ArticleLiterature Review

Impact of Exogenous Testosterone on Reproduction in Transgender Men

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Abstract

Studies show that a subset of transgender men desire children; however, there is a paucity of literature on the effect of gender-affirming testosterone therapy on reproductive function. In this manuscript, we will review the process of gender-affirming hormone therapy for transgender men and what is known about ovarian and uterine consequences of testosterone exposure in transgender men; draw parallels with existing animal models of androgen exposure; summarize the existing literature on parenting experiences and desires in transgender people; discuss considerations for assisted reproductive technologies and fertility preservation; and identify gaps in the literature and opportunities for further research.

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... This limitation is not trivial since comprehensive knowledge of the effects of androgens on ovarian function in normal women is very limited. The closest experimental evidence, appropriately focused on the androgens effect in non-pathological ovaries, have been transgender male (TGM) studies which were unfortunately characterized by limited power and lack conclusive results [41][42][43]. ...
... Collectively, these data suggest an androgen-induced defect in normal folliculogenesis and fertility. Ovarian morphological features similar to those demonstrated in our TC17 model have been described in prior studies of Testosterone Replacement Therapy (TRT)-treated transgender men [43,[64][65][66][67][68]. Indeed, the TC17 mouse model appeared to resemble specifically several of these features: morphological ovarian assessment in denoted partially impaired folliculogenesis with a significant decrease of antral follicles. ...
... To date, only one animal model has been proposed to investigate the impact of testosterone therapy on reproduction in transgender men. This model, by Kinnear et al. utilized subcutaneous administration of testosterone enanthate and mirrored several reproductive perturbations observed in transgender men on T therapy [43,72]. Interestingly, they showed that T therapy-induced interruption of estrous cyclicity is reversible [72]. ...
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Background In the ovarian follicle, the Theca Cells (TCs) have two main functions: preserving morphological integrity and, importantly, secreting steroid androgen hormones. TCs express the essential enzyme 17α-hydroxylase/17,20-desmolase (CYP17), which permits the conversion of pregnenolone and progesterone into androgens. Dysregulation of CYP17 enzyme activity due to an intrinsic ovarian defect is hypothesized to be a cause of hyperandrogenism in women. Androgen excess is observed in women with polycystic ovary syndrome (PCOS) resulting from excess endogenous androgen production, and in transgender males undergoing exogenous testosterone therapy after female sex assignment at birth. However, the molecular and morphological effects of Cyp17 overexpression and androgen excess on folliculogenesis is unknown. Methods In this work, seeking a comprehensive profiling of the local outcomes of the androgen excess in the ovary, we generated a transgenic mouse model (TC17) with doxycycline (Dox)-induced Cyp17 overexpression in a local and temporal manner. TC17 mice were obtained by a combination of the Tet-dependent expression system and the Cre/LoxP gene control system. Results Ovaries of Dox-treated TC17 mice overexpressed Cyp17 specifically in TCs, inducing high testosterone levels. Surprisingly, TC17 ovarian morphology resembled the human ovarian features of testosterone-treated transgender men (partially impaired folliculogenesis, hypertrophic or luteinized stromal cells, atretic follicles, and collapsed clusters). We additionally assessed TC17 fertility denoting a perturbation of the normal reproductive functions (e.g., low pregnancy rate and numbers of pups per litter). Finally, RNAseq analysis permitted us to identify dysregulated genes ( Lhcgr , Fshr , Runx1 ) and pathways (Extra Cellular Matrix and Steroid Synthesis). Conclusions Our novel mouse model is a versatile tool to provide innovative insights into study the effects of Cyp17 overexpression and hyperandrogenism in the ovary.
... Physicians have limited data to draw from when counseling patients about fertility after starting T therapy. Studies to date regarding gender-affirming T therapy and reproduction may leave us with "more questions than answers" (4). As such, counseling about fertility preservation is currently recommended prior to starting gender-affirming T therapy (2,5,6). ...
... As such, counseling about fertility preservation is currently recommended prior to starting gender-affirming T therapy (2,5,6). T therapy has been shown to typically lead to the cessation of menses and the induction of ovarian characteristics of polycystic ovary morphology including collagenization of the tunica albuginea, stromal hyperplasia, and luteinization of stroma cells (4). Studies suggest that many transgender men do not preserve their gametes before beginning T therapy, potentially due to the expensive, invasive, and time-consuming nature of ovarian fertility preservation methods (7,8); however, some of these individuals may later be interested in using their gametes for reproduction. ...
... For individuals interested in fertility after beginning T therapy, there has been minimal research regarding the reversibility of menstrual suppression and possible anovulation if T therapy is paused for reproductive purposes. There are anecdotal reports of clinics pausing T therapy for 1 to 6 months prior to ovarian stimulation for oocyte harvesting, although others have not paused T therapy at all (4). Given the health risks to the fetus posed by in utero T exposure, pausing T therapy is essential before attempting to carry a pregnancy (9). ...
Article
Objective CTo establish if cessation of testosterone (T) therapy reverses T-induced acyclicity in a transgender mouse model that allows for well-defined T cessation timing. Design Experimental laboratory study using a mouse model. Setting University-based basic science research laboratory. Animals A total of 10 C57BL/6NHsd female mice were used for this study. Intervention(s) Postpubertal C57BL/6NHsd female mice received subcutaneously implanted T enanthate (n = 5 mice) or control (n = 5 mice) pellets. Pellets were surgically removed after 6 weeks to ensure T cessation, after which mice were followed 4 cycles after resumption of cyclicity. Main Outcome Measure(s) Primary outcomes included daily vaginal cytology and weekly T levels before, during, and after T enanthate or placebo pellet implantation and removal. Additional secondary outcomes included ovarian follicle distribution and corpora lutea numbers, body metrics, and terminal diestrus hormone levels. Result(s) T-treated mice (100%) resumed cycling within one week of T pellet removal after 6 weeks of T therapy. T levels were significantly elevated during T therapy (p<0.0001) and fell to control levels with surgical pellet removal. There were no detectable differences 4 cycles later in follicle counts, corpora lutea formation, diestrus hormone levels, or body metrics with the exception of persistent increased clitoral area (p<0.0001) between T-treated mice and controls. One T-treated mouse was sacrificed early due to vaginal prolapse and not included in subsequent analyses. Conclusion(s) Our results demonstrate a close temporal relationship between estrous cycle return and T levels dropping to control levels following T pellet removal. The return of regular cyclic ovulatory function is also supported by the formation of corpora lutea and the lack of detectable differences in key reproductive parameters as compared to controls four cycles after T cessation. These results may be relevant to understanding the reversibility of T-induced amenorrhea and possible anovulation in transgender men interested in pausing T to pursue pregnancy or oocyte donation. Results may be limited by duration of T treatment, lack of functional testing, and physiological differences between mice and humans.
... Although successful pregnancies and live births have been reported in transgender men [69,70], the long-term effects of exogenous testosterone on reproductive function remain unknown [1]. Histologic studies of testosterone-exposed ovaries and uteri following gender-affirming surgery have yielded conflicting results [71]. Studies have also conflicted in regard to the impact of testosterone therapy on serum anti-Müllerian hormone (AMH) levels in transgender men, with two studies showing no change in AMH levels and one showing decreased levels [71,72]. ...
... Histologic studies of testosterone-exposed ovaries and uteri following gender-affirming surgery have yielded conflicting results [71]. Studies have also conflicted in regard to the impact of testosterone therapy on serum anti-Müllerian hormone (AMH) levels in transgender men, with two studies showing no change in AMH levels and one showing decreased levels [71,72]. Furthermore, there are no studies to date investigating the health of offspring born from testosterone-exposed oocytes [71]. ...
... Studies have also conflicted in regard to the impact of testosterone therapy on serum anti-Müllerian hormone (AMH) levels in transgender men, with two studies showing no change in AMH levels and one showing decreased levels [71,72]. Furthermore, there are no studies to date investigating the health of offspring born from testosterone-exposed oocytes [71]. Fertility preservation options for transgender men include oocyte and/or embryo cryopreservation, and ovarian tissue cryopreservation [73]. ...
Article
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Purpose of Review The purpose of this review is to provide an up-to-date overview of gender-affirming hormone therapy, including the various hormone regimens available, the efficacy and potential risks of these treatments, and considerations for surveillance and long-term care. Recent Findings Recent studies reaffirm that hormone therapy has positive physical and psychological effects for many transgender individuals. The overall risks of treatment are low. Transgender women may have an increased risk of venous thromboembolism and breast cancer based on recent cohort studies, but these findings have yet to be confirmed with randomized controlled trials. Important long-term considerations include metabolic, cardiovascular, and skeletal health. Summary High-quality, long-term studies on the effectiveness and safety of various gender-affirming hormone treatment regimens are lacking, but the currently available evidence suggests that it is overall safe and effective with appropriate oversight.
... Fertility preservation (FP) is the practice of taking definitive steps to improve the chances of biological reproduction in those who are predicted to have significant infertility (8). The World Professional Association for Transgender Health (WPATH), Endocrine Society, and American Society of Reproduction (ASRM) all recommend counseling transgender individuals on fertility options prior to any medical or surgical treatments (9), though there are few data implicating the adverse impact of gender-affirming medical therapy on fertility outcomes (10). ...
... Animal models investigating ovarian histology following androgen exposure have mainly been studied in the context of polycystic ovary syndrome (PCOS) (23,24). Primate, sheep, and murine PCOS models have documented changes in ovarian histopathology and function; however, most of these studies have involved prenatal and prepubertal androgen exposure (10,23). A recent publication evaluated ovarian follicular morphology and corpora lutea counts with varying doses of postpubertal T subcutaneous injections in 20 female mice (25••). ...
... Hence, there have been anectodical reports, within our own institution as well as others, of transmen choosing to continue T at the time of COS. However, no formal literature has been published to date regarding fertility outcomes in this subpopulation (10). ...
Article
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Purpose of Review This review aims to update readers on recent evidence in order to counsel and guide clinical management of individuals with gender dysphoria seeking fertility preservation (FP). Recent Findings Relevant topics include a discussion of the consistent desire for children in transgender people despite a low utilization rate of FP services, animal models, and human histology depicting the effect of gender-affirming treatment (GAT) on the gonads, varied time for resumption of menses, and start of ovarian stimulation upon discontinuing testosterone (T) in transmen, feasible clinical and experimental options for FP in transgender males and females, worsening dysphoria, and recommended methods to mitigate symptoms, and lastly a short discussion of changes in legislation providing increased insurance coverage of medically indicated FP for transpatients. Summary FP is an important option for transgender patients who desire to retain the ability to become genetic parents. While controlled ovarian stimulation for oocyte or embryo cryopreservation is the standard-of-care for transmen, unique considerations must be made in this population. Recent literature has highlighted the ability of transmen to have viable oocytes and pregnancies despite a history of T use, suggesting that the window of genetic parentage does not close with the start of GAT. FP for transwomen requires ejaculation or extraction with sperm cryopreservation; options for prepubertal transwomen are only in nascent phases. Research is rapidly evolving though many questions remain unanswered. The harmonization of advances in assisted reproduction with legislation advocating for transgender rights will continue to reach new peaks in the coming years.
... Physicians have limited data to draw from while counseling patients about fertility after starting T therapy. Studies conducted to date regarding gender-affirming T therapy and reproduction may leave ''more questions than answers'' (4). As such, counseling about fertility preservation is currently recommended before starting gender-affirming T therapy (2,5,6). ...
... As such, counseling about fertility preservation is currently recommended before starting gender-affirming T therapy (2,5,6). T therapy typically leads to cessation of menses and the induction of ovarian characteristics of polycystic ovary morphology including collagenization of the tunica albuginea, stromal hyperplasia, and luteinization of stromal cells (4). Previous studies have suggested that many transgender men do not preserve their gametes before starting T therapy, potentially because of the expensive, invasive, and timeconsuming nature of ovarian fertility preservation methods (7,8); however, some of these individuals may later be interested in using their gametes for reproduction. ...
... For individuals interested in fertility after beginning T therapy, only a limited amount of research has been conducted regarding the reversibility of menstrual suppression and possible anovulation if T therapy is paused for reproductive purposes. There are anecdotal reports of clinics pausing T therapy for 1 to 6 months before ovarian stimulation for oocyte harvesting, although others have not paused T therapy at all (4). Given the health risks to the fetus posed by in utero T exposure, pausing T therapy is essential before attempting to carry a pregnancy (9). ...
... Gender-affirming hormonal therapy (GAHT) most often comprises oestrogen combined with peripheral androgen receptor blockade for transgender women and testosterone for transgender men. GAHT has negative effects on fertility and the knowledge about reversal of these effects after treatment cessation is still limited (De Roo et al., 2016;Adeleye et al., 2019;Moravek, 2019;Moravek et al., 2020). A high occurrence of sperm abnormalities was found, especially after previous GAHT, in a recent large prospective study on sperm quality in transgender women (Rodriguez-Wallberg et al., 2021). ...
Article
STUDY QUESTION In a transgender population referred for fertility consultation, which factors influence the decision to cryopreserve oocytes and sperm? SUMMARY ANSWER Previous hormonal treatment, gender affirmation surgery and sexual orientation were associated with the decision to undergo fertility preservation and transgender women underwent fertility preservation more frequently than transgender men. WHAT IS KNOWN ALREADY It is well known internationally that fertility preservation and fertility treatment are increasingly requested by transgender men and women. Factors affecting their decisions as well as treatment differences between transgender women and transgender men have been reported, but many studies have had low participation rates and small sample sizes. STUDY DESIGN, SIZE, DURATION This retrospective cohort study, conducted during 2013-2018, included 78 transgender women (assigned male at birth and referred for sperm cryopreservation) and 164 transgender men (assigned female at birth referred for oocyte cryopreservation). PARTICIPANTS/MATERIALS, SETTING, METHODS In 2013, the previous requirement for sterilization before completion of a legal gender change was removed in Sweden. All fertile-aged transgender men and transgender women referred to a tertiary care centre for consultation concerning fertility preservation, fertility treatment or hysterectomy were identified from administrative systems. Demographic, medical and treatment data were extracted from electronic medical records and from an ART database. Logistic regression was applied to analyse factors affecting the decision to cryopreserve gametes among transgender men and transgender women. MAIN RESULTS AND THE ROLE OF CHANCE A majority of transgender men (69.5%) and transgender women (82%), wanted to become parents. Fertility preservation was less frequent in transgender men than in transgender women (26.2% versus 75.6%, respectively). No individuals among those primarily referred for hysterectomy opted for cryopreservation of oocytes. Among transgender men, young age, no previous hormonal treatment and stating homosexual orientation were independent factors associated with the decision to cryopreserve oocytes. Among transgender women, the decision to undergo gender affirmation surgery and stating heterosexual orientation were independent factors associated with a decision to refrain from fertility preservation. Fertility treatments, using IUI or IVF with donor sperm, were mainly performed in partners of transgender men. Ten live births were reported in the group of transgender men and two for transgender women. LIMITATIONS, REASONS FOR CAUTION The main limitation is the retrospective nature of the study, with missing data for many variables. The short study period and the study population being too young to permit observation of long-term outcomes of fertility preservation and fertility treatments are reasons for caution. WIDER IMPLICATIONS OF THE FINDINGS Our results confirm that fertility preservation has been requested by transgender people since the change in Swedish legislation in 2013. Information about aspects of fertility early in the transition process is important, since hormonal and surgical treatments may have a large impact on the decision to undergo fertility preservation. It is important to train fertility clinic staff to identify and handle the specific obstacles, as well as address the need for information and support that transgender people may have when planning for fertility preservation, fertility treatment and pregnancy. STUDY FUNDING/COMPETING INTEREST(S) This research was supported by a grant from the Swedish state, under the ALF agreement between the Swedish government and the county councils (ALFGBG-720291), and by Hjalmar Svensson’s Research Foundation. None of the authors has any conflict of interest to declare. TRIAL REGISTRATION NO N/A
... For example, some TGNB assigned female at birth have partners with sperm and others do not, some engaged in penis-in-vagina sex and some do not, this will of course shape family building options and risks for unintended pregnancies [33,34]. Increasingly there is evidence regarding the successful use of assisted reproductive technologies in supporting family building among TGNB people [35][36][37][38]. ...
Article
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Purpose of review: The visibility of the lesbian, gay, bisexual, transgender, and queer (LGBTQ+) communities, specifically the transgender and nonbinary (TGNB) communities, continues to grow. However, there is little description, much less guidance toward optimizing, the pregnancy-related care of TGNB people. The overarching goal of this paper is to provide guidance that aids in reimagining obstetrics to include people of all genders. Recent findings: This article will review current literature and provide recommendations specific to the hospital birthing environment to help address the lack of knowledge regarding pregnancy-related care of TGNB individuals. This care is further divided into three main times: (1) preconception, antepartum care, and triage, (2) intrapartum, and (3) postpartum. We also discuss considerations for the general medical care of TGNB individuals. Summary: Understanding facilitators and barriers to gender affirming pregnancy-related care of TGNB individuals are first steps toward providing a respectful, affirming, and evidence-based environment for all patients, especially TGNB individuals. Here we provide context, discussion, and resources for providers and TGNB patients navigating pregnancy-related care. Lastly, this review challenges researchers and clinicians with future directions for the care of TGNB individuals in this continually expanding field.
... For testosterone, treatment is expected to impair fertility, but this appears to be reversible and occurs to varying degrees in a given individual. 4 For oestrogen, treatment is likely to impair spermatogenesis, but it is unclear to what extent this impairment is influenced by oestrogen dose and duration, or whether the impairment is reversible should oestrogen be stopped. 2 This suggests that consideration for storage of gametes or reproductive tissue is perhaps more important for those with testes rather than ovaries. ...
... To date, the effects of androgen therapy on the ovary are not fully known. Although some literature data reports that androgen exposure in transmen did not produce damage to oocytes in the tissue [64], other studies described ovarian effects of testosterone exposure in gender dysphoria subjects [65]. For these reasons, the distribution and morphological features of follicles in the CTRL ovarian cortex (AMH values) were compared with those observed in patients with same age which underwent ovarian tissue cryopreservation at our Centre and no differences were found between groups. ...
Article
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Diagnostic imaging has significantly grown over the last thirty years as indispensable support for diagnostic, prognostic, therapeutic and monitoring procedures of human diseases. This study explored the effects of low-dose X-ray medical diagnostics exposure on female fertility. To aim this, cumulus-oocyte complexes (COCs) recovered from the ovaries of juvenile sheep and human ovaries were used as complementary models for in vitro studies. In the sheep model, the effects of low-dose X-rays on oocyte viability and developmental competence were evaluated. In human ovaries originated from two age group (21–25 and 33–36 years old) subjects with gender dysphoria, X-rays effects on tissue morphology, follicular density and expression of apoptosis-related (NOXA, PUMA, Bcl2, Bak, γH2AX) and cell cycle-related genes (p21 and ki67) were investigated. It was noted that in sheep, the minimum dose of 10 mGy did not influence most of examined parameters at oocyte and embryo levels, whereas 50 and 100 mGy X-ray exposure reduced oocyte bioenergetic/oxidative activity but without any visible effects on oocyte and embryo development. In addition, blastocyst bioenergetic/oxidative status was reduced with all used doses. Overall data on human ovaries showed that low-dose X-rays, similarly as in sheep, did not alter any of examined parameters. However, in women belonging to the 33–36 year group, significantly reduced follicular density was observed after exposure to 50 and 100 mGy, and increased NOXA and Bax expression after exposure at 50 mGy. In conclusion, used low-doses of X-ray exposure, which resemble doses used in medical diagnostics, produce weak damaging effects on female fertility with increased susceptibility in advanced age.
... Clinical examples of this effect include polycystic ovarian syndrome (PCOS) and congenital adrenal hyperplasia patients (4). On the other hand, although initial studies using histomorphologic criteria suggested that exposure to exogenous testosterone treatment in female-to-male transexual patients induced polycystic ovary morphology (5,6), more recent studies using both histologic and ultrasound criteria have not confirmed these findings (7)(8)(9). ...
Article
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The management of patients with diminished ovarian reserve (DOR) remains one of the most challenging tasks in IVF clinical practice. Despite the promising results obtained from animal studies regarding the importance of androgens on folliculogenesis, the evidence obtained from clinical studies remains inconclusive. This is mainly due to the lack of an evidence-based methodology applied in the available trials and to the heterogeneity in the inclusion criteria and IVF treatment protocols. In this review, we analyze the available evidence obtained from animal studies and highlight the pitfalls from the clinical studies that prevent us from closing the chapter of this line of research.
Article
Adolescence is a period of flux for many body systems. While fertility potential typically increases after menarche, there are diseases where the opposite occurs and fertility preservation options need to be considered early. In cases of cancer, options vary by pubertal status and can include ovarian tissue cryopreservation, oocyte cryopreservation, sperm cryopreservation, and testicular tissue cryopreservation. Much remains to be learned about fertility and preservation options in those with differences in sexual development (DSDs); however, depending on the form of DSD, fertility preservation may not be necessary. Similarly, traditional fertility counseling in children with galactosemia may need to be changed, as data suggest that fertility rates attributed to other causes of premature ovarian insufficiency may not be as applicable to this disease. Adolescents with Turner's syndrome are at high risk for premature ovarian failure; therefore, it is important to consider options as early as possible since ovarian reserves are depleted quickly. On the other hand, transgender and gender diverse adolescents may even be able to undergo fertility preservation after starting hormone therapy. In all cases, there are additional ethical components including technical/surgical risks in childhood, offering experimental therapies without creating false hope and evaluating children's consent and assent capabilities that must be considered.
Article
STUDY QUESTION Is the functional ovarian reserve in transgender men affected by testosterone therapy? SUMMARY ANSWER Serum anti-Müllerian Hormone (AMH) levels slightly decrease during testosterone treatment but remain within the normal range, suggesting preserved follicular ovarian reserve. WHAT IS KNOWN ALREADY Few small studies have investigated the impact of gender-affirming treatment on reproduction in transgender men. Conflicting results were reached concerning ovarian morphology and AMH levels in this context. STUDY DESIGN, SIZE, DURATION The study consisted of two arms. The first arm was a prospective pilot study, which enrolled 56 transgender men (median age 22.5 [interquartile range (IQR)—19–27.7] years), 27 of whom had polycystic ovary syndrome (PCOS), prior to the initiation of gender-affirming testosterone therapy. A structured assessment was conducted prior to, and at 3 and 12 months after treatment initiation. The second arm was a cross-sectional study that comprised 47 transgender men (median age 24 [IQR—20–31] years) who received testosterone for a median duration of 35 [IQR 13–62] months. The main outcome measures were serum AMH and antral follicle count (AFC) as indices of ovarian follicular reserve. PARTICIPANTS/MATERIALS, SETTING, METHODS The study was conducted at a tertiary center for transgender health. Gender-affirming therapy was administered according to standard practice. AFC was determined by pelvic (abdominal or transvaginal) ultrasound and blood collection for measurements of AMH, testosterone, estradiol, LH and FSH was performed at the designated time-points. MAIN RESULTS AND THE ROLE OF CHANCE Prospective arm for the entire group we observed a decrease of 0.71 ng/ml in AMH levels between baseline and 12 months (P = 0.01). When expressed in age-specific percentiles, AMH went from the 47.37th to the 40.25th percentile at 12 months (P < 0.001). In a sub-group analysis, a decline of 9.52 points in age-specific percentile was seen in subjects with PCOS (P < 0.001), while no changes were detected in the non-PCOS group. Testosterone treatment did not affect AFC over time in the entire cohort. In the sub-group analysis, a mean decrease of 5.0 follicles was detected between baseline and the 12 months assessment (P = 0.047) only in subjects with PCOS. In the cross-sectional study, AMH inversely correlated with age but not with treatment duration. Notably AMH did not deviate from the 50th age-specific percentile. Finally, four men fathered biological children after being under testosterone treatment for up to 12 years. LIMITATIONS, REASONS FOR CAUTION The limited sample size of the pilot study should be kept in mind. An additional limitation is the lack of a control group in the prospective study, as each participant served as his own control. Also, roughly 40% of the ultrasound examinations were performed transabdominally, potentially affecting the accuracy of the AFC measurements. As study participants were quite young, our reassuring data may not apply to older transgender men, either because of an age-related decline in ovarian reserve or to possible long-term effects of testosterone therapy. Furthermore, the chances for fertility preservation may be more limited in subjects with PCOS. WIDER IMPLICATIONS OF THE FINDINGS This is an additional contribution to the emerging evidence that prolonged testosterone treatment may not be a major obstacle to later fertility potential in transgender men desirous of having children. Larger confirmatory studies, and particularly more with reproductive outcome data, are needed for evidence-based fertility counseling prior to treatment initiation in these subjects. STUDY FUNDING/COMPETING INTEREST(S) This study received no funding. The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER N/A.
Article
Background Reproductive health counseling is essential for adolescents and young adults (AYAs). Transgender and gender diverse (TGD) AYAs would benefit from tailored counseling given concerns about iatrogenic infertility and sexual dysfunction, and high rates of interpersonal violence, unplanned pregnancies and sexually transmitted infections, yet there are multiple obstacles to providing this care at the patient/family and clinician levels. Objectives This narrative review summarizes the literature on reproductive health considerations for TGD AYAs, current practices, and clinician barriers and facilitators to providing culturally sensitive reproductive care for TGD AYAs. Specific areas of focus include: reproductive health goals, risks, and access barriers; clinician knowledge practices and challenges; and strategies for improving counseling practices. Materials/Methods PubMed, Google Scholar, Medline, Web of Science, and PsycInfo databases were searched using the following terms: transgender, non‐binary, gender expansive, gender non‐conforming, reproductive health, sexual health, fertility, family planning/building, contraception, sexual dysfunction; gender affirming hormones/surgery, clinician, physician or provider knowledge and attitudes; counseling. Results Many TGD AYAs desire biological children and improved sexual experiences. TGD AYAs may experience infertility and sexual dysfunction associated with transition; have disproportionate HIV/STI risk; experience high rates of interpersonal/sexual violence and trauma; and encounter barriers to accessing competent medical care. Clinicians lack knowledge about reproductive health needs of TGD AYAs; inconsistently discuss family building options; perceive counseling challenges; and desire more training in this area. Discussion Enriched communication training for medical/mental health clinicians is necessary to provide a skilled workforce for TGD AYAs. Web‐based reproductive health training with other populations (e.g., oncology) demonstrates efficacy for improving communication skills and confidence in counseling, Conclusion This review highlights barriers to adequate reproductive care encountered by TGD AYAs, exacerbated in underserved minority youth. Dedicated training for providers, and programs increasing access are important goals for improving care. The need for additional research is also emphasized.
Article
STUDY QUESTION Does testosterone use in females affect reproductive potential, particularly with regard to the production of fertilizable gametes? SUMMARY ANSWER Testosterone (T) injections given to post-pubertal female mice caused virilization and although the ovaries were smaller than controls they were still responsive and produced fertilizable eggs when superovulated. WHAT IS KNOWN ALREADY Studies to examine the effects of testosterone on reproductive potential in transgender males are lacking. Recently, a model was developed that simulates many aspects of testosterone use in transgender males in order to look at reproductive effects of testosterone in female mice. This study found masculinizing effects on the mice but did not find significant deficits on the number of ovarian follicles; however, effects of testosterone use on ovarian stimulation and fertilizability of oocytes were not investigated. STUDY DESIGN, SIZE, DURATION A total of 66, 6-week-old Hsd:NSA (CF-1) female mice and six Hsd:ICR (CD-1) male mice were used for this study. Mice were injected s.c. with 400 µg T or sesame oil once a week for 6 weeks and were either killed 1 week after the sixth injection (active exposure group), or 6–7 weeks after the final T injection (washout group). PARTICIPANTS/MATERIALS, SETTING, METHODS Both active exposure and washout groups were further subdivided into three groups: unstimulated, equine CG (eCG)-stimulated or eCG/hCG-stimulated. eCG-stimulated mice were killed 44–48 h after eCG injection. eCG/hCG-stimulated mice were injected with eCG, followed 48 h later with hCG. Mice were killed ∼13–18 h after the hCG injection. Data collected included daily vaginal cytology, terminal testosterone levels, ovary weights and histology, number of oocytes/eggs collected in each group, and cleavage to the two-cell stage following IVF. MAIN RESULTS AND THE ROLE OF CHANCE Testosterone-treated mice had testosterone levels elevated to the level of male mice and ceased cycling. Ovaries were significantly smaller in testosterone-treated mice, but they contained normal cohorts of follicles and responded to gonadotrophin stimulation by ovulating similar numbers of eggs as controls, that fertilized and cleaved in vitro. LIMITATIONS, REASONS FOR CAUTION Mice were treated for only 6 weeks, whereas many transgender men use testosterone for many years before considering biological children, and developmental competence was not assessed. Importantly, a mouse system may not perfectly simulate human reproductive physiology. WIDER IMPLICATIONS OF THE FINDINGS The current standard of care for transgender men who desire biological children is to cease testosterone therapy prior to ovarian stimulation, but the necessity for stopping testosterone is not known. Our model demonstrates that it is possible for testosterone-suppressed ovaries to respond to gonadotrophic stimulation by producing and ovulating fertilizable eggs, thereby obviating the need for testosterone cessation prior to ovarian stimulation. In time, these results may provide insights for future clinical trials of fertility treatment options for transgender men. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by the Reproductive Endocrinology and Infertility fellowship program through UConn Health Graduate Medical Education (to C.B.B.). The authors have no competing interests. TRIAL REGISTRATION NUMBER N/A.
Article
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Transgender people have experienced significant advances in societal acceptance despite experiencing continued stigma and discrimination. While it can still be difficult to access quality health care, and there is a great deal to be done to create affirming health care organizations, there is growing interest around the United States in advancing transgender health. The focus of this commentary is to provide guidance to clinicians caring for transgender men or other gender nonconforming people who are contemplating, carrying, or have completed a pregnancy. Terms transgender and gender nonconforming specifically refer to those whose gender identity (e.g., being a man) differs from their female sex assigned at birth. Many, if not most transgender men retain their female reproductive organs and retain the capacity to have children. Review of their experience demonstrates the need for preconception counseling that includes discussion of stopping testosterone while trying to conceive and during pregnancy, and anticipating increasing experiences of gender dysphoria during and after pregnancy. The clinical aspects of delivery itself fall within the realm of routine obstetrical care, although further research is needed into how mode and environment of delivery may affect gender dysphoria. Postpartum considerations include discussion of options for chest (breast) feeding, and how and when to reinitiate testosterone. A positive perinatal experience begins from the moment transgender men first present for care and depends on comprehensive affirmation of gender diversity.
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Purpose The purpose of this study was to compare ovarian stimulation and pregnancy outcomes between transgender men (1) with and without a history of testosterone use (HRT) and (2) to cisgender women. Methods Retrospective chart review between January 1st 2015 and March 1st, 2019 of transgender men and cisgender women seeking ovarian stimulation (OS) matched by BMI and age. Outcomes were compared using Fisher’s exact or Wilcoxon’s rank sum tests. Results Thirteen transgender men presented for OS, 7 who used HRT. When comparing transgender men with and without a history of HRT, there were no differences in the baseline follicle count, cycle length, or FSH and hmG used (p = 0.193, 0.306, 0.200, and 0.197, respectively). Transgender men who used HRT had lower peak estradiol and oocytes retrieved compared to transgender men with no HRT use; peak estradiol levels of 1175 pg/mL IQR [559.5–2684]) vs 2713.5 pg/mL IQR [2335–3105]; oocytes retrieved 12 IQR [4–26]) vs. 25.5 [18–28] (p = 0.046. and 0.038, respectively). There were no differences in the estradiol level per oocyte, meiosis II oocyte yield, or maturity rate (MII/oocytes) between the two groups (p = 1.000, 0.148, and 0.147, respectively). Peak estradiol levels were lower among transgender men compared to cisgender women (p = 0.016), but the remaining cycle characteristics were similar between the two groups. Three successful pregnancies were conceived using the oocytes of transgender men who used HRT. Conclusion HRT use may not negatively impact ovarian stimulation outcomes. Clinical pregnancies are possible from the oocytes of transgender men with a history of HRT.
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Objectives: This study aims to identify factors associated with the reproductive planning of trans-masculine adults. Study design: Between 2015 and 2016, providers enrolled 150 trans-masculine adults in a sexual health study assessing sociodemographics, social support, gender affirmation, sexual partnering, and reproductive history and planning. A brief clinical interview assessed contraceptive use and concerns. Bivariate and multivariable logistic regression analyses examined associations between participant characteristics and three outcomes: current contraceptive use, lifetime pregnancy history and reproductive planning. Results: Overall, 37.3% are currently using contraceptives; 5.3% have been pregnant; and 20.0% plan to have biological children (9.3% plan to become pregnant; 12.0% plan to use their oocytes with a surrogate). Participants are less likely to use contraceptives if they are students vs. not, have socially affirmed their gender vs. not and have a partner vs. are single. Greater number of sexual partners is associated with the increased odds of contraceptive use. Further, as social support increases, the odds of having been pregnant decreases. Participants with a nonbinary gender identity are more likely to want to become pregnant than those with a binary gender identity, whereas those who have socially affirmed their gender are less likely to want to become pregnant than those who had not. Finally, participants of color more commonly planned to use their oocytes with a surrogate than white participants. Conclusion: Sociodemographic, gender affirmation, social support and sexual partner factors are associated with contraceptive use and reproductive history among trans-masculine patients. Implications: Healthcare providers must be aware of the diverse reproductive histories and pregnancy goals of trans-masculine individuals in order to provide comprehensive reproductive healthcare counseling and provision. More research is needed to better understand contraception and reproduction desires in trans-masculine individuals.
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Introduction: Ovarian tissue is increasingly being collected from cancer patients and cryopreserved for fertility preservation. Alternately to the autologous transplantation, the development of culture systems that support oocyte development from the primordial follicle stage represent a valid strategy to restore fertility. The aim of this study is to review the most recent data regarding oogenesis in vitro and to provide an up-to-date on the contemporary knowledge of follicle growth and development in vitro. Evidence acquisition: A comprehensive systematic MEDLINE search was performed since February 2018 for English-language reports by using the following terms: "ovary," "animal and human follicle," "in vitro growth and development," "ovarian tissue culture," "fertility preservation," "IVM," "oocyte." Previous published reviews and recent published original articles were preferred in order to meet our study scope. Evidence synthesis: Over time, many studies have been conducted with the aim to optimize the characteristics of ovarian tissue culture systems and to better support the three main phases: i) activation of primordial follicles; ii) isolation and culture of growing preantral follicles; iii) removal from the follicle environment and maturation of oocyte cumulus complexes. While complete oocyte in vitro development has been achieved in mouse, with the production of live offspring, the goal of obtaining oocytes of sufficient quality to support embryo development has not been completely reached into higher mammals despite decades of effort. Conclusions: Over the years, many improvements have been made on ovarian tissue cultures with the future purpose that patients will be provided with a greater number of developmentally competent oocytes for fertility preservation.
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Objective To update the “Endocrine Treatment of Transsexual Persons: An Endocrine Society Clinical Practice Guideline,” published by the Endocrine Society in 2009. Participants The participants include an Endocrine Society–appointed task force of nine experts, a methodologist, and a medical writer. Evidence This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The task force commissioned two systematic reviews and used the best available evidence from other published systematic reviews and individual studies. Consensus Process Group meetings, conference calls, and e-mail communications enabled consensus. Endocrine Society committees, members and cosponsoring organizations reviewed and commented on preliminary drafts of the guidelines. Conclusion Gender affirmation is multidisciplinary treatment in which endocrinologists play an important role. Gender-dysphoric/gender-incongruent persons seek and/or are referred to endocrinologists to develop the physical characteristics of the affirmed gender. They require a safe and effective hormone regimen that will (1) suppress endogenous sex hormone secretion determined by the person’s genetic/gonadal sex and (2) maintain sex hormone levels within the normal range for the person’s affirmed gender. Hormone treatment is not recommended for prepubertal gender-dysphoric/gender-incongruent persons. Those clinicians who recommend gender-affirming endocrine treatments—appropriately trained diagnosing clinicians (required), a mental health provider for adolescents (required) and mental health professional for adults (recommended)—should be knowledgeable about the diagnostic criteria and criteria for gender-affirming treatment, have sufficient training and experience in assessing psychopathology, and be willing to participate in the ongoing care throughout the endocrine transition. We recommend treating gender-dysphoric/gender-incongruent adolescents who have entered puberty at Tanner Stage G2/B2 by suppression with gonadotropin-releasing hormone agonists. Clinicians may add gender-affirming hormones after a multidisciplinary team has confirmed the persistence of gender dysphoria/gender incongruence and sufficient mental capacity to give informed consent to this partially irreversible treatment. Most adolescents have this capacity by age 16 years old. We recognize that there may be compelling reasons to initiate sex hormone treatment prior to age 16 years, although there is minimal published experience treating prior to 13.5 to 14 years of age. For the care of peripubertal youths and older adolescents, we recommend that an expert multidisciplinary team comprised of medical professionals and mental health professionals manage this treatment. The treating physician must confirm the criteria for treatment used by the referring mental health practitioner and collaborate with them in decisions about gender-affirming surgery in older adolescents. For adult gender-dysphoric/gender-incongruent persons, the treating clinicians (collectively) should have expertise in transgender-specific diagnostic criteria, mental health, primary care, hormone treatment, and surgery, as needed by the patient. We suggest maintaining physiologic levels of gender-appropriate hormones and monitoring for known risks and complications. When high doses of sex steroids are required to suppress endogenous sex steroids and/or in advanced age, clinicians may consider surgically removing natal gonads along with reducing sex steroid treatment. Clinicians should monitor both transgender males (female to male) and transgender females (male to female) for reproductive organ cancer risk when surgical removal is incomplete. Additionally, clinicians should persistently monitor adverse effects of sex steroids. For gender-affirming surgeries in adults, the treating physician must collaborate with and confirm the criteria for treatment used by the referring physician. Clinicians should avoid harming individuals (via hormone treatment) who have conditions other than gender dysphoria/gender incongruence and who may not benefit from the physical changes associated with this treatment.
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Cross-sex hormone therapy (XHT) is widely used by transgender people to alter secondary sex characteristics to match their desired gender presentation. Here we investigate the long-term effects of XHT on bone health, using a murine model. Female mice underwent ovariectomy at either 6 or 10 weeks, and began weekly testosterone or vehicle injections. Dual-energy X-ray Absorptiometry (DXA) was performed to measure bone mineral density (BMD) and microCT was performed to compare femoral cortical and trabecular bone architecture. The 6-week testosterone group had comparable BMD to controls by DXA, but reduced bone volume fraction, trabecular number, and cortical area fraction, and increased trabecular separation by microCT. 10-week ovariectomy/XHT maintained microarchitecture, suggesting that estrogen is critical for bone acquisition during adolescence, and that late, but not early, estrogen loss can be sufficiently replaced by testosterone alone. Given these findings, we then compared effects of testosterone to effects of weekly estrogen or combined testosterone/low-dose estrogen treatment after a 6-week ovariectomy. Estrogen treatment increased spine BMD and microarchitecture, bone volume fraction, trabecular number, trabecular thickness, and connectivity density, and decreased trabecular separation. Combined testosterone-estrogen therapy caused similar increases in femur and spine BMD and improved architecture (increased bone volume fraction, trabecular number, thickness, and connectivity density) to estrogen therapy, and were superior compared to mice treated with testosterone-only. These results demonstrate estradiol is critical for bone acquisition and suggest a new cross-sex hormone therapy adding estrogens to testosterone treatments, with potential future clinical implications for treating transgender youth or males with estrogen deficiency.
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Purposes: At the moment of sex reassignment surgery (SRS), the ovarian tissue is sometimes cryopreserved as fertility preservation option for female-to-male trans men, also called trans men. During this preparation, cumulus-oocyte-complexes (COCs) can be found and in vitro matured. It is not known if these oocytes are developmentally competent. In order to use these oocytes for fertility preservation and subsequent fertilization, a normal spindle structure before and after vitrification is necessary. Methods: A total of 680 COCs were collected from trans men (n = 16) at the time of SRS and after testosterone treatment. The COCs were subjected to in vitro maturation and those that reached the metaphase II stage (MII) were collected and split into two groups; group 1 was immediately fixed for spindle staining and group 2 was first vitrified and warmed followed by spindle staining. Statistical analysis was performed by Fisher's exact test. Results: After 48 h in vitro maturation, 38.1% of COCs were at MII stage. Those oocytes were split in two groups: (1) 126 MII oocytes in the noncryopreservation group and (2) 133 MII oocytes underwent cryopreservation through vitrification. The oocyte survival rate, after 2 h warming, was 67.7%. Both the noncryopreserved and the vitrified group showed comparable results concerning normal spindle structure and chromosomes alignment, 85.7% vs. 92.2% (P = 0.27). Conclusions: Spindle structure analysis and chromosomal alignment after vitrification seem normal in in vitro matured COCs collected during the tissue processing of ovaries in trans men at the time of SRS. The MII oocytes do not seem to be morphologically affected by prolonged testosterone treatment.
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Study question: Does long-term exogenous testosterone administration result in polycystic ovarian morphology (PCOM), determined by (3D) transvaginal ultrasound (TVU) in female-to-male transsexuals (FtMs). Summary answer: Long-term exogenous testosterone administration in FtMs does not result in PCOM determined by (3D) TVU. What is known already: The role of androgens in the pathophysiology of polycystic ovary syndrome (PCOS) is still unclear. From animal studies, intra-ovarian androgens have been suggested to disturb folliculogenesis, through a pro-atretic effect on growing follicles. It remains debatable whether exogenous androgens induce PCOM in humans. In the past histomorphologic studies indicated that androgen administration in FtMs could cause PCO-like changes. However, ultrasound morphology is an established criterion for PCOS, TVU data of ovaries after prolonged androgen exposure are lacking. Study design, size, duration: Prospective, observational, case-control study, in an academic setting, performed in 2014-2015, including 56 FtMs and 80 controls. Participants/materials, setting, methods: The study population consisted of adult FtMs treated with long-term testosterone, as part of their cross-sex hormone treatment, and scheduled for sex-reassignment surgery (bilateral salpingo-oophorectomy). Prior to the operation, under anaesthetics TVU measurements (3D transvaginal probe 3-9 MHz; HD11, Philips Ultrasound, Inc.) of the ovaries were performed. The control group consisted of females from a general population who underwent the same TVU and analysis. Antral follicle count (AFC) (3D) and ovarian volume (3D) were calculated using specialized software. PCOM was defined as AFC of 12 or more follicles (2-10 mm) in at least one ovary. Main results and the role of chance: Prevalence rates of PCOM were not significantly different in the FtMs compared to controls, determined by (3D) TVU: 32.1% (17/53) versus 30.7% (23/75), P = 0.87. Limitations, reasons for caution: Testosterone levels in FtMs are supraphysiological, and may not be comparable to the testosterone levels in women with PCOS. However, we applied a unique and ethically acceptable opportunity of exploring the effects of androgens on human ovaries. Wider implications of the findings: This first explorative study shows that long-term exogenous testosterone administration in adult women does not seem to induce PCOM determined by TVU. Study funding/competing interest(s): None. Trial registration number: The trial was registered at the Dutch Trial Register (www.trialregister.nl), registration number NTR4784.
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Context: Testosterone is commonly administered intramuscularly (IM) to treat hypogonadal males and female-to-male transgender (FTM) patients. However, these injections can involve significant discomfort and may require arrangements for administration by others. Objective: We assessed whether T could be administered effectively and safely by the subcutaneously (SC) as an alternative to IM injections. Design: Retrospective cohort study. Setting: Outpatient Reproductive Endocrinology Clinic at an academic medical center. Patients: Sixty-three FTM transgender patients aged >18 years electing to receive SC T therapy for gender transition were included. Fifty-three patients were premenopausal. Intervention: Patients were administered T cypionate or enanthate weekly at an initial dose of 50mg. Dose was adjusted if needed to achieve serum total T levels within the normal male range. Main outcome measurements: Serum concentrations of free and total T and total estradiol (E2), masculinization and surveillance for reactions at injection sites. Results: Serum T levels within the normal male range were achieved in all 63 patients with doses of 50-150mg (median 75/80 mg). Therapy was effective across a wide range of body mass index (BMI) (19.0-49.9 kg/m2). Minor and transient local reactions were reported in 9/63 patients. Among 53 premenopausal patients, 51 achieved amenorrhea and 35 achieved serum E2 concentrations <50 pg/mL. Twenty-two patients were originally receiving IM and switched to SC therapy. All 22 had a mild (n=2) or marked (n=20) preference for SC injections; none preferred IM injections. Conclusions: Our observations indicate that SC T injections are an effective, safe and well-accepted alternative to IM T injections.
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PurposeThis study aims to make an account of the children born following transplantation of frozen-thawed ovarian tissue worldwide with specific focus on the perinatal outcome of the children. Furthermore, perinatal outcome of seven deliveries (nine children) from Denmark is reported. Methods PubMed was searched for papers of deliveries resulting from ovarian tissue cryopreservation (OTC). Seven women underwent OTC prior to chemotherapy. Four of these women still had low ovarian function and had tried to conceive. They therefore had tissue autotransplanted to augment their fertility. The other three women had developed premature ovarian insufficiency (POI) after the end of treatment. ResultsWorldwide, approximately 95 children have been born or will be born in the near future from OTC, including these 9 new children. Information on the perinatal outcome was found on 40 children. The mean gestational age was 39 weeks and the mean birth weight was 3168 g of the singleton pregnancies, which is within internationally recognized normal standards. Furthermore, half the singletons resulted from natural conception and all twins resulted from in vitro fertilization treatment. All seven Danish women became pregnant within 1–3 years after transplantation. They gave birth to nine healthy children. Conclusion The data is reassuring and further suggests that cryopreservation of ovarian tissue is becoming an established fertility preservation method. The seven Danish women reported in this study were all in their early thirties when OTC was performed. Most other reported cases were in the women’s twenties. This suggests that the follicular pool in the thirties is large enough and sufficient to sustain fertility.
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Objective: Female-to-male transition remains a specific clinical indication for long-term testosterone administration. There is a limited number of studies dealing with the effect of androgen treatment on their female receptive targets (mainly breast and uterus) and the knowledge in this field is scarce and, sometimes, contradictory. Materials and Methods: We performed a prospective study including 12 patients aged between 20 years and 32 years, with a diagnosis of gender dysphoria, treated with parenteral testosterone administration before sexual reassignment surgery. Results: Endometrial histology revealed the presence of active endometrium in 10 cases and secretive endometrium in two cases. Multifollicular ovaries were observed in all cases of active endometrium, while corpus luteum was present in the two cases of secretory endometrium. Fibroids or hypertrophic myometrium were observed in 58% of the patients. Estrogen receptor was very high (59%) in the endometrial epithelial cells and low (17%) in the myometrium. Androgen receptor expression was modest in endometrial epithelial cells (24%) and sustained in myometrium (69%). Ki67 expression is steadily present in all uterine compartments, varying from 8% in epithelial endometrium to 2% in the myometrium. Conclusion: Our data suggest that long-term testosterone administration to female-to-male patients during reproductive age induces a low proliferative active endometrium, associated with some hypertrophic myometrial changes.
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Background: Prior to the start of cross-sex hormone therapy (CSH), androgenic progestins are often used to induce amenorrhea in female to male (FtM) pubertal adolescents with gender dysphoria (GD). The aim of this single-center study is to report changes in anthropometry, side effects, safety parameters, and hormone levels in a relatively large cohort of FtM adolescents with a diagnosis of GD at Tanner stage B4 or further, who were treated with lynestrenol (Orgametril®) monotherapy and in combination with testosterone esters (Sustanon®). Methods: A retrospective analysis of clinical and biochemical data obtained during at least 6 months of hormonal treatment in FtM adolescents followed at our adolescent gender clinic since 2010 (n = 45) was conducted. McNemar's test to analyze reported side effects over time was performed. A paired Student's t test or a Wilcoxon signed-ranks test was performed, as appropriate, on anthropometric and biochemical data. For biochemical analyses, all statistical tests were done in comparison with baseline parameters. Patients who were using oral contraceptives (OC) at intake were excluded if a Mann-Whitney U test indicated influence of OC. Results: Metrorrhagia and acne were most pronounced during the first months of monotherapy and combination therapy respectively and decreased thereafter. Headaches, hot flushes, and fatigue were the most reported side effects. Over the course of treatment, an increase in musculature, hemoglobin, hematocrit, creatinine, and liver enzymes was seen, progressively sliding into male reference ranges. Lipid metabolism shifted to an unfavorable high-density lipoprotein (HDL)/low-density lipoprotein (LDL) ratio; glucose metabolism was not affected. Sex hormone-binding globulin (SHBG), total testosterone, and estradiol levels decreased, and free testosterone slightly increased during monotherapy; total and free testosterone increased significantly during combination therapy. Gonadotropins were only fully suppressed during combination therapy. Anti-Müllerian hormone (AMH) remained stable throughout the treatment. Changes occurred in the first 6 months of treatment and remained mostly stable thereafter. Conclusions: Treatment of FtM gender dysphoric adolescents with lynestrenol monotherapy and in combination with testosterone esters is effective, safe, and inexpensive; however, suppression of gonadotropins is incomplete. Regular blood controls allow screening for unphysiological changes in safety parameters or hormonal levels and for medication abuse.
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Transgender people have experienced significant advances in societal acceptance despite experiencing continued stigma and discrimination. While it can still be difficult to access quality health care, and there is a great deal to be done to create affirming health care organizations, there is growing interest around the United States in advancing transgender health. The focus of this commentary is to provide guidance to clinicians caring for transgender men or other gender nonconforming people who are contemplating, carrying, or have completed a pregnancy. Terms transgender and gender nonconforming specifically refer to those whose gender identity (e.g., being a man) differs from their female sex assigned at birth. Many, if not most transgender men retain their female reproductive organs and retain the capacity to have children. Review of their experience demonstrates the need for preconception counseling that includes discussion of stopping testosterone while trying to conceive and during pregnancy, and anticipating increasing experiences of gender dysphoria during and after pregnancy. The clinical aspects of delivery itself fall within the realm of routine obstetrical care, although further research is needed into how mode and environment of delivery may affect gender dysphoria. Postpartum considerations include discussion of options for chest (breast) feeding, and how and when to reinitiate testosterone. A positive perinatal experience begins from the moment transgender men first present for care and depends on comprehensive affirmation of gender diversity.
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This paper describes the success and expansion of ovarian tissue cryopreservation and transplantation as a fertility restoration procedure, with the largest series of 60 live births worldwide reported. By repeating the procedure, ovarian activity can be restored for more than 11 years.
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We have previously reported an approach to ovarian stimulation for the purpose of fertility preservation (FP) in women with breast cancer via embryo freezing with the concurrent use of letrozole. The aim of this study was to provide the pregnancy and FP outcomes when embryos generated with the same protocol are used. In all, 131 women with stage ≤ 3 breast cancer underwent ovarian stimulation and received concurrent letrozole 5 mg per day before receiving adjuvant chemotherapy and cryopreserving embryos. Thirty-three of the 131 women underwent 40 attempts to transfer embryos to their own uterus (n = 18) or via the use of a gestational carrier (n = 22) at a mean age of 41.5 ± 4.3 years with a median 5.25 years after embryo cryopreservation. The overall live birth rate per embryo transfer was similar to the US national mean among infertile women of a similar age undergoing in vitro fertilization-embryo transfer (45.0 v 38.2; P = .2). Seven (38.8%) of the 18 pregnancies were twins with no higher-order pregnancies being encountered. No fetal anomalies or malformations were reported in 25 children after a mean follow-up of 40.4 ± 26.4 months. Seventeen of the 33 women attempting pregnancy had at least one child, translating into an FP rate of 51.5% per attempting woman. Embryo cryopreservation after ovarian stimulation with the letrozole and follicle-stimulating hormone protocol preserves fertility in women with breast cancer and results in pregnancy rates comparable to those expected in a noncancer population undergoing in vitro fertilization. © 2015 by American Society of Clinical Oncology.
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This paper reports on a qualitative study exploring the ways in which transgender adults imagine a place for parenthood in their lives, and/or the ways they have negotiated parenthood with their transgender identity. A total of 13 transgender adults (including parents and non-parents) were interviewed with respect to their thoughts and experiences about family, relationships and parenting. The study sought to understand the possibilities for parenthood that transgender people create, despite barriers imposed by restrictive laws, medical practices and cultural attitudes. Interview data showed how normative assumptions about gender and parenthood shape the way people imagined and desired parenthood. It also showed how participants re-appropriated and resisted normative cultural scripts by either re-imagining parenthood in different terms (such as step-parenthood) or by creating different family forms, such as co-parented families. Participants reported a variety of experiences with healthcare providers when it came to conversations about fertility preservation and family building.
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To investigate the effect of hormonal androgenic treatment on antimüllerian hormone (AMH) serum levels in female-to-male (FtM) transsexual women. Polycystic ovary syndrome (PCOS) is associated with elevated AMH levels. Some hypothesize that the high AMH level is a consequence of androgen-induced excessive development of small antral follicles. However, this role of androgens is not yet clear. Observational, prospective, cohort study. Tertiary academic medical center. Twenty-two FtM transsexual women, healthy native females receiving cross-sex hormone therapy/androgenic treatment. Androgenic treatment with testosterone (T) and an aromatase inhibitor while endogenous hormone secretion was suppressed with the use of a GnRH agonist. Hormone concentrations were measured before and after androgenic treatment (administration of T and aromatase inhibitor). Measured hormones: AMH, inhibin B, T, androstenedione, DHEAS, E2, SHBG, LH, and FSH. AMH concentrations were significantly lower after androgenic treatment (4.4 ± 4.4 μg/L vs. 1.4 ± 2.1 μg/L). Androgenic treatment resulted in a strong suppression of AMH secretion over a relative short period of 16 weeks. Our data underscore the likely important role of androgens in the dynamics of folliculogenesis. It challenges the idea that androgens induce high AMH levels, which is gaining more interest nowadays as an important particular PCOS feature. This strong decline furthermore indicates that AMH must be interpreted in the context of other reproductive endocrine conditions. NTR2493. Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
Article
Hormonal therapy and gender-affirming surgeries in transgender people have known deleterious impacts on future fertility using one's own gametes. This review focuses on fertility preservation, including the effects of medical hormone treatment on fertility, available and experimental options of fertility preservation in transgender adults, including sperm cryopreservation for transwomen and oocyte cryopreservation for transmen, and options for prepubertal transgender adolescents, including testicular and ovarian tissue cryopreservation. Transgender patients continue to face barriers and receive infrequent counseling regarding fertility preservation. Physicians should ideally counsel and discuss fertility preservation options before transgender patients undergo hormone therapy of gender-affirmation surgery.
Article
Objective: To investigate assisted reproductive technology (ART) outcomes in a female-to-male transgender cohort and compare the results with those of a matched cisgender cohort. Design: Matched retrospective cohort study. Setting: In vitro fertilization clinic. Patient(s): Female-to-male transgender patients (n = 26) who sought care from 2010 to 2018. A cisgender cohort (n = 130) was matched during the same time period by age, body mass index, and antimüllerian hormone levels. Intervention(s): Not applicable. Main outcome measure(s): Cycle outcomes, including oocyte yield, number of mature oocytes, total gonadotropin dose, and peak E2 levels. Result(s): The mean number of oocytes retrieved in the transgender group was 19.9 ± 8.7 compared with 15.9 ± 9.6 in the cisgender group. Peak E2 levels were the same between the two groups. The total dose of gonadotropins used was higher in the transgender group compared with the cisgender group (3,892 IU vs. 2,599 IU). Of the 26 patients, 16 performed oocyte banking only. Seven couples had fresh or frozen transfers, with all achieving live births. Conclusion(s): This is the first study of this size investigating ART outcomes in female-to-male transgender patients. The findings may serve to reassure transgender patients and their care providers that outcomes can be excellent even if testosterone therapy has already been initiated. Further investigation needs to be performed on the generalizability of these findings, and whether similar results can be achieved without stopping testosterone therapy.
Article
Study question: Can mice serve as a translational model to investigate the reproductive effects of testosterone (T) therapy commonly used by transgender men? Summary answer: T enanthate subcutaneous injections at 0.45 mg twice weekly can be used in the postpubertal C57BL/6N female mouse to investigate the reproductive effects of T therapy given to transgender men. What is known already: Most models of T treatment in female mice involve prenatal or prepubertal administration, which are not applicable to transgender men who often begin T therapy after puberty. Studies that have looked at the impact of postpubertal T treatment in female mice have generally not investigated reproductive outcomes. Study design, size, duration: A total of 20 C57BL/6N female mice were used for this study. Study groups (n = 5 mice per group) included sesame oil vehicle controls and three doses of T enanthate (0.225, 0.45 and 0.90 mg). Mice were injected subcutaneously twice weekly for 6 weeks. Participants/materials, setting, methods: Daily vaginal cytology was performed prior to initiation of treatment to confirm that all mice were cycling. At 8-9 weeks of age, therapy with subcutaneous T enanthate (0.225, 0.45 or 0.90 mg) or the vehicle control was begun. T therapy continued for 6 weeks, at which point mice were sacrificed and compared to control mice sacrificed during diestrus/metestrus. Data collected included daily vaginal cytology, weekly and terminal reproductive hormone levels, terminal body/organ weights/measurements, ovarian follicular distribution/morphology and corpora lutea counts. Main results and the role of chance: Of the mice treated with 0.90 mg T enanthate, two of five mice experienced vaginal prolapse, so this group was excluded from further analysis. T enanthate administration twice weekly at 0.225 or 0.45 mg resulted in cessation of cyclicity and persistent diestrus. One of five mice at the 0.225-mg dose resumed cycling after 2.5 weeks of T therapy. As compared to controls, T-treated mice had sustained elevated T levels and luteinizing hormone (LH) suppression in the terminal blood sample. T-treated mice demonstrated increases in clitoral area and atretic cyst-like late antral follicles (0.45 mg only) as compared to controls. No reduction in primordial, primary, secondary or total antral follicle counts was detected in T-treated mice as compared to controls, and T-treated mice demonstrated an absence of corpora lutea. Limitations, reasons for caution: Mouse models can provide us with relevant key findings for further exploration but may not perfectly mirror human reproductive physiology. Wider implications of the findings: To our knowledge, this report describes the first mouse model mimicking T therapy given to transgender men that facilitates analysis of reproductive changes. This model allows for future studies comparing duration and reversibility of T-induced changes, on the reproductive and other systems. It supports a role for T therapy in suppressing the hypothalamic-pituitary-gonadal axis in adult female mice as evidenced by LH suppression, persistent diestrus and absence of corpora lutea. The increase in atretic cyst-like late antral follicles aligns with the increased prevalence of polycystic ovary morphology seen in case series of transgender men treated with T therapy. The results also suggest that T therapy does not deplete the ovarian reserve. Study funding/competing interest(s): This work was supported by the American Society for Reproductive Medicine/Society of Reproductive Endocrinology and Infertility Grant and NIH R01-HD098233 to M.B.M. and University of Michigan Office of Research funding (U058227). H.M.K. was supported by the Career Training in Reproductive Biology and Medical Scientist Training Program T32 NIH Training Grants (T32-HD079342, T32-GM07863) as well as the Cellular and Molecular Biology Program. The University of Virginia Center for Research in Reproduction Ligand Assay and Analysis Core is supported by the Eunice Kennedy Shriver NICHD/NIH (NCTRI) Grant P50-HD28934. E.E.M. consults for Allergan. No other authors have competing interests.
Article
Polycystic ovary syndrome (PCOS) is an endocrine disorder with a high prevalence in women of childbearing age. To date, there is no method of efficiently diagnosing PCOS and curing it completely because its pathomechanism remains unclear. Here, we investigated whether metabolic abnormalities maintain the hyperandrogenism and PCOS-like ovaries and whether the symptoms induced by excess androgen are treatable. We ceased the abnormal dihydrotestosterone (DHT) stimulation to determine changes in PCOS-like mice. After ceasing DHT stimulation, the ovarian morphology and gene expression recovered from the DHT-stimulated status. However, after cessation of DHT stimulation, the hypertrophy of adipose tissues and hepatic steatosis were not significantly restored, and fat accumulation-related gene expression and serum metabolic markers in the mice were altered. These findings showed that the reproductive dysfunction was obviously relieved, but because the metabolic abnormalities were not relieved after the cessation of excess androgen for 30 days, it appears that the latter may not maintain the former.
Article
In the last decade it has been revealed that androgens play a direct and important role in regulating female reproductive function. Androgens mediate their actions via the androgen receptor (AR), and global and cell-specific Ar knockout mouse models have confirmed that AR-mediated androgen actions play a role in regulating female fertility and follicle health, development and ovulation. This knowledge, along with the clinical data reporting a beneficial effect of androgens or androgen-modulating agents in augmenting in vitro fertilization (IVF) stimulation in women termed poor responders, has supported the adoption of this concept in many IVF clinics worldwide. On the other hand, substantial evidence from human and animal studies now supports the hypothesis that androgens in excess, acting via the AR, play a key role in the origins of polycystic ovary syndrome (PCOS). The identification of the target sites of these AR actions and the molecular mechanisms involved in underpinning the development of PCOS, is essential to provide the knowledge required for the future development of novel, mechanism-based therapies for the treatment of PCOS. This review will summarize the basic scientific discoveries that have enhanced our knowledge of the roles of androgens in female reproductive function, discuss the impact these findings have had in the clinic, and how a greater understanding of the role androgens play in female physiology may shape the future development of effective strategies to improve IVF outcomes in poor responders and the amelioration of symptoms in patients with PCOS.
Article
Purpose of review: To provide an overview of the current state of knowledge of fertility risks of gender-affirming therapy, review fertility preservation options for transgender individuals and ways to minimize gender dysphoria during fertility treatment, and identify gaps in knowledge. Recent findings: Recent studies have corroborated older data that gender-affirming hormone therapy creates histopathological changes in the gonads; however, the newer data suggests that some function of the gametes may be preserved. One study in transgender men reported successful in-vitro maturation of testosterone-exposed oocytes with normal spindle structures, and recent studies in transgender women reveal early spermatogenesis in estradiol-exposed testes and some recovery of semen parameters following cessation of hormones. Particular attention has recently been given to fertility preservation in transgender adolescents, revealing unmet informational needs in this population and very few are actually pursuing fertility preservation, even with counseling. Summary: There is currently a paucity of data on the fertility effects of gender-affirming hormones, necessitating fertility preservation counseling prior to initiation of therapy. Several modifications can be made to fertility preservation protocols and procedures to decrease gender dysphoria or distress in transgender individuals, but outcome data is still lacking. Achieving high-quality data collection will likely require cooperation across multiple institutions.
Article
Background: As part of transition, transmasculine persons often use testosterone gender-affirming hormone therapy; however, there is limited data on its long-term effects. The impact of exogenous testosterone on uterine pathology remains unclear. While testosterone achieves amenorrhea in the majority of this population, persistence of abnormal uterine bleeding can be difficult to manage. Excess androgens in cisgender females are associated with pathologic uterine processes such as polycystic ovary syndrome, endometrial hyperplasia, or cancer. There are no guidelines for management of abnormal uterine bleeding or endometrial surveillance in this population. Objective: The aim of this study was to describe the characteristics of uterine pathology after the initiation of testosterone in transmasculine persons. Materials and methods: A retrospective, multicenter case series was performed. Uterine pathology reports of transmasculine persons who received testosterone and subsequently underwent hysterectomy were reviewed. The endometrial phase and endometrial thickness were recorded. Results: A total of 94 subjects met search criteria. The mean age of participants was 30 ± 8.6 years, and the mean interval from initiation of testosterone to hysterectomy was 36.7 ± 36.6 months. Active endometrium was found in the majority of patients (n = 65; 69.1%). One patient had complex hyperplasia without atypia. There were no cases of endometrial cancer. Conclusion: Despite amenorrhea in the majority of transmasculine persons on testosterone, endometrial activity persists with predominantly proliferative endometrium on histopathology. Individualized counseling for abnormal uterine bleeding is encouraged in this patient population.
Article
Background: Venous thromboembolism (VTE), ischemic stroke, and myocardial infarction in transgender persons may be related to hormone use. Objective: To examine the incidence of these events in a cohort of transgender persons. Design: Electronic medical record-based cohort study of transgender members of integrated health care systems who had an index date (first evidence of transgender status) from 2006 through 2014. Ten male and 10 female cisgender enrollees were matched to each transgender participant by year of birth, race/ethnicity, study site, and index date enrollment. Setting: Kaiser Permanente in Georgia and northern and southern California. Patients: 2842 transfeminine and 2118 transmasculine members with a mean follow-up of 4.0 and 3.6 years, respectively, matched to 48 686 cisgender men and 48 775 cisgender women. Measurements: VTE, ischemic stroke, and myocardial infarction events ascertained from diagnostic codes through the end of 2016 in transgender and reference cohorts. Results: Transfeminine participants had a higher incidence of VTE, with 2- and 8-year risk differences of 4.1 (95% CI, 1.6 to 6.7) and 16.7 (CI, 6.4 to 27.5) per 1000 persons relative to cisgender men and 3.4 (CI, 1.1 to 5.6) and 13.7 (CI, 4.1 to 22.7) relative to cisgender women. The overall analyses for ischemic stroke and myocardial infarction demonstrated similar incidence across groups. More pronounced differences for VTE and ischemic stroke were observed among transfeminine participants who initiated hormone therapy during follow-up. The evidence was insufficient to allow conclusions regarding risk among transmasculine participants. Limitation: Inability to determine which transgender members received hormones elsewhere. Conclusion: The patterns of increases in VTE and ischemic stroke rates among transfeminine persons are not consistent with those observed in cisgender women. These results may indicate the need for long-term vigilance in identifying vascular side effects of cross-sex estrogen. Primary funding source: Patient-Centered Outcomes Research Institute and Eunice Kennedy Shriver National Institute of Child Health and Human Development.
Article
Objectives: Female-to-male (FTM) transgender men (affirmed males) can experience planned and unplanned pregnancy during and after testosterone therapy. We conducted an exploratory study to understand current contraceptive practices and fertility desires among transgender men during and after transitioning. Study design: Self-identified transgender and transmasculine individuals assigned female at birth, ages 18-45, completed an anonymous online survey derived from standardized family planning surveys. We recruited participants from LGBT health centers, online listservs, and online groups for transgender men and used a mixed-methods analysis to evaluate quantitative and qualitative data. Results: Of the one hundred and ninety-seven participants included in the study, the median age was 30years old, most respondents were white, and 86% were taking masculinizing hormones (testosterone). Of the 60 pregnancies reported, 10 (17%) pregnancies occurred after stopping testosterone, 1 (1.6%) while taking testosterone irregularly, and 5 of 7 abortions occurred in participants who had been using testosterone in the past. Over half of the respondents desired at least one child, and a quarter reported fears of not getting pregnant. The majority of participants reporting using contraception (n=110, 60.1%), with condoms and pills used most commonly (n=90, 49.2% and n=62, 33.9% respectively). Methods of contraception used did not differ between testosterone users and non-users, except for hormonal IUDs (20% testosterone versus 7% non-testosterone). Thirty participants (16.4%) believed that testosterone was a form of contraception, and 10 (5.5%) participants reported that their healthcare providers advised testosterone as contraception. Conclusion: Transgender men use contraception and can experience pregnancy and abortion, even after transitioning socially and hormonally. Transgender men need counseling and care regarding reproductive health, including contraceptive and conception counseling. Implications: Providers should be aware that transgender men may desire pregnancy and use contraception; This study highlights the need for further research regarding fertility, fertility desires, and optimal contraception among transgender men.
Article
Background Many trans individuals undergo medical interventions that result in irreversible loss of fertility. Little is known about their desire to have children and attitudes toward fertility preservation options. Aim To study how the desire for children and the use of fertility preservation options varies among trans women and trans men in different transitioning stages in Germany. Methods In this cross-sectional multi-center study, N = 99 trans women and N = 90 trans men were included. Of these, 26 of each sex were just about to start medical treatment. Outcomes Outcome parameter were the prevalence and determinants of a desire to have children in trans persons. Results Before treatment, a desire for children was significantly higher in trans men compared to trans women (P = .016). In contrast, in those who had already started treatment, a current desire to have children was equally present in about one fourth of participants of both genders while the interest in having children in the future was significantly higher in trans women (69.9%) than in trans men (46.9%; P = .034). Although 76.1% of trans women and 76.6% of trans men indicated that they had at least thought about preserving germ cells before starting medical transition, only 9.6% of trans women and 3.1% of trans men had put this idea into practice. Most trans men in both groups indicated that insemination of a female partner with sperm from an unrelated donor was a suitable option to fulfill their child wish, potentially explaining their low interest in preserving their own germ cells. Finally, a logistic regression analysis accounting for potential confounders revealed that overall trans women were more than twice as likely to have a current desire to have children (odds ratio 2.58), and this wish was on average 5.3% lower with each year of increasing age. Clinical Translation A low level of fertility preservation among trans persons is contrasted by a high level of desire for children. This highlights the importance of counseling trans individuals regarding fertility preservation options. Conclusions To our knowledge, this is the first study that addresses desire to have children in a clinical sample of trans women. It is also the first that investigates this issue among trans men who have not started medical treatment, and the first comparison of both genders. A limitation for the generalization of our results is the special legal context in Germany that forbids oocyte donation for reciprocal in vitro fertilization. Reproductive desire is high among trans individuals, but the use of reproductive options is surprisingly low.
Article
Background The impact of testosterone (T) treatment on anti-doping detection tests in transgender (F2M) men is unknown. We investigated urine and serum sex steroid and LH profiles in T-treated transgender (F2M) to determine whether and, if so, how they differed from hypogonadal and healthy control men. Method Healthy transgender (n=23) and hypogonadal (n=24) men treated with 1000mg injectable T undecanoate aged 18-50 years provided trough urine and blood samples and an additional earlier post-injection sample (n=21). Healthy control men (n=20) provided a single blood and urine sample. Steroids were measured by MS-based methods in urine and serum, LH by immunoassay and UGT2B17 genotype by polymerase chain reaction (PCR). Results Urine LH, hCG, T, epitestosterone (EpiT), androsterone (A), etiocholanolone (Etio), A/Etio ratio, DHEA, DHT, 5α,3α- and 5β, 3α androstenediols did not differ between groups or by time since last testosterone injection. Urine T/EpiT (T/E) ratio was <4 in all controls and 12/68 (18%) samples from T-treated men but there was no difference between testosterone treated groups. Serum estradiol, estrone and DHEA were higher in transgender men and serum T and DHT were higher on earlier compared with trough blood samples but serum LH, FSH, 3α- and 3β 5α diols did not differ between groups. Conclusion Urine anti-doping detection tests in T treated transgender men can be interpreted like T treated hypogonadal men and are unaffected by time since last T dose. Serum steroids are more sensitive to detect exogenous T administration early but not later after the last testosterone dose.
Article
The contributions of estradiol and testosterone to atherosclerotic lesion progression are not entirely understood. Cross-sex hormone therapy (XHT) for transgender individuals dramatically alters estrogen and testosterone levels and consequently could have widespread consequences for cardiovascular health. Yet, no preclinical research has assessed atherosclerosis risk after XHT. We examined the effects of testosterone XHT after ovariectomy on atherosclerosis plaque formation in female mice, and evaluated whether adding low-dose estradiol to cross-sex testosterone treatments after ovariectomy reduced lesion formation. Six-week-old female ApoE -/- C57BL/6 mice underwent ovariectomy and began treatments with testosterone, estradiol, testosterone with low-dose estradiol, or vehicle alone, until sacrifice at 23 weeks of age. Atherosclerosis lesion progression was measured by oil red O stain and confirmed histologically. We found reduced atherosclerosis in the estradiol and combined testosterone/estradiol treated mice compared to those treated with testosterone or vehicle only in the whole aorta (-75%), aortic arch (-80%), and thoracic aorta (-80%). Plaque size was similarly reduced in the aortic sinus. These reductions in lesion size after combined testosterone/estradiol treatment were comparable to those obtained with estrogen alone. Testosterone/estradiol combined therapy resulted in less atherosclerosis plaque formation than either vehicle or testosterone alone after ovariectomy. Testosterone/estradiol therapy was comparable to estradiol replacement alone, while mice treated with testosterone only fared no better than untreated controls after ovariectomy. Adding low-dose estrogen to cross-sex testosterone therapy after oophorectomy could improve cardiovascular outcomes for transgender patients. Additionally, these results contribute to understanding of the effects of estrogen and testosterone on atherosclerosis progression.
Article
There has been a sharp increase in the demand for fertility preservation. This review summarizes the indications and current options and describes new techniques and strategies, including those for women with newly diagnosed malignant disease.
Article
Background: Assisted reproductive technologies, including in vitro fertilization (IVF), can be utilized for fertility preservation and family building in the transgender and gender-nonconforming population. Methods: This is a retrospective case series from an academic tertiary care center. Results: We present three couples with a transgender or gender-nonconforming member who pursued IVF to build their families. The first case involves a transgender man who suspends hormone therapy to undergo IVF. The second involves a transgender woman who uses her previously banked sperm to undergo IVF with her wife. The third involves a gender nonbinary patient and their cisgender wife who create and transfer embryos from both partners. Conclusion: IVF can provide unique family-building opportunities to transgender and gender-nonconforming patients, and providers should seek to broaden their clinical experience with this population.
Article
Background: Non-classic congenital hyperplasia (NCAH) due to 21-hydroxylase deficiency is a common autosomal recessive disorder characterized by androgen excess. Objective and rationale: We conducted a systematic review and critical assessment of the available evidence pertaining to the epidemiology, pathophysiology, diagnosis and management of NCAH. A meta-analysis of epidemiological data was also performed. Search methods: Peer-reviewed studies evaluating NCAH published up to October 2016 were reviewed. Multiple databases were searched including MEDLINE, EMBASE, Cochrane, ERIC, EBSCO, dissertation abstracts, and current contents. Outcomes: The worldwide prevalence of NCAH amongst women presenting with signs and symptoms of androgen excess is 4.2% (95% confidence interval: 3.2-5.4%). The clinical consequences of NCAH expand from infancy, i.e. accelerated growth, to adolescence and adulthood, i.e. premature pubarche, cutaneous symptoms and oligo-ovulation in a polycystic ovary syndrome (PCOS)-like clinical picture. The diagnosis of NCAH relies on serum 17-hydroxyprogesterone (17-OHP) concentrations. A basal 17-OHP concentration ≥2 ng/ml (6 nmol/l) should be used for screening if more appropriate in-house cut-off values are not available. Definitive diagnosis requires a 17-OHP concentration ≥10 ng/ml (30 nmol/l), either basally or after cosyntropin-stimulation. Molecular genetic analysis of the CYP21A2 gene, which is responsible for 21-hydroxylase activity, may be used for confirmation purposes and should be offered to all patients with NCAH along with genetic counseling because these patients frequently carry alleles that may result in classic CAH, the more severe form of the disease, in their progeny. Treatment must be individualized. Glucocorticoid replacement therapy may benefit pediatric patients with accelerated growth or advanced bone age or adult women seeking fertility, whereas adequate control of menstrual irregularity, hirsutism and other cutaneous symptoms is best served by the use of oral contraceptive pills and/or anti-androgens. Some women may need ovulation induction or assisted reproductive technology to achieve pregnancy. Patients with NCAH have a higher risk of miscarriage and may benefit from glucocorticoid treatment during pregnancy. Wider implications: Evidence-based diagnostic and treatment strategies are essential for the proper management of women with NCAH, especially considering that these patients may need different therapeutic strategies at different stages during their follow-up and that appropriate genetic counseling may prevent the occurrence of CAH in their children.
Article
Purpose: To describe fertility preservation (FP) utilization by transgender adolescents within a pediatric gender clinic between July 2013 and July?2016. Methods: A retrospective chart review was conducted to abstract demographic and clinical information among adolescents initiating gender-affirming hormones, including patient age at initial FP consultation, birth-assigned sex, race/ethnicity, and outcome of FP consultation. Results: In our sample of 105 transgender adolescents, a total of 13 (seven transgender men and six transgender women) between the age of 14.2 and 20.6?years were seen in formal consultation for FP before initiating hormones. Of these adolescents, four completed sperm cryopreservation and one completed oocyte cryopreservation. Conclusions: Rates of FP utilization among transgender youth were low, which is consistent with a recently published report of FP utilization among transgender youth at another pediatric institution. Identified barriers to FP in our sample included cost, invasiveness of procedures, and desire not to delay medical transition.
Article
Female-to-male transgender people (trans men) are faced with the risk of losing their reproductive potential owing to gender-affirming hormone treatment and genital reconstructive surgery. This observational, prospective cohort study investigates the effect of prolonged androgen therapy on their ovarian histology and fertility preservation perspectives. Hormone serum levels, ovarian histology and cumulus-oocyte complexes (COC) of 40 transsexual men were analysed at the moment of hysterectomy with bilateral oophorectomy in the context of genital reconstructive surgery after testosterone treatment (58.18 ? 26.57 weeks). In the cortex, most follicles were primordial (68.52% total follicle count) compared with 20.26% intermediate and 10.74%primary follicles. Few secondary follicles (0.46%) and a single antral follicle were found in the sections analysed. In total, 1313 COC were retrieved from the medulla of 35 patients (37.51 ? 33.58 COC per patient). Anti-M?llerian hormone serum levels were significantly correlated with number of COC (Rs 0.787, P < 0.001). After 48?h in-vitro maturation, 34.30% metaphase II oocytes were obtained, with 87.10% having a normal spindle structure. In conclusion, the cortical follicle distribution in trans men, after more than a year of testosterone treatment, seems to be surprisingly normal. This work confirms the presence and in-vitro maturation potential of cumulus-oocyte complexes.
Article
Purpose: Research demonstrates a negative psychosocial impact of infertility among otherwise healthy adults, and distress among adolescents facing the prospect of future infertility due to various medical conditions and treatments that impair reproductive health. Guidelines state that providers should counsel transgender youth about potential infertility and fertility preservation (FP) options prior to initiation of hormone therapy. The purpose of this study was to examine the rates of fertility counseling and utilization of FP among a cohort of adolescents with gender dysphoria seen at a large gender clinic. Methods: An Institutional Review Board-approved retrospective review of electronic medical records was conducted of all patients with ICD-9/10 codes for gender dysphoria referred to Pediatric Endocrinology for hormone therapy (puberty suppression and/or cross-sex hormones) from January 2014 to August 2016. Results: Seventy-eight patients met inclusion criteria. Five children were prepubertal, no hormone therapy was considered, and they were therefore excluded. Of the remaining 73 patients, 72 had documented fertility counseling prior to initiation of hormone therapy and 2 subjects attempted FP; 45% of subjects mentioned a desire or plan to adopt, and 21% said they had never wanted to have children. Conclusions: Utilization rates of FP are low among transgender adolescents. More research is needed to understand parenthood goals among transgender youth at different ages and developmental stages and to explore the impact of gender dysphoria on decision-making about FP and parenthood. Discussions about infertility risk, FP, and other family building options should be prioritized in this vulnerable adolescent population.
Article
This statement explores the ethical considerations surrounding the provision of fertility services to transgender individuals and concludes that denial of access to fertility services is not justified.
Article
Study question: How do transgender men experience fertility preservation (FP) by cryopreservation of oocytes? Summary answer: The procedures required prior to oocyte cryopreservation, such as hormonal ovarian stimulation and transvaginal ultrasound (TVS), have a negative impact on gender dysphoria as they are closely linked to the men's female assigned sex at birth, which is incompatible with their current status. What is known already: Transgender persons often have high dissatisfaction with assigned sex-specific body features, such as the genital organs and androgen/oestrogen-responsive features. Thus, undergoing FP that requires genital-specific examinations, aimed at obtaining oocytes to cryopreserve, could be distressing. As no previous studies have investigated transgender men's experiences of FP involving cryopreservation of oocytes, little is known about their experience of the procedures. Study design, size, duration: This is a prospective study among adult transgender men referred for FP between March 2014 and December 2015. Individual in-depth qualitative interviews were conducted shortly after FP treatment. The interviews lasted between 62 and 111 min (mean 81 min) and were digitally recorded and transcribed verbatim. Participants/materials, setting, methods: Participants were recruited on their first visit to the assisted reproduction clinic for reproductive counseling. There were 15 men, scheduled for FP, who chose to participate in the study (age 19-35); none had given birth and eight had a partner. Data were analyzed by thematic content analysis. Main results and the role of chance: The analysis resulted in three main categories: the journey to FP, reactions to the FP proceedings and strategies for coping. The referral for FP was an important part of the assessment and diagnosis and sometimes lined with frustrating waits and doubts. The reaction to the FP proceedings revealed that the genital examinations and the physical changes associated with discontinuation of testosterone or hormonal stimulation treatment triggered gender incongruence and dysphoria. However, for some, the negative expectations were not met. The participants used several coping strategies in order to manage the procedure, such as focusing on their reasons for undergoing FP, reaching out to friends and family for support and the cognitive approaches of not hating their body or using non-gendered names for their body parts. The results demonstrate the importance of contextual sensitivity during FP procedures. Limitations, reasons for caution: The authors have strived to be reflective about their pre-understanding of the phenomenon. The majority of the participants resided in large urban areas; it is possible that transgender men living in rural areas have different experiences. Wider implications of the findings: As the results are based on qualitative data from 15 transgender men, the results cannot readily be generalized to larger populations. However, the results are suggested to be applicable to other transgender men who want to undergo FP by cryopreservation of oocytes. The results show that transgender men's experience of FP places may elicit gender incongruence and gender dysphoria. However, health care personnel can alleviate distress by using a gender-neutral language and the preferred pronoun. Also, reassuringly, the men also have coping strategies of how to handle the situation. This knowledge is important to ensure adequate professional support for patients with gender dysphoria during FP. Study funding/competing interests: Swedish Society of Medicine, Stockholm County Council and Karolinska Institutet (to K.A.R.-W.). Trial registration number: N/A.
Article
Objectives: To estimate the proportion of US adults who identify as transgender and to compare the demographics of the transgender and nontransgender populations. Methods: We conducted a secondary analysis of data from states and territories in the 2014 Behavioral Risk Factor Surveillance System that asked about transgender status. The proportion of adults identified as transgender was calculated from affirmative and negative responses (n = 151 456). We analyzed data with a design-adjusted χ(2) test. We also explored differences between male-to-female and nontransgender females and female-to-male and nontransgender males. Results: Transgender individuals made up 0.53% (95% confidence interval = 0.46, 0.61) of the population and were more likely to be non-White (40.0% vs 27.3%) and below the poverty line (26.0% vs 15.5%); as likely to be married (50.5% vs 47.7%), living in a rural area (28.7% vs 22.6%), and employed (54.3% vs 57.7%); and less likely to attend college (35.6% vs 56.6%) compared with nontransgender individuals. Conclusions: Our findings suggest that the transgender population is a racially diverse population present across US communities. Inequalities in the education and socioeconomic status have negative implications for the health of the transgender population. (Am J Public Health. Published online ahead of print December 20, 2016: e1-e3. doi:10.2105/AJPH.2016.303571).
Article
Clinical, anthropometric, and endocrine data were examined in 22 corticosteroid-treated, prenatally virilized women with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency and in 22 matched healthy controls. In view of the androgen excess, limited growth, and subfertility associated with CAH, the investigation focused on androgenic/anabolic status and circulating progesterone levels. CAH patients were shorter and had a significantly higher body mass index than the controls. One pregnancy was reported in the CAH group compared to 15 in the controls. Five of the CAH patients were judged as undersubstituted based on greatly elevated circulating levels of 17 α-hydroxyprogesterone. These five patients had elevated serum levels of progesterone (P) and testosterone (T) and elevated ratios between T and sex hormone-binding globulin, but subnormal levels of dehydroepiandrosterone (DHA) and its sulfate. The remaining 17 well substituted patients had elevated follicular phase levels of P, but subnormal levels of all androgens (4-androstene-3, 17-dione, T, DHA, and DHA sulfate) and subnormal T/sex hormone-binding globulin ratios. Contrary to the apprehension that normally guides the treatment of CAH, well substituted patients may be considered hypoandrogenic rather than hyperandrogenic. The elevated levels of P may have a minipill-like effect, which may be one of the causes of the differences in fertility between salt-wasting and simple virilizing CAH.
Article
Androgen and its receptor (AR) plays a critical role in reproductive function, under both physiological and pathophysiological conditions. Female AR global knockout mice are sub-fertile due to both neuroendocrine and ovarian defects. Female offspring from prenatally androgenized heterozygous AR pregnant mice showed rescued estrous cyclicity and fertility. Ar is expressed in granulosa cells, theca interstitial cells, and oocytes in the ovary. We created mice with theca-specific deletion of Ar (ThARKO) by crossing Cyp17-iCre mice that express Cre recombinase under Cyp17 promoter with Ar(fl/fl) mice. ThARKO mice exhibited no significant differences in pubertal onset or fertility compared with control littermates, and neither estrogen and testosterone levels were different between these groups. Therefore, Ar expression in theca cells likely does not influence fertility nor androgen levels in female mice. We then tested the role of AR in theca cells under hyperandrogenemic condition. After treatment with a pathophysiological level of dihydrotestosterone (DHT), control mice (Con-DHT) showed acyclicity and infertility. However, estrous cycles and fertility were altered to a significantly less degree in ThARKO-DHT mice than in Con-DHT mice. Three months after DHT treatment, mRNA levels of Lhcgr (luteinizing hormone receptor) and, Timp1 (tissue inhibitor of metalloproteinase 1, and inhibitor of matrix metalloproteinase (MMP)) were significantly lower in Con-DHT ovary compared to Con-no DHT ovary; whereas mRNA levels of Fshr (follicle stimulating hormone receptor) were significantly higher. Timp1 gene expression was comparable in the ThARKO-DHT ovary and the Con-no DHT ovary. We speculate that the preserved level of Timp1 in ThARKO-DHT mice contributes to retained reproductive function.
Article
A survey was conducted among transsexual women to ask their opinion about the option of freezing sperm, before the start of any medical treatment. We received responses from 121 women. The vast majority feel that the availability of freezing sperm should be discussed and offered by the medical world. A smaller majority would indeed have frozen their own sperm, or at least have seriously considered doing so, if this had been an option. Most women in favour of the idea of sperm freezing were under 40 years of age and identified as lesbian or bisexual. A minority of respondents expressed concern about possible risks of genetically transmitting transsexualism to their children, or considered the whole idea of sperm freezing to be in conflict with their female core identity. Many women expressed regret that they could not become pregnant and have a child themselves.
Article
Hormonal and surgical treatments for transgender people have a devastating effect on the possibility for these patients to reproduce. Additionally, transgender people tend to start sex reassignment treatment at a young age, when reproductive wishes are not yet clearly defined nor fulfilled. The most recent Standards of Care of the World Professional Association for Transgender Health recommend clearly informing patients regarding their future reproductive options prior to initiation of treatment. This review gives an overview of the current knowledge and state-of-the-art techniques in the field of fertility preservation for transgender people. Where genital reconstructive surgery definitely results in sterility, hormone therapy on the other hand also has an important, but partially reversible impact on fertility. The current fertility preservation options for trans men are embryo cryopreservation, oocyte cryopreservation and ovarian tissue cryopreservation. For trans women, sperm cryopreservation, surgical sperm extraction and testicular tissue cryopreservation are possible. Although certain fertility preservation techniques could be applicable in a standardized manner based on clear biological criteria, the technique that eventually will be performed should be the preferred choice of the patient after extended explanation of all possible options.
Article
The sexual behavior of male and female guinea pigs from mothers receiving testosterone propionate during most of pregnancy was studied after the attainment of adulthood. As a part of the investigation, the responsiveness of the females to estradiol benzoate and progesterone and to testosterone propionate was determined. The larger quantities of testosterone propionate produced hermaphrodites having external genitalia indistinguishable macroscopicalty from those of newborn males. Gonadectomized animals of this type were used for tests of their responsiveness to estradiol benzoate and progesterone and to testosterone propionate. The capacity to display lordosis following administration of estrogen and progesterone was greatly reduced. Male-like mounting behavior, on the other hand, was displayed by many of these animals even when lordosis could not be elicited. Suppression of the capacity for displaying lordosis was achieved with a quantity of androgen less than that required for masculinization of the external genitalia. The hermaphrodites receiving testosterone propionate as adults displayed an amount of mounting behavior which approached that displayed by the castrated injected males receiving the same hormone. The data are uniform in demonstrating that an androgen administered prenatally has an organizing action on the tissues mediating mating behavior in the sense of producing a responsiveness to exogenous hormones which differs from that of normal adult females. No structural abnormalities were apparent in the male siblings and their behavior was essentially normal. The results are believed to justify the conclusion that the prenatal period is a time when fetal morphogenic substances have an organizing or “differentiating” action on the neural tissues mediating mating behavior. During adulthood the hormones are activational. Attention is directed to the parallel nature of the relationship, on the one hand, between androgens and the differentiation of the genital tracts, and on the other, between androgens and the organization of the neural tissues destined to mediate mating behavior in the adult.
Article
Androgens have essential roles in the regulation of follicular development and female fertility. Androgen excess is the leading defect in polycystic ovary syndrome (PCOS) patients and involved in the ovarian dysfunction. The aim of this study was to elucidate the regarding regulatory role of androgen in the follicular development of female mouse. Immunohistochemical staining and Western blot analyses were performed to detect androgen receptor (AR) and Connexin 43 (Cx43) expression in ovaries from both control and testosterone-treated group mice. In this study, localizations of AR and Cx43 were dramatically altered in testosterone-treated mouse ovaries. In addition, AR expression was significantly increased, whereas Cx43 expression was markedly decreased after testosterone treatment. Alterations of AR and Cx43 expression by testosterone with concomitant reduction of MII oocytes. Overall, these results suggest the involvement of androgen in the regulation of AR and Cx43 localizations in mouse ovary. Alterations of AR and Cx43 expression by testosterone may affect normal folliculogenesis. Together these findings will enable us to begin understanding the important roles of AR and Cx43 actions in the regulation of follicular development, as well as providing insights into the role of AR and Cx43 actions in the androgen-associated reproductive diseases such as PCOS. Copyright © 2015 Elsevier Ltd. All rights reserved.
Article
Microscopic evaluation of the types of cells present in vaginal smears has long been used to document the stages of the estrous cycle in laboratory rats and mice and as an index of the functional status of the hypothalamic-pituitary-ovarian axis. The estrous cycle is generally divided into the four stages of proestrus, estrus, metestrus, and diestrus. On cytological evaluation, these stages are defined by the absence, presence, or proportion of 4 basic cell types as well as by the cell density and arrangement of the cells on the slide. Multiple references regarding the cytology of the rat and mouse estrous cycle are available. Many contemporary references and studies, however, have relatively abbreviated definitions of the stages, are in reference to direct wet mount preparations, or lack comprehensive illustrations. This has led to ambiguity and, in some cases, a loss of appreciation for the encountered nuances of dividing a steadily moving cycle into 4 stages. The aim of this review is to provide a detailed description, discussion, and illustration of vaginal cytology of the rat and mouse estrous cycle as it appears on smears stained with metachromatic stains. © 2015 by The Author(s).