected, sexual transmission (16, 26–31).
VOL. 2 NO. 2 / APRIL 2021 141

SYSTEMATIC REVIEW
Evidence for SARS-CoV-2 targeting the human men demonstrated mild COVID-19 symptoms (163/299),
reproductive tract and negative results of nucleic acid testing were documented
as early as 4 days after confirmed COVID-19 diagnosis. Not
Evidence for ACE2/TMPRSS2-mediated mechanism for
surprisingly, the majority of viral testing was performed in
SARS-CoV-2 cell entry. SARS-CoV-2 uses the ACE2 receptor
patients during disease recovery. One study, of the 14 re-
and cellular protease TMPRSS2 to enter the target cells. Both
viewed, identified 6 men with positive seminal fluid viral
are essential for viral spread and disease in the infected host
RNA tests (2.0% of all the men from all 14 studies) (9). Of these
(32). Expression of the ACE2 receptor is identified in the
6 men, 4 were in the acute stage of infection and 2 were in re-
ovary, vagina, uterus, and placenta of women (10, 14) and
covery, between 6 and 16 days after COVID-19 diagnosis. The
testis of men (7, 11–13). ACE2 receptor identification in the
investigators of this outlier study (9) provided limited infor-
reproductive tracts led to speculation that SARS-CoV-2 might
mation on the reverse transcription polymerase chain reac-
infect the gonads, be found in seminal and/or vaginal fluid, or
tion test kit they used, the test kit’s limits of detection, gene
attach to sperm and/or oocytes. Furthermore, the evidence of
targets, and cycle threshold and did not describe the semen
SARS-CoV-2-induced orchitis suggested that testicular infec-
collection protocol (9, 53). Since this positive report (9)
tion might damage the testis-blood barrier and permit viral
demonstrated only molecular detection and not viral shed-
shedding into semen.
ding, we and others (37, 40–44) agree with the
It is important to distinguish, however, between the local-
investigator’s (9) own assessment that their results should
ization of receptors, localized inflammation (orchitis), and vi-
be confirmed by others before it influences groups
rus infectivity. Although SARS-CoV also uses ACE2
formulating guidelines or clinical practice. Furthermore, in
receptors, no SARS virus was detected in the testes or vaginal
2 other studies where testing was also obtained within the
fluids in pathologic specimens during the SARS epidemic in
acute stage of infection, the seminal fluids of all 14 men
2002–2003, even in men with pathologically documented in-
tested negative for SARS-CoV-2 (43, 44). Interestingly, 7
flammatory orchitis (8).
men who demonstrated orchitis-like symptoms, identified in
Because TMPRSS2 is highly expressed in the prostate,
2 of the studies, also all tested negative for SARS-CoV-2 in
Song et al. (33) investigated TMPRSS2 and ACE2 co-
their seminal fluid (37, 43).
expression in human prostate epithelial cells. They analyzed
Finally, all 89 prostatic fluids tested were negative for the
24,519 epithelial cells from a normal human prostate data
virus (Table 2) (34–36). One of the 17 testicular biopsies (40,
set using publicly available single-cell RNA sequencing
51) tested positive for SARS-CoV-2 RNA, but the investiga-
data. While 18.65% of these cells expressed TMPRSS2, only
tors (51) of that study questioned their own finding, com-
0.32% of all epithelial cells (78 of 24,519) expressed ACE2.
menting that ‘‘the reverse transcription polymerase chain
Overall, the co-expression of ACE2 and TMPRSS2 in the pros-
reaction likely detected the virus present in the blood rather
tatic cell types investigated was approximately 0.4%–0.6%
than in testicular tissue’’(51).
(33). No SARS-CoV-2 was found in the prostatic fluid of 98
Taken together, these data suggest that SARS-CoV-2 is
men with COVID-19 in 3 different studies, supporting the
not sexually transmitted through sperm or semen (34–37,
aforementioned finding of a very low co-expression of
40–50, 54).
ACE2 and TMPRSS2 in the prostate (34–36).
Recently, it was reported that while the ACE2 receptor is
Evidence for SARS-CoV-2 in the female reproductive
found in reproductive organs, TMPRSS2 is not co-expressed
tract. Table 3 presents the currently published investigations
in testicular cells, sperm, or cumulus-enclosed oocytes (may
of SARS-CoV-2 RNA in the vaginal fluid, cervical smears, and
be expressed at <0.01% of the cells) (13, 32, 37). Since
human oocytes. Specifically, 98.3% (57/58) of the vaginal
TMPRSS2 is required for SARS-CoV-2 cell entry, this finding
fluids tested negative (14, 55–57), and all 35 cervical smears
suggests that SARS-CoV-2 is unlikely to enter testicular cells
tested negative for SARS-CoV-2 as well (56). Vaginal fluid
through an ACE2/TMPRSS2-mediated mechanism (13, 32, 37).
testing was performed as early as 8 days after diagnosis,
Furthermore, 16 oocytes from 2 asymptomatic SARS-
and most of the women (44/58) demonstrated severe
CoV-2-positive egg donors were all negative for the viral
COVID-19 symptoms (14, 55–57). In one study (56), while
RNA (38), and while in 5 of 16 oocytes ACE2 was detectable,
all 35 vaginal fluids tested negative, the infection rate of
TMPRSS2 was undetectable in all oocytes. Since both ACE2
the patients’ sexual partner was 42.9%. Interestingly, 2
and TMPRSS2 are essential for viral spread (32), these data
women with negative vaginal fluid tests engaged in sexual
oppose the proposition that sperm and oocytes might be in-
activity with their partners 14 days before the onset of
fected by SARS-CoV-2 and argue that the virus is not sexually
symptoms and continued until the day samples were
transmitted (13, 37, 39).
collected. One of the partners tested positive for COVID-19,
Evidence for SARS-CoV-2 in the male reproductive and the other did not (56). Only 1 woman (14) tested positive
tract. Tables 1 and 2 depict published global studies inves- for SARS-CoV-2 RNA in the vaginal fluid out of 58 women
tigating the presence of SARS-CoV-2 RNA in the male tested in 4 studies (1.7%) (14, 55–57). This woman was 67-
reproductive tract. Table 1 summarizes findings in the sem- years-old and initially had 2 negative vaginal samples after
inal fluid (9, 36, 37, 40–50), and Table 2 summarizes COVID-19 diagnosis (14). After these initial negative tests,
findings in the testes and prostatic fluid (34–36, 40, 51, 52). she tested positive on 2 occasions and subsequently tested
Of all seminal fluids tested, 98.0% (293/299) were nega- negative again. There was no information about the test kit
tive for the virus (Table 1) (9, 36, 37, 40–50). Most of these used in this case report (14).
142 VOL. 2 NO. 2 / APRIL 2021

VOL. 2 NO. 2 / APRIL 2021
TABLE 1
Severe acute respiratory syndrome coronavirus 2 in the seminal fluid of men with coronavirus disease 2019.
Mean days from Reverse transcription polymerase
Study type Date of No. of Mean age diagnosis Seminal fluid chain reaction
Studies City, country (quality rating) publication men (range) (range) Severity of COVID-19 result Control manufacturer
Song et al. (40) Nanjing, China Cohort (4) 4/16/2020 12 30 (22–38) 29 (14–42) Asymptomatic All negative No Huirui
(1/12), mild (11/12) Biotechnology
Ning et al. (41) Wuhan, China Cohort (4) 4/16/2020 17 35 (23–46) 27 (12–64) Asymptomatic All negative No Sansure
(Preprint) (8/17), mild (9/17) Biotech
a
Pan et al. (37) Wuhan, China Cross-sectional (4) 4/17/2020 34 39 (18–55) 31 (8–75) Mild (34/34) All negative No Anda Gene Ltd
Paoli et al. (42) Rome, Italy Case report (5) 4/23/2020 1 31 8 Mild (1/1) Negativeb No altona
Diagnostics
Li et al. (9) Shangqiu, China Cohort (4) 5/7/2020 38 R15 (NA) 11 (6–16) for NA 84.2% No NA
the 6 men who negative
tested positive (32/38)c
Holtmann et al. (43) Du
€sseldorf, Cohort control (3b) 5/29/2020 18 42 (32–52) NA (8–54) Mild (14/18), All negative N ¼ 14 PE Applied
Germany moderate (4/18)d All negative Biosystems
Guo et al. (44) Shandong, China Case Series (4) 6/29/2020 23 41 (20–62) 31 (26–34) Mild (18/23), All negativee No Huirui
moderate (5/23) Biotechnology
Ma et al. (45) Wuhan, China Cross-sectional (4) 7/4/2020 12 31.5 (25–46) 78.5 (56–109) Mild (1/12), All negative No NA
moderate (11/12)
Rawlings et al. (46) San Diego, USA Cross-sectional (4) 8/7/2020 6 38 (28–45) 12 (6–17) Mild (6/6) All negative No ddPCR
Pavone et al. (47) Palermo, Italy Cross-sectional (4) 8/14/2020 9 41 (28–52) 42 (7–88) Asymptomatic (1/9), All negative No NA
mild (8/9)
Kayaaslan et al. (48) Ankara, Turkey Cross-sectional (4) 9/1/2020 16 33.5 (18–54) 1 (0–7) Mild (16/16) All negative No Bio-Speedy
Li et al. (49) Wuhan, China Cross-sectional 10/23/2020 23 41 (27–55) 26 (4–42) Mild (14/23), All negative N ¼ 22 NA
cohort study (4) moderate (9/23) All negative
Ruan et al. (36) Wuhan, China Cross-sectional (4) 11/4/2020 70 31 (27–36) 80 (64–93) Mild (15%), All negative No DAAN Gene
moderate (42%),
severe (43%)
Temiz et al. (50) Istanbul, Turkey Cross-sectional (4) 11/26/2020 20 37.5 (18–60) (1–5) Mild (20/20) All negative N ¼ 10 Coyote
All negative Bioscience Co.
Total 10 cities, — April to November 299 36 (15–62) 31 (0–109) Asymptomatic (10/299), 98.0% negative Controls: —
5 countries 2020 mild (163/299), (293/299), 2.0% Negative (46/46)
moderate (58/299), positive (6/299)
severe (30/299),
NA (38/299)
Note: NA ¼ not available or not reported.
a
Six men had orchitis during the time of infection and all tested negative (37).
b
Urine was collected and tested on the same day as the seminal fluid and also tested negative (42).
c
Of the 6 positive patients, 4 were at the acute stage of infection, and 2 were in recovery (9).
d
Subjects with a moderate infection demonstrated impaired sperm quality (43).
e
The sperm counts, motility, and morphology of the patients were within the normal range (44).
Tur-Kaspa. COVID-19 affects fertility, not an STD. Fertil Steril Rev 2021.
Fertil Steril Rev®

143
144
SYSTEMATIC REVIEW
TABLE 2
Severe acute respiratory syndrome coronavirus 2 in the testes or prostatic fluid of men with coronavirus disease 2019.
Mean days Reverse transcription
Sample Study type Date of No. of Mean age from diagnosis Severity of polymerase chain
tested Studies City, country (quality rating) publication men (range) (range) COVID-19 Results Control reaction manufacturer
Testes Song et al. (40) Nanjing, China Cohort (4) 4/16/2020 1 67 42 Deceased (1/1) Testicular No Huirui
biopsy: negative Biotechnology
Yang et al. (51) Wuhan, China Case series (4) 5/26/2020 10 65 (42–87) 42 (23–75) Deceased (10/10) Testicular No Liferiver
biopsy: 90.0% Biotechnology
negative (9/10)a,b
Achua et al. (52) New York City, USA Case series (4) 11/30/2020 6 49.5 (22–83) 15 (7–27) Deceased (6/6) Testicular No NA
biopsy: all negative
Total 3 cities, 2 countries — April to 17 60.5 (22–87) 33 (7–75) Deceased (17/17) Testicular No —
November biopsy: 94.1%
2020 negative (16/17), 5.9%
positive (1/17)
Prostatic Quan et al. (34) Shenzhen, China Cohort (4) 3/30/2020 18 60 (20–60þ) NA (3–14þ) Mild (18/18) Prostatic N¼5 BGI
fluid (preprint) fluid: all negative all negative
Zhang et al. (35) Wuhan, China Case series (4) 6/10/2020 10 57 (29–76) 11 (8–17) Mild (10/10) Prostatic No NA
fluid: all negative
Ruan et al. (36) Wuhan, China Cross-sectional (4) 11/4/2020 61 31 (27–36) 80 Mild (15%), Prostatic No DAAN Gene
moderate (42%), fluid: all negative
severe (43%)
Total 2 cities, 1 country — March to 89 49 (20–76) 45.5 (3–17) Mild (37/89), Prostatic Negative —
November moderate (26/89), fluid: 100% (5/5)
2020 severe (26/89) negative (89/89)
a
For the one positive testicular biopsy for SARS-CoV-2, the investigators concluded ‘‘it is likely that reverse transcription polymerase chain reaction detected the virus present in blood rather than in testicular tissue’’ (51).
b
Electron microscopy of testicular tissue for 3 of the reverse transcription polymerase chain reaction-negative patients failed to identify viral particles (51).
VOL. 2 NO. 2 / APRIL 2021
Fertil Steril Rev®
Sixteen oocytes from 2 asymptomatic SARS-CoV-2-

positive egg donors tested negative for the viral RNA (38).
reaction manufacturer
Reverse transcription
and BioPerfectus
This report of testing human oocytes obtained during routine
polymerase chain
Technologies
egg donor in vitro fertilization cycle supports the conclusion
DAAN Gene
QIAGEN
that oocytes obtained from asymptomatic women by in vitro
NA
NA
NA
—
fertilization do not transmit SARS-CoV-2.
COVID-19 during pregnancy and in neonates has been
reviewed elsewhere (7, 58). To date, there is no evidence of
vertical transmission of COVID-19 during vaginal birth (57–
59), supporting the notion that the virus is not transmitted
Control
to newborns during vaginal delivery.

No
No
No
No
No
No
Severe acute respiratory syndrome coronavirus 2 in the reproductive tract of women with coronavirus disease 2019: in vaginal fluid, cervical smear, and oocytes.
All negative
negative
(2/2)
N ¼ 16
Oocyte
100%
result
Evidence for the impact of COVID-19 on fertility

NA
NA
NA
NA
COVID-19 might affect male fertility by damaging the endo-

crine function and/or by temporary or permanent changes
negative
smear result
All negative
(35/35)
Cervical
caused by elevated body temperature and/or orchitis. The ev-

100%
NA
NA
NA
NA
idence of damaged endocrine function is demonstrated by

Twenty-seven patients were diagnosed with COVID-19 on the basis of a positive SARS-CoV-2 throat swab. The other 8 patients were diagnosed on the basis of clinical symptoms (56).
significantly lower serum testosterone to luteinizing hormone

1.7% positive (1/58)
ratios, a measure used as a predictor of compromised testic-

negative (57/58),
negative/then
positive/then
ular function, in patients with COVID-19 compared with

negative
All negative
All negative
All negative
fluid result
those in controls (17). The possible role of testosterone and es-

Vaginal
98.3%
Initially
NA
trogen affecting the prevalence of COVID-19 in men

compared with that in women and their role in the disease’s
severity have been discussed by others (3, 4, 60).
Viral-induced testicular damage may cause hypogonad-
severe (44/58),
ism and infertility in some men. Local inflammatory damage

Severe (10/10)
Severe (34/35)
Asymptomatic
NA (1/58)
Mild (12/12),
Mild (12/12)
Severity of
COVID-19
(2/2)
of the testis-blood barrier might potentially lead to indirect

NA
semen infection. A survey of 91 hospitalized patients with

COVID-19 revealed 11% patients with related testicular
pain, but a clinical presentation of epididymo-orchitis was
from diagnosis
diagnosed in only 1 patient (61).

28 (17–40)
Mean days
23 (8–41)a
26 (8–41)
(range)
Using bedside ultrasound examination of the scrotum in

NA
NA
NA
142 men with a confirmed diagnosis of COVID-19, 22.5% pa-

tients were diagnosed with acute orchitis, epididymitis, or
66 (52–80)
62 (37–88)
32 (24–40)
56 (24–88)
(20–30)
epididymo-orchitis (62). The investigators used imaging

(range)
Mean
age
65
criteria for acute inflammation, including tunica albuginea

All 12 women were pregnant with an average pregnancy of 26.0 " 10.3 weeks’ gestation (57).
thickening; enlargement and heterogeneous echogenicity of

publication women
No. of
the testis, epididymis, or both; an abscess; scrotal wall edema;

12b
10
1
35
58
and hydrocele. The observed risk of acute scrotal inflamma-

July 2020
tion or infection increased with the severity of COVID-19

Date of
4/16/2020
9/30/2020
infection and age. Interestingly, in patients <40 years old,

4/2/2020
5/3/2020
Cross-sectional (4) 7/5/2020

April to
the age of the majority of men seen for infertility, the risk
of acute scrotal inflammation or infection during COVID-19
was only 6.3% compared with 25% in patients >80 years

(quality rating)
Case report (5)
Case report (5)

Study type
old (P¼ .003) (62).

—
Cohort (4)
Cohort (4)
Testicular biopsies from deceased men after SARS and

COVID-19 infections (40, 51) revealed only testicular inflam-
mation and reduced spermatogenesis. Biopsies demonstrated
3 cities, 3 countries
lymphocytic inflammation, reduced spermatogenesis, and

Barcelona, Spain
Sakarya, Turkey
Wuhan, China
Wuhan, China
increased testicular fibrosis, but the seminiferous tubules

country
City,
Rome, Italy
were intact. The findings are presumed to result from the in-
flammatory response and not the virus directly. Furthermore,
electron microscopy failed to demonstrate SARS-CoV-2 viral
particles in the testis (51).
Aslan et al. (57)
Qiu et al. (55)
Cui et al. (56)

et al. (14)
et al. (38)
Two studies investigated semen analyses in patients recov-

TABLE 3
Scorzolini
ering from COVID-19, 8–54 days after diagnosis. One study

Barragan
Studies
demonstrated a decreased sperm count and motility compared

Total
with controls (43), and the other study found the sperm count,
b
a
VOL. 2 NO. 2 / APRIL 2021 145

SYSTEMATIC REVIEW
motility, and morphology to be within normal ranges (44). organs, its co-expression with TMPRSS2, required for
Since elevated body temperature has a known deleterious effect SARS-CoV-2 cell entry, is lacking in testicular and prostatic
on sperm count and motility, the fever, and not the SARS-CoV- cells, sperm, or oocytes. This suggests that the hypothesis
2 infection per se, might have caused the reduction in total that sperm and oocytes may become infected by SARS-
motile sperm counts observed in some patients (39). CoV-2 should be rejected; these cell types are also unlikely
Thus, unless the patient has active COVID-19 and vectors to sexually transmit or infect an embryo (13, 37,
contamination from blood, urine, or feces should be avoided, 39). Lastly, to date, there is no evidence of vertical transmis-
in vitro fertilization treatment and embryo and gamete cryo- sion of COVID-19 during labor (acquisition during passage
preservation seem to pose no significant risk to the embryos through the vaginal canal) (58, 59, 66). Therefore, proposing
produced. that SARS-CoV-2 infection of reproductive tract tissues via
In summary, COVID-19 may cause inflammation in ACE2 receptors leads to sexual or vertical transmission (10,
approximately 5%–10% of men of reproductive age and, 14) is a premature theory and is not supported by current sci-
rarely, even infection of the testes. Such orchitis is highly entific evidence.
correlated with the severity of the disease and age. Sperm Nonetheless, COVID-19 may have temporary or perma-
and oocytes are unlikely to be susceptible to infection by nent detrimental effects on male reproduction. It may involve
SARS-CoV-2, and there is no evidence to support that endocrine alterations in luteinizing hormone and testosterone
COVID-19 is an STD (63). (17) and decreased sperm parameters (43) or may induce an
To date, the possible effects of COVID-19 on the ovary or inflammatory orchitis resulting in fibrosis and further loss
residual ovarian reserve have not been investigated (64). We of testicular function (37, 43, 51). It is not known if, or
suggest that the survivors of COVID-19, especially those how, it might also affect female fertility, ovarian endocrine
suffering from infertility, should be evaluated for their short- function, or ovarian reserve. Prospective and longitudinal
and long-term ovarian and testicular function (54, 60, 63, 65). control studies are warranted to elucidate any possible
long-term consequences of SARS-CoV-2 on human fertility.
There are several limitations for the studies reviewed.
DISCUSSION Because of the exponential rate of viral infections and the
The number of infected patients and information about the variations in international and local characteristics and re-
clinical course of COVID-19 is increasing rapidly (3, 4). Clini- sponses, there remain multiple areas of testing data acquisi-
cians worldwide should continue to follow national and pro- tion and interpretation uncertainty. This has led to
fessional guidelines and the Centers for Disease Control and difficulties in creating best practice protocols to prevent
Prevention, U.S. Food and Drug Administration (FDA), and further spread of SARS-CoV-2. The urgency to develop
World Health Organization websites to stay updated. testing quickly resulted in less rigorous approval processes
To determine if SARS-CoV-2 is sexually transmitted and of SARS-CoV-2 reverse transcription polymerase chain reac-
if guidelines should be specifically updated to address this tion test kits, varying test kit sensitivities and specificities,
concern, this systematic review summarizes recent global and diminished methodological standards for conducting
data of epidemiological investigations, molecular receptor studies. With a rush to publish data and supply frontline pro-
identification, and detection studies of SARS-CoV-2 RNA in viders with data, studies are performed in locations with
the male (in testicular biopsies, seminal, and prostatic fluids) differing prevalence of patient infectivity using different
and female (in vaginal fluids, cervical smears, and oocytes) sampling methods and a lack of controls (65). These problems
reproductive tracts. The available evidence provides no sug- synergize and make data interpretation and, more impor-
gestion that sperm, semen, or the female genital tract trans- tantly, data comparisons difficult.
mits SARS-CoV-2 (34–37, 40–50, 55–57). A recent review A major limitation of the studies that specifically tested
of the 21st century viral pandemics (66) concurs that the male and female reproductive tracts of patients with
current evidence (9, 37, 40–42) does not support that SARS- COVID-19 for SARS-CoV-2 is that, overall, the published ev-
CoV-2 is present in the semen and is therefore unlikely to idence is generally considered low quality, with ratings
be sexually transmitted. Any form of sexual intimacy worsens ranging from 3b to 5 (Tables 1–3). In addition, the
the risks of COVID-19 transmission (67–69), and while SARS- consequences of some study design irregularities are
CoV-2 can be transmitted during sexual contact by aerosols evident in investigations demonstrating the presence of
and fomites, on the basis of currently available information, viral RNA particles but not a contiguous virus in tissues and
it is concluded that the virus is not sexually transmitted. There bodily fluids. Nonetheless, the studies included in this
is the potential for transmission of SARS-CoV-2 via blood review consist of all of the currently published international
(16), urine (17–19), and feces or oral-fecal (20–23), and data through December 11, 2020 and include preprints as
these forms of transmission have been discussed by others well to maximize the inclusion of available data.
(16–23). Homosexual sexual practices have not been There is only 1 publication (out of 14) that describes
reported to transmit the virus. SARS-CoV-2 RNA in the semen of 6 men (9), and in only 1
The identification of viral receptors in human reproduc- case report was SARS-CoV-2 RNA found in vaginal fluid
tive organs raised concerns about the vulnerability of infected (14). Both studies with positive results failed to provide infor-
gametes transmitting the virus sexually by artificial insemi- mation on the specifics of the test kits employed and neither
nation or during vaginal births from mothers to newborns. had a control group for comparison. Moreover, the infectivity
While the ACE2 receptor has been identified in reproductive of the viral particles detected is unknown. Although all
146 VOL. 2 NO. 2 / APRIL 2021

Fertil Steril Rev®
investigations consisted of a small number of patients, they 2. World Health Organization. Middle East respiratory syndrome coronavirus
represent different populations with variable disease severity (MERS-CoV). Available at: https://www.who.int/en/news-room/fact-sheets/
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14. Scorzolini L, Corpolongo A, Castilletti C, Lalle E, Mariano A, Nicastri E.
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VOL. 2 NO. 2 / APRIL 2021 149

CUERPO EDITORIAL
DIRECTOR
Dr. Esteban Sanchez Gaitan, Hospital San Vicente de Paúl, Heredia, Costa Rica.
CONSEJO EDITORIAL
Dr. Cesar Vallejos Pasache, Hospital III Iquitos, Loreto, Perú.
Dra. Anais López, Hospital Nacional Edgardo Rebagliati Martins, Lima, Perú.
Dra. Ingrid Ballesteros Ordoñez, Pontificia Universidad Javeriana, Bogotá, Colombia.
Dra. Mariela Burga, Hospital Nacional Edgardo Rebagliati Martins. Lima, Perú.
Dra. Patricia Santos Carlín, Ministerio de Salud (MINSA). Lima, Perú.
Dr. Raydel Pérez Castillo, Centro Provincial de Medicina Deportiva Las Tunas, Cuba.
COMITÉ CIENTÍFICO
Dr. Zulema Berrios Fuentes, Ministerio de Salud (MINSA), Lima, Perú.
Dr. Gerardo Francisco Javier Rivera Silva, Universidad de Monterrey, Nuevo León, México.
Dr. Gilberto Malpartida Toribio, Hospital de la Solidaridad, Lima, Perú.
Dra. Marcela Fernández Brenes, Caja costarricense del Seguro Social, Limón, Costa Rica
Dr. Hans Reyes Garay, Eastern Maine Medical Center, Maine, United States.
Dr. Steven Acevedo Naranjo, Saint- Luc Hospital, Quebec, Canadá.
Dr. Luis Osvaldo Farington Reyes, Hospital regional universitario Jose Maria Cabral y Baez, Republica
Dominicana.
Dra.Caridad Maria Tamayo Reus, Hospital Pediátrico Sur Antonio María
Béguez César de Santiago de Cuba, Cuba.
Dr. Luis Malpartida Toribio, Hospital Nacional Daniel Alcides Carrión, Callao, Perú.
Dra. Allison Viviana Segura Cotrino, Médico Jurídico en Prestadora de Salud, Colombia.
Mg.Luis Eduardo Traviezo Valles,
Barquisimeto, Venezuela.
Dr.Pablo Paúl Ulloa Ochoa,
Ecuador.
EQUÍPO TÉCNICO
Msc. Meylin Yamile Fernández Reyes, Universidad de Valencia, España.
Lic. Margarita Ampudia Matos, Hospital de Emergencias Grau, Lima, Perú.
Ing. Jorge Malpartida Toribio, Telefónica del Perú, Lima, Perú.
Srta. Maricielo Ampudia Gutiérrez, George Mason University, Virginia, Estados Unidos.
EDITORIAL ESCULAPIO ENTIDAD EDITORA
50 metros norte de UCIMED, SOMEA

Sabana Sur, San José-Costa Rica SOCIEDAD DE MEDICOS DE AMERICA
Teléfono: 8668002 Frente de la parada de buses Guácimo, Limón. Costa Rica
E-mail: revistamedicasinergia@gmail.com Teléfono: 8668002
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e485 Revista Médica Sinergia Vol.5 (5), Mayo 2020 - ISSN:2215-4523 / e-ISSN:2215-5279
http://revistamedicasinergia.com
https://doi.org/10.31434/rms.v5i5.485
Revista Médica Sinergia
Vol.5 Num:5, Mayo 2020, e485
revistamedicasinergia@gmail.com
Infertilidad y factores que favorecen su aparición

Infertility and factors that favor their appearance
1
Dr. Javier Pereira Calvo
Área de salud de Coronado, San José, Costa Rica
https://orcid.org/0000-0001-6127-7853
2
Dra. Yuliana Pereira Rodríguez
Investigadora independiente, Heredia, Costa Rica
https://orcid.org/0000-0001-6045-4379
3
Dr. Luis Quirós Figueroa
Consultorio médico Astorga, San José, Costa Rica
https://orcid.org/0000-0003-4419-1059
RECIBIDO CORREGIDO ACEPTADO

07/01/2020 13/02/2020 01/04/2020
RESUMEN
La infertilidad es un problema frecuente que afecta de manera significativa
a las personas, familias y comunidades. Se define como la incapacidad de
concebir después de doce meses de relaciones sexuales sin protección.
Aproximadamente una de cada seis parejas presenta problemas de
infertilidad, lo cual se atribuye en un cuarenta por ciento a factores
masculinos, cuarenta por ciento a factores femeninos y un veinte por ciento
corresponde a causas desconocidas. Dentro de los factores que aumentan
el riesgo de infertilidad, es posible mencionar la edad avanzada, el
consumo de tabaco, dieta rica en grasas saturadas, obesidad, fármacos e
infecciones.
1
Médico general, graduado
de la Universidad Autónoma PALABRAS CLAVE: infertilidad; sustancias tóxicas; obesidad; dieta;
de Costa Rica (UACA).
cod. MED16280. infección.
javiper_7@hotmail.com
2 ABSTRACT
Médica general, graduada
de la Universidad Latina de Infertility is a frequent problem that significantly affects people, families and
Costa Rica (U.Latina). cod. communities. It is defined as the inability to conceive after twelve months of
MED16212.
yulipr_28@hotmail.com unprotected sex. Approximately one in six couples has infertility problems,
3 which is attributed by forty percent to male factors, forty percent to female
Médico general, graduado
de la Universidad Autónoma factors and twenty percent corresponding to unknown causes. Among the
de Costa Rica (UACA). factors that increase the risk of infertility, it is possible to mention advanced
cod. MED16283 .
alonso979@hotmail.com age, tobacco consumption, diet high in saturated fats, obesity, medications
Infertilidad y factores que favorecen su aparición - Dr. Javier Pereira Calvo; Dra. Yuliana Pereira Rodríguez; Dr. Luis Quirós Figueroa
and infections.
KEYWORDS: infertility; toxic substances; obesity; diet; infection.
INTRODUCCIÓN MÉTODO
La infertilidad se define como la Se utilizó la base de datos SIBDI de la
incapacidad de concebir después de Universidad de Costa Rica, y de ahí se
doce meses de relaciones sexuales sin seleccionaron diferentes artículos de
protección (1,2). Es un problema revisión y de investigación de diversas
frecuente y tiene consecuencias revistas, entre ellas ECM- ginecología y
significativas para las personas, las obstetricia, Revista de perinatología y
familias y la comunidad en general. reproducción humana, Revista
Aproximadamente una de cada seis internacional de andrología, Elsevier,
parejas sufre problemas de infertilidad. Cochrane, entre otras. Se eligieron los
La misma se debe a factores masculinos artículos más relevantes, cuyo contenido
en el 40% de los casos, factores se enfocara en la infertilidad y en los
femeninos en otro 40% y se desconoce factores que impactan en la misma y que
la causa de la infertilidad en el 20% forman parte de la población.
restante de los casos (3). El poder lograr
un embarazo involucra una serie de
GENERALIDADES
condiciones que deben ser óptimas,
como lo son la integridad del eje La infertilidad es un fenómeno habitual
hipotálamo-hipófisis-ovario, interacción hoy en día, aumentando cada año el
de gametos, relaciones sexuales número de parejas que no pueden
regulares, espermatozoides funcionales, concebir. La infertilidad está definida por
moco preovulatorio adecuado, trompas la Organización Mundial de la Salud
permeables y funcionales, así como un
útero acorde para la implantación del sistema reproductivo caracterizada por la
embrión (1). La posibilidad de tener un imposibilidad de lograr un embarazo
hijo vivo y sano puede verse afectado por clínico después de doce meses o más de
factores como el peso, la dieta, el relaciones sexuales regulares sin
tabaquismo, contaminantes ambientales,
infecciones, condiciones médicas y recogen en tres grandes grupos, el factor
medicamentos. femenino y el factor masculino (por
El objetivo de este artículo de revisión es separado o de forma combinada), así
identificar los factores que predisponen a como las causas desconocidas (2).
la infertilidad y determinar los consejos Dentro de las principales causas
previos a la concepción, con el fin de femeninas se encuentran en orden de
ayudar a realizar cambios positivos y, importancia: la anovulación, etiologías
aumentar las posibilidades de un tuboperitoneales, endometriosis,
embarazo (3). etiologías cervicales, etiologías uterinas,
sexológicas, entre otras. En cuanto a las
causas masculinas cabe mencionar las En cuanto a la edad paterna, a pesar

testiculares obstructivas, vasculares de que el potencial biológico
(varicocele), infecciosas, inmunológicas y reproductivo parece permanecer
sexológicas (1). durante la mayor parte de la vida de
Existen factores que pueden afectar las un hombre, se han informado
posibilidades de las personas infértiles cambios significativos en la
de tener un embarazo. La investigación producción de esperma con respecto
sugiere que estos factores pueden tener al envejecimiento, estableciendo la
efectos importantes tanto durante el edad de cuarenta años como corte,
período previo a la concepción como en se ha demostrado que varones
el feto en desarrollo. Brindar mayores de cuarenta años presentan
asesoramiento sobre los factores que mayor tasa de anormalidad en el
afectan la fertilidad a las personas que se volumen de semen, motilidad de
presentan para un tratamiento de espermatozoides así como la
infertilidad, es un primer paso crucial vitalidad de los mismos (1, 2, 4).
para ayudarlos a realizar modificaciones Durante el proceso de
que puedan aumentar sus posibilidades envejecimiento, el cuerpo
de concepción oportuna y así lograr dar a experimenta muchos cambios. En el
luz a un bebé sano y vivo (3). aparato reproductor masculino,
principalmente, disminuye el número
FACTORES QUE INFLUYEN EN LA de células de Leydig, liberadoras de
testosterona, y se produce un
INFERTILIDAD
engrosamiento de la membrana basal
Edad de los túbulos seminíferos lo que
En los últimos años debido a conlleva a alteraciones de la
diferentes razones sociales, entre espermatogénesis en pequeñas
ellas la educación universitaria áreas (1, 2).
asociada a una mayor estabilidad Además, surgen complicaciones
financiera y profesional, se ha como la disfunción eréctil,
presentado un aumento en la consecuencia del incremento en la
prevalencia de la paternidad tardía producción de radicales libres (estrés
(4). Específicamente la edad oxidativo). Surgen también cambios
femenina es considerada un factor en el sistema endocrino, como el
limitante para la fertilidad (1). cese del suministro de esteroides
Con respecto a la edad materna, se mitocondriales que contribuye a
sabe que las mujeres tienen un disminuir las células de Sertoli,
potencial de fertilidad reducido a afectando al correcto funcionamiento
medida que se acercan a la de las células de Leydig y, con ello,
menopausia, debido a la asociación reducir los niveles de testosterona.
entre el envejecimiento y el Esta hormona es fundamental para el
agotamiento de folículos, disminución adecuado desarrollo de los
de la calidad de los ovocitos y la espermatozoides, por lo que su
reparación defectuosa del ADN (2,4). disminución supone serios problemas
Revista Médica Sinergia Vol.5 (5), Mayo 2020 - ISSN:2215-4523 / e-ISSN:2215-5279

e485 http://revistamedicasinergia.com
en la espermatogénesis y en la ovárica, así como afectación de la

calidad seminal (2). espermatogénesis, receptividad del
Otro aspecto relevante a destacar es endometrio y placentación precoz.
que la edad disminuye la frecuencia En un estudio publicado en el año
de relaciones sexuales y la tasa de 2000, se demostró que solo el 47%
embarazo, aumentando el tiempo de los pacientes infértiles fumadores
necesario para conseguirlo. Esto es pensaba que el tabaquismo tenía un
consecuencia principalmente de las impacto negativo en la fertilidad y
alteraciones espermáticas y solo el 30% indicaba haber recibido
endocrinas, aunque influye en un información de parte de su médico
porcentaje mayor la edad materna sobre los efectos negativos del
(2). tabaco. El consumo de tabaco se
Por último, entre los problemas más asocia con aumento significativo de
frecuentes y generalmente asociados retraso en la concepción, superior a
a la edad paterna y materna, un año en mujeres fumadoras y a
destacan el aumento notable de la seis meses en los varones (5).
fragmentación del ADN espermático, En el varón, existe un efecto directo
las aneuploidías y las alteraciones de los tóxicos del tabaco presentes
genéticas. Con el paso de los años, en el plasma seminal sobre la
el número de divisiones celulares vitalidad de los espermatozoides, se
sigue aumentando, así como la asocia con disminución del número y
continua exposición a agentes de la movilidad espermática,
mutagénicos y la replicación y aumento de teratospermia, así como
duplicación de ADN, lo que conlleva cambios nucleares en el esperma,
un incremento de la tasa de error de tales como aumento de aneuploidías,
la replicasa, acumulándose incremento del estrés oxidativo y
mutaciones que desembocan en fragmentación del ácido
desórdenes genéticos. Por tanto, desoxirribonucleico (ADN)
cuanto mayor es el padre, la madre o espermático, favoreciendo a su vez
ambos, mayor es la probabilidad de abortos espontáneos (5, 6).
transmitir tanto mutaciones genéticas Como efecto potencial, el consumo
como enfermedades hereditarias a su de tabaco (al menos una cajetilla al
descendencia (1, 2, 4). día) asociado con edad mayor a 40
años y consumo de alcohol (al menos
Tabaco un vaso al día) se asocia con un
Se ha demostrado que tanto el aumento significativo en la
tabaquismo activo como el pasivo, anormalidad de la vitalidad de los
están asociados con infertilidad y una espermatozoides (4).
mejor posibilidad de lograr un En la mujer, el tabaco se asocia con
nacimiento sano y vivo (3, 4). Los una modificación en el perfil
numerosos productos químicos del hormonal, con niveles elevados de
humo del tabaco son responsables hormona folículo estimulante (FSH) y
de alteraciones en parámetros disminución de síntesis de
hormonales, en la reserva y calidad estrógenos y progesterona,

favoreciendo así un ambiente para la fecundidad femenina y

androgénico perjudicial para el masculina (7, 8, 9).
crecimiento y maduración folicular en La composición de los ácidos grasos
el ovario. Así mismo, diversos de la membrana de los
componentes del tabaco generan un espermatozoides es muy importante
ambiente tóxico en el ovario, para la adecuada función de estos
causando estrés oxidativo, atresia últimos. Esta membrana juega un
acelerada por factores papel fundamental en eventos claves
proapoptósicos y anomalías de de la fertilización como captación,
meiosis con el aumento de reacción del acrosoma y fusión de
aneuploidías. La menopausia se espermatozoides y ovocitos. La
adelanta 2 años en las fumadoras y cantidad de ácidos grados
los marcadores de reserva ovárica poliinsaturados de cadena larga en la
como la hormona antimulleriana son membrana de los espermatozoides
mucho más bajos (5, 6). no puede ser sintetizado
De igual forma se ha descrito que la endógenamente por los humanos,
implantación del embrión se ve por lo que debe ser obtenido de la
afectada por el tabaquismo, de forma dieta, estos se hallan en las nueces,
que en las pacientes que fuman más semillas, aceites vegetales y
de 10 cigarros por día se ha visto una mariscos, es por eso que el consumo
reducción importante en las tasas de de dichos alimentos en varones se ha
embarazo, esto se ha atribuido en asociado con mayor proporción de
modelos animales al efecto que esperma morfológicamente normal y
ejercen diversos metabolitos del parámetros espermáticos más altos
tabaco sobre la maduración (7, 9, 10). Por otro lado, los ácidos
endometrial y la angiogénesis (5). grasos trans y las grasas saturadas,
Adicional a lo anterior, se ha tienen un efecto opuesto en la
relacionado al tabaco con mayor espermatogénesis, se han asociado
riesgo de embarazos extrauterinos, con baja calidad del semen, en
dicho riesgo aumenta de manera especial recuentos más bajos, se
proporcional a la dosis, de manera sabe que la ingesta de grasas
que las pacientes que fuman más de saturadas es inversamente
20 cigarros por día, tiene un riesgo proporcional con el recuento total de
multiplicado por 3.5-3.9 (2, 5, 6). espermatozoides (7).
En las mujeres, se ha evidenciado
Dieta una fuerte asociación entre la ingesta
En diversos metaanálisis, se ha de pescado y un tiempo más corto
demostrado que en los últimos años para lograr la concepción, dichos
la calidad del semen ha disminuido hallazgos son consistentes con el
en hombres, esto se ha asociado en consejo de la ACOG (American
gran parte con el empeoramiento en College of Obstetricians and
la dieta y con la obesidad Gynecologists) en donde se insta a
subsecuente. Se sabe que la dieta las mujeres con deseos de un
corresponde a un factor modificable embarazo y a las embarazadas a

consumir de dos a tres porciones de expresan la ferroportina y que el

una variedad de pescado por hierro está correctamente regulado
semana, siempre y cuando no se en los testículos, lo que indica una
consuman especies como atún necesidad crítica de mantener la
blanco o pez espada más de una vez homeostasis del hierro para una
por semana, esto debido a que función testicular apropiada. Por
dichas especies tienen mayores ejemplo, se ha visto que los niveles
niveles de metilmercurio lo cual de hierro en plasma seminal son más
podría ser perjudicial para el altos en hombres infértiles que en
desarrollo fetal (2, 8). fértiles. Estos datos muestran el
Además, se ha demostrado en potencial efecto perjudicial de
diversos estudios que el consumo de concentraciones relativamente
ácidos grados poliinsaturados se elevadas de hierro sobre la
asocia con aumento en la espermatogénesis. De hecho, para
progesterona lútea, estrógeno y varones adultos se recomienda una
menor riesgo de anovulación, ingesta diaria de hierro de entre 8 y
mientras que el consumo de grasas 45 mg (11).
trans se han asociado a mayor riesgo Se ha comprobado que con el
de infertilidad anovulatoria y consumo de ácido fólico, se genera
endometriosis (8). un efecto contrario en hombres y
Así mismo, se ha demostrado que mujeres. La ingesta de ácido fólico en
una dieta mediterránea, el hombre, afecta de manera
caracterizada por alto consumo de negativa la producción de esperma
frutas, verduras, pescado, aves de (8,10), mientras que en la mujer
corral y productos bajos en grasa, se sucede lo opuesto, ya que el ácido
asocia con mejoras en la fertilidad fólico se ha asociado con menor
masculina y femenina (7, 8, 9). frecuencia de anovulación, además,
Con respecto a la ingesta de la suplementación diaria de esta
oligoelementos, estos son esenciales vitamina antes de la concepción y
para todos los procesos fisiológicos durante los primeros tres meses de
de nuestro cuerpo, incluidos los embarazo, disminuye los riesgos de
mecanismos moleculares y celulares defectos del tubo neural. Por lo
implicados en la función testicular. No tanto, se aconseja que para todas
obstante, el exceso, así como la aquellas mujeres con deseos de
deficiencia de estos elementos podría lograr un embarazo, inicien con el
alterar la espermatogénesis o consumo de
producir estrés oxidativo en el tejido cada día (3, 8, 9).
testicular o los espermatozoides,
produciendo subfertilidad (9, 11). Obesidad
En el caso del hierro, tanto el déficit El sobrepeso y la obesidad en la
como el exceso pueden afectar mujer y en el hombre, está asociado
negativamente a la a un mayor plazo para la concepción,
espermatogénesis. Es interesante además de ser un factor de riesgo
señalar que las células de Sertoli para el desarrollo de enfermedades

crónicas que afectan la evolución de infertilidad. La obesidad de inicio

un embarazo (1). temprano genera una pubertad más
Diversos estudios han asociado la acelerada y una maduración más
obesidad en varones con cambios precoz del eje hipotálamo-hipófisis lo
hormonales que finalmente afectan la que genera afectación en el
fertilidad. Esto se basa en que la desarrollo del sistema reproductivo
obesidad se liga con niveles en las niñas. Se produce una mayor
disminuidos de testosterona, lo que producción de estrógeno asociado a
conlleva a alteraciones en el los niveles elevados de tejido adiposo
espermiograma. El eje hipotálamo- y con la aromatización acelerada de
hipófisis- testículo se ve afectado en andrógenos suprarrenales y ováricos
varones con aumento del índice de se promueve una adrenarquia,
masa corporal, esto es debido a que pubarca y telarca más temprana, lo
la globulina fiadora de hormonas que puede afectar
sexuales se suprime por efecto de la desfavorablemente el eje hipotálamo-
elevación de la insulina lo que genera hipófisis, la función ovárica, calidad
un aumento en la cantidad de de los ovocitos y receptividad
andrógenos libres que son endometrial a largo plazo. Además, la
aromatizados en el tejido graso, obesidad infantil contribuye al
concluyendo en un aumento de los desarrollo y gravedad del síndrome
niveles de estrógenos, los cuales por de ovario poliquístico en la
retroalimentación negativa inhiben en adolescencia, aumentado así el
el hipotálamo la liberación de riesgo de infertilidad anovulatoria
hormona liberadora de posterior (13).
gonadotropinas, por lo que el eje
hipotálamo-hipófisis-testículo Antiinflamatorios no esteroideos
disminuye la producción de Los antiinflamatorios no esteroideos
testosterona (12). (AINES) forman parte de los
Además, existe evidencia de que medicamentos más utilizados a nivel
tanto el sobrepeso como la obesidad, mundial, usados de manera frecuente
conllevan a una disminución en los en personas en edad reproductiva
compuestos antioxidantes del (14).
organismo, lo que su vez, aumenta Desde hace más de veinte años se
los radicales libres; ocasionando un ha descrito el efecto de los AINES
incremento en la fragmentación del sobre la ovulación. Se sabe que los
ADN y daño de la actividad AINES actúan inhibiendo la
mitocondrial espermática, generando ciclooxigenasa 1 y 2, inhibiendo así la
una calidad deficiente del esperma síntesis de prostaglandinas, las
(2). cuales tienen isoformas que son
En la mujer la obesidad también se esenciales para la formación de
ha asociado con infertilidad, incluso enzimas proteolíticas que causan
se ha demostrado que la obesidad rotura de los folículos en el ovario. La
infantil antes de los doce años, se ciclooxigenasa 2 (COX-2) se
asocia con riesgo aumentado de encuentra activa en los ovarios

durante el desarrollo folicular, la enfermedades de transmisión sexual

inhibición de la COX-2 por los AINES (1, 3).
puede causar de forma reversible el Dentro de los agentes patógenos
llamado Síndrome del folículo más estudiados se encuentra
luteinizado no roto, el cual se Chlamydia trachomatis y Neisseria
caracteriza por un fallo en la gonorrhoeae. La totalidad de la
ovulación, no se produce la rotura evidencia que vincula a Neisseria
folicular ni se liberan los óvulos. Es gonorrhoeae y Chlamydia
por esto, que resulta prudente trachomatis con la infertilidad es
aconsejar evitar el uso de AINES, convincente. Estos microorganismos
utilizar en su lugar paracetamol, en el varón se han asociado en su
cuando sea clínicamente apropiado, mayoría a infecciones asintomáticas,
en mujeres con problemas de y en diversos estudios se ha
infertilidad (14). demostrado afectación de la calidad
En el caso de los hombres, con el seminal con reducciones de hasta
uso de AINES sucede lo contrario a 20% en parámetros seminales,
la mujer. Se han utilizado AINES en disminución de la concentración
el tratamiento de la infertilidad espermática, movilidad y morfología.
masculina de manera empírica en los (16).
casos de oligoastenoteratospermia y En el caso de las mujeres, estos
normozoospermia en pacientes sin microorganismos se han asociado a
factores de riesgo para infertilidad. infertilidad de tipo tubárico, la cual
De igual forma, se han utilizado de representa el 30% de la infertilidad
manera no empírica en los casos en femenina en los Estados Unidos (1,
donde se ha identificado una causa 17).
inflamatoria que se traduce en La salpingitis es la principal causa de
leucocitospermia. Dichos pacientes infertilidad de origen tubárico, el
presentan alteración en la efecto negativo en la fertilidad se
concentración, morfología y motilidad presenta principalmente por el
de los espermatozoides, estos desarrollo de adherencias como parte
parámetros mejoran con el uso de de una complicación de esta
AINES. Se sabe que los salicilatos y infección. La misma se genera
el ibuprofeno tienen un efecto debido a que las bacterias ascienden
negativo en la fertilidad masculina, a través de las superficies mucosas
mientras que los inhibidores de la desde el cérvix hasta el endometrio,
COX-2 la favorecen (15). terminando en las trompas de
Falopio. Esta vía ascendente se
Infecciones manifiesta clínicamente como una
Los procesos inflamatorios e enfermedad pélvica inflamatoria
infecciosos del tracto urogenital aguda (EPI). Alrededor del 15% de
juegan un papel importante en la mujeres con EPI desarrollan
fertilidad femenina y masculina. Por infertilidad de origen tubárico, sin
lo tanto, las parejas que buscan embargo, la mayoría de mujeres con
concebir, deben ser valoradas por infertilidad de origen tubárico no

tienen antecedentes de EPI, sino que varón idealmente antes de los 40 años.
han presentado salpingitis Con respecto al tabaco existe una clara
asintomáticas o con mínima asociación del mismo con retraso en la
presentación de síntomas (17). concepción, esto es directamente
Se debe priorizar en la detección y el proporcional a la dosis, se recomienda
tratamiento en el entorno clínico. Se no fumar en pacientes que desean un
ha descrito una posible asociación embarazo. Tanto en hombres como en
entre las tendencias de manejo de la mujeres, la dieta mediterránea se ha
enfermedad y la reducción de las asociado con mejoras en la fertilidad,
morbilidades reproductivas. Es claro mientras que por el contrario, las grasas
que las mujeres que retrasan la trans se han asociado con deterioro de la
búsqueda de atención en los casos misma, a su vez este tipo de grasa se ha
de una infección asintomática tienen asociado con obesidad lo cual tiene un
un mayor riesgo de infertilidad y otras impacto negativo en la fertilidad, se sabe
enfermedades reproductivas (16, 17). que la obesidad cuanto más temprano se
presenta mayor impacto negativo genera.
CONCLUSIÓN Se recomienda un índice de masa
corporal adecuado en las parejas con
Son bien conocidos los factores que deseos de concebir. En mujeres se
influyen en la infertilidad, siendo los recomienda el uso de vitaminas como el
principales la edad, el consumo de ácido fólico previo a la concepción, con el
tabaco, dieta, obesidad, ciertos fin de obtener beneficios en el producto.
medicamentos y las infecciones del Se recomienda evitar el uso de AINES en
tracto urogenital. A raíz de esto, es mujeres con deseos de concebir, en los
posible brindar ciertas recomendaciones varones se ha visto un efecto
a las parejas que desean concebir, por beneficioso. Se insta a fortalecer los
ejemplo, según la evidencia se programas de prevención de infecciones
recomienda tomar en cuenta la edad en del tracto urogenital, con el fin de
el momento de intentar un embarazo, un disminuir una de las más frecuentes
embarazo en edades tempranas se causas de infertilidad prevenible tanto en
asocia a mayor éxito, en el caso del varones como en mujeres.
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medicina. 2019. Marzo. http://dx.doi.org/10.1016/S16365410(18)41696-0
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fertilidad masculina. Med Reprod Embriol Clin. 2019, https://doi.org/10.1016/j.medre.2019.10.001
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4. Gustavo Luis Veron, M.Sc., Andrea Daniela Tissera, B.S.,b Ricardo Bello, M.Sc.,c Fernando Beltramone,
M.D.,d Gustavo Estofan, M.D.,d Rosa Isabel Molina, B.S.,b and Monica Hebe Vazquez-Levin, Ph.D.
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fertility: doctor, what should I eat?. Fertility and Sterility® Vol. 110, No. 4. 2018. September.
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reproduction: an overview. Fertility and Sterility® Vol. 110, No. 4. 2018. September.
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varones jóvenes: relación con la fertilidad. Rev Int Androl. 2018.
https://doi.org/10.1016/j.androl.2018.03.004
12. Aguilar-Roa P, Echavarría-Sánchez M. Relación circunferencia abdominal e insulinorresistencia y su
impacto en parámetros seminales. Perinatol Reprod Hum. 2016.
http://dx.doi.org/10.1016/j.rprh.2016.07.003
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Ph.D.a. Association of childhood obesity with female infertility in adulthood: a 25-year follow-up study.
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http://dx.doi.org/10.1016/j.semerg.2016.01.013
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Rev. cient. cienc. salud 2021; 3(2):11-18
Doi: 10.53732/rccsalud/03.02.2021.11
Artículo Original/ Original Article
Prevalencia de alteraciones del factor masculino en

pacientes que consultan en una clínica de referencia por
infertilidad en el periodo de agosto de 2018 agosto de 2019
Jennifer Olmedo-Samudio*1,2,3 , Juan Manuel Galeano1,3 ,
Oscar Manuel Ruiz-Valdez1,2,3
1
Universidad Nacional de Asunción, Facultad de Ciencias Médicas, Hospital de Clínicas. Cátedra y Servicio
de Ginecoobstetricia. San Lorenzo, Paraguay
2
Clínica Neolife. Medicina y Cirugía Reproductiva. Asunción, Paraguay
3
Universidad del Pacífico, Dirección de Postgrado, Especialización en endocrinología Ginecológica y
Reproductiva. Asunción, Paraguay
Cómo referenciar este artículo/ Olmedo-Samudio J, Galeano JM, Ruiz-Valdez OM. Prevalencia
How to reference this article de alteraciones del factor masculino en pacientes que consultan en
una clínica de referencia por infertilidad en el periodo de agosto de
2018 agosto de 2019. Rev. cient. cienc. salud 2021; 3(2):11-18
RESUMEN
La infertilidad es la incapacidad de una pareja para concebir después de un año

de vida sexual regular sin utilizar un método de planificación familiar. El factor
masculino como causa de infertilidad está presente en el 30 al 50% de los casos.
Objetivo: Determinar la frecuencia del factor masculino alterado en las parejas con
infertilidad atendidas en la Clínica Neolife de Asunción, entre agosto de 2018 a
agosto de 2019. Materiales y métodos: Se realizó un estudio observacional
retrospectivo, descriptivo, de corte transversal. Se revisaron los espermogramas
practicados a parejas con diagnóstico de infertilidad, la recolección y análisis de las
muestras de semen se basó en estándares establecidos por la OMS. Resultados:
De 150 pacientes, 89 (59,3%) mostraron alteraciones en los índices seminales, la
media de edad de este grupo fue 37,8 ± 6,7 años. En cuanto al volumen
espermático, 9 pacientes (6%) presentaron hipospermia, la cantidad de
espermatozoides mostró azoospermia en 5 pacientes (3,3%) y oligozoospermia en
35 (23,3%), por la concentración espermática, 37 pacientes (24,6%) tuvieron
oligozoospermia, por el porcentaje de espermatozoides móviles progresivos, 31
(20,6%) presentaron astenozoospermia, según el porcentaje de formas normales,
59 (39,3%) presentaron teratozoospermia y el recuento de espermatozoides
móviles estuvo disminuido en 52 (34,6%). En el 50,6% de los seminogramas
alterados hubo una alteración aislada, dos alteraciones en el 13,5% y en el 35,9%
restante más de dos. Conclusiones: Una importante proporción de parejas tuvo
alteración del factor masculino. Las principales alteraciones fueron
teratozoospermia, recuento de espermatozoides móviles disminuido e
oligozoospermia.
Palabras Clave: diagnóstico; infertilidad masculina; análisis de semen
Prevalence of alterations of the male factor in patients

consulting at a reference clinic for infertility between august
2018 - august 2019
ABSTRACT
Infertility is the inability of a couple to conceive after one year of regular sexual
life without using a family planning method. The male factor as a cause of infertility
is present in 30 to 50% of cases. Objective: To determine the frequency of the
Fecha de recepción: diciembre 2020 Fecha de aceptación: junio 2021
*Autor correspondiente: Jennifer Olmedo Samudio
email: yen.olm.med100@hotmail.com Cel: +595994760604
Este es un artículo publicado en acceso abierto bajo una Licencia Creative Commons
Olmedo-Samudio et al. Prevalencia de alteraciones del factor masculino
altered male factor in couples with infertility treated at the Neolife Clinic from
August 2018 to August 2019. Material and methods: An observational,
retrospective descriptive, cross-sectional study was carried out. Spermograms of
couples who attended the consultation for infertility were reviewed, collection and
analysis of the semen samples was based on standards established by the WHO.
Results: Of 150 couples, 89 (59.3%) showed alterations in the seminal indexes,
the mean age of this group was 37.8 ± 6.7 years. Regarding sperm volume, 9
patients (6%) presented hypospermia, the amount of sperm showed azoospermia
in 5 patients (3.3%) and oligozoospermia in 35 (23.3%), by the sperm
concentration, 37 patients (24.6%) had oligozoospermia, by the percentage of
progressive motile spermatozoa, 31 (20.6%) had asthenozoospermia, according to
the percentage of normal forms, 59 (39.3%) had teratozoospermia and the count
of motile spermatozoa was decreased in 52 (34.6%). In 50.6% of the altered
seminograms, there was one isolated alteration, in 13.5% two alterations and in
the remaining 35.9% more than two alterations. Conclusions: An import
proportion of couples had alteration of the male factor. The main alterations were
teratozoospermia, decreased motile sperm count, and oligozoospermia.
Key words: diagnosis; male infertility; semen analysis
INTRODUCCIÓN
La infertilidad se define como la incapacidad de una pareja para concebir

después de 12 meses de relaciones sexuales frecuentes, sin utilizar métodos de
planificación familiar. Es un problema que llega a afectar a 1 de cada 6 ó 10
parejas. La mayor parte de los estudios efectuados indica que 15% de todas las
parejas experimentará infertilidad primaria o secundaria en algún momento de su
vida reproductiva(1-4).
El estado de infertilidad depende tanto del factor femenino como del

masculino(5,6); se designa un factor masculino alterado cuando cualquier causa o
causas de infertilidad residen en el hombre(7,8). El factor masculino como causa de
infertilidad está presente en el 30 al 50% de los casos de infertilidad
diagnosticados, de ahí la importancia de una evaluación integral de las alteraciones
masculinas y su fertilidad.(9,10) El sistema reproductor masculino aparentemente
posee funciones simplistas para producir esperma y testosterona, pero los
mecanismos subyacentes son mucho más complejos y aún no se han revelado por
completo(11-13). Estos elusivos mecanismos de las funciones reproductivas
masculinas han conducido a una comprensión deficiente de las causas reales de la
infertilidad masculina en aproximadamente el 50% de los casos (14,15). La alteración
de la fertilidad masculina puede reflejarse en la alteración de los parámetros de los
espermatozoides a través de factores multivariantes a diferentes niveles (16-18).
Las etiologías de la infertilidad masculina pueden actuar a niveles reguladores

pretesticulares o neuroendocrinos. Otros factores pueden afectar directamente los
sitios intratesticulares, afectando así las funciones de las células de Sertoli, las
células de Leydig y las células germinales. También pueden producirse alteraciones
en los estratos postesticulares, lo que perjudica la maduración y el transporte de
los espermatozoides. Además del concepto convencional de fisiopatología de la
infertilidad masculina, existe un advenimiento de la inmunología reproductiva
masculina, así como de la genética reproductiva y la epigenética, cuyas
modulaciones pueden inducir diversas formas de deterioro de la fecundidad
masculina. La evaluación adecuada de la infertilidad masculina en diferentes niveles
es esencial para su manejo eficaz. Se puede adoptar un tratamiento dirigido a un
factor masculino específico con o sin técnicas de reproducción asistida (TRA) para el
manejo de la infertilidad masculina(19).
La Organización Mundial de la Salud (OMS) ha propuesto clasificar la infertilidad

masculina en función de las características del semen(20) donde según la alteración
observada tenemos hipospermia cuando el volumen espermático es menor a 1,5 cc,
azoospermia cuando hay ausencia total de espermatozoides (21), criptozoospermia
Rev. cient. cienc. salud 2021; 3(2):11-18 12

cuando posterior a un lavado y concentración se obtienen espermatozoides en un

muestra previamente calificada como azoospermica(22), oligozoospermia cuando la
cantidad espermática total es menor a 39 millones y/o la concentración
espermática es menor a 15 millones, astenozoospermia cuando el porcentaje de
espermatozoides móviles progresivos es menor al 32%, teratozoospermia cuando la
morfología espermática normal por criterios estrictos de Kruger es menor al 4% y el
recuento de espermatozoides móviles está disminuido si es menor a 5 millones. La
distribución común de las causas de infertilidad puede desconocerse debido a la
escasez de información proveniente de las clínicas de fertilidad en nuestro medio.
El objetivo de este trabajo fue determinar la frecuencia del factor masculino

alterado en asociación con anomalías diagnosticadas, según el número de índices
seminales afectados con base en espermogramas realizados en las parejas con
infertilidad atendidas en la Clínica Neolife en el periodo de 1 año, de tal forma a
conocer las características generales de las parejas con infertilidad que acuden a
nuestra consulta y en qué porcentaje podemos asociar al factor masculino.
MATERIALES Y MÉTODOS
Se realizó un estudio retrospectivo, observacional, descriptivo, de corte

transversal, que incluyó a todas las parejas con diagnóstico de infertilidad que
consultaron en la Clínica Neolife de Asunción, en el periodo de agosto de 2018 a
agosto de 2019 que cumplieron con los criterios de inclusión. Se excluyeron a
aquellas parejas que no concluyeron el protocolo de diagnóstico de infertilidad y,
por lo tanto, cuyas historias clínicas no tuvieron los datos requeridos para el
estudio.
Se realizó una revisión de las historias clínicas de las parejas que consultaron
durante el periodo de estudio, se utilizó un filtro electrónico del sistema informático
VRepro que es el que se utiliza en la clínica, que incluyó a todas las consultas
iniciales de fertilidad desde el 01 de agosto de 2018 al 31 de agosto de 2019. Las
variables estudiadas fueron: la presencia o no de alguna alteración del factor
masculino, la edad, el volumen espermático, la cantidad espermática total, la
concentración espermática, el porcentaje de espermatozoides móviles progresivos,
la morfología espermática y el recuento de espermatozoides móviles.
Análisis de datos: la información fue recolectada de los expedientes clínicos

electrónicos almacenados en el VRepro (Sistema informático específicamente
diseñado para la gestión integral de Centros de Reproducción Asistida). Los datos
se registraron en planilla electrónica Microsoft EXCEL, posteriormente analizados
con EPIINFO (CDC, Atlanta) utilizando estadística descriptiva. Los resultados se
expresaron en forma de proporciones para las variables cualitativas y como media y
desviación estándar para las variables continuas.
Aspectos éticos: los datos de los pacientes se manejaron en el anonimato de

tal forma a resguardar la identidad de los mismos, utilizamos códigos para
identificar los casos para la carga de datos en las planillas, todos los datos se
recolectaron en planillas electrónicas y se analizaron también de forma electrónica.
RESULTADOS
De 150 informes de espermogramas, 89 (59,3%) mostraron alteraciones en los

índices seminales (Figura 1), la media de edad de este grupo fue de 37,8 años +/-
DE 6,7 años. En el 50,6% de los seminogramas alterados hubo solo una alteración
aislada, en el 13,5% dos alteraciones y en el 35,9% restante más de dos
alteraciones.

100
90
80
59,3 %
70
60
50 40,6 %
40
30
20
10
0
NO SI
Figura 1. Frecuencia de alteración del Factor Masculino en parejas atendidas en

la Clínica Neolife en el periodo de un año (n: 150).
En cuanto al volumen espermático encontramos hipospermia en 9 pacientes

(6%), en lo referente a la cantidad total de espermatozoides hallamos azoospermia
en 5 pacientes (3,3%) y oligozoospermia en 35 pacientes (23,3%), según la
concentración espermática se vio oligozoospermia en 37 pacientes (24,6%), por el
porcentaje de espermatozoides móviles progresivos se diagnosticó
astenozoospermia en 31 pacientes (20,6%), según el porcentaje de formas
normales encontramos teratozoospermia en 59 pacientes (39,3%), y el recuento de
espermatozoides móviles hallamos disminuido en 52 pacientes (34,6 %) (Figura 2).
45,00%
40,00%
35,00%
30,00% 39,3%
34,6%
25,00%
20,00%
24,6% 23,3%
20,6%
15,00%
10,00% 6%
3,3%
5,00%
0,00%
Astenozoospermia Azoospermia Hipospermia Oligozoospermia (CC)
Oligozoospermia (CT) REM disminuido Teratozoospermia
Figura 2. Tipos de alteraciones del Factor Masculino
DISCUSIÓN
En el presente estudio se realizó en primer lugar la búsqueda de la presencia o

no de alteración del factor masculino en parejas con diagnóstico de infertilidad y
secundariamente la prevalencia de cada una de las alteraciones posibles en el
espermograma, así como la caracterización de la edad media de los pacientes
estudiados, que consultaron en la Clínica Neolife en el periodo de un año. Los
resultados coinciden con la estadística que se maneja a nivel internacional y con
varias publicaciones sobre el tema, no podemos comparar con estudios nacionales
ya que aún no se han publicado previo al presente estudio.

Respecto a la distribución por edad, Marimuthu et al (2003)(23) realizaron análisis

de semen de sujetos que asistieron a la clínica de fertilidad durante los últimos 11
años, observaron que la edad promedio de los hombres era de 31.2 años. Por su
parte, Salgado et al (2003) informaron en el seminograma de 571 parejas que
consultaron por infertilidad en una clínica de referencia una edad media de 31,89 ±
6,3 años(24). De acuerdo con lo anterior, los estudios mostraron que la mayoría de
los hombres con índices seminales anormales son mayores a 30 años como en el
presente estudio, sin embargo, un poco más jóvenes a nuestros pacientes ya que
estos tenían una media de edad de 37,8 ± 6,7 años.
En una revisión de Kumar et al (2015)(25) se reporta que de todos los casos de

infertilidad, aproximadamente el 40-50% se debe a la infertilidad por "factor
masculino". En nuestro estudio este hallazgo fue del 59,3% que coincide con la
tendencia en aumento de las alteraciones del factor masculino en los últimos años
que reporta esa misma revisión.
En cuanto a la distribución por alteraciones, Salgado et al (2003)(24) observaron

que la astenozoospermia estaba presente en el 8.89% de los casos de la clínica
estudiada, muy inferior a nuestro hallazgo del 20,6%, así como también la
azoospermia reportada por ellos fue del 23,98% muy por encima de nuestro
hallazgo del 3,3%. El porcentaje de casos de astenozoospermia y de azoospermia
como causa de infertilidad en el presente estudio es comparable con el estudio
realizado por Ugboaja et al (2010)(26) y por Hernandez Uribe et al (2001) (27), ambos
en clínicas de referencia, pero el porcentaje de casos de astenozoospermia fue muy
diferente en los estudios realizados por Adenijiv et al (2003) (28) y Salgado et al
(2003)(24) en sus respectivas clínicas. Esta diferencia podría deberse a que los
estudios se realizaron en diferentes áreas geográficas donde diferentes factores
ambientales afectan el índice seminal.
Dentro de las alteraciones de los parámetros seminales llama la atención que en

ninguno de los estudios revisados reporta a la teratozoospermia como causa
principal, como fue el hallazgo en nuestro centro y representó el 39,3% de los
casos con alguna alteración, esto podría ser por la diferencia en cuanto a los
criterios de evaluación utilizados en cada uno de los centros, ya que la evaluación
de la morfología por los criterios estrictos de Kruger (29-34)
utilizaban la guía de análisis seminal anterior a la del 2010 (35-38), actualmente ya

obsoleta, la misma manejaba otros criterios de morfología en comparación con la
última publicada en el 2010(39) que es la que utilizamos en nuestro centro.
Para futuros estudios sería interesante aumentar la cantidad de pacientes

analizados, así como también incluir otros parámetros adicionales como el Test de
TUNEL, el MAR test, el espermocultivo, la bioquímica seminal y el índice de
maduración espermática(40) en cuanto al análisis seminal se refiere, así como
también, el índice de masa corporal, el tabaquismo, la presencia o no y el grado de
varicocele, etc. Debido a que esto fue una limitante en el presente estudio ya que
no todas las parejas se habían realizado todos los estudios y las historias clínicas no
contaban con todos los datos, para de este modo poder evaluar de una forma más
global las posibles causas de alteración del factor masculino y poder así tratarlas
más específicamente según los hallazgos en cada pareja, valiéndonos sobre todo de
las técnicas de selección espermática con las que se cuenta actualmente y de las
TRA para de esta forma poder obtener una mayor tasa de embarazo en curso y
nacido vivo en casa.
En conclusión, encontramos alteración del factor masculino en el 59,3% de las

parejas que consultaron por infertilidad en la Clínica Neolife en el periodo de 1 año.
Las tres principales alteraciones de los índices seminales fueron teratozoospermia,
recuento de espermatozoides móviles disminuido e oligozoospermia, por lo que la
infertilidad masculina es una causa importante de infertilidad con un fuerte impacto
en la psicología y fisiología de la pareja y puede deberse a varias razones. Además,
la literatura actual revela que su tendencia está aumentando en todo el mundo. Por

lo tanto, es necesario analizar los factores que están causando tal aumento de la
infertilidad masculina y se deben hacer intentos para controlar tales factores en un
futuro próximo.
Conflictos de interés: los autores declaran no tener conflictos de interés.
Contribución de los autores: Olmedo Samudio J, Galeano JM, Ruiz Valdez OM

tuvieron la misma participación en: la idea y en el diseño de la investigación,
recolección de los datos, procesamiento estadístico, análisis y discusión de los
resultados, redacción del borrador del trabajo y aprobación de la versión final.
Financiación: Financiación propia.
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www.medigraphic.org.mx
PERINATOLOGÍA Y
REPRODUCCIÓN
HUMANA ARTÍCULO DE REVISIÓN
Volumen 27, Número 1 pp 21-34
Recibido: 2 de diciembre de 2012

Aceptado: 29 de diciembre de 2012
Relación entre infertilidad masculina e infección genitourinaria

por micoplasmas. Una actualización
Francisco Javier Díaz-García,*,‡ Saúl Flores-Medina§,II
* Departamento de Salud Pública, Facultad de Medicina, Universidad Nacional Autónoma de México, México, D. F.
‡ Becario PRIDE “Nivel C”, UNAM, México, D.F.
§ Departamento de Infectología, Instituto Nacional de Perinatología Isidro Espinosa de los Reyes, México, D.F.
II Académico, CECyT 15 Diódoro Antúnez Echegaray, IPN, México, D.F.
RESUMEN ABSTRACT
Por más de 30 años se ha sugerido que las infecciones se- It has been suggested for more than 30 years that seminal
minales causadas por micoplasmas promueven el deterioro infections caused by mycoplasmas provoke impairment of the
de la funcionalidad de los espermatozoides humanos. Sin human sperm functionality. However, the studies have shown
embargo, los estudios al respecto han mostrado resultados conflicting results. This review presents recent evidence
contradictorios. En esta revisión presentamos las evidencias from in vitro studies that confirm adherence and invasive-
recientes de estudios in vitro que confirman que Mycoplasma ness toward human spermatozoa by Mycoplasma hominis,
hominis, Ureaplasma urealyticum, U. parvum y M. genitalium Ureaplasma urealyticum, U. parvum and M. genitalium. We
pueden adherirse e invadir los espermatozoides humanos discuss how those infections can cause: a) sperm oxidative
viables y móviles. Así mismo discutiremos cómo estas infec- stress; b) disruption of energy production mechanisms that
ciones pueden causar: a) estrés oxidativo en los espermato- lead to impaired sperm motility and viability; c) disturbance of
zoides; b) interrupción de los mecanismos de producción de nuclear and cellular organization by effect of bacterial endo-
energía que alteran la movilidad y viabilidad espermática; c) nucleases, phospholipases and aminopeptidases; d) masking
desorganización de la estructura nuclear y celular por efecto of chemotactic receptors and obstruction of fertilization, and
de las endonucleasas, fosfolipasas y aminopeptidasas bacte- e) compromise of sperm’s membrane integrity, with exposure
rianas; d) enmascaramiento de los receptores quimiotácticos of self-antigens and auto-immune responses.
y obstaculización de la fecundación, y e) compromiso de la
integridad de la membrana espermática, con exposición de
autoantígenos y respuesta autoinmune.
Palabras clave: Infertilidad masculina, micoplasmas, Key words: Male infertility, mycoplasmas,
infección espermática. sperm infection.
INTRODUCCIÓN la producción como de la maduración de los esperma-

tozoides.2 Entre los agentes infecciosos que han sido
A nivel mundial, la presencia de alteraciones relacio-
implicados como causantes de infertilidad masculina,
aunque no exentos de controversia, están los micoplas-
nadas con el factor masculino entre parejas infértiles mas urogenitales: Mycoplasma hominis, M. genitalium,
alcanza del 30 al 50% de los casos.1 Se presume que los Ureaplasma parvum y U. urealyticum.3-7 Debido a que
varones infértiles con antecedentes de enfermedades hasta el 60% de los varones sexualmente activos presen-
inflamatorias o de causa infecciosa en el conducto ge- tan colonización uretral por los micoplasmas,8,9 la sola
nitourinario, frecuentemente presentan alteraciones presencia de estos microorganismos en las muestras de
seminales cualitativas y cuantitativas, tanto a nivel de semen frecuentemente es minimizada.8,10-13
Este artículo puede ser consultado en versión completa en http://www.medigraphic.com/inper

22 Perinatol Reprod Hum 2013; 27 (1): 21-34 Díaz-García FJ y col.
Mientras algunos estudios con varones infértiles El estudio de Soffer y colaboradores27 mostró que
muestran hallazgos que no apoyan la asociación entre aproximadamente un tercio de los hombres infértiles
la infección seminal con micoplasmas y la presencia evaluados tuvieron cultivos seminales positivos para
de alteraciones morfofuncionales de los espermatozoi- micoplasmas, pero no encontró asociación entre la
des,10,14-16 hay un número creciente de informes que infección por micoplasma y la presencia de altera-
muestran resultados a favor de tal asociación, principal- ciones morfofisiológicas de los espermatozoides; por
mente con alteraciones de los recuentos de espermato- otra parte, se observó una relación en la producción
zoides, de la movilidad y la viabilidad espermática, con de anticuerpos antiesperma junto con la infección por
la incapacidad de llevar a cabo la reacción acrosómica, Chlamydia trachomatis.27 En otros estudios con pare-
así como presencia de anormalidades morfológicas.6,17-26 jas infértiles, la aplicación de terapia antimicrobiana
Cuadro I. Prevalencia de micoplasmas en muestras de semen de varones infértiles.
No. de % de
Autores (Ref.) País, año Prueba diagnóstica Organismo(s)a
pacientes positivosb
Toth et al (32) EUA, 1978 Cultivo Uu 96 43.7

Busolo et al (18) Italia, 1984 Cultivo Uu + Mh 116 48.3
Levy et al (33) Francia, 1999 Cultivo Uu 92 13.0
Mh 33.8
Andrade Rocha (14) Brasil, 2003 Culture 234
Uu 53.0
Knox et al (34) Australia, 2003 Cultivo, PCR Uu + Up 343 22.0
Sanocka-Maciejewska
Polonia, 2005 Kit comercial de cultivo Mh + Uu 53 16.0
et al (35)
Wang et al (36) China, 2006 Cultivo Uu 346 39.3
Eggert-Kruse et al (37) Alemania, 2007 Cultivo Mh + Uu 145 9.7
PCR-hibridación en
Gdoura et al (3) Túnez, 2007 Mh + Mg + Uu + Up 120 27.5
microplaca
Golshani et al (38) Irán, 2007 PCR múltiple Mh + Uu 200 24.0
Costa de Marfil,
Zinzendorf et al (39) Kit comercial de cultivo Uu + Mh 1,058 60.3
2008
PCR-hibridación en
Gdoura et al (4) Túnez, 2008 Mh + Mg +Uu + Up 104 18.3
microplaca
Al-Daghistani & Abdel- Uu 15.2
Jordania, 2010 PCR 99
Dayem (40) Mh 21.2
Ahmadi et al (41)
Irán, 2010
PCR
Uu
220
40.5
Mh 15.5
Uu 15.6
Salmeri et al (42) Italia, 2012 Kit comercial de cultivo 250
Mh 3.6
PCR, reacción en cadena de la polimerasa (del inglés polymerase chain reaction); Uu, Ureaplasma urealyticum; Mh, Mycoplasma hominis; Up,
U. parvum; Mg, M. genitalium.
a Se considera un solo grupo de los micoplasmas detectados cuando se incluye el signo + entre las especies, excepto donde se indica.
b Los porcentajes también se refieren al grupo de especies de micoplasmas detectados, excepto donde se indican especies individuales.
Relación entre infertilidad masculina e infección genitourinaria Perinatol Reprod Hum 2013; 27 (1): 21-34 23
a los varones infectados con micoplasmas resultó en manera que los hallazgos contribuyan a explicar cómo
un incremento sustancial de la calidad del semen y de estas bacterias interactúan con su hospedero y cómo
los índices de fertilidad.28,29 Esos hallazgos son con- dañan a las células huésped.
sistentes con los bajos índices de embarazo mediante Otras características de los micoplasmas implicadas
fertilización in vitro (FIV) entre parejas infectadas en su patogenicidad, en las que se requiere profundi-
con micoplasmas en comparación con otras parejas zar en su estudio, son: a) la colonización superficial e
no infectadas.30 Sin embargo, la evaluación de los invasión de las células del hospedero;48-54 b) desarrollo
parámetros seminales en diferentes etapas de pre- de sistemas de variabilidad genética y variabilidad
paración del semen para FIV no mostró diferencias antigénica,55-57 y c) capacidad de modulación y evasión
significativas entre el grupo de varones infectados con de la respuesta inmune del hospedero.44,45,55,58,59
micoplasmas y el grupo de no infectados.31 En el momento actual, todavía no se ha podido
En el cuadro I se muestran algunos estudios que han asignar de manera inequívoca una asociación entre
evaluado las frecuencias de aislamiento de micoplasmas las infecciones por micoplasmas y las enfermedades
en varones infértiles.3,4,14,18,32-42 La variabilidad de los del aparato genitourinario humano, incluyendo la
resultados puede explicarse por las diferencias en el infertilidad (Cuadro III).6,8
número de sujetos estudiados, los criterios de selección
clínica y los métodos de laboratorio empleados.
En general, las investigaciones acerca de la asocia- INTERACCIÓN DE LOS MICOPLASMAS
ción entre micoplasmas e infertilidad masculina se CON ESPERMATOZOIDES HUMANOS
han enfocado al estudio de los efectos de la infección
sobre la calidad espermática, dejando de lado la inte-
racción directa entre la bacteria y los espermatozoi- Debido a que la adherencia de los micoplasmas a
des. Para las investigaciones futuras es conveniente las células del hospedero es un prerrequisito para la
que los investigadores consideren las características colonización e invasión subsecuente,58,59 la evidencia
biológicas de los micoplasmas (Cuadro II),43-47 de de interacciones entre micoplasmas y espermatozoi-
Cuadro II. Características que distinguen a los micoplasmas de otras bacterias patógenas de humanos.
Característica Micoplasmasa Eubacteriasb
Tamaño celular ( m) 0.3 – 0.8 >1

Pared celular Ausente Presente
Incorporación de colesterol a la membrana plasmática Sí No
Tamaño genómico (Kb) 580 – 2,220 1,050 – 10,000
Localización intracelular obligada No No
Se tiñen con Gram y/o Ziehl-Neelsen No Sí
Actividades biosintéticas restringidas Sí No
biosintéticos www.medigraphic.org.mx
Dependencia estricta del hospedero para obtener precursores
Sí No
Tropismo hospedero y tejido específico Sí No
Causa de infecciones agudas o fulminantes Raro Frecuente
Detección/aislamiento por métodos convencionales No Sí
Tiempo de detección/aislamiento 48 horas a 5 semanas Promedio 24 horas
Datos tomados de las referencias 43-47.

a Waites KB, Bébéar CM, Robertson JA, Talkington DF, Kenny GE, 2001.
b Cumitech 34, Laboratory diagnosis of mycoplasmal infections. Washington, D.C.: American Society for Microbiology, 2001.
des humanos debiera ser indicativa de un riesgo para electron microscopy).18,61 Sin embargo, las estructuras
la funcionalidad espermática. parecidas a micoplasmas observadas tanto con SEM
como con TEM pudieran ser en realidad estructuras
1. Adherencia e invasividad de micoplasmas subcelulares o artificios por plegamiento membranal;
hacia espermatozoides por tanto, es deseable la confirmación de identidad
mediante técnica inmunogold con anticuerpos especí-
A principios de los años 80, el análisis mediante ficos contra las diferentes especies de micoplasmas.62
microscopia electrónica de barrido (SEM, del inglés La infección experimental de espermatozoides huma-
scanning electron microscopy) de muestras de semen nos purificados, viables y móviles, con M. genitalium, y
de varones infértiles, infectados con U. urealyticum su posterior análisis mediante inmunofluorescencia y
y M. hominis, reveló la presencia de estructuras es- microscopia de transmisión de rayos X, permitieron de-
féricas moderadamente electrodensas adheridas a la terminar la capacidad citoadherente de este micoplasma.7
superficie de la región media de los espermatozoides. Recientemente, U. urealyticum y U. parvum mostraron
Posteriormente se confirmó la presencia de M. hominis una fuerte adherencia hacia espermatozoides humanos
en esas muestras mediante inmunofluorescencia.18 en eyaculados frescos, la cual perduró aun después del
Varios estudios de análisis ultraestructurales de lavado de los espermatozoides.34 Estos datos refuerzan
espermatozoides humanos infectados experimental- la idea de que los procedimientos de lavado de semen no
mente con micoplasmas o ureaplasmas encontraron son totalmente eficaces para eliminar a los micoplasmas.
la presencia de estructuras esféricas adheridas a la ca- Se ha estudiado la interacción de M. hominis con
beza de los espermatozoides, compatibles en tamaño espermatozoides humanos viables y móviles empleando
y morfología con las bacterias.18,22,60,61 Por otro lado, suspensiones viables de esta bacteria, marcadas con
la localización intracelular de los micoplasmas en la un fluorocromo. Por medio de microscopia confocal se
región media de los espermatozoides fue sugerida por observó la adherencia del micoplasma a los espermato-
los hallazgos obtenidos mediante microscopia elec- zoides desde etapas tempranas de incubación (10 minu-
trónica de transmisión (TEM, del inglés transmision tos), sin un patrón definido.50 El análisis posterior de los
Cuadro III. Falla en la asociación epidemiológica de micoplasmas con enfermedades en humanos.
Causa Consecuencia
Ubicuidad de los micoplasmas en sus hospederos humanos Frecuencias de aislamiento/detección similar entre individuos
sanos/asintomáticos/individuos con una condición clínica
particular.
Disponibilidad restringida de los especímenes apropiados de Para su obtención se requiere consentimiento informado y
los sitios afectados (ej. del conducto genital superior) uso de métodos invasivos, lo cual incrementa los costos de
atención médica.
Etiología multifactorial de las enfermedades relacionadas con Se requiere el empleo racional de aproximaciones diag-
micoplasmas (uretritis, prostatitis, infertilidad, etc.) nósticas, es decir, primero se descartan las etiologías más
www.medigraphic.org.mx comunes y frecuentemente se detiene el proceso cuando se
detecta al primer agente sospechoso.
La búsqueda intencionada de micoplasmas es frecuentemente Sólo se considera esta etiología cuando ya han fallado las
el último eslabón de la cadena de diagnóstico. aproximaciones diagnósticas más comunes.
Falta de laboratorios especializados o de referencia Se requiere personal altamente especializado, además de
equipos e instalaciones no convencionales para el manejo de
estos microorganismos.
Datos tomados de las referencias 6 y 8.

espermatozoides infectados, mediante seccionamiento la cara externa de la membrana plasmática, asimétri-

óptico secuencial y su reconstrucción tridimensional, camente distribuidas a lo largo de toda la superficie
reveló la localización intracelular de los micoplasmas celular, dependiendo de la etapa de maduración.64,65
en los espacios citoplasmáticos de la cabeza y de la Se ha sugerido que estas moléculas superficialmente
región media (Figura 1). Bajo esa misma estrategia expuestas en los espermatozoides humanos y murinos
experimental, U. urealyticum infectó aproximadamente funcionan como receptoras para los micoplasmas.66,67
el 1% de los espermatozoides, principalmente en las De hecho, se han identificado sólo glicolípidos sulfatados
regiones de la cabeza y la cola; además de que también como las moléculas receptoras para M. hominis.68,69
se localizó intracelularmente (Figura 2).63 Contrario a Por su parte, se ha demostrado que las proteínas
las afirmaciones de que los micoplasmas se adhieren de choque térmico de 70 kDa (HSP70), de los mico-
preferentemente a espermatozoides defectuosos o que plasmas que infectan a humanos y otros mamíferos,
ya llevaron a cabo la reacción acrosómica, los esper- comparten especificidad de unión a las moléculas
matozoides infectados mostraron acrosomas intactos. de SGG. Durante el proceso de maduración de las
células germinales masculinas en los mamíferos, las
2. Moléculas receptoras en el espermatozoide moléculas de HSP70 selectivamente funcionan como
y las adhesinas bacterianas receptores superficiales de la SGG en las células ad-
yacentes. Así, ante la infección con micoplasmas, la
En las células germinales masculinas las moléculas HSP70 bacteriana puede reconocer a las moléculas
de sulfogalactoglicerolípido (SGG) se encuentran en de SGG de los espermatozoides.70
A B
Figura 1.
Adherencia superficial y localiza-
ción intracelular de M. hominis
en espermatozoides humanos.
A) Se observan grupos de mico-
plasmas, marcados fluorescen-
temente (flechas), adheridos en
www.medigraphic.org.mx diferentes regiones del esperma-
tozoide. B) La infección con M.
hominis correlaciona con altera-
ciones morfológicas, como enro-
llamiento de la cauda alrededor
de la cabeza del espermatozoide
C (punta de flecha). C) Mediante
seccionamiento óptico del campo
mostrado en (A), se determinó la
localización intracelular de los mi-
coplasmas, ya que sólo los cortes
intermedios (entre 2.4 y 4.8 m)
presentan señales fluorescentes.
Si bien, las moléculas de SGG han sido reconocidas liberar ROS, principalmente peróxido de hidrógeno
como los principales receptores para los micoplas- y radicales superóxido que dañan directamente la
mas, representan sólo el 10% del total de lípidos del membrana celular.58,59,73,74
espermatozoide,66,67,69 por lo que se presume que Se puede especular que los micoplasmas adheri-
otras moléculas deben participar como receptores dos a los espermatozoides pueden inducir la hiper-
accesorios. Hasta el momento no se han descrito producción de ROS. Tal exposición de los esperma-
moléculas proteicas espermáticas que funcionen como tozoides a niveles de ROS mayores a los fisiológicos
receptores para micoplasmas. puede resultar en una reducción significativa de la
Mediante ensayos de adherencia Western Blot fluidez membranal y alteración de la capacidad de
con lisados proteicos totales de espermatozoides fertilización.58,59,72,75
humanos, tanto M. hominis como U. urealyticum
reconocieron una proteína de 42.4 kDa, mientras que 2. Alteración de la movilidad y de la viabilidad de
M. hominis reconoció diferencialmente otra proteína los espermatozoides
de 16.5 kDa, y U. urealyticum reconoció otras tres
proteínas de 12.5, 48.6 y 59.7 kDa.63,71 Estos hallazgos A partir de ensayos de interacción in vitro entre
son consistentes con el hecho de que el pretratamien- Ureaplasma spp. y espermatozoides humanos, se han
to de la línea celular HEp-2 con tripsina resultó en observado efectos contradictorios sobre la movilidad
una inhibición del 25 a 50% de la adherencia de M. espermática. Mientras que una interacción a muy corto
penetrans, en comparación con la inhibición del 90% plazo (45 minutos) parece incrementar la movilidad,76
después del tratamiento con metaperiodato para pro- un periodo de incubación más largo (4 a 18 horas) indu-
mover la oxidación de carbohidratos superficiales.51 jo una inhibición significativa.22,23 La explicación a tal
discrepancia parece depender de las condiciones expe-
EFECTOS DE LA INFECCIÓN SOBRE LA CALIDAD rimentales, ya que cuando la producción energética del
espermatozoide se basa en la fosforilación oxidativa (a pH
ESPERMÁTICA ácido), U. urealyticum compite por el ATP mitocondrial,
lo cual reduce tanto la movilidad como la viabilidad; por
el contrario, cuando la vía glicolítica es responsable de
1. Inducción de estrés oxidativo la producción de energía en los espermatozoides (a pH
alcalino), el metabolismo de los ureaplasmas promueve
El estrés oxidativo se ha asociado con alteraciones un efecto sinérgico sobre la glicólisis, que en última ins-
en la movilidad espermática, principalmente como tancia estimula la movilidad de los espermatozoides.77
resultado de la peroxidación lipídica y el agotamiento En el caso del contacto inicial de M. genitalium
de los niveles de ATP. Además, los altos niveles de con espermatozoides purificados, el resultado fue
actividad redox por los espermatozoides se han corre- una aglutinación de estos últimos en forma depen-
lacionado con la inhibición de la reacción acrosómica diente del tiempo, la cual se revirtió al cabo de 18 a
y de la fusión esperma-oocito.72 20 horas de incubación, conservando su viabilidad y
Los espermatozoides pueden generar niveles ba- movilidad.7
jos de especies reactivas de oxígeno (ROS, del inglés Otro estudio con M. hominis mostró citoadheren-
reactive oxygen species), las cuales participan en el cia e invasión de los espermatozoides; sin embargo, no
proceso de capacitación y culminan en la fertiliza-
ción. Otras condiciones anormales como leucocitos-
se observaron efectos perjudiciales sobre la viabilidad
durante el periodo de 24 horas que duró el estudio.50
permia e infecciones bacterianas pueden generar Teniendo en cuenta que la carga de micoplasmas
una concentración elevada de ROS en el semen.72,73 en la uretra de individuos sanos puede ser inferior
Los hallazgos del estudio de Potts y su grupo73 indi- a 1 x 104 unidades cambiantes de color (CCU) por
can que los niveles de ROS seminal en individuos con mililitro,8,78 es posible que los espermatozoides sólo
infección genital por ureaplasmas, aun sin evidencia queden expuestos a la infección con micoplasmas
de leucocitospermia, fueron casi dos veces mayores al momento de la eyaculación. Si esto es cierto, el
que en los individuos sin infección. Se sabe que los mi- tiempo de exposición puede ser insuficiente para
coplasmas adheridos a las células hospederas pueden que el análisis de semen pueda detectar cualquier
influencia real de los micoplasmas sobre la movili- En los años setenta, Toth y asociados32 descri-
dad y viabilidad espermática.8 Por el contrario, si bieron algunas alteraciones morfológicas de los
hay una infección con alta concentración bacteriana espermatozoides en individuos infectados con U.
(prostatitis, uretritis, epididimitis, orquitis), entonces urealyticum, las cuales incluían enrollamiento de
se asegura un tiempo de contacto prolongado entre las colas en diversos grados y presencia de reves-
los espermatozoides y las bacterias. timiento granular de las colas, “fuzzy tails”. Estos
autores propusieron un sistema de clasificación de las
3. Morfología celular y organización nuclear alteraciones morfológicas, el “Índice ureaplasma”,
mediante el cual predijeron o descartaron infeccio-
Los micoplasmas carecen de la mayoría de los nes por U. urealyticum en el 70% de las muestras de
genes implicados en la biosíntesis de aminoácidos, esperma analizadas en ciego. Sin embargo, el 30%
ácidos grasos, cofactores y vitaminas, y por lo tanto restante de los resultados fueron discordantes, por
presentan una dependencia estricta del microambien- lo que este sistema fue poco confiable y ahora está
te celular del hospedero para obtener los precursores prácticamente en desuso.
biosintéticos.44,58,59 La competencia de los micoplas- Después del periodo de 24 horas postinfección,
mas por la adquisición de tales precursores pueden aproximadamente el 1% de los espermatozoides in-
alterar tanto la integridad como la funcionalidad de fectados por M. hominis muestra engrosamiento de
la célula hospedera, con consecuencias sobre la mor- la pieza intermedia, o bien en espiral o de las colas
fología celular y la organización nuclear. dobladas.50 Alteraciones similares se han descrito
Los micoplasmas hidrolizan la arginina para la en muestras de esperma de hombres infectados de
generación de ATP.58,79 En las células infectadas estas forma natural18,32 o en espermatozoides infectados
bacterias agotan rápidamente las reservas celulares in vitro.22,23 Pero a diferencia de estos informes,
de arginina, afectando así la síntesis de proteínas, la la presencia de M. hominis se observó en todos los
división y el crecimiento de la célula hospedera. Debi- espermatozoides morfológicamente alterados y en
do a que las histonas son proteínas ricas en arginina, muchas células de apariencia normal.
se ha sugerido que la utilización de la arginina por Al lado de ROS, las fosfolipasas unidas a la mem-
micoplasmas inhibe la síntesis de histonas y causa brana de algunos micoplasmas y ureaplasmas pueden
daño estructural cromosómico.44,58 aumentar el daño a la membrana de la célula hués-
Vista lateral Eje X

Vista lateral Eje Y
A B C
www.mediggraphic.org mx
5 m
Vista frontal Eje Z 10 m
Figura 2. Adherencia y localización intracelular de Ureaplasma spp. en espermatozoides humanos. A) Sólo se observan ureaplasmas,
marcados fluorescentemente (flechas), adheridos a la región media y a la cabeza del espermatozoide. B) La reconstrucción tridimensional
de los cortes ópticos secuenciales a manera de “sándwich” (vistas laterales X y Y) permite confirmar la capacidad de internalización de
los ureaplasmas al citoplasma espermático, según la presencia de señales fluorescentes intensas. C) Aparentemente, los ureaplasmas se
adhieren per se a espermatozoides con región acrosómica intacta (punta de flecha).
ped.79-82 La actividad de la fosfolipasa podría desenca- germinales masculinas como en el oocito, se enlaza
denar cascadas de señales específicas o liberación de específicamente con residuos de SGG en los procesos
lisofosfolípidos citolíticos capaces de interrumpir la fisiológicos de maduración espermática y en el reco-
integridad de la membrana de la célula huésped.58,83 nocimiento espermatozoide-oocito.91,92 De hecho, tal
Los micoplasmas, al ser incapaces de sintetizar especificidad de unión a SGG también es compartida
sus propios nucleótidos, sintetizan nucleasas solubles por las moléculas de la familia de proteínas de choque
que se anclan a su propia membrana, mediante las térmico (HSP, del inglés heat-shock proteins) de 70 kDa
cuales pueden degradar los ácidos nucleicos de las de mamíferos, e incluso de micoplasmas.70 Tomando
células hospederas, como una forma de obtener los en consideración que la unión entre SLIP-1 y SGG es
precursores para su propia biosíntesis.58,84,85 En el crucial para el proceso de fertilización,91,92 es posible
caso de infección espermática por micoplasmas, varios que los micoplasmas que han infectado previamente
Este documento
autores es elaborado
han sugerido por Medigraphic
la inducción de fragmentación a los espermatozoides puedan inhibir este proceso
del DNA de los espermatozoides, la cual puede tener mediante unión competitiva hacia los residuos de SGG
impacto a largo plazo sobre la fertilidad masculina, en la región acrosómica del espermatozoide.
ya que no sólo puede afectar la fecundación, sino que A la luz de los reportes recientes acerca de la pre-
puede representar una amenaza para eventos poste- sencia de receptores para odorantes (ORs, del inglés
riores, como la implantación del huevo, el desarrollo odorant receptors) y de mecanismos de señalización
del embrión y la resolución del embarazo.50,61,63,86-88 parecidos a los involucrados en procesos olfatorios,
Otros efectos más sutiles de la infección espermática en los espermatozoides de diversos mamíferos93,94
por micoplasmas incluyen: inducción de descondensa- se ha propuesto que los ORs en los espermatozoides
ción nuclear, desnaturalización y rupturas simples de funcionan como receptores quimiotácticos, ya que
las cadenas de DNA.61 Tales efectos aparentemente no se activan por la presencia de moléculas pequeñas
tienen consecuencias a corto plazo sobre la viabilidad, de aldehídos, y se sabe que una vez activados, me-
movilidad y morfología espermática. Otros autores eva- dian señales robustas dependientes de Ca2+ en el
luaron, mediante análisis de dispersión de la cromatina, espermatozoide maduro (capacitado), además de que
la integridad del DNA espermático en 143 hombres pueden participar en respuestas quimiotácticas a con-
infértiles con diferentes infecciones genitourinarias; centraciones reducidas de óxido nítrico.95 Durante el
estos autores encontraron que los varones infectados proceso natural de capacitación los espermatozoides
con C. trachomatis y Mycoplasma spp. mostraron mayor sufren una serie de cambios bioquímicos y funciona-
fragmentación del DNA espermático en comparación les en el interior del conducto genital femenino.96,97
con sujetos fértiles sanos, y que tal fragmentación fue Debido a que sólo los espermatozoides capacitados
significativamente revertida después del tratamiento pueden llevar a cabo la reacción acrosómica con el
con antimicrobianos.87 En modelos celulares, la infec- objetivo de penetrar la zona pelúcida del oocito, tal
ción a largo plazo con micoplasmas indujo fragmenta- proceso de maduración posteyaculatorio es clave para
ción internucleosomal del DNA89 y efectos deletéreos una fertilización exitosa.93,96 Por lo anterior, puede
sobre la estructura cromosómica.90 argumentarse que las deficiencias en la movilidad
espermática o la reducida capacidad de penetración
4. Interferencia en la interacción hacia los oocitos, presumiblemente atribuibles a la in-
espermatozoide-oocito fección seminal con micoplasmas, pudieran ser conse-
Se ha sugerido que la capacidad citoadherente de
cuencias del bloqueo físico de los ORs por la presencia
de bacterias adheridas a la superficie espermática, de
los micoplasmas sobre la superficie de los esperma- manera que puede tornar al espermatozoide errático
tozoides humanos, además de los efectos ya descritos en sus movimientos y no responsivo a la comunicación
anteriormente, provoca un efecto de enmascaramien- química cruzada con las células circundantes.
to de los receptores espermáticos involucrados en la
comunicación química y el reconocimiento del oocito. 5. Interacciones con el sistema inmune
La proteína inmovilizante de sulfolípidos (SLIP,
del inglés sulfolipid immobilizing protein-1), una Es claro que para que un patógeno bacteriano
proteína superficialmente expuesta tanto en células pueda sobrevivir dentro de su hospedero, éste requie-
re desplegar mecanismos que le permitan evadir las los micoplasmas ejercen actividad inmunomoduladora
respuestas inmunes hacia la infección. En el caso de los inespecífica sobre las diferentes células del sistema in-
micoplasmas patógenos de mamíferos, los mecanismos mune. Estas bacterias son capaces de producir efectos
bacterianos de mimetismo molecular y plasticidad fe- diametralmente opuestos, ya sea supresión o estimu-
notípica redundan en un reconocimiento inmune ina- lación policlonal de los linfocitos T y B, inducción de
propiado o ineficiente por parte del hospedero.44,58,59,98 respuestas con citocinas proinflamatorias o inhibitorias,
Se ha establecido que los espermatozoides humanos así como alterar la expresión de los receptores celula-
exhiben antígenos que cruzan inmunológicamente con res del hospedero,44,56,98 cuya consecuencia final es el
algunos antígenos bacterianos. Por ejemplo, mediante establecimiento de infecciones crónicas o persistentes.
inmunoensayos y Western Blot se demostró reacti- Por lo anterior, los marcadores inmunológicos de
vidad cruzada entre antígenos membranales esper- infección genital masculina no siempre se correlacio-
máticos de humanos (hSMP, del inglés human sperm nan con la presencia de infecciones micoplásmicas.
membrane proteins) y antígenos de U. urealyticum.99 De hecho, no se han encontrado asociaciones entre
Adicionalmente, empleando un suero humano que la presencia de leucocitospermia o los perfiles de ci-
contenía anticuerpos antiesperma, se confirmó que los tocinas proinflamatorias y la infección seminal con
anticuerpos presentes en tal suero humano muestran micoplasmas.37,73,101 La expresión de las diversas
reactividad hacia varias proteínas de U. urealyticum, citocinas parece ser una característica dependiente
incluyendo una proteína de 61 kDa.99 También se ha del tipo de células del hospedero y de la especie de
reportado reactividad cruzada entre la subunidad micoplasma infectante.102
UreG de la ureasa ureaplásmica y la proteína espermá-
tica autoantigénica humana (hNASP, del inglés human LÍNEAS PARA UNA INVESTIGACIÓN FUTURA
nuclear autoantigen sperm protein). El mimetismo
molecular entre los antígenos ureaplásmicos y los
del espermatozoide humano puede estar involucrado 1. Abordaje inmunogenético
en la generación del epítopo inmunodominante del
hNASP, además de que pudiera tener un papel clave Gran parte de los estudios acerca de la relación pa-
en la inducción de anticuerpos antiesperma. rásito-hospedero se han enfocado en las propiedades
Dada la existencia de la llamada barrera hemato- de los microorganismos que facilitan la colonización
testicular, las respuestas inflamatorias en contra de del hospedero, pero muy poco se ha estudiado acerca
la infección genital masculina con micoplasmas, con de cómo la variabilidad de la respuesta inmune del
daño directo a las membranas espermáticas por la hospedero puede definir el resultado de la interacción
liberación de productos tóxicos secundarios del meta- microorganismo-hospedero. Por ello, los conceptos
bolismo micoplásmico, pueden provocar la exposición actuales de “patogenicidad y virulencia” no cir-
de “nuevos” antígenos espermáticos a las células cunscriben la complejidad integral de la patogénesis
inmunes efectoras locales, induciendo respuestas microbiana en el contexto de inmunocompetencia e
autoinmunes hacia los espermatozoides.100 inmunocompromiso del hospedero.103-105
Los micoplasmas también exhiben una gran plas- La identificación de los eventos moleculares críti-
ticidad fenotípica, la cual les permite cambiar su cos que llevan a un agente infeccioso a invadir un hos-
mosaico antigénico para generar más de una forma pedero humano, o bien a dicho hospedero a erradicar
alternativa en términos de morfología, estado fisioló-
gico y comportamiento, en respuesta a las condiciones
la infección o sucumbir a ella, requiere de estudios
inmunogenéticos y de epidemiología molecular.105
microambientales. De esta manera, la capacidad Los factores inmunogenéticos asociados al esta-
de los micoplasmas para modificar rápidamente su blecimiento de infecciones del aparato urogenital
repertorio antigénico superficial con la consecuente masculino son especialmente desconocidos; no obs-
variación en la inmunogenicidad de tales antígenos, tante, en la mujer se ha propuesto que la suscepti-
permite a estas bacterias evadir las respuestas inmu- bilidad disminuida hacia la colonización vaginal con
nes primarias del hospedero.44,56-58 U. urealyticum y M. hominis pudiera estar asociada
Si bien los hospederos humanos pueden montar con homocigosidad del alelo 2 del gen receptor anta-
respuestas protectoras de anticuerpos antimycoplasma, gonista de interleucina-1.104
Se sabe que hay alelos específicos del complejo 2. Análisis proteómico

principal de histocompatibilidad de clase I y clase
II que predisponen a los individuos que los portan El índice acelerado de secuenciación genómica ha
al desarrollo de enfermedades con un componente llevado a un creciente acervo de genomas totalmente
fuertemente inflamatorio.98,103 Por ejemplo, entre secuenciados; por ello se hace necesaria la asignación
pacientes con artritis reactiva sexualmente adquirida, de los marcos de lectura abierta (ORFs, del inglés
síndrome de Reiter y espondilitis anquilosante, la open reading frames) en esos genomas.107 Hasta el
incidencia del antígeno HLA-B27 varía entre el 60 y momento, se han secuenciado los genomas completos
90%. En contraste, sólo del 9 al 15% de los individuos de tres especies de micoplasmas patógenos del con-
aparentemente sanos son portadores del antígeno ducto urogenital humano, M. genitalium, M. hominis
HLA-B27.98 Es interesante que los anticuerpos mo- y U. parvum (antes U. urealyticum serovar 3),108-110
noclonales específicos contra el antígeno HLA-B27 lo cual presupone un avance en la identificación de
muestran reactividad cruzada con diversas ureasas nuevas proteínas antigénicas relacionadas con la viru-
microbianas, incluyendo las de U. urealyticum y lencia,107 así como en la caracterización de proteínas
U. parvum. De hecho, se ha determinado que hay antigénicas expresadas diferencialmente o modificadas
homología entre las secuencias de aminoácidos de postraduccionalmente. Este abordaje proteómico ha
la subunidad UreC de la ureasa ureaplásmica y del sido empleado exitosamente para generar “mapas
inmunógeno sintético usado para inducir la produc- proteómicos” a partir de lisados celulares totales de
ción de anticuerpos monoclonales anti-HLA-B27, otros micoplasmas patógenos de mamíferos.111-114
lo cual sugiere que el mimetismo molecular entre
estos dos antígenos puede favorecer la generación CONCLUSIONES
de respuestas autoinmunes, incluyendo respuestas
de anticuerpos antiesperma.98,99
Los hospederos humanos representan microam- La asociación entre infección genital por micoplas-
bientes cada vez más hostiles para los agentes micro- mas y el desarrollo de alteraciones espermáticas ha
bianos, de manera que el proceso de presión selectiva sido materia de controversia entre los andrólogos y
a través de las enfermedades infecciosas puede ser biólogos de la reproducción. No obstante, los datos
una de las causas principales de diversidad genética biológico-experimentales y clínicos presentados en
en los humanos, principalmente en lo que respecta esta revisión tienden más a apoyar tal asociación
al sistema inmune. La aplicación de herramientas de que a refutarla. Considerando que las capacidades
epidemiología genética para develar las interacciones citoadherentes e invasivas de los micoplasmas sobre
moleculares patógeno-hospedero sin duda ayudará los espermatozoides humanos han sido ampliamen-
a esclarecer los eventos críticos en la evolución de te demostradas, sólo queda por esclarecer por qué
las enfermedades infecciosas.105 En este contexto, se observan efectos contrastantes sobre la calidad
la obtención de los perfiles transcripcionales de las espermática. Para ello, el abordaje de investigación
células espermáticas ante las infecciones causadas debe integrar la contribución tanto de los factores del
por micoplasmas puede ser de ayuda para conocer hospedero, como el fondo genético o el estado inmune,
las peculiaridades acerca de cuáles componentes como los del patógeno (determinantes de virulencia,
del sistema inmune y de las vías de señalización propiedades biológicas específicas de especie, biovar,
son estimulados por los patógenos. Por otra parte,
la creciente disponibilidad de genomas bacterianos
serovar y cepa) para esclarecer el escenario actual.
completamente secuenciados permitirá llevar a cabo

estudios genómicos comparativos. Con tales aproxi-
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Revista Colombiana de Obstetricia y
Ginecología
ISSN: 0034-7434
rcog@fecolsog.org
Federación Colombiana de Asociaciones de
Obstetricia y Ginecología
Colombia
Narváez Rosero, Héctor

Actualización en la valoración y manejo de la infertilidad masculina
Revista Colombiana de Obstetricia y Ginecología, vol. 55, núm. 1, 2004, pp. 60-70
Federación Colombiana de Asociaciones de Obstetricia y Ginecología
Bogotá, Colombia
Disponible en: http://www.redalyc.org/articulo.oa?id=195214307008
Sistema de Información Científica

Red de Revistas Científicas de América Latina, el Caribe, España y Portugal
Proyecto académico sin fines de lucro, desarrollado bajo la iniciativa de acceso abierto
Revista Colombiana de Obstetricia y Ginecología Vol. 55 No.1 • 2004 • (60-70)
R
ARTÍCULO
EVISIÓN DE
DETEMA
REVISIÓN
ACTUALIZACIÓN EN LA
VALORACIÓN Y MANEJO
DE LA INFERTILIDAD MASCULINA
ACTUALIZATION IN THE EVALUATION AND
TREATMENT OF THE MALE INFERTILITY
Héctor Narváez Rosero, M.D.*
Recibido: febrero 4/2004 – Revisado: marzo 1/2004 – Aceptado: abril 22/2004
RESUMEN truction is suspected. A laparoscopic approach and

percutaneous embolization have been added to
El factor masculino contribuye al fracaso
traditional surgical approaches for repairing
reproductivo aproximadamente en el 50% de la
varicoceles. Advanced reproductive technologies,
pareja infértil. Las diferentes herramientas dispo-
especially intracytoplasmic sperm injection, and
nibles para el diagnóstico en el hombre, inclu-
current techniques to har vest sperm include
yendo la ecografía transrectal ante la sospecha de
microsurgical sperm aspiration from deferent
obstrucción de los conductos eyaculadores, el
ducts, epididymal and testicular sperm extraction.
abordaje laparoscópico y la embolización percu- These techniques offer a good alternative for the
tánea, han sido agregadas a los accesos quirúrgicos treatment of male infertility.
tradicionales para la reparación del varicocele. Las Key words: male infertility.
tecnologías avanzadas en reproducción, en espe-
cial la inyección intracitoplasmática del esperma- INTRODUCCIÓN
tozoide y las técnicas para recuperar el esperma, Aproximadamente el 15% de todas las parejas
incluyen microaspiración espermática deferencial, que intentan tener hijos están afectadas de infer-
epididimaria y extracción espermática testicular. tilidad .1 Esto es atribuible exclusivamente a un
Todas ofrecen una buena alternativa en el trata- factor masculino en 30% y a una combinación de
miento de la infertilidad masculina. factores, tanto masculinos como femeninos, en un
Palabras clave: infertilidad masculina. 20%.2 En alrededor del 50% de todas las parejas
infértiles, por consiguiente, el factor masculino
SUMMARY contribuye a la falla reproductiva.3
An abnor mal male factor contributes to Para tratar estos pacientes es necesario una eva-
reproductive failure in approximately 50% of luación básica familiar de infertilidad masculina.
infertile couples. Different tools are available for Algunos de los avances más importantes en el ma-
the diagnostic of the male, including transrectal nejo de la infertilidad masculina están en las téc-
ultrasonography, when ejaculator y duct obs- nicas de reproducción asistida (TRA). Esta revi-
* Andrólogo, Universidad Autónoma de Barcelona. Centro de Medicina
sión tiene especial atención en este tema como
Reproductiva del Valle S.A., Cali, Colombia. también en la aplicación de estas técnicas a parejas
A CTUALIZACIÓN EN LA VALORACIÓN Y MANEJO DE LA INFERTILIDAD MASCULINA 61
cuyos problemas de infertilidad provienen del fac- frecuente en estos casos observar obstrucciones
tor masculino severo. del conducto epididimario, ya sea uni o bilateral.5
En procesos inflamatorios, tanto del tracto urina-
HISTORIA CLÍNICA rio como del sistema ductal distal, como la este-
nosis u obstrucción de los conductos eyaculadores
Tiempo de infertilidad de la pareja puede alterar la fertilidad.6 En general, cualquier
En el pasado, las evaluaciones se realizaban des- episodio febril puede comprometer transitoria-
pués de un año de coitos sin protección en la pa- mente la espermatogénesis. La orquitis bilateral
reja. La tendencia actual es que la evaluación pue- por parotiditis antes de la pubertad parece no te-
de empezar cuando los pacientes lo requieran; esto ner efecto, pero la experimentada durante o des-
obedece a que la mujer prefiere prepararse, desde pués de la pubertad está asociada a daño severo
el punto de vista intelectual, antes que procrear. testicular en un 10% de los pacientes.7
Por la misma razón es importante que en parejas
en las cuales las mujeres sean mayores de 35 años, Enfermedades de la
el estudio se inicie lo más pronto posible. Es muy infancia y pubertad
conveniente que la evaluación sea llevada a cabo La criptorquidia, uni o bilateral, está asociada
por profesionales dedicados a la reproducción. frecuentemente con oligozoospermia. Aunque
Las evaluaciones deben ser simultáneas, tanto en alrededor del 30% de los hombres con criptor-
el hombre como en la mujer, en forma eficaz, quidia unilateral y el 50% de los aquellos con
rentable y oportuna. criptorquidia bilateral tienen una concentración
En la anamnesis se debe establecer si hubo o espermática por debajo de los 20 millones por
no la presencia de embarazos con parejas anterio- mililitro, cerca del 80% de los hombres con his-
res o pareja actual y la edad cuando se produje- toria de criptorquidia unilateral son fértiles. En
ron; si hubo o no dificultad para lograr los emba- contraste, la tasa de fertilidad es solo del 50% en
razos y anteriores evaluaciones o tratamientos. parejas en quienes el varón tuvo historia de crip-
torquidia bilateral.7
Historia sexual Los hombres con historia de trauma o torsión
La frecuencia para las relaciones está alrededor testicular unilateral, en aproximadamente el 30 al
de las 48 horas (cada dos días), cuando ocurre la 40%, presentan baja calidad espermática en un aná-
ovulación es más probable para optar a un emba- lisis de semen por razones que todavía no están muy
razo (generalmente la mitad del ciclo femenino). claras.8 Una ruptura en la barrera hemato–testicular
El uso de lubricantes durante la relación pue- puede ser la causa o la susceptibilidad de la torsión
de ser obstáculo para conseguir el objetivo; por testicular para presentar alteraciones en la
tanto, estos deben ser usados sólo si es necesario y espermatogénesis (según la alta incidencia de alte-
en cantidades limitadas. Los lubricantes son ración espermática en la biopsia realizada en el tes-
espermatotóxicos (gel K –Y, Lubifax, surgilube, tículo contralateral).9 La pubertad retrasada o in-
etc.) así como la saliva, con compromiso de la completa puede reflejar una etiología endocrina
motilidad del espermatozoide.4 (como el síndrome de Klinefelter o el hipogona-
dismo idiopático). La ginecomastia también sugiere
Infecciones
un compromiso endocrino subyacente.
Es importante el antecedente de enfermedad
de transmisión sexual (ETS), sobre todo si la hubo Antecedentes patológicos
y no se prescribió ningún tipo de tratamiento, ya Tanto la diabetes mellitus como la esclerosis
sea porque no se consideró necesario como por múltiple son enfermedades que pueden afectar
haber pasado desapercibida la enfermedad. Es muy tanto la potencia como la eyaculación. También
62 R EVISTA C OLOMBIANA DE O BSTETRICIA Y G INECOLOGÍA V OL . 55 N O 1 • 2004
hay datos que sugieren que la diabetes puede al- seminíferos; el encontrar testículos de menor ta-
terar la función testicular.10 maño nos puede ayudar a identificar la causa de la
Cualquier paciente que haya sido tratado con infertilidad como testicular (secretora) o post-
irradiación o quimioterapia como tratamiento testicular (excretora). El testículo normal en el
para el cáncer tiene mayor riesgo de sufrir daño adulto mide 4,6 cm de longitud, 2,6 cm de ancho
en su espermatogénesis. Los pacientes con cáncer y 18,6 mL (12 – 25) de volumen. Debe palparse
testicular son particularmente afectados.11 el epidídimo en forma cuidadosa. Alguna irregu-
El síndrome de inmovilidad ciliar puede alte- laridad puede indicar infección u obstrucción. Fi-
rar secundariamente al espermatozoide sobre su nalmente, palpación de los conductos deferentes
estructura, pudiendo ser la causa de infertilidad para confirmar o descartar agenesia. En pacientes
en hombres con infecciones respiratorias frecuen- con agenesia de estos conductos se incrementa el
tes (síndromes de Kartagener o de Young). 12 ,13 riesgo de transmitir uno o más de los genes de la
fibrosis quística, por lo tanto requieren ser eva-
Antecedentes quirúrgicos
luados genéticamente.14,15
En pacientes con antecedentes de herniorrafia
La palpación de los vasos contiguos debe ha-
cabe pensar en la posibilidad de tener una lesión
cerse cuidadosamente para confirmar o descartar
vascular o ductal iatrogénica.
la presencia de varicocele. Con el paciente de pie,
En pacientes de impotencia causada por pará-
en una habitación con temperatura adecuada, el
lisis en los segmentos T12 – L2, donde la eyacula-
cordón espermático debe palparse entre los de-
ción puede estar alterada.
dos pulgar e índice mientras el paciente realiza la
En historia de cirugía pélvica o retroperitoneal,
maniobra de Valsalva. Un aumento continuo en el
esta sugiere disfunción eyaculatoria con eyacula-
espesor del cordón o la presencia de un impulso
ción incompleta o retrógrada asociada.
discreto (reflujo venoso), una vez terminada la
Antecedentes tóxicos y maniobra de Valsalva, nos sugerirá un varicocele.
medioambientales
Antecedente de exposición a cier- Tabla 1. Medicamentos, toxinas y drogas
tos medicamentos, drogas o tóxicos asociados con infertilidad masculina.
ambientales que puedan afectar la Medicamentos Toxinas Drogas
función testicular (tabla 1). Alopurinol Agente naranja Alcohol
Esteroides Gases anestésicos Heroína
EXAMEN FÍSICO androgénicos
El examen físico inicial puede re- Antihipertensivos Benceno Marihuana
velar información importante acerca Quimioterapia Dibromocloropropano Metadona
de la etiología de la infertilidad mas- Ciclosporina Plomo Tabaco
culina. Se debe tener especial cuida- Eritromicina Manganeso Cocaína
do si hay cierta evidencia de hipogo- Bloqueadores H2
nadismo o un tumor hipofisario. La Ketoconazol
ginecomastia puede indicar una falla
Gentamicina
testicular primaria o una anormali-
Nitrofurantoína
dad secundaria del eje hipotálamo -
Espironolactona
hipofisario.
Cerca del 85% del volumen Sulfasalazina
testicular es debido a los túbulos Tetraciclina
Las clasificaciones del varicocele varían ampliamente; ampolla deferencial. La deferentovesiculografía nos
algunos utilizan en forma subjetiva el tamaño (pe- confirmaría o descartaría la lesión si hubiera imá-
queño, medio o grande) mientras otros emplean una genes dudosas en la ecografía.
escala de clasificación del varicocele más objetiva:
Análisis de semen
Grado 1, cuando se palpa con el paciente de
La valoración preliminar debe incluir dos
pie con la maniobra de Valsalva.
muestras, analizadas en un laboratorio apropiado
Grado 2, cuando se palpa con el paciente de
para este tipo de exámenes. Las muestras seminales
pie pero sin necesidad de la maniobra de Valsalva.
son recolectadas mediante masturbación con un
Grado 3, cuando se observa a distancia con el
tiempo de abstinencia entre dos a siete días. El
paciente de pie.16
examen se realizará después de una hora de reco-
El varicocele subclínico no es evidente al exa-
lectada la muestra, a temperatura de 36,5ºC, con
men físico, pero puede detectarse con el uso de
el propósito de evitar los cambios de la motilidad
ultrasonido. El grado de varicocele no correspon-
espermática. Las características analizadas en la
de directamente al estado de fertilidad, pero tan-
muestra son el volumen, la concentración esper-
to el subclínico como el de mayor grado pueden
mática, la motilidad, la progresión total, la mor-
afectar la fertilidad.17
fología y la vitalidad. Si la muestra analizada pre-
En el pene debe examinarse en busca de posi-
senta un alto número de leucocitos podría ser
bles anormalidades (hipospadias, cur vatura,
indicativa de algún proceso de inflamación o in-
fimosis) que pueden interferir con la deposición
fección. En la tabla 2 se describen los límites ge-
apropiada del esperma dentro de la cavidad vaginal.
neralmente aceptados para la valoración de la ca-
En la valoración prostática es importante de-
lidad seminal.19
terminar su tamaño (en caso de deficiencia andro-
génica) y consistencia (en caso de procesos Evaluación hormonal
inflamatorios). La frecuencia de las alteraciones endocrinas
Finalmente, un buen examen físico nos puede primarias en los hombres infértiles es menor del
llevar al diagnóstico de una enfermedad sistémica
crónica o insospechada que interfiera en la fun-
Tabla 2. Valores normales
ción testicular.
de muestras seminales.
La obstrucción de los conductos eyaculadores
se puede sospechar cuando en el espermograma Volumen 2 – 6 mL
obser vamos disminución en el volumen del PH 7,2 – 8
eyaculado (menor de 1 mL) y generalmente tam- Concentración espermática 20 millones/mL
bién en la menor concentración de esperma- Concentración total 40 millones
tozoides o azoospermia. Motilidad 50% motilidad
progresiva o
EXÁMENES 25% motilidad
COMPLEMENTARIOS rápida
Morfología 30% formas
La ecografía transrectal es un método efectivo
normales
y poco invasivo para diagnosticar la obstrucción
Vitalidad 50% formas vivas
de los conductos eyaculadores.18 Generalmente el
ultrasonido se considera positivo si en la línea Leucocitos 1 millón/mL
media se identifica un quiste posterior al verum WHO Laboratory manual for the examination of Human Semen
montanum, dilatación de las vesículas seminales o la and Sperm-Cervical mocus interaction. 199918
3%.20 Muchos defectos son raros en hombres, en recomendado, debido a que las venas presentes
quienes la concentración es mayor de 50 millo- en el escroto son muy ramificadas, lo cual dificulta
nes/mL. Sin embargo, en aquellos con sospecha su disección y se incrementa el riesgo potencial
de endocrinopatía, el tratamiento hormonal es- de recurrencia y/o lesión arterial que irriga al tes-
pecífico es a menudo exitoso. Por consiguiente tículo. En el abordaje inguinal permite la ligadu-
debe realizarse una evaluación de los niveles en ra de las ramas dilatadas del sistema venoso cremas-
suero de FSH que muestre el funcionamiento térico y de otras ramas dilatadas dentro del canal
cuando la concentración espermática es baja o inguinal. Una modificación del abordaje inguinal
cuando clínicamente hay sospecha de endocrino- es la técnica subinguinal, que involucra la identifi-
patía. La valoración de la LH, la prolactina y la cación del contenido del cordón espermático; en
testosterona también son importantes cuando está esta técnica la incisión se realiza en el anillo exter-
indicada una valoración completa del estado en- no, evitando la apertura de la fascia del oblicuo
docrino reproductivo. externo. Debido a que la ramificación venosa pue-
Una FSH por encima del doble del rango de de estar a esta altura, la adecuada disección y liga-
normalidad usualmente se asocia con azoospermia ción suelen ser algo más difíciles. El abordaje
o severa oligozoospermia, y usualmente indica un retroperitoneal permite la ligadura de la vena es-
defecto de la célula germinal (falla testicular pri- permática.26 Las tasas de recurrencia después de
maria). Un nivel bajo o indetectable de FSH se- la varicocelectomía retroperitoneal están alrede-
ñala hipogonadismo hipogonadotrófico. Los ni- dor del 15%.27
veles de testosterona son altos durante la mañana, La reparación del varicocele laparoscópi-
de este modo la testosterona puede ser medida camente es una alternativa viable a la corrección
antes del medio día. quirúrgica abierta. Aunque eficaz, esta técnica re-
quiere experiencia laparoscópica y no ofrece ven-
VARICOCELE: TRATAMIENTO, tajas significativas de la cirugía abierta.28
ÉXITO Y COMPLICACIONES El uso del microscopio intraoperatorio es un
accesorio importante para la reparación quirúrgi-
La incidencia de varicocele es aproximadamente ca del varicocele; la magnificación permite dife-
del 15%;21 35% con infertilidad primaria y 81% con renciar mejor entre arterias y venas y preservar
infertilidad secundaria.22 Cerca del 95% es del lado las estructuras linfáticas.29 La corrección micros-
izquierdo.23 No obstante, los hombres que presen- cópica del varicocele subinguinal tiene una inci-
tan varicocele no todos aparentemente son infértiles, dencia muy baja ide complicaciones.30
sólo cerca del 5%.24 El varicocele puede estar aso- La mejoría de la calidad seminal luego de la
ciado con déficit en concentración, motilidad o mor- reparación quirúrgica está entre 50 y 90%; con
fología espermática. La asociación simultánea de estas una mejoría mayor en la calidad del semen, cuan-
tres anormalidades se conoce como “stress pattern”. to más grande sea el grado del varicocele.31,32 La
25
Si bien la presencia de este modelo puede estar tasa de embarazo después de la reparación qui-
presente en hombres con varicocele, no determina rúrgica está entre el 30 y el 50%.33
un diagnóstico de esa lesión. El uso de la embolización percutánea es otra
La varicocelectomía es la corrección quirúrgi- técnica para la corrección del varicocele. En manos
ca más comúnmente observada en la población expertas esta técnica puede ser segura y eficaz.34
infértil masculina; se realiza en un tercio de este En un paciente joven el varicocele es un pro-
grupo. Hay varias técnicas quirúrgicas para la co- blema de manejo complejo. El hecho que no todo
rrección del varicocele: escrotal, inguinal y retro- hombre con varicocele sea infértil, supone que la
peritoneal. En general el abordaje escrotal no es corrección quirúrgica no está indicada en el paciente
joven, en quien el estado de fertilidad es desco- fertilización pueden ser bajas. Inicialmente la mi-
nocido. La pregunta es: ¿cuál es el mejor manejo cromanipulación experimental del gameto invo-
en el paciente joven con varicocele? Lo mejor se- lucró la realización de una disección parcial de la
ría prevenir en el futuro la infertilidad, siempre y zona pelúcida para facilitar la fertilización o la in-
cuando no sea necesaria la cirugía. yección del espermatozoide por debajo de la zona
Un parámetro útil es el tamaño testicular. Una pelúcida dentro del espacio perivitelino (SUZI).37
disminución en el tamaño del testículo ipsilateral, Estas técnicas (“disección parcial de la zona” e
a veces al inicio de la exploración, durante o al “inserción subzonal” respectivamente) dieron
final del seguimiento es una evidencia para reali- como resultado modestas tasas de fertilización en
zar la reparación quirúrgica. En un estudio re- casos de infertilidad por factor masculino severo.38
ciente se demostró que la corrección quirúrgica La introducción de la inyección espermática intra-
del varicocele en adolescentes permite recuperar citoplasmática (ICSI) tuvo una significante mejo-
el tamaño del testículo afectado, resultando así el ría en las tasas de fertilización en casos de factor
volumen testicular comparable con el testículo masculino severo.39,40
contralateral.35 Además de mejorar las tasas de embarazo, uti-
El concepto según el cual la corrección del lizando espermatozoides del semen, la ICSI abre
varicocele prepuberal ejerce un efecto protector nuevas perspectivas para adquirir embarazos con
en la función testicular, ha sido soportado por es- la obtención de espermatozoides en el eyaculado
tudios que comparan la masa testicular con la can- o recuperación de espermatozoides del deferen-
tidad de espermatozoides en hombres mayores te, del epidídimo o del testículo. En caso de obs-
operados por varicocele en la etapa prepuberal, trucción ductal no corregida, el espermatozoide
con pacientes con diagnóstico de varicocele y que se puede obtener del deferente, del epidídimo o
no fueron operados.36 Los hombres con varicocele del tejido testicular procesado en el laboratorio.
que no fueron operados tienen una reducción Para la ICSI se requiere literalmente un esperma-
significativa del tamaño testicular y menor tozoide para cada oocito. Su uso está realzando las
concentración de espermatozoides. El intervalo tasas de fertilización y embarazo en un mismo es-
posquirúrgico promedio en el varicocele corre- cenario. En un reporte de 424 embarazos logra-
gido fue de 14,5 años. Si bien la reducción del dos a través de la utilización de la ICSI por factor
tamaño testicular y la concentración espermática masculino severo, los resultados fueron similares
son sugestivas de problemas de fertilidad, no son a aquellos que utilizaron FIV convencional con
una evidencia concluyente al respecto. Aun así, la semen normal.41
mejoría de estos parámetros sugiere que la inter- Ni un solo parámetro del semen parece pre-
vención temprana pueda ser beneficiosa. decir el resultado de la ICSI.42 En un informe se
da a conocer el uso de la ICSI en parejas, donde
TÉCNICAS DE REPRODUCCIÓN los hombres presentaban un número de esper-
ASISTIDA EN EL MANEJO DE LA matozoides menor a 100.000/mL en el eyaculado,
INFERTILIDAD MASCULINA la tasa de fertilización era del 66%.43 En otro re-
porte la tasa de fertilización mediante la ICSI se
La fertilización in vitro (FIV) convencional fue estratificó por el número de espermatozoides mó-
una de las primeras técnicas para el tratamiento viles; cuando el número de espermatozoides mó-
de pacientes con factor masculino severo. Si bien viles fue menor de 500.000, la fertilización fue
la FIV desempeña un papel significativo en el ma- menor del 66%. En otros casos, en los cuales la
nejo de la infertilidad de factor masculino, en ca- cantidad de espermatozoides móviles fue mayor
sos con déficit de calidad del semen, las tasas de de 500.000, la tasa de fertilización fue del 70%.44
Otro estudio no reporta diferencia entre las tasas los espermatozoides no se hallan presentes en el
de fertilización con semen en fresco versus semen eyaculado. Ejemplo de ello son las obstrucciones
congelado o semen obtenido por electro- del conducto deferente cuando no es posible rea-
eyaculación (en fresco 66%; semen congelado 66%; lizar una vasovasostomía (obstrucciones muy
semen obtenido por electroeyaculación 68%).45 distales, determinados casos de lesión en el curso
A través del criterio estricto de morfología de herniorrafias, etc.), obstrucciones de los con-
Svalander y colaboradores compararon las tasas de ductos eyaculadores en los que no es posible o
embarazo utilizando la ICSI, con muestras exce- fracasa las técnicas de vibro y electroestimulación.
lentes (más del 14%), buenas (4 al 14%) o pobres La aspiración espermática a nivel deferencial tam-
(menos del 4%) de la morfología espermática.46 bién está indicada en determinados casos en los
Estos investigadores no encontraron ninguna di- que se asocia hipospermia, astenozoospermia y
ferencia entre estos grupos con respecto a la fer- necrozoospermia.50
tilización, embarazo o tasas de implantación. In- La microaspiración espermática epididimaria
cluso en algunos pacientes con globozoospermia (MESA) involucra la aspiración del contenido
(espermatozoides redondos sin acrosoma) se han espermático del fluido del túbulo epididimario
observado tasas de fertilización normales mediante para el uso de la FIV. La utilización de esta técnica,
la ICSI.47 empleada primero para el tratamiento en hom-
Aunque la presencia de anticuerpos antiesper- bres con agenesia de los conductos deferentes, se
matozoides (AA) es una causa reconocida de infer- ha extendido para incluir el tratamiento de otras
tilidad de factor masculino, el tratamiento de pa- formas de obstrucción de los conductos deferen-
cientes con esta condición generalmente no ha tes y del epidídimo.51
tenido éxito. Nagy y colaboradores encuentran Con el advenimiento de la ICSI la recupera-
tasas de fertilización, de desarrollo embrionario y ción de espermatozoides directamente del testí-
de embarazos logrados a través del uso de la ICSI culo se ha hecho una opción viable. Aunque el
sin que hayan sido influenciadas por la presencia número presente de espermatozoides móviles en
de AA.48 el tejido testicular es a menudo bajo, es adecuado
Ningún parámetro de la muestra seminal pre- para la ICSI, ya que puede obtenerse de una mues-
dice el resultado de la ICSI, pero la edad de la tra de biopsia testicular de un paciente con
pareja y el número de oocitos recuperados afec- azoospermia obstructiva. En el paciente con azoos-
tan notablemente el éxito de la FIV/ICSI. 49 La permia no obstructiva la concentración esper-
edad avanzada de la pareja está asociada a la pro- mática de la muestra es muy baja.
ducción disminuida de oocitos, a la transferencia En un grupo muy selecto de hombres someti-
embrionaria y al fracaso aumentado de lograr el dos a vasectomía y que contemplan la recanalización
embarazo. deferencial (vasovasostomía), la microaspiración
espermática deferencial o la ICSI puede ser una
TÉCNICAS buena alternativa a la vasovasostomía. Los proce-
MICROQUIRÚRGICAS DE dimientos de la microaspiración espermática
deferencial y la ICSI son más costosos, potencial-
ASPIRACIÓN ESPERMÁTICA
mente proponen un riesgo mayor de complica-
La microaspiración espermática deferencial in- ciones médicas y tienen una incidencia más alta de
teresa la aspiración del contenido espermático de gestaciones múltiples que la vasovasostomía.52
pacientes en aquellos casos en los que, a pesar de Como se mencionó anteriormente, en casos
estar conservada la espermatogénesis y la per- de azoospermia obstructiva, la recuperación de
meabilidad del epidídimo, por diferentes causas espermatozoides del tejido testicular (TESE) en
combinación con la ICSI puede ser una buena obstructiva, así como en un pequeño porcentaje
opción. Incluso en pacientes con arresto de la de aquellos que presentan oligozoospermia.59
maduración o el síndrome de sólo células de Pryor y colaboradores, recientemente com-
Sertoli, los escasos y esparcidos túbulos produc- pararon en un estudio a 200 hombres subfér-
tores de espermatozoides pueden existir y per- tiles con 200 hombres con presencia de micro-
mitir la recuperación de un número adecuado de deleciones en el cromosoma Y. Las investigaciones
espermatozoides viables para la ICSI con éxito.53,54 reportaron una incidencia de 7% de dicha
En un estudio realizado en muestras de biopsia microdeleción en el grupo subfértil, comparado
testicular de pacientes con niveles de FSH en suero con una incidencia de 2% entre la cohorte de
tres veces por encima del límite normal, se encon- fertilidad.60 En consecuencia, las microdeleciones
traron espermatozoides maduros en un 30%.55 del cromosoma Y no están necesariamente aso-
ciadas con azoospermia y pueden verse en la po-
CONSIDERACIONES GENÉTICAS blación fértil.
EN EL USO DE LAS TÉCNICAS DE En otro estudio, en el cual se evalúan 370 hom-
REPRODUCCIÓN ASISTIDA EN bres con azoospermia idiopática u oligozoospermia
INFERTILIDAD MASCULINA severa para las deleciones específicas en Yq11,61
dichas deleciones se hallaron en doce de estos
La continua investigación en el área de la re- hombres, localizadas en tres regiones diferentes,
producción masculina ha demostrado que las al- designadas como AZFa, AZFb, AZFc. Se encon-
teraciones genéticas pueden llevar a la regulación traron pacientes diferentes que tenían deleciones
de la producción espermática anormal, desórde- en una misma rubregión para producir alteración
nes en la espermatogénesis u obstrucción del sis- en la misma fase espermatogénica.
tema ductal. La patología de la reproducción mas- Los informes con respecto al impacto de las
culina mediada genéticamente puede, por deleciones del cromosoma Y en la espermato-
consiguiente, causar el fracaso reproductivo génesis han redefinido el concepto de “idiopático”
pretesticular, testicular o postesticular. en la infertilidad masculina. En la actualidad se
Las microdeleciones en el brazo largo del desarrollan métodos mejorados para evaluar las
cromosoma Y (Yq11) en algunos hombres con anormalidades del cromosoma Y y el valor clínico
daño intrínseco del testículo ha sido un tema de de tal comprobación.62 Los defectos de autosoma
interés considerable. La azoospermia causada por pueden ser igualmente interesantes y serán otra
estas deleciones se describieron en 1976.56 La área importante de investigación.
deleción de genes específicos en el factor de Los continuos adelantos en TRA, sobre todo
azoospermia (AZF) en la porción del cromosoma el uso de la ICSI, han permitido a algunos hom-
Y puede llevar a una espermatogénesis anormal o bres con fracaso testicular severo genéticamente
ausente.57 El AZF en el cromosoma Y se ha rela- tener sus propios hijos. Esto ha planteado pre-
cionado con la deleción del intervalo 6 en la ban- guntas con respecto al riesgo de transmitir tales
da q11.23 y contiene cinco millones de pares de anormalidades genéticas a sus descendientes. Aun-
bases.58 Se han identificado hasta la fecha tres genes que la incidencia de malformaciones congénitas
que parece regulan la espermatogénesis que se de- no parece ser mayor en niños que son resultado
nominan: YRRM1 (un gen Y específico con un del uso de las TRA, las anormalidades más sutiles,
ARN de reconocimiento motivado), YRRM2 y como deleciones del cromosoma Y y otras altera-
DAZ (deleción de azoospermia). Las deleciones ciones genéticas, son difíciles de identificar. Ade-
que involucran estos genes se han identificado en más, algunas alteraciones genéticas pueden no ma-
un 18% de los hombres con azoospermia no nifestarse en la primera generación de
descendencia.63 Por tanto, la mejor definición de 13.Handelsman DJ, Conway AJ, Boylan LM, Turtle JR.
cosas así se deja a la tarea importante de investiga- Young’s syndrome. Obstructive azoospermia and
dores que trabajan en este campo de la medicina chronic sinopulmonary infections. N Engl J Med
1984;310:3-9.
reproductiva.
14.Oates RD, Amos JA. The genetic basis of congenital
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Research, Society and Development, v. 10, n. 6, e46510616059, 2021
(CC BY 4.0) | ISSN 2525-3409 | DOI: http://dx.doi.org/10.33448/rsd-v10i6.16059
Male infertility and COVID-19: Is there a relationship?

Infertilidade masculina e COVID-19: Há alguma relação?
Infertilidad masculina y COVID-19: ¿Existe una relación?
Alyne Barreto Mesquita de Goés

ORCID: https://orcid.org/0000-0001-5187-6174
Liga Norte Riograndense Contra o Câncer, Brazil
E-mail: alynebarreto2@hotmail.com
Irami Araújo-Neto
E-mail: irami.neto@uol.com.br
Natália Marcelino Araújo
E-mail: nataliamarcelino4@gmail.com
Pedro Vilar de Oliveira Villarim
E-mail: pedrovilar@ufrn.edu.br
Thais Cristina Loyola da Silva
E-mail: thaiscristinaloyola@outlook.com
Camila Vilar de Oliveira Villarim
E-mail: camilavillarim@gmail.com
Amália Cinthia Meneses Rêgo
Universidade Potiguar, Brazil
Instituto de Ensino, Pesquisa e Inovação da Liga Contra o Câncer, Brazil
E-mail: amalia.rego@liga.org.br
Irami Araújo-Filho
Universidade Potiguar, Brazil
Universidade Federal do Rio Grande do Norte, Brazil
Instituto de Ensino, Pesquisa e Inovação da Liga Contra o Câncer, Brazil
E-mail: irami.filho@uol.com.br
Abstract
In the testicles, the expression of Angiotensin-Converting Enzyme 2 receptors makes it more susceptible to infection
by Sars-CoV-2 and, therefore, to male infertility with significant health problems for the patient. Therefore, this study
aimed to analyze the clinical pathophysiology and the mechanisms involved in the genesis of male infertility from
COVID-19, through the critical analysis of the main scientific evidence on the subject presented so far. From an
integrative review of the literature containing 30 studies selected using inclusion criteria in the period 2020-2021, the
direct and indirect impacts on male fertility in pathophysiological and psychosocial terms were observed in this study,
in addition to therapeutic options, guidelines host and efficient semiological approach. Thus, the impact of the
pandemic, even after one year, is immeasurable. Additional studies to reveal the real consequences and the mechanism
by which the disease can affect male fertility are still needed. It is essential to pay more attention to male genital exams
in patients with COVID-19. The psychobiological consequences of the pandemic in infertile patients should not be
underestimated.
Keywords: COVID-19; COVID-19 virus disease; COVID-19 virus infection; SARS-CoV-2; Male infertility;
Reproductive health.
Resumo
Nos testículos, a expressão de receptores da Enzima Conversora de Angiotensina 2, torna mais suscetível à infecção
pelo Sars-CoV-2 e por conseguinte, à infertilidade masculina com significativos agravos à saúde do paciente. Por isso,
este estudo objetivou analisar a fisiopatologia clínica e os mecanismos envolvidos na gênese da infertilidade masculina
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proveniente da COVID-19, através da análise crítica das principais evidências científicas sobre o assunto apresentadas
até o momento. A partir de uma revisão integrativa da literatura contendo 30 estudos selecionados mediante critérios
de inclusão no período de 2020-2021, observou-se no presente estudo os impactos diretos e indiretos sobre a fertilidade
masculina em termos fisiopatológicos e psicossociais, além de opções terapêuticas, orientações de acolhimento e
abordagem semiológica eficiente. Dessa forma, o impacto da pandemia, mesmo após um ano, é imensurável. Estudos
adicionais para revelar as reais consequências e o mecanismo pelo qual a doença pode afetar a fertilidade masculina
ainda são necessários. É fundamental oferecer mais atenção aos exames genitais masculinos em pacientes portadores
de COVID-19. As consequências psicobiológicas da pandemia em pacientes inférteis não devem ser subestimadas.
Palavras-chave: COVID-19; Doença por vírus COVID-19; Infecção por vírus COVID-19; SARS-CoV-2;
Infertilidade masculina; Saúde reprodutiva.
Resumen
En los testículos, la expresión de los receptores de la enzima convertidora de angiotensina 2 lo hace más susceptible
a la infección por Sars-CoV-2 y, por tanto, a la infertilidad masculina con importantes problemas de salud para el
paciente. Por tanto, este estudio tuvo como objetivo analizar la fisiopatología clínica y los mecanismos implicados en
la génesis de la infertilidad masculina por COVID-19, a través del análisis crítico de las principales evidencias
científicas sobre el tema presentadas hasta el momento. A partir de una revisión integradora de la literatura que
contiene 30 estudios seleccionados con criterios de inclusión en el período 2020-2021, se observaron en este estudio
los impactos directos e indirectos sobre la fertilidad masculina en términos fisiopatológicos y psicosociales, además
de las opciones terapéuticas, guías hospedantes y eficientes. enfoque semiológico. Por lo tanto, el impacto de la
pandemia, incluso después de un año, es inconmensurable. Aún se necesitan estudios adicionales para revelar las
consecuencias reales y el mecanismo por el cual la enfermedad puede afectar la fertilidad masculina. Es fundamental
prestar más atención a los exámenes genitales masculinos en pacientes con COVID-19. Las consecuencias
psicobiológicas de la pandemia en pacientes infértiles no deben subestimarse.
Palabras clave: COVID-19; Enfermedad por virus COVID-19; Infección por el virus COVID-19; SARS-CoV-2;
Infertilidad masculina; Salud reproductiva.
1. Introduction
In December 2019, Sars-CoV-2, known as the new Coronavirus or COVID-19, appeared in China, declared by the
World Health Organization (WHO) as responsible for a new pandemic in March 2020, causing severe respiratory failure, a
response systemic inflammatory, multiple organ dysfunctions, death and even infertility (Dutta et al., 2021).
The virus is transmitted interpersonally by droplets, with greater prevalence, susceptibility and lethality in males. In
the human body, cells that express receptors for Angiotensin-Converting Enzyme 2 (ACE2) are predisposed to infection by Sars-
CoV-2 (Illiano et al., 2020).
In the case of male fertility, since the testicles, specifically Leydig and Sertoli cells, have one of the highest amounts
of ACE2 among the various tissues of the body, the testicular expression of ACE2 was shown to be related to age, affecting
individuals 20-30 years, while those over 60 have lower levels of expression (Illiano et al., 2020; Fu J et al., 2020).
In the context of male reproduction, Sars-CoV-2 activates sensitive pathways through inflammatory responses with
the release of cytokines, induces oxidative stress and affects semen quality, in addition to causing orchitis and psychological
stress, the main causes of male infertility (Olaniyan et al., 2020; Dutta et al., 2021) .
Reproductive health in humans depends on a good quality of life, physical, mental and social well-being. The current
pandemic status of COVID-19, including treatment, prevention and control measures, alters the patient's perception of the
disease, promotes panic, depression, anxiety, fear, post-traumatic stress disorders and, consequently, affects reproductive health
(Li et al., 2020; Esposito et al., 2020).
In this sense, the present review analyzed the clinical pathophysiology and interference in male infertility from
COVID-19, since such an approach requires extensive discussion and scientifically validated responses.
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2. Methodology
The research was carried out through an integrative literature review in search of current evidence on the relationship
between male infertility and COVID-19. The databases PubMed/Medline, Scopus, Scielo, Embase, Web of Science and Google
Scholar were used, known as gray literature. Studies related to male infertility and the new coronavirus were selected, through
the combination of indexes present in the MeSH Platform (Medical Subject Headings) - PubMed/Medline: COVID-19; COVID-
19 Virus Disease; COVID-19 Virus Infection; SARS-CoV-2; Male Infertility; Reproductive Health. Relevant studies published
between 2020-2021, carried out in humans, male, in the cohort modalities, systematic review, case-control, cross-sectional, case
series and randomized clinical trials were included, totaling 30 articles. The analysis, review and selection of articles were carried
out in pairs, in a blind and separate way, based on the reading of the title and abstract, with a third reviewer in case of
disagreement. Studies that addressed other topics, did not have a full text or at least one keyword in the title and abstract, were
excluded from the research (Pereira et al., 2018).
3. Results
In total, 58 studies on the topic were initially found. After applying the exclusion criteria, 30 manuscripts remained,
which were read, analyzed and reviewed in detail and therefore included in this review.
In agreement with the literature, the serious global threat that the pandemic by COVID-19 became evident and the
close relationship of ACE2 in the infection by Sars-CoV-2, especially in the context of male infertility.
Evidently, it is a delicate issue, which causes significant direct and indirect impacts in pathophysiological and
psychosocial terms, as well as influencing the individual's conduct as a person who belongs and lives in society.
In this sense, an efficient semiological approach, reception and thorough investigation as a prophylactic or therapeutic
attitude are necessary. It is important to identify possible consequences in the short, medium and long term, to minimize
individual and collective damages.
The scientific evidence found demonstrated the need for more robust evidence on the involvement of Sars-CoV-2 in
the male reproductive system. Thus, the speed in researching in this context is notorious, due to the increase in male infertility
during and after being affected by the disease.
4. Discussion
Viral infection
The importance of viral infections associated with the male reproductive system has been highlighted in several
studies, leading to the detection of more than 30 viruses that spread in the semen, such as mumps, human immunodeficiency,
hepatitis and zika that cross the blood-testicular barrier, causing as orchitis, epididymitis and changes in sperm count or semen
quality as a whole (Sheikhzadeh et al., 2021; Vishvkarma et al., 2020).
The main viral mechanisms that affect reproduction are the direct invasion of germ cells and dissemination via sex,
attack on the endocrine reproductive system, necessary to maintain secondary sexual characteristics, inflammatory response
induced by a secondary viral infection that seriously affects the testes and fever that interferes in normal reproductive physiology
(Tian et al., 2021).
Such mechanisms coexist and have a synergistic effect. In addition, the male reproductive system can be affected by
antiviral drugs, due to their gonadotoxic effects, such as glucocorticoids and interferons (Tian et al., 2021).
After analyzing more than 3,800 articles, scientists found evidence that at least 11 viruses live in the testis, including
those that cause pneumonia, dengue and extreme acute respiratory syndrome. However, the degree of reproduction and infection
within sperm and germ cells remains unknown (Vishvkarma et al., 2020).
3
Epidemiology
Sars-CoV-2 belongs to the group of Betacoronaviruses, has a predominance through the respiratory tract, is transmitted
from person to person by droplets and has a higher prevalence, susceptibility and lethality in males (Illiano et al., 2020).
It affects all age groups, being more common in the elderly or people with previous comorbidities, cardiovascular and
respiratory diseases, diabetes mellitus, systemic arterial hypertension and neoplasms (Segars et al., 2020).
The testicular expression of the ACE2 showed is related to age, with a greater probability of suffering a testicular
injury due to COVID-19 between 20-30 years, while patients aged 60 years or more have reduced levels of expression (Dutta et
al., 2021; Bahadur et al., 2020).
A systematic review that included 48 studies showed that males are more likely to suffer or die from complications of
COVID-19. It was also observed that the majority of men with the disease were of childbearing age (Younis et al., 2020).
Besides that, the COVID-19 pandemic produces ethical dilemmas for the healthcare system, managers and healthcare
equipment suppliers. The most difficult one is how to equitably distribute scarce resources, which can determine who lives and
who dies (Monte et al., 2020).
Shastri et al. assessed the time of viral elimination after infection and noted that women can achieve earlier immunity
rates than men. To determine the reason for the finding, it was found that the expression of ACE2 was in greater concentration
in the testicular tissue compared to the analyzed ovaries (Efremov et al., 2020; Vishvkarma et al., 2020).
Following this same line of thought, Renu et al. demonstrated that while many carriers of the disease are asymptomatic,
the deleterious reproductive effects in the infected man can be silent and, thus, make these conditions more serious due to a late
diagnosis (Renu et al., 2020).
Finally, despite the foregoing, currently, the diagnostic analysis on the sperm of non-cancer patients, patients in the
postoperative period of elective surgery and related fertility procedures are classified as a low priority in most countries due to
the attention of the government is focused on combating the pandemic caused by COVID-19 (Hallak et al., 2020).
Physiopathology
ACE2 is a transmembrane zinc metallopeptidase, which is homologous to classic ACE, containing a single catalyst.
Both are part of the renin-angiotensin-aldosterone system, which plays a fundamental role in the regulation of blood pressure
and hydroelectrolytic balance (Góes et al., 2020).
When we observe the ACE2 cell receptor and the viral nucleocapsid protein in tissue samples, we can observe that
positive areas are mainly distributed in the cytoplasm of epithelial cells and the cilia of the gastrointestinal glandular epithelial
cells (Bocchese et al., 2020).
ACE acts to catalyze the conversion of angiotensin I to angiotensin II (ANG II), and ACE2 is responsible for the
generation of angiotensin 1-7 (ANG 1-7) from angiotensin II (Younis et al., 2020; Illiano et al.,2020; Dutta et al., 2021;
Sheikhzadeh et al., 2021).
While ANG II exerts deleterious effects via type 1 angiotensin II receptors, the ANG 1-7 receptor axis causes benefits,
balancing and salutary actions on vital organs, such as vasodilation, anti-inflammatory, anti-fibrotic, diuretic action and
natriuretic. ACE2 is widely expressed in the heart, kidneys, lungs, intestines, liver and testicles (Younis et al., 2020; Illiano et
al.,2020; Dutta et al., 2021; Sheikhzadeh et al., 2021).
The cells with greater expression of ACE2 function as a key receptor for Sars-CoV-2, therefore favoring a greater
predisposition to infection by COVID-19 (Illiano et al., 2020 ; Sheikhzadeh et al ., 2021).The innovation in male fertility research
is because the testicular Leydig and Sertoli cells have one of the largest amounts of ACE2 among the various tissues of the body,
4
combined with the property of being the meeting point of most testicular mRNAs, mainly in Leydig cells (Younis et al., 2020;
Vishvkarma et al., 2020).
SARS-CoV-2 activates sensitive pathways through an inflammatory response with the release of cytokines, C reactive
ble
for severe lung injury, microthrombosis, and disseminated vascular coagulation (Dantas, et al.,2021). Besides that, induces
oxidative stress in host tissues and affects semen quality. In addition, the coronavirus causes orchitis and psychological stress,
which are among the main causes of male infertility (Olaniyan et al.,2020; Dutta et al., 2021).
In this sense, patients surviving the COVID-19 infection are at risk of infertility due to testicular atrophy, hypothalamic
pathology, pituitary abnormalities and disturbance of the sexual hormonal profile (Selvaraj et al., 2021).
Recent sequencing of human sperm has demonstrated the presence of ACE2 transcription, validating its expression in
germ cells, spermatocytes and round spermatids. The testicles are the male gonads responsible for the production of sperm, where
the haploid germ cell and the male reproductive hormone (testosterone) are generated (Olaniyan et al., 2020). Therefore, it is
observed that the virus is capable of having the enzymatic potential as a form of penetrating the male reproductive system (Younis
et al., 2020; Vishvkarma et al., 2020; Fu et al., 2020).
The main types of testicular cells with ACE2 expression in the messenger RNA (mRNA) strand are the seminiferous
duct cells, spermatogonia, Leydig cells and Sertoli cells (Younis et al., 2020). The difference in ACE2 levels between testicles
and ovaries means being able to withstand greater vulnerability of deficiency mediated by Sars-CoV-2 in male gonadal functions
(Dutta et al., 2021; Illiano et al., 2020; Sheikhzadeh et al., 2021; Fu et al., 2020).
Research carried out after the Sars-CoV outbreak in 2002, found that orchitis was one of the complications linked to
the interruption of spermatogenesis and apoptosis of germ cells, affecting semen quality. In this study, histopathological
investigations revealed inflammatory infiltrates in the seminiferous tubules (Dutta et al., 2021).
It is worth mentioning that in situ hybridizations of testicular tissue specimens do not recognize viral genomic
materials. In addition, studies have not yet found viral traces in seminal plasma, thus indicating that inflammatory and
immunological reactions play a key role in virus-mediated testicular damage (Dutta et al., 2021).
The IL-6 promotes inflammation, immune response and is associated with the pathogenesis of autoimmune orchitis.
The most serious cases of COVID-19 are accompanied by a high level of IL-6, with receptors expressed in testicular cells, which
justifies male gonadal involvement and the appearance of orchitis as a complication of Sars-CoV-2 (Renu et al., 2020; Haghpanah
et al., 2021).
Clinical and experimental studies have associated hypogonadism with high levels of pro-inflammatory cytokines,
IL1 , IL-6 and TNF- , which in turn are important inflammatory mediators in the pathogenesis of Sars-CoV-2 (Dutta et al.,
2021).
However, an acute critical inflammatory condition, as in the case of COVID-19, can suppress the activity of the
hypothalamic-pituitary-testicular axis (HPT), reduced luteinizing hormone (LH), follicle-stimulating hormone (FSH) and levels
of testosterone (T) as one of the determining factors for the relationship of infertility associated with a viral infection (Selvaraj
et al., 2021).
A study involving 81 male patients with COVID-19 demonstrated lower levels of serum testosterone (T) and higher
levels of LH with a lower T: LH ratio compared to the control group of the same age, suggesting that the coronavirus may cause
male hypogonadism. These findings suggest direct effects of Sars-CoV-2 infection on testicular cells instead of the HPT axis
(Dutta et al., 2021; Liu et al.,2020).
An additional factor about COVID-19 and which affects male fertility is fever, as the increase in testicular temperature
is harmful to spermatogenesis. In addition, there are immunomodulatory therapies with long-term effects on fertility because the
5
testicular microenvironment of modified cytokines has adverse and even neoplastic effects at the cellular level, eventually
favoring the emergence of testicular cancer, a second reason for long-term warning (Younis et al., 2020).
In the same context, another study carried out in Germany showed that patients with moderate infection have a
statistically significant deficiency in sperm quality (concentration, total number of sperm by ejaculation, progressive immobility
and incomplete motility), compared to men who had an infection and patients in the control group (Holtmann et al., 2020).
In contrast to the above, a study carried out in Wuhan, China, between January and March 2020, analyzed 34 male
patients, all symptomatic for COVID-19 and RT-PCR positive, with an average age of 37 years. It was observed that six of these
patients had scrotal discomfort at the time of confirmation, suggestive of orchitis, and a careful genitourinary examination was
not performed. In the end, the presence of Sars-CoV-2 has not been detected in any semen sample ejaculated after 31 days of
infection (Pan et al., 2020).
It is important to highlight the role of Protease Transmembrane Serine 2 (TMPRSS2) as one of the sites of invasion
by SARS-CoV-2, with an expression similar to ACE2, present in the luminal cells of the prostate and released in the seminal
fluid as part of the prostates. Evidence suggests that it is a regulatory factor for maintaining normal reproductive health function,
with a significant role in sodium epithelial homeostasis, angiogenesis and tubulogenesis through its proteolytic cascades (Dutta
et al., 2021; Sheikhzadeh et al., 2021).
Despite the inconsistent level of expression of TMPRSS2 in the male genitalia, its presence was recorded in the
prostate, seminal vesicles and testicles. This discovery exposes the mechanism of invasion and vulnerability of the male
reproductive tract by Sars-CoV-2 and provides the basis for further investigation into the problem in question (Sheikhzadeh et
al., 2021; Fu et al., 2020).
Clinical presentation
The inhaling droplets containing the virus is how the infection is acquired. Besides that, the virus can remain alive on
surfaces for a long time. The viral particles can be detected in the feces, making fecal-oral transmission possible. About the
incubation period, it varies from 7 to 14 days. (Bocchese et al., 2020)
When analyzing the clinical picture, the individual infected with the new coronavirus may be asymptomatic or evolve
from mild to severe intensity, being cough, fatigue, fever, headache, anosmia, ageusia, breathing difficulties and muscle pain,
diarrhea and lymphopenia, most prevalent signs and symptoms (Batiha et al., 2020). An atypical presentation occurs in male
patients who may experience pain and testicular edema, with potential for testicular damage and infertility (Olaniyan et al.,
2020).
Treatment for COVID-19 involves, among other drugs, the use of antiviral medications such as ribavirin. However, it
is known to induce oxidative stress, reduce testosterone levels and alter normal sperm characteristics. Thus, extra care is needed
when prescribing it, associating risk factors and benefits (Selvaraj et al., 2021; Li et al., 2020).
Ribavirin combined with interferon can affect male fertility from a decrease in sperm count. In addition, the drug
causes sperm DNA fragmentation for up to 8 months, so that contraception is performed after antiviral treatment (Li et al., 2020).
Still, about pharmacological treatment, glucocorticoids can expand the interstitial space of the spermatogenic
epithelium, destroying cellular connections and affecting the blood-testicular barrier, in such a way that they allow the entry of
harmful substances in the testis. However, glucocorticoids are used in small doses for a short period in the management of
COVID, thus having a minimal impact on the reproductive system (Li et al., 2020).
Cryopreservation and sperm donation amid the COVID-19 pandemic is another therapeutic option that may have an
impact on the maintenance of semen in cancer patients, highlighting the need to resume fertility services. However, there is still
6
no study on the quality of semen after infection by Sars-CoV-2, but it is known that periods of stress increase the concentration
of cortisol, which is responsible for interfering negatively in this variable (Illiano et al., 2020).
It is important to highlight the role of the brain related to fertility in patients with Sars-CoV-2. Most viruses enter the
human body through the nasal and oral pathways, crossing the central nervous system (CNS), reproducing and dispersing through
the olfactory bulb, lingual nerve or vagus nerve (Vishvkarma et al., 2020). In addition, even if it does not cross the blood-brain
barrier, Sars-CoV-2 induces an immune reaction that activates the cascade of inflammatory cytokines, and therefore brings
harmful consequences to fertility as highlighted earlier (Vishvkarma et al., 2020).
The inflammatory process occurs in several anatomical sites of the CNS such as meninges, brain, spinal cord and in
other different regions causing meningitis, encephalitis, myelitis and more serious conditions such as meningoencephalitis or
encephalomyelitis. Besides that, patients with COVID-19 can have neurological syndromes, loss of involuntary breathing
process, impairment of the brainstem, ataxia, loss of smell, seizures, among others. These manifestations, however, are signs of
a worse prognosis (Góes et al., 2020). In addition, it was observed that brain cells express ACE2 receptors in glial cells and
neurons, making them a possible target for Sars-CoV-2 and, consequently, a potential risk factor for male infertility (Vishvkarma
et al., 2020).
Infertility
Infertility, in turn, is considered the most serious reproductive disorder and in 25% of cases it is idiopathic (Shen et
al., 2020). Over the years, its possible causes have been identified in pre-existing associated pathologies, such as changes in the
immune system (such as viral infections), thyroid dysfunctions and coagulopathies (Pacchiarotti et al., 2020).
In addition, the relationship between the environment and reproductive capacity has proven to have a direct
association. Studies have shown that stress is associated with changes in eating habits and exercise, resulting in a set of variables
that favor reproductive disorders. The diagnosis is based on the exclusion of common causes, using the investigation of the
fertility pattern (Pacchiarotti et al., 2020).
An important aspect of COVID-19 is the duration of disease morbidity in activity, with a median of 22 days and the
high degree of the immune response, which affects the organs that express ACE2 receptors, including the testicles (Li et al.,
2020; Vishvkarma et al., 2020).
Psychosocial aspects
In addition to the pathophysiological aspects, the pandemic caused a severe economic recession, an increase in the
unemployment rate and, consequently, a decline in the birth rate, considering that several couples are no longer able to financially
support their offspring (Trinchant et al, 2020).
When it comes to mental health, reproductive health in humans depends on a huge range of factors, including physical,
mental and social health. The current pandemic status of COVID-19, as well as its treatment, prevention and control measures
associated with it, causes an exacerbated concern about the disease, culminating in a state of panic, depression, anxiety, fear and
post-traumatic stress disorders, which, consequently, affects the reproductive health of people, infected or not (Li et al.,2020;
Esposito et al., 2020; Liu et al., 2020).
Elevated stress levels disrupt homeostasis, activating the central stress response system, which results in deregulation
of the hypothalamic-pituitary-adrenal axis and inhibits reproductive function. In addition, the decrease in fertility during the
period of psychological crisis is related to the reduction of sperm quality and an induced sexual dysfunction, as well as affecting
seminal parameters (Li et al., 2020).
7
Veronica Esposito et al. directed his study to investigate psychological aspects of infertile couples, in order to better
understand the level of suffering. As a result, there was a noticeable increase in the number of cases of depression and anxiety,
with an incidence of 75% and 71% of the scores in the Impact of Event Scale - Review (IES-R) and State-Trait Anxiety Inventory
(STAI), respectively (Esposito et al., 2020).
Based on the association of increased unemployment with male infertility, the turnaround in social life is notorious,
damaging intellectuality, humor and life prospects (Esposito et al., 2020; Shen et al., 2020).
The Lancet Psychiatry" recently discussed the current pandemic situation and highlighted the rise in suicide rates.
The more the disease spreads, the more long-term effects can be felt in different areas of life, generating a greater impact on
populations considered vulnerable, such as men susceptible to infertility, and therefore contributing to the increase in suicidal
behavior rates (Shen et al., 2020).
5. Conclusion
In conclusion, considering that infertility in men is already a worldwide trend and a serious threat to humanity,
understanding the effects of Sars-CoV-2 on testicular physiology has become an important and necessary public health
responsibility, and it is crucial to carry out more studies to reveal the exact impact and the mechanisms by which COVID-19
operates in this field of science.
Unfortunately, the most recent primary studies have limitations in terms of small sample size, testing methods and the
course of the disease, which directly interfere in proving the hypotheses. Additional analyzes are necessary to confirm the results
and evaluate the prevention of testicular damage, as well as the possibility of reversal of the condition, in addition to tracking
reproductive functions in men who are victims of the disease.
It is essential that health professionals pay more attention to male genital examinations, in addition to the organs
primarily involved, with an effective investigation, evaluation and intervention, during or even after the pandemic, to recognize
important signs and symptoms of the respective clinical condition.
Finally, it is possible to affirm, undoubtedly, that the psychobiological consequences of the pandemic in infertile
patients should not be underestimated. In this sense, it is vital to offer prior guidance, psychological support and individualized
action planning, taking into account all the variables involved in this important and complex process that is male fertility.
With a view to the future and increasing evidence on this topic, better research such as randomized trials and systematic
reviews with meta-analysis are essential to obtain an effective understanding of the relationship between male infertility and a
COVID-19. Thus, it is important to establish segments in the scientific literature, aiming to avoid relevant transformations in the
clinical-clinics of the subject addressed.
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10
ARTÍCULO ORIGINAL Rev. Arg. de Urol. . Vol. 86 (2) 2021 (65-71)
ORIGINAL ARTICLE ISSN 0327-3326
Revisión sobre el COVID-19 y la andrología

Review on COVID-19 and andrology
Martina Solé, Omar Layús, Gastón Rey Valzacchi
Servicio de Urología, Hospital Italiano de Buenos Aires.
RESUMEN ABSTRACT
Introducción: - -
navirus altamente contagioso, denominado SARS-CoV-2 (síndrome agudo gious coronavirus emerged, called SARS-CoV-2 (Severe Acute Respiratory
respiratorio severo). A medida que fue avanzando la pandemia, hemos Syndrome). As the pandemic moved forward.we have begun to get to know
empezado a conocer al virus que nos enfrentamos, pero en varios aspec- the virus that we are facing, but in several aspects it has not yet been
tos aún no se han podido sacar conclusiones determinantes. possible to draw decisive conclusions. That is why we carried out a biblio-
Objetivos: graphic review of what is known to date about the relationship between
Objectives:
Material y métodos: Se realizó una búsqueda exhaustiva de la literatura Materials and methods: a comprehensive literature search was conduc-
-
andrología durante el período de pandemia. Todos los trabajos presentan logy during the pandemic period. All the studies show a small sample
un tamaño muestral pequeño y con corto tiempo de seguimiento, por lo
que es difícil sacar conclusiones al momento. the moment.
Conclusiones: Conclusions: there is no conclusive information to state that the virus
se encuentra en el semen y que puede transmitirse por vía sexual. Por lo is found in semen and can be transmitted sexually. Therefore, the man-
tanto, no está establecido el uso obligatorio de preservativo durante la datory use of condoms during the pandemic is not established. So far
leading to hypogonadism and infertility, but the potential risk should not
esterilidad, pero no se debe ignorar el riesgo potencial. be ignored.
Palabras clave: Key words:
Recibido en febrero de 2021.- Aceptado en enero de 2022 Received on February 2021 - Accepted on January 2022
Correspondencia:
martina.sole@hospitalitaliano.org.ar
INTRODUCCIÓN a nosotros nos importa esta vez es la ECA2 (Enzima
A finales de 2019 en Wuhan (China), surgió un Convertidora de Angiotensina II), que su principal
nuevo coronavirus altamente contagioso, denomi- función es convertir la angiotensina II en angioten-
nado SARS-CoV-2 (Síndrome agudo respiratorio sina 1-7 para regular negativamente el SRAA (siste-
severo). ma renina-angiotensina-aldosterona) para lograr un
equilibrio, ya que la angiotensina 1-7 genera, princi-
Se declaró como pandemia, por la OMS, el 11 de
palmente, vasodilatación.3
marzo de 2020.1,2
La ECA2 se encuentra en la membrana plasmáti-
A medida que fue avanzando la pandemia, hemos
ca, principalmente en los pulmones, corazón, intesti-
empezado a conocer al virus que nos enfrentamos,
no, riñones, testículos, entre otros. Se coexpresa junto
pero en varios aspectos aún no se han podido sacar
a la serina proteasa transmembrana 2. Ambas per-
conclusiones determinantes. Es por ello que realiza-
miten la entrada del covid-19 al interior de la célula
mos una revisión bibliográfica de lo que se sabe hasta
por el siguiente mecanismo: la proteína S (Spike) del
el momento sobre la relación entre el covid-19 y la
covid-19 se une a la ECA2, que la utiliza de receptor.
andrología.
Una vez unida, la proteasa transmembrana modifica
Nuestro objetivo es analizar la relación entre: esa unión de una manera que permite la fusión entre
• Covid-19 y el testículo. la membrana viral y la membrana celular del indivi-
• Covid-19 y el semen. duo. De esta forma, el virus puede ingresar a la célula
• Covid-19 y hormonas sexuales masculinas. humana. Este es el mecanismo planteado por el cual
se cree que el virus puede ingresar al testiculo.2
4
SARS-CoV-2: origen, estructura, replicación y
MATERIALES Y MÉTODOS
patogénesis. José Eduardo Oliva Marín. Abril de 2020
Se realizó una búsqueda exhaustiva de la literatura en
En el trabajo publicado por Kharbach Youssef y
la base de datos de PubMed sobre trabajos que abordan
Khallouk Abdelhak, se comenta que hay alrededor
covid-19 y andrología durante el período de pandemia.
de 27 virus con capacidad de ingresar al testículo y
Un revisor realizó una selección de los títulos y alterar su función. Entre los más conocidos están el
los resúmenes, basados en los objetivos de esta revi- zika, el paramixovirus (el virus que provoca paperas),
sión. El mismo investigador revisó, de forma inde- el HIV y el SARS- CoV-1. El SARS.CoV-2, o sea
pendiente, la versión de texto completo de los artícu- el actual coronavirus, tiene una estructura 85% idén-
los para confirmar su elegibilidad para la inclusión. tica al SARS-CoV-1, por lo cual se cree que puede
ingresar al testículo con el mismo mecanismo que
RESULTADOS utiliza el SARS.CoV-1. Sin embargo, el covid-19
Covid-19 y su relación con el testículo tiene entre 10 a 20 veces más afinidad por el ECA2
que utiliza como receptor celular.
El angiotensinógeno es una glicoproteína sinteti-
zada principalmente por el hígado que, por medio de Los dos mecanismos de daño testicular que este
la renina, se convierte en angiotensina I. Luego, por trabajo plantea son:
medio de la ECA (Enzima Convertidora de Angio- • La temperatura alta persistente: puede gene-
tensina), se transforma en angiotensina II, que se- rar un daño en la barrera hematotesticular y,
gún a qué receptor se una va a cumplir determinada como consecuencia, dañar la función testicu-
función. Por ejemplo, cuando se une al receptor 1, lar, tanto la producción de testosterona por las
cumple la función más conocida de la angiotensina células de Leydig como la espermatogénesis.
II, que es la de vasoconstricción; además, estimula la • Daño testicular producido por orquitis au-
liberación de aldosterona para la reabsorción de agua toinmune, secundaria a la reacción generada
y sodio, y así elevar la presión arterial. La enzima que por el virus.5,6
66
Otro trabajo de Yang, M y colaboradores, utili- cable al actual coronavirus, ya que dijimos, anterior-
zaron microscopía electrónica, inmunohistoquímica mente, que tienen una estructura idéntica en el 85%
y RT-PCR para detectar COVID-19 en el tejido con el SARS-CoV-1.
testicular de 12 pacientes postmortem. La media de Por último, con respecto a la relación del co-
edad fue de 65 años. Se observó que dos pacientes vid-19 y el testículo, vemos la opinión de la Aso-
tenían daños leves de las células de Sertoli; 5 pa- ciación Española de Andrología, Medicina Sexual y
cientes, daño moderado; y 4, graves. Con respecto Reproductiva, de la mano de Ferran García, J. y cola-
a las células de Leydig, se vio que los pacientes que boradores, que siguen con la misma línea hasta ahora
padecían covid-19 tenían una cantidad significativa- planteada, donde creen que la respuesta autoinmune
mente menor que en el grupo control (pacientes que e inflamatoria generada por el virus altera la barre-
se habían realizado una orquiectomía por diferentes ra hematotesticular, dando lugar a una orquitis que
causas). Por PCR se detectó virus solamente en 1 de puede dañar el tejido testicular. Ellos recomiendan
los 12 pacientes. Con respecto a esto, dijeron que era a todo paciente que vaya a criopreservar espermato-
un paciente con gran carga viral, que en el testículo zoides, ya sea para tratamiento de fertilización asis-
tenía pocos túbulos seminíferos y mucho tejido fi- tida o por tratamiento oncológico, y que le realicen
brovascular, por lo que piensan que la PCR positiva PCR a las muestras de semen. En caso de detectar
fue tomada de sangre y no de tejido testicular. Por virus, sugieren esperar para repetir el procedimien-
último, evaluaron 3 de estos 12 pacientes con mi- to hasta una vez finalizada la pandemia.9 Esto en la
croscopía electrónica y no hallaron partículas virales. práctica diaria no se realiza, ya que no hay evidencia
La espermatogénesis, en todos los casos, estaba den- clara que justifique esta práctica.
tro del rango normal.7
La publicación de Chuan Huang y colaboradores Covid-19 y el semen
ratifica la teoría que la entrada del virus al testículo Como datos positivos que relacionan al Covid-19
es mediante la unión del covid-19 a la ECA2 y la con el semen, encontramos:
serina proteasa transmembrana 2, la cual permite la Un estudio chino encabezado por Diangeng Li
fusión de membranas que también se expresan en las evaluó el semen de 38 pacientes para identificar la
espermatogonias y en las cel de Leydig. Por lo tanto, presencia o no de covid-19. 15 pacientes estaban
pueden alterar su función secretora y la fertilidad.8 en etapa aguda de la infección (no aclara si esta-
Luego, la carta al editor de Anis Abobaker y Ali ban hospitalizados). Se encontró, en 4 muestras de
Ahmed Raba recuerda un trabajo del año 2002, don- las 15 obtenidas, presencia de covid-19. Luego, de
de estudiaron los testículos de 6 personas fallecidas 23 pacientes recuperados de la infección se encon-
por SARS-CoV-1. En las 6 encontraron orquitis, tró covid-19 en dos de esas muestras. Por lo tanto,
pero no hallaron virus, por lo que hace pensar que plantean que esto se debe a una imperfección de la
el daño es secundario a la respuesta inmunológica barrera hematotesticular secundaria a la inflamación
e inflamatoria, y no por daño directo sobre el tejido generada por dicho virus.10 Este trabajo fue muy cri-
testicular. Esta teoría sobre el SARS-CoV-1 es apli- ticado, ya que es de los pocos que nombran presencia
Rev. Arg. de Urol. . Vol. 86 (2) 2021 (65-71) 67
del virus en semen. No especifica si la muestra de tardaron más de 90 días. Se observó una disminu-
semen fue tomada por masturbación o electroesti- ción estadísticamente significativa de la concentra-
mulación; tampoco dice con qué técnica se estudió el ción total de espermatozoides en el grupo que tardó
semen para identificar al covid-19. Se interpreta que más de 90 días en recuperarse, en comparación con
el frasco estéril de recolección de la muestra podría los que tardaron menos.
estar contaminado por Gotitas de Flügge de los pa- El perfil hormonal de estos pacientes, fue total-
cientes infectados mientras tomaban la muestra de mente normal. Como conclusión, resuelven que no
semen. Por lo tanto, este trabajo no es una fuente hay afectación urogenital directa en los pacientes en
confiable.11,12 recuperación analizados. No se encontró ARN viral
Un estudio retrospectivo de Shufa Zheng y col. en las muestras estudiadas. A su vez, la calidad del
Estudió muestras respiratorias, de materia fecal, sue- semen disminuyó levemente, mientras que los perfi-
ro y orina de 98 pacientes, donde la media de edad les hormonales se mantuvieron normales.14
fue de 55 años. 22 de ellos tenían enfermedad leve Un trabajo publicado en la revista Fertility and
y 74 pacientes, enfermedad grave. Observaron pre- Sterility, liderado por Feng Pan, evaluaron muestras
sencia de covid-19 en el 100% de las muestras res- de semen de 34 pacientes recuperados de covid-19
piratorias, 59% en materia fecal, 41% en suero y solo que tuvieron síntomas leves a moderados. 6 de estos
1.04% en orina, ya que solo se detectó virus positivo pacientes, presentaron malestar testicular, sugestivo
en un solo paciente con enfermedad crítica en el día de orquitis viral en el momento de la infección.
10 de la infección.13 Esto hace creer que también es
No se detectó covid-19 en ninguna muestra de
una muestra contaminada.
semen después de una mediana de 31 días entre
Por otro lado, como datos negativos para la rela- la confirmación de la infección hasta la toma de la
ción covid-19 y semen, vemos este estudio de Yajun muestra.15
Ruan publicado en la revista Andrology, el estudio
con mayor tamaño muestral. Evaluaron la presencia
de covid-19 en muestras de orina, secreción prostáti-
ca y semen de pacientes ya recuperados; todas fueron
muestras analizadas por PCR. También evaluaron
la calidad del semen y los niveles de hormonas. En
total eran 74 pacientes con un rango etario de 20
a 50 años. Fueron divididos, según la gravedad de
la enfermedad, en leve, moderado, severo y críticos.
También se dividieron, según el tiempo de recupe-
ración, en menos de 90 días y más de 90 días. En
los resultados, se observaron que todas las muestras
de orina, secreción prostática y semen fueron nega-
tivas para covid-19. Con respecto a la calidad del
semen, se detectó que en los pacientes que tuvieron
Covid-19 hubo una disminución significativa de la
concentración de espermatozoides total y por ml,
al igual que la movilidad total, en comparación con
el grupo control. Más allá de esto, los resultados de
los pacientes que tuvieron covid-19 están dentro del
rango normal que se espera para un espermograma.
Por otro lado, habían dividido a los pacientes en los
que se recuperaban en menos de 90 días y los que
68
Por último, una carta al editor publicada en la enfermedad. Un dato importante a destacar es que,
revista Biology of Reproduction, comenta una publi- en este trabajo, a dos pacientes a quienes también
cación que evaluaron el semen de 12 pacientes recu- les midieron las hormonas no los incluyeron en el
perados de covid-19. En ninguna muestra se detectó estudio porque finalmente fallecieron, pero observa-
Covid-19. También evaluaron los testículos de un ron niveles de testosterona bajos: 0,51 y 0,45 ng/ml
paciente de 67 años fallecido por Covid-19 y no en- respectivamente.17
contraron virus por PCR.16 Para finalizar con la revisión, en el trabajo de
Rastrelli, G., realizado en la ciudad de Lombardía,
Covid-19 y hormonas sexuales masculinas se midió testosterona total y libre, LH y globulina
Un trabajo encabezado por Yajun Ruan habla de fijadora de hormonas sexuales en 31 pacientes inter-
la relación de las hormonas sexuales y los pacientes nados por covid-19. Los dividieron en 4 grupos se-
infectados por covid-19. La media de edad de los gún su gravedad: los que estaban internados en sala
pacientes fue de 60 años. Midieron hormonas sexua- general, los que fueron a terapia intermedia, los que
les en 39 pacientes internados por COVID-19 y las necesitaron UTI (unidad de terapia intensiva), que
compararon con 22 internados por otras patologías. estaban todos con asistencia respiratoria mecánica;
Todas las muestras fueron tomadas por la mañana y los que fallecieron.18Ellos graficaron, que tanto la
junto al laboratorio de rutina. No se observaron di- testosterona total como la libre, descienden a medida
ferencias significativas entre los grupos en compa- que se agrava la enfermedad.
ración.
También los dividieron según la severidad de la
infección. A los leves y moderados los pusieron en el
mismo grupo llamado “Moderado”, el cual represen-
taba a 20 pacientes. Bajo el título de “Severo” estaban
los que tenían enfermedad severa y crítica, que eran un
total de 19 pacientes. Observamos que no hay ningu-
na diferencia estadísticamente significativa en el valor
de testosterona, FSH (hormona folículoestimulante),
LH (hormona luteinizante), prolactina, estradiol y re-
lación testosterona/LH entre el grupo con enferme-
dad severa y los que tienen enfermedad moderada.
A estos mismos pacientes los dividieron según el
tiempo de infección. Si tenían covid-19 por más de
50 días, estaban en el grupo de “Positivos por largo
tiempo”; si la infección duró menos de 50 días, esta-
ban en el grupo de “Normales” (se consideró desde
que comenzaron los síntomas hasta que el hisopado
nasofaríngeo fue negativo por PCR). Solo se observó
resultado significativo en los pacientes de infección
por largo tiempo, tenían menor nivel de estradiol.
Concluyen que los hombres infectados por Co-
vid-19: la mayoría de las hormonas sexuales perma- También observaron que la testosterona total y
necen dentro de los rangos de referencia. Y no se libre desciende sus valores de manera significativa a
observaron asociaciones significativas entre los nive- medida que la infección por covid-19 empeora.18
les de testosterona y la duración o gravedad de la
Rango de referencia Sala n= 21 UTIM n=6 UTI/ fallecidos n=4 p
Testosterona total
8.6-29 8.8 (4.1-16.2) 5.0 (1.8-7.6) 1.0 (0.2-1.9) 0.005
(nmol/L)
Testosterona libre cal.
<225 146.5 (93.8-287.0) 118.0 (40.8-133.5) 17.5 (5.8-37.0) 0.006
(pmol/L)
SHBG (nmol/L) 18.3-54.1 35.6 (22.0-59.0) 24.0 (19.6-37.4) 21.3 (12.2-39.6) 0.159
LH (U/L) 1.7-8.6 6.6 (4.6-9.6) 16.3 (7.9-20.3) 11.2 (9.0-19.3) 0.043
Concluyen que obsevaron disminución estadísti- No hay información contundente para afirmar que
camente significativa de testosterona total y libre en el virus se encuentra en semen y puede transmitirse
pacientes con enfermedad más grave y que la tes- por vía sexual. Por lo tanto, no está establecido el uso
tosterona total y libre, pueden ayudar a predecir el obligatorio de preservativo durante la pandemia.
riesgo de infección mortal por COVID-19.18 Al presente, no hay evidencia directa para con-
firmar que el COVID-19 causa lesión testicular que
CONCLUSIÓN conduzca al hipogonadismo y a la esterilidad, pero
no se debe ignorar el riesgo potencial.
Todos los trabajos presentan un tamaño muestral
pequeño y corto tiempo de seguimiento, por lo que
es difícil sacar conclusiones al momento.
70
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net].2019[Citado 2021] Disponible en: https:// male fertility?. World J Urol 39, 975–976 (2021).
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ronavirus-2019?gclid=Cj0KCQiA0-6ABhD- 10. Li, D., Jin, M., Bao, P., Zhao, W. Zhang, S. Cli-
MARIsAFVdQv-_pLirXeUIDRMrQgT8YX- nical Characteristics and Results of Semen Tests
vqM4sB-XcjXR0NjL0rk1vnjr wbsljEeZ- Among Men With Coronavirus Disease 2019
MaAkUhEALw_wcBHYPERLINK JAMA Netw. e208292 (2020).
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Int. J. Morphol.,
40(2):474-479, 2022.
Actualización sobre COVID-19 e Histofisiología

del Sistema Reproductor Masculino
Update on COVID-19 and Histophysiology of the Male Reproductive System
Javier Gutiérrez-Martín1; Laura Robles-Gómez1; Paula Sáez-Espinosa1 & María José Gómez-Torres1,2
GUTIÉRREZ-MARTÍN, J.; ROBLES-GÓMEZ, L.; SÁEZ-ESPINOSA, P. & GÓMEZ-TORRES, M. J. Actualización sobre

COVID-19 e histofisiología del sistema reproductor masculino. Int. J. Morphol., 40(2):474-479, 2022.
RESUMEN: La reciente pandemia de la COVID-19 ha sacudido a la sociedad teniendo una importante repercusión en el campo
de la salud y de la investigación. Dada su relevancia, se han llevado a cabo estudios sobre los efectos del SARS-CoV-2 en la fisiología
humana. En concreto, sobre la posible presencia y transmisión del virus a través del sistema reproductor masculino y su posible efecto en
el éxito reproductivo. Conocer si la presencia del virus altera los órganos responsables del desarrollo y maduración de las células de la
serie espermatogénica podría revelarnos su implicación en la calidad seminal. Por ello, nos planteamos esta revisión, con el fin de
analizar las principales evidencias científicas sobre los efectos del SARS-CoV-2 en la histofisiología del sistema reproductor masculino
y sobre la capacidad fecundante de los espermatozoides.
PALABRAS CLAVE: COVID-19; Espermatozoides humanos; Esterilidad masculina; Fragmentación del ADN; Semen.
INTRODUCCIÓN
En diciembre de 2019 fueron notificados numerosos como receptor de la proteína S del SARS-CoV-2, que junto
casos de neumonía grave en la ciudad de Wuhan, China. a la serin proteasa transmembrana 2 (TMPRSS2) actúa como
Posteriormente, se reveló que dichos casos habían sido pro- receptor activador (Lin et al., 2020). La presencia de ECA2
vocados por el virus nombrado como SARS-CoV-2 (del in- en diferentes tejidos del organismo supone la vía de entrada
glés, Severe Acute Respiratory Syndrome Coronavirus-2) del virus en diferentes fluidos que podrían suponer otras vías
(Wu & McGoogan, 2020). Las glucoproteínas presentes en de transmisión aparte del contacto directo por el aire. La
la envoltura que rodea el material genético son denomina- presencia del SARS-CoV-2 en el líquido seminal podría plan-
das proteínas Spike (S) y constituyen la vía de entrada del tear una posible transmisión sexual, ya que las células
virus a las células del huésped. Dichas glucoproteínas pue- intersticiales (célas de Leydig - CL)), las células
den ser detectadas mediante la técnica RT-PCR (del inglés, sustentaculares (células de Sertoli - CS) y las espermato-
Reverse Transcription Polymerase Chain Reaction). Los sín- gonias expresan ECA2. Esto supone una posible vía de en-
tomas de la enfermedad van desde fiebre, tos, congestión na- trada del virus en el testículo, alterando la espermatogénesis
sal o disnea, hasta poder evolucionar en una neumonía atípica, y suponiendo una reducción de la fertilidad masculina
requiriendo hospitalización. Dada la elevada transmisibilidad (Segars et al., 2020).
de la enfermedad a partir de aerosoles por contacto directo
entre personas, la COVID se ha expandido a lo largo de los La espermatogénesis es el proceso por el cual se for-
países siendo declarada en marzo de 2020 como una pandemia man los espermatozoides, iniciándose en la pubertad y con-
global por la Organización Mundial de la Salud (2020). tinuando a lo largo de toda la vida del individuo. Dicho pro-
ceso tiene lugar en las paredes del túbulo seminífero, donde
Principalmente, este virus afecta al aparato respira- se encuentran las CS, formando la barrera hemato-testicular,
torio, pero numerosos estudios señalan que la entrada del y las células de la serie espermatogénica, constituyendo to-
virus en las células del huésped reside en la enzima dos estos componentes celulares el epitelio seminífero. Ad-
convertidora de angiotensina 2 (ECA2), puesto que actúa yacentes a los túbulos seminíferos se hallan las CL agrupa-
1
Departamento de Biotecnología, Facultad de Ciencias, Universidad de Alicante, Alicante, España.
2
Cátedra Human Fertility, Universidad de Alicante, Alicante, España.
Received: 2022-01-14 Accepted: 2022-02-24
474
GUTIÉRREZ-MARTÍN, J.; ROBLES-GÓMEZ, L.; SÁEZ-ESPINOSA, P. & GÓMEZ-TORRES, M. J. Actualización sobre COVID-19 e histofisiología del sistema reproductor masculino.
Int. J. Morphol., 40(2):474-479, 2022.
das en clusters. Éstas llevan a cabo la síntesis de testosterona, cuentran en WOS (86), seguido de Scopus (63) y Pubmed
necesaria para el desarrollo de los caracteres sexuales se- (48). A continuación, se exponen los principales aspectos
cundarios y el mantenimiento del epitelio seminífero (Zhou evidenciados en estos artículos revisados, desarrollados en
et al., 2019). En general, la espermatogénesis consta de tres las diferentes secciones.
fases cuya duración es de 74 días, repitiéndose de manera
cíclica. En primer lugar, la fase espermatogónica, caracteri- Alteraciones hormonales y de la calidad espermática. Las
zada por una serie de divisiones mitóticas por parte de las hormonas sexuales esteroideas pueden ser utilizadas para
espermatogonias para dar lugar a los espermatocitos prima- evaluar el estado de la gónada masculina. Ma et al. (2021)
rios diploides. A continuación, durante la fase evaluaron el nivel sérico de hormonas sexuales masculinas
espermatocítica, los espermatocitos primarios atraviesan la en 81 pacientes infectados por SARS-CoV-2 en edad
barrera hemato-testicular para sufrir una primera división reproductiva siguiendo este principio, comparándolos con
meiótica, dando lugar a los espermatocitos secundarios. Estos 100 pacientes sanos en edad reproductiva. Observaron que
últimos, tras tener lugar una segunda división meiótica, for- la hormona luteinizante (LH) aumentó significativamente,
man cuatro espermátides haploides. Finalmente, durante la pero la proporción de testosterona (T) hormona luteinizante
espermiogénesis, las espermátides sufren una serie de mo- (T/LH) y la proporción hormona folículo estimulante (FSH)
dificaciones hasta dar lugar a los espermatozoides maduros hormona luteinizante (FSH/LH) presentaban bajos niveles en
(Sharma et al., 2019). aquellos pacientes con COVID-19. Además, declararon que
los niveles séricos de LH y el descenso de T/LH podían ser
En base a lo expuesto anteriormente, en esta revi- debido a una disfunción testicular, al ser dañadas las CL. Este
sión nos planteamos realizar un análisis de los principales estudio ofrece la primera evidencia de la influencia del SARS-
trabajos científicos que hayan estudiado el posible impacto CoV-2 sobre los niveles de hormonas sexuales (Ma et al.).
del SARS-CoV-2 en la histofisiología del sistema
reproductor masculino, así como en la calidad espermática. En otro de los estudios realizados, Xu et al. (2021)
seleccionaron 39 hombres positivos en COVID-19, clasifi-
cados según la duración de la desaparición de la carga viral.
MATERIAL Y MÉTODO Los niveles de T se encontraban dentro de los límites fisio-
lógicos pero los niveles de estradiol estaban por encima de
los valores normales. En particular, en aquellos pacientes
La búsqueda bibliográfica se realizó mediante el uso en los cuales la duración de la desaparición de la carga viral
de combinaciones de palabras clave junto con operadores era menor de 50 días. Por ello, asociaron este fenómeno al
booleanos (COVID-19 and DNA fragmentation; COVID- daño celular causado por el virus, a una respuesta
19 and human sperm; COVID-19 and male infertility; inflamatoria elevada o bien, al uso de fármacos como
COVID-19 and semen;), en tres bases de datos diferentes: corticosteroides (Xu et al., 2021).
Scopus, Web of Science (WOS) y Pubmed. La selección de
las publicaciones se llevó a cabo de acuerdo con los siguien- Respecto a la calidad espermática, Holtmann et al.
tes criterios de inclusión: (2020) seleccionaron a 34 varones clasificados en tres gru-
pos: aquellos que habían dado positivo en la detección de
1. Artículos publicados en un periodo de tiempo compren- carga viral por RT-PCR y se encontraban en la fase aguda
dido entre el inicio de la pandemia y la fecha en la que se de la enfermedad, aquellos que habían superado los sínto-
realiza dicha revisión (diciembre 2019-abril 2021). mas y estaban en fase de recuperación y, a modo de control,
2. Artículos originales (Journal Articles) y revisiones hombres con RT-PCR negativa. De todos ellos se tomaron
(Reviews). muestras de semen, en las cuales no fue posible detectar la
3. Estudios publicados en inglés. presencia de SARS-CoV-2. Sin embargo, en aquellos casos
de pacientes que mostraban síntomas moderados se detec-
taron alteraciones de la calidad espermática (concentración,
RESULTADOS número total de espermatozoides por eyaculado, número total
de motilidad progresiva, número total de motilidad comple-
ta, etc) (Holtmann et al.).
Se obtuvieron un total de 78.333 publicaciones du-
rante la búsqueda inicial. Este número disminuyó hasta 89 Efectos patológicos en testículo y epidídimo. Desde el pun-
tras aplicar los criterios de inclusión. De estas 89 publica- to de vista histológico, es posible analizar los efectos pro-
ciones, 34 (38,2 %) eran artículos originales y 55 (61,8 %) vocados por el SARS-CoV-2 en el tejido testicular y
revisiones. Donde la mayoría de estas publicaciones se en- epididimario mediante biopsias. Por otra parte, a partir del
475
Int. J. Morphol., 40(2):474-479, 2022.
estudio de la expresión de la ECA2, es posible determinar si necrosis tumoral a) y MCP-1 (proteína quimioatrayente de
el testículo podría presentar un elevado riesgo de infección monocitos-1) (Li et al., 2020a).
por el virus. De esta forma, se ha conseguido demostrar que
dicho receptor se encuentra ampliamente distribuido en las Por otro lado, la evaluación del patrón de expresión de
células de la serie espermatogénica, las CS y las CL (Shen la ECA2 en células del epitelio testicular se realizó en un es-
et al., 2020). Mientras tanto, Pan et al. (2020) revelaron que tudio mediante técnicas de inmunofluorescencia. Achua et al.
sólo cuatro de las 6.490 células testiculares estudiadas pre- (2020) obtuvieron secciones de tejido testicular de seis pa-
sentaban los genes responsables para la síntesis de ECA2 y cientes fallecidos por COVID-19 y tres pacientes cuyo falle-
TMPRSS2. Por lo tanto, serían necesarias futuras investi- cimiento fue debido a otras causas, a modo de sujetos control.
gaciones para esclarecer la posible correlación entre la ex- La aplicación de inmunofluorescencia mostró cierta correla-
presión de ECA2 y la infección vírica, puesto que también ción entre una baja expresión de ECA2 en pacientes cuya
es necesaria la presencia de TMPRSS2 (Pan et al.). espermatogénesis era normal, y una elevada expresión de esta
en aquellos casos de pacientes cuya espermatogénesis se en-
Para determinar los efectos patológicos, Yang et al. contraba alterada (daños en las CS, hipospermia, arresto de la
(2020) examinaron mediante microscopía óptica (MO) y maduración temprana, etc). La relevancia del artículo recayó
técnicas inmunohistoquímicas a través de marcadores en la detección, mediante microscopía electrónica de trans-
linfocíticos e histiocíticos, el tejido testicular de 12 pacien- misión (MET), de partículas víricas, concretamente de pro-
tes fallecidos por COVID-19. Al analizar las imágenes de teínas Spike, en el tejido testicular de uno de los pacientes
los cortes histológicos observaron que las CS mostraban fallecidos por COVID-19 y de un paciente vivo diagnostica-
hinchazón, vacuolización y rarefacción citoplasmática, ade- do con COVID-19 (Achua et al.).
más de desprendimiento de la membrana basal y pérdida
del lumen de la masa celular intratubular. A diferencia de Presencia del SARS-CoV-2 en muestras seminales. La
las muestras control, el número de CL era significativamente posible presencia de partículas víricas en el semen huma-
menor. Adicionalmente, en el espacio intersticial se detec- no ha causado una gran preocupación en la comunidad cien-
taron edemas e infiltrados inflamatorios leves compuesto tífica, en cuanto al riesgo de transmisión sexual, y el peli-
por linfocitos T e histiocitos. Este trabajo proporciona un gro que podría suponer al realizar técnicas de reproduc-
mejor entendimiento de los efectos del virus sobre el tejido ción asistida. Este tema se continúa investigando actual-
testicular a nivel histológico (Yang et al.). mente y existe bastante controversia entorno al mismo.
Song et al. (2020) publicaron el primer estudio relaciona-
Li et al., revelaron mediante técnicas de do con la detección del virus en el semen humano. Se ob-
inmunohistoquímica alteraciones del tejido del túbulo tuvieron muestras de 13 pacientes de entre 22 y 38 años.
seminífero y epidídimo que podrían haber sido provocadas En ninguna de las muestras seminales analizadas mediante
por la infección vírica. Examinaron tejido testicular y RT-PCR se encontró ARN viral pese a que los pacientes
epididimario de seis pacientes fallecidos por COVID-19. Al siguieran siendo positivos en COVID-19 durante el perio-
analizar los cortes histológicos observaron edema en la par- do de estudio. Se afirmó que no había sido posible la de-
te intersticial, congestión, infiltración de eritrocitos en testí- tección del mismo en la fase aguda, así como durante la
culos, y en epidídimo. También, se pudo observar un estre- fase de recuperación de la enfermedad (Song et al.).
chamiento de los túbulos seminíferos y un mayor número
de células apoptóticas en pacientes con COVID-19 en com- Posteriormente, un grupo de investigación italiano
paración con los casos control. Además, fueron detectados (Paoli et al., 2020), en un varón voluntario de 31 años que
linfocitos T y macrófagos en las células intersticiales del había dado positivo en COVID-19 analizó muestras de se-
tejido testicular, junto a un incremento de Inmunoglobulina men y orina 8 días más tarde de ser diagnosticado. Con el
G en el interior de los túbulos seminíferos en pacientes con objetivo de detectar los genes virales S, los cuales codifican
COVID-19. Por otro lado, seleccionaron a 23 pacientes que para las glicoproteínas Spike y E codifican para la
se encontraban en fase de recuperación de la enfermedad de glicoproteína de envoltura pequeña se utilizaron técnicas de
un rango de edad similar al de los pacientes fallecidos. A RT-PCR a tiempo real. Sin embargo, no fue posible detectar
continuación, se llevó a cabo un análisis de los parámetros la presencia del virus. Desconociéndose si este hecho era de-
seminales de los mismos, mostrando 9 de ellos (39,1 %) bido a la recuperación del paciente o bien, el virus en ningún
oligozoospermia y los 14 restantes (60,9 %) presentaban una momento estuvo presente en dichos fluidos (Paoli et al.).
concentración elevada de leucocitos en el semen. Compa-
rándolo con sujetos control, mostraban una menor concen- Resulta de vital relevancia destacar los resultados ob-
tración espermática y un incremento de factores tenidos por Li et al., debido a la detección vírica en seis
inmunológicos IL-6 (interleucina-6), TNF-a (factor de muestras seminales de 38 pacientes estudiados diagnostica-
476
Int. J. Morphol., 40(2):474-479, 2022.
dos con COVID-19. De esas 6 muestras positivas, 4 corres- pubertad, y éstas de no ser por dicha barrera podrían ser reco-
pondían a pacientes que se encontraban en la fase aguda de nocidas por el organismo como agentes extraños y por tanto
la enfermedad y 2 a pacientes en fase de recuperación (Li et ser atacadas. Se ha demostrado que la entrada de agentes
al., 2020b). patógenos, como virus, al organismo desencadena una pro-
ducción elevada de citoquinas inflamatorias que pueden lle-
Más tarde, fue publicado un estudio realizado por gar a provocar respuestas autoinmunes y la infiltración de
Pan et al., donde muestras de semen fueron obtenidas de 34 leucocitos en el foco de inflamación, que finalmente afecta-
varones adultos, diagnosticados con COVID-19. En el mo- rían al tejido diana. Estos efectos podrían alterar el proceso de
mento de la extracción de la muestra éstos se encontraban espermatogénesis (Xu et al., 2006). En humanos diagnostica-
en fase de recuperación de la enfermedad (aproximadamen- dos con COVID-19 se ha notificado un aumento de IL-6 y su
te 31 días después de ser diagnosticados). Al llevar a cabo la receptor, presente en células testiculares, este hecho podría
detección de genes virales en el semen mediante RT-PCR, justificar aquellos casos en los que pacientes con COVID-19
no se obtuvieron evidencias de la presencia del virus en el manifestaban orquitis (Shen et al.).
mismo. No obstante, 6 de los pacientes mostraron molestias
escrotales relacionadas con la orquitis viral (Pan et al.). A Aquellos casos en los que el estado de la barrera
diferencia de este último, en el estudio de Holtmann et al. hemato-testicular es defectuoso, se pueden formar anticuerpos
los 34 pacientes fueron clasificados en tres grupos: aquellos anti-espermatozoides (ASA). Éstos se encuentran estrecha-
recuperados de la enfermedad que habían dejado de presen- mente relacionados con casos de esterilidad masculina al pro-
tar síntomas en un intervalo de 8-54 días, pacientes en fase vocar alteraciones en la motilidad y concentración espermática
aguda de la enfermedad y pacientes no diagnosticados con (Cui et al., 2015). Puesto que las CS expresan ECA2, el virus
la enfermedad como sujetos control. Como resultado, en al penetrar por esta vía desencadena una respuesta autoinmune,
ninguna de las muestras seminales se pudo detectar carga que provoca la síntesis de ASA, alterando finalmente la
viral mediante RT-PCR. espermatogénesis (Archana et al, 2019). También, los casos
de orquitis provocan un aumento de la síntesis de ASA como
Respuesta Autoinmune. La barrera hemato-testicular for- consecuencia de dicha inflamación (Xu et al., 2006).
mada por las CS supone una defensa de los gametos frente a
respuestas autoinmunes. Puesto que la síntesis de las células Asimismo, la túnica vaginal mantiene la temperatu-
de la serie espermática se produce de forma continua desde la ra de los testículos entre dos y tres grados por debajo de la
corporal. Cuando tiene lugar la in-
fección por SARS-CoV-2 uno de los
síntomas más frecuentes es la fiebre,
provocando un aumento de la tem-
peratura que puede afectar a la co-
rrecta formación de las células
germinales (Xu et al., 2006). Por otra
parte, cabe destacar la cascada de
mecanismos autoinmunes que tienen
lugar como consecuencia de la infec-
ción por SARS-CoV-2, resultando en
una posible esterilidad inmunológica
(Fig. 1).
Fragmentación del material

genético de los espermatozoides.
Algunos casos de esterilidad mascu-
lina son causados por anomalías
morfológicas o parámetros seminales
que pueden ser estudiados mediante
el examen macroscópico y micros-
cópico del seminograma convencio-
Fig. 1. Representación esquemática de los efectos del SARS-CoV-2 sobre el aparato nal. No obstante, algunos casos pue-
reproductor masculino. ARM: aparato reproductor masculino; IL-6: interleucina-6; den ser debidos a alteraciones del ma-
TNF-a: factor de necrosis tumoral a; ASA: anticuerpos anti-espermatozoides. terial genético del espermatozoide. El
477
Int. J. Morphol., 40(2):474-479, 2022.
estudio de la fragmentación del ADN espermático supone son fruto de las limitaciones de los ensayos realizados. Por
un análisis que garantiza el correcto estado del material una parte, el reducido número de individuos seleccionados
genético de los gametos y, por tanto, el potencial éxito para el estudio (tamaño muestral), la heterogeneidad en la
reproductivo. Estas técnicas basadas en el índice de frag- edad de los sujetos, el historial de los pacientes o los facto-
mentación del ADN han ido ganando relevancia como una res exógenos pueden alterar las conclusiones. Del mismo
herramienta en el diagnóstico de la esterilidad masculina modo, cabe señalar el nivel de carga viral en cada paciente,
(Santi et al., 2018). A su vez, existen diferentes factores que la gravedad de los síntomas, o la dificultad y en ocasiones la
pueden causar la fragmentación del ADN celular y suponer imposibilidad de extraer la muestra seminal de los pacien-
un riesgo para la fecundación. Entre ellos, destacan la tes durante la enfermedad, como factores a tener en cuenta.
apoptosis y una concentración elevada de especies reactivas Por otra parte, los estudios analizados afirman la necesidad
de oxígeno (ROS), como consecuencia de una temperatura de tomar nota del número de días tras la recuperación de la
testicular elevada, fármaco o infecciones (Cissen et al., enfermedad en el momento de la extracción de la muestra
2016). Además, varios estudios han demostrado que la in- sumado a un seguimiento del paciente (Song et al.).
fección por agentes patógenos como virus pueden provocar
la fragmentación del ADN (Tangal et al., 2019). En general, la posibilidad de transmisión sexual del
virus y en concreto la alteración de la espermatogénesis han
Teniendo en cuenta la capacidad de algunos virus de alertado a las instituciones más relevantes del área de la
dañar el material genético y el desarrollo de técnicas capa- medicina reproductiva. Estas instituciones han tomado me-
ces de calcular el índice de fragmentación del ADN, cabe la didas de prevención con el objetivo de mejorar la detección
posibilidad de añadir a los análisis convencionales que se de partículas víricas en las muestras durante los tratamien-
realizan de muestras de semen (seminograma y detección tos de fertilidad, así como, minimizar el riesgo de contami-
de carga viral por RT-PCR); estudios del índice de fragmen- nación durante los tratamientos de criopreservación (Porcu
tación del ADN. Esto desempeñaría un papel importante en et al., 2021).
la investigación de los posibles efectos que tiene el SARS-
CoV-2 sobre la esterilidad masculina. Estudios previos han
observado que la inflamación provocada por la infección CONCLUSIONES
vírica puede causar un aumento de ROS que dañarían el
ADN espermático. Además, el estrés oxidativo puede alte-
rar la calidad espermática, principalmente la motilidad, pro- Numerosos estudios pretenden aclarar el mecanismo
vocando daño oxidativo intracelular a los espermatozoides de acción del SARS-CoV-2, así como las secuelas que puede
por la peroxidación lipídica de sus membranas, fragmenta- provocar la COVID-19. Dada esta preocupación, nace la ne-
ción del ADN espermático e inducción de vías apoptóticas cesidad de analizar sobre qué aparatos es capaz de afectar, a
(Haghpanah et al., 2021). parte de las vías respiratorias. Una vez identificados en el
aparato reproductor masculino (ARM) los elementos
moleculares implicados en la entrada e infección del SARS-
DISCUSIÓN CoV-2, podría suponer la transmisión sexual del mismo. No
obstante, sólo en uno de los estudios realizados hasta la fecha
ha sido posible la detección de partículas virales en muestras
Pese a la variedad de publicaciones consultadas, hasta seminales. Gracias a las técnicas de MO y MET ha sido posi-
el momento en el que se realiza esta revisión ninguno de los ble demostrar la presencia del virus y sus efectos en el siste-
autores e instituciones han logrado obtener pruebas lo sufi- ma genital masculino. La infección vírica podría provocar
cientemente concluyentes sobre los efectos perjudiciales que casos de esterilidad masculina al causar daños en diferentes
supone la presencia de carga viral en el aparato reproductor partes del ARM, desde la alteración de los niveles de hormo-
masculino y que podría representar un reservorio del virus. nas sexuales masculinas e histopatologías a nivel del tejido
Es más, de todos los estudios llevados a cabo sólo en uno de testicular y epididimario; hasta el desencadenamiento de una
ellos (Li et al., 2020a,b) ha sido posible detectar carga viral respuesta autoinmune junto con el estrés oxidativo que ter-
en el semen humano, tras seguir una metodología similar minaría dañando el material genético de los espermatozoides.
(detección por RT-PCR), generando bastante controversia Por lo tanto, existen evidencias significativas de su implica-
entre la comunidad científica. ción en la alteración de la función de la gónada masculina.
Sin embargo, es necesario continuar investigando para un
La realización de esta revisión bibliográfica nos ha mejor entendimiento de los efectos del virus sobre los órga-
permitido destacar que las controversias y las diferencias nos sexuales masculinos, además de esclarecer cómo esta
entre las conclusiones obtenidas en los diferentes estudios enfermedad podría afectar a los parámetros de fertilidad.
478
Int. J. Morphol., 40(2):474-479, 2022.
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P.; Zhang, X.; Xiong, C.; et al. No evidence of severe acute respiratory
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Antonelli, G.; Lenzi, A. & Lombardo, F. Study of SARS-CoV-2 in semen
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Porcu, E.; Tranquillo, M. L.; Notarangelo, L.; Ciotti, P. M.; Calza, N.; Zuffa, S.;
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presence and transmission of the virus through the male reproductive of viral contamination during vitrification and storage especially in the
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62, 2021. C.P: 03080
Organización Mundial de la Salud (OMS). Alocución de Apertura del Director
Alicante
General de la OMS en la Rueda de Prensa sobre la COVID-19 celebrada el
11 de marzo de 2020. Ginebra, Organización Mundial de la Salud, 2020. ESPAÑA
Disponible en: https://www.who.int/es/director-general/speeches/detail/who-
director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---11-
march-2020 E-mail: mjose.gomez@ua.es
479
| |
DOI: 10.1111/andr.12907
1,2 1 1 1,2 2
| | | | |
1,2 1,2 1,2
| |
1
Institute of Reproductive and Stem Cell
Engineering, Basic Medicine College, Central
South University, Changsha, China In lately December 2019, a novel coronavirus (SARS-CoV-2) outbreak occurred in
2
Reproductive and Genetic Hospital of
Wuhan, PR China. It is a high contagious virus that has threatened human health
CITIC-Xiangya, Changsha, China
worldwide. SARS-CoV-2 infection, termed COVID-19, causes rapidly developing lung
lesions that can lead to multiple organ failure in a short period. Whenever a novel
Wenbing Zhu, PhD, Reproductive & Genetic
Hospital of CITIC-Xiangya. No. 87, Xiangya virus emerges, reproductive risk assessments should be performed after infection. In
Road, Changsha, Hunan 410008, China.
this review, we show that male fertility might be damaged by coronavirus associated
Email: zhuwenbing0971@sina.com
with (i) direct cytopathic effects derived from viral replication and viral dissemination
in the testis; and (ii) indirect damage to male fertility derived from immunopathol-
China Postdoctoral Science Foundation,
Grant/Award Number: 2019M661521 ogy. In this review, we briefly describe the impaired fertility of humans and animals
infected with coronaviruses to deduce the impact of the new coronavirus on male
fertility. Together with information related to other coronaviruses, we extrapolate
this knowledge to the new coronavirus SARS-CoV-2, which may have a significant
impact on our understanding of the pathophysiology of this new virus.
coronavirus, fertility, male, SARS-CoV-2, testis
| Regarding the critical molecule for SARS-CoV-2 transmission,

the receptor angiotensin I-converting enzyme 2 (ACE2) for virus cell
Coronaviruses are the largest family of positive-stranded RNA vi- entry and transmembrane serine protease 2 TMPRSS2 for priming
ruses, which includes 30 members at present. They are widely the S protein5 are co-expressed in the testis and male genital tract,6
distributed in nature, including infections of humans and other which suggests a high possibility that the virus targets the testis and
mammals. In recent years, new coronaviruses have caused problems male genital tract during infection. It was reported that over 25 vi-
worldwide in cycles, such as severe acute respiratory syndrome ruses could enter human semen and negatively affect spermatozoa
coronavirus (SARS-CoV) occurring in 2002, and Middle East respi- or male fertility,7 such as HSV 8 and HIV.9 Whether SARS-CoV-2 may
ratory syndrome coronavirus (MERS-CoV) being first identified in have the same the effect on males is an important question that was
2012. In 2019, a new highly contagious virus broke out in Wuhan, not answered unambiguously in a preliminary investigation.10
Hubei province, China, termed SARS-CoV-2, representing the sev- To date, studies 11-13 have confirmed the absence of SARS-CoV-2
1
enth member of enveloped RNA coronaviruses. The 2019 novel RNA in the semen of patients with COVID-19. Conversely, The results
coronavirus disease (COVID-19) caused by SARS-CoV-2 has com- of Li et al’s study were inconsistent with those of previous studies and
mon clinical manifestations such as fever, dry cough, and in severe detected of SARS-CoV-2 in 6 of 38 semen samples.14 Similarly, Yang
2-4
cases, multiple organ damage. et al reported that one case (1/12) with a high viral load was positive
Chuan Huang and Xiren Ji contributed equally to this work.
© 2020 American Society of Andrology and European Academy of Andrology
| wileyonlinelibrary.com/journal/andr Andrology. 2021;9:80–87.

HUANG et Al. |
for viral RNA after post-mortem examinations of testicular tissue,15 might result in testicular degeneration and male infertility. SARS coro-
which supported the idea that high viral loads in patients with severe naviruses, whose expressed proteins share 76% amino acid sequence
disease symptoms might reach the threshold to cross the blood-testis identity with those of SARS-CoV-2, were detected in testis somatic
barrier.16 On the other hand, a study showed that compared with pa- cells.36 This observation supports the hypothesis that the SARS-
tients with mild disease, patients with severe COVID-19 have signifi- CoV-2 might concentrate on testis cells to dysregulate their function.
17
cantly lower testosterone levels, suggesting that the co-expression
of ACE2 and TMPRSS2 on Leydig cells might make them susceptible
to SARS-CoV-2 infection and thus compromise testosterone secre- |
tion.18 However, considering the high false-negative results for SARS-
CoV-2 using RT-PCR,19 as well as the limitation of the small sample size Viral replication in cells contributes directly to microscopy-detected
and selection bias mostly obtained from recovering mild cases,10 we lesions, which eventually result in spermatogonia necrosis, 26 such as
still need to be cautious when evaluating these data. Nevertheless, in a ram model of infection by Bluetongue virus (BTV) (an arbovirus
it is well-known that coronaviruses can contribute to high morbidity of ruminants), which showed testicular parenchyma damage and the
20,21
and mortality in both humans and animals. A study has demon- destruction of the Sertoli cells caused by viral replication-induced
strated orchitis in patients with SARS, with detrimental effects in the cytopathic effects.37 Coronaviruses might use a similar mechanism
testis, suggesting that coronavirus can infect the male reproductive in humans to impair male fertility. ACE2 is the crucial determinant of
tract and impair male reproduction. 22 SARS-CoV-2 and SARS-CoV coronavirus infection, tissue tropism, and subsequent viral replica-
share some common clinical manifestations, which supports the hy- tion.38,39 The expression pattern of ACE2 in adult human testis at the
pothesis that the new coronavirus might directly infect the testes and level of single-cell transcriptomes was shown to be predominantly
male reproductive system. Therefore, we should be vigilant about enriched in Leydig and Sertoli cells.6 Besides, alternative receptor
the impact on male reproduction in patients with COVID-19. In addi- Basigin (BSG) and protease Cathepsin L (CTSL) were also detected in
tion, the blood-testis barrier might allow the testes to act as a special Leydig cells,40 which can mediate SARS-CoV-2 into cells. Data from
23
reservoir to protect viruses against antiviral agents, which is a key autopsies of 12 patients with COVID-19 showed a dramatic reduc-
reason for considering the testes as a particularly important organ tion in Leydig cells in the interstitium,15 supporting the speculation
for study in the context of the SARS-CoV-2 pandemic, and it is espe- that SARS-CoV-2 could display tropism for Leydig cells, ultimately
cially important because the coronavirus family has been identified leading to ultrastructural lesions and decreased numbers of Leydig
the culprit causing orchitis in both humans (SARS-CoV)22 and animals cells. Leydig cells occur in clusters between blood vessels and semi-
(feline coronavirus and avian coronavirus).24,25 Using evidence from niferous tubules, producing the vast majority of androgens in men.41
previous studies of coronavirus-infected animals and humans, the The replication of SARS-CoV-2 in testosterone-producing Leydig
implications of this review may help us to understand the impact of cells might disrupt testosterone production. Indeed, a recent study
SARS-CoV-2 on male reproductive capacity. confirmed that patients with COVID-19 suffered hypogonadotropic
hypogonadism as the disease the progressed, implying that the se-
cretory function of Leydig cells might be impaired by the novel coro-
| navirus.17 Testosterone is essential to preserve male fertility and to
support Sertoli cell maturation and the development of Leydig cells.42
Extensive evidence from clinical and laboratory studies implied that
Various viruses can replicate in the male reproductive tract, such as testosterone deficiency is accompanied by atrophy of the testicular
26 27,28
HEV and ZIKV, which eventually lead to testicular atrophy and parenchyma and degradation in the seminiferous tubules,43,44 and in
male infertility. Viral infection of the male genital tract can provide summary, testosterone is necessary for men to maintain the blood-
insights into possible male fertility impairment after SARS-CoV-2 testis barrier, spermatogenesis, and fertility. Alterations in male sex
infection. SARS-CoV-2 enters cells by binding ACE2 and via priming hormone levels induced by SARS-CoV-2 might negatively affect
by TMPRSS2. ACE2 is a membrane-associated secretase that is ex- male reproduction. Therefore, special attention should be paid to
pressed primarily on endothelial cells and is the host cell receptor for andrology examinations and hormone assessments on men recover-
SARS and SARS-CoV-2.29-31 Notably, ACE2 is highly tissue-specific, ing from COVID-19, as well as exploring the possible long-term out-
with significant levels being detected only in the heart, kidneys, tes- comes of SARS-CoV-2 infection.
32-34
tes, and gastrointestinal tract. In the testes, ACE2 is expressed Sertoli cells are the only somatic cells in the tubules that directly
only in spermatogenic cells and testis somatic cells, suggesting a high contact with spermatogenic cells and control the differentiation of
potential for testicular damage and spermatogenesis disruption when spermatogenic cells via paracrine signals.45 Inhibin B is secreted by
the virus combines with this metalloprotease.35 TMPRSS2, as an es- Sertoli cells, and compared with follicle-stimulating hormone (FSH)
sential protease for viral infection, is highly expressed in spermato- or luteinizing hormone (LH), it is an ideal marker for spermatogenesis
gonia and spermatids.18 The co-expression of ACE2 and TMPRSS2 and a better indicator of sterility.46,47 SARS-CoV-2 has a high affinity
in spermatogonia and Leydig cells implied that the testis might be for human ACE2, which suggests that the virus might concentrate
a high-risk organ that is vulnerable to SARS-CoV-2 infection, which on Sertoli cells. Indeed, inhibin B levels decreased after hepatitis E
| HUANG et Al.
virus infection in mice, which was attributed to damage of the Sertoli to determine whether SARS-CoV-2 can be sexually transmitted like
26
cells in the testes. Accumulating evidence suggests that the coro- IBV; however, the results will need to be cautiously interpreted.
navirus family has an affinity for these testes cells, for example, avian Nevertheless, we should remain vigilant to this possibility, which
infectious bronchitis virus (IBV), a subtype of coronavirus, can cause has important implications in reproductive medicine, especially viral
acute respiratory infections in birds,48 and was detected in Sertoli transmission facilitated by ART, such as intracytoplasmic sperm
49
cells of the testes of infected roosters using immunofluorescence. injection (ICSI),56 sperm cryopreservation, and the prevention of
Roosters vaccinated with live attenuated IBV showed significantly transmission. During this epidemic, sperm cryobank must introduce
reduced serum androgen concentrations compared with non-vacci- precautionary measures: First, we recommend that semen from
nated roosters and could cause infertility in roosters.50 Considering SARS-VOV-2-positive men is cryopreserved in a highly secure, sepa-
that IBV causes a similar severe acute respiratory syndrome to SARS- rate container, such as a vapor cryostorage tank. Secondly, all donors
CoV-2, we hypothesized that the same mechanism might be used by must undergo mandatory SARS-COV-2 testing. Thirdly, abstinence
SARS-CoV-2 to spread in Sertoli cells. In addition, roosters vaccinated or condom use might be considered as preventive measure for pa-
with live attenuated IBV might provide an animal model of how SARS- tients with COVID-19.
CoV-2 replicates in cells and causes pathogenic effects in the testis. Virus binding to ACE2-expressing spermatogonia would disrupt
Additionally, coronavirus might directly disrupt the microen- spermatogenesis.6 Rooster vaccination with coronavirus caused
vironment of the testis that supports spermatogenesis. In CoV- a significant reduction in daily sperm production. 25,57 A recent re-
infected roosters, histological analysis revealed the disruption of port also confirmed that semen quality parameters were impaired
seminiferous tubules and loss of the basement membrane, leading in patients with moderate infection of COVID-19.58 Hence, the risk
to the destruction of the spermatogenesis microenvironment, which of SARS-CoV-2 virus infection to semen parameters may not be neg-
contributed to the reduction of the live sperm concentration.51 Thus, ligible. Notably, the long-term impact on semen parameters of SARS-
testicular degeneration is possibly the result of several overlapping CoV-2 infection, as well as semen examination, is required during
factors once a coronavirus infects the male genital tract, and this follow-up patients recovering from COVID-19, especially men who
might also be the case for SARS-CoV-2. plan to have children.
| |
In animal models of coronavirus infection, one of the major clini-

Viruses can be detected in semen directly. SARS-CoV-2 RNA has been cal symptoms is epididymal stone formation.51,59,60 IBV replication
52
isolated from rectal swabs and respiratory tract swabs. Currently, in roosters’ testes might result in severe cellular micropathological
the question of whether the virus can infect semen needs an answer. damage, which in the long-term can lead to the presence of epididy-
According to a recent study of scRNA-seq data in adult human tes- mal stones. The presence of stones is associated with reduced fertil-
tes, ACE2 and TMPRSS2 are highly co-expressed in spermatogonia, ity and adverse effects on sperm function,61 eventually resulting in
which are enriched in the gene ontology (GO) categories relating the collapse of the seminiferous tubules and cessation of spermat-
to viral reproduction and transmission.6 Therefore, it is reasonable ogenesis. The epididymis is a crucial region for sperm maturation,
to hypothesize that there is a high risk of SARS-CoV-2 presence in which is pivotal for spermatozoa to obtain the motile ability and fer-
seminal fluid.53 However, a few case reports have investigated this tile capacity. Dysfunction in this area can compromise sperm matu-
issue, and the presence of SARS-COV-2 in semen remains ambigu- ration and further impair sperm quality, such as decreased sperm
ous.11-14 Notably, gene ontology (GO) enrichment analysis illustrated motility, increased DNA damage, changed membrane lipids, and the
that cell junction and immunity-related GO terms were enriched in acrosome reaction.62 If the behavior of coronavirus infection in hu-
ACE2-positive Leydig/Sertoli cells; therefore, cell-cell junctions might mans is similar to that in animal models, we should pay attention to
6
allow the transfer of SARS-CoV-2, which might represent one expla- the epididymis to protect it from SARS-CoV-2-induced destruction.
nation of the highly contagious nature of this novel coronavirus and In view of these results, we suggest prompting a comprehensive
could have implications for sexual and reproductive behavior.54 Taken genitourinary examination for patients with COVID-19, including al-
together, there is a critical need to verify virus infection semen and terations in semen parameters, such as the acrosome reaction, DNA
whether sexual transmission of SARS-CoV-2 can indeed occur. damage, and sperm motility.
With regard to research on coronavirus infection animals, IBV
has been isolated from testicles and semen in roosters, 51,55 and
when insemination using IBV-spiked semen was performed, IBV |
RNA could be detected in all the hens, and the weight of eggs laid
by the hens inseminated with IBV-spiked semen was significantly re-
duced.55 Knowledge of other coronaviruses present in semen might The testicle is an immunologically privileged organ, the blood-testis
encourage researchers to look at semen and sexual transmission, barrier (BTB) protects the testes against pathogen invasion.63 In
HUANG et Al. |
healthy fertile men, various immune cells and cytokines produced storm introduced by SARS-CoV-2 could be associated with immu-
64
by non-immune cells are indispensable to ensure male fertility, in nopathogenesis, which might contribute to testicular dysfunction
which they maintain the testicular microenvironment balance and and reduced male fertility. Nevertheless, this hypothesis requires
male reproductive health within the intricate and active environ- follow-up confirmation, and the exploration of possible short- and
ment of the seminiferous epithelium. Testicular tissue development long-term consequences on their andrological health.
benefits from immune cells and their cytokines, and the immune re-
sponse is critical to control and eliminate viral infection.65 Cytokines
are important for the immune response to viral infections by regu- |
lating the expansion and location of leukocytes. However, infection
and inflammation might disrupt the immune balance in the body, The blood-testicular barrier might not be a perfect barrier to viruses
either through immune insufficiency or overactivation, possibly under systemic or local inflammation.7 To eliminate the virus infec-
66
leading to devastating effects in humans. Immune pathology asso- tion, an inflammatory cytokines storm can recruit leukocytes, re-
ciated with an uncontrolled immune response might give rise to tes- sulting in inflammation characterized by leukocyte infiltration in the
ticular parenchyma destruction when the BTB is damaged by virus interstitial tissue of the testes, which, as a feature of human testicular
infection,67 and any associated functional impairment could lead to orchitis, might lead to male infertility. Actually, there is a high risk of
male infertility. that men with SARS-CoV-2 might suffer from an orchitis-like syn-
drome.35 Pan et al confirmed that six patients (19%) with COVID-19
suffered from orchitis.11 Recently, a study of 12 deceased patients
| with COVID-19 also revealed viral orchitis characteristics, with T
lymphocyte intrusion into the testicular parenchyma, accompanied
SARS-CoV-2 has proven effects on multiple organs throughout the by significant seminiferous tubular injury.15 Interestingly, the histo-
68
body, accompanied by immunopathological reactions and high cy- pathological features of the testes in patients with SARS also overlap
tokine storms. In the plasma of patients with COVID-19 in intensive with those in patients with COVID-19: all testes being full of leuko-
care units, higher plasma levels of cytokines were detected, imply- cyte infiltration and wide-ranging germ cell deterioration, with thick-
ing that a cytokine storm might aggravate the infection in patients ened basement membranes,83 which supports the hypothesis that
2,3
with COVID-19. Actually, this coincided with the research that the coronavirus-induced adaptive immune response might play a vital
patients with COVID-19 presented a typical profile of hyper inflam- role in the course of testicular damage and eventually affect fertility.
mation, such as TNF-α, IL-6, and IL-1β.69 Cytokines are beneficial to Theoretically, attributed to the hypercoagulable state of vasculitis in
testicular function and sperm production, as well as testicular immu- patients with COVID-19, the testicular damage could be result of tes-
70-72
nity privilege. However, a high concentration of inflammatory ticular segmental vascularization.84 One study has shown evidence
cytokines could contribute to the progression of sexual dysfunc- of direct SARS-COV-2 infection of endothelial cells and diffuse en-
tion.73 Thus, a change in cytokine production can lead to fertility dothelial inflammation,85 Endothelial dysfunction may be subsequent
problems.66,74 Cytokine-mediated suppression of the hypothalamic- to organ ischemia,86 which might provide a rationale for one study
pituitary-testicular axis could lead to a decrease in serum testoster- that described ischemia-related priapism in a patient with COVID-
one, such as IL1 leading to inactivation of the P450/c17 lyase that 19,87 suggesting that vasculitis-orchitis might have a crucial role in
converts progestins into androgens in immunopathogenesis, which the development of the testicular injury caused by SARS-CoV-2 in-
will result in decreased testosterone and sperm production.60,75-77 fection. Moreover, the intrusion of CD68 + macrophages into the
This corroborated the results showing a dramatic decline serum tes- interstitial tissue of the testes could contribute to a decline in steroi-
tosterone in 17 patients with severe COVID-19, which might even dogenesis and testosterone,66 and the change in the hormonal profile
78
predict poor progression of COVID-19 infection. With a history of might contribute to susceptibility to SARS-CoV-2 infection, leading
COVID-19 disease, SARS-CoV-2 infection can attribute to male hy- to a more profound pathophysiological role in COVID-19 patients.88
79
pogonadism, thus it is recommended to measure testosterone lev- During the SARS-CoV-2 outbreak, SARS-CoV-2–infected cats
89
els when a patient is detected as positive for SARS-CoV-2 RNA and also presented a profile of testicular atrophy and were reported
90
conduct appropriate testosterone treatment if necessary. Studies to have acquired the infection from humans. Furthermore, studies
detected dramatic increases in IL6 levels in patients with COVID- on chickens infected with coronavirus IBV also showed that immune
80,81
19. Immunopathologically, high IL6 expression correlates with cells infiltrated into the interstitium of the testis, which was respon-
a systemic inflammatory milieu that disrupts the integrity of the sible for the reduced fertility. 25,91
82
blood-testis barrier. As a result of blood-testis dissemination, the In summary, the coronavirus-induced adaptive immune re-
virus might damage testicular tissue directly. Furthermore, COVID- sponse might lead to testicular damage and endocrine abnormal-
19–induced changes to the cytokine microenvironment might even ity, eventually disrupting spermatogenesis in patients recovering
lead to testicular cancer,64 which could have long-term adverse from COVID-19. However, this hypothesis remains to be confirmed
effects on the recovery of patients, and represents a second long- and studies should be undertaken to establish an animal model
term matter of concern. Hence, it should be noted that the cytokine to determine the underlying pathophysiological mechanisms and
| HUANG et Al.
to mitigate the risk of testicular injury during COVID-19 disease. pathogenic effects in male fertility. We highlighted that male fertility
Precautions against SARS-CoV-2-induced male infertility should might be highly vulnerable to SARS-CoV-2 infection. Infection with
be taken. this novel virus not only seriously threatens an individual's overall
health, but also might lead to male infertility. Perspectives gained
from multi-organ research during the recent epidemic raises the
| possibility that damage to the male reproductive tract might be an
underappreciated result of SARS-CoV-2 infection. Therefore, more
In SARS-infected testes, Immunohistochemistry analysis showed a attention should be paid to the effects on male fertility of SARS-
large amount of IgG precipitation in the seminiferous epithelium of CoV-2 infection, and should this causal link between SARS-CoV-2
the testis, as well as in degraded germ cells and Sertoli cells, sug- infection and male infertility be confirmed, male patients should
gesting that the extensive IgG triggered by a secondary autoim- consider cryopreserving their spermatozoa to preserve fertility.
mune response might aggravate the testicular damage. 22 In addition,
deposits of IgG are associated with autoimmune orchitis (EAO),92
which might activate immune cells in the host to produce antibodies This study was supported by a grant from China Postdoctoral
against the virus, as well as introducing antibodies into semen.93 In Science Foundation (2019M661521).
patients with COVID-19, the positive rate of IgG reached 100%,94
especially antiphospholipid antibodies,95 which are antisperm anti-
bodies that could interfere with fertilization,96 suggesting that male None declared.
patients with COVID-19 should be cautioned against the adverse ef-
fects of a high IgG titer on their reproduction ability.
In healthy testis tissue, immune cells and cytokines are beneficial Wenbing Zhu and Chuang Huang conceived and designed the study.
for the development of spermatogonia. However, the immune imbal- Chuang Huang and Xiren Ji drafted the manuscript. Wenjun Zhou,
ance associated with infection and inflammation can contribute to Zhenghui Huang, Xiangjie Peng, Liqing Fan, and Ge Lin revised the
male sterility. Overall, in addition to the pathogenic effects of coro- drafts. All authors approved the final version of the manuscript.
navirus, the host-induced immune response against the virus also
plays an important role in the overall disease process.
Wenbing Zhu https://orcid.org/0000-0002-9352-2785
|
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Review Article
Impact of COVID-19 on Male Fertility
Alexander B. Collins#, Lei Zhao#, Ziwen Zhu, Nathan T. Givens, Qian Bai,
Mark R. Wakefield, and Yujiang Fang
COVID-19, the clinical condition caused by the SARS-CoV-2 virus, has been associated with massive cytokine storm
and damage to multiple organ systems. Although evidence for the detection of SARS-CoV-2 virus in the testis remains
scarce, testicular damage and dysregulation of gonadotropins associated with inflammation has been reported. Addition-
ally, as a result of the rapidly evolving pandemic, frequently updated medical interventions and public policies leading to
delays of care can play a role in fertility. This narrative review aims to summarize the current literature on how COVID-
19 may influence male fertility. UROLOGY 164: 33−39, 2022. © 2022 Elsevier Inc.
S
ince December 2019, much of the world's news, receptors, investigations into the possible influences of
economy, and focus has been on the Coronavirus COVID-19 on male fertility are being actively explored.6
Disease 2019, or COVID-19 virus. At this time, The hypothalamic-pituitary-gonadal axis (HPG) endo-
October 2021, there are currently 245,563,601 reported crinologically links the brain and testis. This link is
cases, 222,651,377 million people recovered, and achieved through the production of gonadotropins and
4,983,862 million deaths attributed to the virus.1,2 testosterone and the HPG feedback loop. Precise regula-
COVID-19 is now understood to be the clinical disease tion of this axis is required for optimal sex hormone pro-
caused by SARS-CoV-2. The SARS-CoV-2 virus origi- duction and fertility. COVID-19’s effects on the
nated in Wuhan, China. Throughout history, multiple hypothalamic-pituitary-gonadal axis require further evalu-
zoonotic coronavirus pathogens have emerged and coro- ation, however, abnormal levels of gonadotropins have
naviruses have been shown to adapt to different animal been identified in COVID-19 patients.7
hosts.3 SARS-CoV-2 shares over 96% of its genome with The pandemic has dramatically impacted our way of life
the bat coronavirus BatCoV RaTg13, supporting the the- and our medical systems and remains an ongoing and
ory that SARS-CoV-2 evolved from a bat coronavirus evolving public health concern. Staying current with new
with an unknown intermediate host.4 literature is challenging due to the high volume of studies
Clinically, COVID-19 presents with a persistent fever, being published. This narrative review aims to summarize
cough, pneumonia, and loss of smell and taste. There has the current information available investigating the rela-
also been pathological evidence of massive intravascular tionship of COVID-19 and male infertility. We explore
micro-thrombotic phenomenon in multiple organs, this relationship as it relates to hormonal regulation and
including the lungs, heart, kidneys, brain, and testes. The the hypothalamic pituitary axis (HPG), systemic inflam-
interaction of the SARS-CoV-2 viral Spike protein and mation, the potential of direct testicular infection, semen
ACE2 on cells co-expressing ACE2 and the cellular trans- parameters, interactions of medical interventions for
membrane protease serine 2 (TMPRSS2) has been identi- COVID-19, and access to urologic care during the pan-
fied as the mechanism of cellular entry for the SARS- demic.
CoV-2 virus. Although not all tissues that express ACE2
are susceptible to SARS-CoV-2 infection, organ involve-
ment has been found to be positively correlated with
ACE2 expression.5 Since the testes express ACE2
COVID-19 AND THE HYPOTHALAMIC-
PITUITARY-GONADAL AXIS
An adequate hypothalamic-pituitary gonadal axis is cru-
cial for maintaining normal testosterone production. Low
#
These authors contributed equally testosterone secondary to hypergonadotropic hypogonad-
Financial Disclosure: The authors declare that they have no relevant financial interests. ism, or primary hypogonadism, can be congenital as in
Funding Support: This study was supported by the grant from Des Moines University
for Yujiang Fang M.D., Ph.D. (IOER 112-3749). Klinefelter Syndrome, or caused by environmental or bio-
From the Department of Microbiology, Immunology & Pathology, Des Moines Uni- logical disruptions to gonadal function. Low testosterone
versity College of Osteopathic Medicine, Des Moines, IA; the Department of Respiratory secondary to hypogonadotropic hypogonadism can lead to
Medicine, the 2nd People’s Hospital of Hefei and Hefei Hospital Affiliated to Anhui Med-
ical University, Hefei, China; and the Department of Surgery, University of Missouri a secondary testicular failure. Causes for hypogonado-
School of Medicine, Columbia, MO tropic hypogonadism can be congenital, in cases such as
Address correspondence to: Yujiang Fang, Department of Microbiology, Immunol- Kallmann syndrome, or acquired secondarily from numer-
ogy & Pathology, Des Moines University College of Osteopathic Medicine, Des Moines,
Iowa 50312. E-mail: yujiang.fang@dmu.edu ous causes including medication, pituitary lesions, infec-
Submitted: July 27, 2021, accepted (with revisions): December 28, 2021 tion, or inflammation.8 Fertility issues associated with
© 2022 Elsevier Inc. https://doi.org/10.1016/j.urology.2021.12.025 33
All rights reserved. 0090-4295
acquired hypogonadotropic hypogonadism can generally gonadal axis, which is well known to lead to temporary
be corrected by fixing the underlying issue. effects on fertility.19
A selection of studies has produced data to support that
COVID-19 can impact testicular hormone production.
When reviewing these studies, it is important to recall INFLAMMATION AND OXIDATIVE STRESS
that physiological stressors such as illness are associated The blood testes barrier provides privileged immunity to
with fluctuations in baseline hormone levels. A study by the testicles. However, this barrier is imperfect. The pres-
Ma et al. compared 119 reproductive aged males with ence of systemic and local inflammation can increase this
SARS-CoV-2 to 273 age matched controls. They found permeability and allow invasion of immune cells. SARS-
high luteinizing hormone (LH) levels and lower testoster- CoV-2 is a cytopathic virus that creates a proinflammatory
one to LH ratios in SARS-CoV-2 patients. The authors state and can lead to cell pryoptosis. Pryoptosis is an
suggest these findings are associated with the systemic inflammatory form of programmed cell death that leads to
inflammation present in the evaluated patients. These the release of potent pro-inflammatory cytokines. Inflam-
abnormalities could indicate disruption in sex hormone matory cytokines lead to immune cell recruitment that
secretion associated with COVID-19 disease.9 Another can assist in disease clearance and further increase the pro-
study compared 89 COVID-19 patients to 30 patients suf- duction of inflammatory cytokines; in some cases, this can
fering from other respiratory infections and 143 healthy create a cytokine storm, leading to uncontrolled systemic
controls. The COVID-19 patients were found to have sig- inflammation that impacts multiple organ systems.20
nificantly lower testosterone, higher LH and prolactin, Leukocytospermia often accompanies a systemic
and equivalent FSH when compared to both sets of con- increase in IL-6, MCP-1, and TNF-a, and can be associ-
trols.10 Rastrelli et al. found that in a group of 31 patients, ated with systemic inflammation or viral and bacterial
12.9% of patients who died or had severe COVID-19 infections.7 Several studies have reported an increase in
exhibited lower total and free testosterone and elevated inflammatory markers; IL-6, IL-8, and TNF-a, have been
LH when compared to more moderate cases.11 identified in semen samples from patients recovering or
Hypothalamic pathology associated with SARS-CoV-2 suffering from COVID-19 compared to controls.21−23
infection in the brain is still being studied. SARS-CoV-2 Additionally, CD3+, CD68+, and IgG have been identi-
has been shown to cross the blood brain barrier.7 Once fied in the seminiferous tubules of COVID-19 patients.22
past the barrier, it infects ACE2 expressing cells, leading Inflammatory states, as well as states of low oxygen ten-
to neuroinflammation. This inflammation can disrupt nor- sion, are associated with oxidative stress and production
mal physiologic functions such as temperature regulation of free radicals. Both inflammatory cytokines and oxida-
and hormone balance.12−14 Testicular pathology associ- tive stress have been found to damage cellular compo-
ated with hyperthermia has been established previously. nents of testes.24 Oxidative stress leads to Leydig cell
Fevers are the body’s response to systemic inflammation, damage, thus disrupting capacity for testosterone produc-
and over 80% of COVID-19 patients are reported to tion and germinal epithelial damage, which hinders
develop a fever, which tends to be prolonged with an spermatogenesis.7,25 Oxidative stress has been proposed as
average duration of 10 days.15 It has been reported that a a potential mechanism for the testicular damage found in
fever of > 39°C for over 3 days can lead to significant COVID-19 patients. However, few studies have produced
reduction in semen concentration and motility.16 While data to support this claim. Moghimi et al. evaluated the
interpreting these findings, it is worth noting that the production of reactive oxygen species (ROS) and glutathi-
standardized reported definitions of fever for COVID-19 one disulfide (GSH) concentration in an autopsy study of
patients has been poor.17 6 COVID-19 patients versus 6 controls. They revealed a
Few studies have attempted to link circulating gonado- statistically significant increase in ROS and decrease of
tropin levels to neuropathology in COVID-19 patients. GSH in COVID-19 patients when compared to controls.
Neuroimaging findings from a single patient study These findings indicate an increase in oxidative stress and
revealed a hyperintense signaling suggestive of hypotha- a corresponding decrease in cellular defense to oxidative
lamic lesions, as well as an enlarged pituitary gland.13 stress in patients suffering from COVID-19.26
While far from conclusive, these findings suggest that
hypothalamic involvement in COVID-19 patients could
alter regulation of gonadotropin release leading to subse- SARS-COV-2 AND POTENTIAL TESTIS
quent reduction in testosterone levels.7
Although unlikely to lead to permanent effects on fer-
INFECTION
tility, the use of glucocorticoids for the management of SARS-CoV-2 Mechanism of Entry
COVID-19 can impact fertility. Dexamethasone is one of Several known single stranded RNA viruses, including
the only medications proven to reduce mortality in other coronavirus variants like HIV, Mumps, and Zika,
COVID-19 patients and is now routinely administered.18 are known to cause orchitis and can be found in semen.27
A precisely balanced concentration of glucocorticoids is There is conflicting evidence regarding the ability of
required to maintain gonadal function. Exogenous gluco- SARS-CoV-2 to directly infect the testis. The mechanism
corticoid use can disrupt the hypothalamo-pituitary- of proposed entry of SARS-CoV-2 is through the binding
34 UROLOGY 164, 2022

of the SARS-CoV-2 Spike protein (S-protein) viral 19 indirectly, rather than directly, affects testicular
ligand and host ACE2 receptor. The S protein is then function.34
cleaved by a serine protease co-receptor TMPRSS2, lead- Yang et al. studied the testes of 12 men who died from
ing to membrane fusion between the virus and cell.28 The complications associated with COVID-19. RT-PCR iden-
testes express a high level of ACE2 receptors on spermato- tified SARS-CoV-2 RNA in 1 patient’s testes, but elec-
gonia, seminiferous tubules, Sertoli, and Leydig cells. The tron microscopy did not confirm the presence of the
endogenous function of this receptor is not yet fully SARS-CoV-2 virus in any of the 12 patients. Later discus-
understood.5 ACE2 has a regulatory role in the male sions have suggested that this sample was fibrovascular tis-
reproductive system, namely in the modulation of ste- sue and that the viral RNA was present in sampled blood
roidogenesis. Additionally, ACE2 receptors are thought opposed to testicular tissue.35 All 12 patients possessed a
to play a role in fertility. This association is based on a lower number of Leydig cells when compared to controls.
study that observed lower levels of ACE2 in infertile men Additionally, all COVID-19 patients showed evidence of
with severe spermatogenesis impairment when compared seminiferous tubule cellular injury and a diminished popu-
with fertile subjects.29 Men have higher levels of lation with mild lymphocytic inflammation.36 The
TMPRSS2 expression than women. This is likely due to authors postulated that damage to seminiferous tubules
an androgen response element being a transcriptional pro- and Leydig cells may be secondary to viral membrane pro-
motor for TMPRSS2. It is thought that co-expression of teins such as the Spike protein.
ACE2 and TMPRSS2 are required for viral entry into In another autopsy study by Ma et al., testicles from 5
cells.28 COVID-19 patients were studied compared to controls.
There is discrepancy regarding the levels of ACE2 and All 5 patients were found to have degenerated germ cells
TMPRSS2 co-expression on individual cells. Stanley sloughed off into the seminiferous tubules. In 4 of 5
et al. found that levels of ACE2 and TMPRSS2 co- patients, almost all the germ cells lining the seminiferous
expression in testicular cells occurs less than 0.05% of the tubules were lost. There was also a corresponding loss of
time.30 These findings are supported by a study by Pan cells expressing the germ cell marker DDX4. These find-
et al. showing minimal co-expression in individual’s ings were in direct contrast to 3 controls studied. The
cells.31 Lack of co-expression would indicate minimal risk number of Sertoli cells appear consistent between control
of direct infection or an alternate mechanism of entry. and COVID-19 patients studied.37 SARS-CoV-2 nucleic
Levels of ACE2 mRNA and TMPRSS2 in the testis have acid was detected in the testis of 2 of the COVID-19
been also examined in an autopsy study. The study exam- patients using RT-PCR. However, with immunohis-
ining 5 COVID-19 patients found that all patients had tochemistry utilizing an anti-SARS-CoV spike S1 anti-
elevated levels of ACE2 and TMPRSS2 expressed in sem- body, all 5 COVID-19 patients stained positively. These
iniferous tubules compared to controls. Immunohis- findings suggest the ability of SARS-CoV-2 to directly
tochemistry showed increased expression and RT-qPCR infect testicular cells through spike glycoprotein binding.
was notable for increased mRNA levels of ACE2 and Transmission electron microscopy (TEM) also showed
TMPRSS2. Of note, this study did not attempt to prove coronavirus-like particles in the interstitial compartment
co-expression of ACE2 and TMPRSS2 on an individual of the testes of all the COVID-19 patients.37
cell level.32 Increased expression supports the likelihood A study by Achua et al. compared testis tissue from
of direct testicular invasion and damage by SARS-CoV-2. autopsies of 6 COVID-19 men to the tissue of 3 negative
However, it remains unclear whether this increased controls. Using TEM, SARS-CoV-2 viral RNA was iden-
expression of ACE2 and TMPRSS2 is actually co-expres- tified in only 1 of the testis tissues of the COVID-19 biop-
sion. Additionally, increased expression of ACE2 could sies. This tissue sample also showed interstitial
be secondary to underlying comorbidities such as hyper- macrophage and leukocyte infiltration. 3 of the 6
tension, cancer, and smoking, rather than COVID-19 COVID-19 patient biopsies showed impaired spermato-
infection.33 genesis, with a direct association between increased quan-
titative ACE-2 levels and impairment of
SARS-CoV-2 and Testis Histology spermatogenesis.38
Several autopsy studies have attempted to identify the Flaifel et al. examined the testis of 10 patients who died
presence of SARS-CoV-2 virus in the testis. Only a few of from COVID-19. They performed RT-PCR on 6 of the
these studies have successfully reported the presence of samples and failed to identify the presence of viral RNA.
SARS-CoV-2 viral particles in the testes. These studies They did find signs of acute damage including sloughing
have small sample sizes and reports of errors in tissue sam- of spermatocytes and swelling of Sertoli cells in all sam-
pling. Errors in sampling, including the sampling of vascu- ples. The authors also reported finding microthrombi pres-
lar structures, have drawn questions to the validity of viral ent in the testis of 2 of the samples, and postulated that
particle identification in the testis. However, the majority the structural damage may be a result of hypoxic injury.23
of studies support an association between COVID-19 and There have been few reports of testicular pain associ-
a loss of testicular architecture via changes to seminiferous ated with COVID-19. One study looked at 34 men with
tubules, Leydig cells, and germ cells. Contrary to initial mild to moderate COVID-19. 6 men in the study com-
theories, the data from these studies suggest that COVID- plained of scrotal discomfort and tenderness. No further
UROLOGY 164, 2022 35

exam or testing such as ultrasound was completed to con- recovered from COVID-19. The presence of viral RNA
firm or rule out orchitis.31 Another study from Jordan fol- was evaluated with RT-PCR at least 21 days after a nega-
lowed 253 male patients with COVID-19 through their tive COVID-19 test. Of the 43 patients, only 1 had SAR-
hospital stay and 21-day recovery period to observe for CoV-2 RNA detected in their semen. The patient’s
signs and symptoms of orchitis. Each patient was evalu- semen sample was retested and found to be negative.21 In
ated every 2 days by a urologist, but none of the patients studies showing viral RNA in semen, the results may be
were found to have signs or symptoms of orchitis. It was explained by sampling error or urinary or accessory sex
noted that most of the patients were asymptomatic or had organ involvement instead of direct testicular involve-
mild-to-moderate symptoms. It remains unclear if orchitis ment. It is also important to recognize that even if
would develop with higher viral loads, or at a later course COVID-19 is transmissible through semen, it is unlikely
in time.39 In a retrospective cohort study by Liao et al., to provide a significant source of infection in comparison
142 patients who tested positive for COVID-19 under- to respiratory droplets. However, consideration should be
went scrotal ultrasound at time of diagnosis. 22.5% of made for those attempting to become pregnant or those
these patients were found to have increased tunica thick- donating or preserving sperm.51
ness and increased vascular flow consistent with orchitis,
epididymitis, or epididymo-orchitis.40
EFFECTS OF COVID-19 ON DELIVERING
Detection of SARS-CoV-2 in Semen and Sperm UROLOGIC CARE
Parameters
Delayed treatment across multiple pathologies has been
Nearly 30 viruses have been identified in human semen.41
seen during the time of the pandemic, with people
Of these, the most notable are HIV, hepatitis B, herpes
expressing fear of hospitals and avoiding medical care
simplex virus (HSV), and adenoviruses. Several studies
even in emergencies. An estimated 40.9% of surveyed US
have evaluated the presence of SARS-CoV-2 in semen.
adults reported avoiding medical care, with 12% avoiding
Many of these studies have small sample sizes and fail to
urgent or emergency care, and 31.5% avoiding routine
adhere to consistent semen collection parameters. With
care.52 The delayed treatment of testicular pathology, in
the exception of 2 outliers, the majority of studies suggest
cases of testicular cancer or sexually transmitted infec-
that detection of RNA in the semen and sexual transmis-
tions, may impact male fertility. The concept of delayed
sion are unlikely. Additionally, the majority of data sup-
treatment during the era of COVID-19 can be expanded
ports that semen quality, at least temporarily, is affected
to include fertility treatments.
by COVID-19.
In March of 2020, the American Society for Reproduc-
Most semen studies have involved recovering patients
tive Medicine (ASRM) recommended the suspension of
and have found that after 1 month, recovering patients
non-urgent gamete cryopreservation, new fertility treat-
did not have detectable levels of SARS-CoV-2 in their
ment, and elective non urgent diagnostic procedures.
semen.31 The largest study by Ruan et al. consisted of 74
Sperm banking was deemed a low priority except for
patients recovering from COVID-19 and 174 age matched
patients undergoing oncological treatment.51 At that
controls. No SARS-CoV 2 RNA was detected in any of
time, concerns were raised for those suffering from non-
the patients, however, sperm concentration count and
oncological conditions that could benefit from elective
motility were reduced.42 Several other studies with smaller
fertility treatment or gamete cryopreservation. Conditions
sample sizes also failed to identify SARS-CoV 2 RNA in
discussed included patients with hypogonadotropic hypo-
semen samples. Hajizadeh et al. studied semen quality in
gonadism requiring long term treatment, those with infer-
patients recovering from COVID-19; comparing 84 recov-
tility thought to be associated with varicocele, and
ering COVID-19 patients to 104 healthy controls, they
patients suffering from systemic inflammatory or autoim-
found impaired sperm parameters including concentra-
mune disease requiring treatments that maybe gonado-
tion, progressive motility, and morphology in all COVID-
toxic.53 At the time of authorship, restrictions for fertility
19 patients.43 The smaller sample sized studies reported
services have been lifted. It is unclear what effect, if any,
varying reports of reduced sperm parameters, with some
these temporary restrictions had on male fertility. How-
finding reduction, others no change, and some claiming
ever, being aware of previous delays in treatment may aid
an association with severity of COVID-19
providers in assessing fertility concerns.
disease.31,34,34,44−49
Two studies have reported identifying SARS-CoV-2
RNA in the semen. One study analyzed the semen of 38
patients diagnosed with COVID-19, 15 in an acute state
COVID-19 MEDICAL INTERVENTIONS
and 23 recovering. 6 of 38 patients were found to have Therapies for COVID-19
SARS-COV-2 RNA in their semen, 4 of those 6 patients Remdesivir is currently the only drug that is officially FDA
were in the acute stage of infection and 2 were in recov- approved for the treatment of COVID-19. There are 7
ery. Methods of semen collection and limits of detection drugs approved by the FDA under emergency use author-
used for RT-PCR were not published.50 Lastly, Gacci izations (EUA). These medications include Tocilizumab,
et al. evaluated the semen of 43 patients who had Sotrovimab, Bamlanivimab and Etesevimab, Regen-COV
36 UROLOGY 164, 2022

(Casirivimab and Imdevimab), Baricitinib (Olumiant) volunteers provided semen samples before the first vacci-
and Propofol-Lipuro 1%. To our knowledge, there have nation dose and again, 70 days after the second dose
been no conclusive studies to suggest that these drugs administration. Semen samples were analyzed for the fol-
affect male fertility.54,55 lowing parameters: semen volume, sperm concentration,
Many non-FDA approved treatments such as ribavirin, sperm motility and total motile sperm count. No signifi-
ivermectin, chloroquine and a myriad of antivirals have cant decreases in any of the above parameters were
been used in COVID-19 patients. In rat studies, ribavirin found.65 There is a potential for a temporary decrease in
was found to be gonadotoxic at all doses administered for sperm production post-vaccine, related to vaccine
a period of 105 days.56 Some studies have suggested that induced fevering. A fever can temporarily impact sperm
prolonged use of chloroquine may impair sperm quality.57 count, and in the Pfizer vaccine clinical trials, about 16%
In general, effects of antiviral medications on male fertility of men experienced a fever after the second vaccine dose.
require further studies.58 Throughout 2021, ivermectin, However, this brief impact on sperm after vaccination is
an antiparasitic medication, gained traction across social likely of much less magnitude than any potential effects of
media platforms as a potential treatment and prophylaxis having the full clinical syndrome of COVID-19.63
for COVID-19. Claims of associations between ivermectin Although there is limited data on the impact of the
and male infertility also spread through social media.59 COVID-19 vaccines on male fertility, the Society for
These claims stemmed from the misinterpretation of a Male Reproduction and Urology (SMRU) and the Soci-
2011 paper by Indonoji et. al studying sperm parameters ety for the Study of Male Reproduction (SSMR) have
in 37 patients with onchocerciasis treated with ivermec- made two recommendations regarding vaccinations.
tin.60 Although the study identified a decrease in sperm Firstly, the COVID-19 vaccine should not be withheld
parameters including sperm motility and count, it pos- from men desiring fertility who meet criteria for vaccina-
sessed serious limitations, including a lack of control tion. Secondly, the COVID-19 vaccines should be offered
group. Some other studies have shown ivermectin to be to all men desiring fertility and all men not desiring fertil-
gonadotoxic in animal models,61 but there have been no ity when they meet criteria for vaccination.
definitive findings to suggest that ivermectin is associated
with male infertility in humans. Attention should be
brought to the consequences that future medications used LIMITATIONS
for COVID-19 treatment may have on fertility.
It is important to note that the data that has been pre-
sented on COVID-19 and infertility has surfaced within
COVID-19 Vaccines
the short time frame since the virus was recognized in
COVID-19 is responsible for mobilizing a collaborative
2019. Sample sizes are generally small and many clinical
effort to create a novel vaccine in record time. Prior to
studies are performed at single sites, making it unwise to
the COVID-19 vaccine, the fastest vaccine approved was
draw definitive conclusions from their findings. This is an
the vaccine for the mumps virus in the 1960s, which took
evolving virus and will continue to require dynamic
4 years to develop. The COVID-19 vaccine was con-
research to truly understand it’s lasting impacts on the
ceived, created, and approved for emergency use by the
male reproductive tract and fertility.
FDA in under 1 year. In August 2021, the Pfizer vaccine
received full approval by the FDA.
Despite the pandemic ravaging the world, there is still
vaccine hesitancy. Potential fertility implications after CONCLUDING STATEMENTS
receiving a COVID-19 vaccine are a source of anxiety for While much is left to be studied, COVID-19 does appear
many patients, as reproductive toxicity was not evaluated to impact male fertility, at least temporarily. From review
in clinical trials.62 A vaccine that uses the actual virus of the current literature, it has become evident that
could theoretically also directly affect the testes. However, COVID-19 can lead to a reduction in testosterone pro-
the Pfizer and Moderna vaccines are only mRNA vac- duction and a state of temporary hypogonadism. It was
cines, which stimulate the recipient’s immune system to originally hypothesized that since the testes are prone to
produce the SARS-CoV-2 spike protein, and thus does direct infection by the SARS-CoV-2 virus due to their
not bind to receptors via the same mechanism that ACE2 expression, male fertility is adversely affected.
SARS-COV-2 virus does.63 The Johnson & Johnson vac- Although controversy remains, the data supports that a
cine utilizes viral vector technology, combining SARS- reduction in testosterone production is more likely associ-
CoV-2 spike gene with a weakened adenovirus. This leads ated with indirect testicular damage due to systemic or
to expression of the spike protein on cellular surfaces for local inflammation. Additionally, with the rapidly evolv-
immune cell interaction.64 Although unlikely, there is a ing pandemic, it is important to maintain vigilance for
theoretical risk for expressed spike protein interaction in potential interventions and delays of care that can lead to
the testis. lasting effects on fertility. Moving forward, further studies
A single centered prospective study out of the Univer- are required to investigate the potential long term fertility
sity of Miami investigated the effects of COVID-19 vacci- effects of the COVID-19 disease, treatments, and vac-
nation on semen parameters. A sample of 45 healthy male cines.
UROLOGY 164, 2022 37

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UROLOGY 164, 2022 39

Review Article
Asian Pacific Journal of Reproduction
subsequently named severe acute respiratory syndrome coronavirus 2

The coronavirus disease 2019 (COVID-19) pandemic caused by (SARS-CoV-2) due to its similarity to SARS-CoV . This infectious
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) illness was declared a global pandemic by the World Health
may have a ripple effect that puts men at a risk of infertility. This Organization on the 11th March 2020 . Although there are claims
article reviews the possible link between SARS-CoV-2 infection that the first case was transmitted from animal to human , human-
and male reproduction following speculations that the single- to-human transmission is fast spreading with a high mortality rate.
stranded RNA viruses could directly invade the testes. SARS-CoV-2 Established mode of transmission is through respiratory droplets
enters the human lung cells angiotensin converting enzyme 2 from sneezing and coughing with symptomatic and possibly
(ACE2). ACEs, its products, angiotensin-(1-7), and its receptor, asymptomatic infected persons being the primary source of spread.
MAS receptor, are expressed in the testes. Although the binding As on the 2nd September, 2020, 11:35 GMT, (about eight months
of SAR-CoV-2 to ACE2 could lead to excess angiotensin with from the outbreak), 26 149 876 cases of COVID-19 and 866 015 of
possible enhanced inflammation, angiotensin could also promote mortalities from COVID-19 has been reported .
sperm motility. In addition, the pathophysiology of SAR-CoV-2,
especially in relation to male fertility, is yet to be fully understood;
the suppression of androgen observed in COVID-19 infected men
calls for the need for andrological assessment in infected male.
Studies have shown that similar to SARS-CoV, SARS-CoV-2
SARS-CoV-2; COVID-19; Angiotensin enters the human cells by binding to angiotensin-converting
converting enzyme; Steroidogenesis; Spermatogenesis enzyme 2 (ACE2) . ACE2 is a zinc-containing transmembrane
aminopeptidase that was initially identified as a variant of ACE.
It is widely expressed, especially in the lung type alveolar cells,
endothelial cells of the arteries and veins, arterial smooth muscle
cells, enterocytes of the small intestine, cortical neurons and glia .
Coronaviruses (CoV) are single-stranded RNA viruses that Primarily, ACE2 acts as a counterbalance to ACE.
primarily target the human respiratory system. Microscopically,
CoV has glycoprotein spikes on its envelope which gives it a crown-
like appearance. The betacoronaviruses (coronaviridae family) have To whom correspondance may be addressed. E-mail: akhigberoland@gmail.com
several genera that affect humans and other vertebrates like mice, This is an open access article distributed under the terms of the Creative Commons
Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix,
bats, cats, dogs, and bats . The -CoV and -CoV cause infection tweak and buid upon the work non-commercially, as long as the author is credited
and the new creations are licensed under the identical terms.
of the respiratory, gastrointestinal, and central nervous systems For reprints contact: reprints@medknow.com
in human and several mammals, while the -CoV and -CoV ©2020 Produced by Wolters Kluwer- Medknow.
primarily affect birds . All rights reserved.
How to cite this article: Akhigbe RE, Hamed MA. Possible links between COVID-
At the tail of December 2019, there was an outbreak of a 19 and male fertility. 2020; 9(5): 211-214.
pneumonia-like infection, now called coronavirus disease 2019 Article history: Received: 16 July 2020; Revision: 2 September 2020; Accepted:
(COVID-19) caused by a novel coronavirus (2019-nVoV) that was 6 September 2020; Available online: 12 September 2020
Renin activates angiotensinogen to angiotensin . This is
cleaved by ACE into angiotensin , which exerts its effect through
angiotensin type 1 receptor (AT1R) and angiotensin type 2 Studies have revealed the presence of SARS-CoV-2 RNA in stool,
receptor (AT2R). In addition, ACE also cleaves the C-terminal urine, and blood samples. Although urine and blood reportedly have
dipeptidyl residue to inactivate bradykinin and enkephalins. ACE2 a low SARS-CoV-2 RNA detection frequency, the detection rate
cleaves phenylalanine from angiotensin and hydrolyzes it into in the stool is relatively high with longer clearance time than in the
angiotensin-(1-7) which exert their activities through AT2R and nasopharyngeal swabs from respiratory secretions . This infers
MAS receptors . The spike S1 protein of SARS-CoV-2 binds that the virus could be contracted and spread through other means
to the enzymatic domain of ACE2, peptidase domain, on the cell besides respiratory droplets.
surface and results in endocytosis and translocation of both the virus Studies have elucidated the roles of ACE, ACE2 and AT2R in
and enzyme into the cells . The viral entry is facilitated by priming male reproduction (Figure 1). ACE has been reported to be well
of the S protein by the host serine protease, transmembrane protease distributed in human prostate, testis, epididymis, and semen .
serine 2 . Following viral entry, it replicates, increases the pH of It has been linked to testicular development in puberty , germ
endosomes and lysosome and activates p38 mitogen activated protein cell maturation , regulation of epididymal fluid and electrolyte
kinases and extracellular regulated protein kinases, which causes balance , and sperm capacitation . On the other hand, ACE2 has
hyper-inflammatory response. In the incident of COVID-19, ACE2 been reported to be expressed in adult testicular Leydig cells, and
becomes overwhelmed, causing a rise in the level of angiotensin speculated to play a key role in steroidogenesis . A study by Reis
that cannot be hydrolyzed to angiotensin-(1-7) due to unavailability confirmed the expression of ACE2, angiotensin-(1-7) and MAS
of ACE2. This explains the pulmonary manifestations of the viral receptors in the Leydig and Sertoli cells, as well as their possible
infection. roles in steroidogenesis and spermatogenesis . AT1R, which has
Angiotensinogen
Rennin
Angiotensin
S
ACE M
M
N
E
SARS-CoV-2
Testicular development
Germ cell maturation
Epididymal fluid and electrolyte balance
Sperm capacitation
ACE 2
Angiotensin Angiotensin 1-7
MAS receptor
Steroidogenesis
Sperm motility Spermatogenesis
Possible link between SARS-CoV-2 and male reproduction. ACE: Angiotensin converting enzyme; S: Spike glycoprotein; M: Membrane
protein; N: RNA and nucleocapsid protein; E: Envelope.
been reported to be expressed in developing human spermatids and are at more risk for worse outcomes and mortalities independent
mature sperm cell , has been linked to sperm capacitation and on age . The observed higher prevalence, poorer outcome and
acrosome reaction . AT2R has been documented to be expressed increased mortality in male are likely not SARS-CoV-2-specific. It
in human testis, epididymis, prostrate and sperm cells . Studies has been established that men are more susceptible to infection than
have shown that exposure of human sperm cells to angiotensin and women. Estrogen exerts more vigorous immune system response
angiotensin enhances sperm motility . when compared to testosterone, thus suppressing inflammatory
There are lots of speculations about the male gender preponderance cytokine release with resultant increased poor outcome and death
to COVID-19 infection, and COVID-19-induced male infertility. in male from viral respiratory infections . In addition, it is not
Although studies of Xu reported infiltration of inflammatory unlikely that the X chromosome which carries the highest number of
cells into the testes of SARS-CoV-infected patients, no similar immune-related genes accounts for the robust immunologic response
reports have been documented on SARS-CoV-2 infection. Semen seen in females . Health-related risky behaviour which impairs
samples from patients who recovered from COVID-19 and testicular immune system response such as smoking and poor utilization
biopsies from a dead COVID-19 patient did not detect SARS- of medicare may also explain the higher morbidity and mortality
CoV-2 RNA . This finding was corroborated by other studies seen in men. When compared with the female counterpart, a higher
that reported absence of SARS-CoV-2 viral RNA in the semen percentage of men smoke and lower percentage of them utilizes
of male patients with active or resolving infection . On the medicare .
contrary, COVID-19 confirmed patients had significantly higher
serum luteinizing hormone (LH) and prolactin, but normal levels of
circulatory testosterone when compared to their healthy counterparts,
indicating a likely initial suppression of testosterone biosynthesis
which resulted in a negative feedback thus stimulating increased SAR-CoV-2 remains novel and much is yet to be unraveled about
LH release . These findings suggest that the testis is possibly not this highly contagious virus. The higher prevalence and mortality
directly infected and male are not more predisposed to the virus, but from COVID-19 observed in men are likely secondary to hormonal
the viral infection could impair androgen production. Interestingly, factor, genetic makeup, and health-related risky behaviour. Although
a cohort study revealed that 6 out of 38 (15.8%) COVID-19 just a study has demonstrated direct testicular invasion of the virus,
confirmed patients expressed SARS-CoV-2 in their semen; 4 out the suppression of androgen observed in COVID-19 infected men
of the 6 COVID-19 confirmed patients (66.7%) were in the acute suggests the need for andrological assessment in infected men.
stage of infection while 2 out of the 6 COVID-19 confirmed patients Studies evaluating the direct testicular invasion of SARS-CoV-2
(33.3%) were recovering . Although it is unclear whether or not ACE2 or other mechanisms, and the likely effect of the viral
the expressed virus was viable, this calls for caution especially infection on male fertility are necessary to better understand the
in patients who require assisted reproductive technology possible pathophysiology of SARS-CoV-2 on male reproduction and
fertilization interventions. A repeat SARS-CoV-2 RNA testing also unravel new preventive strategies and therapeutic opportunities.
might be necessary in semen donors to reduce the chance of possible
spread and increase the success rate of the artificial reproductive
technology.
Since ACE2, angiotensin-(1-7), and MAS receptors are expressed
in the testis, SARS-CoV-2 could invade the testes and alter testicular The authors declare that they have no conflict of interest.
functions. Also, the binding of the virus to ACE2 could lead to
an excess of angiotensin which would give rise to a robust
inflammatory response with subsequent impairment of the Leydig
and Sertoli cell functions. Although there are limited studies with
a small sample size that evaluated the presence of the virus in the Roland Eghoghosoa Akhigbe and Moses Agbomhere Hamed
testes or semen, it is important to note that no study has reported the contributed equally to the study.
presence of the virus in the testes or semen. Since angiotensin is
known to promote sperm motility, excess angiotensin following
overwhelmed ACE2 could precipitate inflammation, and may
not override its positive effect on sperm motility, especially if the
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European Review for Medical and Pharmacological Sciences 2021; 25: 1109-1113
Relationship between COVID-19 and the male

reproductive system
T.-T. MENG1, R.-J. DONG2, T.-G. LI1
Department of Emergency Medicine, Shengjing Hospital of China Medical University, Shenyang, China
1
Department of Immunology, Key Laboratory of Immune Microenvironment and Diseases of

2
Educational Ministry of China, School of Basic Sciences, Tianjin Medical University, Tianjin, China
Tingting Meng and Ruijie Dong contributed equally to this work
Abstract. – OBJECTIVE: The objective of this Introduction

review is to provide currently available informa-
tion on the potential effects of coronavirus dis-
ease 2019 (COVID-19) on male fertility. government of Hubei Province posted a bulletin
MATERIALS AND METHODS: This is a mini-re-
view. Due to the similarity between the COVID-19 -
and severe acute respiratory syndrome (SARS) spiratory syndrome coronavirus 2 (SARS-CoV-2)
virus, we searched for the following keywords: to undergo fertility tests. SARS-CoV-2 is the
“SARS-CoV, male reproductive system, infer- pathogen that has caused the coronavirus dis-
tility, COVID-19, SARS-CoV-2, and orchitis”. By
reviewing and analyzing the literature, we ana- damage many organs in the body, especially the
expression of angiotensin-converting enzyme 2
(ACE2) in the testes, and the impact of SARS-
CoV-2 on the male reproductive system.
RESULTS: SARS-CoV-2 enters the body disease and the male reproductive system.
through the ACE2 receptor. The high expres-
sion of ACE2 on the surface of spermatogonia SARS-CoV-2 and COVID-19
and supporting cells in the testes, as well as the At the end of 2019, a novel coronavirus disease
immune response caused by COVID-19, can lead
to testicular spermatogenesis dysfunction and leading to Severe Acute Respiratory Syndrome
reduced sperm count.
CONCLUSIONS: COVID-19 infection can affect
male reproductive function, and standard treat- of the World Health Organization (WHO), pa-
ment strategies should be established in time to
help male patients infected with COVID-19.
Key Words:
deaths. The emergence of the novel coronavirus
COVID-19, SARS-CoV-2, Male reproductive system,
Orchitis, SARS. -
ed information on this virus. Gradually, more
information on the virus has been obtained as
Abbreviations the disease continuously spreads. On February
ACE2: angiotensin converting enzyme 2; BTB: coronavirus pneumonia as COVID-19. Infected

Blood-testis barrier; COVID-19: Coronavirus dis- people typically develop symptoms such as fever,
ease 2019; MERS: Middle East respiratory syndrome; -
MERS-CoV: MERS coronavirus; RBD: receptor binding
domain; S: spike protein; SARS: severe acute respirato-
toms may appear 2-14 days after exposure or even
ry syndrome; SARS-CoV: SARS coronavirus; SARS- longer after exposure, and an infected person
CoV-2: SARS coronavirus 2; WHO: World Health Or- can infect another person via aerosol-mediated
ganization. transmission1. As COVID-19 spreads from one
Corresponding Author: Tiegang Li, MD; e-mail: Kangkang875@outlook.com 1109

T.-T. Meng, R.-J. Dong, T.-G. Li
person to another2 via this mode of transmission,

infected individuals should be isolated to reduce 9,10
. Of
the possibility of transmission.
of coronavirus that infect humans. Among the than 90% by National Center for Biotechnology
Information amino acid blast2.
respiratory syndrome coronavirus (MERS-CoV), ACE2 is a carboxypeptidase that binds to en-
causing COVID-19 and MERS, respectively, are dothelial cells; it is highly expressed in multiple
infectious and harmful, and the other four virus- human organs, such as the lungs, heart, gastroin-
es have little impact on people. SARS-CoV and testinal tract, testes, and so on11. SARS-CoV-re-
MERS-CoV caused infectious disease outbreaks lated studies12,13 have reported that SARS-CoV
in 2003 and 2012, respectively. The seventh type, enters cells by binding to the ACE2 receptor
-
Although SARS-CoV-2 has affected a larger pop-
-
coronavirus13. Researchers analyzed the mo-
SARS and MERS . Immunocompromised indi-
3-5
lecular structure of the novel coronavirus and
underlying diseases such as diabetes, high blood

pressure, heart disease, and so on, are at a higher
-
9
replacement therapy for COVID-19 treatment; animals as the intermediate hosts, but it is still
this is a method of replacing plasma that has not unclear if this host is a bat, pangolin, or mink.
The Relationship Between

The Structure and Origin of SARS-CoV-2 SARS-CoV and Orchitis
The spike (S), membrane, envelope, and nu- Recent evidence14,15
cleocapsid proteins are the four main structural CoV-2 acts on the ACE2 receptor to enter cells
proteins of coronavirus particles6. The corona- and this could cause pathological injuries in mul-
tiple organs, including the lungs, heart, kidney,
is a distinct feature of coronaviruses, but also
the most variable part of the coronavirus . The on the cell surface. In addition, many viruses,
virus binds to the angiotensin converting enzyme such as the HIV and mumps virus can invade
2 (ACE2) located on the host cell membrane
through the virus surface enzyme of its S glyco- lead to male infertility and testicular cancer14.
protein and enters the cell. The S protein mediates Among these organs, testicular ACE2 expression
the connection of the virus to the host receptors; is abundant, mainly concentrated in testicular
it is cleaved by an enzyme of the host cell into spermatogonial cells, interstitial cells, and sup-
- reproductive function.
main of the S protein and constitute the stalk of The testicular parenchyma is composed of tes-
the spike, respectively6. All coronaviruses rely ticular lobules that contain seminiferous tubules,
on spike proteins to infect other cells. The S1 the site of sperm production, and interstitial cells,
-
infection, completing the invasion process by tion of androgens. The seminiferous tubules are
the virus. The S2 proteins use their functional made up of spermatogenic cells and supporting
cells, and the spermatogonia are the precursor
cell membrane . This process decides the charac- cells of spermatogenic cells. The supporting cells
teristics of virus transmission and pathogenesis.
Genomic data from SARS-CoV-2 suggest that tubules and play an important role in the forma-
its S1 protein contains some unique adaptations, tion and development of spermatozoa. Androgens
promote spermatogenesis and the development of
1110
Relationship between COVID-19 and the male reproductive system
- use the same ACE2 receptor to invade cells and

tenance of male secondary characteristics and this indicates that the pathogenesis of their infec-
sexual function. tions is similar. Second, they have approximately
Although SARS-CoV has not been detect-
ed in the testes, SARS-CoV infection can still (fever, cough, and dyspnea) caused by their in-
cause severe immune damage to the testes and fection are very similar. Therefore, it is not sur-
cells. These pathological changes may be directly have the same complications or sequelae as those
caused by the local replication of SARS-CoV-me-
diated cytopathic effects, or indirectly as a result Although SARS-CoV and SARS-CoV-2 are
of a harmful immune response and cytokine highly similar, there are still some differenc-
response to a viral infection or systemic toxicity es among them. The receptor binding domain
due to respiratory failure15. At present, there is no (RBD) in the S protein is the most variable part
direct evidence to prove that SARS-CoV can di- of the coronavirus13
rectly infect the testicle, but this possibility cannot amino acids of the RBD are essential for ACE2
be ruled out. Currently, testicular injury is a more receptor binding and selection of hosts; these
convincing explanation for the complications or .
Moreover, several key residues in SARS-CoV-2
-
-
that compared to SARS-CoV, SARS-CoV-2 is
have persistent fever. When the human body is
in a state of high fever for a long time, changes
in testicular temperature occur, and germ cells rapidly among the population .
15
. Under normal ACE is an important part of the renin-angioten-
circumstances, the appropriate temperature for sin-aldosterone system and plays a crucial role in
body temperature. High temperature has been

reported to induce cell apoptosis14,16. heart, kidneys, lungs, liver, and intestinal tissues,
Macrophages in the testicular mesenchyme -
can secrete tumor necrosis factor, interleukins,
that men are more likely to contract SARS-
local regulation of testicular function in a para- 20,21
. The
crine or autocrine manner. A prominent feature high infection rate and susceptibility rate of men
of the testes infected by SARS-CoV is leukocyte had undoubtedly aggravated the harm caused
14
. Macrophages and leukocytes cells by COVID-19 to men. A large-scale prospective
express ACE2 and can affect testosterone produc- cohort study22 conducted in the United Kingdom
tion by testicular interstitial cells, destroying the
blood testicular barrier and spermatogonial cells. COVID-19 are men. A recently performed sin-
cytokines they produce may activate an auto-

immune response in the seminiferous tubules to highly expressed in the spermatogonia and Ley-
dig and Sertoli cells23
is a large amount of IgG deposition in the vas a high potential of SARS-CoV-2 infection in hu-
deferens epithelium, including that in some de- man testes. If the spermatogonia are infected and
generated germ and supporting cells. This result destroyed by the SARS-CoV-2, spermatogenesis
suggests that SARS-CoV may not directly infect -
the testes, but that it triggers a secondary autoim- phasize the risk posed by COVID-19 to testicular
mune response. Like other viral orchitis, SARS cells and the process of spermatogenesis.
orchitis is an autoimmune orchitis14. -
SARS-CoV-2 and Orchitis of the blood-testis barrier (BTB). The BTB pro-
SARS-CoV and SARS-CoV-2 are highly sim- vides protection from autoimmune cell destruc-
tion, making the testes an immune-privileged
1111
T.-T. Meng, R.-J. Dong, T.-G. Li
site. The composition of BTB includes its phys- son to believe that the sequelae or complications
ical and immunomodulatory components. The
physical components comprise a layer of Sertoli of this, it is necessary that infected men be exam-
cells connected by tight junctions24; the immuno- ined for fertility soon after recovery, especially
modulatory components are mainly composed of
- to have children. Furthermore, measures should
ry factors by testicular cells, most prominently, be taken to safeguard the reproductive health of
25,26
. The high
expression of ACE2 on Sertoli cells makes the to screen these patients. We can help these pa-
physical barrier of BTB vulnerable to attack by tients by formulating screening criteria and via
viruses. When cells are attacked by viruses, the timely screening and formulating standard treat-
- ment strategies.
as T-lymphocytes and macrophages to gather in

the testes. Although the immune system plays Conflict of Interest
an important anti-viral role, excess production
of immune factors is also disadvantageous and
may cause orchitis. The massive release of in-
Financial Disclosure
-
adaptive immune response after a SARS-CoV-2 tionships relevant to this article to disclose.
infection, but it may also lead to uncontrolled
the number of lymphocytes and the dysfunction Funding

- -
mune response. This may even lead to secondary
autoimmune orchitis . 345 Talent Project.
The direct evidence for the effect of COVID-19
on male reproductive function comes from a
Authors’ Contribution
-
- script.
-
-
didymides from decreased COVID-19 patients
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Prostate Cancer and Prostatic Diseases (2022) 25:27–38
https://doi.org/10.1038/s41391-021-00388-3
REVIEW ARTICLE
Is COVID-19 a risk factor for progression of benign prostatic

hyperplasia and exacerbation of its related symptoms?: a systematic
review
Abdolreza Haghpanah 1,2 Fatemeh Masjedi
●
1 ●
Mehdi Salehipour 2 ●
Alireza Hosseinpour 1,3 ●
Jamshid Roozbeh 1 Anahita Dehghani 1

●
Received: 17 November 2020 / Revised: 28 April 2021 / Accepted: 30 April 2021 / Published online: 18 May 2021
© The Author(s), under exclusive licence to Springer Nature Limited 2021
Abstract
Background To explore the potential mechanisms of SARS-CoV-2 in targeting the prostate gland, leading to exacerbation of
benign prostatic hyperplasia (BPH) symptoms and greater risks of BPH complications such as acute urinary retention.
Methods A categorized and comprehensive search in the literature has been conducted by 10 April 2021 using international
1234567890();,:
databases including PubMed, Embase, Web of Science, Scopus, and Cochrane Library in line with the PRISMA guidelines
1234567890();,:
recommendations. PICO strategy was used to formulate the research question. The following terms were used: urology,
COVID-19, coronavirus, BPH, inflammation, androgen receptors, LUTS, IPSS, PSA, and SARS-CoV-2 or a combination of
them. Studies with irrelevant purposes and duplicates were excluded. The selected studies were performed on humans and
published in English.
Results The research revealed 89 articles. After title screening and considering exclusion criteria, 52 papers were included
for the systematic review. BPH is a common condition affecting older men. SARS-CoV-2 infects the host cell by binding to
angiotensin converting enzyme 2 (ACE2). A hyperactivated RAS system during infection with SARS-CoV-2 may lead to
activation of pro-inflammatory pathways and increased cytokine release. Thus, this virus can lead to exacerbation of lower
urinary tract symptoms (LUTS) and trigger inflammatory processes in the prostate gland. Since androgen receptors (AR)
play an important role in the BPH pathophysiology and infection with SARS-CoV-2 may be androgen-mediated, BPH
progression and its related symptoms can be a complication of COVID-19 through AR involvement and metabolic
disturbances.
Conclusions Based on the current findings, SARS-CoV-2 can possibly damage the prostate and worsen BPH and its related
LUTS through ACE2 signaling, AR-related mechanisms, inflammation, and metabolic derangement. We encourage future
studies to investigate the possible role of COVID-19 in the progression of BPH-related LUTS and examine the prostatic
status in susceptible patients with relevant available questionnaires (e.g., IPSS) and serum biomarkers (e.g., PSA).
Introduction
The outbreak of the ongoing global Coronavirus disease

2019 (COVID-19) pandemic that was caused by Severe
acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
was first identified in late 2019 in Wuhan, China; since
* Fatemeh Masjedi then, the world has faced a great global catastrophe; this
masjedi_f@sums.ac.ir
life-threatening crisis has proven challenging to overcome
1
Shiraz Nephro-Urology Research Center, Shiraz University of [1]. The most common manifestation of the novel cor-
Medical Sciences, Shiraz, Iran onavirus seems to be pneumonia [2]; however, it is now
2
Department of Urology, School of Medicine, Shiraz University of widely accepted that the virus can present with symptoms
Medical Sciences, Shiraz, Iran outside the respiratory tract including digestive tract
3
Student Research Committee, Shiraz University of Medical symptoms such as nausea, vomiting, and diarrhea [3].
Sciences, Shiraz, Iran Angiotensin-converting enzyme 2 (ACE2) appears to be a
28 A. Haghpanah et al.
receptor for SARS-CoV-2, to which the virus binds to, prostate gland, leading to progression of BPH, or exacer-
enters, and infects the host cell [4]. Moreover, recent studies bation of its related LUTS.
have found that co-expression of ACE2 and TMPRSS2 in
an organ is crucial for the virus to be able to infect the organ
[5]. Previously, it was believed that the virus mainly Materials and methods
infected the lungs although discovering the co-expression of
ACE2 and TMPRSS2 in other organs such as the kidneys, Search strategy and selection criteria
testes, and prostate raises the question of whether or not the
virus can affect the aforementioned organs [6]. A categorized and comprehensive search in the literature
Benign prostatic hyperplasia (BPH) is a histologic was conducted by 10 April 2021 using international data-
diagnosis defined as excessive growth of the epithelial and bases including PubMed, Embase, Web of Science, Scopus,
stromal cells located in the transition zone of the prostate and Cochrane Library in line with the recommendations
gland. BPH is the most common cause of benign prostatic from the Preferred Reporting Items for Systematic Reviews
enlargement (BPE), benign prostatic obstruction, and and Meta Analyses (PRISMA) guidelines [21]. All the
bladder outlet obstruction in older men [7–9]. Lower urin- records in English were included for investigating their
ary tract symptoms (LUTS) are considered a consequence eligibility, both published and peer-reviewed on-line pub-
of a wide range of etiologies such as BPH and non-prostatic lications. Additional sources were identified from citations
conditions including dysfunction of the bladder [10, 11]. of the retrieved literature. There was no limitation on
Furthermore, international prostate symptom score (IPSS), sample size. Published reports of experiences with the
as a validated questionnaire, and serum prostate-specific SARS-CoV-2 have increased greatly in the past months, but
antigen (PSA) measurement are considered to evaluate the no randomized trials to date regarding possible treatments
patients with BPH [10, 12]. have been identified regarding possible treatments. Most
There are different risk factors related to the development reports related to BPH or male prostate problems involved
of BPH such as LUTS, prostate growth, old age, sex-related small cohorts, case reports, and editorials. Similarly, prior
hormones, and chronic inflammation [13]. The prevalence publications of other coronaviruses were limited in number.
of BPH is increased in an age-dependent manner. It is We reviewed all the titles for considering their eligibility.
estimated that 8% and 50% of male population at the 4th Full-text articles were then reviewed and evaluated for
and 6th decade of life, respectively, are diagnosed with inclusion by authorship teams. The authors acknowledge
pathological BPH [14]. that the number of publications about the novel SARS-
Recent studies have shown that males are more suscep- CoV-2 is increasing at an exponential rate and there may be
tible to SARS-CoV-2 infection and elder population seems bias toward reporting of positive findings. We used a broad
to develop more severe cases of COVID-19 and subse- inclusive search strategy in order to prevent missing any
quently they are more susceptible to hospitalization relevant records. Two experienced investigators conducted
[15, 16]. Furthermore, a significant number of patients with the systematic search. Population, intervention, comparison,
COVID-19 are asymptomatic carriers [17, 18]. As men- and outcome strategy was used to formulate the research
tioned before, BPH increases in an age-dependent manner question: “Are BPH patients infected with SARS-CoV-2 at
and then, a considerable number of older males are diag- greater risk of developing LUTS and BPH-related compli-
nosed with BPE [14]. Thus, one can hypothesize that a cations compared to the normal population?” (Table 1). The
remarkable group of older male patients with COVID-19 following phrases were searched in different databases:
including severe cases may have BPH as a comorbid con- “severe acute respiratory syndrome coronavirus 2,” “2019
dition and this condition may be exacerbated by COVID- nCoV,” “SARS-CoV-2,” “coronavirus,” “COVID-19,”
19. Recently, emerging studies have proposed that LUTS “benign prostatic hyperplasia,” “inflammation,” “androgen
may be increased early symptoms of COVID-19 and IPSS,
especially in older males, may be possible complications of Table 1 PICO strategy was used to formulate the research question:
“Are BPH patients infected with SARS-CoV-2 at greater risk of
this disease [19, 20]. To date, no study has investigated the
developing LUTS and BPH-related complications compared to the
potential mechanisms of SARS-CoV-2 in causing BPH- normal population?”.
related complications, LUTS or exacerbation of a pre-
viously diagnosed BPE in severe cases, and asymptomatic P (Population) Patients with BPH
carriers of COVID-19 and the underlying mechanisms I (Intervention or Infection with SARS-CoV-2
exposure)
resulting in this condition as a complication of COVID-19
C (Comparison) Normal population
are not elucidated.
O (Outcome) Lower urinary tract symptoms (LUTS)
In this review, the main purpose was to explore the
and BPH-related complications
potential mechanisms of SARS-CoV-2 in targeting the
Is COVID-19 a risk factor for progression of benign prostatic hyperplasia and exacerbation of its. . . 29
receptors,” “lower urinary tract symptoms,” “bladder outlet grouping of the relevant studies about mechanisms of pro-
obstruction,” “benign prostatic enlargement,” “international gression of BPH as a consequence of SARS-CoV-2
prostate symptom score,” “prostate specific antigen,” infection.
“cytokine storm,” “angiotensin-converting enzyme 2
receptor,” “ACE2,” “5-α reductase inhibitor,” and “prostate
involvement” or a combination of them in the titles/ Results
abstracts.
Potential mechanism of SARS-CoV-2 infection in the
Data extraction BPH progression through RAS dysregulation
Two authors (AH and FM) independently screened for The renin–angiotensin system (RAS) is a hormonal cascade
inclusion, using the pre-specified criteria. If it was clear that regulates the blood pressure and cardiovascular func-
from the abstract that the study did not meet the selection tion through its components including angiotensin-II (Ang-
criteria through reviewing the abstract, it was excluded. If it II), and angiotensin converting enzyme (ACE) and RAS
was unclear, the full paper was retrieved. Then, for relevant hyperactivity is associated with hypertension [22, 23].
records, the full text was evaluated; discrepancies were Augmented Ang-II level is associated with cellular growth
resolved via consensus after discussion between two of the and its activity is mainly mediated by angiotensin-II type 1
authors. receptor (AT1R) [24].
The search revealed 89 manuscripts after removal of It is well-established that RAS components are locally
duplicates and inappropriate articles. Fifty-five manuscripts present in the prostate gland [24, 25]. Ang-II has been
were related to prostate gland and coronaviruses. Small detected in epithelial basal layer of the prostate and AT1R
cohorts, case reports, comments on guidelines, guidelines, was found in the smooth muscle cells of both vessels and
editorials were retrieved. After exclusion, 52 manuscripts the stoma of the prostate gland in some studies [25, 26].
were included in the review based on relevance and There is evidence that the expression of ACE and Ang-II
new data. was markedly increased in patients with BPH. Moreover,
The PRISMA flow chart demonstrating the process for AT1R expression is downregulated in patients with BPH
the systematic search of the literature and selection of the due to increased level of Ang-II [26]. Thus, this highlights
studies is shown in Fig. 1. Furthermore, Table 2 showed the potential role of RAS in the development of BPH, and
RAS blockade can be suggested as a therapeutic option in
patients with BPH.
ACE2 is an enzyme that is known to counterbalance the
effects of ACE by cleaving Ang-II to Ang (1–7), a product
that binds to Mas receptor. Studies have demonstrated that
ACE2 has anti-fibrotic and anti-inflammatory activities and
acts as a vasodilator [27–30]. As mentioned before, Ang-II
is remarkably increased in BPH and it has been revealed
that Ang-II leads to downregulation of ACE2 and subse-
quently, a decrease in Ang (1–7) will be observed [26].
Given that Ang-II leads to cellular growth and ACE2-Ang-
(1–7)/Mas receptor pathway counterbalances ACE and
Ang-II functions, the potential role of ACE2 as a novel
therapeutic option for treating BPH [31] is emphasized
(Fig. 2).
Studies on SARS-CoV-2 characteristics have deli-
neated that the virus binds to ACE2 receptor, which is
expressed in many human tissues such as lung, kidney,
prostate, and pancreas, and infects the target tissue. Thus,
there is mounting concern about the possibility of the
mentioned organs involvement as targets of SARS-CoV-2
[6]. It has been demonstrated that serine protease
Fig. 1 Article’s selection process: the PRISMA flow chart. Litera- TMPRSS2 is necessary for priming the viral spike protein
ture search according to the Preferred Reporting Items for Systematic and the co-expression of TMPRSS2 and ACE2 is crucial
Reviews and Meta Analyses (PRISMA) guidelines. for cell entry. Moreover, it has been suggested that when
30
Table 2 Grouping the relevant studies about mechanisms of progression of BPH as a consequence of SARS-CoV-2 infection.
Subheadings of the results Main finding Year References
RAS dysregulation studies The main host cell receptor for the viral entry of SARS-CoV-2 is angiotensin-converting enzyme 2 (ACE2). Analysis 2020 Xu et al. [6]
of RNA-seq profiling data of 27 organ types (including prostate) verified the ACE2 expression in the epithelial cells.
Hyperactivation of the renin–angiotensin aldosterone system (RAAS) results in the augmentation of the bioactive 2018 Singh et al. [31]
peptide hormone angiotensin-II, which downregulates the ACE2-angiotensin 1–7/Mas receptor pathway and
upregulates angiotensin receptor type 1-mediated signaling, and finally may lead to proliferation of cellular elements
in the prostatic tissue. ACE2, Ang-(1–7), and the Mas receptor can be employed as a novel target of treatment in
BPH/LUTS.
The presence of Ang-II peptide in the basal layer of the epithelium and AT(1) receptors on stromal smooth muscle, 2002 Dinh et al. [26]
suggests that Ang-II may mediate paracrine functions on cellular growth and smooth muscle tone in the prostatic
tissue. AT(1) receptor downregulation in BPH may be induced by hyperstimulation of the receptor secondary to a rise
in the local levels of Ang-II in BPH.
The prevailing presence of AT(1) receptors in the periurethral region of the prostatic tissue suggests a potential role 2001 Dinh et al. [24]
for Ang-II in modulating smooth muscle cell tone, cellular growth, and possibly micturition. This can suggest a key
role for Ang-II in modulating the sympathetic transmission in prostate.
A localized concentration of angiotensin converting enzyme (ACE) is observed in the glandular epithelium of 2001 Nassis et al. [25]
prostatic tissue and an abnormal increase in its expression at protein and mRNA level is seen in BPH.
Inflammation-related studies COVID-19-induced cytokine storm increases the activity of the RAAS and complement system. 2020 Mahmudpour et al. [41]
Viral or bacterial infections may induce local inflammation characterized by proliferation in inflammatory cytokines, 2019 Madersbacher et al. [13]
chemokines, and growth factors. Epithelial and stromal cell growth of the prostate is triggered by this inflammatory
response.
There is a strong correlation between acute and chronic inflammation seen in prostatic enlargment and LUTS, which 2016 Bushman et al. [38]
can be a primary reason of prostatic fibrosis and hence, bladder outlet obstruction (BOO).
Expression of androgen receptor variant 7 (AR-V7) secondary to nuclear factor-kappa B (NF-κB) activation in the 2016 Austin et al. [39]
prostatic tissue is linked with increased severity of BPH.
Inflammation in the prostate seems to be a major risk factor for prostatic growth and exacerbation of the related 2011 Chughtai et al. [32]
symptoms. Stromal-derived IL-8 is a possible candidate in the link between chronic inflammation and proliferation in
stromal cells.
Inflammatory cytokines IL-6, IL-8, and IL-17 are responsible for induction of fibromuscular growth through inducing 2006 Kramer et al. [34]
COX-2 expression or an autocrine or paracrine loop. Toll-like receptor signaling triggers the immune response, which
is mediated predominantly by macrophages and T cells. Conversely, anti-inflammatory markers including
macrophage inhibitory cytokine-1 are diminished in symptomatic BPH tissues.
All BPH-derived specimens showed a rise in CD45+ leukocytes such as CD3+ T lymphocytes, CD11c+ 1992 Theyer et al. [35]
macrophages and CD20+ B lymphocytes when compared to normal prostate.
Androgen related studies Transmembrane protease, serine 2 (TMPRSS2), which is a serine protease essential for priming of the viral spike 2020 Wambier et al. [51]
protein, requires androgen receptor activity for its gene transcription.
Androgenic alopecia is a common finding in a remarkable portion of the male patients hospitalized due to COVID- 2020 Wambier et al. [52]
19.
Alteration in AR signaling pathway in stromal and epithelial cells of the prostatic tissue is considered a major 2019 Vickman et al. [71]
underlying cause for chronic inflammation and BPH development.
A. Haghpanah et al.
Table 2 (continued)
Subheadings of the results Main finding Year References
Infiltration of macrophages potentiates the proliferation of stromal cells through androgen receptor (AR)-signaling 2017 Xu et al. [50]
pathway, although transitional and peripheral zones of the prostate appear to respond differently due to variable
responses to AR signaling in the mentioned zones.
A drop in the expression of AR in luminal cells of patients with BPH correlates with a higher degree of regional 2016 Zhang et al. [48]
prostatic inflammation.
Proliferation of epithelial cells leads to the growth of the stromal cells via epithelial–stromal cell interaction and 2013 Izumi et al. [43]
epithelial–mesenchymal transition (EMT). Overall, AR signaling is responsible for infiltrating macrophages and
epithelial and stromal cell proliferation and consequently development of BPH.
Androgen receptor (AR)/inflammatory cytokine CCL3-dependent pathway is an important underlying mechanism in 2012 Wang et al. [49]
infiltration of macrophges and subsequently stromal cell proliferation in the prostate.
TGF-β seems to be the main marker in EMT and BPH is characterized by promoted growth of mesenchymal-like 2009 Alonso-Magdalena et al. [45]
cells in prostatic epithelium and endothelium.
High levels of dehydrotestosterone (DHT) are associated with pathologic prostate growth in the adult prostate tissue. 2003 Carson III et al. [55]
5-α reductase inhibitors (5-ARIs) may impair the ability of the lungs in regeneration and may be associated with 2020 Adamowicz et al. [54]
worse outcomes in COVID-19.
Taking 5-ARIs, which are prescribed in androgenetic alopecia and benign prostatic hyperplasia, is associated with 2020 McCoy et al. [56]
decreased symptoms and severity of COVID-19.
Finasteride, which is a single receptor 5-alpha reductase inhibitor (5-ARI), acts by blocking dihydrotestosterone 2020 Dhurat et al. [72]
(DHT). Dutasteride, a dual receptor DHT blocker, has a higher potency than its predecessor, finasteride.
Finasteride treatment can augment estradiol levels and also block posttraumatic cytokine secretion of alveolar 2011 Zeckey et al. [59]
macrophages (AM), as well as decrease concentration of MCP-1 and MIP-1β in lung tissue.
Finasteride administration prevents the increase in cytokine plasma levels, decreases DHT, and increases 17beta- 2007 Frink et al. [58]
estradiol plasma concentrations. Neutrophil infiltration and edema formation in the lung are also reduced by
finasteride.
Finasteride, a selective inhibitor of the type 2 isoenzyme, can cause a significant drop in serum DHT level, although 2004 Clark et al. [57]
Is COVID-19 a risk factor for progression of benign prostatic hyperplasia and exacerbation of its. . .
dutasteride by inhibiting both isoenzymes can decrease DHT levels more significantly.
Metabolic derangement related Since ACE2 is expressed in metabolic tissues such as pancreatic beta cells, adipose tissue, the small intestine, and the 2020 Rubino et al. [65]
studies kidneys, it is plausible that SARS-CoV-2 may deteriorate pre-existing metabolic abnormalities or even lead to new
onset ones.
Pre-existing cardiovascular disease seems to be linked with worse outcomes and increased risk of death in patients 2020 Nishiga et al. [66]
with COVID-19, whereas COVID-19 itself can also induce myocardial injury, arrhythmia, acute coronary syndrome,
and venous thromboembolism.
The localization of ACE2 expression in the endocrine part of the pancreas suggests that SARS coronavirus enters and 2010 Yang et al. [64]
damages islets causing acute diabetes.
Metabolic syndrome (MetS), defined as a set of metabolic abnormalities such as high visceral adiposity and insulin 2017 Ngai et al. [63]
resistance, appear to be a common condition in patients with BPH and LUTS and probable underlying mechanisms
leading to BPH are sex-related hormonal change, systemic inflammation, insulin resistance, and aberrant lipid profile.
Diabetes-induced hyperglycemia and the subsequent insulin resistance is related to the increased risk of BPH 2014 Breyer et al. [60]
and LUTS.
31
Fig. 2 The role of the ACE2 and the detrimental effect of SARS- to the cellular signaling that opposes the Ang-II effects on BPH pro-
CoV-2 in the RAAS during progression of BPH/LUTS. Renin gression and does not stimulate aldosterone secretion. The SARS-
cleaves angiotensinogen into angiotensin I (Ang I), and the circulating CoV-2 disturbs the balance of RAAS by downregulating the ACE2
Ang I is hydrolyzed to Ang-II by ACE. Ang-II activates the AT1R to expression levels. Conclusively, the disproportion between AT1R and
lead to pro-hypertrophy, pro-fibrosis, pro-oxidant, pro-inflammation, Mas R/megalin R axes in infected patients with SARS-CoV-2 con-
vasoconstrictor response, and to increase aldosterone synthesis. ACE2 tributes to the development of BPH/LUTS and more severe inflam-
directly hydrolyzes Ang I and Ang-II to generate Ang 1–9 and Ang matory reactions.
1–7, respectively. Ang 1–7 binds to the Mas R/megalin R, which leads
the virus binds to ACE2 receptor through its spike protein, future studies to investigate the possibility of BPH pro-
it leads to downregulation of ACE2 [4]. Given the fact gression as a result of COVID-19.
that ACE2, which is a component of ACE2/Ang-(1–7)/
Mas system, counteracts the proliferative and inflamma- The possible role of inflammation in the progression
tory effects of Ang-II by controlling and inhibiting of BPH symptoms secondary to SARS-CoV-2
infection and inflammation it can be concluded that infection
infection with SARS-CoV-2 and a subsequent down-
regulation of ACE2 can lead to aggravation of a pre- A correlation between the development of BPH and chronic
viously diagnosed BPE. Therefore, diminished ACE2 inflammation has been assumed. This inflammation can be
expression and following ACE2 loss of function in the triggered by etiologies such as bacterial or viral infection
cellular membranes of the prostate tissue, due to viral [13, 32]. First, bacterial or viral infection can lead to loca-
invasion, can be trigger signals for progression of BPH lized prostatic inflammation and subsequently production of
(Fig. 2). Consequently, this highlights the urgent need for different inflammatory cytokines such as IL-6, IL-8, IL10,
Fig. 3 The story of androgens and androgen receptors (AR) in the androgen-responsive elements for its gene transcription. 5-alpha
development of BPH and severity of COVID-19. There are bidir- reductase inhibitors (5-ARIs) increase androgen levels and possibly
ectional interactions between BPH and COVID-19. Increased pro- the severity of COVID-19 via inhibiting the conversion of testosterone
duction of dihydrotestosterone (DHT) and AR activity through to dihydrotestosterone. On the other hand, these inhibitors probably
promoting growth in the prostate epithelial and stromal cells and reduce the complications of COVID-19 by reducing DHT production,
triggering a localized inflammation led to the development and pro- increasing estradiol levels, and suppressing some inflammatory
gression of BPH. TMPRSS2, which is an essential serine protease for mechanisms.
priming of the spike protein of SARS-CoV-2, requires AR activity and
and TNF-β by stromal prostatic cells and infiltrated lym- in the interstitium [35]. Furthermore, inflammatory media-
phocytes and macrophages [13, 33–35]. Moreover, it has tors seem to play a major role in the progression and
been demonstrated that the inflammatory process in the severity of BPH and LUTS [38]. There is evidence that
prostate can result in the release of self-antigens, trigger an nuclear factor-kappa B (NF-κB) pathway is activated in
autoimmune response, and subsequently cause tissue BPH patients and is closely associated with the disease
damage [36]. severity [39]. Notably, systemic inflammation may con-
It has been suggested that prostatic inflammation is a risk tribute to LUTS-related irritative symptoms especially in
factor for BPH progression [13]. A study has demonstrated overweight males [40]. As a result, accumulating evidence
that stromal nodules containing a remarkable number of B- suggests the potential role of inflammatory mediators and
and T-cell lymphocytes were detected in specimens from infiltrated inflammatory cells in BPH progression and
patients with BPH, whereas these nodules were not detected severity.
in normal prostates [37]. Theyer et al. investigated the Studies have revealed that ACE2 and its product Ang
characterization of the leukocytes in BPH and found a (1–7) seem to function as an antiproliferative and anti-
significant increase in CD45+ leukocytes including macro- inflammatory agent and modulate leukocyte infiltration and
phages, B-cell, and T-cell lymphocytes were mainly present cytokine secretion by counterbalancing the Ang-II effects
[41]. Moreover, Ang (1–7) seems to have anti-inflammatory essential for priming of the viral spike protein, requires AR
effects through suppressing the NF-κB pathway and cyto- activity for its gene transcription [51] (Fig. 3). Male patients
kines such as IL-6, tumor necrosis factor (TNF)-α, and IL-8 with androgenic alopecia appear to be at greater risk of
[41, 42]. SARS-CoV-2 induces the suppression of ACE2 in developing severe cases of COVID-19 and hence, hospita-
order to gain entry to the target cells [4]. These results lization supports the hypothesis that COVID-19 is
provide evidence that infection with SARS-CoV-2 and androgen-mediated [52, 53].
subsequently suppression of ACE2 may lead to activation As mentioned before, AR are widely expressed in both
of pro-inflammatory pathways, increased cytokine release, epithelial and stromal cells of the prostatic tissue and play a
and consequently cause inflammatory responses in vulner- major role in the development of BPH [43, 44]. Moreover,
able organs such as the prostate. Although the inflammatory infection with SARS-CoV-2 seems to be androgen-
mechanism in progression of BPH and its symptoms is still mediated [51]. Thus, given that AR play a pivotal role in
obscure and needs to be elucidated, it can be hypothesized pathophysiology of BPH, one can conclude that causing
that SARS-CoV-2 can lead to development of irritative progression of BPH may be a complication of COVID-19
symptoms of BPH and trigger inflammatory process in the and further studies should be conducted to investigate this
prostate gland, so prospective studies can help to clarify possibility (Fig. 3).
this issue. It has been shown that high levels of DHT play a major
role in pathophysiology of BPH; thus, decreasing the level
Evidence for the role of androgen receptors in BPH of DHT through inhibition of 5-alpha reductase enzyme
development as a consequence of SARS-CoV-2 with agents such as finasteride and dutasteride is a key
infection therapeutic option proposed for BPH treatment [54, 55].
Adamowicz et al. has suggested that 5-alpha reductase
The theory that androgen receptors (AR) play a key role in inhibitors (5-ARIs) impair the ability of the lungs in
the development of BPH is well-established [43]. AR are regeneration through augmenting the androgen levels in the
widely expressed in both epithelial and stromal cells of epithelium of the lungs [54]; thus, it has been hypothesized
the prostate. First, studies have revealed that AR result in that patients taking 5-ARIs such as finasteride and
promoting growth in the prostate epithelial cells [44]. dutasteride have more propensity to develop COVID-19
Although it has been demonstrated that BPH consists of and they may develop more severe cases.
more stromal cells rather than epithelial cells, prolifera- On the other hand, a new study has also revealed that
tion of epithelial cells lead to the growth of the stromal using 5-ARIs may be associated with less severe symp-
cells via epithelial–stromal cell interaction and toms of COVID-19, although it may take weeks to reach
epithelial–mesenchymal transition [45]. While there is no an effective level in order to decrease DHT [56, 57].
definite solidarity regarding any alteration in AR expres- However, caution should be exercised when attempting to
sion throughout BPH progression, a rise in stromal to draw conclusions about the mechanism of action and
epithelial AR ratio is noted in BPH that plays a key role in efficacy of these drugs that have variable effects on mul-
the progression of BPH [46]. Next, accumulating evi- tiple tissues.
dence suggests that AR induce stromal cell proliferation The results of previous studies revealed that pretreatment
and consequently lead to development of BPH. AR play a with finasteride reduced the levels of systemic cytokines
role in increased recruitment of migrating macrophages and pro-inflammatory mediators such as macrophage
into the prostate stromal cells; therefore, they cause pro- inflammatory protein-1b and TNF-α released from isolated
motion of stromal cell proliferation and subsequently lead alveolar macrophages, and increased estradiol levels
to BPH progression [43]. Contemporary data has assumed [58, 59]. These results suggest that inhibition of 5-alpha
that modified AR expression can also contribute to BPH reductase leads to the conversion of testosterone to 17beta-
progression by triggering a localized inflammation [47]. A estradiol, which produces salutary effects on the immune
drop in AR expression in prostatic luminal cells followed response.
by a rise in epithelial cells results in local inflammation Therefore, it can be concluded that the use of these
mostly involving IL-1-dependent pathway. Moreover, inhibitors on the one hand can result in the deterioration
stromal cells proliferation in transition zone is related to of the COVID-19 progression by increasing androgens,
this localized inflammation via recruitment of macro- and on the other hand, contribute to the better functioning
phages in C-C Motif Chemokine Ligand 3-dependent of the immune system by reducing DHT, increasing
mechanism [48–50] (Fig. 3). estradiol production, and regulating immune responses
A recent study by Wambier et al. has hypothesized that (Fig. 3).
SARS-CoV-2 infection may be androgen-mediated. It has Overall, controversy exists regarding the role of andro-
been suggested that TMPRSS2, which is a serine protease gen pathways in the pathophysiology of COVID-19 and this
Fig. 4 Bidirectional interaction between BPH and COVID-19. metabolic syndrome) in older men with BPH. New onset of diabetes,
Benign prostatic hyperplasia (BPH) was considered as a possible cardiovascular complications, and metabolic derangement may lead to
comorbid condition for COVID-19, due to high prevalence of under- BPH development as consequences of SARS-CoV-2 infection.
lying comorbidities (cardiovascular disease, diabetes mellitus, and
should encourage future studies to clarify the possible effect change, provoking inflammation and oxidative stress [60].
of anti‐androgens on COVID‐19 patients. Furthermore, males diagnosed with hypertension appear to
be at a greater risk of more severe LUTS compared to the
Evidence for the possible role of diabetes, ones without hypertension [61]. Besides, MetS, which is
cardiovascular dysregulation, and metabolic defined as a set of metabolic abnormalities such as high
syndrome (MetS) in BPH aggravation and SARS-CoV- visceral adiposity and insulin resistance, is a common
2 infection as a potential culprit condition in patients with BPH and LUTS and the majority
of the studies support the hypothesis that there seems to be
The possible association between some metabolic disorders an association between MetS and BPH and its related LUTS
including diabetes, cardiovascular diseases, and MetS and [62]. Although the exact underlying mechanism is not fully
development of LUTS has been extensively studied. There determined, probable culprits are sex-related hormonal
is evidence of a propensity for development of BPH and change, systemic inflammation, insulin resistance, and
LUTS in patients with diabetes. This can be explained by aberrant lipid profile [63].
some factors associated with diabetes-induced hyperglyce- ACE2, which is the main entry receptor for SARS-CoV-
mia such as proliferation in prostate gland induced by 2, is found throughout the metabolic organs such as adipose
insulin and related trophic factors, sex steroid hormonal tissue and pancreatic beta cells, raising concerns regarding
the possibility of key metabolic organs involvement by the the present time and only a few studies have proposed BPH
virus and resulting in new onset or exacerbation of pre- management during the SARS-CoV-2 pandemic. However,
existing metabolic conditions such as diabetes. Interest- our literature review showed that different mechanisms such
ingly, there are case reports of newly detected diabetes in as ACE2 signaling alteration, AR-related mechanisms,
patients infected with SARS-CoV [64]. Thus, these findings inflammation, and metabolic derangement might lead to
suggest that COVID-19 may deteriorate pre-existing meta- aggravation of BPH-related LUTS and its complications
bolic abnormalities or even lead to new onset ones includ- (e.g., AUR) over and after the course of infection with
ing diabetes [65]. SARS-CoV-2.
Studies have found that patients with an underlying Overall, since infection with SARS-CoV-2 seems to be
cardiovascular disease are more susceptible to worse out- an unraveled challenge for the human being, a deeper
comes of COVID-19 if infected. Moreover, studies have investigation regarding the possibility of COVID-19 leading
shown that COVID-19 can cause venous thromboembo- to exacerbation of BPH symptoms and worsening of the
lism, acute coronary syndrome, and myocardial injury [66]. previously diagnosed condition may help the scientists and
Taken together, the hypothesis that SARS-CoV-2 can clinicians discover novel mechanisms of infection of this
result in new onset comorbid conditions such as diabetes disease in addition to better management of it.
and cardiovascular diseases or exacerbate the previously
diagnosed comorbidities has gained recognition. Since these Acknowledgements The authors wish to thank Dr Nasrin Shokrpour,
comorbidities are considered a risk factor for developing professor of English at Shiraz University of Medical Sciences, and Ms
LUTS and BPH and their pathophysiology are connected in Sheryl Thomas-Nikpoor, Language Editor, Springer Publications for
some ways, these findings suggest a potential route for her invaluable comments in editing this paper. We also appreciate
Center for Development of Clinical Research of Namazi Hospital for
development of LUTS and BPH secondary to exacerbation their helpful assistance.
or new onset development of comorbid metabolic condi-
tions and further studies should investigate this possibility Author contributions A Ha, FM, and A Ho researched data for the
(Fig. 4). article; MS and JR made substantial contributions to discussions of
content; A Ha, FM, A Ho, and AD wrote the article; and MS and JR
reviewed and edited the manuscript before submission.
Conclusions and future prospective Funding This study was supported by the Vice Chancellor of
Research Affairs, Shiraz University of Medical Sciences (Academic
The pandemic caused by the new coronavirus represents an Grant Number: 99-01-18-23730).
extraordinary scenario in modern medicine that affects
many aspects of daily healthcare. Since BPH has a high Compliance with ethical standards
prevalence and is more common in older men who are more
prone to COVID-19, we suggest a closer monitoring of Conflict of interest The authors declare no competing interests.
older patients who are more susceptible to both BPH-related
Publisher’s note Springer Nature remains neutral with regard to
LUTS and also COVID-19 infection during this pandemic. jurisdictional claims in published maps and institutional affiliations.
In general, BPH and its related LUTS progress slowly
over a long period of time. It is demonstrated that the
chance of presenting with acute urinary retention (AUR) in References
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ISSN 0006!2979, Biochemistry (Moscow), 2021, Vol. 86, No. 4, pp. 389!396. © Pleiades Publishing, Ltd., 2021.
Published in Russian in Biokhimiya, 2021, Vol. 86, No. 4, pp. 459!468.
MINI!REVIEW
COVID!19 Pandemic and Male Fertility:

Clinical Manifestations and Pathogenic Mechanisms
Adel Abdel!Moneim
Molecular Physiology Division, Faculty of Science, Beni!Suef University, 62511 Beni!Suef, Egypt
e!mail: adel_men2020@yahoo.com; adel.hassan@science.bsu.edu.eg
Received October 21, 2020
Revised January 3, 2021
Accepted January 7, 2021
Abstract—The novel coronavirus disease!2019 (COVID!19) pandemic, caused by severe acute respiratory syndrome coro!
navirus 2 (SARS!CoV!2), has been a major public health emergency worldwide with over 118.27!million confirmed
COVID!19 cases and 2.62!million deaths recorded, as of March 12, 2021. Although this disease primarily targets lungs,
damages in other organs, such as heart, kidney, liver, and testis, may occur. Testis is the cornerstone of male reproduction,
while reproductive health is the most valuable resource for continuity of the human race. Given the unique nature of SARS!
CoV!2, the mechanisms of its impact on the testes have yet to be fully explored. Notably, coronaviruses have been found to
invade target cells through the angiotensin!converting enzyme 2 receptor, which can be found in the respiratory, gastroin!
testinal, cardiovascular, urinary tract, and reproductive organs, such as testes. Coronavirus studies have suggested that testes
might be a potential target for SARS!CoV!2 infection. The first etiopathogenic concept proposed by current hypotheses
indicates that the virus can invade testes through the angiotensin!converting enzyme 2 receptor. Next, the activated inflam!
matory response in the testes, disease!associated fever, and COVID!19 medications might be implicated in testicular alter!
ations. Although evidence regarding the presence of SARS!CoV!2 mRNA in semen remains controversial, this emphasizes
the need for researchers to pay closer attention to sexually transmitted diseases and male fertility after recovering from
COVID!19. In this review the latest updates regarding COVID!19!associated testicular dysfunction are summarized and
possible pathogenic mechanisms are discussed.
DOI: 10.1134/S0006297921040015
Keywords: COVID!19, SARS!CoV!2, testis, manifestations, pathogenicity, male fertility
INTRODUCTION the male sex as one of the risk factors for COVID!19 [3].
Although COVID!19 primarily manifests as an acute res!
The novel coronavirus disease!2019 (COVID!19) piratory illness, it can also affect other organs such as the
pandemic, caused by the severe acute respiratory syn! kidney, heart, testes, and liver [4].
drome coronavirus 2 (SARS!CoV!2), is the current glob! Previously testicular damage and spermatogenesis
al public health issue with exponential rise in infections abnormalities were observed in patients infected with
worldwide [1]. COVID!19 pandemic has affected 213 SARS: all SARS!CoV!infected testes displayed wide!
countries with more than 118.27!million confirmed cases spread germ cell destruction, few or no spermatozoon in
and 2.62!million disease!associated deaths as of the seminiferous tubules, and leukocyte infiltration [5].
March 12, 2021 [2]. Recent reports indicate that almost Thus, due to the similarities between SARS!CoV and
58% of those infected with SARS!CoV2 are male, making SARS!CoV!2, the orchitis!like syndrome in male
patients with SARS!CoV!2 has been suspected [6]. The
Abbreviations: ACE2, angiotensin!converting enzyme 2; main host receptor of SARS!CoV or SARS!CoV2 is
CD3, cluster of differentiation 3; COVID!19, the novel coron!
angiotensin!converting enzyme 2 (ACE2) receptor. The
avirus disease!2019; FSH, follicle!stimulating hormone;
HIV, human immunodeficiency virus; IL, interleukin; ACE2 receptors are widespread and highly expressed in
LH, luteinizing hormone; SARS!CoV, severe acute respiratory the heart, lungs, kidneys, and testes [7]. This suggests that
syndrome coronavirus; SARS!CoV!2, severe acute respiratory SARS!CoV!2 could likely exert adverse effects on repro!
syndrome coronavirus 2; T, testosterone; TMPRSS2, trans! ductive system in males through ACE2 or other factors,
membrane protease serine 2. leading to testicular damage in male patients. Notably,
389
390 ABDEL!MONEIM
more attention should be given to the potential risk of study that showed substantial reduction in the serum
SARS!CoV!2 infection on the male fertility [8]. Testes testosterone levels in 113 patients (51.1%) with severe
are the cornerstone of male reproduction, while repro! COVID!19, suggesting this parameter as a negative predic!
ductive health is the most valuable resource for continu! tor of COVID!19 progression [15]. In addition, the recent
ity of the human race. However, little is known about the study on 119 men with COVID!19 observed that the
potential short! and long!term impact of COVID!19 on infected men had slightly lower overall serum testosterone
the male reproductive system. This review provides levels, markedly higher serum LH, and lower testosterone:
insights into clinical manifestations and possible patho! LH and follicle!stimulating hormone (FSH): LH ratios
genicity of the SARS!CoV!2 infection in relation to tes! compared to 273 age!matched healthy men [16].
ticular injury based on the latest studies. Similarly, the German study revealed that the critically ill
male COVID!19 patients exhibited elevated LH and FSH
levels with decreased testosterone and dihydrotestosterone
COVID!19 AND CLINICAL MANIFESTATIONS levels [17]. Interestingly, the serum LH elevation in male
RELATED TO TESTICULAR INJURY patients with COVID!19 could possibly inhibit the hypo!
thalamic–hypophyseal–testicular axis and perhaps
Testis orchitis. Previous studies have reported that a explain the primary Leydig cell injury [18]. Moreover, low
number of viruses could infect testes, including mumps testosterone level had been the most important predictive
virus, human immunodeficiency virus (HIV), and SARS! hormonal factor for in!hospital mortality in the group of
CoV [5, 9]. Regarding the novel SARS!CoV!2, which aged male patients [19]. Accordingly, COVID!19 may
shares 76% amino acid sequence homology with the induce acute male hypogonadism that is clinically mani!
SARS!CoV, one can hypothesize that SARS!CoV!2 may fested as a reduction in testosterone levels (table).
have the ability to invade testes. Indeed, Gagliardi et al. Virus detection in seminal fluid. To date, no records on
reported the case of orchi!epididymitis associated with the sexual transmission of SARS!CoV!2 exist, while evi!
SARS!CoV!2 infection [10]. Moreover, six patients with dence regarding the presence of SARS!CoV!2 in semen
SARS!CoV showed signs of orchitis and testicular injury remains limited. Recently, the contradictory findings have
including reduced numbers of germ cells and apoptotic been reported regarding the presence of SARS!CoV!2 in
death with interstitial leukocyte infiltration. Additionally, the semen of patients diagnosed with COVID!19.
histopathological findings showed inflammatory infiltra! Meanwhile, individuals infected with SARS!CoV!2
tions and accumulation of immunoglobulin!G (IgG), should take all possible precautions to minimize the possi!
particularly in seminiferous epithelium, interstitium, ble risk of transmitting the infection via sexual intercourse
degenerated germ cells, and Sertoli cells [5]. This finding [20]. Although actual fertility situation in the patients
is consistent with the results presented in the study of diagnosed with COVID!19 is still to be explored, the
Pan et al., where 6 out of 34 men who recovered from American Society for Reproductive Medicine (ASRM)
SARS!CoV!2 infection developed signs of scrotal dis! and the Society for Assisted Reproductive Technology
comfort [11]. Additionally, the study of serious COVID! (SART) had already published warnings regarding the
19 cases in Brazil identified fibrin microthrombi orchitis SARS!CoV!2 transmission via sexual intercourse [21].
in two of the investigated testes [12]. Similarly, post! Importantly, among the 38 patients with COVID!19 who
mortem examination of 12 COVID!19 male patients in provided semen specimens, 6 patients (15.8%) had posi!
China showed marked seminiferous cellular damage, tive results for SARS!CoV!2 RNA, including 4 of 15
reduced Leydig cell number, and moderate lymphocytic patients (26.7%) who were at the acute stage of infection
inflammation [13]. One study suggested that the orchitis and 2 of 23 patients (8.7%) who were recovering [22].
may have resulted from vasculitis considering correlation In contrast, Pan et al. reported no virus in patients’
between the COVID!19 and coagulation disorders, and semen 29!36 days after recovery, although viral orchitis
that the segmental vascularization of the testes could symptoms were observed in 19% of the patients with
cause an orchitis!like syndrome [6]. The aforementioned COVID!19 and six men displayed mild scrotal discomfort
findings could suggest that SARS!CoV!2 infection may at the time of disease [11]. Furthermore, Song et al. [23]
contribute to testicular ultrastructural lesions and orchitis collected 12 semen samples from the COVID!19 patients
in the severely infected males. and one postmortem testicular biopsy. SARS!CoV!2
Sex hormone abnormalities. Regarding androgen RNA was not detected in the semen samples and testicu!
secretion, the decreased total testosterone and calculated lar biopsy. The authors concluded, based on the fact that
free testosterone with elevated luteinizing hormone (LH) SARS!CoV!2 was not identified in the semen and testis
levels recorded in the severe cases of COVID!19, have been samples, that the probability of testicular infection during
significantly correlated with the increased plasma lactate the early and symptomatic phase of the infection is low
dehydrogenase and ferritin levels and as well as with high! but cannot be ruled out, when certain organs such as
er neutrophil counts and reduced lymphocyte counts [14]. lung, heart, and gut are infected. In line with this,
These results are in agreement with the findings of another Holtmann et al. [24] found no SARS!CoV!2 RNA in the
BIOCHEMISTRY (Moscow) Vol. 86 No. 4 2021

COVID!19 AND MALE FERTILITY 391
Testicular dysfunction manifestations and pathogenicity associated with SARS!CoV!2 infection
Testicular dysfunction Number References

of cases
Clinical viral orchitis recorded in 6 patients; no virus detected in the semen 34 [11]
manifestations
seminiferous cellular damage was observed in the specimens from 12 patients died from 12 [13]
COVID!19; no virus detected in testes in 11 deceased patients, but 1 was positive
decreased levels of total and free testosterone; increased serum level of LH was detected 31 [14]
significant reduction in the serum testosterone level in 113 patients (51.1%) 221 [15]
with severe COVID!19
moderate decrease in the testosterone levels; LH level was higher; testosterone:LH 119 [16]
level and FSH:LH ratio were lower
LH and FSH levels were elevated; both testosterone and dihydrotestosterone levels 35 [17]
decreased
SARS!CoV!2 RNA was not detected in 12 semen samples and testicular biopsy 12 [23]
six patients (15.8%) had positive SARS!CoV!2 38 [22]
no virus was detected in 34 semen samples 34 [24]
Infection via ACE2 and TMPRSS2 expression detected mainly in seminiferous duct cells, sper! [7, 27, 28!33]
ACE2 receptor matogonia, Leydig cells, primordial germ cells, and Sertoli cells
Inflammatory cytokines could cause orchitis in patients by inducing inflammatory response [5, 33, 36, 37]
response and
persistent fever hyper!inflammatory conditions with persistent fever affect testis function [39!43]
Drug!related glucocorticoids and stress cause testes injury; ribavirin reduced testosterone levels [22, 45]
testicular injury and inhibited spermatogenesis
lopinavir/ritonavir could inhibit spermatogenesis [46]
chloroquine phosphate affects spermatogenesis and epididymal function [47]
Note. Designations: ACE2, angiotensin!converting enzyme 2; FSH, follicle!stimulating hormone; LH, luteinizing hormone; SARS!CoV, severe
acute respiratory syndrome coronavirus; TMPRSS2, transmembrane protease serine 2.
semen of 34 recovered or acutely infected males with semen parameters such as sperm concentration, total
SARS!CoV!2 43 days after diagnosis on average. sperm count, and the total number of progressive motili!
Furthermore, among the 12 deceased patients with ty was observed in the recovered participants with mild
COVID!19, 11 were negative for SARS!CoV!2 RNA in symptoms and need for hospitalization compared to the
the testicular tissue, while one was positive for the virus. control group. This finding indicates that SARS!CoV!2
However, the patients with COVID!19 had been found to infection has short!term effects on spermatogenesis in
display seriously damaged seminiferous tubules, patients with mild symptoms associated with COVID!19
decreased Sertoli cells, and mild inflammatory infiltrates [24]. Notably, Yang et al. [13] stated that COVID!19 can
in the interstitium [13] (table). Therefore, evidence avail! induce testicular tissue injury and affect fertility, particu!
able from 132 cumulative patients over 7 studies revealed larly in young men, which highlights the need for exam!
that the virus was present in the semen of 7 (5%) patients ining testicular function after recovery.
with COVID!19 [11, 13, 22!26].
Moreover, Ma et al. [16] reported that 4 patients with
COVID!19 (33.3%, 4/12) had low sperm motility. COVID!19 AND TESTICULAR PATHOGENICITY
Duration between the semen collection and the disease
onset ranged from 56 days to 109 days (with a median of Direct testicular invasion of SARS!CoV!2. ACE2
78.5 days). However, a marked negative effect on the receptors, which are omnipresent and highly expressed in

392 ABDEL!MONEIM
several organs such as heart, gut, lungs, kidneys, testes, SARS!CoV!2 induced inflammatory response. While
and brain [7], directly influence invasion of the three cytokines play a vital role in the testicular function, they
coronavirus strains into human cells: SARS!CoV, NL63, also participate in pathological processes [35]. Elevated
and SARS!CoV!2. Seminiferous tubules represent up to concentrations of cytokines following viral infection can
90% of the human testis tissues, the Sertoli cells and the influence spermatogenesis and steroidogenesis, thereby
germ cells express ACE2 making them a potential site for seriously impacting fertility [36] (figure). Notably, testic!
SARS!CoV!2 infection that subsequently impacts sper! ular inflammation causes upregulation of interleukin
matogenesis (figure). Interestingly, testicular cells showed (IL)!1β, IL!1α, IL!6, and tumor necrosis factor!α,
the highest level of ACE2 mRNA in the seminiferous duct which produce harmful effects on the germ cells and
cells, spermatogonia, Leydig cells, primordial germ cells, inflammatory conditions in testes that interfere with the
and Sertoli cells. Considerable seminiferous tubular dam! process of spermatogenesis [37]. Moreover, ACE2 present
age, decreased number of Leydig cells, and moderate on Leydig cells may also influence local microvascular
lymphocyte inflammation was reported in the studies of flows and permeability and promote inflammation that
patients with COVID!19 [7, 27]. The physiological roles interferes with the role of Leydig cells, thereby inhibiting
of ACE2 in Leydig cells include control of steroidogene! testosterone production and damaging seminiferous
sis and spermatogenesis, modulation of testosterone syn! tubular cells [5]. The SARS!CoV!2 could invade the male
thesis, and regulation of the local vascular regulatory sys! reproductive tract during acute infection through ACE2
tem to balance the volume of interstitial fluid by control! present on the cells of seminiferous tubules. The virus
ling conversion of Angiotensin II to Angiotensin I could probably stay for only a few days due to the privi!
[14, 28]. Additionally, histopathological studies of biop! leged immune status of testes [22]. In particular, the
sies from COVID!19 male patients showed impaired immunosuppressive characteristics of Sertoli cells and
spermatogenesis in three out of six samples. Also, histo! testicular macrophages are known to play a vital role in
logical staining of one sample from the patient with suppressing inflammation and reducing testicular damage
COVID!19 demonstrated interstitial macrophage and associated with viruses. Nevertheless, the COVID!19!
leukocyte infiltration. Furthermore, immunofluores! associated inflammation may temporarily affect integrity
cence analysis of six biopsies derived from the COVID!19 of the blood!testis barrier (BTB), which could negatively
patients demonstrated direct correlation between the impact spermatogenesis [33]. SARS!CoV!2 could cause
increased ACE2 levels and impaired spermatogenesis an increase of ACE2 expression and promote typical
indicating possible mechanism of infection of testis by inflammatory response that could interfere with the func!
SARS!CoV!2 [29]. Since the expression of ACE2 is high tion of Leydig and Sertoli cells. Proinflammatory
in testes, Li et al. [30] concluded that SARS!CoV!2 cytokines released by Leydig and Sertoli cells may acti!
enters the testicular interstitium via the circulation route vate the autoimmune response and damage the seminifer!
during peak viremia and that Leydig cells could be one of ous epithelium, leading to autoimmune orchitis [5].
the initial targets. Moreover, the testicular ACE2 expres! Accordingly, despite their privileged immune status,
sion has been related to age, the largest ACE2 expression testes cannot be protected from the general immune
was observed in 30!years!old patients, while 60!year!old response. Infiltration of leukocyte as well as CD3+ T lym!
patients showed the lowest expression in testes [31] sug! phocytes and CD68+ macrophages into the interstitial tis!
gesting that younger males with COVID!19 were at sig! sue of testis can generate interferons that may also
nificantly higher risk for testicular damage compared to decrease testosterone production [36]. Moreover, testos!
older males. terone depletion has also been associated with autoim!
Efficient entry of SARS!CoV!2 into the host cells mune diseases and elevation of the inflammatory bio!
depends not only on the presence of ACE2 receptors but markers such as C!reactive protein (CRP), IL!6, and
also on the transmembrane protease serine 2 TNF!α [38].
(TMPRSS2), which cleaves S protein of the human coro! COVID!19!associated fever. The hyperactivated
naviruses on the membrane priming them for viral entry immune responses along with cytokine storms following
into the cells [32]. In addition to ACE2, TMPRSS2 is SARS!CoV!2 infection affect many organs, including
also expressed in spermatogonia, Leydig cells, and Sertoli heart, liver, kidney, and testes. Interestingly, fever, is an
cells, providing potential route of entry for SARS!CoV!2 additional risk of the COVID!19 that may affect male fer!
into these cells [33]. The virus is expected to bind to tility. More importantly, hyperinflammatory condition
ACE2 and TMPRSS2 in the testicular tissue to induce its with persistent fever, fulminant, and fatal hypercytokine!
adverse effects. Importantly, Abobaker and Raba [34] mia have been associated with multi!organ failure [39].
highlighted the possibility for testicular injury and subse! High inflammatory response associated with fever,
quent male infertility after SARS!CoV!2 infection, which immune cell activation, and inflammatory mediators
might be caused by either direct viral invasion through such as interferons and cytokines can affect testicular
ACE2 receptors or indirectly via the inflammatory function [40, 41] (figure). The hypothesis that fever and
immune response. elevation of testicular temperature contribute to sperm

Summary of the probable pathogeneses of COVID!19!induced testicular injury. Designations: ACE2, angiotensin!converting enzyme 2;
SARS!CoV!2, severe acute respiratory syndrome coronavirus 2. (Color version the figure is available in online version of the article and can
be accessed at: https://www.springer.com/journal/10541)
deficiency has been generally accepted. Given that sper! viral infection [42]. Moreover, participants with verified
matogenesis could be affected by COVID!19!associated COVID!19!associated fever tended to have lower motile
fever, semen parameters such as sperm concentration and sperm count, sperm concentration, and total sperm
motility could be decreased for 72 to 90 days after the count [43].

394 ABDEL!MONEIM
COVID!19 and gonadal!toxic drugs. Interferon!α lower degree of spermatogenesis as well as increased
and ribavirin (in combination with interferon or thickening of the cell membrane and interstitial fibrosis
lopinavir/ritonavir), as well as chloroquine phosphate, [52]. Moreover, the male patients with chronic HCV
have been recommended for COVID!19 treatment [44]. infection showed lower total serum testosterone, sperm
Animal studies have revealed that ribavirin administration count, and progressive sperm motility, and abnormal
reduced testosterone levels and inhibited spermatogenesis sperm morphology compared to the healthy controls
[45], while lopinavir/ritonavir has also been observed to [53]. Altered sperms morphology with decreased sperms
inhibit spermatogenesis in rats probably due to oxidative motility, viability, and concentration were observed in the
stress and inflammation [46]. Unfortunately, testicular semen from patients with chronic HBV infection com!
dysfunction could be also caused by glucocorticoids and pared to the healthy individuals [54].
infectious diseases!related stress due to psychological Notably, Ebola RNA may be found in seminal fluid
crises induced by COVID!19 [22] (figure). Additionally, for periods exceeding 13 months after infection [55].
chloroquine phosphate has been found to affect spermato! Moreover, the study on virus persistence following the
genesis and epididymal function in male rats, which indi! 2014!2016 Ebola virus outbreak had reported the presence
cates that certain medication can affect testicular function of Ebola RNA in seminal fluid up to 565 days after infec!
in the male patients with COVID!19 [47] (table). tion [56]. Additionally, among a cohort of 135 male
Unfortunately, the aforementioned primary studies patients with Ebola who were followed!up from 2015 to
on male fertility have some limitations related to sample 2017, 8% reported erectile dysfunction, whereas 12%
size, research methodology, and disease course. Further showed decreased libido [57]. Regarding the Zika virus,
comprehensive investigations at all levels are therefore Counotte et al. [58] reported the presence of Zika RNA in
required to improve the levels of evidence and under! semen for a median duration of 40 to 370 days. However,
standing of the impact of SARS!CoV!2 on male repro! Avelino!Silva et al. [59] found normal levels of the serum
duction and testicular health. Fortunately, many sex hormone and absence of the Zika RNA in the semen
researchers have recently launched a highly promising samples from six patients 1!year post!Zika infection,
multidimensional andrological research project in men although impaired motility was observed in three samples
called the PROTEGGIMI study (prospective multidi! and low sperm count was reported in one sample.
mensional andrological translational research project) to
develop international collaboration for the data registry in
hormonal and genomic studies in hopes of filling the gaps CONCLUSIONS
in the current knowledge on association between SARS!
CoV!2 and male frailty [48] The current review suggests that the recent coron!
avirus pandemic COVID!19 could have various effects on
male reproductive health. Although, the data on the male
THE IMPACT OF LONG!TERM VIRAL reproductive system in patients with COVID!19 have
INFECTION ON REPRODUCTIVE FUNCTION been scarce with most relevant evidence coming from the
small!scale studies without available long!term follow!up
Given the novelty of the COVID!19 pandemic, long! data. Taken together, several etiopathogenic hypotheses
term studies on its influence on male fertility have been have been suggested implying that the SARS!CoV!2
unavailable. Nonetheless, several studies have addressed infection might be responsible for impairment of testicu!
the effects of long!term viral infection on male reproduc! lar function. ACE2 is primarily expressed in spermatogo!
tive function. Several viruses, such as human papillo! nia and Leydig and Sertoli cells of the human testes,
maviruses, hepatitis B (HBV), hepatitis C viruses (HCV), which may lead to a testicular dysfunction in patients
human herpes viruses, influenza viruses, cytomegalo! infected with SARS!CoV!2. Moreover, testicular damage
viruses, HIV, mumps virus, Zika viruses, and Ebola virus! may be attributed to the inflammatory responses and
es have been known to cause orchitis and influence male fever!associated inflammation, as well as medications
fertility [49]. Interestingly, the study on 298 patients with used in the severe cases. Thus, clinical and translational
mumps orchitis found that 24% of adults and 38% of ado! (short!/long!term) investigations in larger cohorts of cur!
lescents exhibited seminal abnormalities for up to three rently infected subjects are needed to evaluate the impact
years after recovery. At least 24% of adults and 38% of of COVID!19 on human spermatogenesis, determine
young individuals had abnormal ejaculation even three protective and curative approaches against testicular
years after orchitis [50]. Ultrasonography of eight patients injuries, and establish clear conclusions.
with mumps orchitis revealed atrophic testes with an
oblong shape, heterogeneous low echogenicity, and
decreased vascularity 40 to 230 days after the initial diag! Ethics declarations. The author declares no conflicts
nosis [51. Histological characteristics of testis from 57 of interest. This article does not contain any studies with
autopsied patients with chronic HIV, suggested a slightly human participants or animals performed by the author.

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World Journal of Urology (2021) 39:975–976
https://doi.org/10.1007/s00345-020-03208-w
LETTER TO THE EDITOR
Does COVID-19 affect male fertility?

Anis Abobaker1 · Ali Ahmed Raba2
Received: 6 April 2020 / Accepted: 8 April 2020 / Published online: 21 April 2020
© Springer-Verlag GmbH Germany, part of Springer Nature 2020
Dear Editor, the level of testicular cells, four main cell types; seminif-
erous duct cells, spermatogonia, Leydig cells and Sertoli
Multiple cases of pneumonia caused by a novel corona virus cells, show higher rate of ACE2 mRNA expression [2–4].
(SARS-COV2) have been reported in Wuhan city in China If the virus causes damage to these cells, the process of
in December 2019 [1]. Since then, the infection has spread spermatogenesis could be affected which might pose risk
world-wide, leading to acute respiratory distress syndrome to male fertility. Interestingly, the testicular expression of
(SARS) named as “COVID-19” by the World Health Organ- ACE2 is age related [4]. The highest expression recorded in
ization (WHO) [1]. On 11/03/2020, the disease has been patients aged 30, which is higher than those in their twen-
declared as a global pandemic by WHO [1]. Angiotensin ties, whereas 60-year-old patients show the lowest level of
converting enzymes 2 (ACE2) receptors play a key role in expression [4]. This might indicate that young male patients
pathogenesis of COVID-19. Binding of SARS-COV2 virus are at higher risk of testicular damage by COVID-19 than
to ACE2 receptors facilitate its cell entry and replication older patients. In one study, examination of autopsy speci-
[2]. Therefore, cells that show high level of ACE2 expres- men of testis of six patients who died due to SARS-Cov
sion have the potential to be targeted and damaged by the infection in 2002 showed an evidence of orchitis [5]. Histo-
virus [2]. Multiple studies detected high ACE2 expression pathological examination revealed inflammatory infiltrates,
level in testicular cells, mainly in seminiferous duct cells, mainly in seminiferous tubules [5]. Immunohistochemistry
spermatogonia, Leydig cell and Sertoli cells [2–4]. Based showed IgG deposition mainly in seminiferous epithelium,
on the results of these studies, it is concluded that the testis interstitium, degenerated germ cells and Sertoli cells [5].
could be a potential target for direct damage by SARS-COV2 These are almost the same cell types that show high ACE2
virus. Another study performed following the outbreak of expression [2–4]. Interestingly, in-situ hybridization does
SARS-COV infection in 2002 showed that orchitis was a not detect viral genomic materials in the testicular tissue
recognised complication of SARS [5]. The main question specimens [5]. This indicates that testicular damage is due
is whether COVID-19 has the potential to cause testicular to inflammatory and immunological response rather than
damage and infertility in male patients. So far there is no direct damage by the virus.
definitive answer as a follow-up of reproductive function of There is a theoretical possibility of testicular damage and
recovered male patients is required. subsequent infertility following COVID-19 infection. The
SARS-cov2 virus binds to ACE2 receptors and enter the possibility of testicular damage is caused by either direct
cells to complete its replication cycle [2]. This is considered viral invasion through binding of SARS-COV2 virus to
as the main pathological mechanism of direct cell infection ACE2 receptors or secondary to immunological and inflam-
and damage by the virus. Therefore, cells with increased matory response. Follow-up studies of reproductive func-
ACE2 expression are potential target of viral invasion [2]. tion of recovered male patients is required to investigate this
Among different body tissues, testis shows nearly the high- possibility.
est level of ACE2 mRNA and protein expression [2]. At
* Ali Ahmed Raba Author contributions AA designed the study and drafted the initial
ali.raba@ucdconnect.ie manuscript. AAR reviewed and revised the manuscript for important
intellectual content.
1
Spire Fylde Coast Hospital, Blackpool, UK
2
UCD School of Medicine and Medical Sciences, Dublin,
Ireland
13
Vol.:(0123456789)
976 World Journal of Urology (2021) 39:975–976
Funding No financial or nonfinancial benefits have been received or avirus-2019/events-as-they-happen?fbclid=IwAR2_cYFiF9cPKu

will be received from any party related directly or indirectly to the bBCvhuLADnFpS7P1FmqL1M0TicVGPOw5ngB37EuZozQ4U
subject of this article. . Accessed 31 Mar 2020
2. Fan C, Li K, Ding Y, Lu W, Wang J (2020) ACE2 expression in
kidney and testis may cause kidney and testis damage after 2019-
Compliance with ethical standards nCoV infection, medRxiv
3. Wang Z, Xu X (2020) scRNA-seq Profiling of Human Tes-
Conflict of interest The authors declare that they have no conflicts of tes Reveals the Presence of ACE2 Receptor, a Target for
interest. SARS-CoV-2 Infection, in Spermatogonia, Leydig and Sertoli
Cells. medRxiv
Research involving human participants and/or animals This article 4. Shen Q, Xiao X, Aierken A, Liao M, Hua J (2020) The ACE2
does not contain any studies with human participants or animals per- expression in Sertoli cells and germ cells may cause male repro-
formed by any of the authors. ductive disorder after SARS-CoV-2 infection. medRxiv
5. Xu J, Qi L, Chi X, Yang J, Wei X, Gong E, Peh S, Gu J (2006)
Informed consent No informed consent was needed. Orchitis: a complication of severe acute respiratory syndrome
(SARS)1. Biol Reprod 74(2):410–416
Publisher’s Note Springer Nature remains neutral with regard to

Reference jurisdictional claims in published maps and institutional affiliations.
1. Who.int (2020) Coronavirus disease (COVID-19)—events as they

happen. https://www.who.int/emergencies/diseases/novel-coron
13
Am J Physiol Endocrinol Metab 318: E878–E880, 2020.
First published May 19, 2020; doi:10.1152/ajpendo.00183.2020.
PERSPECTIVES
Is there an impact of the COVID-19 pandemic on male fertility? The ACE2

connection
X Johnny S. Younis,1,2 Zaid Abassi,3,4 and Karl Skorecki2
1
Reproductive Medicine, Department of Obstetrics and Gynecology, Baruch Padeh Medical Center, Poriya, Israel; 2Azrieili
Faculty of Medicine in Galilee, Bar-Ilan University, Safed, Israel; 3Department of Physiology, Rappaport Faculty of
Medicine, Technion, Haifa, Israel; and 4Laboratory Medicine, Rambam Health Care Campus, Haifa, Israel
Submitted 28 April 2020; accepted in final form 14 May 2020
Younis JS, Abassi Z, Skorecki K. Is there an impact of the kidney. We shall also discuss the physiological role of ACE2 in
COVID-19 pandemic on male fertility? The ACE2 connection. Am J the testis and the theoretical adverse effects of SARS-CoV-2 on
Physiol Endocrinol Metab 318: E878 –E880, 2020. First published the male reproductive system, as the virus may have the potential
May 19, 2020; doi:10.1152/ajpendo.00183.2020.—The viral pan- to use ACE2 as a route to infect this part of the body. Since there
demic of the coronavirus disease 2019 (COVID-19), generated by a
novel mutated severe acute respiratory syndrome coronavirus (SARS-
is only anecdotal evidence and concern in the literature as to the
CoV-2), has become a serious worldwide public health emergency, adverse effect of the coronavirus family, specifically SARS-
evolving exponentially. While the main organ targeted in this disease CoV-2, on male fertility, we call for urgent targeted research on
is the lungs, other vital organs, such as the heart and kidney, may be this topic to clarify this aspect from the current wave of the
implicated. The main host receptor of the SARS-CoV-2 is angiotensin pandemic.
converting enzyme 2 (ACE2), a major component of the renin-
angiotensin-aldosterone system (RAAS). The ACE2 is also involved SARS-COV-2 AND ITS HOST RECEPTOR
in testicular male regulation of steroidogenesis and spermatogenesis.
As the SARS-CoV-2 may have the potential to infect the testis via SARS-CoV-2, which belongs to the Betacoronavirus genus,
ACE2 and adversely affect male reproductive system, it is essential to has been recently sequenced (14) and has been shown to have
commence with targeted studies to learn from the current pandemic, many similarities with the original SARS-CoV, first reported in
with the possibility of preemptive intervention, depending on the 2002. Spike proteins of SARS-CoV-2 and SARS-CoV have
findings and time course of the continuing pandemic. almost identical three-dimensional structures in the receptor-bind-
ing domain that maintains van der Waals forces. They have been
shown to share 76.5% identity in amino acid sequences and to
INTRODUCTION
possess a high rate of homology (32). Similar to most viruses, the
SARS-CoV and SARS-CoV-2 enter the host cell (type 2 alveolar
The pandemic of novel coronavirus disease 2019 (COVID- epithelial cells) by receptor binding followed by endocytosis,
19), mediated by the severe acute respiratory syndrome coro- genome replication, exocytosis, and budding (7). While both
navirus (SARS-CoV-2) viral infection, is a serious, geometri- viruses have been shown to recognize human angiotensin-con-
cally expanding, worldwide public health emergency, with verting enzyme 2 (ACE2) receptor as their host receptor, SARS-
newly recognized manifestations being appreciated and re- CoV-2 binds to ACE2 receptor more efficiently than SARS-CoV,
ported daily. The very high contagiousness of COVID-19 is increasing its damaging pathogenicity and its ability of SARS-
largely attributed to its rapid community transmission, high CoV-2 to transmit from person to person (8, 25, 26). ACE2
virulence, and sustained surface viability. The presentation of receptor recognition is the first step of viral infection, as it is the
COVID-19 varies considerably from rare asymptomatic cases, key determinant of host cell and tissue tropism, pathogenicity, and
to mild flu-like symptoms, including high fever, to severe subsequent viral replication. However, ACE2, the entry receptor
respiratory illness. The SARS-CoV-2 pathogen is a single- of the virus, also plays a crucial role against lung injury (33).
stranded RNA virus, with the gravest clinical pathophysiology,
being a severe acute respiratory syndrome (SARS). The newly ACE2 A PART OF THE RENIN-ANGIOTENSIN SYSTEM
evolved virus has an estimated 10- to 15-fold greater mortality
rate than the usual seasonal Haemophilus influenzae-mediated ACE2 is a transmembranal zinc metallopeptidase with high
respiratory illness (2a). Critical cases are characterized by homology to the classic ACE, but contains a single catalytic
rapid respiratory deterioration, septic shock, and/or multiple domain. Both ACE isoforms are part of the renin-angiotensin-
organ dysfunction or failure (3, 29). Contemporary infection aldosterone system (RAAS), a cardinal endocrine system that
rates and rolling updates are continuously displayed on the plays a key role in the regulation of blood pressure and fluid
World Health Organization (WHO) COVID-19 website. balance. Whereas ACE catalyzes the conversion of angiotensin
In this perspective report, we focus on the role of angiotensin- I (ANG I) into angiotensin II (ANG II), ACE2 is responsible
converting enzyme 2 (ACE2) as a key receptor for SARS-CoV-2 for the generation of angiotensin 1–7 (ANG 1–7) from ANG II.
in different organs of the body, including the lung, heart, and While ANG II exerts deleterious effects on the heart, lungs,
kidneys, and the brain via angiotensin II type 1 (AT1) receptors
(10), the ANG 1–7-Mas receptor axis provokes beneficial
Correspondence: J. S. Younis (jyounis@poria.health.gov.il). balancing and salutary actions on these vital organs, as evident
E878 0193-1849/20 Copyright © 2020 the American Physiological Society http://www.ajpendo.org
Downloaded from journals.physiology.org/journal/ajpendo (181.199.041.063) on June 22, 2022.
COVID-19 AND MALE FERTILITY E879
by vasodilatory, anti-inflammatory, antifibrotic, and diuretic/ As cytokines contribute to testicular function and maintenance
natriuretic actions (21, 22). Interestingly, ACE2 is widely of male reproductive health, and to the pathologies associated
expressed in many organs, including the heart, kidney, lung, with their abnormal activity in this organ, COVID-19-induced
intestine, liver, and testis (4, 28). changes in cytokines profile may have further implications to
male fertility (13). In addition, immunomodulatory therapies may
ACE2 IN THE TESTIS provoke potential long-term effects on male fertility and are a
matter of concern. Furthermore, cytokine microenvironment de-
Among several extra-respiratory organs, ACE2 is highly
viations within the testis may have tumorigenic adverse effects on
expressed in the human testis (5, 23). This raises the question
the cellular level, leading eventually to testicular cancer, a second
of whether COVID-19 in males, via the ACE2, may have
long-term matter of concern (13).
adverse reproductive implications, especially in young men
planning to have children. WHAT EVIDENCE SO FAR?
Typical components of the RAAS have been found in the testis
and epididymis in the human and mammalian animal models (2, To the best of our knowledge, no clinical studies on male
11, 18, 20). For instance, the receptor Mas has been identified in fertility investigated survivors from the previous coronavirus ep-
rat testis (16a) and mouse (1) testis; it starts to increase around idemics, SARS-CoV (commenced in 2002) and MERS-CoV
puberty and reaches its maximal expression during reproductive (commenced in 2012). This may be due to the fact that these
life. ACE2 expression in the testis is restricted to the Leydig and viruses are much less contagious in comparison to the SARS-
Sertoli cells in humans (6). Similarly, Mas mRNA in the testis is CoV-2, and the epidemics were short-lived and of limited scope:
localized to Leydig and Sertoli cells, being much more pro- to date, only 8,098 and 2,538 people were infected worldwide by
nounced in Leydig cells (1). Knockout mammalian models, spe- the SARS-CoV and MERS-CoV, respectively (WHO website). It
cifically to various components of the RAAS, such as Mas- is also possible that the effect of these previous epidemics on male
knockout mice showed aberrant expression of genes involved in fertility were not explored in targeted studies. One study analyzed
mitochondrial function and testicular steroidogenesis (11, 30). the pathological changes of testes from six patients who died of
However, unlike the case for alveolar cells, it is not yet known SARS, suggesting SARS-CoV orchitis (31). All biopsies dis-
whether cells involved in spermatogenesis depend on intact ANG played widespread germ cell destruction with few or no sperma-
1–7 for functional integrity, and this can be studied as a basic tozoon in the seminiferous tubules. SARS viral genomic se-
question in relevant model systems. quences by in situ hybridization were not detected in all speci-
Recently, the expression pattern of ACE2 in adult human mens, although immunohistochemistry demonstrated abundant
testis at the level of single-cell transcriptomes was shown to be IgG precipitation, indicating possible immune response as the
predominantly enriched in spermatogonia, Leydig, and Sertoli cause of the damage.
cells (27). In the clinical setting, ANG 1–7 and Mas were In contrast, as of April 28, 2020, the number of confirmed
detected in the seminiferous tubules, as well as in the intersti- cases of SARS-CoV-2 is 3,073,356, and the pandemic contin-
tial compartment, mainly Leydig cells, in men with normal ues to evolve. The highly contagious nature of the SARS-
spermatogenesis. However, neither components of the RAAS CoV-2 virus, using ACE2 as the receptor of entry to both the
were found in the seminiferous tubules of infertile men with lungs and testis, it is imperative to seize the opportunity to
nonobstructive azoospermia (20). investigate the impact of the COVID-19 pandemic on male
Taken together, the RAAS, specifically ACE2, seems to play fertility. One non-peer-reviewed retrospective study examined
an important role in male reproduction. Accumulating evi- the impact of SARS-CoV-2 on male sex hormones in 81
dence suggests that the RAAS components are involved in hospitalized patients, in their third to sixth decade of age (15).
human male regulation of steroidogenesis, testosterone produc- Serum luteinizing hormone levels were higher in the SARS-
tion, and spermatogenesis in the testis. CoV-2 group compared with controls, while there were no
differences in serum follicular stimulating hormone or testos-
ADDITIONAL CONCERNS terone levels. Another recent non-peer-reviewed study exam-
ined 34 recovering adult Chinese male patients, 20 –55 yr of
An additional concern of the COVID-19 pandemic that
age, following confirmed COVID-19 diagnosis. While six men
might impact male fertility is fever. Particularly high and
had mild scrotal discomfort at the time of disease, suggesting
sustained elevation in body temperature is a major manifesta-
viral orchitis, in none of these men was SARS-CoV-2 detected
tion of the COVID-19 pandemic, which complicates more than
in their semen 29 –36 days following recovery (17). One major
80% of patients (12). The concept that fever and elevation of
limitation of both studies is the fact that the authors did not
testicular temperature result in impairment of spermatogenesis
report sperm counts and viability of COVID-19 patients.
is widely accepted (9).
More importantly, emerging evidence indicates that a sub- CONCLUSIONS
group of patients with severe COVID-19 might have a second-
ary cytokine storm syndrome (hemophagocytic lymphohistio- ACE2 is abundant in the adult human testis, as it is in the lungs,
cytosis) (16). This is an underrecognized, hyperinflammatory kidney, and heart, and the SARS-CoV-2 virus uses ACE2 as its
syndrome characterized by sustained fever, with fulminant and receptor of entry. Clinical and translational studies are needed
fatal hypercytokinemia with multiorgan failure. These patients without delay to determine the effects of SARS-CoV-2 on human
have a particular serum blood cytokine profile with cytopenia spermatogenesis and steroidogenesis in the testis, to inform med-
and hyperferritinemia. These findings also suggest that immu- ical consultation with infected men, especially those in the repro-
nomodulatory therapy (IL-6 antagonist) may improve mortal- ductive years. This may be of greater importance for men already
ity rate considerably in these patients (16, 24). known to have a sperm production problem. The issue of sperm
AJP-Endocrinol Metab • doi:10.1152/ajpendo.00183.2020 • www.ajpendo.org

E880 COVID-19 AND MALE FERTILITY
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AJP-Endocrinol Metab • doi:10.1152/ajpendo.00183.2020 • www.ajpendo.org

| |
DOI: 10.1111/and.13654
S H O R T C O M M U N I C AT I O N
Could COVID-19 have an impact on male fertility?
Ester Illiano | Francesco Trama | Elisabetta Costantini
Andrology and Urogynecology Clinic, Santa

Maria Terni Hospital, University of Perugia, Abstract
Terni, Italy The pandemic caused by Severe acute respiratory syndrome coronavirus 2 (SARS-
Correspondence CoV-2) has led to several hypotheses of functional alteration of different organs. The
Francesco Trama, Andrology and direct influence of this virus on the male urogenital organs is still to be evaluated.
Urogynecology Clinic, Santa Maria Terni
Hospital, University of Perugia, Piazzale However some hypotheses can already be made, especially in the andrological field,
Tristano di Joanuccio 1, Zip Code 05100 for the biological similarity of the SARS-CoV and SARS-CoV2. As well as SARS-CoV,
Terni, Italy.
Email: francescotrama@gmail.com SARS CoV-2 uses the ‘Angiotensin Converting Enzyme-2’ (ACE2) as a receptor to
enter human cells. It was found that ACE2, Angiotensin (1-7) and its MAS receptors
are present, over in the lung, also in the testicles, in particular in Leydig and Sertoli
cells. A first hypothesis is that the virus could enter the testicle and lead to alterations
in testicular functionality. A second hypothesis is that the binding of the virus to the
ACE2 receptor, could cause an excess of ACE2 and give rise to a typical inflamma-
tory response. The inflammatory cells could interfere with the function of Leydig and
Sertoli cells. Both hypotheses should be evaluated and confirmed, in order to pos-
sibly monitor fertility in patients COVID-19+.
KEYWORDS
angiotensin-converting enzyme 2, COVID-19, male infertility
Betacoronaviruses (Coronaviridae family) have a positive-sense RNA localised areas (132,758 confirmed cases, 4,955 deaths; Puliatti
genome, which are 26–32 kilobases in length. They are called coro- et al., 2020). The first case was transmitted from animal to human,
naviruses due to their ‘crown-like’ appearance with spiked glycopro- but now human–human transmission occurs through respiratory
teins in the outer layer (Su et al., 2016). Coronaviruses have been droplets from coughing and sneezing, with symptomatic individuals
identified in various hosts, including mammals such as camels, bats, being the main vehicle for its spread. The incubation period varies
mice, cats, and dogs (Su et al., 2016). Most of the coronaviruses that from a minimum of 3 days to a maximum of 15 days.
are pathogenic to humans are associated with rather mild respiratory One recent theory proposed that the SARS-CoV-2 virus uses
symptoms (Su et al., 2016). the ‘angiotensin-converting enzyme 2’ (ACE2) as a receptor to
At the end of December 2019, a novel Coronavirus (2019-nCoV, enter human cells (Lu et al., 2020), which is similar to the mech-
subsequently named severe acute respiratory syndrome coronavi- anism of the entry of SARS-CoV into cells (Dimitrov, 2003). The
rus 2 [SARS-CoV-2] due to its similarity to SARS-CoV; the disease extracellular domain of ACE2 is a cell surface receptor for the
is known as coronavirus disease-19 [COVID-19]) was identified glycoproteins (S domain) on the SARS-CoV-2 envelope (Lu et al.,
in Wuhan (China). This virus appears to be more contagious than 2020). Viral glycoproteins comprise an exocellular domain, a trans-
those previously encountered. In fact, on 30 January 2020, the membrane domain and an intracellular domain. The exocellular do-
World Health Organization (WHO) declared it to be a Public Health main is formed by an S1 unit that bonds to the ACE2 peptidase
Emergency of International Concern (PHEIC) as it had spread to domain (PD) through the receptor-binding domain (RBD; Lu et al.,
18 countries (with 7,818 confirmed cases; Puliatti et al., 2020). On 2020); a second S2 unit facilitates membrane fusion simultane-
12 March 2020, WHO declared it a pandemic, with the virus hav- ously with virus–receptor binding (Lu et al., 2020; Figure 1). The
ing spread to every continent (123 countries), affecting broad and PD domain breaks angiotensin I down into angiotensin-(1-9), which
Andrologia. 2020;52:e13654. © 2020 Blackwell Verlag GmbH | 1 of 3

https://doi.org/10.1111/and.13654
| ILLIANO et AL.
Another aetiopathogenic hypothesis could be that SARS-CoV-2

infection causes an indirect inflammatory/immune response in
testicles.
Indeed, a high concentration of testicular inflammatory infiltra-
tion has been observed in patients infected by SARS-CoV (Xu et al.,
2006). The inflammatory cells could interfere with the function of
Leydig cells, thereby impeding testosterone production, as well as
destroy the cells of seminiferous tubules (Xu et al., 2006). The cy-
tokines produced by the inflammatory cells could activate an auto-
immune response and develop antibodies within the seminiferous
tubules (Xu et al., 2006).
Link between SARS CoV2 and ACE2 However, in an acute phase, these functional alterations of the
Leydig cells may not potentially be evident.
Ma et al. (2020), in a recent retrospective study on COVID-19
is then transformed into angiotensin (1-7) by other enzymes (ACE; patients, showed that they had significantly higher serum lutei-
Dimitrov, 2003). ACE2 can also directly convert angiotensin II into nising hormone (LH) and prolactin than healthy men, but without
angiotensin (1-7) (Dimitrov, 2003). angiotensin II binds to the ART1 changes in the levels of serum testosterone. The authors explained
receptor and can cause inflammation and fibrosis. ACE2 antago- these results with an early subtle negative feedback between tes-
nises the activation of the classical rennin–angiotensin system tosterone and LH. Probably in the early stage, impaired testoster-
(RAS) and protects against organ damage. one production may stimulate the release of LH which can maintain
In the COVID-19 infection process, ACE2 receptors are sat- testosterone level temporarily, and only after some time, the clinical
urated by binding with the virus, giving rise to the increased hypogonadism emerges.
availability of angiotensin II, which cannot be converted These aetiopathogenic hypotheses should be taken into con-
(Dimitrov, 2003). The excess angiotensin II explains the pulmo- sideration in cases where COVID-19 is diagnosed in young men,
nary symptoms that are characteristic of COVID-19. The process in order to be able to implement a stricter long-term andrological
is blocked by the conversion of angiotensin II into angiotensin (1-7) screening and follow-up programme.
by ACE2. Angiotensin (1-7) binds to the ART2 and MAS receptors Unfortunately, these primary studies have several limitations
(Dimitrov, 2003). of small sample size, test methods, the course of disease. Further
Reis et al. (2010) has also confirmed the presence of ACE2, an- studies are required to confirm the results and to evaluate the pre-
giotensin (1-7) and its MAS receptors in the testicles, specifically in vention of testicular damage and the possibility of reversing it with
Leydig and Sertoli cells. new treatments that could be introduced in the market in the short
The primary function of the Leydig cells is to produce sex ste- term.
roid hormones, particularly testosterone. As such, the presence of
MAS receptors might suggest that angiotensin (1-7) modulates the ORCID
secretion of testosterone (Reis et al., 2010). The presence of MAS Ester Illiano http://orcid.org/0000-0001-5660-1815
receptors and angiotensin (1-7) in the seminiferous tubules may also Francesco Trama https://orcid.org/0000-0001-9291-2426
explain the involvement of Sertoli cells and germinal cells (Reis et al., Elisabetta Costantini http://orcid.org/0000-0001-9639-2886
2010). Although the testicular expression of ACE2 may indicate the
possible entry of the virus into the testicles, the literature concern- REFERENCES
ing SARS-CoV is not consistent and concordant. Zhao et al. (2003), Dimitrov, D. S. (2003). The secret life of ACE2 as a receptor for the
encountered the presence of SARS-CoV in the testicular epithelial SARSvirus. Cell, 115(6), 652–653. https://doi.org/10.1016/S0092
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cells and in the Leydig cells, whereas Ding et al. (2004), encountered
Ding, Y., He, L. I., Zhang, Q., Huang, Z., Che, X., Hou, J., … Jiang, S.
direct infection in other organs, but not in the testicles. (2004). Organ distribution of severe acute respiratory syndrome
In a recent study, Song et al. (2020) collected 12 semen sam- (SARS) associated coronavirus (SARS-CoV) in SARS patients:
ples from survived COVID-19 patients and testicular biopsies from Implications for pathogenesis and virus transmission pathways.
The Journal of Pathology, 203, 622–630. https://doi.org/10.1002/
a dead COVID-19 patient. In the semen samples and in testicular
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biopsy, tissues were not detected 2019-nCov RNA. These results Lu, R., Zhao, X., Li, J., Niu, P., Yang, B., Wu, H., … Tan, W. (2020).
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There are currently no studies assessing the possible entry of
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SARS-CoV-2 in testicles via ACE2 or other mechanisms, but it could (2020). Effect of SARS-CoV-2 infection upon male gonadal
be a possible aetiopathogenic hypothesis of future infertility in pa- function: A single center-based study. medRxiv. https://doi.
tients who acquire SARS-CoV-2 infection. org/10.1101/2020.03.21.20037267
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Puliatti, S., Eissa, A., Eissa, R., Amato, M., Mazzone, E., Dell'Oglio, P., … Xu, J., Qi, L., Chi, X., Yang, J., Wei, X., Gong, E., … Gu, J. (2006). Orchitis:
Rocco, B. (2020). COVID-19 and urology: A comprehensive review of A complication of severe acute respiratory syndrome (SARS). Biology
the literature. BJU International. https://doi.org/10.1111/bju.15071 of Reproduction, 74(2), 410–6.
Reis, A. B., Araújo, F. C., Pereira, V. M., Dos Reis, A. M., Santos, R. A., Zhao, J. M., Zhou, G. D., Sun, Y. L., Wang, S. S., Yang, J. F., Meng, E. H.,
& Reis, F. M. (2010). Angiotensin (1–7) and its receptor Mas are ex- … Zhang, T. H. (2003). Clinical pathology and pathogenesis of severe
pressed in the human testis: Implications for male infertility. Journal acute respiratory syndrome. Zhonghua Shi Yan He Lin Chang Bing Du
of Molecular Histology, 41, 75–80. https://doi.org/10.1007/s1073 Xue Za Zhi, 17, 217–221.
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Detection of 2019 novel coronavirus in semen and testicu-
How to cite this article: Illiano E, Trama F, Costantini E. Could
lar biopsy specimen of COVID-19 patients. medRxiv. https://doi.
COVID-19 have an impact on male fertility?. Andrologia.
org/10.1101/2020.03.31.20042333
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Epidemiology, genetic recombination, and pathogenesis of coronavi-
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tim.2016.03.003
Received: 4 November 2020 | Accepted: 9 November 2020
DOI: 10.1002/jmv.26667
REVIEW
The other side of COVID‐19 pandemic:

Effects on male fertility
Cemile Merve Seymen
Department of Histology and Embryology,

Gazi University Institute of Health Sciences, Abstract
Tunus Street, No:35, Ankara, 06540, Turkey
The outbreak of novel coronavirus disease 2019 (COVID‐19) has become a major
Correspondence pandemic threat worldwide. According to the existing clinical data, this virus not
Cemile Merve Seymen, Department of only causes respiratory diseases and affects the lungs but also induces histo-
Histology and Embryology, Gazi University
Institute of Health Sciences, Tunus Street, pathological or functional changes in various organs like the testis and also the male
No: 35, Tunus‐Ankara 6540, Turkey. genital tract. The renin‐angiotensin system (RAS), also ACE 2 and TMPRSS2 play an
Email: cmerveseymen@gmail.com
important role in the cellular entry for SARS‐CoV‐2. Because the male genital
system presents high ACE 2 expression, the importance of this pathway increases in
COVID‐19 cases. As the COVID‐19 pandemic has affected the male genital system
in direct or indirect ways and showed a negative impact on male reproduction, this
paper focuses on the possible mechanisms underlying the damage caused by
COVID‐19 to the testis and also other components of the male genital tract.
KEYWORDS
coronavirus, genital tract, pandemics
1 | INTRODUCTION underlying the damage caused by COVID‐19 to the testis and also
the male genital tract.
At the end of December 2019, a novel coronavirus that is sig-
nificantly contagious than the seasonal flu formally named severe
acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2); also known 2 | CORONAVIRIDAE A ND S A RS‐C O V ‐2
as coronavirus disease‐19 (COVID‐19) exploded in Wuhan (China)
and had spread rapidly worldwide.1,2 The outbreak was declared Coronaviridae family (Betacoronaviruses) are single‐chain, positive‐
as a global pandemic in March 2020 by the World Health sense RNA genome, which is 26–32 kilobases in length with spiny
Organization (WHO).3 extensions that are seen at the electron microscopic level. Because
According to the existing clinical data, this virus not only causes of these extensions, they received the name “corona,” which means
respiratory diseases and affects the lungs but also induce histo- “crown” in Latin. In addition to many subspecies found in animals,
pathological changes in various organs of a nonrespiratory system, there are several subspecies of these viruses found in humans that
such as the kidney,3,4 liver, brain, and heart.4 SARS‐CoV‐2 was also can be transmitted from person to person and often cause cold, such
found in semen analysis of male patients and like many other viruses, as HCoV‐229E, HCoV‐OC43, HCoV‐NL63, and HKU1‐CoV.2,6
such as mumps, hepatitis, herpes simplex, influenza, and human im- Coronaviruses have previously caused more serious, highly
munodeficiency viruses (HIV), it could infect the testis, the male pathogenic, and lethal diseases, such as middle east respiratory
genital tract and cause damage to male fertility.4,5 syndrome coronavirus (MERS‐CoV) and severe acute respiratory
There is a very limited number of data about the effects of syndrome coronavirus (SARS‐CoV).4,7
COVID‐19 on male fertility, so it has become an important topic for SARS‐CoV‐2 has four main structural proteins: spike surface
researchers. This paper focuses on the possible mechanisms glycoprotein, small envelope protein, matrix protein, and nucleocapsid
1396 | © 2020 Wiley Periodicals LLC wileyonlinelibrary.com/journal/jmv J Med Virol. 2021;93:1396–1402.

SEYMEN | 1397
protein. This virus binds to host receptors via spike surface glyco-
protein from its receptor binding sites.8,9
3 | T H E RE N I N ‐A N G I OT E N SI N ‐
ALDO S T E R O NE S Y ST EM (R AAS)
The RAAS is a hormonal cascade system that regulates arterial pressure

and fluid balance for homeostatic control in the body. When blood
pressure is reduced, this hormonal cascade begins with the biosynthesis
of renin from the juxtaglomerular cells in the kidney. Renin stimulates the
formation of angiotensin (Ang) I (or Ang 1‐9) from angiotensinogen, re-
leased primarily by the liver.10,11 Additionally, angiotensinogen messen-
ger RNA (mRNA) expression has been detected in many other tissues,
such as the kidney, brain, heart, adrenal gland, ovary, placenta, and adi-
pose tissue.12 Angiotensin I is then converted to angiotensin II (or Ang
1‐7) by the angiotensin‐converting enzyme (ACE), found predominantly
on the surface of vascular endothelial cells of the lungs. Angiotensin II is
the most functional molecule and creates vasoconstriction in blood
F I G U R E 1 Summary of RAS
vessels, which increases blood pressure and also stimulates the release of
the hormone aldosterone from the adrenal cortex. Aldosterone increases
sodium and water reuptake from kidney tubules into the blood.
It increases the amount of fluid in the body and therefore, blood 4 | THE ACE 2 EXPRESSION IN MALE
pressure.10,11 Additionally, angiotensin III (or Ang 2‐8) and angiotensin IV REPRODU CTIVE SY STEM
(or Ang 3‐8) are known as other products of RAAS.13 Angiotensin II
needs receptors to demonstrate its physiological and pathophysiological The typical and main components of RAAS have been demonstrated in
actions, so at least four angiotensin II receptor subtypes have been the male reproductive tract, especially in the testis, epididymis, and also
described; AT1R, AT2R, AT3R, and AT4 R locate in different tissues.11,14 prostate gland.19,20 The RAAS components associated with the reg-
ACE 2 has recently been identified enzyme and a novel homolog ulation of steroidogenesis, testosterone production, spermatogenesis,21
of ACE, attached to the cell membranes of cells and expressed in and sperm contractility in the testis and epididymis.19
72 different human tissues such as the lungs, gastrointestinal system, First, among several nonrespiratory organs, ACE 2 is highly ex-
heart, kidney, and testis.15 Unlike ACE, the activity of ACE 2 is not pressed in the human testis and also in the male genital tract and
affected by ACE inhibitors11 and does not catalyze the formation of seems to play an important role in male reproduction.21 It was de-
angiotensin II‐like ACE.15 ACE 2 catalyzes the generation of vaso- termined that the mRNA expression of ACE 2 was expressed in both
dilator Ang 1‐7 from vasoconstricting angiotensin II by separating germ and somatic cells of the testis.22 Studies have shown that ACE 2
10
phenylalanine and Ang 1‐9 from angiotensin I, suggesting that ACE expression is observed in spermatogonia, Leydig cells, and Sertoli cells,
2 may act to provide negative feedback regulation of the RAAS.11,15 predominantly.23,24 ACE 2 in Leydig cells function in testosterone or
Like angiotensin II, also Ang 1‐7 needs a receptor to demonstrate its steroidogenesis regulation, production, and local vascular regulation
10
function and this receptor is termed as MasR. So finally, RAAS to balance the interstitial fluid volume via modulating the conversion
regulates blood pressure and renal function by the pressor and de- of angiotensin II to angiotensin I, also ACE 2 in seminiferous epithe-
pressor arms; the pressor arm is ACE/angiotensin II/AT1R and the lium functions in maintaining healthy spermatogenesis.24 Additionally,
depressor arm is ACE 2/Ang 1‐7/MasR.16,17 These two arms show a small percentage of the prostate hillock and club cells express
antagonistic biological responses because angiotensin II and Ang 1‐7 ACE 2.20 The expression level of ACE 2 was related to age; it has been
differ only in the single amino acid at the C‐terminal biochemically, found that the expression of ACE 2 increases from a young age to the
which gives them the opposite functions16 (Figure 1). middle age.22 ACE 2 expression starts to increase around puberty and
Interestingly, ACE 2 has recently been identified as the reaches its maximum expression during reproductive life.21
entry point into cells for some coronaviruses, including SARS and Furthermore, the male reproductive tract and also the testis
SARS‐CoV‐2.10 As mentioned above, there are studies that show represent both source and target for active angiotensin peptides and
that this enzyme is detected in different parts of the body, such as their receptors.19 For instance, Ang 1‐7 and its receptor Mas have been
enterocytes, renal tubules, gallbladder, cardiomyocytes, male identified in the human testis.19,21 Ang 1‐7 and MasR were detected
reproductive cells, placental trophoblasts, ductal cells, eye, and in the seminiferous tubules (including Sertoli cells), in the interstitial
vasculature; and hence it might increase the effects of the virus compartment, mainly Leydig cells, and is much more pronounced in
over the entire system.18 Leydig cells.21
1398 | SEYMEN
Researchers also investigated the differences in ACE 2/Ang 1‐7/ the conversion of angiotensin II to Ang 1‐7 and also angiotensin
MasR expressions between fertile and infertile men, and accordingly, I to Ang 1‐9 in the cell, so the amount of angiotensin II increases.
the expressions were found higher in men with normal spermato- This accumulation may lead to toxicity7,26,28 and contributed to
genesis. The testicular samples of infertile men with impaired sper- acute respiratory distress syndrome, inflammation, myocardial in-
matogenesis expressed MasR and ACE 2 mRNA at lower jury, neurological frequency, and gastrointestinal reflections28
concentrations. Additionally, neither component of the RAAS was (Figure 2).
determined in the seminiferous tubules of infertile men with non- SARS‐CoV‐2 causes progressive respiratory failure and alveolar
obstructive azoospermia.19,21 Studies have indicated that MasR damage in the lungs because of the high expression of ACE 2 in the
knockout mice showed aberrant testicular steroidogenesis.21 type II alveolar cells,26 but as mentioned above, many vital tissues
include ACE 2 expressions except the lungs; therefore, these tissues
are also in danger of SARS‐CoV‐2 infection.25
5 | SARS ‐C O V‐ 2 R EC E P TO R FUNC T IO N According to data from different countries, the possibility of
OF ACE 2 becoming COVID‐19 increases in young people where the ACE 2 is
more expressed, but in contrast, the disease is more severe in
It has recently been identified that like SARS and HCoV‐NL63 cor- the older population. In addition to chronic diseases, the most
onaviruses; also SARS‐CoV‐2 uses the same receptor, ACE 2, for entry appropriate mechanism that can explain the severe progression of
into the cells through its surface spike (S) proteins.7,25,26 Endocytosis of the disease in the older population may be the increased level of
the virus is achieved through S protein (7). The binding affinity between angiotensin II caused by a decreased level of ACE 2.29 When the
ACE 2 and SARS‐CoV‐2 is nearly 10 to 20 fold higher than ACE 2 and systemic effects of increased angiotensin II levels are evaluated,
SARS affinity.26 According to some studies, the risk of infection with the parallel clinical findings are observed with severe COVID‐19 cases,
virus decreased in mice if ACE 2 expression was reduced.27 such as increasing pulmonary edema and apoptosis, lung
After binding of the virus, ACE 2 expression decreases/ fibroproliferation due to an increase in extracellular matrix produc-
downregulates on the cell surface. This reduction causes to reduce tion, endothelitis, and thrombus formation.7
F I G U R E 2 Summary of SARS‐CoV‐2
receptor function of ACE 2. ACE,
angiotensin‐converting enzyme; SARS‐CoV‐2,
severe acute respiratory syndrome
coronavirus 2
SEYMEN | 1399
6 | SARS ‐C O V‐ 2 IN T H E M AL E orchitis. Also, genital complaints, such as scrotal discomfort, were re-
RE P R O D U C T I V E SY S T E M ported in 19% COVID‐19 patients.33 Similarly, Özveri et al. observed
slightly increased vascularity, suggesting spermatic cord inflammation
6.1 | Structural and functional changes of testis on ultrasound examinations in a COVID‐19 positive patient with a
and epididymis in the case of COVID‐19 complaint swelling sensation and pain in his testis. No abnormality
overlying scrotal skin and sperm count analysis were observed
According to several studies, it is known that viruses could infect the according to their examinations.30
5
testis directly. Yang et al. examined the postmortem testis tissues If we look at the mechanisms of these changes caused by SARS‐
from 12 COVID‐19 patients and searched them by light and electron CoV‐2 in the testis, as mentioned above, this virus uses ACE 2 for entry
microscopy. As a result, they observed that swelling, vacuolation, and into the cells through its surface spike (S) proteins. S proteins have two
cytoplasmic dilution in the Sertoli cells additionally, detachment subunits, S1 and S2, which are responsible for receptor recognition and
between the basement membrane and seminiferous tubules, loss and membrane fusion. Studies have shown that SARS‐CoV‐2 enters into the
cell debris into the lumen of seminiferous tubules. The number of host cell through the binding of its C‐terminal domain of the S1 subunit
Leydig cells was found significantly lower than the control group. to ACE 2. Additionally, some studies have reported that the level of
Edema and inflammatory infiltrate composed of T lymphocytes and autophagy receptor SQSTM1/p62 in SARS‐CoV‐2 infected cells has
histiocytes were seen in the interstitial tissue; so taken together, increased, suggesting a decrease in autophagy flux. So, SARS‐CoV‐2
significant seminiferous tubular injury, reduced number of Leydig itself or via ACE 2 can directly induce or inhibit the autophagy pathway
cells, and lymphocytic inflammation were recognized in the testis of to achieve virus survival. As a result, SARS‐CoV‐2 may cause male
COVID‐19 patients.3 There have many studies that support these reproductive disorders by regulating the level of autophagy in male
findings and have said that SARS coronaviruses damage multiple germ cells.4 On the contrary, another hypothesis is that testis degen-
organs, including testis and generally cause leukocyte infiltration, eration in the COVID‐19 cases is attributed to an increase in testicular
impaired spermatogenesis, widespread germ cell destruction with temperature as an indirect effect of the inflammation.5
very few or no spermatozoa in the seminiferous tubules, thickened Another molecule effective at entering the cell of the SARS‐CoV‐2
basement membrane, and macrophage (+) stainings in the testis. So, is host proteases like transmembrane serine protease 2 (TMPRSS2),
these studies emphasized that, like other SARS viruses, SARS‐CoV‐2 which cleaves the viral S protein to induce a conformational change
also poses a high risk of injury to the testicular cells and tissue25,30 that allows to a fusion of the virus and host cell membranes.34
5
and damage the blood‐testis barrier. TMPRSS2 is the key molecule for the successful infection process.35
In addition to these structural effects of SARS‐CoV‐2 in the testis, This protease is more expressed in human tissues than ACE 2;
many other studies also provide information that SARS viruses can co‐expression of ACE 2 and TMPRSS2 has been shown in the testis,
5,25,30,31
cause orchitis in humans. Because of the SARS virus and endometrium, and placenta. Researchers investigated the coexpres-
SARS‐CoV‐2 sharing 78% genetic homology and in the same sion of these two molecules in the testis and accordingly, they found
family/genus, it would be correct to predict that SARS‐CoV‐2 will also that ACE 2 is predominantly expressed in myoid cells, spermatogonia,
have such an effect.25 Also, Xu et al.32 examined the postmortem testis Leydig, and Sertoli cells, while TMPRSS2 is expressed in spermato-
tissues from six patients who died from SARS‐CoV‐1 infection (at this gonia and (elongated) spermatids of the testicular tissue34 (Figure 3).
point, it would be correct to know that SARS‐CoV‐2 is closely related Orchiepididymitis is most frequently caused by viruses and re-
to SARS‐CoV‐1 with 85% identity) and found that all six patients have latively frequent in adolescents; Gagliardi et al.36 reported the first
F I G U R E 3 Comechanism of TMPRSS2 and

ACE 2 in the fusion process of the testis.
ACE, angiotensin‐converting enzyme;
SARS‐CoV‐2, severe acute respiratory
syndrome coronavirus 2; TMPRSS2,
transmembrane serine protease 2
1400 | SEYMEN
described case of orchiepididymitis associated with a 14‐year‐old neuronal death for SARS‐CoV‐2. Importantly, the central nervous
COVID‐19 patient. system plays a critical role in endocrine control and spermatogenesis.31
The Hypothalamic‐Pituitary‐Gonadal Axis (HPGa) exerts a vital role in
reproduction; in other words, HPGa can inhibit the body's reproductive
6.2 | Semen characteristics and prostate functions via hormones.31,38
connection in the case of COVID‐19 Gonadotropin‐releasing hormone (GnRH) expressing neurons from
the hypothalamus secretes GnRH and it activates the release of the
Recent studies have reported that SARS‐CoV‐2 is easily found in follicle‐stimulating hormone (FSH) and luteinizing hormone (LH) from
human bodily fluids.35 The presence of a virus in a semen sample is the pituitary gland. A low level of GnRH causes a decrease in FSH and
still a topic of discussion and research due to the small number of LH, resulting in impaired function of the Sertoli and Leydig cells.31
studies. For example, two different studies have analyzed SARS‐CoV‐2 Ma et al.39 showed that COVID‐19 patients had significantly higher
presence in semen samples and according to these studies, SARS‐CoV‐2 serum LH levels but decreased testosterone/LH and FSH levels than
(+) semen samples were found in two patients from 23 cured patients healthy men, suggesting potential hypogonadism. Taken together,
and four patients from 15 patients in the acute phase. Another study patients with COVID‐19 have been found to present a reduced
reported that SARS‐CoV‐2 was not detected in the semen samples testosterone/LH ratio, indicating possible subclinical damage to male
of 34 COVID‐19 patients.31 gonadal function.5 Additionally, activation of the HPGa and subsequent
It is also known that the prostate gland secretes prostate fluid, alterations in hormone concentrations play a critical role in poor sperm
one of the main seminal components, and muscles of the gland help quality.38
31
in pushing the seminal fluid through the urethra during ejaculation. From another point of view, panic physiology in the case of
The critical point is that, as we mentioned above, a small percentage COVID‐19, stress, and negative moods, such as depression and an-
of the prostate hillock and club cells express ACE 220 and also xiety, are associated with a lower secretion of sex hormone‐binding
TMPRSS2 is highly expressed by the epithelium of the human globulin, higher secretion of cortisol and prolactin, lower sperm
37
prostate; so it is more likely to get SARS‐CoV‐2 infection, which count/sperm concentration/semen volume, and higher sperm DNA
may affect its secretions.31 These mechanisms could explain the fragmentation, and also induced sexual dysfunction.38
23
SARS‐CoV‐2 (+) semen samples of the studies. Therefore, besides its direct effects on testis, SARS‐CoV‐2 may
If the presence of the virus in semen is definitively proved by studies, affect fertility indirectly via the central nervous system.31
assisted reproduction techniques will also be affected. For instance, We can summarize the direct and indirect effects of SARS‐CoV‐2
testing all male patients like HIV or Hepatitis B/C cases, and using in the male genital tract as listed in the following table:
Testis Epididymis Poor semen quality Hormones
Direct effects Structural degenerations orchitis Orchitis Virus (+) in semen Breakdown of HPGa
pain autophagy regulation
Indirect effects Increase of testicular temperature – Prostate fluid pushing during ejaculation stress –
hypogonadism breakdown of HPGa
7 | CO N C L U S I O N
appropriate sperm washing techniques, or paying extra attention to In conclusion, all preliminary findings mentioned above suggest that
35
sperm freezing for COVID‐19 positive patients. the COVID‐19 pandemic affects the male genital system in direct or
On the contrary, another hypothesis is that poor semen para- indirect ways and shows a negative impact on male reproductive
meters in the COVID‐19 cases are attributed to panic physiology as health, inducing spermatogenic failure. Additional studies are ne-
an indirect effect of the inflammation.38 We would like to evaluate cessary to answer all the questions and further investigations are
this connection and also hormonal differences in the case of warranted, but ACE 2 and TMPRSS2 play an important role in the
COVID‐19 under a separate heading. cellular entry for SARS‐CoV‐2. As the male genital system presents
high ACE 2 expression, the importance of this pathway increases in
COVID‐19 cases.
6.3 | Effect of SARS‐CoV‐2 on male fertility via
the brain, stress factors—hormonal connection
ACKNOWLEDGM E NT
Like SARS‐CoV‐2, most viruses enter the human body through nasal The authors thank all the researchers who contributed to the pre-
and oral routes, and viral particles may break the blood‐brain barrier. It paration of this review.
has been reported that the brain cells (glial cells and neurons) also
express ACE 2 receptors, making them a possible target to induce
SEYMEN | 1401
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CATEDRA DE UROLOGIA

Infección por SARS-CoV-2: implicaciones para la salud

Recibido el 15 de junio de 2020; aceptado el 26 de junio de 2020

PALABRAS CLAVE Resumen

932 197 696.

Resultados: No se ha confirmado la orquitis como una posible complicación de la infección

Introducción [Términos MeSH] O ‘‘testis’’ [Todos los campos]) AND (‘‘virus

Probablemente la presencia de virus en el semen esté más Conclusiones

Clinical Characteristics and Results of Semen Tests

JAMA Network Open. 2020;3(5):e208292. doi:10.1001/jamanetworkopen.2020.8292 (Reprinted) May 7, 2020 1/3

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JAMA Network Open. 2020;3(5):e208292. doi:10.1001/jamanetworkopen.2020.8292 (Reprinted) May 7, 2020 2/3

Downloaded From: https://jamanetwork.com/ on 06/18/2022

JAMA Network Open. 2020;3(5):e208292. doi:10.1001/jamanetworkopen.2020.8292 (Reprinted) May 7, 2020 3/3

Downloaded From: https://jamanetwork.com/ on 06/18/2022

Impacto de la pandemia SARS-CoV-2 (COVID-19) en el

Autor para correspondencia: gacetamedica@acmbilbao.org (Gaceta Médica de Bilbao).

Orchitis: A Complication of Severe Acute Respiratory Syndrome (SARS)1

ABSTRACT Pathological studies revealed that the lungs of SARS

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TABLE 1. Clinical data for the 6 SARS cases.

Immunohistochemistry designed based on SARS coronavirus genome sequence (GenBank, Accession

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FIG. 1. Hematoxylin-eosin stain. A) Testis

FIG. 2. TUNEL stain. A) Testis from the

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FIG. 3. IHC stain with CD68 (A and C)

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written informed consent was waived.

viral reproduction and

SARS-CoV-2 infection on male reproductive function,

[1] Li, Q, Guan X, Wu P, et al. Early Transmission Dynamics in Wuhan, China, of

[10] Li N, Wang T, Han D. Structural, cellular and molecular aspects of immune

Fertil Steril Rev® Vol. 2, No. 2, April 2021 2666-5719/$36.00

140 VOL. 2 NO. 2 / APRIL 2021

VOL. 2 NO. 2 / APRIL 2021 141

142 VOL. 2 NO. 2 / APRIL 2021

Fertil Steril Rev®

Sixteen oocytes from 2 asymptomatic SARS-CoV-2-

to newborns during vaginal delivery.

Evidence for the impact of COVID-19 on fertility

COVID-19 might affect male fertility by damaging the endo-

caused by elevated body temperature and/or orchitis. The ev-

idence of damaged endocrine function is demonstrated by

signiﬁcantly lower serum testosterone to luteinizing hormone

ratios, a measure used as a predictor of compromised testic-

ular function, in patients with COVID-19 compared with

those in controls (17). The possible role of testosterone and es-

trogen affecting the prevalence of COVID-19 in men

ism and infertility in some men. Local inﬂammatory damage

of the testis-blood barrier might potentially lead to indirect

semen infection. A survey of 91 hospitalized patients with

diagnosed in only 1 patient (61).

Using bedside ultrasound examination of the scrotum in

142 men with a conﬁrmed diagnosis of COVID-19, 22.5% pa-

epididymo-orchitis (62). The investigators used imaging

criteria for acute inﬂammation, including tunica albuginea