Genetic Determinants Of Dermatologic Changes During Gender-Affirming Therapy: A Prospective Cohort Study

Gender-affirming hormone therapy (GAHT) induces profound endocrine changes that affect multiple organ systems, including the skin. Although several dermatological manifestations associated with GAHT have been described, the biological mechanisms underlying the marked interindividual variability in cutaneous response remain poorly understood. In particular, the contribution of androgen receptor AR gene polymorphisms has received limited attention. Aim of the study: To characterize the longitudinal dermatological effects of GAHT and to investigate the association between AR CAG and GCC repeat polymorphisms and the development of androgen-dependent dermatological manifestations. Materials and Methods: A prospective cohort study was conducted on 59 transgender individuals attending the Center for Gender Identity of the University Hospital of Padua between April 2025 and May 2026. Clinical, dermatological, hormonal, and genetic data were collected at baseline and after 3, 6, and 12 months of GAHT. Dermatological outcomes included acne vulgaris, seborrheic dermatitis, seborrhea, androgenetic alopecia, sweating patterns, skin characteristics, and genital changes. Longitudinal analyses were performed using mixed-effects regression models. Associations between AR polymorphisms and dermatological outcomes were evaluated according to sex assigned at birth (SAAB). Results: Masculinizing GAHT was associated with a progressive increase in acne vulgaris, seborrheic dermatitis, seborrhea, androgenetic alopecia, sweating, and skin oiliness, whereas feminizing GAHT produced opposite or stabilizing dermatological changes. Hormonal variations were consistent with the expected endocrine effects of GAHT. Genetic analyses demonstrated significantly higher acne prevalence and seborrhea levels among AFAB participants carrying the CAG- long genotype compared with the CAG-short genotype, whereas no significant associations were observed for the GCC polymorphism or for androgenetic alopecia. Conclusions: This study confirms the profound impact of GAHT on androgen-dependent dermatological manifestations and provides preliminary evidence that AR CAG repeat length may contribute to the individual variability of cutaneous responses to masculinizing hormone therapy. These findings support the importance of integrating dermatological care into multidisciplinary gender-affirming services and provide a rationale for future larger studies investigating the role of genetic determinants in personalized dermatological management during GAHT.