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Evevident
Original paper
2002JAMAOB/GYN

Women's Health Initiative

Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial

RCTPreventive / women's health

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Overview

Combined estrogen-progestin therapy increased breast cancer, CHD, stroke, and VTE risk despite fewer fractures and colorectal cancers.

Clinical takeaway

WHI ended routine use of combined hormone therapy for chronic disease prevention in postmenopausal women and shifted HRT toward symptom-directed, individualized use.

Key result

Combined HRT increased coronary heart disease (HR 1.29) and invasive breast cancer (HR 1.26); the trial was stopped early.

Practice impact

Do not prescribe systemic combined HRT for primary prevention of chronic disease; use selectively for menopausal symptoms after risk discussion.

Evidence

Study design

Randomized, double-blind, placebo-controlled prevention trial (stopped early for harm).

Enrollment

16,608

Follow-up

Mean 5.2 years (stopped early).

Geography

United States

Clinical question

Does combined estrogen-progestin therapy prevent chronic disease in healthy postmenopausal women?

Population

  • Postmenopausal women aged 50-79 with an intact uterus.

Intervention

Conjugated equine estrogen 0.625 mg plus medroxyprogesterone acetate 2.5 mg daily.

Comparator

Placebo.

Primary outcome

Coronary heart disease (primary efficacy) and invasive breast cancer (primary safety), summarized by a global index.

Combined estrogen-progestin therapy increased coronary heart disease, stroke, venous thromboembolism, and breast cancer, outweighing reductions in fracture and colorectal cancer.

Hazard ratio / 1.29 / CI nominal 95% CI 1.02-1.63

Key results

  • Coronary heart disease: HR 1.29 (nominal 95% CI 1.02-1.63).
  • Invasive breast cancer: HR 1.26 (nominal 95% CI 1.00-1.59); stroke HR 1.41; pulmonary embolism HR 2.13.
  • Hip fracture (HR 0.66) and colorectal cancer (HR 0.63) were reduced.
  • The global index of risks and benefits favored placebo, prompting early termination.

Harms

  • Increased coronary heart disease, stroke, pulmonary embolism, and invasive breast cancer.
  • The excess breast-cancer and cardiovascular risk drove early termination of the estrogen-progestin arm.

Clinical Use

When to cite

  • When explaining why menopausal hormone therapy should not be used for chronic disease or cardiovascular prevention.

Practice impact

  • Do not prescribe systemic combined HRT for primary prevention of chronic disease; use selectively for menopausal symptoms after risk discussion.

Applicability

  • Most applicable to postmenopausal women with an intact uterus considered for systemic combined hormone therapy for chronic-disease prevention.

Limitations

  • Tested one specific oral regimen (conjugated equine estrogen plus medroxyprogesterone) in a relatively older cohort (mean age 63).
  • Findings differ by age, time since menopause, hysterectomy status, and formulation.
  • The separate estrogen-alone arm (women post-hysterectomy) showed a different, more favorable risk profile.

Common misinterpretations

  • WHI addresses hormone therapy for chronic-disease prevention, not short-term symptom relief in recently menopausal women.
  • The 'timing hypothesis' suggests risk-benefit is more favorable when therapy starts near menopause onset rather than years later.

Citation

Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333. doi:10.1001/jama.288.3.321

Overall health risks exceeded benefits from use of combined estrogen plus progestin for an average 5.2-year follow-up among healthy postmenopausal US women.