Anna E. Mazzucco, PhD, Elizabeth Santoro, RN, MPH, Maushami DeSoto, PhD, and Jae Hong Lee, MD, MPH

Do women need to “replace” hormones as they age? Millions of women struggle with the decision about hormones during and after menopause: should I go on, should I stay on, or should I go off?

For decades, women were told that hormone therapy was like a fountain of youth that would protect them against many of the diseases and symptoms of aging that increase after menopause. Since estrogen alone was known to increase the risk of uterine cancer, doctors usually prescribed a combination of estrogen and progestin, unless a woman had a hysterectomy and therefore was at no risk of uterine cancer.

In addition to its proven effectiveness for decreasing hot flashes, night sweats, and vaginal dryness, in the 1980’s and 1990’s hormone therapy was thought to decrease osteoporosis, prevent heart disease, improve memory and concentration, reduce wrinkles, and improve mood. Women were encouraged to start hormone therapy before menopause started and to continue to take it for years, if not decades, in order to improve their health and their quality of life.

However, the research evidence is now clear: the risks of hormones outweigh the benefits for the vast majority of women.

What the Research Says

In December 2017, the experts at the U.S. Preventive Services Task Force issued a clear recommendation:  post-menopausal women should NOT take hormones to prevent chronic health conditions, such as increasing bone strength to avoid fractures. The reason is that the risks of these hormones outweigh the benefits.¹

This recommendation is just the latest evidence that taking hormones to “replace” those that are reduced in menopause if often bad for your health. Previous evidence came from the Women’s Health Initiative (WHI), sponsored by the National Institutes of Health (NIH), which included more than 27,000 women in three different trials to study the effect of hormones on women’s bodies.^2,3,4 The 3 trials were: 1) the Estrogen Plus Progestin Trial, 2) the Women’s Health Initiative Memory Study, and 3) the Estrogen-alone Trial.

The researchers found that women taking a combination of estrogen and progesterone hormones were more likely to develop breast cancer, stroke, and blood clots, and at least as likely to develop heart disease, compared to women taking placebo. Those on estrogen alone were at an increased risk for strokes and at a significantly increased risk for deep vein, thrombosis.† The Memory Study revealed that women taking a combination of estrogen plus progesterone were twice as likely to develop Alzheimer’s Disease and other forms of dementia compared to women on placebo.

All the three trials were stopped early for ethical reasons when it became clear that women taking hormones were more likely to be harmed than helped. While there are some short-term benefits to taking hormones, the researchers concluded that for most women, the risks of hormone therapy outweigh the benefits.

Following release of these findings, use of hormone therapy in the U.S. dropped significantly.  Since then, several large studies have pointed out that breast cancer incidence also dropped a few years after the decline in hormone use for menopause.^5,6 This unexpected and unprecedented drop in breast cancer incidence suggests that HRT has a more dramatic impact on breast cancer risk than previously thought.⁷ In 2021, a meta-analysis of more than 4,000 women in 4 different studies of women previously being treated for breast cancer, found that those who subsequently took hormone therapy (combined estrogen plus progesterone) were much more likely to have a recurrence of cancer than breast cancer survivors who took a placebo.⁸ The women who had estrogen receptor positive breast cancer prior to hormone therapy were 80% more likely to have a recurrence than women taking placebo, which was a statistically significant difference that did not occur by chance. The women who had estrogen receptor negative breast cancer were 19% more likely to have a recurrence than the women taking placebo, which was a small difference that might have occurred by chance.

In 2009, a study found that hormone therapy increased the risk of dying of lung cancer among women who smoked or previously smoked, compared to smokers or former smokers who did not take hormone therapy. For more information click here.

In 2010 the University of California at San Francisco did a study of nearly 700,000 women. The researchers found that taking hormones may actually promote the growth of tumors in the breast which increases the incidence of invasive cancer and the risk of ductal carcinoma in situ (DCIS), a form of non-invasive pre-cancer. You can read more about that study by clicking here.

Experts who promote the use of HRT have criticized the WHI for enrolling women after menopause rather than just before or in the earliest stages.  So, it is important to note that in 2014, a study of 727 women in early menopause showed that hormone therapy did not prevent atherosclerosis (artery thickening), as had been claimed previously.  Following women on HRT for 4 years, the researchers from the Kronos Longevity Research Institute, a pro-HRT research institute, and other institutions, found no difference in artery thickening between the women who took HRT and those who didn’t.⁹ In 2015, the same group published an article admitting that hormone therapy also had no impact on “cognitive decline,” despite claims that it would prevent Alzheimer’s and memory loss.¹⁰ Although the authors focused on a small improvement in mood related to using hormone pills for 4 years (but not found with hormone creams), they downplayed the more important finding: no impact on depression as measured by the valid and reliable Beck Depression Inventory.

What are the Risks and Benefits of Hormone Therapy?

To emphasize that lost hormones don’t necessarily need to be replaced, the term “hormone replacement therapy” has been changed to “hormone therapy.” Experts now advise women to use hormone therapy only for severe symptoms of menopause that reduce the quality of life, such as severe hot flashes, night sweats, insomnia, and vaginal dryness. Women are urged to take hormones at the lowest dose that is effective and for the shortest possible period of time. However, even short-term use (less than one year) increases some risks; for example, the increase in heart disease comes primarily from the first year of hormone use.

Hormone therapy may be recommended in severe cases of vulvar and vaginal atrophy‡ as well as for treating severe postmenopausal osteoporosis when non-estrogen medications or other strategies are unsuccessful or impossible. A decision to use any combination of estrogen and progestin should be discussed with a physician who is expert on the topic, and specific criteria for the indication, dose, and duration of these hormones must be met prior to their prescription and administration.

Risks:

Compared to women taking placebo, within 5 years the women who received estrogen plus progestin experienced:

— 41% more strokes

— 29% more heart attacks

— twice as many blood clots

— 22% more heart disease of all types

— 26% more breast cancer

— 37% fewer cases of colorectal cancer

— one-third fewer hip fractures

— 24% fewer bone fractures of any type

— no difference in the overall death rate

It’s important to note that only 2.5% of the women in the study experienced health problems. So, while the percentage increase in some diseases was rather large, the risk for most patients remained relatively small. That does not mean these risks are not important however.

To provide a better sense of the additional risks that come with combination hormone therapy, the study data can be summarized more simply. Compared to a group of 10,000 women taking placebo, 10,000 women taking combination hormone therapy will experience:

— 7 more heart attacks

— 8 more strokes

— 8 more cases of breast cancer

— 18 more blood clots

— 6 fewer cases of colorectal cancer

— 5 fewer hip fractures

Research Evidence

The Women’s Health Initiative was a major 15-year research program to address the most common causes of death, disability and poor quality of life in post-menopausal women – cardiovascular disease, cancer, and osteoporosis. The WHI was launched in 1991 and consisted of a set of clinical trials and an observational study. The clinical trials were designed to test the effects of post-menopausal hormone therapy, diet modification, and calcium and vitamin D supplements on heart disease, fractures, and breast and colorectal cancer.

The hormone trial had two studies: the estrogen-plus-progestin study of women with a uterus and the estrogen-alone study of women without a uterus. (Women with a uterus were given progestin in combination with estrogen, a practice known to prevent endometrial cancer.) In both hormone therapy studies, women were randomly assigned to either the hormone medication being studied or to placebo. Those studies ended several years ago, and the women are now participating in a follow-up phase, which will last until 2010.

Estrogen plus Progestin Trial (stopped in July 2002)

Compared with women in the placebo those on estrogen plus progestin had:

• Increased risk of heart attack
• Increased risk of stroke
• Increased risk of blood clots
• Increased risk of breast cancer
• Reduced risk of colorectal cancer
• Fewer fractures
• No protection against mild cognitive impairment and increased risk of dementia (study included only women 65 and older)
• Increased risk of dying of lung cancer

Women’s Health Initiative Memory Study (stopped in May 2003)

• Women taking hormones had twice the risk for developing dementia
• Hormones provided no protection against mild cognitive impairment/memory loss

Estrogen-alone Trial (stopped in February 2004)

• Estrogen increased risk for stroke
• Estrogen decreased risk for hip fracture
• No positive or negative effect on breast cancer

Compared to placebo women on estrogen alone had:

• Increased risk of stroke
• Increased risk of blood clots
• Uncertain effect for breast cancer
• No difference in risk for colorectal cancer
• No difference in risk for heart attack
• Reduced risk of fracture

Links to Research summaries of the Women’s Health Initiative studies  –

Estrogen Plus Progestin Trial: 2002

The Women’s Health Initiative Memory Study: 2005

The Estrogen-alone Trial: 2004

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† Deep vein thrombosis refers to a blood clot deep inside the veins, usually in the legs.

‡ Symptoms include thinning and inflammation of the vaginal walls and changes in the vulva.

All articles are reviewed and approved by Dr. Diana Zuckerman and other senior staff.

The National Center for Health Research is a nonprofit, nonpartisan research, education and advocacy organization that analyzes and explains the latest medical research and speaks out on policies and programs. We do not accept funding from pharmaceutical companies or medical device manufacturers. Find out how you can support us here.

References:

1. Jin J. Hormone therapy for primary prevention of chronic conditions in postmenopausal women. ^JAMA. 2017;318(22):2265-.
2. Writing Group for the Women’s Health Initiative Investigators, Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-33.
3. Craig MC, Maki PM, Murphy DG. The Women’s Health Initiative Memory Study: findings and implications for treatment. The Lancet Neurology. 2005;4(3):190-4.
4. Anderson GL, Limacher M, Assaf AR, Bassford T, Beresford SA, Black H, Bonds D, Brunner R, Brzyski R, Caan B, Chlebowski R. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004;291(14):1701-12.
5. Ravdin PM, Cronin KA, Howlader N, Berg CD, Chlebowski RT, Feuer EJ, Edwards BK, Berry DA. The decrease in breast-cancer incidence in 2003 in the United States. New England Journal of Medicine. 2007;356(16):1670-4.
6. Katalinic A, Rawal R. Decline in breast cancer incidence after decrease in utilisation of hormone replacement therapy. Breast Cancer Research and Treatment. 2008;107(3):427-30.
7. Colditz GA. Decline in breast cancer incidence due to removal of promoter: combination estrogen plus progestin. Breast Cancer Research. 2007;9(4):1-3.
8. Poggio F, Del Mastro L, Bruzzone M, Ceppi M, Razeti MG, Fregatti P, Ruelle T, Pronzato P, Massarotti C, Franzoi MA, Lambertini M. Safety of systemic hormone replacement therapy in breast cancer survivors: a systematic review and meta-analysis. Breast Cancer Research and Treatment. 2021:1-7.
9. Harman SM, Black DM, Naftolin F, Brinton EA, Budoff MJ, Cedars MI, Hopkins PN, Lobo RA, Manson JE, Merriam GR, Miller VM. Arterial imaging outcomes and cardiovascular risk factors in recently menopausal women: a randomized trial. Annals of Internal Medicine. 2014;161(4):249-60.
10. Gleason CE, Dowling NM, Wharton W, Manson JE, Miller VM, Atwood CS, Brinton EA, Cedars MI, Lobo RA, Merriam GR, Neal-Perry G. Effects of hormone therapy on cognition and mood in recently postmenopausal women: findings from the randomized, controlled KEEPS–cognitive and affective study. PLoS Medicine. 2015;12(6):e1001833.