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.

Skin manifestations in adults with gender dysphoria on hormone treatment in the outpatient clinic of Hospital de San José, Bogotá-Colombia.

BACKGROUND: Comprehensive healthcare for patients with gender dysphoria includes access to gender-affirming hormone therapy. It may cause cutaneous and adnexal side effects, which often affect quality of life, are underdiagnosed, and do not receive timely treatment. The literature on this subject is scarce. The main objective was to identify skin manifestations secondary to hormone treatment in adults with gender dysphoria. METHODS: Observational, descriptive, cross-sectional study. A search was performed in the database of patients with gender dysphoria older than 18 years treated at the dermatology and/or endocrinology outpatient clinic of the Hospital de San José de Bogotá in the period 2015-2021. Medical records of patients on hormone therapy with skin manifestations were selected, while patients using other medications as possible triggers were excluded. RESULTS: In total, 85 patients were included, with a predominance of young transgender men (average age was 27 ± 9 years) in whom the main manifestation was acne (87%), followed by androgenetic alopecia and acanthosis nigricans. Transgender women presented more acne, androgenetic alopecia, hypertrichosis, seborrheic dermatitis, and melasma. The majority received treatment, mainly topical therapies. More than half of the patients were treated by the endocrinology and dermatology services. CONCLUSIONS: Skin manifestations in patients with gender dysphoria on hormone therapy are frequent, so they should be known and taken into account in the multidisciplinary approach to these patients, which should involve dermatologists. This is the first Colombian and Latin American study focused on documenting skin manifestations in patients with gender dysphoria undergoing hormone therapy.

Changes to hypothalamic volume and associated subunits during gender-affirming hormone therapy.

BACKGROUND: Among its pleiotropic properties, gender-affirming hormone therapy (GHT) affects regional brain volumes. The hypothalamus, which regulates neuroendocrine function and associated emotional and cognitive processes, is an intuitive target for probing GHT effects. We sought to assess changes to hypothalamus and hypothalamic subunit volumes after GHT, thereby honouring the region's anatomical and functional heterogeneity. METHODS: Individuals with gender dysphoria and cisgender controls underwent 2 MRI measurements, with a median interval of 145 days (interquartile range [IQR] 128.25-169.75 d, mean 164.94 d) between the first and second MRI. Transgender women (TW) and transgender men (TM) underwent the first MRI before GHT and the second MRI after approximately 4.5 months of GHT, which comprised estrogen and anti-androgen therapy in TW or testosterone therapy in TM. Hypothalamic volumes were segmented using FreeSurfer, and effects of GHT were tested using repeated-measures analysis of covariance. RESULTS: The final sample included 106 participants: 38 TM, 15 TW, 32 cisgender women (CW) and 21 cisgender men (CM). Our analyses revealed group × time interaction effects for total, left and right hypothalamus volume, and for several subunits (left and right inferior tubular, left superior tubular, right anterior inferior, right anterior superior, all p corr < 0.01). In TW, volumes decreased between the first and second MRI in these regions (all p corr ≤ 0.01), and the change from the first to second MRI in TW differed significantly from that in CM and CW in several subunits (p corr < 0.05). LIMITATIONS: We did not address the influence of transition-related psychological and behavioural changes. CONCLUSION: Our results suggest a subunit-specific effect of GHT on hypothalamus volumes in TW. This finding is in accordance with previous reports of positive and negative effects of androgens and estrogens, respectively, on cerebral volumes.

The influence of sex steroid treatment on insular connectivity in gender dysphoria.

BACKGROUND: Sex-specific differences in brain connectivity were found in various neuroimaging studies, though little is known about sex steroid effects on insular functioning. Based on well-characterized sex differences in emotion regulation, interoception and higher-level cognition, gender-dysphoric individuals receiving gender-affirming hormone therapy represent an interesting cohort to investigate how sex hormones might influence insular connectivity and related brain functions. METHODS: To analyze the potential effect of sex steroids on insular connectivity at rest, 11 transgender women, 14 transgender men, 20 cisgender women, and 11 cisgender men were recruited. All participants underwent two magnetic resonance imaging sessions involving resting-state acquisitions separated by a median time period of 4.5 months and also completed the Bermond-Vorst alexithymia questionnaire at the initial and final examination. Between scans, transgender subjects received gender-affirming hormone therapy. RESULTS: A seed based functional connectivity analysis revealed a significant 2-way interaction effect of group-by-time between right insula, cingulum, left middle frontal gyrus and left angular gyrus. Post-hoc tests demonstrated an increase in connectivity for transgender women when compared to cisgender men. Furthermore, spectral dynamic causal modelling showed reduced effective connectivity from the posterior cingulum and left angular gyrus to the left middle frontal gyrus as well as from the right insula to the left middle frontal gyrus. Alexithymia changes were found after gender-affirming hormone therapy for transgender women in both fantasizing and identifying. CONCLUSION: These findings suggest a considerable influence of estrogen administration and androgen suppression on brain networks implicated in interoception, own-body perception and higher-level cognition.

Incidence of Idiopathic Intracranial Hypertension in Individuals With Gonadotropin-Releasing Hormone Analogue Treatment for Gender Dysphoria in Sweden.

This cohort study examines the incidence of idiopathic intracranial hypertension (IHH) among individuals in Sweden undergoing gonadotropin-releasing hormone analogue (GnRHa) treatment for gender dysphoria.

A systematic review of hormone treatment for children with gender dysphoria and recommendations for research.

AIM: The aim of this systematic review was to assess the effects on psychosocial and mental health, cognition, body composition, and metabolic markers of hormone treatment in children with gender dysphoria. METHODS: Systematic review essentially follows PRISMA. We searched PubMed, EMBASE and thirteen other databases until 9 November 2021 for English-language studies of hormone therapy in children with gender dysphoria. Of 9934 potential studies identified with abstracts reviewed, 195 were assessed in full text, and 24 were relevant. RESULTS: In 21 studies, adolescents were given gonadotropin-releasing hormone analogues (GnRHa) treatment. In three studies, cross-sex hormone treatment (CSHT) was given without previous GnRHa treatment. No randomised controlled trials were identified. The few longitudinal observational studies were hampered by small numbers and high attrition rates. Hence, the long-term effects of hormone therapy on psychosocial health could not be evaluated. Concerning bone health, GnRHa treatment delays bone maturation and bone mineral density gain, which, however, was found to partially recover during CSHT when studied at age 22 years. CONCLUSION: Evidence to assess the effects of hormone treatment on the above fields in children with gender dysphoria is insufficient. To improve future research, we present the GENDHOR checklist, a checklist for studies in gender dysphoria.

Update on bioethical, medical and fertility issues in gender incongruence during transition age.

PURPOSE: Many issues still remain unresolved in the management of pubertal patients with gender incongruence (GI). The aim of this review is to discuss the main aspects of the treatment of these patients to provide a practical approach for clinicians. METHODS: A comprehensive literature search within PubMed was performed to provide updates of available evidence regarding the impact on bioethical, medical and fertility issues in gender incongruence during transition age. RESULTS: Gender Affirming Hormone Treatment (GAHT) and Gender Affirming Surgery (GAS) can induce unsatisfaction with change, future regrets, and the risk of infertility. This raises ethical issues especially in the management of pubertal patients that remain unresolved. Therapy with GnRH analogues (GnRHa) is intended to delay puberty, so as to give the adolescent a longer period of time to decide whether to continue with the treatments. At the level of physical changes, this therapy may have an effect on bone mineralization and body composition; however, long-term longitudinal data are not yet available. An important feature related to the use of GnRHa is the risk of fertility. Gamete cryopreservation is the most established method of fertility preservation (FP) and should be counselled to transgender adolescents. However, these patients are not always interested in having biological children. CONCLUSION: Based on the current evidence, there is a need to conduct further research to clarify certain issues and to standardize clinical practice and improve counselling in transgender adolescent decision making and avoid regrets in the future.

A National Survey of United States-Based Endocrinologists Who Prescribe Gender-Affirming Hormone Therapy.

OBJECTIVE: The World Professional Association for Transgender Health Standards of Care Version 7 recommended that before initiating gender-affirming hormone therapy (GAHT), patients should seek a psychosocial evaluation from a mental health professional documenting a diagnosis of persistent gender dysphoria. The Endocrine Society published guidelines in 2017 recommending against an obligatory psychosocial evaluation, which was affirmed in the recently published World Professional Association for Transgender Health Standards of Care Version 8 from 2022. Little is known about how endocrinologists ensure appropriate psychosocial assessment for their patients. This study assessed the protocols and characteristics of U.S.-based adult endocrinology clinics that prescribe GAHT. METHODS: An anonymous electronic survey sent to members of a professional organization and the "Endocrinologists" Facebook group was responded by 91 practicing board-certified adult endocrinologists who prescribe GAHT. RESULTS: Thirty-one states were represented by the respondents. Overall, 83.1% of GAHT-prescribing endocrinologists reported accepting Medicaid. They reported working in university practices (28.4%), community practices (22.7%), private practices (27.3%), and other practice settings (21.6%). Overall, 42.9% of the respondents reported that their practice required documentation of a psychosocial evaluation from a mental health professional before initiating GAHT. CONCLUSION: Endocrinologists who prescribe GAHT are divided about requiring a baseline psychosocial evaluation before prescribing GAHT. Further work is needed to understand the impact of psychosocial assessment on patient care and facilitate the uptake of new guidelines into clinical practice.

Impact of Hormone Treatment on Psychosocial Functioning in Gender-Diverse Young People.

Purpose: Few studies have assessed the effects of hormonal treatments such as gonadotropin-releasing hormone agonists (GnRHa) and gender-affirming hormones (GAH) on mental health outcomes in clinically referred gender-diverse young people from a younger age. Where this research has been conducted, findings have been mixed. This study investigated a cohort of young people before treatment, 1 year into GnRHa, and 1 year into GAH treatment to understand psychological and behavioral impacts over time. Methods: Thirty-eight young people (28 assigned female and 10 assigned male) referred to endocrinology, younger than 15 years at/beyond Tanner stage two, who received GnRHa followed by GAH treatment, were assessed in a retrospective analysis study. Young people completed the Youth Self Report (YSR), the Body Image Scale, and the Utrecht Gender Dysphoria Scale, while caregivers completed the Child Behavior Checklist (CBCL) and the Social Responsiveness Scale-2 at all time points. Results: Dissatisfaction with primary sexual characteristics (p = 0.02), gender dysphoria (p = 0.01), and social motivation (p = 0.04) improved significantly over time. Self-harm and suicidality also showed a general decrease. Caregivers reported a significant reduction in internalizing (p = 0.03) behaviors on the CBCL after GnRHa. Other subcategories of the YSR and CBCL were within normal ranges with no significant difference (p > 0.05). Conclusion: These findings demonstrate some improvements in psychological and behavioral outcomes in young people concurrently receiving psychosocial support and hormone treatment. Future research with larger and more diverse samples is warranted to further understand generalizability.

Children and adolescents in the Amsterdam Cohort of Gender Dysphoria: trends in diagnostic- and treatment trajectories during the first 20 years of the Dutch Protocol.

BACKGROUND: Twenty years ago, the Dutch Protocol-consisting of a gonadotropin-releasing hormone agonist (GnRHa) to halt puberty and subsequent gender-affirming hormones (GAHs)-was implemented to treat adolescents with gender dysphoria. AIM: To study trends in trajectories in children and adolescents who were referred for evaluation of gender dysphoria and/or treated following the Dutch Protocol. METHODS: The current study is based on a retrospective cohort of 1766 children and adolescents in the Amsterdam Cohort of Gender Dysphoria. OUTCOMES: Outcomes included trends in number of intakes, ratio of assigned sex at birth, age at intake, age at start of GnRHa and GAH, puberty stage at start of GnRHa, proportions of adolescents starting and stopping GnRHa, reasons for refraining from GnRHa, and proportions of people undergoing gender-affirming surgery. RESULTS: A steep increase in referrals was observed over the years. A change in the AMAB:AFAB ratio (assigned male at birth to assigned female at birth) was seen over time, tipping the balance toward AFAB. Age at intake and at start of GnRHa has increased over time. Of possibly eligible adolescents who had their first visit before age 10 years, nearly half started GnRHa vs around two-thirds who had their first visit at or after age 10 years. The proportion starting GnRHa rose only for those first visiting before age 10. Puberty stage at start of GnRHa fluctuated over time. Absence of gender dysphoria diagnosis was the main reason for not starting GnRHa. Very few stopped GnRHa (1.4%), mostly because of remission of gender dysphoria. Age at start of GAH has increased mainly in the most recent years. When a change in law was made in July 2014 no longer requiring gonadectomy to change legal sex, percentages of people undergoing gonadectomy decreased in AMAB and AFAB. CLINICAL IMPLICATIONS: A substantial number of adolescents did not start medical treatment. In the ones who did, risk for retransitioning was very low, providing ongoing support for medical interventions in comprehensively assessed gender diverse adolescents. STRENGTHS AND LIMITATIONS: Important topics on transgender health care for children and adolescents were studied in a large cohort over an unprecedented time span, limited by the retrospective design. CONCLUSION: Trajectories in diagnostic evaluation and medical treatment in children and adolescents referred for gender dysphoria are diverse. Initiating medical treatment and need for surgical procedures depends on not only personal characteristics but societal and legal factors as well.

Commentary on Levine et al.: A Tale of Two Informed Consent Processes.

This commentary compares two recently published informed consent recommendations for gender dysphoria. One key difference identified is in their assessment of the strength of the evidence base for the gender affirming treatment model. An evaluation of both authors' citations supports the claims of a weak evidence base for the use of puberty blockers and gender affirming hormonal treatments in youth with gender dysphoria. This commentary then reflects on the implications of this. In particular, it asks whether it would be best practice to provide gender affirming treatments for youth only under clinical research conditions, rather than as routine clinical practice.

Toward a Standard of Medical Care: Why Medical Professionals Can Refuse to Prescribe Puberty Blockers.

That a standard of medical care must outline services that benefit the patient is relatively uncontroversial. However, one must determine how the practices outlined in a medical standard of care should benefit the patient. I will argue that practices outlined in a standard of medical care must not detract from the patient's well-functioning and that clinicians can refuse to provide services that do. This paper, therefore, will advance the following two claims: (1) a standard of medical care must not cause dysfunction, and (2) if a physician is medically rational to not provide some service which fails to meet the above condition (i.e. fails to be a standard of medical care), then she may refuse to do so. I then apply my thesis to the prescription of puberty blockers to children with gender dysphoria.

The role of ethical analysis in conducting a health technology assessment of medical treatments for gender dysphoria.

OBJECTIVES: Treatment seeking for gender dysphoria (GD) has increased manifold in western countries. This has led to increased interest on evidence-base of treatments, but also discussions related to human rights, identity politics, gender-related structures, and medicalization. Combining these discourses into coherent health policy is difficult. Health technology assessment (HTA) is the golden standard for assessing whether a medical intervention should be included in a health system. A comprehensive HTA should include medical, safety, and cost-utility perspectives, but often also ethical, societal, organizational, and legal concerns. Still, ethics is often omitted in practice. This paper aims to demonstrate how integrated ethical analysis influenced a HTA of complex and controversial topics like GD. METHODS: A HTA of medical treatments of GD was conducted using integrated ethical analysis based on the EUnetHTA-model. This integrates ethical thinking into the whole HTA, explicitly analyses ethical topics, and balances arguments using several ethical theories. RESULTS: Integrating ethics had a significant impact on the HTA process and recommendations. It influenced how the HTA was planned and executed, emphasized autonomy and justice when creating the recommendations, and helped the workgroup to understand the complexity of combining different stakeholders' discourses. Tensions between scientific evidence, expectations, and values became explicit. CONCLUSIONS: Comprehensive HTA provides an important, integrative approach to considering complex and controversial topics in health systems. HTA emphasizes multidisciplinary and multi-stakeholder approach but simultaneously forces a pragmatic, results-oriented, and evidence-based approach on all argumentation. Ethical analysis can facilitate interactions between stakeholders, bridge different discourses, and help formulate widely acceptable guidelines and policy decisions.

Cardiovascular outcomes in transgender individuals in Sweden after initiation of gender-affirming hormone therapy.

AIMS: We compared the incidence of cardiovascular disease (CVD) in transgender participants with a diagnosis of gender dysphoria (GD) with and without gender-affirming hormone therapy (GAHT) to the incidence observed in the general population. METHODS AND RESULTS: The population-based cohort included all individuals >10 years in Sweden linked to Swedish nationwide healthcare Registers (2006-16). Two comparator groups without GD/GAHT were matched (1:10) on age, county of residence, and on male and female birth-assigned sex, respectively. Cox proportional models provided hazard ratios (HRs) and 95% confidence intervals (CI) for CVD outcomes. Among 1779 transgender individuals [48% birth-assigned males (AMAB), 52% birth-assigned females (AFAB)], 18 developed CVD, most of which were conduction disorders. The incidence of CVD for AFAB individuals with GD was 3.7 per 1000 person-years (95% CI: 1.4-10.0). Assigned male at birth individuals with GD had an incidence of CVD event of 7.1 per 1000 person-years (95% CI: 4.2-12.0). The risk of CVD event was 2.4 times higher in AMAB individuals (HR: 2.4, 95% CI: 1.3-4.2) compared with cisgender women, and 1.7 higher compared with cisgender men (HR: 1.7, 95% CI: 1.0-2.9). Analysis limited to transgender individuals without GAHT yielded similar results to those with GAHT treatment. CONCLUSION: The incidence of CVD among GD/GAHT individuals was low, although increased compared with matched individuals without GD and similar to the incidence among GD/no GAHT individuals, thus not lending support for a causal relationship between treatment and CVD outcomes. Larger studies with longer follow-up are needed to verify these findings, as well as possible effect modification by comorbidity.

Puberty Blockers for Children: Can They Consent?

Gender dysphoria is a persistent distress about one's assigned gender. Referrals regarding gender dysphoria have recently greatly increased, often of a form that is rapid in onset. The sex ratio has changed, most now being natal females. Mental health issues pre-date the dysphoria in most. Puberty blockers are offered in clinics to help the child avoid puberty. Puberty blockers have known serious side effects, with uncertainty about their long-term use. They do not improve mental health. Without medication, most will desist from the dysphoria in time. Yet over 90% of those treated with puberty blockers progress to cross-sex hormones and often surgery, with irreversible consequences. The brain is biologically and socially immature in childhood and unlikely to understand the long-term consequences of treatment. The prevailing culture to affirm the dysphoria is critically reviewed. It is concluded that children are unable to consent to the use of puberty blockers.

Clinical practice guidelines for transsexual, transgender and gender diverse minors.

Some people, including minors, have a gender identity that does not correspond to the sex assigned at birth. They are known as trans* people, which is an umbrella term that encompasses transgender, transsexual, and other identities not conforming to the assigned gender. Healthcare units for trans* minors require multidisciplinary working, undertaken by personnel expert in gender identity, enabling, when requested, interventions for the minor and their social-familial environment, in an individualized and flexible way during the gender affirmation path. This service model also includes hormonal treatments tailored as much as possible to the individual's needs, beyond the dichotomic goals of a traditional binary model. This guide addresses the general aspects of professional care of trans* minors and presents the current evidence-based protocol of hormonal treatments for trans* and non-binary adolescents. In addition, it details key aspects related to expected body changes and their possible side effects, as well as prior counselling about fertility preservation.

Association between pre-treatment IQ and educational achievement after gender-affirming treatment including puberty suppression in transgender adolescents.

BACKGROUND: Concerns exist regarding effects of puberty suppression on neurodevelopment. Intelligence is strongly correlated with educational achievement in the general population. This study aimed to examine the association between pre-treatment intelligence and educational achievement after gender-affirming treatment including puberty suppression in transgender adolescents to contribute to the emerging understanding of the effect that gender-affirming treatment including puberty suppression may have on cognitive development. METHODS: IQ was measured in 72 adolescents (45 trans boys, 27 trans girls) at clinical entry (mean age 12.78 years), educational achievement was evaluated after gender-affirming treatment (mean age 20.40 years). RESULTS: IQ pre-treatment and educational achievement post-treatment were positively associated (Nagelkerke R = 0.71). DISCUSSION: The association between IQ pre-treatment and educational achievement post-treatment in transgender adolescents who received gender-affirming medical treatment including puberty suppression appears to be similar to the general population. This may reflect that gender-affirming medical treatment including puberty suppression does not negatively affect the association between IQ and educational achievement.