THE JOURNAL OF PEDIATRICS • www.jpeds.

com COMMENTARY

Understudied and Under-Reported: Fertility Issues in Transgender

Youth—A Narrative Review
Leena Nahata, MD1, Diane Chen, PhD2, Molly B. Moravek, MD, MPH3, Gwendolyn P. Quinn, PhD4, Megan E. Sutter, PhD5,
Julia Taylor, MD, MA6, Amy C. Tishelman, PhD7, and Veronica Gomez-Lobo, MD8

I
nfertility, or the concern for infertility, has been shown in preservation options in pediatrics, and transgender youths’ at-
many studies to be associated with psychosocial distress titudes toward biological parenthood. This article will report
among affected adults,1,2 and may result from numerous on the results of the narrative review; discuss appropriate fer-
genetic or pediatric conditions and treatments.3 Fertility pres- tility preservation options for youth with gender dysphoria;
ervation technologies have been developed to expand future and propose medical and psychological recommendations for
parenthood options for youth and others at risk for infertil- best practices related to fertility counseling and intervention,
ity.3 Although these rapid technological advances have facili- based on the known literature to date.
tated improvements in clinical care, significant knowledge gaps A literature search was conducted to inform this narrative
exist with regard to who is at risk and could benefit from fer- review, based on applicable PRISMA items. We searched
tility preservation technologies, which methods have ad- PubMed, Google Scholar, Medline, Web of Science, and PsycInfo
equate evidence to support integration in clinical care, and how databases for English-language studies (no date restrictions on
to optimize access to, and utilization of, established options. publication year), with the following search terms: transgender,
Much of the work in this area has been conducted in pe- gender identity disorder, gender dysphoria, transsexual, re-
diatric oncology, as chemotherapy and radiation are known productive health, fertility, fertility preservation, ovarian stimu-
to impair gonadal function, and research has informed dose- lation, prepubertal ovaries, testes, gender-affirming hormones,
specific risk assessments for many of the most common treat- cross-sex hormones, pubertal suppression, GnRH agonist, tes-
ments.4,5 An important limitation of this research is that sexual tosterone, estrogen, antimullerian hormone (AMH), adolescent,
orientation or gender identity are rarely assessed within study parent, pregnancy, and attitudes. Search results included a
populations, and 1 study has suggested perspectives on par- variety of publication types including guidelines, commentaries,
enthood may be different in those within the lesbian, gay, bi- case series, qualitative, and quantitative research. We also manu-
sexual, transgender, or questioning (LGBTQ) population ally searched the references of each selected article. All authors
compared with non-LGBTQ identified cancer survivors.6 Or- agreed upon which articles to include. Given the dearth of re-
ganizations such as the American Academy of Pediatrics, Ameri- search in this area, inclusion was broad and based on assess-
can Society of Pediatric Oncology, and American Society for ment of relevance of content, utility of findings, and appraisal
Reproductive Medicine have published guidelines urging pro- of study methodology and reporting. Human studies were pri-
viders to counsel youth with cancer about their infertility risk; oritized for inclusion, though relevant animal studies were also
discuss fertility preservation options, distinguishing those that included as they related to hormone functioning and fertility.
are established (sperm, oocyte, and embryo cryopreservation),
from those that are experimental (testicular and ovarian tissue
cryopreservation); and to document these discussions and re- Effects of Hormone Therapy on Fertility
ferrals in the medical record.7-9
Using this framework, increasing attention has been paid Effects of Estrogen Therapy on the Testicle
to other populations at risk for infertility,3,10,11 including the Few studies specific to the transgender community exist to guide
rapidly expanding transgender population seeking hor- conversations about the long-term effects of gender-affirming
monal therapies.12 Though little is known about long-term fer- hormones on testicular function and fertility. Studies of the
tility outcomes after these treatments, the American Society effects of estrogen secreting tumors in male subjects have docu-
for Reproductive Medicine Endocrine Society, and World Pro- mented spermatogenesis after tumor removal even after pro-
fessional Association for Transgender Health recently pub- longed (months to years) abnormal hormonal function.16,17
lished guidelines highlighting the need to discuss infertility risk
and fertility preservation options with youth prior to hor-
monal interventions.13-15 The purpose of the narrative review
was to identify what is known about fertility implications related From the 1Nationwide Children’s Hospital/The Ohio State University, Columbus, OH;
2Ann and Robert H. Lurie Children’s Hospital/Northwestern University, Chicago, IL;

to hormonal treatments in youth (estrogen, testosterone, and 3University of Michigan, Ann Arbor, MI; 4New York University School of Medicine,

New York, NY; 5H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL;
gonadotropin-releasing hormone [GnRH] agonists), fertility 6University of Virginia, Charlottesville, VA; 7Boston Children’s Hospital/Harvard

Medical School, Boston, MA; and 8Washington Hospital Center/Children’s National

Medical Center/Georgetown University, Washington, DC
The authors declare no conflicts of interest.
AMH Antimullerian hormone
GnRH Gonadotropin-releasing hormone 0022-3476/$ - see front matter. © 2018 Elsevier Inc. All rights reserved.
https://doi.org10.1016/j.jpeds.2018.09.009

265
THE JOURNAL OF PEDIATRICS • www.jpeds.com Volume 205 • February 2019

Studies examining the use of high dose estrogen for the treat- Gonadal Effects in Adolescents who have
ment of prostate disease have been reported to cause azo- Undergone Puberty Suppression
ospermia and atrophy due to gonadotropin suppression and There is a paucity of literature on the effects of pubertal sup-
Leydig cell dysfunction with variable reversibility.18,19 Animal pression by GnRH agonists in transgender youth on future re-
data suggest that the role of physiologic estrogen in testicular production, although studies of GnRH agonists used for male
function and fertility is more complex.20 contraception have demonstrated reversible suppression of sper-
The few available studies of transgender women on estro- matogenesis.40 Schagen et al reported a decrease in testicular
gen therapy rely on small sample sizes (n = 1 to n = 11) and volume among the majority of 49 transgender youth receiv-
heterogeneous treatment protocols (low or high dose estro- ing GnRH agonists.41 Similarly, a study on the effect of GnRH
gen, estrogen + anti-androgens, oral vs transdermal) result- agonist treatment in girls with central precocious puberty
ing in incomplete and often conflicting results.21 Prolonged showed a decrease in ovarian and uterine size during treat-
estrogen exposure has been reported to result in atrophy and ment, with increase to normal size and resumption of men-
absent or impaired spermatogenesis,22,23 while normal sper- strual function approximately 1 year after cessation of therapy.42
matogenic activity and complete reversibility have also been Currently, no studies address whether fertility can be gained,
reported.24-26 One recent study reported heterogeneous results either naturally or with exogenous gonadotropins, in
among 108 transgender women presenting for gender-affirming transgender individuals who underwent pubertal suppres-
surgery after gender-affirming hormone treatment ranging from sion in adolescence, followed directly by gender-affirming
normal spermatogenesis (24%) to tubular shadows/atrophy hormone therapy. Fertility can be gained in those who undergo
(1.85%).27 pubertal suppression and then discontinue GnRH agonists to
allow endogenous puberty to progress, though there may be
Effects of Testosterone Therapy on the Ovary negative psychosocial implications of this process for some
Despite the fact there have been a few pregnancies in youth who may progress through puberty incongruent with
transgender men widely publicized in the popular press, the their affirmed gender identity.
overall pregnancy rate has not been published,28 and the effect
of long-term gender-affirming hormone therapy on fertility Overview of Current Fertility Preservation
in transgender men is considered unknown. There is 1 pub- Options
lished study on pregnancy in transgender men, of whom 61%
of participants were on testosterone prior to pregnancy.29 Of A wide range of fertility preservation methods are consid-
these subjects, 84% used their own oocytes for pregnancy, and ered in children, adolescents, and young adults with cancer,
32% conceived while still on testosterone.29 Importantly, this and in part inform options for transgender individuals de-
study only included subjects who had a live birth, so does not pending on sex assigned at birth and pubertal development
capture overall conception or miscarriage rates in this popu- (Table I and Table II).43 For pubertal (Tanner stages 2-3 and
lation.29 beyond) assigned male subjects, sperm cryopreservation is a
Most of the data on the effects of testosterone therapy on safe, established, and cost-effective fertility preservation
the ovaries of transgender men have come from case series ex- method.44 Noninvasive methods (masturbation) are pre-
amining the ovaries at the time of gender-affirming surgery ferred, though sperm may be retrieved by electroejaculation45
with salpingo-oophorectomy, with conflicting results.30-37 Four or extracted with percutaneous aspiration or microdissec-
of these studies reported a definitive adverse effect on the his- tion extraction of the testicular sperm for those who are un-
tology of the ovary, reporting a polycystic ovarian morphol- willing or unable to masturbate, or who are azoospermic.46,47
ogy (stromal hyperplasia, multiple cystic follicles, collagenized These alternate methods could benefit individuals whose erec-
outer cortex, and/or luteinization of stromal cells) in the ma- tions have decreased after starting gender-affirming therapy,
jority of ovaries examined.30,32,33,36 Three of the studies con- or for those who experience psychological distress with mas-
cluded that there is minimal to no adverse effect on the turbation. At present, testicular tissue cryopreservation for pre-
ovaries,31,34,35 and the remaining study was somewhere in and postpubertal assigned male subjects is an experimental
between.37 Of note, all of these studies were performed in adults, fertility preservation option48,49; because no human births have
and the average duration of testosterone therapy was less than been reported to date, this procedure should only be per-
4 years in all 8 studies, so it is unclear whether these data can formed under an institutional review board-approved proto-
be applied to an individual who initiated gender-affirming hor- col for those who are at high risk for infertility.50
mones in adolescence, and then desires fertility more than a Among assigned female subjects who have experienced men-
decade later. There are also 2 studies that evaluated AMH levels arche, embryo cryopreservation is an established fertility pres-
in transgender men after gender-affirming hormone therapy; ervation method, and requires sperm from a partner or donor
1 study showed a decrease in AMH, and the other showed no and postpubertal egg from the patient. In 2013, oocyte
change, and both studies had the patients on additional cryopreservation became an established method of fertility pres-
hormone-affecting medications (GnRH agonist, aromatase in- ervation in this population with improved cryopreservation
hibitor, and/or progestin) making it difficult to isolate the spe- techniques,51 and successful pregnancies have been reported.52
cific effect of testosterone, and any potential effect on ovarian However, it remains unclear whether ovaries can be effec-
reserve.38,39 tively stimulated in youth who have started GnRH agonists in
266 Nahata et al
February 2019 COMMENTARY

Table I. Fertility preservation methods for assigned male patients

Sperm cryopreservation (pubertal only) Estimated costs*
• Pubertal individuals (Tanner 2-3 and beyond) who are not on hormone therapy Preservation
may collect sperm through masturbation. • $400-$1000 for collection
o Alternative methods such as testicular sperm extraction or electroejaculation • $200-$500/y for storage
(under anesthesia) may be considered if the person is unable or unwilling to • $45-$100 for thawing
masturbate prior to initiating estrogen and androgen blocking therapy. Thawing and fertilization
o Individuals undergoing puberty suppression prior to beginning estrogen therapy • Additional costs may be incurred with use of sperm, which will require
would require progression through early endogenous puberty (which could either intrauterine inseminations or in vitro fertilization, depending on
lead to potentially distressing irreversible changes to the voice, hair, facial/ sample quality.
body structure) so an adequate sperm sample can be obtained through the
methods described above.
Testicular tissue cryopreservation (prepubertal) Estimated costs*
• Based on current knowledge, we recommend against offering testicular tissue Preservation
cryopreservation to minors. • $5000-$10 000 for surgery (may be free at some centers if done through a
o Although estrogen may cause irreversible damage to sperm production, to research protocol)
date, there has never been a human pregnancy reported through testicular • $150 for transportation to storage site
tissue cryopreservation. • $100-$1000/y for storage
• Testicular cryopreservation may be performed at the time of gonadectomy, but Tissue thawing and use
patients should be counseled regarding the experimental nature, lack of • Costs are unknown as it is unclear if pregnancy will be achieved through in
documented pregnancy, and costs of storage of testicular tissue. vitro sperm maturation or testicular tissue transplant.

*Costs may vary widely between centers across the US and internationally.

the early stages of puberty (ie, in cases where endogenous Attitudes toward Fertility Preservation
puberty has never progressed). Ovarian tissue cryopreservation
is an experimental method for assigned female subjects who Transgender adults have wide-ranging attitudes toward and ex-
have not reached menarche or cannot delay treatment to induce periences of fertility preservation and parenthood; prior re-
ovulation to pursue established fertility preservation methods53 search shows 18%-54% of transgender adults express desires
and has resulted in more than 100 successful live births.54,55 for children.58-61 Parenting desires are associated with younger
Notably, nearly all of these births have resulted from postpu- age and support from family,61 and currently not having a
bertal ovarian tissue56; live births have only been reported with child.59,60 The experience of parenting children after medical
reimplantation of the tissue back into the donor57; and because transition has been described by some as a meaningful part
removal of 1 complete ovary is often required in pediatric pa- of life, connecting individuals to the larger community.62 Two
tients, this procedure is only offered to those at moderate- recent case series document transgender adults using as-
high risk for infertility.53 sisted reproductive technologies and cryopreserved gametes to

Table II. Fertility preservation methods for assigned female patients

Oocyte and embryo cryopreservation (Pubertal only) Estimated costs*
• Late- and postpubertal individuals may undergo stimulation and oocyte Preservation
retrieval for oocyte or embryo cryopreservation. • $5000-$20 000 for monitoring, oocyte retrieval, and lab procedures
o Individuals who have undergone pubertal suppression prior to beginning tes- • $4000-$5000 for medications
tosterone therapy may require progression through early endogenous puberty • $100-$1000/y for storage
(which could lead to potentially distressing irreversible chest tissue growth Thawing, fertilization, and implantation
and hip widening) prior to ovarian stimulation and oocyte retrieval and • $3000-$10 000 for lab and medical procedures
cryopreservation. • $100-$1000 for medications
Ovarian tissue cryopreservation (Pre-pubertal or pubertal) Estimated costs*
• Although ovarian tissue cryopreservation remains experimental, to date there Preservation
have been over 100 pregnancies reported in individuals who have had tissue • $10 000-$20 000 for surgery (may be free at some centers if done through a
re-implanted. research protocol)
• Given the documented pregnancies in transgender men even while on • $150 for transportation to storage site
testosterone therapy, and the fact that ovarian tissue cryopreservation is • $100-$1000/y for storage
generally reserved for those at moderate-high risk of infertility, we believe that Autologous tissue transplantation after thawing
the risks of ovarian tissue cryopreservation outweigh the benefits, and it • $10 000-$20 000 for surgery
should not be offered to adolescents prior to initiating testosterone therapy.
• Adults who consider undergoing ovarian tissue cryopreservation at the time of
oophorectomy should be counseled:
o Pregnancy may be more likely when ovaries remain in situ.
o All pregnancies have resulted from ovarian tissue transplantation back into
the same individual.
o To date there have not been any pregnancies from in-vitro maturation of oocytes
from cryopreserved ovarian tissue.
o It is unlikely that pregnancy would result from transplantation of tissue into
another individual.

*Costs may vary widely between centers across the US and internationally.

Understudied and Under-Reported: Fertility Issues in Transgender Youth—A Narrative Review 267
THE JOURNAL OF PEDIATRICS • www.jpeds.com Volume 205

build biological families.63,64 It is important to note that quali- many wondered if their attitudes toward biological parent-
tative work with adult transgender men demonstrates varying hood may change in the future.68
psychosocial experiences with fertility preservation. Some Similarly, in a recent mixed-methods study of a more gender-
transgender men who temporarily discontinued testosterone diverse sample of 156 community-recruited transgender and
to pursue fertility preservation experienced worsening gender gender-nonconforming 14- to 17-year-olds (in which just over
dysphoria with resumption of menses, whereas others felt the one-half identified as genderqueer), 36% expressed interest in
experience was less distressing than anticipated.65 In previ- biological parenthood; however, an additional 26% expressed
ously studied samples of transgender adults, 38% of transgender uncertainty about biological parenthood desires. Notably, 60%
men59 and 51% of transgender women60 indicated they would of this sample were interested in learning more about their fer-
have considered gamete (ie, sperm or egg) cryopreservation tility options, which was consistent with qualitative reports
if this technology had existed and been offered to them. Among pointing to the need for additional information about “fer-
transgender women, identifying as lesbian or bisexual and tility for people who are transitioning from one gender to
younger age are associated with greater likelihood of consid- another.”69 A validated questionnaire was recently developed
ering sperm cryopreservation.60 Many transgender men and to explore fertility-related attitudes among transgender ado-
women also agree that fertility preservation should be offered lescents and may be useful for future work in this area; efforts
prior to gender-affirming medical treatment.60,62 Regardless of should be made in this future research to examine fertility-
individual desires, provider and systemic barriers such as cost related perspectives of nonbinary or gender fluid adolescents
(Table I and Table II), and discrimination/refusal of ser- as well.68 It is also important to note that fertility desires are
vices, may impede transgender individuals’ ability to pursue not the only consideration in making decisions about pursu-
reproductive services. ing fertility preservation; risks of worsening gender dyspho-
Few studies have specifically examined fertility desires and ria to pursue gamete cryopreservation is an important
parenting intentions among a growing population of individual factor, as documented in a recent case report of 2
transgender youth seeking gender-affirming hormonal thera- transmasculine adolescents who ultimately made different de-
pies in adolescence. To date, 2 studies have reported low fer- cisions about fertility preservation.70
tility preservation utilization rates in this population, with 1 There is also limited research on the perspectives of parents
institution identifying that out of 72 transgender youth coun- of transgender youth regarding their children’s future fertil-
seled on fertility, only 2 (3%) pursued fertility preservation ity. One European study ranking priorities among parents of
(both assigned male subjects).66 Another pediatric institu- transgender youth ranked “future children” as their lowest pri-
tion reported 5 patients (4 assigned male patients) out of 105 ority, particularly among parents of children assigned male.71
(5%) pursued fertility preservation.67 In a pilot study of 25 Strang et al in a study of transgender youth fertility attitudes
transgender youth surveyed about their fertility-related atti- identified that 65% of parents felt it was important to learn
tudes, only 24% expressed a desire to have their own biologi- the impact of gender-affirming hormone treatment on their
cal child and none had pursued fertility preservation; however, child’s ability to have children in the future.68 Of these, 56%

Table III. Fertility counseling for transgender youth

• Ensure all providers are educated about the impacts of various medical interventions on fertility potential, fertility preservation options, and resources for families.
• Develop a structured protocol for counseling, tailored to youths' developmental stage (eg, pre-adolescents; early adolescents; late adolescents; adults), and include
caregivers when the patient is a minor. Talking points can be adapted from medical decision-making guides, such as the one published by the Ottawa Hospital
Research Institute* and can include the following:
o Clarify decisions that need to be made regarding fertility.
o Review knowledge of parenting options (eg, fertility preservation option; alternate parenting options like adoption), along with benefits and risks of each.
o Discuss personal values and the personal meaning of each option.
o Review personal supports for decision-making; discuss differences of opinion within the family.
o Either come to a decision or, if uncertainty persists, ensure adequate knowledge and continue to explore values and options to minimize decisional regret.
• Whenever possible, employ an interdisciplinary team model:
o Medical providers should discuss the medical implications of interventions on fertility, options available for fertility preservation, and alternative options for family
building.
o When available, mental health staff should meet with youth and families to better understand the unique concerns of the child/adolescent and caregivers, in-
cluding cultural, structural, mental health and other considerations, and ensure youth and families have an adequate understanding of topics discussed with medical
providers.
• Allow adequate time for discussion and decision-making. Counseling and informed consent should ideally be a multi-session process, allowing time for
contemplation, with the recognition that attitudes toward fertility preservation can modify with time and youth/caregiver reflection. However, this timeline must be
balanced to account for potential distress that may occur with waiting to initiate treatment, to determine an individualized plan for each youth/family, including the
potential option to temporarily discontinue hormonal intervention in the future to pursue fertility preservation and the risks/benefits of this.
• Use a flexible approach within the structured protocol that can be modified based on possible developmental and mental health challenges of the youth and
parents.
o A different approach may be necessary in cases in which family conflict is high, and/or if a child/adolescent is experiencing significant mental health morbidities
in the absence of intervention.
o Developmental diagnoses, such as autism spectrum disorders, can co-occur with gender dysphoria, and approaches to counseling should be modified to ensure
adequate communication, sometimes in consultation with other providers with the necessary expertise (eg, autism spectrum disorder specialists).

*https://decisionaid.ohri.ca/docs/das/OPDG.pdf.

268 Nahata et al
February 2019 COMMENTARY

wanted their child to consider fertility preservation methods.68 3. Johnson EK, Finlayson C, Rowell EE, Gosiengfiao Y, Pavone ME, Lockart
Conversely, Lawlis et al asked 118 transgender and gender- B, et al. Fertility preservation for pediatric patients: current state and future
possibilities. J Urol 2017;198:186-94.
nonconforming youth and their parents (n = 103) to endorse 4. Green DM, Nolan VG, Goodman PJ, Whitton JA, Srivastava D, Leisenring
items of health concern among a list of 22 concerns. Con- WM, et al. The cyclophosphamide equivalent dose as an approach for
cerns about fertility were endorsed by only 8 (7%) youth and quantifying alkylating agent exposure: a report from the Childhood Cancer
10 (10%) of parents.72 The majority of parents were more Survivor Study. Pediatr Blood Cancer 2014;61:53-67.
focused on issues such as their child’s mental health con- 5. Chow EJ, Stratton KL, Leisenring WM, Oeffinger KC, Sklar CA, Don-
aldson SS, et al. Pregnancy after chemotherapy in male and female sur-
cerns and how to keep their child safe at school.72 vivors of childhood cancer treated between 1970 and 1999: a report from
the Childhood Cancer Survivor Study cohort. Lancet Oncol 2016;17:567-
76.
Conclusions 6. M Russel A, Galvin KM, Harper MM, Clayman ML. A comparison of het-
erosexual and LGBTQ cancer survivors’ outlooks on relationships, family
Transgender youth may be interested in becoming biological building, possible infertility, and patient-doctor fertility risk communi-
cation. J Cancer Surviv 2016;10:935-42.
parents, and should be counseled about potential risk of fer-
7. Fallat ME, Hutter J. Preservation of fertility in pediatric and adolescent
tility impairment and fertility preservation options before ini- patients with cancer. Pediatrics 2008;121:e1461-9.
tiation of hormonal or surgical therapies which may impact 8. Practice Committee of American Society for Reproductive Medicine. Fer-
reproductive potential. Based on the current state of knowl- tility preservation in patients undergoing gonadotoxic therapy or gonad-
edge (with limited information about the impact of hor- ectomy: a committee opinion. Fertil Steril 2013;100:1214-23.
9. Oktay K, Harvey BE, Partridge AH, Quinn GP, Reinecke J, Taylor HS, et al.
monal therapies on fertility), we suggest fertility preservation
Fertility preservation in patients with cancer: ASCO clinical practice guide-
methods be limited to those deemed “standard of care” for pu- line update. J Clin Oncol 2018;36:1994-2001.
bertal youth not on hormone therapy (Table I and Table II). 10. Hirshfeld-Cytron J, Gracia C, Woodruff TK. Nonmalignant diseases and
Similar to onco fertility standards of care, the approach to fer- treatments associated with primary ovarian failure: an expanded role for
tility counseling should use the diverse skill sets represented fertility preservation. J Womens Health (Larchmt) 2011;20:1467-77.
11. Vakeesan B, Weidman DR, Maloney AM, Allen L, Lorenzo AJ, Gupta AA.
on interdisciplinary teams, with a structured protocol to ensure
Fertility preservation in pediatric subspecialties: a pilot needs assess-
that issues of fertility and alternative family building options ment beyond oncology. J Pediatr 2018;194:253-6.
are adequately discussed with each child and family (Table III). 12. Wiepjes CM, Nota NM, de Blok CJM, Klaver M, de Vries ALC, Wensing-
Prior studies indicate it is relatively rare for transgender youth Kruger SA, et al. The Amsterdam Cohort of Gender Dysphoria Study
to opt for fertility preservation interventions.66,67 Although (1972-2015): trends in prevalence, treatment, and regrets. J Sex Med
2018;15:582-90.
reasons for this reluctance are not entirely clear, a number of
13. Ethics Committee of the American Society for Reproductive M. Access
barriers exist,11,69 including developmental (age), cognitive (focus to fertility services by transgender persons: an Ethics Committee opinion.
on establishing gender identity), structural (cost, invasive- Fertil Steril 2015;104:1111-5.
ness), and provider (knowledge, resources) challenges. Ethical 14. Coleman E, Bockting W, Botzer M, Cohen-Kettenis P, DeCuypere G,
concerns centering on the principles of autonomy (parent/ Feldman J, et al. Standards of care for the health of transsexual, transgender,
and gender-nonconforming people, version 7. Int J Transgenderism
child decisional conflict about hormonal therapies and fertil-
2012;13:165-232.
ity preservation) and justice (inability to access fertility 15. Hembree WC, Cohen-Kettenis PT, Gooren L, Hannema SE, Meyer WJ,
preservation treatments because of due to cost) are common.73 Murad MH, et al. Endocrine treatment of gender-dysphoric/gender-
Further research is needed to develop evidence-based strate- incongruent persons: an endocrine society clinical practice guideline. J
gies to overcome these barriers, examine effects of gender- Clin Endocrinol Metab 2017;102:3869-903.
16. Gabrilove JL, Nicolis GL, Mitty HA, Sohval AR. Feminizing interstitial cell
affirming hormones on gametes, 74 and identify optimal
tumor of the testis: personal observations and a review of the literature.
strategies to obtain gametes without requiring pubertal changes Cancer 1975;35:1184-202.
that do not align with the individual’s gender identity in in- 17. Mineur P, De Cooman S, Hustin J, Verhoeven G, De Hertogh R. Femi-
dividuals who undergo puberty suppression. ■ nizing testicular Leydig cell tumor: hormonal profile before and after uni-
lateral orchidectomy. J Clin Endocrinol Metab 1987;64:686-91.
18. Lu CC, Steinberger A. Effects of estrogen on human seminiferous tubules:
Submitted for publication Apr 23, 2018; last revision received Aug 14, 2018;
accepted Sep 5, 2018
light and electron microscopic analysis. Am J Anat 1978;153:1-13.
19. Oshima H, Sarada T, Ochiai K, Tamaoki B. Effects of a synthetic estro-
Reprint requests: Leena Nahata, MD, Nationwide Children’s Hospital, 700
gen upon steroid bioconversion in vitro in testes of patients with pros-
Children’s Dr, Columbus, OH 43205. E-mail: leena.nahata@
nationwidechildrens.org
tatic cancer. Invest Urol 1974;12:43-9.
20. Hess RA, Bunick D, Lee KH, Bahr J, Taylor JA, Korach KS, et al. A role
for oestrogens in the male reproductive system. Nature 1997;390:509-
12.
References 21. Schneider F, Kliesch S, Schlatt S, Neuhaus N. Andrology of male-to-
female transsexuals: influence of cross-sex hormone therapy on testicu-
1. Armuand GM, Wettergren L, Rodriguez-Wallberg KA, Lampic C. lar function. Andrology 2017;5:873-80.
Desire for children, difficulties achieving a pregnancy, and infertility dis- 22. Schulze C. Response of the human testis to long-term estrogen treat-
tress 3 to 7 years after cancer diagnosis. Support Care Cancer 2014;22:2805- ment: morphology of Sertoli cells, Leydig cells and spermatogonial stem
12. cells. Cell Tissue Res 1988;251:31-43.
2. Gorman JR, Su HI, Roberts SC, Dominick SA, Malcarne VL. Experienc- 23. Leavy M, Trottmann M, Liedl B, Reese S, Stief C, Freitag B, et al. Effects
ing reproductive concerns as a female cancer survivor is associated with of elevated beta-estradiol levels on the functional morphology of the
depression. Cancer 2015;121:935-42. testis—new insights. Sci Rep 2017;7:39931.

Understudied and Under-Reported: Fertility Issues in Transgender Youth—A Narrative Review 269
THE JOURNAL OF PEDIATRICS • www.jpeds.com Volume 205

24. Venizelos ID, Paradinas FJ. Testicular atrophy after oestrogen therapy. His- on adult height, body mass index, bone mineral content, and reproduc-
topathology 1988;12:451-4. tive function. J Clin Endocrinol Metab 2008;93:190-5.
25. Thiagaraj D, Gunasegaram R, Loganath A, Peh KL, Kottegoda SR, Ratnam 43. Anderson RA, Mitchell RT, Kelsey TW, Spears N, Telfer EE, Wallace WH.
SS. Histopathology of the testes from male transsexuals on oestrogen Cancer treatment and gonadal function: experimental and established strat-
therapy. Ann Acad Med Singapore 1987;16:347-8. egies for fertility preservation in children and young adults. Lancet Dia-
26. Lubbert H, Leo-Rossberg I, Hammerstein J. Effects of ethinyl estradiol betes Endocrinol 2015;3:556-67.
on semen quality and various hormonal parameters in a eugonadal male. 44. Meseguer M, Molina N, Garcia-Velasco JA, Remohi J, Pellicer A, Garrido
Fertil Steril 1992;58:603-8. N. Sperm cryopreservation in oncological patients: a 14-year follow-up
27. Schneider F, Neuhaus N, Wistuba J, Zitzmann M, Hess J, Mahler D, et al. study. Fertil Steril 2006;85:640-5.
Testicular functions and clinical characterization of patients with Gender 45. Adank MC, van Dorp W, Smit M, van Casteren NJ, Laven JS, Pieters R,
Dysphoria (GD) undergoing Sex Reassignment Surgery (SRS). J Sex Med et al. Electroejaculation as a method of fertility preservation in boys di-
2015;12:2190-200. agnosed with cancer: a single-center experience and review of the litera-
28. Obedin-Maliver J, Makadon HJ. Transgender men and pregnancy. Obstet ture. Fertil Steril 2014;102:199-205, e1.
Med 2016;9:4-8. 46. Hsiao W, Stahl PJ, Osterberg EC, Nejat E, Palermo GD, Rosenwaks Z, et al.
29. Light AD, Obedin-Maliver J, Sevelius JM, Kerns JL. Transgender men who Successful treatment of postchemotherapy azoospermia with microsur-
experienced pregnancy after female-to-male gender transitioning. Obstet gical testicular sperm extraction: the Weill Cornell experience. J Clin Oncol
Gynecol 2014;124:1120-7. 2011;29:1607-11.
30. Futterweit W, Deligdisch L. Histopathological effects of exogenously ad- 47. Jensen CF, Ohl DA, Hiner MR, Fode M, Shah T, Smith GD, et al. Mul-
ministered testosterone in 19 female to male transsexuals. J Clin Endocrinol tiple needle-pass percutaneous testicular sperm aspiration as first-line treat-
Metab 1986;62:16-21. ment in azoospermic men. Andrology 2016;4:257-62.
31. Ikeda K, Baba T, Noguchi H, Nagasawa K, Endo T, Kiya T, et al. Exces- 48. Wyns C, Curaba M, Vanabelle B, Van Langendonckt A, Donnez J. Options
sive androgen exposure in female-to-male transsexual persons of repro- for fertility preservation in prepubertal boys. Hum Reprod Update
ductive age induces hyperplasia of the ovarian cortex and stroma but not 2010;16:312-28.
polycystic ovary morphology. Hum Reprod 2013;28:453-61. 49. Picton HM, Wyns C, Anderson RA, Goossens E, Jahnukainen K, Kliesch
32. Pache TD, Chadha S, Gooren LJ, Hop WC, Jaarsma KW, Dommerholt S, et al. A European perspective on testicular tissue cryopreservation for
HB, et al. Ovarian morphology in long-term androgen-treated female to fertility preservation in prepubertal and adolescent boys. Hum Reprod
male transsexuals. A human model for the study of polycystic ovarian syn- 2015;30:2463-75.
drome? Histopathology 1991;19:445-52. 50. Gassei K, Orwig KE. Experimental methods to preserve male fertility and
33. Spinder T, Spijkstra JJ, van den Tweel JG, Burger CW, van Kessel H, treat male factor infertility. Fertil Steril 2016;105:256-66.
Hompes PG, et al. The effects of long term testosterone administration 51. Practice Committees of American Society for Reproductive M, Society
on pulsatile luteinizing hormone secretion and on ovarian histology in for Assisted Reproductive T. Mature oocyte cryopreservation: a guide-
eugonadal female to male transsexual subjects. J Clin Endocrinol Metab line. Fertil Steril 2013;99:37-43.
1989;69:151-7. 52. Rienzi L, Romano S, Albricci L, Maggiulli R, Capalbo A, Baroni E, et al.
34. De Roo C, Lierman S, Tilleman K, Peynshaert K, Braeckmans K, Caanen Embryo development of fresh ‘versus’ vitrified metaphase II oocytes after
M, et al. Ovarian tissue cryopreservation in female-to-male transgender ICSI: a prospective randomized sibling-oocyte study. Hum Reprod
people: insights into ovarian histology and physiology after prolonged an- 2010;25:66-73.
drogen treatment. Reprod Biomed Online 2017;34:557-66. 53. Practice Committee of American Society for Reproductive M. Ovarian
35. Van Den Broecke R, Van Der Elst J, Liu J, Hovatta O, Dhont M. The female- tissue cryopreservation: a committee opinion. Fertil Steril 2014;101:1237-
to-male transsexual patient: a source of human ovarian cortical tissue for 43.
experimental use. Hum Reprod 2001;16:145-7. 54. Donnez J, Dolmans MM. Ovarian cortex transplantation: 60 reported live
36. Grynberg M, Fanchin R, Dubost G, Colau JC, Bremont-Weil C, Frydman births brings the success and worldwide expansion of the technique towards
R, et al. Histology of genital tract and breast tissue after long-term tes- routine clinical practice. J Assist Reprod Genet 2015;32:1167-70.
tosterone administration in a female-to-male transsexual population. 55. Jensen AK, Macklon KT, Fedder J, Ernst E, Humaidan P, Andersen CY.
Reprod Biomed Online 2010;20:553-8. 86 successful births and 9 ongoing pregnancies worldwide in women
37. Loverro G, Resta L, Dellino M, Edoardo DN, Cascarano MA, Loverro M, transplanted with frozen-thawed ovarian tissue: focus on birth and peri-
et al. Uterine and ovarian changes during testosterone administration in natal outcome in 40 of these children. J Assist Reprod Genet 2017;34:325-
young female-to-male transsexuals. Taiwan J Obstet Gynecol 2016;55:686- 36.
91. 56. Donnelly L. Woman gives birth to baby using ovary frozen in her child-
38. Caanen MR, Soleman RS, Kuijper EA, Kreukels BP, De Roo C, Tilleman hood in ‘world first’. The Telegraph. 2016.
K, et al. Antimullerian hormone levels decrease in female-to-male trans- 57. Pacheco F, Oktay K. Current success and efficiency of autologous ovarian
sexuals using testosterone as cross-sex therapy. Fertil Steril 2015;103:1340- transplantation: a meta-analysis. Reprod Sci 2017;24:1111-20.
5. 58. Tornello SL, Bos H. Parenting intentions among transgender individu-
39. Tack LJ, Craen M, Dhondt K, Vanden Bossche H, Laridaen J, Cools M. als. LGBT Health 2017;4:115-20.
Consecutive lynestrenol and cross-sex hormone treatment in biological 59. Wierckx K, Van Caenegem E, Pennings G, Elaut E, Dedecker D, Van de
female adolescents with gender dysphoria: a retrospective analysis. Biol Peer F, et al. Reproductive wish in transsexual men. Hum Reprod
Sex Differ 2016;7:14. 2012;27:483-7.
40. Linde R, Doelle GC, Alexander N, Kirchner F, Vale W, Rivier J, et al. Re- 60. De Sutter P, Kira K, Verschoor A, Hotimsky A. The desire to have chil-
versible inhibition of testicular steroidogenesis and spermatogenesis by dren and the preservation of fertility in transsexual women: a survey. Int
a potent gonadotropin-releasing hormone agonist in normal men: an ap- J Transgenderism 2002;6:215-21.
proach toward the development of a male contraceptive. N Engl J Med 61. Riggs DW, Power J, von Doussa H. Parenting and Australian trans and
1981;305:663-7. gender diverse people: an exploratory survey. Int J Transgenderism
41. Schagen SE, Cohen-Kettenis PT, Delemarre-van de Waal HA, Hannema 2016;17:59-65.
SE. Efficacy and safety of gonadotropin-releasing hormone agonist treat- 62. von Doussa H, Power J, Riggs D. Imagining parenthood: the possibili-
ment to suppress puberty in gender dysphoric adolescents. J Sex Med ties and experiences of parenthood among transgender people. Cult Health
2016;13:1125-32. Sex 2015;17:1119-31.
42. Pasquino AM, Pucarelli I, Accardo F, Demiraj V, Segni M, Di Nardo R. 63. Maxwell S, Noyes N, Keefe D, Berkeley AS, Goldman KN. Pregnancy out-
Long-term observation of 87 girls with idiopathic central precocious comes after fertility preservation in transgender men. Obstet Gynecol
puberty treated with gonadotropin-releasing hormone analogs: impact 2017;129:1031-4.

270 Nahata et al
February 2019 COMMENTARY

64. Broughton D, Omurtag K. Care of the transgender or gender- transgender and gender-nonconforming adolescents. J Adolesc Health
nonconforming patient undergoing in vitro fertilization. Int J 2018;63:62-8.
Transgenderism 2017;1-4. 70. Chen D, Simons L. Ethical considerations in fertility preservation for
65. Armuand G, Dhejne C, Olofsson JI, Rodriguez-Wallberg KA. Transgender transgender youth: a case illustration. Clin Pract Pediatr Psychol 2018;6:93-
men’s experiences of fertility preservation: a qualitative study. Hum Reprod 100.
2017;32:383-90. 71. Chiniara LN, Viner C, Bonifacio HJ, Palmert MR. What are the perspec-
66. Nahata L, Tishelman AC, Caltabellotta NM, Quinn GP. Low fertility pres- tives among transgender youth and their parents regarding future fertil-
ervation utilization among transgender youth. J Adolesc Health 2017;61:40- ity? Insights from the fertility and reproductive health survey of transgender
4. youth (FROST) study. Horm Res Paediatr 2017;88(Suppl 1):1-2.
67. Chen D, Simons L, Johnson EK, Lockart BA, Finlayson C. Fertility pres- 72. Lawlis SM, Donkin HR, Bates JR, Britto MT, Conard LAE. Health con-
ervation for transgender adolescents. J Adolesc Health 2017;61:120-3. cerns of transgender and gender nonconforming youth and their parents
68. Strang JF, Jarin J, Call D, Clark B, Wallace GL, Anthony LG, et al. upon presentation to a transgender clinic. J Adolesc Health 2017;61:642-8.
Transgender youth fertility attitudes questionnaire: measure develop- 73. Johnson EK, Finlayson C. Preservation of fertility potential for gender and
ment in nonautistic and autistic transgender youth and their parents. J sex diverse individuals. Transgend Health 2016;1:41-4.
Adolesc Health 2018;62:128-35. 74. Feldman J, Brown GR, Deutsch MB, Hembree W, Meyer W, Meyer-
69. Chen D, Matson M, Macapagal K, Johnson EK, Rosoklija I, Bahlburg HF, et al. Priorities for transgender medical and healthcare re-
Finlayson C, et al. Attitudes toward fertility and reproductive health among search. Curr Opin Endocrinol Diabetes Obes 2016;23:180-7.

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