A European Network for the Investigation of Gender Incongruence in adolescents.

BACKGROUND: Knowledge regarding the effects and side effects of gender-affirming hormone therapy (GAHT) in adults is rapidly growing, partly through international research networks such as the European Network for the Investigation of Gender Incongruence (ENIGI). However, data on the effects of puberty suppression (PS) and GAHT in transgender and gender diverse (TGD) youth are limited, although these data are of crucial importance, given the controversies surrounding this treatment. AIM: We sought to present a detailed overview of the design of the ENIGI Adolescents study protocol, including the first baseline data. METHODS: The ENIGI Adolescents study is an ongoing multicenter prospective cohort study. This study protocol was developed by 3 European centers that provide endocrine care for TGD adolescents and were already part of the ENIGI collaboration: Amsterdam, Ghent, and Florence. OUTCOMES: Study outcomes include physical effects and side effects, laboratory parameters, bone mineral density, anthropometric characteristics, attitudes toward fertility and fertility preservation, and psychological well-being, which are measured in the study participants during PS and GAHT, up to 3 years after the start of GAHT. RESULTS: Between November 2021 and May 2023, 172 TGD adolescents were included in the ENIGI Adolescents protocol, of whom 51 were assigned male at birth (AMAB) and 121 were assigned female at birth (AFAB); 3 AFAB participants reported a nonbinary gender identification. A total of 76 participants were included at the start of PS, at a median (IQR) age of 13.7 (12.9-16.5) years in AMAB and 13.5 (12.4-16.1) years in AFAB individuals. The remaining 96 participants were included at start of GAHT, at a median (IQR) age of 15.9 (15.1-17.4) years in AFAB and 16.0 (15.1-16.8) years in AMAB individuals. At the time of this report the study was open for inclusion and follow-up measurements were ongoing. CLINICAL IMPLICATIONS: In response to the rising demand for gender-affirming treatment among TGD youth, this ongoing study is fulfilling the need for prospective data on the effects and safety of PS and GAHT, thus providing a foundation for evidence-based healthcare decisions. STRENGTHS AND LIMITATIONS: This study has a strong multicenter, prospective design that allows for systematic data collection. The use of clinical and self-reported data offers a broad range of outcomes to evaluate. Nevertheless, the burden of additional measurements and questionnaires may lead to withdrawal or lower response rates. Few participants with a non-binary gender identity have been included. CONCLUSION: With the ENIGI Adolescents study we aim to create a comprehensive dataset that we can use for a wide range of studies to address current controversies and uncertainties and to improve healthcare for TGD adolescents.

Mortality trends over five decades in adult transgender people receiving hormone treatment: a report from the Amsterdam cohort of gender dysphoria.

BACKGROUND: Increased mortality in transgender people has been described in earlier studies. Whether this increased mortality is still present over the past decades is unknown. Therefore, we aimed to investigate trends in mortality over five decades in a large cohort of adult transgender people in addition to cause-specific mortality. METHODS: We did a retrospective cohort study of adult transgender people who visited the gender identity clinic of Amsterdam University Medical Centre in the Netherlands. Data of transgender people who received hormone treatment between 1972 and 2018 were linked to Statistics Netherlands. People were excluded if they used alternating testosterone and oestradiol treatment, if they started treatment younger than age 17 years, or if they had ever used puberty-blockers before gender-affirming hormone treatment. Standardised mortality ratios (SMRs) were calculated using general population mortality rates stratified by age, calendar period, and sex. Cause-specific mortality was also calculated. FINDINGS: Between 1972 and 2018, 8831 people visited the gender identity clinic. 4263 were excluded from the study for a variety of reasons, and 2927 transgender women and 1641 transgender men were included in the study, with a total follow-up time of 40 232 person-years for transgender women and 17 285 person-years for transgender men. During follow-up, 317 (10·8%) transgender women died, which was higher than expected compared with general population men (SMR 1·8, 95% CI 1·6-2·0) and general population women (SMR 2·8, 2·5-3·1). Cause-specific mortality in transgender women was high for cardiovascular disease, lung cancer, HIV-related disease, and suicide. In transgender men, 44 people (2·7%) died, which was higher than expected compared with general population women (SMR 1·8, 95% CI 1·3-2·4) but not general population men (SMR 1·2, 95% CI 0·9-1·6). Cause-specific death in transgender men was high for non-natural causes of death. No decreasing trend in mortality risk was observed over the five decades studied. INTERPRETATION: This observational study showed an increased mortality risk in transgender people using hormone treatment, regardless of treatment type. This increased mortality risk did not decrease over time. The cause-specific mortality risk because of lung cancer, cardiovascular disease, HIV-related disease, and suicide gives no indication to a specific effect of hormone treatment, but indicates that monitoring, optimising, and, if necessary, treating medical morbidities and lifestyle factors remain important in transgender health care. FUNDING: None.

Sustained Breast Development and Breast Anthropometric Changes in 3 Years of Gender-Affirming Hormone Treatment.

CONTEXT: Breast development is important for most trans women. An important limitation of current breast development measurement methods is that these do not allow for 3D volume analyses. OBJECTIVES: To examine breast development and change in anthropometry during the first 3 years of gender-affirming hormone treatment using 3D imaging. Associations with clinical or laboratory parameters and satisfaction with the gained breast development were also studied. DESIGN: Prospective cohort study. SETTING: Specialized tertiary gender identity clinic in Amsterdam, the Netherlands. PARTICIPANTS: Participants were 69 adult trans women with a median age of 26 years (interquartile range, 21-38). INTERVENTIONS: Gender-affirming hormone treatment. MAIN OUTCOME MEASURES: Volumetric and anthropometric breast development and satisfaction. RESULTS: Breast volume increased by 72 cc (95% confidence interval [CI], 48-97) to 100 cc (standard deviation 48). This resulted in a cup-size

Fracture Risk in Trans Women and Trans Men Using Long-Term Gender-Affirming Hormonal Treatment: A Nationwide Cohort Study.

Concerns about bone health in transgender people using gender-affirming hormonal treatment (HT) exist, but the fracture risk is not known. In this nationwide cohort study, we aimed to compare the fracture incidence in transgender people using long-term HT with an age-matched reference population. All adult transgender people who started HT before 2016 at our gender-identity clinic were included and were linked to a random population-based sample of 5 age-matched reference men and 5 age-matched reference women per person. Fracture incidence was determined using diagnoses from visits to hospital emergency rooms nationwide between 2013 and 2015. A total of 1089 trans women aged <50 years (mean 38 ± 9 years) and 934 trans women aged ≥50 years (mean 60 ± 8 years) using HT for median 8 (interquartile range [IQR] 3-16) and 19 (IQR 11-29) years, respectively, were included. A total of 2.4% of the trans women aged <50 years had a fracture, whereas 3.0% of the age-matched reference men (odds ratio [OR] = 0.78, 95% confidence interval [CI] 0.51-1.19) and 1.6% of the age-matched reference women (OR = 1.49, 95% CI 0.96-2.32) experienced a fracture. In trans women aged ≥50 years, 4.4% experienced a fracture compared with 2.4% of the age-matched reference men (OR = 1.90, 95% CI 1.32-2.74) and 4.2% of the age-matched reference women (OR = 1.05, 95% CI 0.75-1.49). A total of 1036 trans men (40 ± 14 years) using HT for median 9 (IQR 2-22) years were included. Fractures occurred in 1.7% of the trans men, 3.0% of the age-matched reference men (OR = 0.57, 95% CI 0.35-0.94), and 2.2% of the age-matched reference women (OR = 0.79, 95% CI 0.48-1.30). In conclusion, fracture risk was higher in older trans women compared with age-matched reference men. In young trans women, fracture risk tended to be increased compared with age-matched reference women. Fracture risk was not increased in young trans men. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Frequency, Determinants, and Satisfaction of Breast Augmentation in Trans Women Receiving Hormone Treatment.

INTRODUCTION: As breast development in trans women (male sex assigned at birth, female gender identity) who receive gender-affirming hormone treatment is often moderate, they may choose breast augmentation as part of their treatment. AIM: The aim of the study was to investigate the frequency, determinants, and satisfaction of breast augmentation among trans women receiving hormone treatment. METHODS: Trans women who started hormone treatment between 1972 and 2018 at our center received an anonymous questionnaire. MAIN OUTCOME MEASURE: The questionnaire contained questions about the start date of hormone treatment, the current age of the respondent, whether or not she underwent breast augmentation, what her considerations in this decision were, and, if the respondent did have breast implants, whether she was satisfied with the result and/or experienced health complaints she attributed to her breast implants. RESULTS: A total of 3,073 questionnaires were distributed, of which 773 were retrieved back (median age of the respondents: 50 years, interquartile range: 35-59). Age and year of start of hormone treatment was comparable between responders and nonresponders. The frequency of breast augmentation varied from 70% in trans women who started hormone treatment between 1980 and 2000 to 20% in those who started between 2010 and 2015. Trans women underwent breast augmentation median 2 years after the start of hormone treatment (interquartile range: 2-4), and 80% was satisfied with the result. Approximately one-third experienced health complaints they attributed to their breast implants. People who considered breast augmentation reported financial limitations as an important reason not to undergo breast augmentation. CLINICAL IMPLICATIONS: This study shows that it is important to discuss pros and cons of breast augmentation to support trans women in making a well-informed decision. STRENGTHS & LIMITATIONS: This is the largest study performed on the frequency and satisfaction of breast augmentation among trans women, which also includes health complaints and considerations in the decision whether or not to undergo breast augmentation. One of the limitations was that we were unable to link other clinical data. CONCLUSION: 4 of 5 trans women either chose or considered breast augmentation as part of their gender-affirming treatment. Most of the trans women who underwent breast augmentation were satisfied with the result, although approximately one-third experienced health complaints they attributed to their breast implants. Reasons not to undergo breast augmentation included financial limitations. This study shows that it is important to discuss with trans women the positive effects and possible side-effects of breast augmentation to help them make a well-informed decision whether or not to undergo breast augmentation. de Blok CJM, Staphorsius AS, Wiepjes CM, et al. Frequency, Determinants, and Satisfaction of Breast Augmentation in Trans Women Receiving Hormone Treatment. J Sex Med 2020;17:342-348.

Prevalence of Sexual Dysfunctions in Transgender Persons: Results from the ENIGI Follow-Up Study.

INTRODUCTION: Studies about sexual functioning in trans persons have mainly focused on sexual functioning after genital gender-affirming surgery, have had small sample sizes, and have not explored the broad range of possible sexual dysfunctions. Measuring sexual functioning in trans persons during transitioning is important to determine the kind of care trans persons may need in order to regain their sexual health. AIM: The first aim of the present study was to explore the prevalence of sexual function disturbances and dysfunctions (with distress) in trans women and trans men 4 to 6 years after initial clinical entry. The second aim was to compare the prevalence of sexual dysfunctions among the various treatment trajectories and between trans persons with or without further genital treatment intentions. METHODS: An online follow-up questionnaire was filled out by 518 trans persons (307 identifying predominantly feminine, 211 identifying predominantly masculine) as a part of the European Network for the Investigation of Gender Incongruence initiative. All participants had their initial clinical appointments in gender clinics in Ghent, Amsterdam, or Hamburg. MAIN OUTCOME MEASURE: The main outcome measures were the prevalence of sexual dysfunctions and medical treatment data, measured via self-report items. RESULTS: The most frequent sexual dysfunctions experienced by trans women and trans men were difficulties initiating and seeking sexual contact (26% and 32%, respectively) and difficulties achieving an orgasm (29% and 15%, respectively). Compared with trans women after hormone treatment and non-genital surgery, trans women after vaginoplasty less often experienced arousal difficulties, sexual aversion, and low sexual desire. Compared with trans men without medical treatment, trans men after a phalloplasty experienced sexual aversion and low sexual desire less often. No significant differences were found between participants with or without further genital treatment intentions. CLINICAL IMPLICATIONS: Clinicians should consider sexual counseling after medical treatments, paying particular attention to potential social and psychological barriers to the sexual health of their patients. STRENGTHS & LIMITATIONS: This study included all trans persons irrespective of treatment decisions, and focused on a broad range of potential sexual difficulties taking the distress criteria into account. Limitations include the cross-sectional design, the limited power for the comparison of treatment groups and the absence of validated questionnaires about sexual functioning for transgender persons. CONCLUSION: Sexual dysfunctions among trans men and women were very common among the various treatment groups and were unrelated to intentions to have further genital treatment. Although medical treatment may be helpful or even essential to developing good sexual health, a significant group of trans persons experienced sexual dysfunctions after genital surgery. Kerckhof ME, Kreukels BPC, Nieder TO, et al. Prevalence of Sexual Dysfunctions in Transgender Persons: Results from the ENIGI Follow-Up Study. J Sex Med 2019; 16:2018-2019.

Kisspeptin Expression in the Human Infundibular Nucleus in Relation to Sex, Gender Identity, and Sexual Orientation.

CONTEXT: Since the discovery of its central role in reproduction, our functional neuroanatomical knowledge of the hypothalamic kisspeptin system is predominantly based on animal studies. Although sex differences in kisspeptin expression have been shown in humans in adulthood, the developmental origin of this sex difference is unknown. OBJECTIVES: Our objectives were to determine the following: 1) when during development the sex difference in kisspeptin expression in the infundibular nucleus would emerge and 2) whether this sex difference is related to sexual orientation or transsexuality. DESIGN AND SETTING: Postmortem hypothalamic tissues were collected by The Netherlands Brain Bank, and sections were stained for kisspeptin by immunohistochemistry. PATIENTS: Hypothalami of 43 control subjects were categorized into three periods: infant/prepubertal (six girls, seven boys), adult (11 women, seven men), and elderly (six aged women, six aged men). Eight male-to-female (MTF) transsexuals, three HIV(+) heterosexual men, and five HIV(+) homosexual men were also analyzed. MAIN OUTCOME MEASURE: We estimated the total number of kisspeptin-immunoreactive neurons within the infundibular nucleus. RESULTS: Quantitative analysis confirmed that the human infundibular kisspeptin system exhibits a female-dominant sex difference. The number of kisspeptin neurons is significantly greater in the infant/prepubertal and elderly periods compared with the adult period. Finally, in MTF transsexuals, but not homosexual men, a female-typical kisspeptin expression was observed. CONCLUSIONS: These findings suggest that infundibular kisspeptin neurons are sensitive to circulating sex steroid hormones throughout life and that the sex reversal observed in MTF transsexuals might reflect, at least partially, an atypical brain sexual differentiation.

Puberty suppression and executive functioning: An fMRI-study in adolescents with gender dysphoria.

Adolescents with gender dysphoria (GD) may be treated with gonadotropin releasing hormone analogs (GnRHa) to suppress puberty and, thus, the development of (unwanted) secondary sex characteristics. Since adolescence marks an important period for the development of executive functioning (EF), we determined whether the performance on the Tower of London task (ToL), a commonly used EF task, was altered in adolescents with GD when treated with GnRHa. Furthermore, since GD has been proposed to result from an atypical sexual differentiation of the brain, we determined whether untreated adolescents with GD showed sex-atypical brain activations during ToL performance. We found no significant effect of GnRHa on ToL performance scores (reaction times and accuracy) when comparing GnRHa treated male-to-females (suppressed MFs, n=8) with untreated MFs (n=10) or when comparing GnRHa treated female-to-males (suppressed FMs, n=12) with untreated FMs (n=10). However, the suppressed MFs had significantly lower accuracy scores than the control groups and the untreated FMs. Region-of-interest (ROI) analyses showed significantly greater activation in control boys (n=21) than control girls (n=24) during high task load ToL items in the bilateral precuneus and a trend (p<0.1) for greater activation in the right DLPFC. In contrast, untreated adolescents with GD did not show significant sex differences in task load-related activation and had intermediate activation levels compared to the two control groups. GnRHa treated adolescents with GD showed sex differences in neural activation similar to their natal sex control groups. Furthermore, activation in the other ROIs (left DLPFC and bilateral RLPFC) was also significantly greater in GnRHa treated MFs compared to GnRHa treated FMs. These findings suggest that (1) GnRHa treatment had no effect on ToL performance in adolescents with GD, and (2) pubertal hormones may induce sex-atypical brain activations during EF in adolescents with GD.

A genetic analysis of coffee consumption in a sample of Dutch twins.

Caffeine is by far the most commonly used psychoactive substance. Caffeine is consumed regularly as an ingredient of coffee. Coffee consumption and coffee preference was explored in a sample of 4,495 twins (including 1,231 pairs) registered with the Netherlands Twin Registry. Twin resemblance was assessed by tetrachoric correlations and the influence of both genetic and environmental factors was explored with model fitting analysis in MX. Results showed moderate genetic influences (39%) on coffee consumption. The remaining variance was explained by shared environmental factors (21%) and unique environmental factors (40%). The variance in coffee preference (defined as the proportion of coffee consumption relative to the consumption of coffee and tea in total) was explained by genetic factors (62%) and unique environmental factors (38%).