Breaking Down Barriers to Reproductive Care for Transgender People

There are an estimated 1.4 million transgender adults in the United States, representing 0.6% of the population.1Flores A.R. Herman J.L. Gates G.J. et al.How many adults identify as transgender in the United States? Los Angelos. The Williams Institute, California2016Google Scholar Transgender and gender diverse (TGD) individuals have gender identities that differ from their recorded sex at birth, and medical/surgical interventions are often pursued to better align these. Gender-affirming medical therapy, including pubertal suppression and initiation of gender-affirming hormone therapy (GAHT), improves quality of life and psychological outcomes.2De Vries A.L. McGuire J.K. Steensma T.D. Wagenaar E.C. Doreleijers T.A. Cohen-Kettenis P.T. Young adult psychological outcome after puberty suppression and gender reassignment.Pediatrics. 2014; 134: 696-704Crossref PubMed Scopus (408) Google Scholar,3Murad M.H. Elamin M.B. Garcia M.Z. et al.Hormonal therapy and sex reassignment: a systematic review and meta-analysis of quality of life and psychosocial outcomes.Clin Endocrinol (Oxf). 2010; 72: 214-231Crossref PubMed Scopus (337) Google Scholar Surgical treatment that includes gonadectomy unquestioningly results in sterilization, but the impact of long-term–GAHT on future reproductive function is still unknown. The World Professional Association for Transgender Health, Endocrine Society, and the American Society for Reproductive Medicine all recommend counseling on the potential risk for fertility impairment and options for fertility preservation (FP) prior to initiating GAHT.4Hembree W.C. Cohen-Kettenis P.T. Gooren L. et al.Endocrine treatment of gender-dysphoric/gender-incongruent persons: an endocrine society clinical practice guideline.J Clin Endocrinol Metab. 2017; 102: 3869-3903Crossref PubMed Scopus (694) Google Scholar, 5Coleman E. Bockting W. Botzer M. et al.Standards of care for the health of transsexual, transgender, and gender-nonconfirming people, version 7.Int J Transgend. 2012; 13: 165-232Crossref Scopus (1576) Google Scholar, 6Ethics Committee of the American Society for Reproductive MedicineAccess to fertility services by transgender persons: an Ethics Committee opinion.Fertil Steril. 2015; 104: 1111-1115Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar Recent advances in assisted reproductive technology (ART) have allowed TGD patients to consider both reproductive and transition goals at initiation and throughout GAHT. Options for FP include oocyte or embryo cryopreservation for transgender men (recorded female at birth, identify as male/masculine) and sperm cryopreservation with semen from ejaculation or testicular sperm extraction for transgender women (recorded male at birth, identify as female/feminine). There are currently no studies addressing fertility potential of gonads treated with pubertal suppression and subsequent GAHT, but the viability of FP options for gonads that have not undergone endogenous puberty is questionable. Ovarian tissue and testicular cryopreservation with in vitro maturation are promising options for prepubescent patients, but testicular cryopreservation is still considered experimental (with no live births to date), and the small numbers of live births after ovarian cryopreservation (no longer experimental as of 2020) were from post-pubescent tissue.7Mayhew A.C. Gomez-Lobo V. Fertility options for the transgender and gender nonbinary patient.J Clin Endocrinol Metab. 2020; 105: 3335-3345Crossref Scopus (4) Google Scholar Although TGD youth and adults desire to have children and build families, overall prioritization and utilization of FP is low at less than 5%, often due to the desire to move forward with medical transition without delay.8Auer M.K. Fuss J. Nieder T.O. et al.Desire to have children among transgender people in Germany: a cross-sectional multi-center study.J Sex Med. 2018; 15: 757-767Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 9Von Doussa H. Power J. Riggs D. Imagining parenthood: the possibilities and experiences of parenthood among transgender people.Cult Health Sex. 2015; 17: 1119-1131Crossref PubMed Scopus (65) Google Scholar, 10Tornello S.L. Bos H. Parenting intentions among transgender individuals.LGBT Health. 2017; 4: 115-120Crossref PubMed Scopus (72) Google Scholar, 11Wierckx K. Van Caenegem E. Pennings G. et al.Reproductive wish in transsexual men.Hum Reprod. 2012; 27: 483-487Crossref PubMed Scopus (184) Google Scholar, 12Nahata L. Tishelman A.C. Caltabellotta N.M. Quinn G.P. Low fertility preservation utilization among transgender youth.J Adolesc Health. 2017; 61: 40-44Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 13Chen D. Simons L. Johnson E.K. Lockart B.A. Finlayson C. Fertility preservation for transgender adolescents.J Adolesc Health. 2017; 61: 120-123Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 14De Sutter P. Kira K. Verschoor A. Lockart B.A. Finlayson C. The desire to have children and the preservation of fertilityin transsexual women: a survey.Int J Transgend. 2002; 6Google Scholar A cross-sectional survey of transgender youth and parents within a gender clinic showed that the majority of youth are unwilling to delay GAHT for up to 3 months to preserve fertility; 34% would have pursued FP while continuing GAHT if that were an option.15Persky R.W. Gruschow S.M. Sinaii N. Carlson C. Ginsberg J.P. Dowshen N.L. Attitudes toward fertility preservation among transgender youth and their parents.J Adolesc Health. 2020; 67: 583-589Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Another cross-sectional survey showed that transgender youth ranked having children as lowest among 8 life priorities, because they did not want to delay or stop GAHT.16Chiniara L.N. Viner C. Palmert M. Bonifacio H. Perspectives on fertility preservation and parenthood among transgender youth and their parents.Arch Dis Child. 2019; 104: 739-744Crossref PubMed Scopus (29) Google Scholar TGD youth may not consider long-term reproductive health implications, and many may wish to have children after transition. A survey of 50 transgender men who had already completed gender-affirming genital surgery reported that 77% had not considered FP at the time of GAHT initiation, but 54% currently reported a desire for children.11Wierckx K. Van Caenegem E. Pennings G. et al.Reproductive wish in transsexual men.Hum Reprod. 2012; 27: 483-487Crossref PubMed Scopus (184) Google Scholar Additional barriers to FP include cost, invasiveness of procedures, patient perception of mistreatment, discrimination or bias, lack of awareness, and insufficient training of health care providers.13Chen D. Simons L. Johnson E.K. Lockart B.A. Finlayson C. Fertility preservation for transgender adolescents.J Adolesc Health. 2017; 61: 120-123Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar,16Chiniara L.N. Viner C. Palmert M. Bonifacio H. Perspectives on fertility preservation and parenthood among transgender youth and their parents.Arch Dis Child. 2019; 104: 739-744Crossref PubMed Scopus (29) Google Scholar,17James-Abra S. Tarasoff L.A. Green D. et al.Trans people’s experiences with assisted reproduction services: a qualitative study.Hum Reprod. 2015; 30: 1365-1374Crossref PubMed Scopus (75) Google Scholar The literature on FP outcomes in transgender men has previously been limited to case series and observational studies of oocyte or embryo cryopreservation prior to the initiation of GAHT. Although fertility rates after testosterone initiation are largely unknown, the available published data support the continued potential for conception while on this treatment, especially if doses are too low or there is noncompliance. In one survey of transgender men who had a live birth, 80% had been on testosterone and resumed menses within 6 months of cessation, 84% had used their own oocytes for conception, and 32% had conceived while still on testosterone.18Light A.D. Obedin-Maliver J. Sevelius J.M. Kerns J.L. Transgender men who experienced pregnancy after female-to-male gender transitioning.Obstet Gynecol. 2014; 124: 1120-1127Crossref PubMed Scopus (249) Google Scholar The duration of testosterone use, however, was short at less than 2 years for over half the participants. Another recent study looked at longer durations of previous testosterone use when describing 7 successful pregnancies among transgender men after in vitro fertilization (IVF).19Leung A. Sakkas D. Pang S. Thornton K. Resetkova N. Assisted reproductive technology outcomes in female-to-male transgender patients compared with cisgender patients: a new frontier in reproductive medicine.Fertil Steril. 2019; 112: 858-865Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar The outcomes of egg retrieval and ovarian stimulation for oocyte cryopreservation were similar among transgender men who had never been on testosterone versus transgender men who had been on testosterone and cisgender women. The duration of testosterone use had no impact on outcomes, with the longest duration being 17 years; however, all patients had to stop testosterone until the return of menses (an average of 4 months). Most published literature have reported a recommendation between 1 and 6 months off testosterone for transgender men undergoing fertility treatments.20Neblett II, M.F. Hipp H.S. Fertility considerations in transgender persons.Endocrinol Metab Clin North Am. 2019; 48: 391-402Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar,21Safer J.D. Tangpricha V. Care of transgender persons.N Engl J Med. 2019; 381: 2451-2460Crossref PubMed Scopus (55) Google Scholar Temporary cessation of GAHT may lead to anxiety and increasing gender dysphoria, especially when it leads to resumption of menses and regression of desired secondary sex characteristics. Additionally, the process of ovarian stimulation may take several weeks with multiple injections of gonadotropins that result in elevated estradiol levels as well as serial transvaginal ultrasounds which may be traumatic for transgender men. In their case report “Successful IVF in a cisgender female carrier using oocytes retrieved from a transgender man maintained on testosterone,” Greenwald et al22Greenwald P. Dubois B. Lekovich J. Pang J.H. Safer J. Successful IVF in a cisgender female carrier using oocytes retrieved from a transgender man maintained on testosterone.AACE Clin Case Rep. 2021; https://doi.org/10.1016/j.aace.2021.06.007Abstract Full Text Full Text PDF Scopus (1) Google Scholar showed for the first time that successful egg retrieval and live birth is possible without interrupting testosterone treatment.22Greenwald P. Dubois B. Lekovich J. Pang J.H. Safer J. Successful IVF in a cisgender female carrier using oocytes retrieved from a transgender man maintained on testosterone.AACE Clin Case Rep. 2021; https://doi.org/10.1016/j.aace.2021.06.007Abstract Full Text Full Text PDF Scopus (1) Google Scholar They reported the case of a 33-year-old transgender man on subcutaneous testosterone therapy for 10 years who presented with his cisgender female partner for reciprocal IVF, a process that utilizes an embryo from the patient’s oocyte and anonymous donor sperm (with intracytoplasmic sperm injection) which is then implanted into the partner’s uterus. After the patient undergoes a 14-day course of gonadotropin controlled ovarian stimulation, 20 oocytes are retrieved, 16 are mature, 13 are fertilized with intracytoplasmic sperm injection, and 5 of those progress to blastocyst stage where they are sent for preimplantation genetic testing. Only one embryo is chromosomally normal, suggesting a higher aneuploidy rate of 80% versus the expected 31% for someone that age. That embryo is transferred into the partner’s uterus for an uncomplicated pregnancy and a child reportedly healthy at 2 years of age. This is, therefore, also the first report on the health of offspring conceived using an oocyte from an individual on testosterone while the oocyte was harvested. By showing that a successful live birth is possible after prolonged, uninterrupted testosterone treatment, Greenwald et al22Greenwald P. Dubois B. Lekovich J. Pang J.H. Safer J. Successful IVF in a cisgender female carrier using oocytes retrieved from a transgender man maintained on testosterone.AACE Clin Case Rep. 2021; https://doi.org/10.1016/j.aace.2021.06.007Abstract Full Text Full Text PDF Scopus (1) Google Scholar paved the way for expanded reproductive options and increased utilization of ART among transgender men.22Greenwald P. Dubois B. Lekovich J. Pang J.H. Safer J. Successful IVF in a cisgender female carrier using oocytes retrieved from a transgender man maintained on testosterone.AACE Clin Case Rep. 2021; https://doi.org/10.1016/j.aace.2021.06.007Abstract Full Text Full Text PDF Scopus (1) Google Scholar They also highlight many gaps in the knowledge with regards to treatment approach, outcomes, and the impact of testosterone on fertility and egg quality. This patient was likely on a sub-therapeutic dose of testosterone (as evidenced by his breakthrough spotting) and on maximal doses of gonadotropins for ovarian stimulation, suggesting that even higher doses or increased time for controlled ovarian stimulation may be needed for transgender men on therapeutic testosterone regimens that suppress menses. Although this patient had a successful oocyte yield in response to gonadotropins, the high aneuploidy rate warrants further investigation.22Greenwald P. Dubois B. Lekovich J. Pang J.H. Safer J. Successful IVF in a cisgender female carrier using oocytes retrieved from a transgender man maintained on testosterone.AACE Clin Case Rep. 2021; https://doi.org/10.1016/j.aace.2021.06.007Abstract Full Text Full Text PDF Scopus (1) Google Scholar Studies on ovarian morphology in response to testosterone exposure are conflicting.23De Roo C. Lierman S. Tilleman K. et al.Ovarian tissue cryopreservation in female-to-male transgender people: insights into ovarian histology and physiology after prolonged androgen treatment.Reprod Biomed Online. 2017; 34: 557-566Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 24Homburg R. Androgen circle of polycystic ovary syndrome.Hum Reprod. 2009; 24: 1548-1555Crossref PubMed Scopus (86) Google Scholar, 25Canen M.R. Schouten N.E. Kuijper E.A.M. et al.Effects of long-term exogenous testosterone administration on ovarian morphology, determined by transvaginal (3D) ultrasound in female-to-male transsexuals.Hum Reprod. 2017; 32: 1457-1464Crossref PubMed Scopus (21) Google Scholar It has been shown that androgen excess can accelerate the growth of early follicular development and slow the rate of atresia of early antral follicles to give a polycystic ovarian morphology, and the high oocyte yield in response to ovarian stimulation in this case and previous studies supports those findings.18Light A.D. Obedin-Maliver J. Sevelius J.M. Kerns J.L. Transgender men who experienced pregnancy after female-to-male gender transitioning.Obstet Gynecol. 2014; 124: 1120-1127Crossref PubMed Scopus (249) Google Scholar,23De Roo C. Lierman S. Tilleman K. et al.Ovarian tissue cryopreservation in female-to-male transgender people: insights into ovarian histology and physiology after prolonged androgen treatment.Reprod Biomed Online. 2017; 34: 557-566Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar How the potential impact of testosterone use on ovarian morphology translates to egg quality is unknown and has only begun to be investigated. A study reporting on the outcomes of in vitro maturation of oocytes collected from ovaries exposed to testosterone at the time of gender-affirming surgery showed that the number of cumulus-oocyte complexes retrieved was high, the maturation and survival rates were comparable, and there was no relationship between the duration of testosterone use and the number of observed follicles.23De Roo C. Lierman S. Tilleman K. et al.Ovarian tissue cryopreservation in female-to-male transgender people: insights into ovarian histology and physiology after prolonged androgen treatment.Reprod Biomed Online. 2017; 34: 557-566Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar The mean duration of testosterone use was only 58 weeks, and the oocyte potency was evaluated by spindle appearance, rather than embryo yield and quality, suggesting that future studies are needed. There are currently no guidelines for FP or reproductive care of TGD individuals. FP counseling and support services should be standard of care, and many TGD youth and adults report a desire for fertility counseling.26Riggs D.W. Bartholomaeus C. Fertility preservation decision making amongst Australian transgender and non-binary adults.Reprod Health. 2018; 15: 181Crossref PubMed Scopus (39) Google Scholar It has traditionally been preferable to pursue FP prior to the initiation of GAHT due to the unknown reproductive effects of GAHT, but more patients are presenting at younger ages when parenting wishes are not yet defined and may evolve over time. Fertility counseling, therefore, needs to be an ongoing conversation even after the initiation of GAHT. A lack of clarity regarding risks to reproductive function and fertility-related outcomes while on GAHT makes this counseling more complicated. There are currently very little data with which to counsel transgender men who have already been on testosterone about the success of ovarian stimulation for current or future fertility relative to individuals without high dose testosterone exposure. Additionally, there are no current guidelines for instructing clinicians on how long testosterone needs to be stopped, or if it needs to be stopped at all, prior to ovarian stimulation and no standard stimulation protocols available for patients exposed to testosterone. Individual centers may not see enough reproductive age patients interested in both GAHT and fertility in order to address these questions with the urgency that is needed. Hence, future studies will require pooling of data across multiple institutions for large prospective analyses on fertility protocols, outcomes, and medical and psychological risks to patients and their offspring. This case report by Greenwald et al22Greenwald P. Dubois B. Lekovich J. Pang J.H. Safer J. Successful IVF in a cisgender female carrier using oocytes retrieved from a transgender man maintained on testosterone.AACE Clin Case Rep. 2021; https://doi.org/10.1016/j.aace.2021.06.007Abstract Full Text Full Text PDF Scopus (1) Google Scholar brings up important questions with regards to ART in transgender men, and in doing so, highlights the need for more research to break down barriers to reproductive care for this under-studied, vulnerable patient population.22Greenwald P. Dubois B. Lekovich J. Pang J.H. Safer J. Successful IVF in a cisgender female carrier using oocytes retrieved from a transgender man maintained on testosterone.AACE Clin Case Rep. 2021; https://doi.org/10.1016/j.aace.2021.06.007Abstract Full Text Full Text PDF Scopus (1) Google Scholar The authors have no multiplicity of interest to disclose. Successful In Vitro Fertilization in a Cisgender Female Carrier Using Oocytes Retrieved From a Transgender Man Maintained on TestosteroneAACE Clinical Case ReportsVol. 8Issue 1PreviewHealth care providers routinely discontinue testosterone in transgender men undergoing oocyte retrieval. To date, there is little literature to support such discontinuation. The sudden drop in testosterone levels can be distressing for transgender men. The objective of this report was to describe a case study of successful reciprocal in vitro fertilization (IVF) using oocytes retrieved from a transgender man who remained on testosterone during the entire course of gonadotropin controlled ovarian stimulation and retrieval. Full-Text PDF Open Access