Fertility Desires and Reproductive Needs of Transgender People

Challenges and Considerations for Clinical Practice

Eva Feigerlová; Véronique Pascal; Marie-Odile Ganne-Devonec; Marc Klein; Bruno Guerci

Disclosures

Clin Endocrinol. 2019;91(1):10-21. 

In This Article

Methods

The authors searched the PubMed database for English- and French-language papers using the keywords "gender dysphoria" or "transgender" and associated terms "fertility," "parent*" and "child*" or "offspring" to summarize our current knowledge of the fertility desires and parental needs of transgender people. To complete the literature search, other relevant and freely available sources on this topic were included (articles in press, scientific journals not indexed in PubMed and conference abstracts).

Effects of Cross-sex Hormonal Therapy on Fertility Potential

Transgender women. Little is known about the long-term effects of oestrogens and anti-androgens on testicular function and morphology. As detailed in Table 1, most of the existing data were obtained from small retrospective studies or case reports. Impaired steroidogenesis was reported in a 28-year-old transgender woman treated for 1.5 years with ethinyl-oestradiol (0.5-1 mg/d).[26] Other small studies examining orchidectomy specimens (n = 4-11 subjects)[27–31] reported the various effects of oestrogens administered for 1.5 to 13 years on the morphology and function of Sertoli and Leydig cells. Similarly, the heterogeneous effects of oestrogens combined with anti-androgens were described, ranging from severe impairment of spermatogenesis and involution of Leydig cells to conserved spermatogenesis and unaltered Leydig cell count.[32,33] In line with the previous observations, a recent larger series[34–37] indicates heterogeneous morphological changes in testicular tissue with variable effects on germ cells (Table 1). A multicentre study[37] including 108 subjects on different treatment regimens (anti-androgens with different doses of oestrogens, oestrogens only, or spironolactone and oestrogens in combination) showed unaltered spermatogenesis in 24% of orchidectomy specimens. Whether the treatment duration is an important factor to consider is not known. Arrested spermatogenesis was observed in transgender women on hormonal treatment for a median time of 5 years (107/135), whereas in those (6/135) treated for a median of 3 years, spermatogenesis was unaltered.[35] Similarly, our knowledge is limited concerning the potential for reversibility of the effects of oestrogens and/or anti-androgens on testicular function after treatment cessation. Impaired semen quality was reported in transgender women (n = 7) who had their semen cryopreserved during hormone-affirming therapy compared to those (n = 3) who discontinued their medication in the median time of 4.4 months before the semen collection and those who had conserved their sperm prior to hormonal treatment (n = 18).[38] For each of these groups, the median semen concentration was 2.4 M/mL, 39.0 M/mL and 63.6 M/mL, respectively, and the total motile count was 0.2, 39.1 and 63.2mol/L, respectively[38] (Table 1). The data from 30 studies, including 1549 healthy eugonadal men (aged 18-51 years) receiving male hormonal contraception for 16-78 weeks,[39] indicate the satisfactory recovery of spermatogenesis to the threshold of 20 million spermatocytes per millilitre in a median of 3.4 months after treatment cessation. However, compared to long-term hormonal therapy in transgender men, the maximum treatment duration in these studies was only 78 weeks.

Altogether, it is likely that spermatogenic suppression is reversible; however, the evidence is unclear. Safety thresholds for sex steroid levels, which would predict satisfactory sperm quality, are not known. Similarly, the optimal interval between the cessation of gender-affirming treatment and the timing of fertility preservation remains to be determined.

Transgender men. Studies examining ovariectomy specimens in transgender men exposed to exogenous androgens over prolonged periods are summarized in Table 1. Chronic administration of testosterone in these subjects led to follicular atresia, hyperplasia of ovarian stroma and morphological changes reminiscent of polycystic ovaries.[40–43] Currently, no clear documentation exists on whether the administration of androgens induces typical polycystic ovarian morphology (PCOM). Caanen et al[44] assessed ovarian morphology using 3D transvaginal ultrasound (TVU) in 56 transgender men (age 20-26 years) on testosterone treatment for 23-35 months (Table 1). The frequency of PCOM, based on the Rotterdam diagnostic criteria,[45] was similar in transgender men (32.1%) and control subjects (30.7%).[44]

Furthermore, it remains unresolved whether the effects of androgens on ovarian morphology and function are reversible and whether the long-term administration of testosterone impairs luteinizing hormone (LH) pulse amplitude.[46,47] Successful pregnancies were reported in transgender men previously treated with testosterone.[48,49] In the study by Light et al,[48] transgender men (n = 41), who retained functioning ovaries and a uterus, were able to conceive and carry a pregnancy. Sixty-one per cent of transgender men had testosterone treatment before pregnancy and 88% used the oocytes from their own ovaries. The majority of transgender men in this study became pregnant spontaneously within 4 months, 15% of subjects reported preconception consultation, 7% of subjects required fertility drugs to get pregnant, and 12% needed assisted reproductive technology (artificial insemination, in vitro fertilization and gamete intrafallopian transfer).[48] In another study,[24] testosterone use over one year did not induce ovarian morphological changes, with most follicles in the ovarian cortex being primordial (69% of total follicle count). After the in vitro maturation of retrieved cumulus-oocyte complexes, 34% of oocytes recovered were at metaphase II, with 87% having a normal spindle structure.[24]

Currently, no safety thresholds are known regarding the dose of exogenous androgens or the treatment duration. Similarly, only a few studies have examined the effects of androgen exposure on the uterus (Table 1). Low proliferative active endometrium and hypertrophic changes in the myometrium with a low proliferative response of endometrial cells were reported in transgender men receiving androgen treatment over prolonged periods of time.[50] Notably, the persistence of endometrial activity in transgender men exposed to exogenous testosterone was observed and might be responsible for abnormal uterine bleeding.[51]

Children With Gender Dysphoria

In children with gender dysphoria, pubertal suppression with gonadotropin-releasing agonists (GnRH-a) might be prescribed at Tanner stage 2 of puberty to avoid the development of undesired secondary sex characteristics.[52,53] To induce phenotypic changes in desired sex in transgender youth, cross-sex hormone treatment is concomitantly initiated with puberty blocking, which compromises the maturation of germ cells. Our current knowledge is limited regarding the recovery of reproductive functions after stopping cross-hormone therapy in transgender youth.[12]

Thus far, available data have come from studies conducted on adolescents with central precocious puberty. In these subjects, treatment with GnRH-a leads to the inhibition of germ cell maturation, which appears reversible after treatment cessation.[54] However, the time necessary to obtain satisfactory spermatogenesis after the interruption of GnRH-a in boys with precocious puberty is not known.[55,56] In girls with precocious puberty on prolonged GnRH-a treatment, the evidence is unclear concerning the recovery of spontaneous ovulation and the satisfactory response to ovulation inductors.[56]

According to international guidelines,[22,23] fertility preservation should thus be discussed with transgender youth before pubertal suppression, keeping in mind that techniques for the in vitro maturation of immature germ cells are still mostly experimental.[57] For more information, the reader is redirected to one of the recent reviews on this topic.[25,58]

Fertility Desires and Perceived Barriers

Transgender and gender nonconforming people express the desire to have biological children and to have families.[15,59–61] One of the first studies by De Sutter et al[62] (Table 2) included 121 transgender women, of which 77% considered that the possibility of fertility preservation should be counselled before medical transition. Fifty-one per cent would have preserved sperm if the option had been offered. Only one-third of the respondents expressed uneasiness about the incongruence of frozen gametes with their self-identified gender identity. Wierck et al[15] examined reproductive desires in 50 adult transgender men (22% already having children). Fifty-four per cent of the study participants expressed a desire to have biological children, and 38% of these individuals would have opted for the preservation of gametes if it had been proposed prior to medical transition. In another study[61] conducted via questionnaires administered to 108 persons assigned male at birth and 103 persons assigned female at birth, 21% (40/187) of the respondents without children expressed the desire to have children. Twenty-four per cent of all participants considered their fertility to be important; however, 61% of these subjects reported a lack of information on fertility preservation options, and many of these individuals indicated regret at not preserving gametes before initiating treatment. In a recent large survey[63] conducted in Australia on a sample of 409 transgender and nonbinary persons, 95% of the participants declared that fertility preservation should be proposed by healthcare providers. Thirty-three per cent (114/345) of the respondents without children expressed desire for fertility preservation, and only 7% (28/398) of these individuals had undergone gamete preservation. Among the factors playing a role in decision-making were interest in genetic relationships, cost, delay in treatment initiation and already having children.

Only a few studies assessed fertility desires in transgender children and adolescents.[13,14] To evaluate fertility desires in transgender children, a 15-item instrument, the Transgender Youth Fertility Attitudes Questionnaire,[13] has recently been developed. This instrument is adapted for children with autistic spectrum disorders, the prevalence of which is higher in children with gender dysphoria than in the general population.[64] The instrument was pilot tested on a small sample of transgender children (n = 25, age range 13-19 years) and their parents (n = 26). Four children included in the study were on puberty blockers, 5 were on oestrogen or testosterone, and 3 were on puberty blockers and oestrogen or testosterone. A majority of transgender youth (84%) and their parents (96%) declared that it was important to learn about the effects of hormonal treatment on fertility. Both children (92%) and their parents (76%) declared that they were aware of existing fertility options. Fifty-six per cent of the transgender youth expressed a desire to have their own or to adopt children, and 65% of their parents wished that their children would have children in the future. Only 12% of transgender youth wished to have their own biological children. Nearly half of transgender youth indicated that their desire to have a biological child might change in the future. More than half of the transgender youth indicated that they would not envisage the preservation of gametes for themselves. Fifty-four per cent of parents wished their child would preserve their gametes, but only 29% wanted their child to undergo fertility preservation. Interestingly, none of the children included in this study underwent fertility preservation.[13] Based on these observations, there may be a high number of subjects changing attitudes regarding their future fertility. To our knowledge, there are no studies examining whether the feelings of transgender people about wanting their own biological children might change in the future.

In another study by Nahata et al,[65] nearly half of the participants reported no desire to have biological children. A recent online survey[14] conducted on a sample of 156 (age range 14-17 years) gender nonconforming adolescents revealed that 36% of these individuals want to have biological children. Only 14% of the survey participants reported discussing the effects of hormonal treatment on fertility with their healthcare providers, and 61% expressed the need for more information about fertility-related issues. As summarized in Table 2, fertility preservation among transgender people is low and is more frequent among transgender females. Among the identified barriers to fertility preservation are cost, lack of information, invasiveness of procedures and desire not to delay medical transition.

Experience With Fertility Preservation

Scarce data are available on the experience of transgender and gender nonconforming people with fertility preservation. In transgender youth, the utilization of fertility preservation methods is low.[65,66] Based on the retrospective chart reviews of two different gender clinics including 73 (age range 9-18 years)[65] and 105 subjects (age range 14-21 years),[66] only a limited number of individuals (< 5%) opted for fertility preservation. In a recent online survey conducted in Australia on a sample of 409 transgender and gender nonconforming adults,[63] only 7% of the participants reported having undergone fertility preservation. Among the reasons for refusal of fertility preservation were financial burden, fear of invasive procedure and desire not to delay hormonal treatment.[63,65] In another interview-based survey of nine transgender persons and their partners (n = 11)[67] who had experienced assisted reproduction services, several institutional barriers to satisfy the needs in this population, such as a lack of awareness and insufficient training of healthcare providers, were identified. Armuand et al[68] prospectively followed 15 adult transgender men (age range 19-35 years) undergoing oocyte preservation; the study participants reported the recrudescence of gender dysphoria upon interruption of testosterone treatment, during hormonal stimulation and/or while being exposed to pelvic examinations. The study further showed that the distress experienced by transgender persons could be alleviated in the presence of a supportive healthcare environment.

Pregnancies and Parental Roles

Transgender persons desire to have children, create families and assume parental roles[16,48,60,69] in a manner reaffirming their self-identified gender identities. Functional lactation was successfully induced using the dopamine antagonist domperidone in a transgender woman desiring to breastfeed her adopted child.[70] Pregnancies and successful deliveries were reported in transgender men who had not undergone hysterectomy.[16,48,71,72] There are no exact data on the number of transgender men who had carried a pregnancy.[73] Medical risks exist, and concerns may be raised.[74]

Data self-reported by a small sample of transgender men who experienced pregnancy with prior testosterone use (n = 25) compared to those without prior testosterone (n = 16)[48] show hypertension (16% vs 6%), preterm labour (12% vs 6%) and gestational diabetes (8% vs 0%). There was no significant difference in birth outcomes and birthweight (n = 42 neonates); however, testosterone levels were not measured during pregnancy. Due to a small sample size and self-reported retrospective data, no conclusion can be drawn. The postpartum depression reported by some subjects[48] appeared to be worsened by the absence of gender-sensitive care.

There is a lack of clinical awareness; no guidelines are currently available. Healthcare providers should guide transgender persons as early as pretransition and preconception periods and anticipate postnatal care and follow-up. Testosterone therapy should be interrupted, and conception should be planned ideally when the menstrual cycle resumes. For those who want to breast (chest)feed, testosterone can be reinitiated after the breastfeeding period, as limited data are available concerning effects on the breastfed child.[75]

Contraception and Teratogenicity of Androgens and Anti-androgens

Our current knowledge is insufficient in terms of optimal contraceptive methods. Transgender men and gender nonconforming persons assigned female at birth are at a risk of pregnancy after vaginal intercourse. They can conceive and become pregnant, despite testosterone treatment.[48] Similarly, GnRH-a therapy used to suppress ovarian function is not effective in preventing pregnancy. Contraception should be advised to these individuals if they have not undergone hysterectomy or ovariectomy and if they do not desire to conceive.[76] Nonhormonal copper intrauterine devices or progestogen-only methods of contraception (pills, injections, transdermal implants and progestin-containing intrauterine devices) can be recommended as there are no interferences with cross-sex hormone therapy. Combined oestrogen and progestogen contraception may interfere with cross-sex hormone regimen and are thus not counselled.[76] Emergency contraceptive method, including nonhormonal copper intrauterine device, ulipristal acetate and levonorgestrel, should be recommended after unprotected vaginal intercourse. The use of condoms is advised as a protection against sexually transmitted diseases and as a method of contraception, if properly used. Transgender women or gender nonconforming persons assigned male at birth, who have not undergone orchidectomy, should be informed that cross-sex hormone treatment regimens such as oestrogens, anti-androgens (finasteride, cyproterone acetate or spironolactone) and GnRH-a do not have contraceptive properties.

Androgens and anti-androgens are potential teratogens. Notably, androgenic agents may impair foetal growth.[77,78] In animals, testosterone administration during foetal or late postnatal life alters the development of the reproductive system.[79,80] In humans, prenatal exposure to androgens leads to masculinization of the female foetus[81] and induces changes in anogenital distance, used as a marker of androgen exposure during a critical period of testis development.[82]Testosterone administration is contraindicated in pregnancy.[23] Transgender persons receiving testosterone treatment should be informed that testosterone is not a method of contraception.[48] In a recent online survey[59] involving 197 transgender men (age range 18-45 years), 60 pregnancies were reported by the study respondents. Of these pregnancies, 1.6% occurred in subjects currently receiving testosterone, and 17% occurred in subjects with prior testosterone use. Sixty per cent of the participants used contraception, preferentially condoms (49%) or oral pills (34%). Surprisingly, 16% of the survey respondents considered testosterone as a contraceptive modality, and 6% were advised by their healthcare providers on the use of testosterone as a method of contraception. In another study[83] conducted in 26 transgender men receiving testosterone, two subjects desired pregnancy while being on testosterone.

Regarding anti-androgens, impaired genital differentiation was described in animals upon treatment with the 5-alpha-reductase inhibitor finasteride.[84,85] The teratogenic effects of cyproterone acetate and spironolactone are based on findings in rodent embryofoetal studies, showing that exposure to cyproterone acetate during embryogenesis in mice induces exencephaly, cleft palate, heart and urinary tract abnormalities;[86] exposure to spironolactone leads to alterations in the endocrine and reproductive systems of both male and female rodents.[87]

Taken together, healthcare providers should make efforts to deliver sensitive care and guidance to transgender persons according to their individual needs. They should advise to transgender and gender nonconforming persons on the choice of contraceptive methods and emergency contraception and inform on potential teratogenic effects of androgens and anti-androgens.

Outcomes of Children Raised by Transgender Parents

Little is known about the psychosocial outcomes of children with a transgender parent or the needs of transgender parents. To date, several small studies are available to guide clinicians and healthcare providers. Regarding children raised in families before their parent's gender transition, Green et al[88] reported no negative impact of the parent's gender transition on the psychosexual development and gender identity of the children (n = 16, mean age 11 years). In another study[89] examining 18 children of transgender parents, one girl presented gender dysphoria-related problems in adolescence. The authors further highlighted some concerns in a parent-child relationship in the case of existing parental conflict. Few studies have addressed the outcomes of children raised in families after a parent's transition.[17,90] White et al[17] assessed the parent-child relationship at six years after the transition in 27 parents (age range 33-61 years) of 55 children (age 8-35 years). In this study, the children were evaluated indirectly via reports given by their transitioned parent. A majority of children remained in contact with their transgender parent, and the rupture of contact was noted for 5% of children at the time of transition and for 10% of children at 6 years after the transition. Adaptation to the parent's new gender identity appeared easier in children who were younger during the transition period. In contrast, adaptation was more difficult in the presence of a conflicting relationship between the parents. Psychopathological disorders in these children were reported at a similar frequency as that observed in the general population. Recently, the outcomes of 42 children born by artificial donor insemination to couples of transgender men and cisgender women have been reported.[90] After a 12-year follow-up, there were no difficulties in the relationship between children and their parents. The psychosocial development and well-being of the children were normal, and no gender identity concerns were raised.[90]

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