The Women's Health Initiative randomized trials of menopausal hormone therapy and breast cancer: findings in context

Menopause. 2023 Apr 1;30(4):454-461. doi: 10.1097/GME.0000000000002154. Epub 2023 Jan 22.


Importance and objective: The menopausal hormone therapy (MHT) association with breast cancer has been controversial for more than 40 years. Most recently, findings from cohort studies have been discordant compared with those from the Women's Health Initiative (WHI) randomized trials. In cohort studies, both estrogen therapy and estrogen plus progestin were associated with higher breast cancer incidence. In contrast, in the WHI randomized trials, findings for estrogen plus progestin are concordant with cohort study reports, whereas estrogen therapy significantly reduced breast cancer incidence. In addition, concerns have been raised regarding the WHI findings from both trials. In this report, we briefly summarize findings for MHT on breast cancer from cohort studies and the WHI randomized trials. The report focus is addressing, point-by-point, concerns raised regarding the WHI findings.

Methods: For cohort studies, we relied on the latest findings from (1) the meta-analysis of the Collaborative Group on Hormonal Factors in Breast Cancer and (2) the Million Women's Study. To identify commentaries and editorials, "Menopause" and "Climacteric" were searched from 2002 to present; PubMed and Google Scholar were searched for commentaries, editorials, and breast cancer, MHT, estrogen, conjugated equine estrogen, estradiol, "hormone replacement therapy," and "HRT."

Discussion and conclusions: Thirty commentaries challenging WHI findings were identified. All were reviewed, and issues needing response were identified. Findings from the meta-analysis from the Collaborative Group on Hormonal Factors in Breast Cancer and the Million Women Study were summarized and compared with finding in the two WHI randomized trials evaluating estrogen therapy and estrogen plus progestin. Based on the randomized clinical trials, estrogen therapy, for women with prior hysterectomy, decreases breast cancer incidence and mortality. In contrast, estrogen plus progestin increases breast cancer incidence, which persists through two decades. Women considering estrogen plus progestin use for vasomotor symptoms should understand the breast cancer risk.

Publication types

  • Meta-Analysis

MeSH terms

  • Breast Neoplasms* / chemically induced
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / epidemiology
  • Cohort Studies
  • Estrogen Replacement Therapy / adverse effects
  • Estrogens / adverse effects
  • Female
  • Humans
  • Menopause
  • Neoplasms*
  • Progestins / adverse effects
  • Randomized Controlled Trials as Topic
  • Women's Health


  • Progestins
  • Estrogens