The term "estrogen" refers to various natural and synthetic molecules that affect estrogen receptors in the body including in the brain. Estrogen-containing menopausal hormone therapy typically consists of estrogen(s) combined with a progestogen and is approved for the treatment of menopausal symptoms such as hot flushes. Clinical trials have reported that when menopausal hormone therapy is initiated within ten years of menopause or under the age of 60, cognitive functions are neither improved nor worsened. When initiated after this window, estrogen-progestogen therapy may increase dementia risk.
Multiple meta-analyses and systematic reviews of clinical trials have assessed the effects of estrogen-containing menopausal hormone therapy on cognitive functions in menopausal women. Our search identified:
Despite the alarming findings from the Women’s Health Initiative Memory Study a few decades ago which found that estrogen-progestogen menopausal hormone therapy increased the risk of cognitive impairment and dementia in women over the age of 65 [1], subsequent carefully designed clinical trials have confirmed that estrogen-progestogen menopausal hormone therapy initiated close to the onset of menopause neither harmed nor benefited cognitive functions [2; 3; 4]. In one of the clinical trials called Kronos Early Estrogen Prevention Study (KEEPS), two types of menopausal hormone therapies (oral synthetic estrogen + bioidentical progestogen and transdermal bioidentical estrogen + bioidentical progesterone) were tested against placebo for four years in recently menopausal women [3]. These women were followed up for ten years after the end of the four-year intervention and there were still no differences in cognitive functions (measured using a battery of eleven cognitive tests) across the menopausal hormone therapy and placebo groups [5]. In the same follow-up study, neither form of the menopausal hormone therapy affected levels of amyloid (a biological marker of Alzheimer’s disease) or the volume of the hippocampus (a brain region important for memory) compared to placebo [6].
In women who had undergone abrupt menopause induced by surgical removal of ovaries and the uterus, estrogen-alone therapy improved global cognition compared to placebo [7]. However, people with an intact uterus should not take estrogen-alone therapy, because a progestogen is needed to prevent excessive thickening and growth (e.g., cancer) of the endometrium [8].
The literature is mixed and inconsistent regarding the relationship between the effects of estrogen-containing menopausal hormone therapy and the APOE4 variant, with some studies showing no interactions [3], other studies showing potential benefit of menopausal hormone therapy in APOE4 carriers compared to non-carriers [9], and others showing potential harm in APOE4 carriers [10].
For more information on what the APOE4 gene allele means for your health, read our APOE4 information page.
Based on a meta-analysis of four small clinical trials, estrogen-containing menopausal hormone therapy has produced mixed effects on cognitive function in Alzheimer’s disease patients [11]. The included clinical trials were small in size and varied in formulations and duration, and therefore, the effects of estrogen-containing menopausal hormone therapies in Alzheimer’s patients are considered inconclusive.
Most mid-life women can safely use physician-supervised menopausal hormone therapy for several years to treat symptoms of menopause if started within ten years of menopause or before the age of 60, though risks of specific adverse events can vary by the therapy type, dose, route, duration, and one’s medical history [8]. The risks are higher for women over the age of 60 or beyond ten years after menopause, and for younger women with specific health risks, such as a history of blood clots, breast/uterine/ovarian cancer, heart/liver/gallbladder disease, or unexplained vaginal bleeding. Estrogen-containing menopausal hormone therapy has been associated with slightly increased risks of breast cancer and ovarian cancer [8]. Women with a uterus must take an effective progestogen along with estrogen to reduce the risk of endometrial cancer [8]. Risks of venous thromboembolism and stroke are higher in women who start therapy after age 60 or beyond ten years post-menopause [8; 12]. However, transdermal estrogen combined with progestogen appears to be associated with lower risks of thromboembolism and stroke than oral estrogen with progestogen [8].
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.
The decision to start, continue, or stop estrogen-containing menopausal hormone therapy should be made carefully with a healthcare provider to balance potential benefits against harm in a personalized manner, including considerations for personal medical history and risk factors [13]. For people with an intact uterus with moderate to severe symptoms of menopause, doctors typically prescribe a combination hormone therapy including estrogen(s) and progestogen (the progestogen is included to prevent excessive thickening and growth of the endometrium) [8]. For women with a prior hysterectomy (surgical removal of the uterus) who have moderate to severe symptoms of menopause, doctors can prescribe estrogen-alone therapy. Estrogen-alone and estrogen-progestogen therapies come in different forms including pills, skin patches, vaginal rings, gels, or sprays. The terms “estrogens” and “progestogens” encompass a broad range of natural and synthetic molecules that affect estrogen and progesterone receptors in the body. Different types of menopausal hormone therapy can have different effects and risk profiles. Estrogens naturally found in the human body include 17β-estradiol, estrone, estriol, and 17α-estradiol. 17β-estradiol is the dominant natural estrogen present in women before menopause.
Full scientific report (PDF) on Cognitive Vitality Reports
Information on menopausal hormone therapies from the Menopause Society