Sex hormones in Systemic Sclerosis: A pathway to sex-specific therapeutics

Systemic sclerosis (SSc) is a rare autoimmune disorder characterized by fibrosis, vascular remodeling, and immune dysregulation, with a higher prevalence in females. Males, however, often exhibit more severe disease phenotypes, suggesting that sex hormones may influence disease progression. Despite this, limited research explores sexual dimorphism at the hormonal level. This study investigates the role of sex hormones in SSc severity using preclinical models and patient data. The Fra-2 transgenic (Tg) mouse model of SSc was employed to compare disease severity between male and female mice. Castration experiments, including ovariectomies in females and orchiectomies in males, were performed to assess the role of sex hormones. Parallel clinical studies examined testosterone levels in male SSc patients and their correlation with disease severity. Furthermore, 3D skin and lung models and organ-on-chip systems derived from patient cells were developed to study testosterone’s role in fibrosis in a physiologically relevant context. In the Fra-2 Tg model, females exhibited more severe disease phenotypes than males. Orchiectomy worsened disease in males, whereas ovariectomy did not exacerbate disease in females. Testosterone supplementation in orchiectomized males significantly improved lung function, reduced fibrosis, inflammation, immune response, and vascular remodeling. These protective effects were not observed in ovariectomized females. Ongoing 3D model studies also highlight testosterone’s role in reducing fibroblast activation and collagen deposition. These findings suggest testosterone plays a protective role in SSc pathology, with potential therapeutic implications. Further research may inform sex-specific therapeutic strategies to improve patient outcomes.