Approach to the Patient: Hormonal Therapy in Transgender Adults With Complex Medical Histories.

While endocrinologists continue to initiate gender-affirming hormone therapy (GAHT) in healthy transgender and gender diverse (TGD) patients, they may also encounter more TGD patients in their clinics with complex medical histories that influence the patient-provider shared decision-making process for initiating or continuing GAHT. The purpose of this Approach to the Patient article is to describe management considerations in 2 adults with thromboembolic disease and 2 adults with low bone mineral density in the setting of feminizing and masculinizing GAHT.

Gender-affirming hormone therapy, mental health, and surgical considerations for aging transgender and gender diverse adults.

As the transgender and gender diverse (TGD) population ages, more transfeminine and transmasculine individuals present to clinic to initiate or continue their gender-affirming care at older ages. Currently available guidelines on gender-affirming care are excellent resources for the provision of gender-affirming hormone therapy (GAHT), primary care, surgery, and mental health care but are limited in their scope as to whether recommendations require tailoring to older TGD adults. Data that inform guideline-recommended management considerations, while informative and increasingly evidence-based, mainly come from studies of younger TGD populations. Whether results from these studies, and therefore recommendations, can or should be extrapolated to aging TGD adults remains to be determined. In this perspective review, we acknowledge the lack of data in older TGD adults and discuss considerations for evaluating cardiovascular disease, hormone-sensitive cancers, bone health and cognitive health, gender-affirming surgery, and mental health in the older TGD population on GAHT.

Change in Visceral Fat and Total Body Fat and the Effect on Cardiometabolic Risk Factors During Transgender Hormone Therapy.

INTRODUCTION: Excess visceral fat increases the risk of type 2 diabetes and cardiovascular disease and is influenced by sex hormones. Our aim was to investigate changes in visceral fat and the ratio of visceral fat to total body fat (VAT/TBF) and their associations with changes in lipids and insulin resistance after 1 year of hormone therapy in trans persons. METHODS: In 179 trans women and 162 trans men, changes in total body and visceral fat estimated with dual-energy X-ray absorptiometry before and after 1 year of hormone therapy were related to lipids and insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR)] with linear regression analysis. RESULTS: In trans women, total body fat increased by 4.0 kg (95% CI 3.4, 4.7), while the amount of visceral fat did not change (-2 grams; 95% CI -15, 11), albeit with a large range from -318 to 281, resulting in a decrease in the VAT/TBF ratio of 17% (95% CI 15, 19). In trans men, total body fat decreased with 2.8 kg (95% CI 2.2, 3.5), while the amount of visceral fat did not change (3 g; 95% CI -10, 16; range -372, 311), increasing the VAT/TBF ratio by 14% (95% CI 10, 17). In both groups, VAT/TBF was not associated with changes in blood lipids or HOMA-IR. CONCLUSIONS: Hormone therapy in trans women and trans men resulted in changes in VAT/TBF, mainly due to changes in total body fat and were unrelated to changes in cardiometabolic risk factors, which suggests that any unfavorable cardiometabolic effects of hormone therapy are not mediated by changes in visceral fat or VAT/TBF.

Low feasibility of in vitro matured oocytes originating from cumulus complexes found during ovarian tissue preparation at the moment of gender confirmation surgery and during testosterone treatment for fertility preservation in transgender men.

OBJECTIVE: To study the feasibility of in vitro maturation of ovarian tissue oocytes for fertility preservation in transgender men on testosterone treatment. DESIGN: Cross-sectional study SETTING: University hospital PATIENT(S): Eighty-three transgender men enrolled from November 2015 to January 2019 INTERVENTION(S): In vitro maturation of cumulus-oocyte complexes (COCs) harvested at the time of gender confirmation surgery, and fertilization through intracytoplasmic sperm injection. MAIN OUTCOME MEASURE(S): In vitro maturation, fertilization, and blastulation rates; comparison of morphokinetics with vitrified-warmed oocytes; and analysis of the genetic profiles of embryos. SECONDARY OUTCOMES: association between serum hormone levels; COCs' morphologic characteristics, and vitrification rate. RESULT(S): All participants were on testosterone treatment for a median of 83 (64[Quartile 1]; 113.2[Quartile 2]) weeks. A total of 1,903 COCs (mean per participant, 23 ± 15.8) were collected. The in vitro maturation rate was 23.8%, vitrification rate was 21.5%, and survival rate after warming was 72.6% (n = 151). Intracytoplasmic sperm injection was performed in 139 oocytes. The rate of normal fertilized oocytes was 34.5%, and 25 (52.1%) embryos reached day 3. One blastocyst was achieved on day 5. Aberrant cleavage patterns and early embryo arrest were observed in 22 (45.8%) and 44 (91.7%) zygotes, respectively. Compared with vitrified-warmed donor oocytes, a delay was observed in pronuclei disappearance, t2 (time to reach 2 cell stage) timings, and CC1 (the duration of the 1st cell cycle) and SS3 (synchronization of cleavage pattern (calculated as t8-t5) time intervals. A normal genetic pattern was seen in 42% embryos. The proportion of vitrified oocytes was negatively associated with progesterone (odds ratio, 0.76) and positively associated with antimüllerian hormone serum levels (odds ratio, 1.23). The highest vitrification rate was achieved by the morphologic characteristic 344 at day 0 and by 433 at day 2. CONCLUSION(S): Ovarian tissue oocytes matured in vitro show low developmental capacity in transgender men, when collected under testosterone treatment.

Is there a need for liver enzyme monitoring in people using gender-affirming hormone therapy?

CONTEXT: Individuals with gender dysphoria can receive gender-affirming hormone therapy. Different guidelines mention a severe risk of liver injury within the first months after the start of treatment with anabolic androgenic steroids, anti-androgens, and oral contraceptives, which is potentially fatal. OBJECTIVE: The incidence of liver injury in a transgender population using gender-affirming hormone therapy. DESIGN: Multicentre prospective study with 1933 transgender individuals, who started with hormone therapy between 2010 and 2020. METHODS: The following parameters were analysed before hormone therapy, after 3 months, and after 12 months of hormone therapy: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyltransferase (GGT). Both male and female reference values were considered. Liver injury was defined as either an elevation of 2× upper limit of normal (ULN) of ALP, 3× ULN of ALT, or 3× ULN of AST. RESULTS: 889 transgender women and 1044 transgender men were included in the analysis. The incidence of liver injury within 12 months after the start of hormone therapy, without attribution to alcohol abuse, medical history, or comedication was 0.1 and 0.0%. in transgender women according to female and male reference intervals respectively, and 0.6 and 0.4% in transgender men (female and male reference intervals). CONCLUSION: The incidence of liver injury is found to be very low. We, therefore, conclude that liver enzyme monitoring within the frame of the risk of liver injury due to hormone therapy is not necessary for a transgender population.

Positive and Negative Affect Changes during Gender-Affirming Hormonal Treatment: Results from the European Network for the Investigation of Gender Incongruence (ENIGI).

Improving transgender people's quality of life (QoL) is the most important goal of gender-affirming care. Prospective changes in affect can influence QoL. We aim to assess the impact of initiating gender-affirming hormonal treatment (HT) on affect. In the European Network for the Investigation of Gender Incongruence (ENIGI) study, we prospectively collected data of 873 participants (451 transwomen (TW) and 422 transmen (TM)). At baseline, psychological questionnaires including the Positive and Negative Affect Schedule (PANAS) were administered. The PANAS, levels of sex steroids and physical changes were registered at each follow-up visit during a 3-year follow-up period, starting at the initiation of hormonal therapy. Data were analyzed cross-sectionally and prospectively. Over the first three months, we observed a decline in positive affect (PA) in both TM and TW. Thereafter, PA reached a steady state in TW, whereas in TM there was also a second decline at 18 months. In both TM and TW there was no persisting difference comparing baseline to the 36-months results. Concerning negative affect (NA), we observed a decline during the first year in TM, which sustained during the second year and was not different anymore at 36 months compared to baseline. In TW though, we did not find any change of NA during the entire follow-up. Even if some of these results show significant differences, they should be considered with caution, since there was no control group and the absolute differences are small. No association between affect and the level of sex steroids was observed. Baseline QoL and psychological burden are related to affect independently from gender but are not necessarily good predictors of the evolution of one's affect during the gender-affirming process. Further research is necessary to investigate these preliminary results.

Characterisation of testicular function and spermatogenesis in transgender women.

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 (<50 ng/dl) were found in 92% of the participants prior to surgery. The mean time between initiation of HT and surgery was 685 days. In 88% (85/97) of the sections, MAGE-A4 staining was positive. Further staining could not reveal complete spermatogenesis in any participant. 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.

Organizing the voice questionnaire for transgender persons.

Background: The validated Transsexual Voice Questionnaire Male to Female (TVQMtF) and the adapted TVQ Female to Male (FtM) (TVQFtM) are both 30-item-long questionnaires used to evaluate self-perception of voice in transgender persons. They are part of a series of questionnaires completed by transgender persons during follow-up of cross-sex hormone therapy (CSHT). Aim: The aim of this study was to examine if these questionnaires can be organized. Methods: The TVQMtF or the TVQFtM was filled out at the start of CSHT, by 145 trans women and 83 trans men. Data were analyzed by factor analyses on both the questionnaires. Results: The factor analyses resulted in a three-factor solution for both the TVQMtF and the TVQFtM. The three factors were labeled as anxiety and avoidance, vocal identity, and vocal function. Conclusion: Both the questionnaires can be organized into three factors. This could contribute to making shorter versions of the questionnaires. Shorter versions would be useful to hormone prescribing physicians to track down more quickly voice problems in trans people undergoing virilizing or feminizing hormone treatment.

Parental desire and fertility preservation in assigned male at birth transgender people living in Belgium.

Introduction: Transgender people who chose to proceed with gender affirming hormonal and/or surgical therapy, may face reduced options for fulfilling their parental desire in the future. The ideas and concerns of adult transgender people regarding fertility preservation and parental desire have never been reported in a large, non-clinical sample of assigned male at birth (AMAB) transgender people. Methods: A web-based survey on fertility and parenthood in (binary and non-binary) transgender people was conducted in Belgium. AMAB people were selected for this analysis. Results: We included 254 AMAB persons, of which 196 (77.2%) self-identified as transgender women (TW), 14 (5.5%) as cross-dressers and 44 (17.3%) as gender non-binary (GNB) people. Fifty-five (21.6%) respondents had a current/future parental desire, parental desire was already fulfilled in 81 (31.9%) and not present in 57 people (22.4%) (other: 19.2%). TW were more likely to express a parental desire, compared to GNB people and cross-dressers (P = 0.004). In total, 196 AMAB people previously sought medical assistance, of which 30 (15.3%) considered the loss of fertility due to the transitioning process undesirable. The majority (68.2%) did not want fertility preservation (FP). Fourteen people (9.8%) had proceeded with FP. The main reasons not to proceed with FP included not feeling the need (70; 68.0%), not desiring a genetic link with (future) child(ren) (20; 19.4%) and having to postpone hormone treatment (15; 14.6%). TW were more likely to have a parental desire and to have cryopreserved or to consider cryopreserving gametes, compared to GNB people. Conclusion: Parental desire and FP use were lower in the current non-clinical sample than in previous research on clinical samples. This can possibly be explained by the barriers transgender people face when considering fertility options, including postponing hormone therapy. Also, GNB persons have different needs for gender affirming treatment and FP.

Vaginal bleeding and spotting in transgender men after initiation of testosterone therapy: A prospective cohort study (ENIGI).

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.

Lower Serum Estradiol Levels in Assigned Female at Birth Transgender People with Initiation of Testosterone Therapy: Results from the European Network for the Investigation of Gender Incongruence.

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.

Sexual Desire Changes in Transgender Individuals Upon Initiation of Hormone Treatment: Results From the Longitudinal European Network for the Investigation of Gender Incongruence.

INTRODUCTION: Several steps in the transitioning process may affect sexual desire in transgender people. This is often underexposed by those providing gender-affirming care. AIM: To prospectively assess sexual desire during the first 3 years of hormonal therapy (HT) in transgender people. METHODS: This prospective cohort study was part of the European Network for the Investigation of Gender Incongruence. At baseline, different psychological questionnaires were administered. Sex steroids were measured at each follow-up visit. Data were analyzed cross-sectionally and prospectively. MAIN OUTCOME MEASURE: Prospective analysis of total, dyadic (with another person), and solitary (with oneself) sexual desire in 766 participants (401 transgender women [TW], 364 transgender men [TM]) was carried out using the Sexual Desire Inventory (SDI) questionnaire during a 3-year follow-up period, starting at the initiation of HT. Other factors associated with prospective changes were assessed. RESULTS: In TW, total, dyadic, and solitary SDI scores decreased during the first 3 months of HT. However, after 36 months, total and dyadic SDI scores were higher than baseline scores. Solitary scores after 36 months were comparable with baseline scores. In TM, total, dyadic, and solitary SDI scores increased over the first 3 months, remaining stable thereafter. However, total and dyadic SDI scores after 36 months were comparable with baseline scores, whereas solitary scores remained higher than baseline. Factors associated with a prospective increase in SDI scores included having undergone gonadectomy, no longer experiencing menstrual bleeding or higher gender dysphoria levels at baseline (in TM only). CLINICAL IMPLICATIONS: This study offers clear data on the time course of sexual desire after starting HT and thereby helps to inform people who want to start HT. Transgender people can be informed that changes in sexual desire after initiating HT are temporary. Over a longer period of time, the current research does not suggest induction of hypoactive sexual disorder in TW or long-term increased sexual desire in TM. STRENGTH & LIMITATIONS: Strengths include the prospective design of this large multicentric study, the well-defined cohort, controlling for HT, sex steroids, and other factors. Limitations include performing a data lock, the absence of an objective measure of sexual desire, and the timing of laboratory measurements. CONCLUSION: Gender-affirming HT only induces short-term changes in sexual desire in transgender people. Over a longer period of time, a net increase in dyadic sexual desire in TW receiving feminizing HT and sexual desire scores comparable with baseline in TM receiving virilizing HT, were observed. Defreyne J, Elaut E, Kreukels B, et al. Sexual Desire Changes in Transgender Individuals Upon Initiation of Hormone Treatment: Results From the Longitudinal European Network for the Investigation of Gender Incongruence Study. J Sex Med 2020;17:812-825.

Effects of Gender-Affirming Hormone Therapy on Insulin Sensitivity and Incretin Responses in Transgender People.

OBJECTIVE: The long-term influences of sex hormone administration on insulin sensitivity and incretin hormones are controversial. We investigated these effects in 35 transgender men (TM) and 55 transgender women (TW) from the European Network for the Investigation of Gender Incongruence (ENIGI) study. RESEARCH DESIGN AND METHODS: Before and after 1 year of gender-affirming hormone therapy, body composition and oral glucose tolerance tests (OGTTs) were evaluated. RESULTS: In TM, body weight (2.8 ± 1.0 kg; P < 0.01), fat-free mass (FFM) (3.1 ± 0.9 kg; P < 0.01), and waist-to-hip ratio (-0.03 ± 0.01; P < 0.01) increased. Fasting insulin (-1.4 ± 0.8 mU/L; P = 0.08) and HOMA of insulin resistance (HOMA-IR) (2.2 ± 0.3 vs. 1.8 ± 0.2; P = 0.06) tended to decrease, whereas fasting glucose (-1.6 ± 1.6 mg/dL), glucose-dependent insulinotropic polypeptide (GIP) (-1.8 ± 1.0 pmol/L), and glucagon-like peptide 1 (GLP-1) (-0.2 ± 1.1 pmol/L) were statistically unchanged. Post-OGTT areas under the curve (AUCs) for GIP (2,068 ± 1,134 vs. 2,645 ± 1,248 [pmol/L] × min; P < 0.01) and GLP-1 (2,352 ± 796 vs. 2,712 ± 1,015 [pmol/L] × min; P < 0.01) increased. In TW, body weight tended to increase (1.4 ± 0.8 kg; P = 0.07) with decreasing FFM (-2.3 ± 0.4 kg; P < 0.01) and waist-to-hip ratio (-0.03 ± 0.01; P < 0.01). Insulin (3.4 ± 0.8 mU/L; P < 0.01) and HOMA-IR (1.7 ± 0.1 vs. 2.4 ± 0.2; P < 0.01) rose, fasting GIP (-1.4 ± 0.8 pmol/L; P < 0.01) and AUC GIP dropped (2,524 ± 178 vs. 1,911 ± 162 [pmol/L] × min; P < 0.01), but fasting glucose (-0.3 ± 1.4 mg/dL), GLP-1 (1.3 ± 0.8 pmol/L), and AUC GLP-1 (2,956 ± 180 vs. 2,864 ± 93 [pmol/L] × min) remained unchanged. CONCLUSIONS: In this cohort of transgender persons, insulin sensitivity but also post-OGTT incretin responses tend to increase with masculinization and to decrease with feminization.

Parental desire and fertility preservation in assigned female at birth transgender people living in Belgium.

OBJECTIVE: To study the considerations and concerns of transgender people regarding fertility preservation and parental desire in a large, nonclinical sample. Gender-affirming care can reduce fertility. Previous research on fertility in transgender people (mainly focused on people visiting health care professionals) shows low fertility preservation use. DESIGN: A web-based survey on fertility and parenthood. SETTING: Not applicable. PATIENT(S): Transgender people assigned female at birth (AFAB) were selected for this analysis (n = 172 or 40.4% of the total sample) of which 116 (67.4%) self-identified as transgender men (TM) and 56 (32.6%) as gender nonbinary (GNB) people. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Data on parental desire and fertility preservation were assessed in a large, nonclinical sample of AFAB transgender people. RESULT(S): Sixty-seven (39.0%) respondents had a current/future parental desire. Parental desire rates did not differ between TM and GNB persons. Barriers for fulfilling the parental desire (multiple response) included assumed difficulties in the adoption procedure (41.3%), fear of discrimination against the child (38.0%) or being discriminated against as a transgender parent (32.6%), and the cost for using personal genetic material (32.6%). Nine percent had cryopreserved reproductive cells or tissue. CONCLUSION(S): Even though parental desire rates in this cohort are in line with earlier research, fertility preservation use was lower in the current study. These numbers reflect the barriers transgender people face when considering fertility options, including cost and the need to postpone hormone therapy. In addition, GNB persons have different needs for gender-affirming treatment and subsequently for fertility preservation.

Health considerations for transgender women and remaining unknowns: a narrative review.

Transgender (trans) women (TW) were assigned male at birth but have a female gender identity or gender expression. The literature on management and health outcomes of TW has grown recently with more publication of research. This has coincided with increasing awareness of gender diversity as communities around the world identify and address health disparities among trans people. In this narrative review, we aim to comprehensively summarize health considerations for TW and identify TW-related research areas that will provide answers to remaining unknowns surrounding TW's health. We cover up-to-date information on: (1) feminizing gender-affirming hormone therapy (GAHT); (2) benefits associated with GAHT, particularly quality of life, mental health, breast development and bone health; (3) potential risks associated with GAHT, including cardiovascular disease and infertility; and (4) other health considerations like HIV/AIDS, breast cancer, other tumours, voice therapy, dermatology, the brain and cognition, and aging. Although equally deserving of mention, feminizing gender-affirming surgery, paediatric and adolescent populations, and gender nonbinary individuals are beyond the scope of this review. While much of the data we discuss come from Europe, the creation of a United States transgender cohort has already contributed important retrospective data that are also summarized here. Much remains to be determined regarding health considerations for TW. Patients and providers will benefit from larger and longer prospective studies involving TW, particularly regarding the effects of aging, race and ethnicity, type of hormonal treatment (e.g. different oestrogens, anti-androgens) and routes of administration (e.g. oral, parenteral, transdermal) on all the topics we address.

Transmasculine Hormone Therapy.

Prescribing gender-affirming hormonal therapy in transgender men (TM) not only induces desirable physical effects but also benefits mental health. In TM, testosterone therapy is aimed at achieving cisgender male serum testosterone to induce virilization. Testosterone therapy is safe on the short term and middle term if adequate endocrinological follow-up is provided. Transgender medicine is not a strong part of the medical curriculum, although a large number of transgender persons will search for some kind of gender-affirming care. Because hormonal therapy has beneficial effects, all endocrinologists or hormone-prescribing physicians should be able to provide gender-affirming hormonal care.

No correlation between serum testosterone levels and state-level anger intensity in transgender people: Results from the European Network for the Investigation of Gender Incongruence.

INTRODUCTION: Anger is a state of emotions ranging from irritation to intense rage. Aggression implies externalizing anger through destructive/punitive behaviour. The World Professional Association for Transgender Health (WPATH) Standards of Care, Edition 7 (SOC7) guidelines warn about aggression in transgender men (TM) on testosterone treatment. We aimed to assess whether anger intensity increases in TM and decreases in transgender women (TW) after initiation of gender affirming hormone therapy and to identify predictors for anger intensity in transgender people. METHODS: This prospective cohort study was part of the European Network for the Investigation of Gender Incongruence (ENIGI). Anger intensity was prospectively assessed in 898 participants (440 TM, 468 TW) by STAXI-2 (State-Trait Anger Expression Inventory-2) State Anger (S-Anger) during a three-year follow-up period, starting at the initiation of hormone treatment. Data were analysed cross-sectionally and prospectively. RESULTS: There was no change in STAXI-2 S-Anger scores. At three, twelve and thirty-six months of gender affirming hormone therapy, STAXI-2 S-Anger scores were not correlated to serum testosterone levels, although there was a correlation with various psychological measures after three and twelve months. TM experiencing menstrual spotting after three months had higher STAXI-2 S-Anger scores compared to those without (median 26.5 [18.0-29.8] versus 15.0 [15.0-17.0], P = 0.020). Changes in STAXI-2 S-Anger scores were not correlated to changes in serum testosterone levels after three, twelve and thirty-six months in TM or TW. CONCLUSIONS: State-level anger intensity is associated with psychological and/or psychiatric vulnerability, but not exogenous testosterone therapy or serum testosterone levels in transgender people.

Cardiometabolic Effects of Testosterone in Transmen and Estrogen Plus Cyproterone Acetate in Transwomen.

CONTEXT: The impact of gender-affirming hormone therapy (HT) on cardiometabolic parameters is largely unknown. OBJECTIVE: The effects of 1 year of treatment with oral or transdermal administration of estrogen (plus cyproterone) and transdermal or IM application of testosterone on serum lipid levels and blood pressure (BP) were assessed in transgender persons. DESIGN AND METHODS: In this prospective, observational substudy of the European Network for the Investigation of Gender Incongruence, measurements were performed before and after 12 months of HT in 242 transwomen and 188 transmen from 2010 to 2017. RESULTS: Mean values are reported. In transmen, HT increased diastolic BP (2.5%; 95% CI, 0.6 to 4.4) and levels of total cholesterol (TC; 4.1%; 95% CI, 1.5 to 6.6), low-density lipoprotein-cholesterol (LDL-C; 13.0%; 95% CI, 9.2 to 16.8), and triglycerides (36.9%; 95% CI, 29.8 to 44.1); high-density lipoprotein-cholesterol levels decreased (HDL-C; 10.8%; 95% CI, -14.0 to -7.6). In transwomen, HT slightly decreased BP (systolic BP, -2.6%, 95% CI, -4.2 to -1.0; diastolic BP, -2.2%, 95% CI, -4.0 to -0.4) and decreased levels of TC (-9.7%; 95% CI, -11.3 to -8.1), LDL-C (-6.0%; 95% CI, -8.6 to 3.6), HDL-C (-9.3%; 95% CI, -11.4 to -7.3), and triglycerides (-10.2%; 95% CI, -14.5 to -5.9). CONCLUSION: Unfavorable changes in lipid profile were observed in transmen; a favorable effect was noted in transwomen. HT effects on BP were negligible. Long-term studies are warranted to assess whether and to what extent HT in trans individuals results in a differential effect on cardiovascular disease outcomes.

Effects of Gender-Affirming Hormones on Lipid, Metabolic, and Cardiac Surrogate Blood Markers in Transgender Persons.

BACKGROUND: Gender-affirming hormonal therapy consists of testosterone in transgender men and estrogens and antiandrogens in transgender women. Research has concluded that gender-affirming therapy generally leads to high satisfaction rates, increased quality of life, and higher psychological well-being. However, given the higher incidence of cardiometabolic morbidity and mortality in cisgender men compared with cisgender women, concerns about the cardiometabolic risk of androgen therapy have been raised. CONTENT: A literature research was conducted on PubMed, Embase, and Scopus, searching for relevant articles on the effects of gender-affirming hormone therapy on cardiometabolic risk and thrombosis. After screening 734 abstracts, 77 full text articles were retained, of which 11 were review articles. SUMMARY: Studies describing a higher risk for cardiometabolic and thromboembolic morbidity and/or mortality in transgender women (but not transgender men) mainly covered data on transgender women using the now obsolete ethinyl estradiol and, therefore, are no longer valid. Currently, most of the available literature on transgender people adhering to standard treatment regimens consists of retrospective cohort studies of insufficient follow-up duration. When assessing markers of cardiometabolic disease, the available literature is inconclusive, which may be ascribed to relatively short follow-up duration and small sample size. The importance of ongoing large-scale prospective studies/registries and of optimal management of conventional risk factors cannot be overemphasized.