Effectiveness and safety of different estradiol regimens in transgender women (TREAT study): Protocol for a randomized controlled trial

BACKGROUND: Current guidelines for gender-affirming hormone therapy (GAHT) for transgender women are mostly based on clinical experience from experts in the field and treatments used on postmenopausal women. While care is currently provided with the best available evidence, there is a critical gap in knowledge about the safest and most effective estradiol routes of administration for GAHT in transgender women; this statement is supported by the World Professional Association for Transgender Health on their Standards of Care for the Health of Transgender and Gender Diverse People, version 8. Furthermore, the reported rates of cardiometabolic adverse events in transgender women highlight the importance of investigating changes in lipoproteins, glucose, and insulin sensitivity, among other markers while receiving GAHT. OBJECTIVE: This study aims to evaluate the degree of testosterone suppression achieved at 1, 6, and 12 months in treatment-naive transgender women when randomized to GAHT with estradiol and spironolactone as antiandrogens. As a secondary aim, this study will assess the treatment effect on metabolic and coagulation factors from baseline to 6 and 12 months after initiating GAHT. METHODS: This is a prospective pilot, open-label, randomized clinical trial conducted at an adult transgender clinic in a tertiary medical center. The 3 treatment arms include once-daily sublingual 17-β estradiol, twice-daily sublingual 17-β estradiol, and transdermal 17-β estradiol. All participants received spironolactone as an antiandrogen. Transgender women aged 18 to 45 years who are being evaluated for the initiation of GAHT with 17-β estradiol and did not have a history of coagulopathy, cigarette smoking, liver disease, dyslipidemia requiring treatment, or use of gonadotropin-releasing hormone agonist were eligible to enroll. The main outcome is the total testosterone suppression at 1 and 6 months after the initiation of GAHT, and the secondary outcome is to assess treatment effect in a lipid panel; homeostatic model assessment for insulin resistance; coagulation factors II, IX, and XI; Von Willebrand factor; activated protein C resistance; protein C; and protein S at baseline, 6 months, and 12 months after therapy is initiated. RESULTS: This study was funded in March 2022, and enrollment concluded in August 2022. It was concluded in July 2023, and currently, the results are being analyzed for publication. CONCLUSIONS: The Transgender Estradiol Affirming Therapy (TREAT) study offers a rigorous and reproducible approach to answer important questions regarding GAHT in transgender women, specifically, the most effective 17-β estradiol regimen to suppress testosterone levels to 50 ng/dL, as currently recommended. TRIAL REGISTRATION: ClinicalTrials.gov NCT05010707; https://clinicaltrials.gov/study/NCT05010707. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/53092

Assessment of sociodemographic and psychiatric characteristics of transgender adults seen at a Midwest tertiary medical center

BackgroundThe National Academy of Medicine has formally identified transgender adults as an understudied population in critical need of health research. While national surveys, like the US Transgender survey, have characterized higher rates of depression, anxiety, suicidality and socioeconomic need in the transgender community, studies have not examined the impact of sociodemographic and clinical characteristics on mental health related outcomes.ObjectiveTo describe the sociodemographic and mental health characteristics of transgender adults seen at a large Midwest transgender clinic and to determine factors associated with self-reported mental health conditions.MethodsDescriptive, retrospective, cross-sectional study of new transgender patients 18 years and older seen at a large Midwest transgender clinic between December 2019 and June 2022.ResultsA total of 482 charts were reviewed. During their initial evaluation, 11.6% (56/482) reported having a history of suicide attempt and 81.3% (392/482) reported a mental health diagnosis with the most common being depression, anxiety, attention deficit disorder, and post-traumatic stress disorder. Multivariable logistic regression results show no single factor was significantly associated with mental health diagnosis after adjusting for the effect of age and race. Patients who were new to gender affirming hormone therapy (54%, 254/468) are 2.0 (95% CI 1.4-2.9) times more likely to report having a mental health care provider than patients who were seen for continuation of therapy (46%, 214/468). Ten records with race not disclosed, 3 records with gender identity “other” and 2 records with gender identity not disclosed were excluded from analysis.ConclusionThis study reinforces the finding that transgender adults have an increased lifetime prevalence of mental health conditions. The higher prevalence of mental health conditions in our clinic was not associated with sociodemographic factors included in the study. Furthermore, transgender patients are less likely to have seen mental healthcare providers after initiation of gender affirming hormone therapy

Co-occurring autism, ADHD, and gender dysphoria in children, adolescents, and young adults with eating disorders: an examination of pre- vs. post-COVID pandemic outbreak trends with real-time electronic health record data

BackgroundIncidence rates of autism, attention-deficit/hyperactivity disorder (ADHD), and gender dysphoria (GD) are rising not only in the general population, but particularly among children, adolescents, and young adults with eating disorders (EDs). While ED rates have risen during the COVID pandemic, trends in co-occurring autism, ADHD, and GD have yet to be investigated in detail or at scale by way of large electronic medical record data.ObjectivesTo investigate trends in rates of co-occurring autism, ADHD, and GD among children, adolescents, and young adults with EDs in years prior to and during the COVID-19 pandemic.MethodsWe utilized a de-identified multinational electronic health records database (TriNetX) with 48,558 individuals aged 5-26 diagnosed with eating disorders (EDs) at least twice between 2017 and 2022. The primary predictor variable differentiated between the years of each person’s index (first) ED diagnosis (2017-2019 vs. 2020-2022). The primary outcome variable was the rate of new co-occurring psychiatric diagnoses of autism, ADHD, and GD in the year following each patient’s first ED diagnosis. We applied propensity score-matched multivariable logistic regressions to compare primary outcomes between 2017-2019 and 2020-2022.ResultsOur analysis included 17,445 individuals diagnosed with EDs in 2017-2019 (8% autism, 13.5% ADHD, 1.9% GD) and 31,113 diagnosed with EDs in 2020-2022 (8% autism, 14.6% ADHD, 3.2% GD). After 1:1 propensity score matching, 17,202 individuals from the 2017-2019 cohort were matched to peers mirroring the 2020-2022 cohort. Those diagnosed in 2020-2022 showed a 19% (aOR[95%CI]=1.19[1.07-1.33]), 25% (aOR=1.25[1.04-1.49]), and 36% (aOR=1.36[1.07-1.74]) increase in odds for autism, ADHD, and GD diagnoses, respectively, within the 365 days after the index EDs diagnosis, compared to the 2017-2019 cohort.DiscussionRates of autism, ADHD, and GD are significantly higher in individuals with ED in the post-pandemic 2020-2022 cohort in comparison to the pre-pandemic 2017-2019 cohort, even after controlling for baseline levels of co-occurring psychiatric diagnoses. Such findings reveal a critical gap in our current understanding of the totality of ways in which COVID-19 may have impacted the onset and clinical course of EDs, autism, ADHD, and GD among children, adolescents, and young adults

Defining clinical subgroups and genotype–phenotype correlations in NBAS-associated disease across 110 patients

Purpose: Pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause an autosomal recessive disorder with a wide range of symptoms affecting liver, skeletal system, and brain, among others. There is a continuously growing number of patients but a lack of systematic and quantitative analysis. ----- Methods: Individuals with biallelic variants in NBAS were recruited within an international, multicenter study, including novel and previously published patients. Clinical variables were analyzed with log-linear models and visualized by mosaic plots; facial profiles were investigated via DeepGestalt. The structure of the NBAS protein was predicted using computational methods. ----- Results: One hundred ten individuals from 97 families with biallelic pathogenic NBAS variants were identified, including 26 novel patients with 19 previously unreported variants, giving a total number of 86 variants. Protein modeling redefined the β-propeller domain of NBAS. Based on the localization of missense variants and in-frame deletions, three clinical subgroups arise that differ significantly regarding main clinical features and are directly related to the affected region of the NBAS protein: β-propeller (combined phenotype), Sec39 (infantile liver failure syndrome type 2/ILFS2), and C-terminal (short stature, optic atrophy, and Pelger-Huët anomaly/SOPH). ----- Conclusion: We define clinical subgroups of NBAS-associated disease that can guide patient management and point to domain-specific functions of NBAS