Fertility Counseling for Transgender Adolescents: A Review

Journal of Adolescent Health xxx (2020) 1e8

www.jahonline.org Review article

Fertility Counseling for Transgender Adolescents: A Review Timothy C. Lai, M.D. a, Rosalind McDougall, Ph.D. b, Debi Feldman, M.B.B.S. (Hons) a, c, Charlotte V. Elder, M.B.B.S. (Hons) a, d, e, and Ken C. Pang, Ph.D. a, c, f, * a

Royal Children's Hospital, Parkville, Victoria, Australia Melbourne School of Population and Global Health, University of Melbourne, Parkville, Victoria, Australia Murdoch Children's Research Institute, Parkville, Victoria, Australia d Austin Hospital, Heidelberg, Victoria, Australia e Mercy Hospital for Women, Heidelberg, Victoria, Australia f Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia b c

Article history: Received August 12, 2019; Accepted January 2, 2020 Keywords: Transgender; Fertility

A B S T R A C T

International guidelines in transgender health recommend fertility counseling before the commencement of puberty suppression, estrogen, or testosterone, given the potential for these treatments to impair fertility. However, these recommendations provide little actual guidance to clinicians. Consequently, differences in knowledge and attitudes may lead to clinicians adopting different approaches and goals in the fertility counseling they provide. This review draws attention to the disparity between the rates of desire for genetic parenthood among transgender individuals and the actual rates of fertility preservation (FP) and examines different factors in fertility counseling that affect clinical practice and contribute to this disparity. These factors include how a lack of strong evidencedfor the effects of hormone therapy on future fertility and success rates of some FP optionsdimpacts upon counseling, transgender peoples' experiences of fertility counseling and preservation, consideration of a young person's developmental stage and the roles of parents and clinicians in the decision-making process, considerations shaping transgender adolescents' decisions to preserve fertility, and access barriers to FP. In doing so, this review highlights the complexities and issues that clinicians must consider when providing fertility counseling to transgender adolescents anddin partdhelps to address the lack of detailed clinical guidelines in this area. Ó 2020 Society for Adolescent Health and Medicine. All rights reserved.

Conflicts of interest: The authors have no conflicts of interest relevant to this article to disclose. Financial Disclosure: The authors have no financial relationships relevant to this article to disclose. Authors' Contributions: T.C.L. screened studies for inclusion/exclusion, carried out the analyses, drafted the initial manuscript, and revised the final manuscript. R.M., D.F., C.V.E., and K.C.P. all reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. * Address correspondence to: Ken C. Pang, Ph.D., Murdoch Children's Research Institute, Parkville, Victoria 3052, Australia. E-mail address: [email protected] (K.C. Pang). 1054-139X/Ó 2020 Society for Adolescent Health and Medicine. All rights reserved. https://doi.org/10.1016/j.jadohealth.2020.01.007

IMPLICATIONS AND CONTRIBUTION

Although international guidelines recommend fertility counseling for transgender, these recommendations provide little guidance to clinicians. This review highlights the disparity between the desire for genetic parenthood among transgender individuals and rates of fertility preservation and examines the complexities and issues that clinicians must consider when providing fertility counseling to transgender adolescents.

Transgender and gender diverse (TGD) people have a gender identity different to the sex they were assigned at birth. For some, differences between their physical sex characteristics and gender identity lead to significant distress known as gender dysphoria. Current clinical guidelines [1e3] recommend up to three distinct stages of medical and surgical transition in young TGD people (Box 1). Although not all TGD people choose to transition medically or surgically, those who wish to do so may face significant impairment to their fertility. Gender-affirming

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Box 1. Medical and surgical transition in young TGD people consists of up to three different stages. The first stage involves the use of gonadotropin-releasing hormone analogs (GnRHa) after the onset of puberty (i.e., from Tanner stage 2 onward) to delay puberty and prevent the development of secondary sexual characteristics, allowing for further emotional and cognitive maturation before possible commencement of stage 2 treatment [1,4]. The second stage involves the use of gender-affirming hormonesdestrogen or testosteronedto induce secondary sexual characteristics of the appropriate gender when an adolescent is mature enough to do so [1]. The third stage involves reconstructive chest and/or genital surgeries and is typically accessed only when an adolescent meets the legal age of majority to consent for such procedures [1,2]. Importantly, not all TGD young people will undertake each of these interventions, with treatments tailored to each individual’s circumstances and desires and the exact timing often dependent on local clinical practices.

terms and keywords. PubMed was searched for articles not yet indexed in MEDLINE. The search terms in Medline were as follows: (“transgender persons” or “transgender” or “LGBT” or “gender dysphoria” or “sexual and gender minorities”) and (“fertility” or “cryopreservation” or “cryo-preservation” or “fertility preservation” or “reproductive techniques” or “reproductive techniques, assisted” or “family planning services” or “adoption”). Similar or equivalent search terms were used to search Embase, PsycINFO, and PubMed, and duplicates removed. Of note, our search strategy was not limited to adolescents and thus included studies on adult TGD populations. This was deliberate because knowing what TGD individuals desire and experience as adults in relation to their fertility and parenthood is directly relevant when considering what a TGD adolescent might desire and experience in the future. Additional papers were identified manually via reference lists of relevant retrieved articles. Search results were screened for relevance by title and abstract. Articles were identified as eligible if they focused on fertility in TGD health care. Non-English language articles were excluded, and no date restrictions were set. The search process was performed according to PRISMA guidelines and is depicted in Figure 1. Results

surgeries that remove ovaries/uterus or testes cause permanent sterility [1,5,6] anddalthough the case is less clearcut for puberty blockers and gender-affirming hormones [1,5,6]dthe current consensus is that they are all likely to impair fertility, with the reproductive effects of gonadotropin-releasing hormone analogs (GnRHa) and testosterone likely to be reversible on cessation [7e9], and the permanent sequelae of estrogen on sperm production unclear [10e17]. Many people desire genetic parenthood in the general population, and infertility may affect their mental health and quality of life [18]. TGD people are at greater risk of poor mental health and reduced quality of life because of stigma and discrimination [19], and infertility may further compound this. Advising TGD youths of the risks of hormonal and surgical treatment is imperative for informing decisions around transitioning and potential implications for fertility [1,2,6,20,21]. Current clinical guidelines recommend fertility counseling before the commencement of hormonal therapy on the basis that some TGD people may want to become genetic parents later [1,2]. However, these guidelines lack detail, reflecting a paucity of research and evidence in this area. For example, World Professional Association for Transgender Health guidelines are limited to one page and simply advise clinicians to discuss reproductive optionsd including sperm cryopreservation, testicular biopsy, and oocyte/ embryo cryopreservationdbefore commencing treatments that may impact fertility [2]. This lack of guidance is problematic, as fertility counseling for TGD youths is extremely challenging for various reasons. This review examines the current literature regarding fertility counseling and fertility preservation (FP) for TGD adolescents, highlighting the knowledge gaps and complexities that clinicians must navigate in this new area of practice. Methods MEDLINE (OVID), Embase (OVID), PsycINFO, PubMed, and Google Scholar were searched on February 26, 2019, using MeSH

Of 384 records identified, this review includes a total of 81 articles after systematic exclusion, and the salient findings among these articles are described below. Parenthood desires exceed rates of FP Many TGD people express a desire for parenthood. A study of 79 TGD youth found that the majority desired parenthood (66% and 67% of trans males and females, respectively), but most did not expect to have a biological child [22]. A German study of 99 adult transwomen and 90 transmen found that 69.9% of transwomen and 46.9% of transmen desired future children [23]. Moreover, around half of TGD adults have a specific desire for genetically related children, and 37.5% of adults would have accessed FP if it were offered at the time of transition [6,20,24]. Despite this, the rates of FP among TGD individuals are much lower than the rates of desire for genetic parenthood. For example, in one study, 76.1% of adult transwomen and 76.6% of adult transmen had considered preserving gametes; however, only 9.6% and 3.1% (respectively) had actually done so before initiating gender-affirming hormones [23]. Similarly, among adolescents, two U.S. studies found that 8.7%e14.2% of trans girls and 0%e1.3% of trans boys had sought FP procedures [21,25], whereas a Canadian study showed 0% of 79 TGD adolescents had pursued FP [22]. Interestingly, a recent study showed that 38% of Dutch trans girls had cryopreserved sperm after counseling [26], indicating that FP rates vary enormously across clinical settings and raising the possibility that health care providers and systems may not be meeting patient needs. Effects of hormone therapy on fertility Gonadotropin-releasing hormone analogs. GnRHa are used following the onset of pubertal changes (i.e., from Tanner Stage 2 onward) to delay puberty and allow for time to consider potentially irreversible interventions [2,4]. From studies investigating their use in central precocious puberty, GnRHa are believed to

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Records iden fied from Medline (n = 178)

Records iden fied from Embase (n = 28)

Records iden fied from PsycINFO (n = 156)

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Addi onal records iden fied through PubMed/Google Scholar/reference list checking (n = 22)

Duplicate records excluded (n = 29)

Total records iden fied (n = 384)

Ar cles screened for relevance via tle + abstract (n = 355) Records excluded (n = 270) Full-text ar cles assessed for eligibility (n = 85)

Records excluded (n = 4) 2 not focussed on fer lity 2 not focussed on trans health

Studies included in review (n = 81)

Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram of study selection.

reversibly suspend pubertal development without long-term impairment of fertility [7,8]. However, most TGD youths do not cease GnRHa before commencing gender-affirming hormones, and no empirical data exist examining long-term fertility outcomes for this population [1e3,5,27,28]. Therefore, counseling regarding FP is recommended to be conducted before the initiation of GnRHa [1,2]. Testosterone. Testosterone can cause anovulation and amenorrhea in TGD individuals assigned female at birth [1]. Notably, however, testosterone is unable to suppress the menstrual cycle or act as a contraceptive in some people, and unplanned pregnancies have occurred while on testosterone [29]. Similar to GnRHa, testosterone's effect on fertility appears to be reversible: menstruation usually returns within 6 months of cessation [9], and a prospective cohort study demonstrated normal follicle development after discontinuation of testosterone therapy [30], echoing the demonstration of normal in vitro maturation of oocytes collected from the ovaries of transmen at the time of gender-affirming surgery [31]. Moreover, many successful cases of pregnancy in transgender men have been reported [1,5,9,32], although actual fecundity rates have not yet been characterized. Estrogen. Estrogen therapy variably impairs spermatogenesis [1,5,24]. In a study of 28 transwomen on estrogen treatment, some subjects experienced azoospermia after prolonged estrogen exposure, although others were able to produce specimens

suitable for intrauterine insemination [33]. Consistent with this, a review of 11 publications on the influence of estrogen therapy on testicular morphology noted that the impact of estrogen on the quantity of sperm and Leydig/Sertoli cell morphology was highly variable [12]. Similarly, studies on the effects of estrogen from estrogen-secreting tumors or therapeutically administered as treatment for prostatic disease have shown mixed results of azoospermia and varying degrees of testicular atrophy [10e17,34,35]. At present, it is still unclear to what extent loss of sperm production is dependent on estrogen dose or treatment duration. Moreover, it is unknown whether impairment of spermatogenesis is reversible should estrogen be stopped. Given these uncertainties, it is difficult to predict the long-term ramifications of estrogen therapy in transgender individuals, emphasizing the need for and potential challenges of fertility counseling. FP options Gamete cryopreservation. In postpubertal, cisgender individuals, gamete cryopreservation is the most established method of FP, but there are little data on its long-term usage and/or success in TGD adolescents. Oocyte cryopreservation involves stimulation of follicular development with 2 weeks of daily hormone injections, invasive monitoring via transvaginal ultrasounds, and transvaginal oocyte collection, all of which may increase gender dysphoria [36,37]. Similarly, although masturbatory semen

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samples are commonly used for gamete collection [11], this may not be feasible in TGD adolescents, given their dysphoria and/or physical maturity issues [5,38]. Vibratory or electrostimulation, percutaneous epididymal sperm aspiration, or testicular tissue biopsies represent possible alternatives to obtain and freeze sperm in such cases. Finally, likely gamete quality should also be taken into consideration before efforts to undertake cryopreservation. For example, oocytes during puberty appear suboptimal compared with that of early adulthood [39], raising the likelihood that fecundity would be enhanced if oocyte collection was delayed until after puberty. Previous studies have also shown poor semen parameters in transwomen and the subsequent need for more involved methods of assisted reproduction (e.g., intracytoplasmic sperm injection) [40], and this should also be borne in mind.

Cryopreservation of immature gonadal tissue Mature gametes do not usually develop until midpuberty [1]. If FP is desired before this time, immature germ cells can be collected via gonadal tissue biopsy and cryopreserved with the hope of using this tissue as a source of mature gametes in the future. Such biopsies are performed in pediatric hematology and oncology, although they are not widely accessible and remain in the research realm, given the uncertainties of future success. In one case, ovarian tissue from a 13-year-old, premenarchal girl was frozen before chemotherapy and reimplanted 12 years later, after which a spontaneously conceived healthy baby boy was born 2 years later [41]. However, it remains unclear whether cryopreserved ovarian tissue taken earlier in puberty or testicular tissue taken before the appearance of mature sperm will successfully provide a reservoir of mature gametes. With recent advances in stem cell technologies, hope exists that such tissue may someday be grown into mature gametes in vitro. Although there has been some success with this approach in mouse models, it has yet to be proven in humans [42]. Thus, the collection and freezing of immature gonadal tissue remain largely experimental, and patients considering such procedures must be counseled accordingly.

Experiences of FP There are many accounts of both adult and adolescent trans females undergoing FP, with most detailing negative experiences. For one third of TGD adults, the idea of storing or using sperm was incongruent with their gender identity and induced dysphoria [20,21], making it difficult to shake off a “male” past and gendered connotations of “fatherhood” [20,43]. For others, the collection process itself (e.g., masturbation) was distressing [5,20,21,26], although not for all [25]. In adult trans males, many experiences related to FPd including testosterone withdrawal and oocyte harvestdhave been described. Testosterone withdrawal may bring physiological and psychological challenges [44], including increased dysphoria (e.g., because of loss of muscle mass, fat redistribution, and return of menses), lack of energy, mood swings, and depression [32,44,45]. Meanwhile, the invasive nature of oocyte harvesting may exacerbate dysphoria and act as a barrier to FP [36,37,44,46].

Experiences of pregnancy Recently, in association with changes in public opinion and greater acceptance of more diverse family units, the number of trans males becoming pregnant and having children has increased. For example, in Australia, gender restrictions on pregnancy-related Medicare items were lifted in 2013, and in the ensuing 6 years, 214 males successfully claimed for management of labor via Medicare (Item #16519) [47]. Transmale experiences of pregnancy are highly relevant to the provision of fertility counseling, and clinicians should be cognizant of the many challenges that exist when providing fertility counseling to trans males. To begin, many trans males view pregnancy as incongruent with their gender identity [46,48], and among those who have become pregnant, some reported having done so as a functional sacrifice to attain biological children, especially in the context of having partners who were unable to do so [32]. For many, it was psychologically difficult, but they found different ways to cope, including reminding themselves of their goal to have biological children, obtaining support from family, and reconstructing their own narratives of what it means to be a parent [32,44,45,49]. Paradoxically, others found comfort in pregnancy, finally getting something positive out of a body with which they did not identify [32,43,50]. Unfortunately, there were also numerous reports of negative interactions with obstetric providers and clinics. The female-oriented approach in the obstetric field led to regular misgendering and a lack of suitable facilities, such as male bathrooms [29,32,50,51]. Even after pregnancy concluded, problems continued, with breast(chest)feeding a regular cause of further misgendering [50,52]. Unsurprisingly, transmen who pursued pregnancy faced an increased risk of loneliness and postpartum depression [29]. Other factors to consider when providing fertility counseling Ability to consider future fertility. Fertility counseling in TGD adolescents may occur from an early age, when limited foresight regarding future family planning is likely [1]. In particular, there is concern over the intellectual, emotional, and social maturity of TGD adolescents to allow prediction of future desires and comprehension of ramifications of decisions regarding transitioning and fertility [5,21,24,45,53], and it has been hypothesized that the low uptake of FP among TGD adolescents is because of fertility counseling taking place before it is developmentally appropriate for young people to adequately consider these issues [36,52]. Consistent with this, >25% of TGD adolescents aged between 14 and 17 years stated that they were unsure of their intentions regarding genetic parenthood [54], and 48% of TGD adolescents in another study thought that their desires regarding parenthood might change over time [55]. Moreover, because many TGD adolescents are highly focused on commencing their medical transition, questions have been raised whether, for some TGD youths, it might be only after medically transitioning that they will feel mentally and emotionally equipped to explore relationships and consider having children in the future [21,25,45]. After all, it has been recognized that mental health issues negatively impact longterm decision-making abilities, thus setting up a potential catch-22 situation wherein parenting desires are only realized after gender dysphoria has improved with hormone therapyd but after fertility has been impaired [27,56].

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Parental pressure. Given the above, most clinical discussions around fertility are unsurprisingly raised not by TGD adolescents but rather their parents [57]. However, parents may struggle to weigh up their child's reproductive options with their priorities to medically transition [52,58]. Moreover, parental values may differ from their adolescents anddas legal guardiansdparents can exert significant decision-making influence over FP choices [59]. For example, in one study, 20% of parents reported that they would be disappointed if their child could not have their own biological offspring, and consistent with this, 25% of TGD adolescents felt pressured to have children by their family [55]. These pressures to be a genetic parentdwhether real or perceiveddare likely to exacerbate gender dysphoria and alienate TGD youths, who might simply react by dismissing the option of parenthood altogether [21,32]. Role of the clinician. Clinicians' own views may influence the nature of their counseling [60]. For instance, some TGD adults have expressed discomfort with clinicians encouraging FP, raising concerns they were pushed into FP [61]. Conversely, some TGD people have felt implicitly discouraged from pursuing FP through a lack of information regarding FP options [61]. Rather than being encouraging or discouraging, TGD people prefer that clinicians act as knowledgeable providers of information [61]. Nevertheless, it is possible that even a neutral discussion of FP by cliniciansdhowever essential, considering the alternative risk of future infertility and regretdmight potentially add to the pressure to be a genetic parent and create more distress. Clinicians perceive multiple barriers to the provision of adequate fertility counseling, including a lack of specific clinical knowledge, embarrassment, as well as insufficient training in discussing fertility with trans patients [57,62]. For example, some clinicians identified a lack of detailed information comparing and contrasting different FP options for different populations at different developmental stages as a significant obstacle to providing counseling [27]. In addition, uncertainties around the effects of gender-related hormone therapy on fertility may contribute to variation in provider practices. For instance, although testosterone therapy is not an adequate contraceptive [29], 5.5% of adult trans males reported that their practitioner had advised them that testosterone was a suitable contraceptive [63]. Such inaccurate beliefs are concerning not only because unplanned pregnancies have occurred while on testosterone but also because exposure to testosterone may have teratogenic effects [1,29,64]. Equal rights to genetic parenthood. Historically, concerns were raised about TGD peoples' abilities to parent [20,65], and TGD parents were denied access to their children by family courts following custody disputes in an attempt to “protect” children from their trans parent [66]. However, studies have shown no evidence of ill effect on childhood development and positive outcomes [67,68]. For example, in a study following 52 children of TGD fathers from 2000 to 2015, all had normal development without significant psychological morbidity or changes to gender identity [69]. Moreover, having children may be a protective factor for trans adults, positively contributing to mental health and quality of life in trans parents [6,70]. Thus, in accord with the ethical principles of equality and nondiscriminationdwhich posit that individuals should not be treated differently based on characteristics, such as sexual orientation or gender identityd transgender adolescents should have equal access to FP measures and genetic parenthood [71].

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Delay of transition TGD youths frequently perceive an urgency to commence hormonal therapy to alleviate gender dysphoria. Some are likely to see fertility counseling and FP as an unnecessary obstacle or delay to transition [20,24,25], especially if pubertal progression in an early TGD adolescent is permitted to allow for gamete development for FP. Such pubertal progression would likely cause further gender dysphoria, which must be weighed against the potential benefits of FP. For example, a TGD adolescent in one study expressed sadness that they had not pursued FP, but ultimately reasoned that medical transition was more important for their mental health [46], and >90% of 111 TGD adults surveyed elsewhere agreed that loss of fertility was not important enough to delay transitioning [20]. Moreover, another study of TGD adults reported that some participants voiced concerns that simply expressing their desire for FP might not only delay but even potentially prevent their access to gender-affirming hormones [61]. Finally, in a study of 15 transmen who actually underwent FP, the resultant delays in medical transition were described as frustrating, with patients feeling like they had put their lives on hold to access FP [44].

Sexual orientation and different routes to parenthood Future partners must be considered when providing fertility counseling to trans adolescents [67]. Although some adolescents may not yet be certain of their sexual orientation, pragmatically, a TGD individual assigned male at birth who envisages having a partner with testes may be less likely to cryopreserve sperm or testicular tissue. Previous studies confirm this theory, with the majority of adult trans females who froze sperm either lesbian or bisexual rather than heterosexual or asexual [20,24]. Sexual orientation will also have practical implications for how cryopreserved gametes can be used in the future. For instance, the use of cryopreserved oocytes from a TGD individual assigned female at birth will require not only a recipient uterus but also sperm, and their future partner's biological sex will determine to what extent they can be involved in the conception/pregnancy and whether a donor and/or surrogate may need to be involved [49,72]. Similarly, the use of cryopreserved sperm may require a donor egg and/or surrogate if the TGD individual's partner is biologically male [46]. Although approximately half of TGD adults want to have children, not all will want genetic offspring and may seek other routes to parenthood, including fostering, adoption, or donor gametes [38,73]. Indeed, previous studies have found that TGD adolescents and adults may prefer adoption or fostering to having a genetic child [46,54,73]. Consistent with this, in a recent study of 72 TGD youths who had received fertility counseling, only two opted for FP, 45% of participants indicated a desire to adopt [21], whereas another study of TGD adolescents reported that 70.5% were interested in adoption [54]. This is consistent with adult-based studies, where adoption was also regarded as a popular option, acceptable to 64.1% of transmen and 46.6% of transwomen [23]. However, it should be noted that there has been no research into the actual experiences and uptake of adoption among prospective TGD parents, and it is quite possible that the realities of the adoption process do not match the hopes and expectations of TGD adolescents [27,56].

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Barriers to accessing FP Although a recent public survey of U.S. citizens showed the majority support transgender parenting, TGD individuals encounter significant stigma and lack of knowledge when trying to access FP services [53]. Although some have reported positive experiences [51], others have faced discrimination on the basis of cis- and hetero-normative assumptions, with some even being refused access because of being transgender [32,44] and others opting to perform insemination with a known sperm donor at home [32]. In addition, the aforementioned lack of clinician training in fertility for TGD adolescents acts as a further barrier to access. Cost is also a significant factor, especially because FP for TGD adolescents is rarely covered by insurance [49]. For example, in some Australian and U.S. centers, sperm cryopreservation costs several hundred dollars for the initial collection and then several hundred dollars per annum for ongoing storage, whereas oocyte cryopreservationdat between USD 5000e10,000dis even more expensive [60,61]. Not surprisingly, cost barriers have been identified as one of the major factors by some TGD people choosing not to access FP [23,46,54,60,74] and are especially problematic, given that many TGD people already face significant financial burdens associated with medical and surgical transition [24,75]. Discussing costs is, therefore, a practical consideration during fertility counseling. Discussion To provide optimal fertility counseling to TGD adolescents, clinicians from varied backgroundsdfrom pediatrics, psychology, psychiatry, endocrinology, gynecology, and andrologydall need not only be knowledgeable about the effects of genderrelated treatments on fertility and relevant FP options but also maintain a neutral stance and navigate the many complexities and uncertainties in the field. For example, to address possible parental pressure on TGD adolescents to pursue FP, clinicians should first solicit an open understanding of both parental and patient views and then to try to reach a consensus based on each party's values and desires. Moreover, to help clinicians working in this complex space, the development of fertility counseling guidelines for TGD adolescents will be highly beneficial and accords with the desire of clinicians for decision aids in this area [76]. Given that knowledge among FP providers was lowest regarding transgender patients when compared with lesbian, gay, bisexual, queer, and intersex groups [77], such guidelines would help to increase clinician knowledge, standardize practices, and improve access to FP. In the oncofertility field, gaps in provider knowledge and inconsistent offering of FP have been associated with low rates of FP, whereas standardization of counseling has led to improvements in this regard [27], and we would expect the same to be true for TGD adolescents. Of course, clinical guidelines will not by themselves lead to an improvement in practice; it will be important to provide ancillary education and professional development programs to increase knowledgeability and professionalism, two attributes highly valued by TGD individuals who have experienced fertility services [51,61]. For clinicians, opportunities to positively impact the future reproductive outcomes of TGD adolescents extend beyond their individual patients. Specifically, clinicians are increasingly called on to act as advocates to reduce social inequities [78], and we

believe that clinicians have an important role to play in advocating for systemic changes that provide equitable, genderaffirming care for TGD individuals across the reproductive health spectrum. For example, addressing the many barriers to FP that have already been described (e.g., lack of clinician knowledge and training, stigma, discrimination, and cost) will be critical and could involve changes to medical school and specialty training curricula, improved diversity training for staff, and advocacy efforts with medical insurers to enable FP measures to be covered by insurance. Many of these same barriers also exist when TGD individuals try to access assisted reproductive services and obstetric care, and clinicians can play an important role in promoting change across these settings as well. Finally, as noted earlier, many TGD people may seek nongenetic routes to parenthood, including fostering, adoption, or donor gametes [38,73]. At this stage, however, it is unclear to what extent TGD individuals are able to access such services. Nevertheless, it seems likely that they would face similar barriers to those encountered in other contexts, and clinicians could again play a leading role in advocating for the removal of such barriers via the relevant social and reproductive services. As well as clinical guidelines, improved education/training, and advocacy efforts, further research is required to address the many knowledge gaps that exist in this field and act as an impediment to fertility counseling [27]. In compiling this review, notable limitations within the existing literature were that few studies were prospective, and most were based on relatively small adult samples. Drawing definitive conclusions regarding TGD adolescents was, therefore, problematic, highlighting the importance of prospective research with this population, including how their fertility desires and potential regrets change over time, as well as their subsequent experiences and uptake of using not only their cryopreserved gametes but also alternative means to parenthood (e.g., surrogacy/third-party assisted reproduction, adoption, and fostering). Moreover, there are outstanding questions concerning the effects of hormones on fertility. For instance, does proceeding directly to genderaffirming hormone therapy without respite from puberty blockers increase the likelihood of infertility [27]? How much estrogen does it take to cause infertility in TGD individuals assigned male at birth [12] and is this effect reversible? And how long should testosterone be ceased before pregnancy and when can it be recommenced [29]? Addressing these various questions should, therefore, be an important focus for future research. Summary Gender-related hormonal therapies may have detrimental effects on fertility. Thus, fertility counseling for TGD adolescents before the commencement of such hormones is essential. However, fertility counseling in this context is highly complex and challenging for a variety of reasons. First, many TGD adolescents are not in a strong position to consider their future fertility needs, given their age and developmental stage as well as their general desire not to delay medical transition for FP. Second, both parents and clinicians have an influential role in the counseling discussions to which they may bring their own agendas and biases. Third, there are many unanswered questions that directly impact the clinician's ability to provide counseling, including those related to the impact of gender-related hormone therapies on fertility, future desire of TGD adolescents to be genetic parents, and likely utilization rates of cryopreserved

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gametes. Fourth, sexual orientation, preferred routes to parenthood (e.g., adoption) as well as experiences of FP and pregnancy may all be different in TGD adolescents compared with their cisgender peers and must each be taken into consideration during fertility counseling. Last but not least, barriers to optimal fertility care exist not only because of a lack of detailed clinical guidelines and clinician knowledge but also as a result of cost and other systemic problems (including discrimination) associated with the provision of health care, and efforts to remove these barriers will be important heading forward. Acknowledgments K.C.P. was supported by the Royal Children's Hospital Foundation. References [1] Telfer MM, Tollit MA, Pace CC, et al. Australian standards of care and treatment guidelines for transgender and gender diverse children and adolescents. Med J Aust 2018;209:132e6. [2] Coleman E, Bockting W, Botzer M, et al. Standards of care for the health of transsexual, transgender, and gender-nonconforming people, version 7. Int J Transgenderism 2012;13:165e232. [3] Hembree WC, Cohen-Kettenis PT, Gooren L, et al. Endocrine treatment of gender-dysphoric/gender-incongruent persons: An endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2017;102:3869e903. [4] Knudson G, De Sutter P. Fertility options in transgender and gender diverse adolescents. Acta Obstet Gynecol Scand 2017;96:1269e72. [5] Johnson EK, Finlayson C. Preservation of fertility potential for gender and sex diverse individuals. Transgend Health 2016;1:41e4. [6] Wierckx K, Van Caenegem E, Pennings G, et al. Reproductive wish in transsexual men. Hum Reprod 2012;27:483e7. [7] Bangalore Krishna K, Fuqua JS, Rogol AD, et al. Use of gonadotropinreleasing hormone analogs in children: Update by an international consortium. Horm Res Paediatr 2019;91:357e72. [8] Carel JC, Eugster EA, Rogol A, et al. Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics 2009;123: E752e62. [9] Light AD, Obedin-Maliver J, Sevelius JM, et al. Transgender men who experienced pregnancy after female-to-male gender transitioning. Obstet Gynecol 2014;124:1120e7. [10] Lu CC, Steinberger A. Effects of estrogen on human seminiferous tubules: Light and electron microscopic analysis. Am J Anat 1978;153:1e13. [11] Nahata L, Chen D, Moravek MB, et al. Understudied and under-reported: Fertility issues in transgender youthdA narrative review. J Pediatr 2019; 205:265e71. [12] Schneider F, Kliesch S, Schlatt S, et al. Andrology of male-to-female transsexuals: Influence of cross-sex hormone therapy on testicular function. Andrology 2017;5:873e80. [13] Venizelos ID, Paradinas FJ. Testicular atrophy after oestrogen therapy. Histopathology 1988;12:451e4. [14] Leavy M, Trottmann M, Liedl B, et al. Effects of elevated beta-estradiol Levels on the functional morphology of the testis - new insights. Sci Rep 2017;7:39931. [15] Lübbert H, Leo-Roßberg I, Hammerstein J. Effects of ethinyl estradiol on semen quality and various hormonal parameters in a eugonadal male. Fertil Sterility 1992;58:603e8. [16] Schneider F, Neuhaus N, Wistuba J, et al. Testicular functions and clinical characterization of patients with gender dysphoria (GD) undergoing sex reassignment surgery (SRS). J Sex Med 2015;12:2190e200. [17] Schulze C. Response of the human testis to long-term estrogen treatment: Morphology of Sertoli cells, Leydig cells and spermatogonial stem cells. Cell And Tissue Res 1988;251:31e43. [18] Armuand GM, Wettergren L, Rodriguez-Wallberg KA, et al. Desire for children, difficulties achieving a pregnancy, and infertility distress 3 to 7 years after cancer diagnosis. Support Care Cancer 2014;22:2805e12. [19] Valentine SE, Shipherd JC. A systematic review of social stress and mental health among transgender and gender non-conforming people in the United States. Clin Psychol Rev 2018;66:24e38. [20] De Sutter P, Verschoor A, Hotimsky A, et al. The desire to have children and the preservation of fertility in transsexual women: A survey. Int J Transgenderism 2002;6. [21] Nahata L, Tishelman AC, Caltabellotta NM, et al. Low fertility preservation utilization among transgender youth. J Adolesc Health 2017;61:40e4.

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