Back to the Future: Is GnRHa treatment in transgender and gender diverse adolescents only an extended evaluation phase?

PURPOSE: The main aim of the present study was to explore several hormone, physical and psychological functioning changes during GnRH analogs (GnRHa) treatment in Transgender and gender diverse adolescents (TGDA). The potential relationship between the physical and hormone effects of GnRHa and psychological well-being, along with its magnitude, was assessed for the first time. METHODS: This prospective multidisciplinary study included 36 TGDA (22 assigned female at birth, and 14 assigned male at birth) who received psychological assessment followed by Triptorelin prescription referring to the Florence Gender Clinic. This study consisted of three time points: first referral (T0), psychological assessment (T1); treatment with intramuscular injections of Triptorelin for three up to twelve months (T2). Psychometric questionnaires were administered at each time, clinical and biochemical evaluations were performed at T1 and T2. RESULTS: The following results were found: (i) GnRHa showed efficacy in inhibiting puberty progression in TGDA; (ii) an increase in psychopathology was observed before starting GnRHa (T1) as compared to baseline levels; (iii) during GnRHa treatment (T2), a significant improvement in psychological functioning, as well as decrease in suicidality, body uneasiness, depression and anxiety levels were observed; (iv) hormone and physical changes (in terms of gonadotropin and sex steroids levels, height and body mass index percentiles, waist-hip ratio, and acne severity) observed during Triptorelin treatment significantly correlated with a reduction in suicidal ideation, anxiety and body image concerns. CONCLUSIONS: Psychological improvement in TGDA on GnRHa seems to be related to the objective body changes induced by GnRHa. Therefore, the rationale for treatment with GnRHa may not only be considered an extension of the evaluation phase, but also the start of a medical (even if reversible) gender-affirming path, especially in TGDA whose puberty has already progressed.

Prevalence and Correlates of Sexually Transmitted Infections in Transgender People: An Italian Multicentric Cross-Sectional Study.

The burden of sexually transmitted infections (STIs) in the transgender population remains an underestimated issue. The aims of the present study were to evaluate the prevalence of either self-reported and serological STIs and to describe socio-demographic and clinical characteristics of transgender individuals with STIs. A consecutive series of 705 transgender individuals (assigned-male at birth, AMAB n = 377; assigned-female at birth, AFAB n = 328) referring to six Italian gender clinics were included. Sociodemographic and clinical information was collected during the first visit. In a subsample of 126 individuals prevalence of STIs (human immunodeficiency virus, HIV; hepatitis C, HCV; hepatitis B, HBV; syphilis) were evaluated through serology tests. The self-reported prevalence of HIV, HBV, HCV and syphilis infection in the total sample were 3.4%, 1.6%, 2.6% and 2.0%, respectively. In the subsample who underwent serological tests, higher rates of serological prevalence were found (9.5%, 4.0%, 5.6% and 7.9% for HIV, HBV, HCV and syphilis, respectively). When comparing transgender people with or without self-reported STIs, unemployment, previous incarceration, justice problems and sex work resulted more frequent in the first group (p< 0.03 for all). Regarding health status, we observed higher rates of lifetime substance abuse and psychiatric morbidities in trans people with at least one reported STI (p < 0.05). The prevalence of STIs exceeded that reported in general population and STIs correlates underline the importance of stigma and discrimination as determinants of transgender health.

A Novel Compound Heterozygous Mutation of HSD17B3 Gene Identified in a Patient With 46,XY Difference of Sexual Development.

INTRODUCTION: Deficiency of the 17ß-hydroxysteroid dehydrogenase type 3 (17 ß-HSD3) is a rare autosomal recessive 46,XY Difference of sex development (DSD), resulting from pathogenetic variants in the HSD17B3 gene, which lead to absent or reduced ability to convert Δ4-androstenedione to testosterone in the fetal testes. AIM: This study aimed to present the clinical and genetic characteristics of an Italian patient receiving a diagnosis of 17 ß-HSD3 deficiency in adulthood. The patient was raised as female and underwent early surgical interventions to correct virilized genitalia, leading to a significant sexual distress. METHODS: At the time of the referral, a 20-gene Next Generation Sequencing custom-panel for DSD was performed on patient's genomic DNA. RESULTS: A novel compound heterozygous mutation in HSD17B3 gene was identified, detecting a new variant (c.257_265delAGGCCATTG, p.) CONCLUSION: Novel genotype causing 17 ß-HSD3 deficiency is presented. Furthermore, the patient's clinical history stresses the importance to actively involve these individuals in the decision-making process avoiding surgical intervention when the patient is not able to give fully informed consent. Cocchetti C, Baldinotti F, Romani A, et al. A Novel Compound Heterozygous Mutation of HSD17B3 Gene Identified in a Patient With 46,XY Difference of Sexual Development. Sex Med 2022;10:100522.

The ENIGI (European Network for the Investigation of Gender Incongruence) Study: Overview of Acquired Endocrine Knowledge and Future Perspectives.

Literature on the efficacy and safety of gender-affirming hormonal treatment (GAHT) in transgender people is limited. For this reason, in 2010 the European Network for the Investigation of Gender Incongruence (ENIGI) study was born. The aim of this review is to summarize evidence emerging from this prospective multicentric study and to identify future perspectives. GAHT was effective in inducing desired body changes in both trans AMAB and AFAB people (assigned male and female at birth, respectively). Evidence from the ENIGI study confirmed the overall safety of GAHT in the short/mid-term. In trans AMAB people, an increase in prolactin levels was demonstrated, whereas the most common side effects in trans AFAB people were acne development, erythrocytosis, and unfavorable changes in lipid profile. The main future perspectives should include the evaluation of the efficacy and safety of non-standardized hormonal treatment in non-binary trans people. Furthermore, long-term safety data on mortality rates, oncological risk, and cardiovascular, cerebrovascular and thromboembolic events are lacking. With this aim, we decided to extend the observation of the ENIGI study to 10 years in order to study all these aspects in depth and to answer these questions.

Psychological Wellbeing and Perceived Social Acceptance in Gender Diverse Individuals.

BACKGROUND: Over the last few years, the gender binary has been questioned, highlighting the existence of gender diverse people, who identify as neither (exclusively) male nor female. AIM: The present study evaluated the possible differences in terms of psychological wellbeing between binary and gender diverse individuals, as well as the role of perceived social acceptance and religious fundamentalism as possible mediators of psychopathology in gender diverse people. Furthermore, the diversity of gender-affirming hormonal treatment requests according to gender identification was investigated. METHODS: A sample of 563 transgender people aged 18-70 was enrolled (n = 264 assigned female at birth, AFAB and n = 299 assigned male at birth, AMAB), all individuals referring to several Italian gender clinics. A subdivision of the study population based on the gender identity visual analog scale (GI-VAS) median was performed, in order to distinguish between gender diverse and binary transgender individuals. Moreover, a linear regression analysis was performed entering logarithmically transformed GI-VAS (Log GI-VAS) into the models with psychometric scales. OUTCOMES: Psychometric and sociodemographic data, as well as information regarding requests for gender-affirming treatments, were extrapolated from the clinical interviews conducted during the first referral. RESULTS: Gender diverse individuals showed significantly less intense gender dysphoria and higher levels of depression and anxiety compared to binary ones; accordingly, a less binary gender identity correlated with higher levels of depression and anxiety and lower levels of gender dysphoria. The depressive symptomatology in gender diverse people was partially mediated by perceived discrimination and humiliation. Moreover, gender diverse AMAB people sought a non-standard hormonal treatment more often than their binary counterpart. CLINICAL IMPLICATIONS: The present study highlights the importance for transgender health professionals, when planning gender-affirming hormonal treatments, to offer flexible interventions, tailored on the patient's needs and goals. STRENGTHS & LIMITATIONS: Strengths included exploring whether and how perceived discrimination may affect mental health in gender diverse people. Limitations included the enrolled sample of people referring to different gender clinics, which is not fully representative of the transgender population. CONCLUSION: This study highlights the importance of evaluating each individual's unique health care needs, exploring each single request and its underlying reasons. Romani A., Mazzoli F., Ristori J., et al. Psychological Wellbeing and Perceived Social Acceptance in Gender Diverse Individuals. J Sex Med 2021;18:1933-1944.

Does Gender-Affirming Hormonal Treatment Affect 30-Year Cardiovascular Risk in Transgender Persons? A Two-Year Prospective European Study (ENIGI).

BACKGROUND: Cardiovascular (CV) implications of long-term gender affirming hormonal treatment (GAHT) in transgender individuals still remain largely unknown. AIM: To evaluate changes in the 30-year Framingham cardiovascular disease (CVD) risk in a large cohort of transgender individuals after the start of GAHT. METHODS: In a multicenter prospective study, a consecutive series of 309 participants (165 transmen and 144 transwomen) was evaluated during a 2-year follow-up. Prospectively, after the start of GAHT a physical examination was performed and blood samples were drawn. CVD risk was calculated for each person, according to the Framingham 30-year CVD risk estimate. MAIN OUTCOME MEASURE: Changes in CV risk factors and 30-year Framingham CVD risk during GAHT. CLINICAL IMPLICATIONS: In transmen testosterone-induced lipid profile alterations may have a clinical relevance on the individual long-term CVD risk. STRENGTHS & LIMITATIONS: The strength of the present study is the possibility to predict long-term CV outcomes in transgender individuals receiving GAHT based on a short observation; whereas the main limitation is that CVD risk prospective changes mainly represent the expression of risk factors changes during GAHT. RESULTS: In transwomen a significant decrease in triglycerides, total cholesterol and LDL-cholesterol was observed during the 2-year follow-up (P < .05), whereas unfavorable lipid changes - such as increased total cholesterol, triglycerides, and LDL cholesterol levels and decreased HDL cholesterol levels (P < .05)- occurred after the start of GAHT in transmen. These changes in risk factors led to an increase in the risk of general and hard CVD events based on lipid profile over time in transmen (P = .001 and P = .005, respectively). No significant changes in general and hard CVD risk based on lipid profile were observed in transwomen over time. CONCLUSIONS: Our findings confirmed the unfavorable lipid changes in transmen after the start of GAHT even during a longer follow-up, empathizing the potential clinical impact of these modifications on individual long-term CVD risk. Cocchetti C, Castellini G, Iacuaniello D, et al. Does Gender-Affirming Hormonal Treatment Affect 30-Year Cardiovascular Risk in Transgender Persons? A Two-Year Prospective European Study (ENIGI). J Sex Med 2021;18:821-829.

Neural Correlates of Gender Face Perception in Transgender People.

To date, MRI studies focused on brain sexual dimorphism have not explored the presence of specific neural patterns in gender dysphoria (GD) using gender discrimination tasks. Considering the central role of body image in GD, the present study aims to evaluate brain activation patterns with 3T-scanner functional MRI (fMRI) during gender face discrimination task in a sample of 20 hormone-naïve transgender and 20 cisgender individuals. Additionally, participants were asked to complete psychometric measures. The between-group analysis of average blood oxygenation level dependent (BOLD) activations of female vs. male face contrast showed a significant positive cluster in the bilateral precuneus in transmen when compared to the ciswomen. In addition. the transwomen group compared to the cismen showed higher activations also in the precuneus, as well as in the posterior cingulate gyrus, the angular gyrus and the lateral occipital cortices. Moreover, the activation of precuneus, angular gyrus, lateral occipital cortices and posterior cingulate gyrus was significantly associated with higher levels of body uneasiness. These results show for the first time the existence of a possible specific GD-neural pattern. However, it remains unclear if the differences in brain phenotype of transgender people may be the result of a sex-atypical neural development or of a lifelong experience of gender non-conformity.

Hormonal Treatment Strategies Tailored to Non-Binary Transgender Individuals.

INTRODUCTION: To date no standardized hormonal treatment protocols for non-binary transgender individuals have been described in the literature and there is a lack of data regarding their efficacy and safety. OBJECTIVES: To suggest possible treatment strategies for non-binary transgender individuals with non-standardized requests and to emphasize the importance of a personalized clinical approach. METHODS: A narrative review of pertinent literature on gender-affirming hormonal treatment in transgender persons was performed using PubMed. RESULTS: New hormonal treatment regimens outside those reported in current guidelines should be considered for non-binary transgender individuals, in order to improve psychological well-being and quality of life. In the present review we suggested the use of hormonal and non-hormonal compounds, which-based on their mechanism of action-could be used in these cases depending on clients' requests. CONCLUSION: Requests for an individualized hormonal treatment in non-binary transgender individuals represent a future challenge for professionals managing transgender health care. For each case, clinicians should balance the benefits and risks of a personalized non-standardized treatment, actively involving the person in decisions regarding hormonal treatment.

Brain Sex Differences Related to Gender Identity Development: Genes or Hormones?

The complex process of sexual differentiation is known to be influenced by biological and environmental determinants. The present review has the aim of summarizing the most relevant studies on the biological basis of sexual development, and in particular, it focuses on the impact of sex hormones and genetic background on the development of sexual differentiation and gender identity. The authors conducted a search of published studies on Medline (from January 1948 to December 2019). The evidence suggests that the sexual dimorphic brain could be the anatomical substrate of psychosexual development, on which gonadal hormones may have a shaping role during prenatal and pubertal periods. Additionally, according to several heritability studies, genetic components may have a role, but a promising candidate gene has not been identified. Even though growing evidence underlines the primary role of biological factors on psychosexual development, further studies are necessary to better explain their complex interactions.

Sexual habits among Italian transgender adolescents: a cross-sectional study.

Recent studies showed that transgender (TGN) adolescents are more at risk of negative sexual outcomes than their peers. However, little is known about the psychopathological and sociodemographic correlates of sexual-related experiences in TGN adolescents. This cross-sectional study aimed at overcoming this limitation describing this association in a sample of 18 transgirls and 32 transboys recruited at the Gender Clinic of the University of Florence between 2015 and 2020. Clinical, sociodemographic, and sexual-related features were collected through a face-to-face interview and anamnestic forms. Self-report questionnaires were administered to evaluate gender dysphoria (Gender Identity/Gender Dysphoria Questionnaire for Adolescents and Adults), emotional and behavioral problems (Youth Self Report), and body uneasiness (Body Uneasiness Test). The percentage of subjects reporting to have had at least one romantic relationship in life was 62.5% among transboys and 16.7% in transgirls (ORsex = 8.65, p < 0.01), whereas 28.1% of transboys and 5.6% of transgirls were sexually active (ORsex = 6.63, p > 0.05). A worse psychological functioning and risk-taking behaviors were associated with being sexually active (p < 0.05). These results underline the deep interconnection between psychological vulnerability and sexual-related features in TGN adolescents, confirming the importance of developing gender inclusive sex education programs to prevent negative sexual outcomes in this population.

Management of hypoactive sexual desire disorder in transgender women: a guide for clinicians.

Hypoactive sexual desire disorder (HSDD) represents a common condition among transgender women. However, to date no specific guidelines for the management of HSDD in transgender persons are available. The aim of the present narrative Review is to evaluate evidence-based treatment for HSDD and to suggest treatment options for HSDD in transgender women. Clinically relevant publications on the management of HSDD (from 1985 to 2020) were searched in PubMed and Medline databases, using the following terms: "sexual desire", "sexual health", "HSDD", "transgender", "gender-affirming treatment", "sexual therapy", "testosterone treatment", "Central nervous system-active medications", and variants. Since sexual desire could be affected by several factors, a comprehensive assessment of HSDD- exploring biological, psychological, and social domains- is recommended, in order to identify possible predisposing, precipitating and maintaining factors. Among treatment options, transgender women may benefit of different sex therapy strategies and/or central nervous system-active medications-such as flibanserin, bremelanotide, bupropion and buspirone-and transdermal testosterone, bearing in mind that this option could be poorly accepted by patients due to the risk of virilizing effects. The lack of data regarding the efficacy of HSDD treatment options in transgender women emphasize the need for literature to focus more on this topic in the future.

Hormonal Treatment Effect on Sexual Distress in Transgender Persons: 2-Year Follow-Up Data.

INTRODUCTION: As far as we know, no studies to date have investigated the psychobiological correlates of sexual distress (SD) nor the impact of hormonal treatment (HT) on SD in transgender persons. AIM: To evaluate the psychobiological correlates of SD and assess the effects of HT on SD in transgender persons without gender-affirming surgery. METHODS: A consecutive series of 301 transgender persons (160 transwomen and 141 transmen) was considered for the cross-sectional study, and a subset of 72 subjects was studied in a 2-year follow-up. A physical examination was performed. Blood samples were drawn for determination of cortisol levels. Subjects completed psychometric measures. During 2 years of HT, the evaluation of SD was prospectively repeated. MAIN OUTCOME MEASURE: Psychobiological correlates of SD in transgender population. Changes in SD during gender affirming hormonal treatment. CLINICAL IMPLICATIONS: Knowing how hormonal treatment influence SD will help care providers when counseling transgender people. STRENGTHS & LIMITATIONS: To the authors' knowledge, this is the first study prospectively evaluating the impact of gender affirming hormonal treatment on sexual distress in transgender individuals. The main limitations are represented by the small size of the sample and the use of questionnaires validated only in the cisgender population. RESULTS: SD showed a positive correlation with body uneasiness (P < .0001) and with dissatisfaction toward gender-related body parts or shapes (all P < .05). In addition, SD correlated positively with general psychopathology (P < .0001), alexithymia, social anxiety, and humiliation scales (all P < .05). In transmen, SD was positively associated with autism levels (P < .005), as well as with cortisol levels (P < .02). A significant correlation between SD and perceived discrimination was observed in transwomen (P < .05). In transwomen, SD was positively associated with hair density and negatively with breast growth (both P < .05). Finally, in transmen, a negative correlation was found between SD and hair density (P < .05). When the impact of HT on SD was evaluated, a significant reduction of SD was observed across time in both transwomen and transmen (P = .001 and P = .01, respectively). CONCLUSIONS: The present results support the efficacy of HT in reducing SD in transgender persons. Ristori J, Cocchetti C, Castellini G, et al. Hormonal Treatment Effect on Sexual Distress in Transgender Persons: 2-Year Follow-Up Data. J Sex Med 2020;17:142-151.