Expert author: Laura Gravelsins, PhD, Postdoctoral fellow, Centre for Addiction and Mental Health; Liisa Galea, PhD, Senior Scientist, Centre for Addiction and Mental Health, | Editors: Romina Garcia de leon, Janielle Richards (blog coordinators)
Published: August 15th, 2025
*Menopause hormone therapy = MHT
For some basics on menopause, please check out our 3 part series on: menopause, reproductive hormones in menopause, and hormone therapy. For a more comprehensive review of menopause and MHT please read Dr. Gravelsins and Dr. Galea’s review.
“MHT is dangerous, and could increase the risk of cancers (breast, ovarian, and endometrial), heart disease, stroke, and dementia”
To date, unfortunately, one of the most influential MHT studies is the Women’s Health Initiative Study (WHIS), a large randomised clinical trial that administered continuous oral conjugated equine oestrogen (CEE) and medroxyprogesterone acetate (MPA) or continuous oral CEE-alone therapy (only in those with a hysterectomy) or placebo to females 50-79 years. However, there are methodological aspects of this study that were overlooked, leading to many misconceptions about MHT. For one, this study used only one dose, one route of administration, and one type of hormone. It is important to note that many types of MHT are available, with varying doses and combinations of oestrogens, progestins and possibly androgens.We know now that different doses, routes of administration (oral, transdermal, vaginal etc) and hormones (for instance estradiol (E1) versus estrone (E2)) can have differing effects.
Another issue is that the average age of this study was 63 which is nearly 13 years past the average age of menopause onset. Initiating MHT closer to menopause may have more benefits for brain health (discussed further below). There are also many types of menopause such as surgical menopause (surgical removal of the ovaries) or spontaneous menopause, and response to MHT can vary depending on the type of menopause, which was not considered. Further, this study had very few exclusion criteria and participants with high risk for cardiovascular disease that were obese or smoked were included. Lastly, individuals with vasomotor symptoms (like hot flashes, night sweats) were discouraged from participating, yet these individuals may benefit from MHT the most. So, all in all, the findings of this study must be contextualized.
Follow-up studies looking at the effects of CEE, stratifying by age and time since menopause observed that increased risk of heart disease was only observed in those ages 60 years and beyond 10 years since menopause. Another study looking at long-term effects of CEE in cognition found no differences with those taking placebos (these women were 50-55 at the start of the trial).
Additionally, whether CEE was taken with concurrent MPA also mattered for health outcomes, as risks for breast cancer, heart disease, and pulmonary embolism were only increased in those taking CEE and MPA concurrently, but not those taking CEE alone. In fact, other studies have shown reduced risk with CEE alone. Generally, if you have an intact uterus you must be prescribed proestrogen/progestin because of the increased risk for uterine/endometrial cancer. These findings reinforce that the type of MHT is a key determinant of health outcomes. While some formulations show significant benefits, others can show the opposite or no effect.
However, this may depend on the route of administration as vaginal, and transdermal oestrogen have not shown to increase the risk of cancers (breast, lung, colorectal) even with history of cancer, or in those beyond age 65.
“MHT increases the risk for dementia”
MHT formulations containing E2 (estradiol) are more likely associated with beneficial effects compared with formulations containing E1(estrone), perhaps because of their different binding properties. In fact, E2 binds with nearly two-thirds as much strength as E1 to oestrogen receptors. E1 is the main component of CEE which is the MHT administered in the WHIS study. Studies have shown greater verbal memory benefits with E2 over CEE in younger postmenopausal women, and decreased rates of white matter hyperintensity volume compared to placebos in younger spontaneously menopausal women. In research on rodents with surgical menopause (ovariectomy), E2 increases, but E1 decreases hippocampal neurogenesis. E2 has also been seen to facilitate while E1 impairs working memory. Given the nuance between hormone types, it is incredibly important for the overgeneralization of MHT to come to halt.
“Is there a window of opportunity for MHT?”
Starting MHT closer to the onset of menopause provides cognitive benefits that are not observed in those that began further from onset. MHT can be seen as preventative as opposed to curative for brain health disorders, this hypothesis is supported by the “healthy cell bias of oestrogen” such that oestrogen benefits healthy neurons but not those that are already compromised.
“If there is a critical window for the use of MHT– do I have to stop using MHT at the age of 60?”
These broad guidelines may be unhelpful for certain females who could benefit from MHT use beyond 60. It’s important to seek treatment for menopausal symptoms, which can continue well beyond menopause (in fact, some continue to have hot flashes into their 70s or later). MHT is one of the most effective medications for combatting menopausal symptoms. The ovaries continue to secrete low levels of hormones even after menopause is reached. Thus, it’s also important to support females with earlier ovarian failure or surgically induced menopause who may not have this support of hormones. Indeed, two large observational studies showed that MHT without progesterone was associated with reduced mortality and reductions in a variety of cancers (except breast cancer), stroke, heart disease past the age of 65.
“If MHT is safe, why are there black box labels on them?”
Like all medications, there are risks and benefits associated with MHT use. The U.S Food and Drug Administration (FDA) approved estrogen-containing products, contain boxed warnings regarding cancer, dementia, and cardiovascular health risks and cite the WHIS study. Many researchers studying MHT, and menopause have advocated for the removal of these boxed warnings. This year, the U.S. Food and Drug Administration (FDA) assembled a panel with experts who unanimously called for the removal of a black box warning on vaginal estrogen for menopause. Indeed, for vaginal or transdermal administrations, there are many studies indicating associations with reduced risk of cancer, stroke, and heart disease. Again, many of the cautions against MHT have overgeneralized due to the overreliance on the WHIS study, that used conjugated equine estrogenes (CEE) that is comprised of 50% estrone and 0.5% estradiol. It was also based on a single dosing, continuous treatment, and given to an older group of women that were already at risk for cancers, and cardiovascular diseases.
“Why would I take vaginal MHT for my physiological symptoms? Vaginal estradiol only works locally, right?”
Although vaginal estradiol is typically administered in lower doses, and has higher concentrations in the vaginal environment, it can have widespread, systemic effects. Studies have shown lower risk for osteoporosis, dementia, cardiovascular disease, lung and colorectal cancer and more associated with their use, suggesting that the effects extend far beyond local action in the vagina.
“Natural remedies are safer and more effective than MHT”
While some alternative therapies may offer slight improvement in symptoms, their effectiveness is inconsistent and fails to match MHT in efficacy of treating vasomotor symptoms or other complaints. Additionally, these alternative therapies are extremely understudied and require more research to evaluate the safety and efficacy.
“MHT causes weight gain”
Studies have shown that women taking MHT do not gain more weight than non-users. Weight changes in midlife are more often attributed to aging, lifestyle factors, and shifting metabolism during the menopausal period rather than MHT. If anything, studies have found that those that took MHT gained less weight (over a 3 year period) than those that did not. Another study found similar findings claiming that the use of MHT stunted weight gain that is common during the menopause transition, compared to those that did not take MHT.
“Symptoms will be worse when MHT is stopped”
Stopping MHT can lead to the return of menopausal symptoms (in approximately 40%), even with tapering of MHT. However, there is no evidence to date that shows that discontinuation makes symptoms worse than they were before starting. Most guidelines suggest stopping MHT at 60 years of age, or 10 years after menopause. However these guidelines are still basing their evidence on the WHIS study even though menopausal symptoms can persist well beyond these points. In addition, 60 years of age is not the best marker, given that it should be linked to the age of menopause, such that if someone went through menopause at 40 compared to 57, recommendations should change. Moreover, given the benefits of vaginal and transdermal oestradiol in those beyond age 65, there are doubts about whether there should be a push to stop treatment (especially for those with persistent symptoms well into their 70’s).
