Short-term vaginal prasterone therapy induces steroid receptor modulation and extracellular matrix remodeling in human vaginal mucosa

Abstract Prasterone (dehydroepiandrosterone, DHEA) is increasingly used in the treatment of genitourinary syndrome of menopause (GSM), although its molecular effects on vaginal tissue remain insufficiently characterized. This prospective study evaluated the short-term impact of vaginal prasterone on steroid receptor expression, epithelial morphology, extracellular matrix composition, and the proteomic profile of the vaginal mucosa. Ten women aged 41–67 years received intravaginal prasterone (6.5 mg daily) for eight weeks. Vaginal biopsies were obtained before and after treatment, and serum estradiol and DHEA-S levels were assessed. Immunohistochemical analysis demonstrated a significant increase in cumulative ERα expression across epithelial layers ( p = 0.0379), with the most pronounced changes in the superficial epithelium and stromal compartment. Progesterone receptor expression showed stromal upregulation accompanied by epithelial downregulation. Epithelial thickness increased by 17.5 μm following therapy. Proteomic analysis using LC–MS/MS identified 87 proteins with altered abundance, including enrichment of extracellular matrix components and upregulation of collagen IV (COL4A1 and COL4A2). In contrast, several inflammation- and remodeling-related proteins, including IL18, LCN2, SERPINE2, and PRSS27, were downregulated. These findings indicate that short-term vaginal prasterone therapy promotes steroid receptor modulation and extracellular matrix remodeling in human vaginal mucosa while reducing inflammatory signaling pathways. Patient-reported outcomes assessed using the WHOQOL-BREF questionnaire indicated a trend toward improvement in quality of life following treatment, with the largest median increases observed in the physical (Domain 1) and environmental (Domain 4) domains. However, these changes did not reach statistical significance ( p > 0.05), and no significant differences were observed in overall quality of life or perceived health status.