Heterogeneity in Multisystem Estrogenic and Site-Specific Microbiome Responses to Menopausal Hormone Therapy among Perimenopausal Women

Menopausal hormone therapy (MHT) alleviates climacteric symptoms, but still, microbiome-wide effects and efficacy determinants remain uncharacterized. In this six-month longitudinal study of 356 perimenopausal women receiving oral MHT, we integrated serial clinical assessments with multi-site metagenomic profiling. MHT elicited multi-system estrogenic responses, including neuroendocrine restoration, symptom alleviation, metabolic shifts, and uterine changes. MHT induced site-specific microbiome remodeling, most prominently in vaginal and urinary niches, with moderate oral and minimal gut changes. Generally, MHT reduced Gardnerella vaginalis and increased Lactobacillus crispatus levels in vagina. Baseline vaginal L. crispatus abundance strongly predicted subsequent urogenital restoration. Additionally, baseline urogenital community states stratified therapeutic trajectories: vaginal G. vaginalis-dominated individuals showed transitions toward eubiosis, whereas diversified communities improved less. MHT efficacy corresponded to serum estrogen elevation, linked to baseline gut community type. Individuals with a Phocaeicola vulgatus-driven community type exhibited greater hormonal responsiveness and superior outcomes than those dominated by Prevotella copri. These findings support a precision MHT framework integrating gut community and urogenital typing to guide stratification and targeted interventions.