Menopausal Hormone Therapy in Clinically Vulnerable Women: A Narrative Review of Guidelines and Real-World Evidence

Background and Objectives: Menopausal hormone therapy (MHT) is the most efficacious treatment for vasomotor symptoms and genitourinary conditions associated with menopause. Modern menopause care increasingly encompasses women with multimorbidity, renal or hepatic impairment, previous malignancies or thromboembolic disorders, advanced age, and polypharmacy—groups frequently underrepresented in randomized clinical trials. This evidence gap prompts significant inquiries about the relevance of trial-based recommendations to actual clinical practice. Materials and Methods: This narrative review offers a concentrated assessment of prominent worldwide clinical guidelines regarding menopausal hormone therapy through thematic synthesis. We examined position statements from the North American Menopause Society (NAMS), the European Menopause and Andropause Society (EMAS), NICE clinical guidelines, the ACOG Practice Bulletin on menopausal symptom management, the Endocrine Society clinical practice guideline, and pertinent UK guidance from RCOG, BMS, and BGCS. Data from systematic reviews, meta-analyses, and extensive observational studies were analyzed to contextualize guideline recommendations for populations often underrepresented in clinical trials, including women aged ≥65 years and individuals with multimorbidity or polypharmacy. Results: Only the NICE and EMAS recommendations expressly acknowledge clinical vulnerability or complexity (multimorbidity, frailty, and cancer survivorship) as foundational principles. NAMS and ACOG delineate risk categories but fail to offer a cohesive taxonomy of vulnerability. Polypharmacy and drug–drug interactions are inconsistently addressed across guidelines, and there is a deficiency of standardized prescribing algorithms. While routine safety monitoring is universally advocated, the intervals for follow-up and methods for risk categorization differ. Observational evidence consistently indicates route-dependent variations in cardiovascular and thromboembolic risk, with transdermal estrogen linked to a more advantageous safety profile in higher-risk individuals. Conclusions: Present menopausal therapy guidelines are methodologically sound; however, they insufficiently address the complexities of multimorbidity, polypharmacy, and organ dysfunction. A systematic conceptual framework that incorporates areas of clinical vulnerability may facilitate personalized benefit–risk evaluation in practical applications. Future guideline revisions should enhance clarity by incorporating polypharmacy concerns, monitoring strategies, and systematic risk stratification methods for clinically complicated patients.