The term "estrogen" refers to a broad range of natural and synthetic molecules that affect estrogen receptors. Estrogen hormone therapy usually consists of estrogens alone or combined with a progestogen and can be used to treat symptoms of menopause. While estrogens do have some potentially beneficial effects on the brain, clinical studies have shown inconsistent and sometimes negative results. In women over age 65, estrogens may increase the risk of dementia.
Multiple meta-analyses and systematic reviews of clinical trials have assessed the effects of estrogen-containing hormone therapy on cognitive functions in menopausal women. Our search identified:
• 2 meta-analyses of randomized clinical trials testing the effects of estrogen-containing hormone therapy on cognitive function and risk for dementia
• 1 systematic review of epidemiological studies examining the relationship between hormone therapy use and incidence of dementia
• 4 long-term randomized controlled clinical trials
• 6 observational research studies
• Numerous clinical trials on different formulations of hormone therapy
• Numerous preclinical studies on possible mechanisms of action
Estrogen and/or progestogen hormone therapy are unlikely to protect women against dementia. Based on the Women's Health Initiative study, a huge clinical trial, women over 65 years of age can increase their risk of dementia by starting estrogen plus progestogen treatment . In women within a few years of menopause, the evidence is mixed, but recent studies showed that hormone therapy did not produce cognitive benefits .
These results were a disappointment since earlier studies had reported that women taking estrogen hormone therapy had a substantially lower risk of developing dementia . In preclinical studies, estrogen was shown to improve energy production, reduce oxidative stress, increase brain cell survival during damage, enhance the release of protective chemicals, and improve memory. However, a recent systematic review of 15 epidemiologic studies reported that hormone therapy did not affect the risk of dementia and that the earlier reports may have been the result of other shared features of women who chose to use hormone therapy. Preclinical studies have since shown that while estrogen can protect healthy cells from new damage, it may also harm already unhealthy neurons .
Several studies suggest that the negative effects of estrogen-containing hormone therapy, such as brain aging and increased dementia risk, could be worse in APOE4 carriers. An inconsistent and contradictory body of evidence suggests that some of estrogen's brain benefits may depend on APOE and specific APOE alleles .
In clinical trials, estrogen hormone therapy has generally not improved cognition or function in Alzheimer's patients .
Most mid-life women can safely use physician-supervised hormone therapy for several years to treat symptoms of menopause . However, the risks are higher for long-term treatment, for older women, and for younger women with specific health risks. Women with a uterus must take estrogen along with an effective progestogen to reduce the risk of endometrial cancer. Hormone therapy can increase the risk of breast cancer, blood clots, stroke, deep vein thrombosis, pulmonary embolus, and gallbladder disease. Oral estrogen and estrogen plus progestogen therapy can increase the risk of stroke , which may be reduced by transdermal or intranasal delivery of the hormones .
NOTE: This is not a comprehensive safety evaluation or complete list of potentially harmful drug interactions. It is important to discuss safety issues with your physician before taking any new supplement or medication.
Estrogen hormone therapy is available in several forms, both with and without prescription. Some progestogen therapies are used for only half of the month, which can effectively protect against endometrial cancer risk and might be safer for breast cancer risk than continuous progestogen treatment [12-14]. Also, unlike oral treatment, transdermal estrogens such as gels, creams, and sprays do not appear to increase the risk of stroke .
Experts agree that hormone therapy should be physician-supervised and used at the lowest dose and for the shortest possible duration to alleviate hot flashes and other menopausal symptoms. The U.S. Preventive Services Task Force does not recommend it for preventing or treating chronic conditions such as cognitive aging or dementia. Bioidentical estrogen hormones, which have the same chemical and molecular structure as those produced in the body, are available either as FDA-approved drugs or as custom-made formulations compounded by a pharmacist for specific patients. While custom-prepared compounded hormones may be appealing, these hormones have not been rigorously tested, particularly for long-term health, and their quality can vary.
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Menopause Map from the Hormone Health Network is a resource on the risks and benefits of hormone therapy during menopause.
The North American Menopause Society 2012 Position Statements for patients (PDF) and health-care providers (PDF)
Recommendation summary from the U.S. Preventative Services Task Force 2012 (2017 update in progress)
Informational resources on hormone therapy from the U.S. Department of Health & Human Services
Information on the benefits, risks, and current recommendations on hormone therapy from the American Congress of Obstetricians and Gynecologists
Information on issues surrounding compounded bioidentical hormones from the American Congress of Obstetricians and Gynecologists and the North American Menopause Society (PDF)