Fertility, Contraception, and Fertility Preservation in Trans Individuals

Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

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.

cme plus

This article has been certified by the North Rhine Academy for Continuing Medical Education. The CME questions on this article can be found at http://daebl.de/RY95. The submission deadline is 6 April 2024.

Participation is possible at cme.aerztebatt.de

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– e6). In many cases, certain treatment options, such as hormone therapy or surgical intervention, lead to improvements in quality of life (e4, e7– 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-Müllerian 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.

Material and methods

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).

eFigure 1.

Flowchart of PRISMA criteria Literature search, fertility and fertility preservation

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).

eTable 1. Literature quality assessment using the Newcastle-Ottawa scale*.

Study	Selection	Comparability	Exposure experience	Total score (max. 9)
Caanen 2015 (12)	**		***	5
Yaish 2021 (13)	**		***	5
De Roo 2017 (11)	**		**	4
Borrás 2021 (9)	**		**	4
Marschalek 2020 (14)	**		**	4
Taub 2020 (10)	**		**	4
Kanj 2019 (18)	**		***	5
Berglin 2022 (17)	***	*	***	7
Stark 2019 (16)	**		***	5
Reynolds 2021 (15)	***	*	**	6
Leung 2019 (20)	***	*	**	6
Adeleye 2019 (19)	***	*	**	6
Amir 2020 (22)	***	*	**	6
Amir 2020 (21)	**	**	**	6
Mattelin E 2022 (23)	*		**	3
de Nie 2022 (25)	**		**	4
Rodriguez-Wallberg 2021 (26)	**		*	4
Marsh 2019 (27)	**	*	***	6
Amir 2022 (28)	**		**	4
de Nie 2020 (24)	**		**	4
Adeleye 2019 (30)	**		**	4
Barnard 2019 (29)	**		**	4
Schneider 2015 (33)	**		***	5
Sinha 2021 (32)	**		***	5
de Nie 2022 (31)	**		***	5
Peri 2021 (34)	**		***	5

*1 The stars show the degree of assessment. Maximum of *** stars per category achievable

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.

Results

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-Müllerian 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– 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– 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– 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– 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.

Discussion

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-Müllerian hormone level either remained the same (9– 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– 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– 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– 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– 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– 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.

Conclusion

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.

Table 1. Contraception and fertility preservation options as well as potential effects of gender-affirming hormone therapy in trans persons.

	Trans men	Trans women
Contraception	Hormonal contraceptives – (combined) oral contraception – Implanon – Hormonal IUD Non-hormonal contraceptives: – Copper IUD – Diaphragm/portio cap*	Condom
Fertility	AMH ↔ Normal distribution of follicles in ovary sections	Impaired semen quality already prior to GAHT and during GAHT
Fertility preservation	Cryopreservation of oocytes/ embryos after controlled ovarian stimulation Cryopreservation of ovarian tissue	Cryopreservation of sperm/ testicular tissue

* Rarely used; AMH, anti-Müllerian hormone; GAHT, gender-affirming hormone therapy

Table 2. Fertility in trans men*¹.

Author/year/country	Inclusion criteria	Study participants (n)	Results
Caanen M 2015 NLD/BEL (12)	TM prior to GAHT	22	AMH concentration significantly reduced after 16 weeks of GAHT
Yaish I 2021 ISR *2, *3 (13)	1. TM prior to GAHT 2. TM during GAHT	56 35	Pilot: AMH decrease after 12 months of GAHT Sub-group analysis: decrease only in PCOS group (n = 27 with PCOS) Cross-section: AMH correlation with age, but not GAHT duration
De Roo C 2017 NLD/BEL (11)	TM GAHT min. of 12 months	40	AMH within normal range
Borrás A 2021 ESP (9)	TM GAHT min. of 24 months	70	AMH within normal range
Marschalek 2020 AUT (14)	TM GAHT min. of 12 months	20	Histomorphology Normal cortical distribution of follicles
Taub 2020 USA (10)	TM 12 weeks i.m. testosterone	32	No change in AMH level

*¹Study designs of all presented studies: IIb, prospective cohort study, except *² = pilot study and *³ = III, cross-sectional study

AMH, anti-Müllerian hormone; GAHT, gender-affirming hormone therapy; GnRH, gonadotropin-releasing hormone; PCOS, polycystic ovary syndrome; T, testosterone; TM, trans man

AUT, Austria; BEL, Belgium; ESP, Spain; ISR, Israel; NLD, Netherlands; USA, United States of America

Table 3. Evidence table: Contraception in trans men.

Author/year/country/evidence level	Inclusion criteria	Study participants	Results
Kanj 2019 USA (18)* Evidence level III	TM 11–25 years No GnRH analogs	231 TM	135 (58%) with ongoing contraception (49 DMPA, 71 COC/POP, 13 LNG-IUD, 1 etonogestrel implant, 1 hysterectomy)
Berglin 2022 USA (17) Evidence level III	TM and cis women 18–45 years	1 573 TM 715 658 cis women	Use of contraception TM 2009: 0.7% 2019: 4.1% Women 2009: 5.6% 2019: 6.7%
Stark 2019 USA (16)* Evidence level III	TM	150 TM	n = 71 Sexual intercourse with men n = 56 (37%) Current use of contraception (24% condom, 8% IUD, 2.7 COC, 4% other)
Reynolds 2021 USA (15) Evidence level IIb	18–25 years	182 385 cis women 2904 TM	Any contraception: TM: 86.8% with last vaginal intercourse Women: 88.1% with last vaginal intercourse Barrier method: TM: 41.0% with vaginal intercourse Women: 48.8% with vaginal intercourse Emergency contraception: TM: 11.4% Women: 18.8%

Evidence level IIb Quasi-experimental study; Evidence level III non-experimental, descriptive study (e.g., comparative studies, correlational studies, case-control studies); *Limitations: no control group

DMPA, depot medroxyprogesterone acetate; GnRH, gonadotropin-releasing hormone; COC, combined oral contraceptives;

LNG-IUD, levonorgestrel-releasing intrauterine device; TM, trans man; POP, progestogen-only pill

USA, United States of America

Table 4. Fertility preservation in trans men*.

Author/year/country	Inclusion criteria	Study participants (n)	Results
Leung 2019 USA (20)	TM versus reproductive couples	26 130	No differences in number of oocytes retrieved,mature oocytes, E2 level
Adeleye 2019 USA (19)	TM prior to GAHTdis continued GAHT vs. cis women	6 7 13	TM versus women: no differences in number of oocytes retrieved, mature oocytes, E2 level
Amir 2020 ISR (22)	TM prior to GAHT Discontinued GAHT versus cis women	6 6 12	No differences in number of oocytes retrieved, mature oocytes, E2 level
Amir 2020 ISR (21)	TM prior to GAHT versus cis women 13–18a	9 39	No differences in number of oocytes retrieved, mature oocytes, E2 level
Mattelin E 2022 SWE (23)*	TM TW	164 78	43 TM oocyte cryopreservation 4.7% previous GAHT 59 TF (76%) sperm cryo 16.9% previous GAHT 6 azoospermia

*Limitations: no control group, evidence level III according to Agency for Health Care Policy and Research (AHCPR)

ART, assisted reproductive technology; E2, estradiol; GAHT, gender-affirming hormone therapy; MII, mature oocytes;

TW, trans women; TM, trans men

ISR, Israel; SWE, Sweden; USA, United States of America

Table 5. Fertility and fertility preservation in trans women.

Author/year/country/evidence level	Inclusion criteria	Study participants (n)	Intervention	Results
de Nie 2022 NLD (25) EL IIb	TF prior to GAHT	n = 113	Semen analysis	1,8 % Azoospermie 13.3% OAT 16.8% oligozoospermia 7.9% asthenozoospermia 60.2% normozoospermia
Rodriguez-Wallberg 2021 SWE (26), EL IIb	TF prior to versus during GAHT	n = 161 n = 16	Semen analysis	Significantly decreased sperm concentration and total sperm count
Marsh C 2019 USA (27)* EL IIa	TF prior to GAHT versus fertile cis men	n = 22 n = 17	Semen analysis Depression, Anxiety and Stress Scale	N = 3 azoospermia 27.3% (vs. 0% control) oligozoospermia 26.3% (vs. 11.8% control) asthenozoospermia 73.3% (vs. 29.4% control)
Amir H. 2022 ISR (28) EL III	TW prior to GAHT 14–18a	n = 25	Semen analysis Tanner stages	72% teratozoospermia 28% oligozoospermia 16% cryptozoospermia 52% hypospermia
de Nie I 2020 NLD (24); EL III	TW prior to GAHT 16–52a	n = 260	Semen analysis Demography, medical history	Reduced volume, concentration, motility, and total count of sperm
Adeleye AJ 2019 USA (30) EL III	TW prior to GAHT versus during GAHT versus GAHT stop (at least 3 months)	n = 18 n = 5 n = 3	Semen analysis E2+ spironolactone (± finasteride, progesterone)	Concentration, motility and total sperm count reduced in TW with previous GAHT vs prior to GAHT, and in TW during GAHT vs previous GAHT
Barnard E 2019 USA (29) EL III	TW prior to GAHT after GAHT 16–24a	n = 10 n = 8 n = 2	Semen analysis	N = 8 prior to GAHT Morphology impaired
Schneider F 2015 DEU (33) ELIIa	TW Orchiectomy, GAHT STOP 6 weeks before surgery versus 2 weeks before surgery versus no STOP	n = 108	Spermatogenesis in histological specimens, histopathological findings	Normal spermatogenesis in 24% not related to GAHT STOP
Sinha A 2021 USA (32) EL III	TW Orchiectomy; GAHT duration (0–36 m, 36–60 m, >60 m)	n = 85	Spermatogenesis in histological specimens, histopathological findings, E2+spironolactone	Spermatogenesis 28.2%, active spermatogenesis 8.2%
de Nie I 2022 NLD (31) ELIII	TW during GAHT Orchiectomy	n = 214	Spermatogenesis in histological specimens, immune/histopathological findings, Tanner stages at start of GAHT (2–3, 4–5, adults), GAHT discontinuation before surgery (J/N) E2+triptorelin or CPA	4.7% mature sperm (at start of GAHT ≥Tanner stage IV, irrespective of discontinuation) 88.3% immature germ cells (with 100% at start of GAHT Tanner stage II to III) 7% no germ cells (at start of GAHT as adult)
Peri A 2021 AUS/CHE (34) ELIII	TW prior to GAHT< 18a	n = 25	Testicular biopsy before therapy start, Tanner stages	Tanner 2 (n = 4) 0% with spermatozoa Tanner stage III (n = 11) 73%, Tanner stage IV 4+ V (n = 6) 100%

* Limitations; no control group; IIa controlled study without randomization; IIb quasi experimental study, prospective cohort study;

III non-experimental, descriptive study (e.g., comparative studies, correlational studies, case-control studies)

EL, evidence level; GAHT, gender-affirming hormone therapy; OAT, oligoasthenoteratozoospermia; TW, trans women

AUS, Austria; CHE, Switzerland; DEU, Germany; ISR, Israel; NLD, Netherlands; SWE, Sweden; USA, United States of America

Questions on the article in issue 14/2023:

Fertility, Contraception, and Fertility Preservation in Trans Individuals

The submission deadline is 6 April 2024. Only one answer is possible per question. Please select the answer that is most appropriate.

Question 1

What does the acronym GAHT stand for?

1. “Gender-assimilating hormone therapy“

2. “Gender-adapting homeopathy treatment“

3. “Gender-affirming holistic treatment“

4. “Gender-affirming hormone therapy“

5. “Gender-adapting hormone therapy“

Question 2

What prefix is assigned to persons who identify with their sex assigned at birth?

1. “trans“

2. “fis“

3. “his“

4. “gis“

5. “cis“

Question 3

About how many trans persons are estimated to live in Germany at present?

1. 12 700

2. 17 500

3. 27 500

4. 52 700

5. 75 200

Question 4

The level of which of the following hormones can—according to the statement in the text– be used to determine the ovarian reserve in the context of fertility preservation?

1. Progestin

2. Anti-Müllerian hormone

3. GnRH

4. Estrogen

5. Androgen

Question 5

What is described by the term “tucking”?

1. Concealment of the breasts by applying bandages

2. Raising the pitch of the voice to make it sound female

3. Concealment of penis and testes through special clothing

4. Lowering the pitch of the voice to make it sound male

5. Feminization of the gait pattern

Question 6

What is the approximate percentage of trans men who choose oocyte cryopreservation following appropriate counseling according to a retrospective study from Sweden?

1. About one quarter

2. About half

3. About one eighth

4. About one third

5. About three quarters

Question 7

At what stage of pubertal development can successful sperm cryopreservation be achieved in trans girls?

1. Tanner stage 0

2. Tanner stage I

3. Tanner stage II

4. Tanner stage III

5. Tanner stage IV

Question 8

The administration of letrozole is mentioned in the text in connection with which treatment goal?

1. Acceleration of female sexual maturation during puberty

2. Boosting of estrogen effects during ovarian stimulation

3. Reduction of androgen effects during virilizing treatment.

4. Reduction of estrogen effects during ovarian stimulation

5. Delaying of male sexual maturation during puberty

Question 9

Which of the following drug combinations can be used for gender-affirming hormone therapy in trans women?

1. Estrogen and spironolactone

2. Progesterone and cyproterone acetate

3. Estrogen and FSH

4. Estrogen and progesterone

5. Progesterone and AMH

Question 10

Which substance can be offered to adolescents from Tanner stage II onward to reversibly suppress the irreversible pubertal development to the biological sex?

1. GnRH antagonist

2. Cyproterone acetate

3. GnRH agonist

4. Anti-FSH

5. Progesterone

eFigure 2.

Flowchart of PRISMA criteria Literature search Contraception

GAHT, gender-affirming therapy; MSM, men who have sex with men

eTable 2. Evidence table (long version) Fertility in trans men.

Author/year/country	Study design Evidence level according to AHCPR	Inclusion criteria	Study participants (n)	Intervention	Results	Limitations/comments
Caanen M 2015 NLD/BEL (12)	Prospective cohort study IIb	TM prior to GAHT	n = 22	8 wks pre-treatment with GnRH agonist (= baseline), 16 weeks T+ letrozole+ GnRH agonist	AMH concentration significantly reduced after 16 weeks of GAHT	Small study population No T monotherapy No control group
Yaish I 2021 ISR (13)	1. Pilot study 2. Cross-sectional study III	1. TM prior to GAHT 2. TM during GAHT	n = 56 n = 35	AMH AFC	Pilot: AMH reduction after 12 months of GAHTSubgroup analysis: Reduction only in PCOS group (n = 27 with PCOS) No effect on AFC Cross-section: AMH correlation with age, but not GAHT duration n = 4 TM with biological children after GAHT of up to 12 years	Small study population 40% of ultrasonographies transabdominal No control group Young study population
De Roo C 2017 NLD/BEL (11)	Prospective cohort study IIb	TM GAHT at least for 12 months Hysterectomy and oophorectomy	n = 40	AMH Histomorphology	AMH within normal range Normal cortical distribution of follicles High number of cumulus–oocyte complexes	Small study population No control group
Borrás A 2021 ESP (9)	Prospective cohort study IIb	TM GAHT for at least 24 months Hysterectomy and oophorectomy	n = 70	AMH AFC Histomorphology	AFC and AMH in female normal range Normal cortical distribution of follicles	No control group n = 5 PCOS
Marschalek 2020 AUT (14)	Prospective cohort study IIb	TM GAHT for at least 12 months Hysterectomy and oophorectomy	n = 20	FACS-Analyse Histomorphology	87.5% vital cells Normal cortical distribution of follicles	Small study population No control group
Taub 2020 USA (10)	Prospective cohort study IIb	TM i.m. testosterone for 12 weeks	n = 32	Ovulation suppression by testosterone AMH	1 definite ovulation, 12 questionable ovulations No change in AMH	Small study population No control group Short period of observation

Ia Meta-analyses of randomized controlled trials

Ib randomized controlled trial

IIa controlled study without randomization

IIb quasi-experimental study, prospective cohort study

III non-experimental, descriptive study (e. g., comparative studies, correlational studies, case-control studies)

IV case reports, expert opinions, consensus conferences

AFC, antral follicle count; AMH, anti-Müllerian hormone; FACS, fluorescence-activated cell sortin g; GAHT, gender-affirming hormone therapy;

GnRH, gonadotropin releasing hormone; PCOS, polycystic ovary syndrome; T, testosterone; TM, trans man

AUT, Austria; BEL, Belgium; ESP, Spain; ISR, Israel; NLD, Netherlands; USA, United States of America

eTable 3. Evidence table: Contraception in trans men.

Author/year/country	Study design Evidence level (AHCPR)	Inclusion criteria	Study participants (n)	Intervention	Results	Limitations/comments
Kanj 2019 USA (18)	Retrospective study II	TM 11–25 years No GnRH analogs	n = 231 TM	Use of hormonal contraceptives	N = 135 with ongoing contraception (49 DMPA, 71 COC/POP, 13 LNG-IUD, 1 etonogestrel implant, 1 hysterectomy) Aim of use: amenorrhea in n = 124	Small study population No control group
Berglin 2022 USA (17)	Retrospective study III	TM and reproductive women18–45 years	n = 1573 TM n = 715 658 women	Use of long-acting hormonal contraceptives	TM 2009: 0.7% 2019: 4.1% Women 2009: 5.6% 2019: 6.7%	Only long-acting contraceptives recorded Sex of sexual partner not recorded
Stark 2019 USA (16)	Prospective survey III	TM	n = 150 TM	Contraception use Family planning	n = 71 Intercourse with men n = 56 current use of contraception (24% condom, 8% IUD, 2.7 COC, 4% other) n = 8 have already been pregnant n = 32 desire to have biological children	Small study population No control group
Reynolds 2021 USA (15)	Prospective survey IIb	18–25 years	n = 182 385 reproductive women n = 2 904 TM	Contraception use	Any contraception: TM: 86.8% with last vaginal intercourse Women: 88.1% with last vaginal intercourse Barrier method: TM: 41.0% with vaginal intercourse Women: 48.8% with vaginal intercourse Emergency contraception: TM: 11.4% Women: 18.8%	No survey of TM without vaginal intercourse Use for suppression of menstruation not recorded

Ia meta-analyses of randomized controlled trials; Ib randomized controlled trial; IIa controlled study without randomization

IIb quasi-experimental study; III non-experimental, descriptive study (e. g., comparative studies, correlational studies, case-control studies)

IV case reports, expert opinions, consensus conferences

DMPA, depot medroxyprogesterone acetate; GnRH, gonadotropin-releasing hormone; COC; combined oral contraceptives;

LNG-IUD, levonorgestrel-releasing intrauterine device; POP, progestogen-only pill; TM, trans man, USA, United States of America

eTable 4. Evidence table (long version): Fertility preservation in trans men.

Author/year/country	Study design Evidence level (AHCPR)	Inclusion criteria	Study participants (n)	Intervention	Results	Limitations/comments
Leung 2019 USA (20)	Retrospective cohort study EL III	TM versus reproductive couples	n = 26 n = 130	ART Oocyte cryopreservation	No differences in number of retrieved oocytes, MII oocytes, E2 level	Small study population 38.5% TM prior to start of GAHT 1–8 mts GAHT stop before ART 2 TM with live births + 5 female partners of TM with live births
Adeleye 2019 USA (19)	Retrospective cohort study EL III	TM prior to GAHT Discontinued GAHT versus reproductive women	n = 6 n = 7 n = 13	ART Oocyte cryopreservation	TM versus women: No differences Number of retrieved oocytes, MII oocytes, E2 level TM discontinued GAHT versus prior to GAHT low E2 levels (p = 0.046) and few oocytes (p = 0.038)	Very Small study population 1–13 mts GAHT stop before ART
Amir 2020 ISR (22)	Retrospective cohort study EL III	TM prior to GAHT Discontinued GAHT versus reproductive women	n = 6 n = 6 n = 12	ART Oocyte cryopreservation	No differences in number of retrieved oocytes, MII oocytes, E2 level	Small study population 5–21 mts GAHT stop before ART
Amir 2020 ISR (21)	Retrospective cohort study EL III	TM prior to GAHT versus reproductive women 13–18a	n = 9 n = 39	Oocyte cryopreservation	No differences in number of retrieved oocytes, MII oocytes, E2 level	Small study population No GAHT
Mattelin E 2022 SWE (23)	Retrospective cohort study EL III	TM TW	n = 164 n = 78	Oocyte cryopreservation ART Semen cryopreservation	43 TM oocyte cryopreservation 4.7% previous GAHT 1 PG with cryopreserved oocytes 15 PGs (14 in female partner) 59 TF (76%) sperm cryopreservation 16.9% previous GAHT 6 azoospermia 3 pregnancies (female partner)	No control group No data on GAHT discontinuation Persons explicitly referred to fertility preservation counselling

Evidence level (EL) III non-experimental, descriptive study (e. g., comparative studies, correlational studies, case-control studies)

ART, assisted reproductive technology; EL, evidence level; E2, estradiol, GAHT, gender-affirming hormone therapy; MII, mature oocytes;

PG, pregnancy TW, trans woman; TM, trans man

ISR, Israel; SWE, Sweden; USA, United States of America