Precision Pharmacological Stratification and Targeted Management of Pathological Menopause: Evidence-Based Hormone Replacement Therapy Optimization, Non-Hormonal Pharmacotherapy, and Personalized Strategies in Premature Ovarian Insufficiency and Iatrogenic Forms

Background Pathological menopause, which encompasses premature ovarian insufficiency (POI), early menopause, and iatrogenically induced variants, represents a critical and often devastating deviation from the normative reproductive aging trajectory. Affecting approximately 3.5% to 5% of women globally, it precipitates an abrupt and profound cessation of ovarian endocrine function. This early-onset hypoestrogenism subjects affected individuals to severe vasomotor symptoms (VMS), genitourinary syndrome of menopause (GSM), and exponentially accelerates the longitudinal risk of cardiovascular disease, osteoporosis, and neurocognitive decline. Methods This comprehensive systematic review synthesizes high-impact evidence from recent international clinical guidelines spanning 2024 to 2026, including comprehensive frameworks from the European Society of Endocrinology (ESE), the American Society for Reproductive Medicine (ASRM), and the International Menopause Society (IMS). A systematic analysis of phase 3 clinical trials, pharmacogenomic studies, artificial intelligence-driven predictive models, and regenerative medicine research was conducted to outline precision management algorithms for highly stratified patient cohorts. Results The optimization of menopausal hormone therapy (MHT) relies heavily on pharmacological risk stratification, emphasizing the shift toward transdermal 17β-estradiol combined with micronized progesterone to mitigate venous thromboembolism (VTE) and oncological risks. Estetrol (E4), a native fetal estrogen with selective tissue activity, emerges as a highly favorable alternative demonstrating neutral cardiovascular and hemostatic profiles in the recent E4COMFORT phase 3 trials. For patients with absolute contraindications to MHT, particularly breast cancer survivors experiencing iatrogenic menopause, the approval of neurokinin-3 (NK3) receptor antagonists (fezolinetant and elinzanetant) represents a paradigm shift in mitigating VMS via direct hypothalamic modulation without systemic endocrine effects. Furthermore, the integration of pharmacogenomic testing (e.g., CYP2D6, ESR1) and artificial intelligence-driven predictive models significantly enhances therapeutic individualization. Regenerative frontiers, particularly hypoxic mesenchymal stem cell-derived exosomes acting via the SIRT3/PGC-1α pathway, offer unprecedented potential for ovarian follicle rescue and functional restoration. Conclusion The contemporary management of pathological menopause necessitates an immediate departure from standardized, empirical protocols in favor of precision, biomarker-guided stratification. By synthesizing advanced pharmacotherapy, non-hormonal innovations, and resolving profound global health equity gaps, this multidisciplinary approach ensures optimized long-term health span and quality of life for women experiencing premature estrogen deprivation.

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