Maartje Klaver

A European network for the investigation of gender incongruence : endocrine part

INTRODUCTION Cross-sex hormone therapy is an essential part of gender affirming treatment of transgender individuals. Studies systematically describing the physical and psychological effects of hormonal treatment of transgender persons are scarce. AIM The aim of the current protocol is to evaluate clinical and side-effects of cross-sex hormonal treatment in trans persons. METHODS The European Network for the Investigation of Gender Incongruence (ENIGI) is a multicenter prospective study. Because of the relatively low prevalence of the condition and small number of specialized centers, international collaboration is warranted. Four European treatment centers, Ghent, Oslo, Florence, and Amsterdam, developed a common study and treatment protocol. MAIN OUTCOME MEASURES Outcome measures include hormonal and metabolic parameters, bone density, secondary sex and anthropometric characteristics, and physical and psychological well-being. RESULTS Thus far, 333 trans women and 343 trans men have been included in the ENIGI Endocrine protocol. The study is still ongoing. CONCLUSION In recent years, the number of trans persons seeking gender affirming treatment has increased. However, well-designed prospective studies evaluating safety and effectiveness of current hormonal treatment protocols are lacking. Therefore we started the ENIGI collaboration. In this article we give a detailed description of the study protocol, objectives, and design of the ENIGI Endocrine protocol.

Cross‐sex hormone therapy in transgender persons affects total body weight, body fat and lean body mass: a meta‐analysis

Weight gain and body fat increase the risk of cardiometabolic disease. Cross‐sex hormone therapy in transgender persons leads to changes in body weight and body composition, but it is unclear to what extent. We performed a meta‐analysis to investigate the changes in body weight, body fat and lean body mass during cross‐sex hormone therapy in transgender persons. We searched the PubMed database for eligible studies until November 2015. Ten studies reporting changes in body weight, body fat or lean mass in hormone naive transgender persons were included, examining 171 male‐to‐female and 354 female‐to‐male transgender people. Pooled effect estimates in the male‐to‐female group were +1.8 kg (95% CI: 0.2;3.4) for body weight, +3.0 kg (2.0;3.9) for body fat and −2.4 kg (−2.8; −2.1) for lean body mass. In the female‐to‐male group, body weight changed with +1.7 kg (0.7;2.7), body fat with −2.6 kg (−3.9; −1.4) and lean body mass with +3.9 kg (3.2;4.5). Cross‐sex hormone therapy increases body weight in both sexes. In the male‐to‐female group, a gain in body fat and a decline in lean body mass are observed, while the opposite effects are seen in the female‐to‐male group. Possibly, these changes increase the risk of cardiometabolic disease in the male‐to‐female group.

Prolactin levels during short- and long-term cross-sex hormone treatment: an observational study in transgender persons.

The cause of prolactin alterations in transgender persons is often assigned to oestrogens, but the precise cause and time course during different phases of cross‐sex hormone treatment (CHT) remain unclear. In this study, we prospectively examined prolactin levels in 55 female‐to‐males (FtMs) and 61 male‐to‐females (MtFs) during the first year of CHT. Because long‐term prolactin data were not available in this population, we studied these levels in a retrospective population of 25 FtMs and 38 MtFs who underwent gonadectomy. FtMs were treated with testosterone and MtFs with estradiol, with or without the anti‐androgen cyproterone acetate (CPA) (after gonadectomy CPA is cessated). During the first year of CHT, prolactin decreased with 25% (95CI: −33%, −12%) in FtMs and increased with 193% (95CI: 156%, 219%) in MtFs. Eighteen MtFs developed hyperprolactinemia (≥0.6 IU L−1). In the retrospective population, post‐gonadectomy levels in FtMs were lower than baseline levels (−39%; 95CI: −51%, −20%) while in MtFs post‐gonadectomy levels and baseline levels were comparable (−6%; 95CI: −24%, 15%). No hyperprolactinemia was found after gonadectomy. In conclusion, in FtMs, prolactin decreased consistently during CHT and in MtFs, prolactin increased during pre‐surgical CHT but normalised after gonadectomy. It is likely that CPA induces increasing prolactin levels in MtFs.

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.

Prospective evaluation of hematocrit in gender-affirming hormone treatment : results from European Network for the Investigation of Gender Incongruence

In trans persons on gender‐affirming hormonal treatment, a decrease (in trans women) or increase (in trans men) in hematocrit is often observed. Reference ranges for evaluation of hematocrit levels in trans persons have not been established. This prospective cohort study is part of the European Network for the Investigation of Gender Incongruence (ENIGI). At the Ghent and Amsterdam sites, we included 625 hormone‐naïve trans persons. Gender‐affirming hormonal treatment was initiated at the first visit. In trans men, serum hematocrit (Hct) levels increased during the first year (+4.9 Hct %, 95% CI 3.82–5.25), with the most pronounced increase during the first 3 months (+2.7 Hct %, 95% CI 1.94–3.29). Trans men receiving testosterone esters had a larger increase in serum hematocrit levels compared to trans men receiving testosterone undecanoate (Δ 0.8 Hct %). Of 192 trans men, 22 (11.5%) developed serum hematocrit levels ≥50.0%. Trans men on testosterone undecanoate were less likely to develop hematocrit levels ≥50% or ≥52%, compared to trans men on testosterone esters, and were less likely to develop hematocrit levels ≥50%, compared to trans men on testosterone gel. In trans women, serum hematocrit had dropped by 4.1 Hct % (95% CI 3.50–4.37) after 3 months, after which only small decreases were observed. In conclusion, serum hematocrit levels can be found in the reference range of the perceived gender as from 3 months after the initiation of gender‐affirming hormonal treatment.

Changes in regional body fat, lean body mass and body shape in trans persons using cross-sex hormonal therapy: results from a multicenter prospective study

OBJECTIVE Cross-sex hormonal therapy (CHT) in trans persons affects their total body fat and total lean body mass. However, it is unknown how separate body regions are affected and whether these changes alter body shape. Therefore, the aim of this study was to determine the effects on body fat and lean body mass in separate body regions and on body shape after one year of CHT. DESIGN AND METHODS In a multicenter prospective study at university hospitals, 179 male-to-female gender dysphoric persons, referred to as transwomen, and 162 female-to-male gender dysphoric persons, referred to as transmen, were included. All underwent whole-body dual-energy X-ray absorptiometry and anthropometric measurements before and after one year of CHT. RESULTS In transwomen, increases in body fat ranged from +18% (95% CI: 13%;23%) in the android region to +42% (95% CI: 37%;46%) in the leg region and +34% (95% CI: 29%;38%) in the gynoid region. In transmen, changes in body fat ranged from -16% (95% CI: -19;-14%) in the leg region and -14% in the gynoid region (95% CI: -16%;-12) to no change in the android region (+1%, 95% CI: -3%;5%). Waist-to-hip ratio (WHR) decreased in transwomen (-0.03, 95% CI: -0.04;-0.02) mainly due to an increase in hip circumference (+3.2 cm, 95% CI: 2.3;4.0). Transmen have a decrease in hip circumference (-1.9 cm, 95% CI: -3.1;-0.7) resulting in an increase in WHR (+0.01, 95% CI: 0.00;0.02). CONCLUSIONS CHT causes a more feminine body fat distribution and a lower WHR in transwomen and a more masculine body fat distribution with a lower hip circumference in transmen.

Breast Development in Transwomen After 1 Year of Cross-Sex Hormone Therapy: Results of a Prospective Multicenter Study

Context Breast development is a key feature of feminization and therefore important to transwomen (male-to-female transgender persons). It is not exactly known when breast development starts after initiating cross-sex hormone therapy (CHT) and how much growth may be expected. Objective To investigate breast development in transwomen during their first year of CHT and whether clinical or laboratory parameters predict breast development. Design This study was performed as part of the European Network for the Investigation of Gender Incongruence, which is a prospective multicenter cohort study. Setting Gender clinics in Amsterdam, Ghent, and Florence. Participants Transwomen who completed the first year of CHT (n = 229). Intervention CHT. Main Outcome Measures Breast development in centimeter and cup size. Results The median age of the included transwomen was 28 years (range, 18 to 69). Mean breast-chest difference increased to 7.9 ± 3.1 cm after 1 year of CHT, mainly resulting in less than an AAA cup size (48.7%). Main breast development occurred in the first 6 months of therapy. Serum estradiol levels did not predict breast development after 1 year of CHT (first quartile, 3.6 cm [95% confidence interval (CI), 2.7 to 4.5], second quartile, 3.2 cm [95% CI, 2.3 to 4.2], third quartile, 4.4 cm [95% CI, 3.5 to 5.3], and fourth quartile, 3.6 cm [95% CI, 2.7 to 4.5]). Conclusion This study shows that, after 1 year of CHT, breast development is modest and occurs primarily in the first 6 months. No clinical or laboratory parameters were found that predict breast development.