Safety of gender affirming treatment in assigned female at birth transgender people and association of androgen and estrogen ß receptor polymorphisms with clinical outcomes.

PURPOSE: Gender affirming hormone treatment (GAHT) with androgens in assigned female at birth (AFAB) people with Gender Incongruence (GI) can induce and maintain variable phenotypical changes, but individual response may be genetically determined. To clarify the role of AR and ERß polymorphisms we prospectively evaluated AFAB subjects undergoing virilizing GAHT. METHODS: Fifty-two AFAB people with confirmed GI were evaluated before (T0) and after 6 (T6) and 12 months (T12) of testosterone enanthate 250 mg i.m. every 28 days. Hormone profile (testosterone, estradiol), biochemical (blood count, glyco-metabolic profile) and clinical parameters (Ferriman-Gallwey score, pelvic organs) were evaluated at each time-point, as well as number of CAG and CA repeats for AR and ERß, respectively. RESULTS: All subjects have successfully achieved testosterone levels within normal male ranges and improved their degree of virilization, in absence of significant side effects. Hemoglobin, hematocrit and red blood cells were significantly increased after treatment, but within normal ranges. Ultrasound monitoring of pelvic organs showed their significant reduction already after 6 months of GATH, in absence of remarkable abnormalities. Furthermore, a lower number of CAG repeats was associated with a higher Ferriman-Gallwey score post treatment and a higher number of CA repeats was associated with uterine volume reduction. CONCLUSION: We confirmed safety and efficacy of testosterone treatment on all measured parameters. This preliminary data hints a future role of genetic polymorphisms to tailor GAHT in GI people, but evaluation on a larger cohort is necessary as the reduced sample size could limit data generalization at this stage.

Epigenetic Effects of Gender-Affirming Hormone Treatment: A Pilot Study of the ESR2 Promoter's Methylation in AFAB People.

Virilization of gender-incongruent subjects to whom were assigned the female gender at birth (AFAB) is achieved through testosterone administration. Inter-individual differences in the timing and acquisition of phenotypic characteristics, even if the same hormone preparations and regimens are used, are frequently observed. Polymorphisms of sex hormone receptors and methylation of their gene promoters, as well of several imprinted genes as H19, may underlie the differential response to treatment. Thus, the aim of this study was to examine the possible relationship between the CpG methylation profile of the estrogen receptor 2 gene (ESR2) and H19 promoters and their influence on phenotype modifications in a cohort of AFAB people at baseline (T0) and after 6 mo (T6) and 12 mo (T12) of testosterone therapy (testosterone enanthate, 250 mg i.m. every 28 d). A total of 13 AFAB subjects (mean age 29.3 ± 12.6) were recruited. The percentage of methylation of the ESR2 promoter significantly increased at T6 (adj. p = 0.001) and T12 (adj. p = 0.05), while no difference was detected for H19 (p = 0.237). Methylation levels were not associated with androgen receptor (AR)/estrogen receptor beta (ERß) polymorphisms nor hormone levels at baseline and after six months of treatment. On the other hand, total testosterone level and patient age resulted in being significantly associated with ESR2 methylation after twelve months of treatment. Finally, the difference in ESR2 promoter methylation between T6 and baseline was significantly associated with the number of CA repeats of the ERß receptor, adjusted vs. all considered variables (R2 = 0.62, adj. R2 = 0.35). No associations were found with CAG repeats of the AR, age, and estradiol and testosterone levels. Despite the small sample size, we can hypothesize that treatment with exogenous testosterone can modify the ESR2 methylation pattern. Our data also indicated that epigenetic changes may be regulated, suggesting that the modulation of estrogen signaling is relevant shortly after the beginning of the treatment up to T6, with no further significant modification at T12. Furthermore, estrogen receptor methylation appears to be associated with the age of the subjects and exogenous testosterone administration, representing a marker of androgenic treatment. Nonetheless, it will be necessary to increase the number of subjects to evaluate how epigenetic regulation might play a relevant role in the modulation of phenotypical changes after testosterone treatment.

Psychological Well-Being of Trans* People in Italy During the COVID-19 Pandemic: Critical Issues and Personal Experiences.

Introduction: The COVID-19 pandemic represents risk to physical health and psychological well-being. Specifically, it causes concerns among minoritized communities, such as transgender/non-binary individuals. The study investigates the experience of this group in Italy during the pandemic and identifies risk factors that exerted negative impacts on psychological well-being and physical health. Methods: The study developed an online questionnaire to investigate psychological status, access to medical health services, and factors such as predictors of risk outcomes among transgender/non-binary people during lockdown restrictions. Responses were collected (n = 256) on April 2020. Descriptive analysis, univariate analysis of variance, and t-test were conducted. Results: The respondents confirmed several issues, such as worries about the future (58.2%), negative emotions (46.9%), and self-uncertainty (52.7%) during the pandemic. Difficulties in undertaking hormone therapy and access to health facilities were reported. Living with family members represented a significant stressor for psychological well-being, whereas lack of support from LGBT + communities was reported. Subjects undergoing psychological therapy during the pandemic reported increases in depression, anxiety, somatization, and lack of privacy in the household. Conclusions: The study findings provide a framework for critical aspects experienced by transgender/non-binary individuals during the pandemic. Specifically, the study provides evidence of the vulnerability of this population underlined by multiple difficulties. Policy Implications: The study findings provide an overview of the experience of transgender and non-binary people during the pandemic, insights regarding risk factors, and aspects that require adequate attention and care. Supplementary Information: The online version contains supplementary material available at 10.1007/s13178-021-00633-3.

Molecular Analysis of DPY19L2, PICK1 and SPATA16 in Italian Unrelated Globozoospermic Men.

This study aims to evaluate genetic contribution and sperm DNA fragmentation (SDF) in a cohort of 18 unrelated globozoospermic Italian men (Group G). Semen samples were assessed according to the WHO 2010 Laboratory Manual and compared with 31 fertile controls. We focused our genetic analysis on the exons of the main globozoospermia-associated genes, performing qualitative PCR to assess deletion of DPY19L2 and sequencing to detect mutations of SPATA16 and PICK1. SDF was evaluated using the TUNEL assay. In Group G, 10 patients had a complete form of globozoospermia, whereas 8 patients had a partial form. Molecular analysis revealed deletion of DPY19L2 in six of the patients, all of them with complete globozoospermia, while no mutations were found in the examined exons of PICK1 and SPATA16. TUNEL analysis showed a higher SDF% in Group G. Our findings confirm DPY19L2 defects as the most frequent genetic alteration in Italian patients contributing to globozoospermic phenotypes. Furthermore, spermatozoa with acrosomal defects could also display high levels of SDF as a possible consequence of abnormally remodeled chromatin. The possible effect on offspring of chromatin structure abnormalities and altered DNA integrity should be carefully evaluated by clinicians, especially regarding the feasibility and safety of artificial reproductive techniques, which represent the only treatment that allows these patients to conceive.

The Body I Live in. Perceptions and Meanings of Body Dissatisfaction in Young Transgender Adults: A Qualitative Study.

Body dissatisfaction in individuals with Gender Incongruence (GI) represents a primary source of suffering. Several studies have highlighted how this suffering has psychological, physical, and biological implications. This work aims to explore experiences related to body dissatisfaction and investigate the issues associated with living in a body perceived as incongruent for individuals with GI. Thirty-six individuals, aged between 18 and 30 years old and at stage T0 of hormone treatment, participated in the study. Body dissatisfaction and experiences related to it were investigated using the Clinical Diagnostic Interview. The Consensual Qualitative Research methodology was applied to the transcripts of the interviews. Several themes emerged: experiences with GI development, experiences with puberty and bodily changes, perception of one's body, psychological problems and complex behavioral patterns related to body dissatisfaction. Results pointed out the complexity implied in the relationship with one's body for individuals with GI, highlighting specific aspects of body dissatisfaction among these individuals (e.g., eating disorders, sexual difficulties, social withdrawal). This study underlines the need for a deeper understanding of some aspects of GI to better define guidelines for a correct assessment of it. In this way it will be easier to avoid negative outcomes for the psychological and general health of transgender people.

Androgenetic alopecia: effects of oral finasteride on hormone profile, reproduction and sexual function.

PURPOSE: Androgenetic Alopecia (AGA) is a common non-cicatricial alopecia. AGA treatment with finasteride was reported to have sexological side effects and its induced hormonal alterations could damage spermatogenesis. Thus, in patients affected by AGA undergoing oral therapy with Finasteride 1 mg/die, we aimed to evaluate the presence of modification in sperm parameters, hormone profile and sexual function. METHODS: We retrospectively evaluated 55 male subjects aged 18-45 years with AGA who underwent systemic therapy with Finasteride 1 mg/die. Each subject underwent semen and blood hormone analysis, IIEF15 questionnaire administration at baseline (T0) at 6 (T6) and 12 (T12) months after the beginning of therapy and 1 year after treatment discontinuation (TD). RESULTS: At T6 we detected a statistically significant worsening of total sperm number (232.4 ± 160.3 vs. 133.2 ± 82.0; p = 0.01 vs. T0) and abnormal forms (79.8 ± 6.0 vs. 82.7 ± 5.7; p < 0.05 vs. T0). No difference was found for all sperm parameters at T12 and T24, except for the percentage of abnormal forms (79.8 ± 6.0 vs. 82.6 ± 4.8; p < 0.05 T24 vs. T0). Testosterone levels were increased at T0 vs. T6 (22.1 ± 7.1 vs. 28.0 ± 8.0 ng/mL; p < 0.05). No significant differences of IIEF15 questionnaire were detected across the study. CONCLUSIONS: Finasteride is associated with significant seminological and testosterone alterations, but no sexual dysfunctions were reported during treatment of these andrologically healthy subjects. Although, sperm parameters seem to return comparable to baseline after treatment discontinuation, it is advisable to perform a careful andrological evaluation before treatment.

Polymorphic Cytosine-Adenine-Guanine Repeat Length of Androgen Receptor Gene and Gender Incongruence in Trans Women: A Systematic Review and Meta-Analysis of Case-Control Studies.

INTRODUCTION: It has been hypothesized that gender incongruence in transgender women could result from an antenatal impaired androgen activity on the developing brain. As the length of polymorphic cytosine-adenine-guanine (CAG) repeat sequences in the androgen receptor (AR) gene is inversely correlated with AR transcriptional activity, some studies explored a possible association between long CAG repeats and gender incongruence in trangender women. Yet results remain inconclusive. AIM: To systematically evaluate whether a difference exists in the length of AR CAG repeat sequences between trans women and men without gender incongruence. METHODS: A thorough search of Medline, Scopus, Cochrane Library, Web of Science, and CINAHL databases was carried out to identify suitable case-control studies. Methodological quality of the included articles was assessed using the Newcastle-Ottawa Scale. In the absence of between-studies heterogeneity, as assessed by the Cochrane's Q and I2 tests, standardized mean differences (SMDs) in the length of AR CAG repeats were combined using a fixed effect model. Funnel plot and trim-and-fill analysis were used to assess publication bias. MAIN OUTCOME MEASURE: The association of gender incongruence in transgender women with longer length of AR CAG repeat sequences was evaluated by calculating pooled standardized mean difference with 95% confidence interval (CI). RESULTS: 5 studies included in the quantitative analysis collectively provided information on 795 trans women and 1,355 control men. At the overall estimate, the MtF group exhibited a significantly longer length of AR CAG repeat sequences (pooled standardized mean difference: 0.13, 95% CI: 0.04 to 0.22; P = 0.005; I2 = 0%, Pfor heterogeneity = 0.51). Sensitivity analysis demonstrated the high stability of the result. Funnel plot revealed a possible publication bias, and the trim-and-fill test detected 2 putative missing studies. Nevertheless, the significant association persisted even when pooled estimate was adjusted for publication bias. CLINICAL IMPLICATIONS: These findings could suggest a contribution of a genetically mediated impairment in androgen signaling in development of gender incongruence for transgender women. STRENGTH & LIMITATIONS: This is the first meta-analysis exploring the relationship between AR CAG repeat polymorphism and gender incongruence. However, interactions with other functional genetic variants were not explored, and caution should be exercised when generalizing these results because of the possible variability in the distribution of CAG repeats among different populations and ethnic groups. CONCLUSION: Trans woman population exhibits significantly longer polymorphic CAG repeat sequences in the AR gene. Further studies are warranted to elucidate whether, how and to what extent multiple functional variants in sex hormone signaling genes could be associated with gender incongruence/dysphoria. D'Andrea S, Pallotti F, Senofonte G, et al. Polymorphic Cytosine-Adenine-Guanine Repeat Length of Androgen Receptor Gene and Gender Incongruence in Trans Women: A Systematic Review and Meta-Analysis of Case-Control Studies. J Sex Med 2020;17:543-550.