As menopause approaches, heart health takes center stage, with the risk of heart attacks, strokes, and other vascular conditions rising sharply. Heart disease is the leading cause of death for women, and women are also at higher risk for Alzheimer’s Disease than men. This has sparked an important question: could menopause hormone therapy offer women cardiovascular and brain protection during this critical phase of life? To answer that, let’s delve into how menopause impacts heart and vascular health and uncover the latest research on how hormones may play a role.
Estrogen and the Cardiovascular and Neurologic Systems
Menopause triggers a significant decline in estrogen, a hormone that plays a protective role in cardiovascular health. Estrogen maintains the elasticity of arteries, promotes healthy cholesterol levels, improves insulin sensitivity, reduces inflammation, and aids in blood flow. So it is of no surprise that the precipitous drop in estrogen at menopause is associated with an increase in the incidence of cardiovascular events. Additionally, the drop in estrogen levels affects the brain’s estrogen receptors, particularly in areas like the hippocampus and prefrontal cortex, potentially impacting memory, mood, and executive functions.
The Timing Hypothesis
The timing hypothesis, or critical window hypothesis, proposes that the cardiovascular benefits of estrogen therapy are most effective when started early in menopause (within 10 years of onset and under age 60). If estrogen is introduced when the endothelium (arterial lining) is still healthy, it can have beneficial effects. However, initiating therapy later, when arteries are stiffer and significant plaque has formed, may have no benefit or even increase risks. Research shows estrogen improves endothelial vasodilation primarily in the early postmenopausal years. Furthermore, women are more likely to develop non-calcified, soft plaques, which are prone to rupture. Late initiation of estrogen may destabilize these plaques, raising the risk of cardiovascular events.
The concept originated from observational studies in the 1990s, which showed that healthy women who started menopausal hormone therapy (MHT) near the onset of menopause seemed to have a lower risk of coronary heart disease. Then came the Women’s Health Initiative (WHI), a landmark randomized controlled trial designed to assess the risks and benefits of MHT. The subsequent age-stratified analysis found that for women in their 50s, hormone therapy was associated with a 24% lower risk of heart disease, but for those in their 70s, hormone therapy was linked to a 26% higher risk of heart disease. These findings reinforced the hypothesis that age and vascular health at the time of MHT initiation influence outcomes. Also note that the WHI investigated synthetic hormones like medroxyprogesterone acetate, a synthetic progestin that may have detrimental effects on the blood vessels unlike the bio-similar micronized progesterone commonly used today.
The Danish Osteoporosis Prevention Study (DOPS) is another study frequently cited to support the idea that MHT reduces cardiovascular risk. The DOPS study’s strengths include its focus on low-risk, recently postmenopausal women and long duration with follow-up, reflecting a more real-world situation with hormone therapy compared to the WHI, which had an older, higher-risk population. However, this study also had many limitations. It was unblinded and without a placebo control. Knowing their treatment could have influenced participants’ health behaviors, doctor visits, and how outcomes were assessed. Secondly, the outcomes of heart attack, heart failure, and death were all grouped into one composite endpoint, making it difficult to determine how hormone therapy affected each outcome individually. For example, while all-cause mortality was reduced, it was unclear if the reduction in heart attacks alone reached statistical significance.
Two other studies, Early vs. Late Intervention Trial with Estradiol (ELITE) and the Estrogen in the Prevention of Atherosclerosis Trial (EPAT) both demonstrated that early initiation of oral estradiol slowed the progression of carotid artery thickening. This suggests possible cardiovascular benefit, though surrogate markers are not as reliable as real-world outcomes like heart attacks or strokes. The Kronos Early Estrogen Prevention Study (KEEPS), unlike the ELITE and EPAT studies, found no major impact on carotid artery thickness over four years of MHT, though they also studied a younger population and used a lower dose.
In summary, while we do have research to support estrogen therapy closer to the menopause transition, uncertainties remain about making broad-based recommendations for cardiovascular protection. What is the optimal estrogen formulation (transdermal or oral)? Dose? Type of progestogen? For how long? A couple of studies looked at surrogate markers, not real-world cardiovascular outcomes. The aforementioned studies also used oral estrogens (conjugated equine estrogen or estradiol) with and without synthetic progestins, while women today are often on preferred formulations of transdermal estradiol and body-identical progesterone for their reduced risk of blood clots and strokes. Thus, the heterogeneity in these studies complicates general applicability.
What About Dementia?
The timing of hormone initiation also seems to apply to brain health as well, with earlier intervention potentially offering protective cognitive benefits, with later initiation elevating dementia risk. While estrogen has many other neuroprotective effects, its effects on vascular health are also critical for optimal blood flow to the brain to prevent neurologic disease. Dr. Lisa Mosconi, a neuroscientist specializing in women’s brain health, has conducted extensive research on this topic. Her studies also support that timing matters. In a meta-analysis of 51 studies, Dr. Mosconi and her team found that mid-life estrogen therapy was associated with a 32% lower rate of dementia, whereas late-life initiation did not significantly reduce dementia rates. The Women’s Health Initiative Memory Study (WHIMS) found that women aged 65 and older who began HT had a higher incidence of dementia compared to those not on HT. Again, we must keep in mind the heterogeneity of many of these studies and the fact that 1) transdermal estrogen is safer than oral versions and 2) progesterone is much safer than the synthetic progestins used in many of these studies.
Moving Forward
In conclusion, the timing hypothesis highlights the potential for MHT to protect heart and vascular health when started early, but more robust research is needed to confirm these benefits with modern formulations. For now, MHT is recommended for symptom relief and prevention of osteoporosis, with cardiovascular benefits seen as secondary. For women over 60 (or beyond 10 years from the menopause transition), benefits may outweigh the risks for continuing extended use beyond age 60-65 for treating persistent symptoms and preventing osteoporosis. However, this risk is higher for women starting hormones for the first time beyond 10 years of the menopause transition. Women considering long-term HT should also note that extended use of combined estrogen-progestin therapy (EPT) shows a small increased risk of breast cancer, though that risk can be mitigated using low-dose transdermal or vaginal estrogens. Furthermore, estrogen alone in women with hysterectomies shows a decreased risk of breast cancer.
Equally important is the need for individualized risk assessment and shared decision-making when considering MHT. This involves evaluating personal cardiovascular risk factors such as blood pressure, lipids such as LDL/Apo-B and lipoprotein(a), glucose levels, autoimmune disease, family history of blood clots, personal and family history of cardiovascular disease, and smoking history. In some cases, coronary artery calcium scores or even advanced imaging like coronary CT angiography may be useful to assess plaque burden. By incorporating these personalized measures, women and their clinicians can better balance the potential benefits of MHT with individual risk, ensuring a more tailored and informed approach.
Finally, we must not forget that women can support their heart health significantly during menopause through lifestyle measures such as consistent exercise, a high-fiber/Mediterranean diet, avoiding tobacco, and keeping cholesterol and blood pressure under control. We, at Peninsula Doctor, will continue to keep a close eye on the data and work with our patients to make the most informed decisions to protect both their cardiovascular and overall health in this critical life stage.
Dr. Judy Kim
