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Background: Venous thromboembolism (VTE) is a rare side effect of hormonal therapy in transgender persons. Prothrombotic genetic variants can increase this risk. For this reason, previous VTE and/or genetic thrombophilia may be considered by some as contraindications to hormonal treatment. Aim: To formulate directions for clinical practice about the indications for thrombophilia screening and when to consider combination therapy of therapeutic anticoagulation and hormonal treatment as a safe alternative to withholding hormonal treatment. Methods: We conducted a literature search and describe a case series. All adult patients with gender dysphoria and a known prothrombotic genetic variant or history of VTE were invited by letter to participate in this study. Results: In our center, thrombophilia screening before start of hormonal treatment was restricted to those with a personal or family history of VTE. Sixteen individuals with a history of VTE and/or an underlying prothrombogenic condition were described. The time of follow up varied from 4 months to 20 years. Seven trans women had a positive thrombophilia screening (2 Factor V Leiden (FVL), 1 FVL + anticardiolipin antibodies, 1 FVL + high Factor VIII coagulant activity, 1 protein C deficiency, 1 prothrombin mutation, 1 positive lupus anticoagulant). Three trans women experienced an unprovoked VTE after start of hormonal therapy of which one lead to a positive thrombophilia screening. One VTE event in a trans woman was assumed to be provoked by surgery. Five trans men were identified with a prothrombogenic mutation (3 FVL, 1 protein C deficiency, 1 prothrombin mutation). One trans man, with a negative thrombophilia screen, experienced multiple provoked VTE events before start of hormonal therapy. Conclusion: Based on our literature review and case series we offer guidance when confronted with patients with previous VTE and/or genetic thrombophilia requesting hormonal interventions.

Background Initiating feminizing gender-affirming hormone therapy (GAHT) in transgender women causes a steep decline in serum testosterone. It is unknown if testosterone concentrations change further and whether adrenal androgen levels change during feminizing GAHT and after gonadectomy. This limits clinical decision making in transgender women with symptoms attributed to GAHT or gonadectomy. Methods Transgender women (n = 275) initiating estradiol and cyproterone acetate (CPA) were included at baseline, and had follow-up visits after 3 months, 12 months, and 2 to 4 years. During follow-up, 49.5% of transgender women underwent a gonadectomy. Total testosterone (TT), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS), and androstenedione (A4) were measured using liquid chromatography tandem mass spectrometry. Results After 3 months of GAHT, mean TT, calculated free testosterone (cFT), and A4 decreased by 18.4 nmol/L (95% CI, −19.4 to −17.4, P < 0.001 [ie, −97.1%]), 383 pmol/L (95% CI, −405 to −362, P < 0.001 [ie, −98.3%]), and 1.2 nmol/L (95% CI, −1.4 to −1.0, P < 0.001 [ie, −36.5%]), respectively, and remained stable thereafter. DHEA and DHEAS decreased by 7.4 nmol/L (95% CI, −9.7 to −5.1 [ie, −28.0%]) and 1.8 µmol/L (95% CI, −2.2 to −1.4 [ie, −20.1%]), respectively, after 1 year and did not change thereafter. After gonadectomy, CPA therapy is stopped, which induced no further change in TT, cFT, DHEA, DHEAS, and A4 compared with those who did not undergo gonadectomy. Conclusions Our findings confirm that after an initial drop, testosterone levels in transgender women remain stable. Adrenal androgens decrease in the first year of CPA and estrogen supplementation and remain unchanged after gonadectomy. Androgens did not change after gonadectomy and cessation of CPA. Correlates with clinical symptoms remain to be elucidated.

Transgender persons identify with a gender different from the one they were assigned at birth. Although describing oneself as transgender is not a new phenomenon, media attention has lately been increasing exponentially, thanks to progressive changes in laws and change in societal attitudes. These changes also allow more people nowadays to (openly) identify as transgender and/or seek gender-affirming treatment. However, simultaneously, not much is presently understood about the underlying neurobiology, and specifically the brain structure and brain function of transgender persons. One major question in neuroimaging and neuroscience has been to determine whether, at the brain level, transgender people resemble more their gender identity, their sex assigned at birth, or have a unique neural profile. Although the evidence is presently inconsistent, it suggests that while the brain structure, at least before hormonal treatment, is more similar to sex assigned at birth, it may shift with hormonal treatment. By contrast, on “sex-stereotypical tasks,” brain function may already be more similar to gender identity in transgender persons, also before receiving gender-affirming hormone treatment. However, studies continue to be limited by small sample sizes and new initiatives are needed to further elucidate the neurobiology of a ‘brain gender’ (sex-dimorphic change according to one’s gender). Transgender-Personen identifizieren sich mit einem anderen Geschlecht als dem bei der Geburt zugewiesenen. Obwohl Menschen, die sich mit einem anderen Geschlecht identifizieren, kein neues Phänomen sind, so ist die mediale Aufmerksamkeit in den letzten Jahren diesbezüglich exponentiell gestiegen. Dies ist auch den gesetzlichen Verbesserungen und einer Veränderung in der gesellschaftlichen Einstellung zu dem Thema zu verdanken. Zur gleichen Zeit aber weiß man noch nicht viel über die Gehirnstruktur und Gehirnfunktion bei transgender Menschen. Eine Hauptfrage in den Neurowissenschaften ist es, ob die Gehirne von Transgender-Personen jenen ähneln des Geschlechtes, dem sie bei der Geburt zugewiesen wurden, des Geschlechtes mit dem sie sich identifizieren, oder ob sie ein unabhängiges neuronales Profil aufzeigen. Obwohl die Befunde derzeit widersprüchlich sind, zeigen sie in die Richtung, dass sich die Gehirnstruktur vor der hormonellen Behandlung nur unwesentlich verändert. Auf der anderen Seite gleicht die neuronale Aktivität bei “geschlechtstypischen Aufgaben” von Transgender-Personen der neuronalen Aktivität ihres identifizierten Geschlechts (auch schon vor der Hormonbehandlung). Trotzdem sind Studien weiterhin limitiert, da sie oft mit kleinen Stichproben auskommen müssen und neue Initiativen zur Bestätigung der ersten Befunde nötig sind.

Literature on the efficacy and safety of gender-affirming hormonal treatment (GAHT) in transgender people is limited. For this reason, in 2010 the European Network for the Investigation of Gender Incongruence (ENIGI) study was born. The aim of this review is to summarize evidence emerging from this prospective multicentric study and to identify future perspectives. GAHT was effective in inducing desired body changes in both trans AMAB and AFAB people (assigned male and female at birth, respectively). Evidence from the ENIGI study confirmed the overall safety of GAHT in the short/mid-term. In trans AMAB people, an increase in prolactin levels was demonstrated, whereas the most common side effects in trans AFAB people were acne development, erythrocytosis, and unfavorable changes in lipid profile. The main future perspectives should include the evaluation of the efficacy and safety of non-standardized hormonal treatment in non-binary trans people. Furthermore, long-term safety data on mortality rates, oncological risk, and cardiovascular, cerebrovascular and thromboembolic events are lacking. With this aim, we decided to extend the observation of the ENIGI study to 10 years in order to study all these aspects in depth and to answer these questions.

Background Minority stress via discrimination, stigmatization, and exposure to violence can lead to development of mood and anxiety disorders and underlying neurobiochemical changes. To date, the neural and neurochemical correlates of emotion processing in transgender people (and their interaction) are unknown. Methods This study combined functional magnetic resonance imaging and magnetic resonance spectroscopy to uncover the effects of anxiety and perceived stress on the neural and neurochemical substrates, specifically choline, on emotion processing in transgender men. Thirty transgender men (TM), 30 cisgender men, and 35 cisgender women passively viewed angry, neutral, happy, and surprised faces in the functional magnetic resonance imaging scanner, underwent a magnetic resonance spectroscopy scan, and filled out mood- and anxiety-related questionnaires. Results As predicted, choline levels modulated the relationship between anxiety and stress symptoms and the neural response to angry and surprised (but not happy faces) in the amygdala. This was the case only for TM but not cisgender comparisons. More generally, neural responses in the left amygdala, left middle frontal gyrus, and medial frontal gyrus to emotional faces in TM resembled that of cisgender women. Conclusions These results provide first evidence, to our knowledge, of a critical interaction between levels of analysis and that choline may influence neural processing of emotion in individuals prone to minority stress.

Much research has been conducted on sexual differences of the human brain to determine whether and to what extent a brain gender exists. Consequently, a variety of studies using different neuroimaging techniques attempted to identify the existence of a brain phenotype in people with gender dysphoria (GD). However, to date, brain sexual differences at the metabolite level using magnetic resonance spectroscopy (1H-MRS) have not been explored in transgender people. In this study, 28 cisgender men (CM) and 34 cisgender women (CW) and 29 transgender men with GD (TMGD) underwent 1H-MRS at 3 Tesla MRI to characterize common brain metabolites. Specifically, levels of N–acetyl aspartate (NAA), choline (Cho), creatine (Cr), glutamate and glutamine (Glx), and myo-inositol + glycine (mI + Gly) were assessed in two brain regions, the amygdala-anterior hippocampus and the lateral parietal cortex. The results indicated a sex-assigned at birth pattern for Cho/Cr in the amygdala of TMGD. In the parietal cortex, a sex-assigned at birth and an intermediate pattern were found. Though assessed post-hoc, exploration of the age of onset of GD in TMGD demonstrated within-group differences in absolute NAA and relative Cho/Cr levels, suggestive for a possible developmental trend. While brain metabolite levels in TMGD resembled those of CW, some interesting findings, such as modulation of metabolite concentrations by age of onset of GD, warrant future inquiry.

BACKGROUND: Previous studies have cross-sectionally described amenorrhea in cohorts of transgender men on intramuscular or subcutaneous testosterone injections. It remains uncertain which testosterone preparations most effectively suppress vaginal bleeding and when amenorrhea occurs after testosterone initiation. AIM: To investigate the clinical effects of various testosterone preparations on vaginal bleeding and spotting in transgender men. METHODS: This prospective cohort study was part of the European Network for the Investigation of Gender Incongruence (ENIGI). Data on the persistence and intensity of vaginal bleeding and spotting, serum sex steroid levels and body composition were prospectively and cross-sectionally assessed in 267 transgender men during a three-year follow-up period, starting at the initiation of various testosterone preparations. RESULTS: After three months of testosterone, 17.9% of transgender men reported persistent vaginal bleeding and 26.8% reported spotting. The percentages reporting vaginal bleeding and spotting decreased over the first year of testosterone (bleeding 4.7% and spotting 6.9% at 12 months, respectively), with no participants reporting vaginal bleeding or spotting after 18 months of testosterone. Factors associated with vaginal bleeding or spotting included lower serum testosterone levels and being on testosterone gel as compared to injections (e.g., esters or undecanoate preparations). If vaginal bleeding persisted, starting progestogens at three months resulted in a decrease in the intensity of vaginal bleeding and spotting. DISCUSSION: Transgender men and hormone-prescribing providers can be reassured that vaginal bleeding and spotting usually stop within three months after testosterone initiation. If not, serum testosterone levels should be measured and testosterone dose adjusted to achieve serum testosterone levels in the physiologic male range. Adding a progestin can be considered after three to six months if bleeding persists. Providers should be aware that cessation of bleeding can be more difficult to achieve in transgender men with lower serum testosterone levels or those on testosterone gel.

STUDY QUESTION Does gender-affirming treatment prevent full spermatogenesis in transgender women (TW)? SUMMARY ANSWER Adequate hormonal therapy (HT) leads to complete suppression of spermatogenesis in most TW, if serum testosterone levels within female reference ranges are obtained. WHAT IS KNOWN ALREADY Gender-affirming treatment in transgender individuals may involve gender-affirming HT. The effects on spermatogenesis in TW remain unclear. In order to add information from a referral centre for transgender care, we wish to compare results of earlier studies with our population of TW who received a standard hormone treatment. STUDY DESIGN, SIZE, DURATION This was a prospective cohort study part of the European Network for the Investigation of Gender Incongruence (ENIGI), conducted between 15 February 2010 and 30 September 2015. There were 162 TW were included in the ENIGI study at the Ghent University Hospital in Belgium. Participants are included in ENIGI when they first start HT, and follow-up visits occur over the next 3 years. PARTICIPANTS/MATERIALS, SETTING METHODS The study included 97 TW who initiated HT with cyproterone acetate (CPA) plus oestrogens and proceeded with gonadectomy at the Ghent University Hospital. Testicular tissue retrieved during gonadectomy was processed and stained for four different germ cell markers by the Biology of the Testis lab at the Vrije Universiteit Brussel. Subsequent immunohistochemical staining was performed for melanoma-associated antigen A4 (MAGE-A4, marker for spermatogonia and early spermatocytes), boule homologue, RNA-binding protein (BOLL, marker for secondary spermatocytes and round spermatids), cAMP-responsive element modulator (CREM, marker for round spermatids) and acrosin (marker for acrosome visualization). Serum levels of sex steroids were measured prior to surgery. MAIN RESULTS AND THE ROLE OF CHANCE Suppressed testosterone levels ( LIMITATIONS, REASONS FOR CAUTION Testicular function of the participants prior to initiation of HT was not assessed, although all participants presented with cisgender male serum testosterone values before initiation of HT. The current study only reports on people using CPA at a fixed dose and may therefore not be applicable to all TW. WIDER IMPLICATIONS OF THE FINDINGS HT leads to complete suppression of spermatogenesis in most TW, if serum testosterone levels within female reference ranges are obtained. Serum testosterone levels are associated with the sperm maturation rate. It is important to discuss sperm preservation before the start of hormone therapy. If serum testosterone levels remain higher, spermatogenesis may still occur. STUDY FUNDING/COMPETING INTEREST(S) D.V.S. is a post-doctoral fellow of the Fonds Wetenschappelijk Onderzoek (FWO; 12M2819N). Processing of the testis specimens was funded by the Biology of The Testes (BITE) research group (Department of Reproduction, Genetics and Regenerative medicine at Vrije Universiteit Brussel (VUB)). There are no competing interests. TRIAL REGISTRATION NUMBER N/A.

Introduction: Aromatization of exogenous testosterone might result in increased estradiol levels. Concerns have been raised about undesired estrogenic effects in assigned female at birth (AFAB) transgender people. How serum estradiol levels change after initiation of testosterone therapy and if these levels should be monitored, remains unclear. Methods: This prospective cohort study was part of the European Network for the Investigation of Gender Incongruence (ENIGI). Serum levels of sex steroids were assessed in 746 AFAB transgender people during a three-year follow-up period, starting at the initiation of hormone treatment. Results: Estradiol levels decreased from median [P25-P75] 45.5[24.0-102.2]pg/mL to 36.5[25.0-46.2]pg/mL over three years (P

Background: Previous studies have cross-sectionally described amenorrhea in cohorts of transgender men on intramuscular or subcutaneous testosterone injections. It remains uncertain which testosterone preparations most effectively suppress vaginal bleeding and when amenorrhea occurs after testosterone initiation.Aim: To investigate the clinical effects of various testosterone preparations on vaginal bleeding and spotting in transgender men.Methods: This prospective cohort study was part of the European Network for the Investigation of Gender Incongruence (ENIGI). Data on the persistence and intensity of vaginal bleeding and spotting, serum sex steroid levels and body composition were prospectively and cross-sectionally assessed in 267 transgender men during a three-year follow-up period, starting at the initiation of various testosterone preparations.Results: After three months of testosterone, 17.9% of transgender men reported persistent vaginal bleeding and 26.8% reported spotting. The percentages reporting vaginal bleeding and spotting decreased over the first year of testosterone (bleeding 4.7% and spotting 6.9% at 12 months, respectively), with no participants reporting vaginal bleeding or spotting after 18 months of testosterone. Factors associated with vaginal bleeding or spotting included lower serum testosterone levels and being on testosterone gel as compared to injections (e.g., esters or undecanoate preparations). If vaginal bleeding persisted, starting progestogens at three months resulted in a decrease in the intensity of vaginal bleeding and spotting.Discussion: Transgender men and hormone-prescribing providers can be reassured that vaginal bleeding and spotting usually stop within three months after testosterone initiation. If not, serum testosterone levels should be measured and testosterone dose adjusted to achieve serum testosterone levels in the physiologic male range. Adding a progestin can be considered after three to six months if bleeding persists. Providers should be aware that cessation of bleeding can be more difficult to achieve in transgender men with lower serum testosterone levels or those on testosterone gel.

Purpose: Concerns have been raised about undesired estrogenic effects in assigned female at birth (AFAB) transgender people on testosterone therapy. How serum estradiol levels change after initiation of testosterone therapy and if these levels should be monitored remain unclear. Methods: This prospective cohort study was part of the European Network for the Investigation of Gender Incongruence. Serum levels of sex steroids were assessed in 746 AFAB transgender people during a 3-year follow-up period, starting at the initiation of hormone treatment. Results: Estradiol levels decreased from median [P25-P75] 45.6 [24.0-102.2] pg/mL to 36.5 [25.0-46.2] pg/mL over 3 years (p < 0.001); a change was already noticeable during the first 3 months (mean -17.1 pg/mL, 95% confidence interval -23.8 to -10.6, p < 0.001). Serum estradiol levels were lower in people without endogenous estradiol production from ovarian source (contraceptive users or post hystero-oophorectomy) at baseline and after 3 months, compared with people with endogenous estradiol production. Using long-acting testosterone undecanoate injections resulted in a more prominent decrease in serum estradiol values over 12 months, compared with short-acting mixed testosterone esters (p < 0.001) or testosterone gel (p = 0.001). Changes in serum estradiol were positively correlated to changes in luteinizing hormone (ρ = 0.107, p < 0.001) and negatively correlated to changes in follicle-stimulating hormone levels (ρ = -0.167, p < 0.001) and body mass index (ρ = -0.082, p < 0.001). Conclusion: Testosterone administration in AFAB transgender people resulted in decreasing serum estradiol levels. Our results suggest that testosterone therapy leads to central suppression of estradiol production, with partial restitution due to aromatization.

Background: Much research has been conducted on sexual dimorphisms of the human brain to determine whether and to what extent a brain gender exists. Consequently, a variety of studies using different neuroimaging techniques attempted to identify the existence of a brain phenotype in people with gender dysphoria (GD). However, to date, brain sexual dimorphisms at the metabolite level in transgender people have not been explored using magnetic resonance spectroscopy (1H-MRS). Methods: In this study, 29 transgender men, 30 cisgender men and 35 cisgender women underwent 1H-MRS at 3 Tesla MRI to characterize common brain metabolites. Specifically, absolute levels of N –acetyl aspartate (NAA), choline (Cho), creatine (Cr), glutamate (Glu), myo-inositol (mI) and their respective ratios were assessed in two brain regions, i.e. the amygdala-anterior hippocampus and the lateral parietal cortex. Influences of nicotine consumption, physical activity, education and psychopathology were considered. Results: The results indicated a sex-assigned at birth pattern for choline and glutamate ratios in the amygdala-anterior hippocampus of trans men. In the lateral parietal cortex cis men and cis women differed in the majority of metabolites (i.e. mI; Cr; NAA/Cr; Cho/Cr; mI/Cr; NAA/mI). Moreover, except for mI, trans men did not differ from either cisgender group, showing a pattern subtly moving towards the experienced gender identity. Post-hoc, careful exploration of the age of onset of GD in transgender men demonstrated the possibility of a developmental trend in absolute NAA levels, as a measure of neuronal function. Conclusion: We found sex-typical 1H-MRS spectra and they appear to be brain region specific. While the brain metabolite levels in trans men mostly resembled that of cis women, interesting findings such as modulation by age of onset warrant future enquiry to address potential neurobiological underpinnings of GD.