Systemic testosterone induces structural, immunological, and sex steroid receptor changes in human XX skin.

Skin-resident cells express multiple sex steroid receptors, making the cutaneous microenvironment sensitive to hormonal fluctuations. Transgender individuals assigned female at birth receiving gender-affirming hormone treatment (GAHT) with systemic testosterone often undergo several surgical procedures, underscoring the importance of understanding how GAHT influences skin biology and wound-healing capacity. This study aimed to characterize how XX (genotype) skin responds to systemic testosterone exposure. Discarded skin samples from plastic surgeries were collected from XX patients with and without testosterone treatment and analyzed for sex steroid receptor expression, immune cell markers, and structural integrity components. In testosterone-treated skin, we observed, in dermis, a 2.77-fold increase in androgen receptor-positive cells, elevated estrogen receptor α- and progesterone receptor-positive cell counts, a 43% reduction in CD45 positive immune cells, and a 2.93-fold increase in collagen density compared with untreated controls. In the epidermis, testosterone treatment resulted in reduced progesterone receptor-positive cell numbers and increased fibronectin expression. Collectively, testosterone-treated XX skin exhibited features resembling a male skin phenotype, potentially driven by altered sex steroid receptor expression, shifts in immune cell infiltration, and changes to structural organization. These findings highlight the need for further studies to elucidate the mechanisms underlying testosterone-induced skin remodeling and its implications for surgical outcomes.