Reappraising the safety of menopausal hormone therapy for women—implications for the clinic

Abstract

Menopausal hormone therapy (MHT) is currently the most effective treatment for vasomotor and other estrogen deficiency-related symptoms. Despite its proven efficacy, concerns regarding long-term safety, particularly breast cancer, venous thromboembolism, and cardiovascular disease, have influenced clinical practice and patterns of MHT use over the past decades. This review summarizes the evolution of evidence regarding the safety of systemic MHT, from the introduction of conjugated equine estrogens in the 1940s through landmark randomized clinical trials to contemporary evidence and international guideline recommendations. Early concerns regarding endometrial safety with estrogen-only treatment were largely resolved by the addition of progestogens for women with an intact uterus. The Women's Health Initiative trial fundamentally changed perceptions of MHT cardiovascular safety, but subsequent analyses established the “timing hypothesis,” demonstrating that the benefit–risk profile depends on age and time since menopause at treatment initiation. More recent evidence has highlighted clinically relevant differences between estrogen formulations, routes of administration, and type of progestogen. Transdermal estradiol is associated with a lower risk of venous thromboembolism than oral estrogen, while micronized progesterone and dydrogesterone may offer a more favorable breast safety profile than some synthetic progestins, although randomized evidence is lacking. Current evidence supports an individualized approach to MHT, with treatment decisions based on symptom burden, age, time since menopause, route of estrogen administration, type of progestogen, and individual risk factors. For healthy women initiating therapy before age 60 years or within 10 years of menopause, the overall benefit–risk profile is favorable. Future research should focus on optimizing formulation-specific safety, generating comparative randomized evidence, and further refining personalized treatment strategies to maximize benefits while minimizing risks.