Testosterone-Based Gender-Affirming Hormone Therapy, Menopause, and Menopause Hormone Therapy: Implications for Reproductive Tract Immunity and Viral Pathogenesis

Sex hormones shape reproductive tract immunity and influence host defense against viral infection. However, much of our understanding of hormone-mediated immunity derives from cisgender populations and systemic studies. Comparatively less is known about the effects of sustained hormonal change within reproductive tissues. This gap is particularly relevant to transgender men (TGM) taking testosterone-based gender-affirming hormone therapy (GAHT) and to menopausal women using menopause hormone therapy (MHT). Although biologically distinct, these populations provide complementary contexts for examining how sustained androgen exposure, ovarian hormone decline, and therapeutic hormone use influence reproductive tract immunity. In this review, we examine hormone-associated changes in reproductive tract epithelial, stromal, and immune cells including the reproductive tract microbiome and virome. We consider their implications for the acquisition, replication, persistence and pathogenesis of HIV-1, HPV, HSV and CMV. Understanding these tissue specific, hormone-immune-virus interactions may help identify gaps in viral prevention, screening, vaccination, and treatment efforts across diverse hormonal and reproductive contexts.