The Timing Hypothesis: Hormone Therapy for Treating Symptomatic Women During Menopause and Its Relationship to Cardiovascular Disease

J Womens Health (Larchmt). 2019 May;28(5):705-711. doi: 10.1089/jwh.2018.7201. Epub 2018 Nov 28.


The risks and benefits of menopausal hormonal therapy (HT) have been evaluated extensively over the past three decades. While the efficacy of HT for management of menopausal symptoms, including vasomotor symptoms and vaginal dryness is well established, its relationship to cardiovascular outcomes is complex. The timing hypothesis, which posits that the cardiovascular effects of HT depend on the timing of initiation of HT in relation to menopause, has helped shape our understanding of the cardiovascular outcomes related to HT. Based on results from female monkey studies, the timing hypothesis provides a framework to explain discrepancies in results between multiple observation studies and the Women's Health Initiative (WHI) hormone therapy trials. The WHI trials closed early in 2002 in part because of increased cardiovascular events seen in women on treatment. Subanalysis of the WHI results by age group, and more recent randomized control studies, including the Kronos Early Estrogen and Prevention Study (KEEPS) and Early Versus Late Intervention Trial (ELITE), demonstrate that the risk of adverse cardiovascular events for HT are low for women <60 years of age or within 10 year from menopause. Although current data does not support using HT for primary prevention of cardiovascular disease, it does suggest that HT can be safely used to treat symptoms in appropriately selected women close to menopause.

Keywords: cardiovascular health; hormone therapy; postmenopausal hormone therapy.

MeSH terms

  • Age Factors
  • Cardiovascular Diseases / epidemiology
  • Cardiovascular Diseases / prevention & control*
  • Clinical Trials as Topic
  • Estrogen Replacement Therapy / adverse effects*
  • Estrogens / pharmacology
  • Estrogens / therapeutic use
  • Female
  • Hot Flashes / drug therapy
  • Humans
  • Menopause / drug effects*
  • Menopause / physiology
  • Risk
  • Risk Assessment
  • Time Factors


  • Estrogens