Valentin Nicolae Varlas 1 *
1 Department of Obstetrics and Gynecology, Faculty of Dental Medicine, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
* Correspondence to: Valentin Nicolae Varlas, Department of Obstetrics and Gynecology, Faculty of Dental Medicine, Carol Davila University of Medicine and Pharmacy, 37 Dionisie Lupu Street, 020021 Bucharest, Romania. E-mail: valentin.varlas@umfcd.ro
Abstract
The Women’s Health Initiative (WHI) trials of 2002 and 2004, and the class-wide boxed warning that the US Food and Drug Administration (FDA) placed on estrogen-containing products from 2003, cut the use of menopausal hormone therapy (MHT) by more than half. This review restates what the WHI showed and synthesizes the evidence accumulated since by age at initiation, time since menopause, route, progestogen, dose, duration and endpoint: coronary disease, stroke, venous thromboembolism (VTE), breast, endometrial and ovarian cancer, dementia, fracture and mortality. Started before age 60 or within 10 years of menopause, MHT has not been shown to increase coronary events or all-cause mortality and reduces fractures; oral estrogen raises the risk of VTE and stroke, whereas low-dose transdermal estradiol has not been so associated in observational studies; combined therapy raises breast cancer incidence in proportion to duration, less so with micronized progesterone or dydrogesterone; low-dose vaginal estrogen has not been associated with systemic risk. In November 2025 the FDA announced removal of the boxed-warning language on cardiovascular disease, breast cancer and probable dementia, and the first revised labels were approved in February 2026; European Union product information keeps the class warnings worded by the Pharmacovigilance Risk Assessment Committee in 2020. The neurokinin 3 receptor antagonist fezolinetant and the dual neurokinin 1 and 3 receptor antagonist elinzanetant, authorized in the European Union in 2023 and 2025, outperform paroxetine, desvenlafaxine and gabapentin in indirect comparisons, with liver monitoring required for fezolinetant. We close with a prescribing framework for the European clinician.