Hormone therapy and breast cancer risk

Combined hormone therapy, estrogen plus a progestogen, increases breast cancer risk by a small absolute amount after several years of use: in the Women’s Health Initiative, about 9 additional cases per 10,000 women per year. Estrogen alone, used by women who have had a hysterectomy, did not increase risk in that trial and over 20 years was linked to fewer cases and fewer deaths. The type of progestogen and the duration of use appear to matter, and a personal history of breast cancer remains a reason not to use systemic hormone therapy.

What the randomized trial showed

The WHI is the only large randomized trial with breast cancer as a prespecified safety outcome. Its two arms tested conjugated equine estrogen 0.625 mg daily, with medroxyprogesterone acetate 2.5 mg in women with a uterus and alone in women with a hysterectomy. After more than 20 years of follow-up:

	Estrogen plus progestin (16,608 women)	Estrogen alone (10,739 women)
Median years on treatment	5.6	7.2
Invasive breast cancer, per year	0.45% vs 0.36% on placebo	0.30% vs 0.37% on placebo
Hazard ratio for incidence	1.28 (1.13 to 1.45)	0.78 (0.65 to 0.93)
Deaths from breast cancer	71 vs 53 (HR 1.35, not significant)	30 vs 46 (HR 0.60, significant)

In the original 2002 report the excess with combined therapy was 8 invasive cancers per 10,000 women per year; the longer analysis puts it at 9. In pooled trial data the increase emerges after about 5 years of use, which is why many guidelines mention that time frame.

Putting the number in perspective

The Menopause Society’s 2022 position statement describes the combined-therapy risk as rare: fewer than one additional case per 1,000 women per year, or about three additional cases per 1,000 women who use the WHI regimen for 5 years. It compares that to the increase associated with two daily alcoholic drinks, obesity, or low physical activity, and notes it is slightly greater than the risk from one daily glass of wine.

For context, about 1 in 8 US women develops breast cancer in her lifetime. Hormone therapy shifts that baseline by a small amount, and the size of the shift depends on what you take and for how long.

What observational studies add

Randomized data stop at about 7 years of use. For longer use, the main source is a 2019 meta-analysis that pooled individual data from prospective studies worldwide, including 108,647 women who developed breast cancer.

Type of therapy	Relative risk, years 1 to 4 of use	Relative risk, years 5 to 14
Estrogen plus progestogen	1.60	2.08 (2.30 with daily progestogen, 1.93 with intermittent)
Estrogen only	1.17	1.33
Vaginal estrogen	No increase	No increase

The authors translated this into absolute terms. For a woman of average weight starting at 50 and using therapy for 5 years, the estimated extra cases between ages 50 and 69 were about 1 in 50 for estrogen plus daily progestogen, 1 in 70 for estrogen plus intermittent progestogen, and 1 in 200 for estrogen alone. Ten years of use roughly doubled those figures. Some excess persisted more than 10 years after stopping, and little excess followed less than a year of use.

These numbers are higher than the WHI’s. Observational studies cannot fully separate the effect of the drug from differences between women who choose it, and they pool many different products. The two sources agree on the direction of the effect and on the importance of the progestogen.

A 2020 UK analysis of 98,611 cases estimated that recent long-term users of estrogen alone had 3 to 8 extra cases per 10,000 women-years, and users of combined therapy 9 to 36, depending on age.

Does the type of progestogen matter?

Possibly, and this is one of the most important open questions. The WHI used medroxyprogesterone acetate. In the French E3N cohort of 80,377 postmenopausal women followed for about 8 years:

Regimen	Relative risk of breast cancer
Estrogen alone	1.29
Estrogen plus micronized progesterone	1.00 (0.83 to 1.22)
Estrogen plus dydrogesterone	1.16
Estrogen plus other synthetic progestins	1.69 (1.50 to 1.91)

The UK analysis found a similar spread among progestogens, from 1.24 for dydrogesterone to 1.88 for norethisterone. The Menopause Society summarizes this as “some but not all observational data” favoring micronized progesterone and calls for randomized trials. Guidelines do not yet state that micronized progesterone is safer for the breast, but many US clinicians prefer it for this reason among others. See our guide to micronized progesterone.

Does the route of estrogen matter?

Not for breast cancer. The E3N cohort found no difference between oral and transdermal estrogen, and The Menopause Society notes that oral and transdermal estrogens appear to have similar effects on the number of breast cancers diagnosed. The patch’s advantage is for blood clots, not the breast.

Duration, stopping, and screening

Risk rises with years of use in every dataset. After stopping, it declines but can remain elevated for a decade after long use. Combined therapy also increases breast density in some women, which can make mammograms harder to read; in the WHI, women on combined therapy had more follow-up mammograms and biopsies than women on placebo. Keep up routine screening and tell the imaging center that you use hormone therapy.

Who should not use systemic hormone therapy

A personal history of breast cancer or another estrogen-sensitive cancer is a contraindication. Observational studies of survivors are mixed, and the two randomized trials in survivors reached opposite conclusions, so systemic therapy is generally avoided and considered only with an oncologist for severe symptoms that fail other treatments.

A family history is different. Available evidence suggests hormone therapy does not further raise the relative risk in women with a family history or a prior benign breast biopsy, although their absolute risk is higher because their baseline is higher. Women with BRCA variants who have had their ovaries removed at a young age have a low absolute risk, and hormone therapy is considered acceptable for them.

Low-dose vaginal estrogen is not associated with breast cancer and remains an option for many survivors after discussion with their oncologist.

Questions to ask

• Am I a candidate for estrogen alone, or do I need a progestogen?
• If I need a progestogen, is micronized progesterone an option, and why or why not?
• How does my family history change the numbers for me?
• How long do you anticipate I will use this, and how will we revisit it?
• What screening schedule should I follow while on hormone therapy?

If you want a clinician with focused menopause training for this conversation, see how to find a menopause specialist or search our OB-GYN directory.