Fertility, Contraception, and Fertility Preservation in Trans Individuals.

An increasing number of persons around the world are receiving the diagnosis of gender incongruence, and most of them are in their reproductive years. Safe contraception and fertility preservation are important issues for counseling.

This review is based on pertinent publications retrieved by a systematic search in the PubMed and Web of Science databases, employing the search terms �fertility,� �contraception,� �transgender,� �gender-affirming hormone therapy� (GAHT), �ovarian reserve,� and �testicular tissue.� 908 studies were included, 26 of which entered the final analysis.

Most of the available studies on fertility in trans persons undergoing GAHT reveal a marked effect on spermatogenesis, but no impairment of ovarian reserve. No studies are available on trans women; the data show that 59�87% of trans men use contraceptives, often mainly in order to suppress menstrual bleeding. Fertility preservation measures are mainly used by trans women.

GAHT mainly impairs spermatogenesis; thus, counseling on fertility preservation should always be given before GAHT. More than 80% of trans men use contraceptives, mainly for their other effects such as suppression of menstrual bleeding. GAHT is not in itself a reliable method of contraception, and persons about to undergo GAHT should always receive contraceptive counseling. The terms �transgender� and �gender incongruence� describe the discrepancy between gender assigned at birth and the self-perceived gender�thus, �trans man� (TM) and �trans woman� (TW) refer to the self-perceived gender. The prefix �cis�, in contrast, describes persons who identify with the sex assigned at birth. The prefixes �cis� and �trans� do not allow conclusions about the persons� sexual orientation. The prevalence of trans persons in Germany is currently reported to be 17�33 per 100 000 inhabitants (e1), corresponding to up to 27 500 persons Gender incongruence leads to an enormous level of distress on the part of those affected; consequently, they are more likely to experience depression and suicidal ideation, apart from being increasingly the target of discrimination (e2, e3, e4, e5, e6). In many cases, certain treatment options, such as hormone therapy or surgical intervention, lead to improvements in quality of life (e4, e7, e8, e9, e10). A meta-analysis revealed significantly poorer quality of life in trans persons compared to the general population (standardized mean difference −0.78, [95% confidence interval: −1.08; −0.48], Z = 5.16, p<0.00001), while no significant difference was found for trans persons undergoing gender-affirming hormone therapy (GAHT) (standardized mean difference = −0.42 [−1.15; 0.31], Z = 1.13; p = 0.26) (e8). Natural conception may occur in persons undergoing gender-affirming hormone therapy in the absence of previous genital surgery or gonadectomy; it is contraindicated especially under testosterone therapy which causes virilization of the embryo (development of male sexual characteristics, such as clitoral hypertrophy). Given the possibility of natural conception, certain partner constellations (trans man with man; trans woman with woman) require reliable contraception. The Transgender Center Innsbruck (TGCI) currently provides care for about 500 trans persons (300 trans men, 200 trans women). Of the 300 trans men currently treated, at least one-third report having sex with a cis man, while of the about 200 trans women in TGCI care at least half have cis women as sexual partners. While the majority of trans women opt to undergo gender reassignment surgery, only few trans men chose to take this step due to the high complication rate. In trans men, testosterone is used for gender-affirming hormone therapy (e11, e12). Since, especially at the start of treatment, amenorrhea is rarely achieved by testosterone therapy alone, progesterone or a GnRH agonist are used in addition (e13). In trans women, estrogen (oral, transdermal, nasal routes of administration) is used for gender-affirming hormone therapy. Given that estrogen alone does not provide sufficient suppression of androgen production in the gonads, the additional use of antiandrogens, such as spironolactone, cyproterone acetate or GnRH agonists, is required (1). GnRH agonists may be offered as a fully reversible intervention in trans adolescents from the onset of puberty (Tanner stage II) to suppress the irreversible effects of a pubertal development in the sex assigned at birth (1, 2). If gender-affirming hormone therapy is considered, it is provided in a time-delayed manner (e.g., from 16 years of age) (1, 2). Currently, there is no guideline for the management of trans adolescents available in Germany; in Austria, the Federal Ministry of Health has issued a recommendation (e14). Since any gender-affirming hormone therapy can result in impaired fertility, current guidelines and treatment recommendations require that the possibility of fertility preservation is discussed with the patient before such therapy is started (1, 3, e15). In trans men, measuring anti-M�llerian hormone (AMH) levels is one way of determining the ovarian reserve, i.e. the number of oocytes present within the ovary. There is a direct correlation between a reduced ovarian reserve and decreased AMH levels. In addition, antral follicle count (AFC) by transvaginal ultrasonography may be used to determine the number of antral follicles. Fertility preservation options include cryopreservation of sperm or testicular tissue in trans women and cryopreservation of oocytes, embryos or ovarian tissue in trans men. (4, 5, e15). For oocyte retrieval, ovarian stimulation with follicle-stimulating hormone (FSH) must be performed first, followed by follicular puncture. The oocytes obtained can be cryopreserved (un)fertilized, and can later be fertilized by insemination with partner sperm or donor sperm. Should they wish to have children, either the trans man himself can carry the pregnancy to term, or the partner. A majority of trans men refuse to get pregnant. If it is a male partner and the trans man does not want to or cannot carry the pregnancy to term himself, there is the option of surrogacy. However, surrogacy is currently prohibited by law in Germany and in Austria. If a trans woman has a female partner, it is possible to fertilize the oocytes with the sperm of the trans woman. In the case of a male partner, both donor oocytes and surrogacy are required, neither of which is currently permitted by law in Germany. In the United States, 70 pregnancies were reported in trans men among 1,694 trans, nonbinary, and queer respondents (6). About 20�40 % of trans persons state that they desire to have children (7, 8). During pregnancy of a trans man, testosterone therapy must be withheld to avoid the risk of impaired fetal development. This systematic review highlights aspects of both contraception and fertility or fertility preservation in trans persons.

This review is based on pertinent publications retrieved by a systematic search in the PubMed and Web of Science databases from December 2021 to June 2022. The search followed the Preferred Reporting Items For Systematic Reviews And Meta-Analysis (PRISMA) statement and employed the search terms �fertility,� �contraception,� �transgender,� �gender-affirming hormone therapy,� �ovarian reserve,� and �testicular tissue.� The review was registered in the Open Science Framework under osf.oi/pxz68 (www.doi.org/10.17605/OSF.IO/PXZ68). The search was conducted using the PICO framework (Population: trans persons under gender-affirming therapy; Intervention: fertility, fertility preservation, contraception; Comparison: no restriction; Study type: original research), using the search terms �transgender� AND �� fertility� OR �fertility preservation� AND �gender-affirming hormone therapy,� �transgender� AND �contraception,� �transgender� AND �ovarian reserve,� and �transgender� AND �testicular tissue.� No restriction on publication date was applied. Duplicates were removed and each of the remaining publications was screened by two authors independently. Original research articles, published in peer-reviewed journals in English or German, were included. We included studies in adults as well as in children and adolescents. The selection process was documented in a PRISMA flowchart (eFigures 1, 2). The selected studies were grouped by topic and the relevant data were summarized in tables. The extracted data were evaluated in terms of their level of evidence and qualitatively analyzed (eTable 1). Of the 908 screened studies, 26 were included in our analysis: 4 on the topic of contraception in trans men; 6 on the topic of fertility in trans men; 5 on the topic of fertility preservation in trans men; 12 on the topic of fertility and fertility preservation in trans women, one of which included both trans women and trans men.

Options for contraception and fertility preservation as well as their effects on fertility in trans men and trans women are listed in Table 1. Trans men Fertility Table 2 and eTable 2 provide a summary of the included studies on fertility in trans men. Five prospective studies investigated the value of the anti-M�llerian hormone (AMH) test and/or the antral follicle count (AFC) in trans men. They found no effect of gender-affirming hormone therapy on these parameters (9, 10, 11) or in two studies a decrease in AMH concentrations after gender-affirming hormone therapy over 16 weeks (12) and over 12 months, respectively, in a subgroup with polycystic ovary syndrome with unchanged AFC (13). Likewise, three studies, investigating the distribution of follicles in the ovarian cortex in histological sections of ovaries obtained from trans men who underwent adnexectomy, showed normal findings (9, 11, 14). In a 12-week prospective observational study, blood and urine samples of 32 trans men undergoing testosterone therapy were analyzed to determine the rate of those with ovulation: one confirmed and twelve questionable ovulations were observed. 41% of the study participants reported spotting/bleeding during the study period (10). Contraception Table 3 and eTable 3 provide a summary of the included studies on contraception in trans men. The two surveys found, on the one hand, similar levels of contraceptive use among trans men and cis women (>80%) (15) and, on the other, use of contraceptives during the last vaginal intercourse by 79% of the trans men surveyed (16). A retrospective cross-sectional study revealed an increase in the use of long-acting hormonal contraceptives (such as extended-cycle pills and hormonal IUDs) over a 10-year period in both trans men and cis women (17). In another retrospective study, 59% of trans men used hormonal contraceptives to prevent pregnancy, with the majority using contraceptives for menstrual suppression rather than contraception. Only 15% of trans men had sexual intercourse with a male partner, of which only two-thirds used hormonal contraception. Half of the sexually active trans men discontinued the use of contraceptives as soon as they stopped menstruating (18). Fertility preservation The findings for the topic �Fertility preservation in trans men� are summarized in Table 4 and e Table 4. The number of oocytes obtained after ovarian stimulation for the purpose of fertility preservation or starting a family did not differ in any of the included four studies between trans men and cis women of the same age (19, 20, 21, 22), even when adolescent youths were included in the study (21). Another study without a control group showed not only that an average of 12 oocytes were obtained after stimulation in trans men, but also that up to 26% of trans men decided to opt for oocyte cryopreservation after receiving pertinent counselling (23). Trans women Fertility and fertility preservation Data on fertility and fertility preservation in trans women are summarized in Table 5. Three prospective and four retrospective studies evaluated semen quality before and during gender-affirming hormone therapy in trans women and compared the results with findings in cis men (23, 24, 25, 26, 27, 28, 29). A significant reduction in semen quality was demonstrated in all studies, even before the start of gender-affirming hormone therapy. In 1.8% (25) to 10.3% (27), azoospermia already was present before the initiation of gender-affirming hormone therapy. Gender-affirming hormone therapy was found to be associated with a progressive reduction in sperm concentration and motility as well as total sperm count (30). These effects were also observed in adolescent trans women (28). In addition, it was demonstrated that constant wearing of tight underwear as well as �tucking� is associated with a reduction in motile sperm count to <5 million/mL (25). �Tucking� is a technique whereby an individual hides the crotch bulge of the penis and testicles by moving the penis between the buttocks, and moving the testes up into the inguinal canals. These positions are secured with tight underwear or so-called �gaffs.� A retrospective study with 242 trans persons in Sweden showed that 25% of trans men and 75% of trans women opted for fertility-preserving measures following prior counseling (23). Since all of these trans persons were explicitly referred for fertility-preservation counselling, these figures are only in part comparable with those of a regular counseling situation in Germany, especially given the fact that the reimbursement of costs is regulated differently in Sweden. In three studies, histological analyses of spermatogenesis were performed on testicular specimens from trans women who underwent genital-affirming surgery (31, 32, 33). In orchiectomy specimens, active spermatogenesis was demonstrated in 8.2% (32) and 24% (33), respectively, regardless of the prior duration of gender-affirming hormone therapy. De Nie et al. showed a correlation between pubertal development (Tanner stages I-V) at the start of gender-affirming hormone therapy and detection of mature spermatozoa. When gender-affirming hormone therapy was started in Tanner stage II-III individuals, 100% of detectable sperm were immature, whereas when the therapy was started in Tanner stage IV individuals, 4.7% mature sperm were detectable (31). Likewise, Peri et al. were able to detect sperm in 73% of testicular biopsies from trans girls (n = 25) prior to the start of gender-affirming hormone therapy only from Tanner stage III onwards; from Tanner stage IV onwards, sperm were detectable in 100% of patients and could be cryopreserved (34). Contraception No studies on the topic of �Contraception in trans women� were identified.

This systematic search of the literature is the first review on fertility, contraception and fertility preservation in trans persons. A total of 26 studies were included; of these, 22 on the topic of �Fertility and fertility preservation,� and 4 on the topic of �Contraception.� While studies on fertility have been conducted by research groups throughout the world, and in Europe in particular, all studies on the use of contraceptives in trans individuals have come from the United States. Fertility Gender-affirming hormone therapy in trans men appears to have little or no effect on fertility. The antral follicle count (AFC) remained unchanged (9, 11, 13), whereas the anti-M�llerian hormone level either remained the same (9, 10, 11, 13) or decreased (12, 13) in the few available studies. Suppression of ovarian function without loss of ovarian reserve appears to occur, similar to that seen in patients with polycystic ovary syndrome. Here, studies on larger populations are urgently needed, which in particular consider relevant contributing factors such as polycystic ovary syndrome or endometriosis. Histological evaluation of orchiectomy specimens from trans women found normal spermatogenesis in about one-quarter of cases (31, 32, 33). The extent to which different forms of gender-affirming hormone therapy have different effects on sperm production remains unknown at present and should be further investigated in prospective studies. Contraception Reports of current use of (safe) contraceptives among trans men range from 4% to 87% (15, 16, 17, 18); however, it is often not stated whether sexual intercourse with a cis man occurs and thus contraception is required. Gender-affirming hormone therapy in trans men does not provide reliable inhibition of ovulation (10) and in trans women it does rarely achieve complete suppression of spermatogenesis (23, 32, 33, 34); consequently, counseling on contraception should play an important role in the care of trans persons. Fertility preservation Several smaller studies have shown that comparable outcomes can be achieved in trans men even after the start of gender-affirming hormone therapy, if fertility preservation measures have been taken (19, 20, 21, 22, 23). For trans men, the greatest barriers to the acceptance of fertility preservation measures are, on the one hand, recurrent vaginal ultrasound examinations as part of stimulation monitoring (and the accompanying confrontation with one�s own female sex characteristics, which is perceived as distressing), and the frequently required temporary discontinuation of testosterone therapy and the resulting increases in estrogen levels. Here, two recent case reports have demonstrated that ovarian stimulation is possible even in patients receiving ongoing testosterone therapy; the additional administration of letrozole to reduce the estrogenic effects of stimulation also seems to be useful. (37). On the other hand, the high costs associated with this approach are a major barrier for these patients, as fertility preservation measures for trans persons are currently not covered by statutory or private health insurance. In contrast to the data in trans men, studies in trans women show a reduction in semen quality even before the start of gender-affirming hormone therapy, with the latter further aggravating these sperm abnormalities (24, 25, 26, 27, 32). The reduced semen quality seems to be linked to various practices, such as wearing tight underwear or tucking (25, 27). Whether these changes are reversible is still unknown; this question should be addressed in future studies. Thus, the presented studies may offer some perspective on the need for immediate fertility preservation treatment before the start of gender-affirming hormone therapy; however, further data, particularly prospective data, are needed for a definitive conclusion. Ongoing gender-affirming hormone therapy and practices such as tucking or wearing of tight underwear should be temporarily discontinued before the start of fertility preservation measures. How long the discontinuation period should be remains uncertain; current data have shown an improvement in semen quality after three months, however, there is not enough data available (30). Thus, before gender-affirming hormone therapy is started, patients should be informed about the risk of irreversible azoospermia and associated infertility. In addition, given the available data, all trans women and trans girls from Tanner stage III onward should be offered fertility preservation in the form of semen cryopreservation or cryopreservation of testicular biopsies prior to starting gender-affirming hormone therapy (31, 34). Masturbation for an ejaculation to obtain semen for cryopreservation can be traumatizing for trans women due to their rejection of their own male sexual characteristics; consequently, this approach can be a barrier to the utilization of fertility preservation measures.

Gender-affirming hormone therapy may lead to impaired fertility, especially in trans women. Nevertheless, gender-affirming hormone therapy in trans persons is not a reliable contraceptive method. Thus, addressing the need for reliable contraception is a key element in the provision of care for trans persons. Counseling about the possibility of fertility preservation should be provided prior to the start of gender-affirming hormone therapy (1, 3, 38, 39). For fertility preservation, especially in trans women, it is crucial that they are seen in a reproductive medicine center as early as possible; the fact that the costs of fertility preservation measures are currently not covered by health insurances should also be discussed. In trans men, by contrast, fertility preservation measures can be taken even if they are already receiving gender-affirming hormone therapy; however, evidence from studies is limited and prospective studies are not available. Conflict of interest statement B.B. received consultancy fees from Organon. She received fees for continuing medical education events from Bayer, Jenapharm and Merck. She received reimbursement of travel expenses from IBSA and astropharma. The remaining authors declare no conflict of interest. Manuscript received on 6 July 2022; revised version accepted on 27 January 2023 Translated from the original German by Ralf Thoene, MD. Corresponding author Dr. med. univ. Elisabeth Reiser Universit�tsklinik f�r Gyn�kologische Endokrinologie und Reproduktionsmedizin Medizinische Universit�t Innsbruck Anichstra�e 35, 6020 Innsbruck, Austria [email protected] Cite this as: Feil K, Reiser E, Braun AS, B�ttcher B, Toth B: Fertility, contraception, and fertility preservation in trans individuals. Dtsch Arztebl Int 2023; 120: 243�50. 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