Then and Now: What We Have Learned From the WHI.

Abstract

This narrative review aims to highlight key learning points from the Women's Health Initiative (WHI) studies, providing a nuanced appraisal of menopausal hormone therapy (MHT) risks and benefits in postmenopausal women. A structured PubMed search was conducted using MeSH terms and keywords for MHT, bone health, cardiovascular and metabolic disease, cancer (breast, endometrial, ovarian, colorectal), and cognitive outcomes. The search included clinical trials, observational studies, and systematic reviews published in the English language. WHI data reveal that both combined conjugated equine estrogen-medroxyprogesterone acetate (CEE-MPA) and CEE-only therapy significantly reduce hip, vertebral, and total fracture risk, with further skeletal protection from calcium and vitamin D co-administration. Cardiovascular outcomes are strongly influenced by timing: initiation before age 60 or within 10 years of menopause may confer benefit, while delayed initiation (≥65 years) increases risks of coronary events and stroke, supporting the "window of opportunity" hypothesis. CEE-MPA therapy increases invasive breast cancer incidence (especially in prior users), while estrogen-only therapy is associated with a marginal nonsignificant reduction in breast cancer risk. Both regimens lowered colorectal cancer incidence during active treatment. Early MHT initiation has no effect on cognitive function, whereas late initiation increases dementia risk. WHI findings underscore the importance of individualized, time-sensitive MHT use, with benefits and risks shaped by formulation, timing, and patient characteristics. These insights continue to inform evolving clinical practice.