EAU GUIDELINES ON MALE

INFERTILITY

(Limited text update March 2016)

A. Jungwirth (Chair), T. Diemer, G.R. Dohle, Z. Kopa, C. Krausz,

H. Tournaye

Eur Urol 2004 Nov;46(5):555-8

Eur Urol 2012 Jan;61(1):159-63
Eur Urol. 2012 Aug;62(2):324-32

Introduction
‘Infertility is the inability of a sexually active, non-contracept-
ing couple to achieve spontaneous pregnancy in one year.’
(World Health Organization 2000).

Epidemiology and aetiology

About 15% of couples do not achieve pregnancy within one
year and seek medical treatment for infertility.

Male fertility can be reduced as a result of:

• congenital or acquired urogenital abnormalities;
• malignancies;
• urogenital tract infections;
• increased scrotal temperature (e.g. as a consequence of
varicocele);
• endocrine disturbances;
• genetic abnormalities;
• immunological factors.

Prognostic factors
The main factors influencing the prognosis in infertility are:
• duration of infertility;

226 Male Infertility

• primary or secondary infertility;
• results of semen analysis;
• age and fertility status of the female partner.

Diagnostic evaluation
The diagnosis of male fertility should focus on a number of
prevalent disorders (Table 1). Simultaneous assessment of the
female partner is preferable, even if abnormalities are found in
the male, since data show that in 1 out of 4 couples both male
and female partners have pathological findings.

Semen analysis
A comprehensive andrological examination is indicated if
semen analysis shows abnormalities compared with reference
values (Table 1).

Male Infertility 227

 Table 1: Lower reference limits (5th centiles and their 95%
CIs) for semen characteristics

Parameter Lower reference

limit (range)
Semen volume (mL) 1.5 (1.4-1.7)
Total sperm number (106/ejaculate) 39 (33-46)
Sperm concentration (106/mL) 15 (12-16)
Total motility (PR + NP) 40 (38-42)
Progressive motility (PR, %) 32 (31-34)
Vitality (live spermatozoa, %) 58 (55-63)
Sperm morphology (normal forms, %) 4 (3.0-4.0)
Other consensus threshold values pH > 7.2
Peroxidase-positive leukocytes (106/mL) < 1.0
Optional investigations
MAR test (motile spermatozoa with < 50
bound particles, %)
Immunobead test (motile spermatozoa < 50
with bound beads, %)
Seminal zinc (μmol/ejaculate) ≥ 2.4
Seminal fructose (μmol/ejaculate) ≥ 13
Seminal neutral glucosidase (mU/ejacu- ≤ 20
late)
CIs = confidence intervals; MAR = mixed antiglobulin reaction
NP = non-progressive; PR = progressive.

It is important to differentiate between the following:

• oligozoospermia: spermatozoa < 15 million/mL;
• asthenozoospermia: < 32% progressive motile spermato-
zoa;
• teratozoospermia: < 4% normal forms.

228 Male Infertility

 Recommendations GR
Perform semen analyses according to the guidelines A*
of the WHO Laboratory Manual for the Examination
and Processing of Human Semen (5th edn).
Perform further andrological assessment when semen A*
analysis is abnormal in at least two tests.
Adhere to the 2010 WHO Manual for the standard- C
ised investigation, diagnosis and management of the
infertile male for diagnosis and evaluation of male
subfertility.
*Upgraded following panel consensus.

Primary Spermatogenic Failure

Diagnostic evaluation
Routine investigations include semen analysis and hormonal
determinations. Other investigations may be required depend-
ing on the individual situation.

Semen analysis
In non-obstructive azoospermia (NOA), semen analysis shows
normal ejaculate volume and azoospermia after centrifuga-
tion. A recommended method is semen centrifugation at
3000 g for 15 min and a thorough microscopic examination by
phase contrast optics at ×200 magnification of the pellet. All
samples can be stained and re-examined microscopically.

Hormonal determinations
In men with testicular deficiency, hypergonadotropic hypo-
gonadism is usually present, with elevated levels of follicle-
stimulating hormone (FSH) and luteinising hormone (LH), and
sometimes low levels of testosterone. Generally, the levels
of FSH correlate with the number of spermatogonia and are
elevated when spermatogonia are absent or markedly dimin-

Male Infertility 229

 ished. Spermatocytic arrest is typically associated with normal
FSH.

Testicular biopsy
Testicular biopsy and testicular sperm extraction (TESE) can
be part of intracytoplasmic sperm injection (ICSI) treatment in
patients with clinical evidence of NOA.

Recommendations GR
For men who are candidates for sperm retrieval, give A
appropriate genetic counselling - also when testing for
genetic abnormalities was negative.
In men with NOA, perform simultaneous testicular A
biopsy with multiple TESE (or micro TESE) to define
spermatogenesis and diagnose ITGCNU.
ICSI = intracytoplasmic sperm injection; ITGCNU = intratubu-
lar germ cell neoplasma of unclassified type; TESE = testicular
sperm extraction; NOA = non-obstructive azoospermia.

Genetic Disorders in Infertility

Current routine clinical practice is based on the screening

of genomic DNA from peripheral blood samples, however,
screening of chromosomal anomalies in spermatozoa is also
feasible and can be performed in selected cases.

Recommendations GR
Obtain standard karyotype analysis in all men with B
damaged spermatogenesis (spermatozoa < 10 million/
mL) who are seeking fertility treatment by IVF.
Provide genetic counselling in all couples with a A
genetic abnormality found in clinical or genetic inves-
tigation and in patients who carry a (potential) inherit-
able disease.

230 Male Infertility

 For all men with Klinefelter’s syndrome, provide long- A
term endocrine follow-up and androgen replacement
therapy, if necessary.
Do not test for microdeletions in men with obstructive A
azoospermia (OA) when ICSI is used because sper-
matogenesis should be normal.
Inform men with Yq microdeletion and their partners A
who wish to proceed with ICSI that microdeletions will
be passed to sons, but not to daughters.
In men with structural abnormalities of the vas defer- A
ens (unilateral or bilateral absence), test the man and
his partner for CFTR gene mutations.
IVF = in vitro fertilisation; OA = obstructive azoospermia;
FSH = follicle-stimulating hormone; ICSI = intracytoplasmic
sperm injection; TESE = testicular sperm extraction;
CFTR = transmembrane conductance regulator; CF = cystic
fibrosis.

Obstructive Azoospermia

Obstructive azoospermia (OA) is the absence of spermatozoa

and spermatogenetic cells in semen and post-ejaculate urine
due to obstruction. Sometimes, the vas deferens is absent
(CBAVD or CUAVD). Obstruction in primary infertile men is
frequently present at the epididymal level.

Diagnostic evaluation
Clinical examination should follow suggestions for the diag-
nostic evaluation of infertile men. The following findings indi-
cate OA:
• At least one testis with a volume > 15 mL, although a
smaller volume may be found in some patients with OA
and concomitant partial testicular failure.
• Enlarged and hardened epididymis.

Male Infertility 231

 • Nodules in the epididymis or vas deferens.
• Absence or partial atresia of the vas.

Semen analysis
At least two examinations must be carried out at an interval of
one to two months, according to the WHO. When semen vol-
ume is low, a search must be made for spermatozoa in urine
after ejaculation. Absence of spermatozoa and immature
germ cells in semen smears suggest complete seminal duct
obstruction.

Hormone levels
Serum FSH levels may be normal, but do not exclude a testicu-
lar cause of azoospermia.

Ultrasonography
In addition to physical examination, a scrotal ultrasound may
be helpful in finding signs of obstruction (e.g., dilatation of rete
testis, enlarged epididymis with cystic lesions, or absent vas
deferens) and may demonstrate signs of testicular dysgenesis
(e.g., non-homogeneous testicular architecture and microcal-
cifications) and testis tumours.

Testicular biopsy
In selected cases, testicular biopsy is indicated to exclude
spermatogenic failure. Testicular biopsy should be combined
with extraction of testicular spermatozoa (i.e. TESE)
for cryopreservation.

Recommendations GR
For azoospermia caused by vasal or epididymal B
obstruction, perform microsurgical vasovasostomy or
tubulovasostomy.

232 Male Infertility

 Use sperm retrieval techniques, such as MESA, TESE, B
and PESA only when cryostorage of the material
obtained is available.
CBAVD = Congenital Bilateral Absence of the Vas Deferens;
CUAVD = Congenital Unilateral Absence of the Vas Deferens

Varicocele

Varicocele is a common abnormality which may be associated

with the following andrological conditions:
• Failure of ipsilateral testicular growth and development.
• Symptoms of pain and discomfort.
• Male subfertility.
• Hypogonadism.

Diagnostic evaluation
The diagnosis of varicocele is made by clinical examination
and should be confirmed by colour Duplex analysis. In centres
where treatment is carried out by antegrade or retrograde
sclerotherapy or embolisation, diagnosis is additionally con-
firmed by X-ray.

Disease management
Several treatments are available for varicocele. Current evi-
dence indicates that microsurgical varicocelectomy is the
most effective with the lowest complication rate among the
varicocelectomy techniques.

Recommendations GR
Treat varicoceles in adolescents with progressive fail- B
ure of testicular development documented by serial
clinical examination.
Do not treat varicoceles in infertile men who have A
normal semen analysis and in men with a subclinical
varicocele.

Male Infertility 233

 Treat varicoceles in men with a clinical varicocele, A
oligospermia and otherwise unexplained infertility in
the couple.

Hypogonadism

Idiopathic hypogonadotropic hypogonadism

Idiopathic hypogonadotropic hypogonadism is characterised
by low levels of gonadotropins and sex steroid in the absence
of anatomical or functional abnormalities of the hypothalam-
icpituitary-gonadal axis.

Hypergonadotropic hypogonadism
Many conditions in men are associated with hypergonado-
tropic hypogonadism and impaired fertility (e.g. anorchia,
maldescended testes, Klinefelter’s syndrome, trauma, orchitis,
systemic diseases, testicular tumour, varicocele etc).

Recommendations GR
Provide testosterone replacement therapy for symp- A
tomatic patients with primary and secondary hypog-
onadism who are not considering parenthood.
In men with hypogonadotropic hypogonadism, induce A*
spermatogenesis by an effective drug therapy (hCG/
hMG/rFSH).
Do not use testosterone replacement for the treat- A*
ment of male infertility.
*Upgraded following panel consensus.
FSH = follicle-stimulating hormone; LH = luteinising hormone.

Cryptorchidism

The aetiology of cryptorchidism is multifactorial, involving

disrupted endocrine regulation and several gene defects. It

234 Male Infertility

has been postulated that cryptorchidism may be a part of the
so-called testicular dysgenesis syndrome (TDS), which is a
developmental disorder of the gonads caused by environmen-
tal and/or genetic influences early in pregnancy. Besides
cryptorchidism, TDS may include hypospadias, reduced fertil-
ity, increased risk of malignancy, and Leydig cell dysfunction.

Recommendations GR
Do not use hormonal treatment of cryptorchidism in A
adults.
If undescended testes are corrected in adulthood, B
perform simultaneous testicular biopsy for detection
of ITGCNU (formerly CIS).
CIS = carcinoma in situ; ITGCNU = intratubular germ cell neo-
plasia of unclassified type.

Idiopathic Male Infertility

Recommendation GR
Use medical treatment of male infertility only for cases A
of hypogonadotropic hypogonadism.
No recommendation can be made for treatment with B
gonadotropins, anti-oestrogens and antioxidants even
for a subset of patients.

Male Infertility 235

 Male Contraception

Recommendations GR
Vasectomy is the gold standard for the male contribu- A
tion to permanent contraception.
Cauterisation and fascial interposition are the most A
effective techniques for the prevention of early
recanalisation.
Inform patients seeking vasectomy about the surgi- A*
cal method, risk of failure, potential irreversibility, the
need for post-procedure contraception until clear-
ance, and the risk of complications.
To achieve pregnancy, MESA/PESA/TESE - together B
with ICSI is a second-line option for men who decline
a vasectomy reversal and those with failed vasectomy
reversal surgery.
*Upgraded following panel consensus
MESA = microsurgical epididymal sperm aspiration;
PESA = percutaneous epididymal sperm aspiration;
TESE = testicular sperm extraction; ICSI = intracytoplasmic
sperm injection.

Male Accessory Gland Infections and Infertility

Diagnostic evaluation
Ejaculate analysis
Ejaculate analysis clarifies whether the prostate is involved as
part of a generalised male accessory gland infection and pro-
vides information about sperm quality.

Microbiological findings
After exclusion of urethritis and bladder infection, >106 perox-
idase-positive white blood cells (WBCs) per millilitre of ejacu-
late indicate an inflammatory process. In this case, a culture

236 Male Infertility

should be performed for common urinary tract pathogens.

Epididymitis

Inflammation of the epididymis causes unilateral pain and

swelling, usually with acute onset.

Diagnostic evaluation
Ejaculate analysis
Ejaculate analysis according to WHO criteria, might indicate
persistent inflammatory activity.

Disease management
Antibiotic therapy is indicated before culture results are
available.

Recommendation GR
Instruct patients with epididymitis that is known B
or suspected to be caused by N. gonorrhoeae or
C. trachomatis to refer their sexual partners for
evaluation and treatment.

Male Infertility 237

 Germ Cell Malignancy and Testicular Microcalcification
(TM)

Recommendations GR
As for all men, encourage patients with TM and with- B
out special risk factors (see below) to perform self-
examination because this might result in early detec-
tion of TGCT.
Do not perform testicular biopsy, follow-up scrotal B
ultrasound, routine use of biochemical tumour mark-
ers, or abdominal or pelvic CT, in men with isolated TM
without associated risk factors (e.g. infertility, cryptor-
chidism, testicular cancer, and atrophic testis).
Perform testicular biopsy for men with TM, who B
belong to one of the following high-risk groups: infer-
tility and bilateral TM, atrophic testes, undescended
testes, a history of TGCT.
If there are suspicious findings on physical examina- B
tion or ultrasound in patients with TM and associated
lesions, perform surgical exploration with testicular
biopsy or orchidectomy.
Follow men with TGCT because they are at increased B
risk of developing hypogonadism and sexual dysfunc-
tion.
TM = testicular microlithiasis; TGCT = testicular germ cell
tumour; CT = computed tomography.

Disorders of Ejaculation
Disorders of ejaculation are uncommon, but important causes
of male infertility.

238 Male Infertility

Diagnostic evaluation
Diagnostic management includes the following recommended
procedures.
1. Clinical history
2. Physical examination
3. Post-ejaculatory urinalysis
4. Microbiological examination
5. Optional diagnostic work-up

This diagnostic work-up can include:

• neurophysiological tests (bulbocavernosus evoked
response and dorsal nerve somatosensory evoked poten-
tials);
• tests for autonomic neuropathy;
• psychosexual evaluation;
• videocystometry;
• cystoscopy;
• transrectal ultrasonography;
• uroflowmetry;
• vibratory stimulation of the penis.

Disease management
The following aspects must be considered when selecting
treatment:
• Age of patient and his partner.
• Psychological problems of the patient and his partner.
• Couple’s willingness and acceptance of different fertility
procedures.
• Associated pathology.
• Psychosexual counselling.

Male Infertility 239

 Recommendations GR
Offer aetiological treatments for ejaculatory disorders B
before performing sperm collection and ART.
To treat disorders of ejaculation, offer pharmacological A
treatment of either dapoxetine on demand (a short-
acting SSRI that is the only approved pharmacological
treatment for premature ejaculation) or other off-label
antidepressants, i.e. daily SSRIs and clomipramine,
that are not amenable to on-demand dosing.
Alternatively offer topical anaesthetics or tramadol. A
ART = assisted reproduction technique; SSRIs = selective sero-
tonin reuptake inhibitors.

Semen cryopreservation

Recommendations GR
Offer cryopreservation of semen to all men who are A
candidates for chemotherapy, radiation or surgical
interventions that might interfere with spermatogen-
esis or cause ejaculatory disorders.
Offer simultaneous sperm cryopreservation if testicu- A
lar biopsies will be performed for fertility diagnosis.
If cryopreservation is not available locally, inform C
patients about the possibility of visiting, or transfer-
ring to a cryopreservation unit before therapy starts.

240 Male Infertility

Take precautions to prevent transmission of viral, C
sexually transmitted or any other infection by cryos-
tored materials from donor to recipient, and to prevent
contamination of stored samples. These precautions
include testing of the patient and the use of rapid
testing and quarantine of samples until test results
are known. Do not store samples from men who are
positive for hepatitis virus or HIV. It must not be stored
in the same container as samples from men who have
been tested and are free from infection.

This short booklet text is based on the more comprehensive

EAU Guidelines (ISBN 978-90-79754-98-4), available to all members of
the European Association of Urology at their website,
http://www.uroweb.org.

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