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 (rho = 0.107, p < 0.001) and negatively correlated to changes in follicle-stimulating hormone levels (rho = -0.167, p < 0.001) and body mass index (rho = -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

Bone mineral density increases in trans persons after 1 year of hormonal treatment : a multicenter prospective observational study

Sex steroids are important determinants of bone acquisition and bone homeostasis. Cross-sex hormonal treatment (CHT) in transgender persons can affect bone mineral density (BMD). The aim of this study was to investigate in a prospective observational multicenter study the first-year effects of CHT on BMD in transgender persons. A total of 231 transwomen and 199 transmen were included who completed the first year of CHT. Transwomen were treated with cyproterone acetate and oral or transdermal estradiol; transmen received transdermal or intramuscular testosterone. A dual-energy X-ray absorptiometry (DXA) was performed to measure lumbar spine (LS), total hip (TH), and femoral neck (FN) BMD before and after 1 year of CHT. In transwomen, an increase in LS (+3.67%, 95% confidence interval [CI] 3.20 to 4.13%, p < 0.001), TH (+0.97%, 95% CI 0.62 to 1.31%, p < 0.001), and FN (+1.86%, 95% CI 1.41 to 2.31%, p < 0.001) BMD was found. In transmen, TH BMD increased after 1 year of CHT (+1.04%, 95% CI 0.64 to 1.44%, p < 0.001). No changes were observed in FN BMD (–0.46%, 95% CI –1.07 to 0.16%, p = 0.144). The increase in LS BMD was larger in transmen aged ≥50 years (+4.32%, 95% CI 2.28 to 6.36%, p = 0.001) compared with transmen aged <50 years (+0.68%, 95% CI 0.19 to 1.17%, p = 0.007). In conclusion, BMD increased in transgender persons after 1 year of CHT. In transmen of postmenopausal age, the LS BMD increased more than in younger transmen, which may lead to the hypothesis that the increase in BMD in transmen is the result of the aromatization of testosterone to estradiol

Bone health in adult trans persons: An update of the literature

Purpose of review Hormonal treatment in trans persons can affect bone health. In this review, recent studies published on this topic in adults are discussed. Recent findings Before starting hormonal treatment, trans women were found to have lower bone mineral density than cis men, which seems to be related to lower vitamin D concentrations and lower lean body mass, whereas this was not found in trans men. Short-term and long-term studies show that hormonal treatment does not have detrimental effects on bone mineral density in trans women and trans men. Low estradiol concentrations were associated with a decrease in bone mineral density in trans women. Summary Based on the reassuring findings in these studies, regularly assessing bone mineral density during hormonal treatment does not seem necessary. This confirms the Endocrine Society Guideline stating that bone mineral density should be measured only when risk factors for osteoporosis exist, especially in people who stop hormonal treatment after gonadectomy. The relationship with estradiol concentrations indicate that hormone supplementation should be adequate and therapy compliance should be stimulated. As vitamin D deficiency frequently occurs, vitamin D supplementation should be considered. Future research should focus on fracture risk and long-term changes in bone geometry

The risk of psychosis for transgender individuals:A Dutch national cohort study

Background The stressful minority position of transgender persons may result in a high risk of psychosis. Conflicting data suggest that the observed risk depends on setting of recruitment. We assessed the relative risk of non-affective psychotic disorder (NAPD) in a large, representative cohort of transgender persons. Methods This cohort was composed using: data on legal sex change from the Dutch population registry and data on dispensing of cross-sex hormones (route 1), and a registry of insurance claims from mental health care including persons with a diagnosis of gender identity disorder (DSM-IV) or gender dysphoria (DSM-5) (route 2). They were matched by sex at birth, calendar year and country of birth to controls from the general population. Transgender persons (N = 5564) and controls (N = 27 820), aged 16-60 years at 1 January 2011, were followed until the first insurance claim for NAPD in 2011-2019. Results The incidence rate ratio (IRR) of NAPD for transgender persons selected exclusively through route 1 (N = 3859, IRR = 2.00, 95%-CI 1.52-2.63) was increased, but significantly lower than the IRRs for those selected exclusively through route 2 (N = 694, IRR = 22.15, 95%-CI 13.91-35.28) and for those found by both routes (N = 1011, IRR = 5.17, 95%-CI 3.57-7.49; p value for differences in IRR &lt; 0.001). Conclusions This study supports the social defeat-hypothesis of NAPD. The results also show the presence of a substantial number of transgender persons with severe psychiatric problems who have not (yet) taken steps to gender-affirmative care

Toward a Lowest Effective Dose of Cyproterone Acetate in Trans Women: Results from the ENIGI Study

Context: Cyproterone acetate (CPA) is a competitive inhibitor of the androgen receptor and exerts negative hypothalamic feedback. It is often used in combination with estrogens in trans women to achieve feminization. However, CPA has been associated with side effects such as changes in liver enzyme concentrations and increases in prolactin concentrations. The question is whether the testosterone-lowering effect, as well as these side effects, are dose dependent. Objective: To assess the lowest effective dose of CPA in trans women to prevent side effects. Methods: This longitudinal study, conducted at gender identity centers in Amsterdam, Ghent, and Florence, is part of the European Network for the Investigation of Gender Incongruence (ENIGI), a multicenter prospective cohort study. Participants were trans women (n=882) using estrogens only or in combination with 10, 25, 50, or 100 mg CPA daily. The primary outcome measure was the concentration of testosterone at 3 and/or 12 months of hormone therapy. Results: Using estrogens only (without CPA) led to testosterone concentrations of 5.5 nmol/L (standard error of the mean [SEM] 0.3). All doses of CPA resulted in testosterone concentrations below the predefined threshold of suppression of 2 nmol/L (10 mg, 0.9 nmol/L, SEM 0.7; 25 mg, 0.9 nmol/L, SEM 0.1; 50mg, 1.1 nmol/L, SEM 0.1; 100 mg, 0.9 nmol/L, SEM 0.7). Higher prolactin and lower high-density lipoprotein concentrations were observed with increasing doses of CPA. No differences in liver enzyme concentrations were found between the doses. Conclusion: Compared with higher doses of CPA, a daily dose of 10 mg is equally effective in lowering testosterone concentrations in trans women, while showing fewer side effects

Gender-Affirming Hormone Treatment Decreases Bone Turnover in Transwomen and Older Transmen

Sex steroids play a key role in bone turnover and preserving BMD; hence, gender-affirming hormone treatment (HT) in transgender people affects bone metabolism. Most studies have looked into the effect of HT on changes in BMD; however, they do not provide insights into changes in bone metabolism caused by HT. This study investigated changes in bone turnover markers (BTMs) and sclerostin, as well as their correlations with change in BMD in transwomen and transmen during the first year of HT. Transwomen received estradiol and antiandrogens; transmen received testosterone. Sclerostin; P1NP; alkaline phosphatase (ALP); CTx; and BMD of the total hip, the femoral neck, and the lumbar spine were evaluated at baseline and after 1 year of HT. There were 121 transwomen (median age 30 years, interquartile range [IQR] 24 to 41 years) and 132 transmen (median age 24 years, IQR 21 to 33 years) included in the study. In transwomen, ALP decreased in 19% (95% CI, –21 to–16), CTx in 11% (95% CI, –18 to–4), and sclerostin in 8% (95%CI, –13 to–4) of study participants after 1 year of HT. In contrast, in transmen P1NP, ALP, and sclerostin increased in 33% (95% CI, 24 to 42), 16% (95% CI, 12 to 20), and 15% (95% CI, 10 to 20) of study participants, respectively, after 1 year of HT. No age differences were seen in transwomen, whereas in transmen aged ≥50 years a decrease in all BTMs was found in contrast with the other age groups. These transmen had low estrogen concentration at the start of HT based on their postmenopausal state before the start of HT; their estradiol concentrations increased during testosterone treatment. Changes in BTMs and BMD were weakly correlated (correlation coefficient all <0.30). To conclude, 1 year of HT resulted in decreased bone turnover in transwomen and older transmen, whereas it increased in younger transmen. The decrease in bone resorption in older transmen shows the importance of estrogen as a key regulator of bone turnover

Occurrence of Acute Cardiovascular Events in Transgender Individuals Receiving Hormone Therapy: Results from a Large Cohort Study

In hypogonadal/postmenopausal individuals, hormone therapy has been associated with an increased risk for cardiovascular events (CVEs). A steeply growing population that often receives exogenous hormones is transgender individuals. Although transgender individuals hypothetically have an increased risk of CVEs, there is little known about the occurrence of CVEs in this population.1 Therefore, we determined the incidences of acute/spontaneous strokes (ischemic/hemorrhagic, transient ischemic attack, or subarachnoid hemorrhage), myocardial infarctions (MIs), and venous thromboembolic events (VTEs) in transwomen and transmen receiving transgender hormone therapy (THT). Subsequently, we compared these incidences with those reported in women and men from the general population

The effect of transdermal gender-affirming hormone therapy on markers of inflammation and hemostasis

Background Cardiovascular risk is increased in transgender persons using gender-affirming hormone therapy. To gain insight into the mechanism by which sex hormones affect cardiovascular risk in transgender persons, we investigated the effect of hormone therapy on markers of inflammation and hemostasis. Methods In this exploratory study, 48 trans women using estradiol patches plus cyproterone acetate (CPA) and 47 trans men using testosterone gel were included. They were between 18 and 50 years old and did not have a history of cardiovascular events. Measurements were performed before and after 3 and 12 months of hormone therapy. Results After 12 months, in trans women, systemic and endothelial inflammatory markers decreased (hs-CRP -66%, (95% CI -76; -53), VCAM-1-12%, (95% CI -16; -8)), while platelet activation markers increased (PF-4 +17%, (95% CI 4; 32), β-thromboglobulin +13%, (95% CI 2; 24)). The coagulation marker fibrinogen increased transiently, after 3 months (+15%, (95% CI 1; 32)). In trans men, hs-CRP increased (+71%, (95% CI 19; 145)); platelet activation and coagulation markers were not altered. In both trans women and trans men, leptin and adiponectin changed towards reference values of the experienced gender. Conclusions Platelet activation and coagulation marker concentrations increased in trans women using transdermal estradiol plus CPA, but not in trans men using testosterone. Also, concentrations of inflammatory markers decreased in trans women, while hs-CRP increased in trans men. Our results indicate that hormone therapy may affect hemostasis in transgender persons, which could be an underlying mechanism explaining the increased cardiovascular risk in this population

Bone geometry and trabecular bone score in transgender people before and after short- and long-term hormonal treatment

Background: Gender-affirming hormonal treatment (HT) in adult transgender people influences bone mineral density (BMD). Besides BMD, bone geometry and trabecular bone score are associated with fracture risk. However, it is not known whether bone geometry and TBS changes during HT. Purpose: To investigate the bone geometry and TBS in adult transgender people at different time points, up to 25 years, of HT. Methods: A total of 535 trans women and 473 trans men were included, who were divided into three groups at time of their DXA: 20–29 years, 30–39 years, and 40–59 years. Subsequently, each group was divided into different HT durations: baseline, or after 5, 15, or 25 years of HT. Hip structure analysis was performed to measure subperiosteal width, endocortical diameter, average cortical thickness, and section modulus. TBS was calculated based on lumbar spine DXA images. Results: In trans women in all age groups and in young trans men, no differences were observed in periosteal width, endocortical diameter, average cortical thickness, and section modulus for different durations of HT. In trans men aged 40–59 years, subperiosteal width, endocortical diameter, and section modulus were slightly higher in the groups who were using HT compared to the (peri- or postmenopausal) baseline group. In younger trans women, TBS tended to be higher in those using HT compared to the baseline groups, and in older trans women TBS was higher in those using HT for 25 years versus baseline (+0.04, 95%CI +0.00; +0.08). In younger trans men, TBS tended to be lower in those who used HT compared to the baseline groups, and in older trans men TBS was lower in those using 5 years HT versus baseline (−0.05, 95%CI −0.08; −0.01). Conclusion: No differences in cortical bone geometry parameters were found during different HT-durations. TBS increased in trans women and decreased in trans men, indicating that estrogens have positive effects on TBS. These data may be helpful in determining what sex reference values for calculating T-scores and Z-scores in adult transgender people should be used