Randomized Trial Evaluation of the Benefits and Risks of Menopausal Hormone Therapy Among Women 50-59 Years of Age

Am J Epidemiol. 2021 Feb 1;190(3):365-375. doi: 10.1093/aje/kwaa210.


The health benefits and risks of menopausal hormone therapy among women aged 50-59 years are examined in the Women's Health Initiative randomized, placebo-controlled trials using long-term follow-up data and a parsimonious statistical model that leverages data from older participants to increase precision. These trials enrolled 27,347 healthy postmenopausal women aged 50-79 years at 40 US clinical centers during 1993-1998, including 10,739 post-hysterectomy participants in a trial of conjugated equine estrogens and 16,608 participants with a uterus in the trial of these estrogens plus medroxyprogesterone acetate. Over a (median) 18-year follow-up period (1993-2016), risk for a global index (defined as the earliest of coronary heart disease, invasive breast cancer, stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and all-cause mortality) was reduced with conjugated equine estrogens with a hazard ratio of 0.82 (95% confidence interval: 0.71, 0.95), and with nominally significant reductions for coronary heart disease, breast cancer, hip fracture, and all-cause mortality. Corresponding global index hazard ratio estimates of 1.06 (95% confidence interval: 0.95, 1.19) were nonsignificant for combined estrogens plus progestin, but increased breast cancer risk and reduced endometrial cancer risk were observed. These results, among women 50-59 years of age, substantially agree with the worldwide observational literature, with the exception of breast cancer for estrogens alone.

Keywords: benefits versus risks; estrogens; global index; hazard ratio; menopausal hormone therapy; multivariate failure times; progestin.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Coronary Disease / epidemiology
  • Estrogen Replacement Therapy / statistics & numerical data*
  • Estrogens, Conjugated (USP) / administration & dosage
  • Female
  • Hip Fractures / epidemiology
  • Humans
  • Medroxyprogesterone Acetate / administration & dosage
  • Middle Aged
  • Neoplasms / epidemiology
  • Postmenopause
  • Proportional Hazards Models
  • Pulmonary Embolism / epidemiology
  • Stroke / epidemiology


  • Estrogens, Conjugated (USP)
  • Medroxyprogesterone Acetate