Women's Health Initiative (WHI): Risks and benefits of hormone replacement therapy (HRT) and estrogen replacement therapy (ERT)

Hormone replacement therapy (HRT) was part of a large set of clinical trials called the Women's Health Initiative (WHI). The HRT portion of the study was ended 3 years early because of a small but unacceptable increase in the rate of breast cancer among the women taking a combination of 0.625mg of estrogen plus 2.5mg of progestin daily. As WHI data has been analyzed, risks of blood clots, heart disease, ovarian cancer, and dementia have also been identified. Experts do not yet know whether lower-dose, shorter-term HRT reduces or eliminates these risks.

HRT use slightly raises the risk of several serious health problems. This means that in a small number of women, using HRT causes a serious health problem:

• HRT-related breast cancers first become apparent after 4 years of HRT use. The number of HRT-related breast cancers increased with each additional year of HRT use. Women taking HRT generally had larger, more advanced tumors than women who developed breast cancer while taking placebo treatment.¹
• HRT slightly increases stroke risk in all healthy postmenopausal women, regardless of risk factors.^{1, 2} The increase in strokes first becomes apparent during the second year of HRT use.³
• In women who are 10 or more years past menopause, HRT slightly raises the risk of heart disease. Early signs of heart disease can first become apparent during the first year of hormone use.^{4, 5, 6}
• HRT slightly raises the risk of blood clots in the lungs (pulmonary embolism) and legs (deep vein thrombosis) in all healthy postmenopausal women regardless of risk factors.³
• HRT raises the risk for Alzheimer’s disease and other dementias in women ages 65 and older. The increased risk first becomes apparent in women taking HRT for more than 4 years. The WHI researchers have concluded that HRT does not provide protection from dementia or cognitive impairment, as was previously believed.⁷
• HRT slightly raises ovarian cancer risk. This means that for a small number of women, taking HRT causes ovarian cancer.⁸
• Among HRT users, the number of abnormal mammograms increases by approximately 4% per year, first apparent after 1 year of HRT use. (Daily estrogen plus progestin increased breast density compared with estrogen alone or placebo.) Although the abnormal mammograms required additional medical evaluation, they were not linked to the increase in breast cancer. Studies are ongoing to determine the significance of this finding.⁹

Estrogen replacement therapy (ERT) use causes stroke and ovarian cancer in a small number of women. For this reason, the Women's Health Initiative ERT trial was stopped sooner than originally planned. Other ERT results show that women using ERT had no change in heart disease risk and had fewer hip fractures (a sign of estrogen's bone-protecting effect).¹⁰

Serious health events caused or prevented by HRT, per 1,000 women (estrogen 0.625 mg plus progestin 2.5 mg) ^{1, 11}

Health event	After 2 years of HRT use	After 5.2 years of HRT use
Blood clots (venous thromboembolism)	6 more*	9 more
Coronary artery disease	3 more**	4 more
Breast cancer	No change***	4 more
Stroke	1 more****	4 more
Colorectal cancer	No change	3 fewer#
Hip fractures	1 fewer	2 fewer
Death	No change	No change
* Risk is greatest during the first 2 years of use. ** First signs appear during the first year of use. *** Risk first appears after 4 years of use. **** Risk first appears after 1 year of use. # Benefit appears after 3 years of use.

Estrogen, progestin, and breast, ovarian, and endometrial cancer risks

Taking estrogen with progestin (HRT) or estrogen without progestin (ERT) raises the risk of breast cancer and ovarian cancer. Taking estrogen raises the risk of endometrial (uterine) cancer.^{12, 8} These increased cancer risks are relatively low for the general population of postmenopausal women. But your personal risk that hormone therapy may stimulate cancerous cell growth may be significantly lower or higher, depending on your risk factors. For more information about cancer risk factors, see the topics Breast Cancer, Ovarian Cancer, and Endometrial Cancer.

Citations

1. Rossouw JE, et al. (2002). Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women's Health Initiative randomized controlled trial. JAMA, 288(3): 321–333.

2. Manson JE, et al. (2003). Estrogen plus progestin and the risk of coronary heart disease. New England Journal of Medicine, 349(6): 523–534.

3. Wassertheir-Smoller S (2003). Effect of estrogen plus progestin on stroke in postmenopausal women. The Women's Health Initiative: A randomized trial. JAMA, 289(20): 2673–2684.

4. Grodstein F, et al. (2006). Hormone therapy and coronary heart disease: The role of time since menopause and age at hormone initiation. Journal of Women's Health, 15(1): 35–44.

5. Prentice RL, et al. (2006). Combined analysis of Women's Health Initiative observational and clinical trial data on postmenopausal hormone treatment and cardiovascular disease. American Journal of Epidemiology, 163(7): 589–599.

6. Rossouw JE, et al. (2007). Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA, 297(13): 1465–1477.

7. Shumaker SA, et al. (2003). Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. The Women's Health Initiative memory study: A randomized controlled trial. JAMA, 289(20): 2651–2662.

8. Beral V, et al. (2007). Ovarian cancer and hormone replacement therapy in the Million Women Study. Lancet, 369(9574): 1703–1710.

9. Chlebowski T, et al. (2003). Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: The Women's Health Initiative randomized trial. JAMA, 289(24): 3243–3253.

10. Women's Health Initiative Steering Committee (2004). Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. JAMA, 291(14): 1701–1712.

11. Solomon CG, Dluhy RG (2003). Rethinking postmenopausal hormone therapy. New England Journal of Medicine, 348(7): 579–580.

12. Million Women Study Collaborators (2003). Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet, 362(9382): 419–427.