Breast cancer is the question most women ask before starting hormone therapy, and the one most often misquoted. The answer depends on which hormones were used, for how long, and when treatment started. The Women’s Health Initiative tested two regimens in separate randomized trials, and they did not show the same thing.
Estrogen with progestin
In the WHI trial of conjugated estrogen plus medroxyprogesterone, 16,608 women with a uterus were randomized to the combination or to placebo. Invasive breast cancer was more common in the hormone group: 199 cases versus 150, a hazard ratio of 1.24. Abnormal mammograms were also more frequent after one year (9.4% versus 5.4%), which the authors read as a possible effect on detection as well as on disease. Tumors found in the hormone group were slightly larger and more often at a regional or advanced stage.
Estrogen alone
The WHI estrogen-alone trial enrolled 10,739 women who had had a hysterectomy, with a median treatment of 7.2 years. During treatment, invasive breast cancer was lower in the estrogen group (hazard ratio 0.79, 95% confidence interval 0.61 to 1.02), a difference that was not statistically significant. In the early years after stopping, it was significantly lower (0.55; 0.34 to 0.89). Later the hazard ratio rose above 1 (1.17; 0.73 to 1.87), and across the whole post-treatment period the difference was not significant. A 2020 report with a median of 20.3 years of follow-up found fewer breast cancer deaths with estrogen alone. That is a secondary finding, since the trial was not designed to prevent breast cancer.
Why the two regimens differ
The 2015 analysis of both trials concluded that breast cancer risk and benefit need recalculating for each regimen. Its authors described greater adverse influence after stopping the combined regimen, and somewhat greater benefit after estrogen alone. The mechanism is not settled. Observational studies point in a different direction from the estrogen-alone trial, and the WHI investigators describe that discordance as difficult to reconcile.
Timing and duration
The 2022 position statement of The Menopause Society says the risk of hormone therapy depends on type, dose, duration, route, timing of initiation and whether a progestogen is used. Transdermal routes and lower doses may reduce the risk of venous clots and stroke. For longer use, it asks for a documented reason, such as persistent symptoms, with periodic review. It notes that randomized data on use beyond age 60 or 65 are limited, and that observational studies suggest a potential rare breast cancer risk with longer duration.
How physicians weigh it
Physicians weigh breast cancer risk against the symptom being treated, the woman’s age and years since menopause, her cardiovascular and breast history, and the route and dose. The 2024 WHI review says that for women under 60 with low-to-average risk of heart disease and breast cancer, in early menopause and wanting treatment for bothersome hot flashes, benefits may outweigh risks. It also says the evidence does not support estrogen-based therapy to reduce chronic disease risk.
What this does not say
- The estrogen-alone findings apply to women without a uterus. Women with a uterus need a progestogen to protect the lining of the uterus, and it was the combined regimen that raised breast cancer incidence in the trial.
- Trial populations were mostly healthy women aged 50 to 79, and the results are averages for conjugated estrogens and medroxyprogesterone at the studied doses. Our products are compounded or generic versions, and the trials did not test them.
- Several confidence intervals include 1, and the WHI was not designed to prevent breast cancer. One trial is not a verdict on every regimen, route or woman.
How we use this
Our physicians weigh your own history, including breast screening and family history, against your symptoms before any prescription. Where a progestogen is needed, we explain what it does for the uterus and what the WHI found with the combined regimen.
We do not present either WHI trial as proof that hormone therapy is safe or unsafe for you. The numbers come from the trials, the decision is yours, and we make it together.
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- 1.Chlebowski RT et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative randomized trial. JAMA 2003;289:3243-53. JAMA
- 2.Chlebowski RT et al. Differing patterns of breast cancer risk after hormone therapy with estrogen plus progestin or estrogen alone (Women’s Health Initiative; 2015 analysis, summary). JAMA Oncology, via ASCO Post
- 3.Chlebowski RT et al. Estrogen alone and breast cancer and mortality: 20-year Women’s Health Initiative follow-up (summary). JAMA 2020, via American Family Physician
- 4.The 2022 hormone therapy position statement of The North American Menopause Society. Menopause 2022;29:767-94. Menopause
- 5.Manson JE et al. The Women’s Health Initiative randomized trials and clinical practice: a review. JAMA 2024;331:1748-60. JAMA