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Menopause Transition and Cardiovascular Disease Risk: Implications for Timing of Early Prevention
A Scientific Statement from the American Heart Association, 2020.
Condensed for easy reading by Sylvia Morgan M.D. OB/GYN
Cardiovascular disease (CVD) is the leading cause of death for women. Women’s risk for CVD increases significantly after menopause. Mean life expectancy of women in the United States is 81 years. Therefore, women live up to 40% of their lives in menopause. Previous studies on hormones compared pre-menopausal women with post-menopausal women. There is no data available on the effects of menopausal hormone use on women’s cardiometabolic health during the perimenopausal phase (prior to menopause)- a time when most women suffer from severe symptomatology due to the declining endogenous estradiol (estradiol made by the body).
In 2002 the Women’s Health Initiative (WHI) was reported across the nation in newspapers and on television, stating menopausal hormones caused more breast cancer and more heart attacks. Fifty percent of women on hormones, stopped their hormones without talking to their physicians. The WHI study had many flaws. But after the WHI study, doctors were less likely to prescribe hormones.
The WHI study was divided between women of the ages 50-59, 60-69 and 70-79. The WHI study was heavily weighted towards the two-thirds of women who were distant from menopause (60-79 years of age). The overall results of the WHI study did not show an advantage of hormone therapy. At the 5 year follow up of the WHI study, the arm of recently menopausal women between the ages of 50-59 years, were studied and showed that hormone therapy was protective against CVD.
Menopause transition (MT), often called perimenopause, begins with changes in the menstrual cycle or the start of other menopausal related symptoms and it ends only after 12 months has passed without a menstral cycle. During this time there is a loss of ovarian function resulting in the decline of estrogen produced in the ovary. Perimenopause lasts an average of four years but has been noted to last as long as 10 years. The median age of natural menopause is 50 years. Premature menopause is the occurrence of menopause before the age of 40 years. Early menopause occurs between 40 and 45 years of age. Early age of natural menopause is a marker for greater CVD risks. The guidelines from the North American Menopause Society endorse the use of menopausal hormone therapy with premature, early or surgical menopause until the time of natural menopause or the median age of 50 years. (If no contraindications exist)
Since the WHI study, which came out over 20 years ago, women going through menopause have shown a distinct pattern of changes that occur in sex hormones that result in adverse changes in a woman’s body. The declining endogenous estradiol levels during perimenopause have been associated with significant detrimental changes affecting a wide range of cardiovascular risk factor: increased lipids resulting in increased plaque in the blood vessels or atherosclerosis, vascular health changes resulting in arterial stiffness, weight gain with increased central/visceral fat and a decrease in lean muscle mass. Central/visceral fat is associated with a high risk of mortality. Some evidence suggests a link between menopause and an increased risk of type 2 diabetes. All these changes increase the risk factors for CVD. These studies have contributed to our understanding of the relationship between perimenopause and CVD risks and the hypothesis that perimenopause contributes to the increased risk of coronary heart disease.
Meta-analysis of 10 studies, which included 213,976 women, reported the presence of menopausal related symptoms: hot flashes and night sweats (vasomotor symptoms), mood changes (depression, anxiety), sleep and cognitive disturbances. All of these symptoms are related to declining estrogen and are strongly linked to higher CVD risks.
Observational studies before 1991 reflect the clinical practice of initiation of hormone therapy near menopause. The Nurses’ Health Study showed a lower risk of mortality among current users compared with those who had never used hormones. Women who took hormones in the PEPI (Post menopausal Estrogen/Progestin Interventions study) gained less weight and had less increase in waist circumference than women on placebo. PEPI conjugated estrogen-based hormone regimens were associated with decrease in fasting glucose and fasting insulin. The Study of Women’s Health Across the Nation (SWAN), the Melbourne Women’s Midlife Study, the Penn Ovarian Aging Study and the Seattle Women’s Health Study were specifically designed to address relative contributions of chronological and reproductive aging to cardiometabolic health. These studies, although not designed to do so, gave us important data to analyze regarding health measures closer to menopause. The KEEPS trial (Kronos Early Estrogen Prevention Study) of menopausal hormone therapy use and atherosclerosis progression in recently menopausal women demonstrated a difference in heart fat deposition and coronary artery calcification. DOPS Study (Danish Osteporosis Prevention Study) showed that after 10 years of menopausal hormone therapy use, the primary end point of heart failure, myocardial infarction and death was reduced. The SWAN study also reported an association between estradiol levels and lower progression of carotid interadventitial diameter (less plaque) over time. The 5-year ELITE (Early Versus Late Intervention Trial with Estradiol) also showed reduced plaque progression with Estradiol.
Literature supporting a critical role for the timing of the initiation of hormone use relative to menopause appears to be associated with reduced CVD risks.
To reduce the burden of CVD while improving quality of life in the perimenopausal women, future studies should include menopausal hormone therapy starting during the perimenopausal phase along with other lifestyle interventions ie. diet, weight loss, exercise, smoking cessation, controlling BP, and the optimization of cholesterol levels and fasting blood sugar levels. Women who smoke die 11 years earlier than women who have never smoked.
New evidence suggests that the effects of menopausal hormone therapy on the progression of atherosclerosis and CVD events vary by age or time since menopause when hormone therapy was initiated. The effects of menopausal hormones on CVD outcomes and all of causes mortality may decrease by 30% to 48% when hormone therapy is initiated in women <60 years of age or <10 years since menopause without other risks. Whereas null or harmful effects may occur when hormone use is initiated at an older age or after a greater length of time since menopause. More studies are needed during the perimenopausal phase regarding the initiation of estradiol. [The American College of Obstetrics and Gynecology states that low dose birth control pills may be used in the peri- menopausal women with irregular menstrual cycles until the age of 55 years.] 1 Perimenopausal women should be given individualized counseling on menopausal hormone therapy and given the options of treatment, especially if they are experiencing vasomotor symptoms.
A Finnish study of 1.97 million women-years reported a >2-fold increase in cardiac and stroke deaths in the first year after stopping menopausal hormone therapy (median age at starting 52 years: median age at stopping, 59 years).
More studies are needed.
The 2011 AHA guidelines for CVD prevention did not address the literature now available about the significant adverse cardiometabolic health related changes that occur during perimenopause. The purpose of this scientific update by the AHA, according to the authors, was to provide contemporary literature on the accelerated increased CVD risks that occur during the menopause transition and the studies regarding menopausal hormones close to menopause. Current recommendations from leading specialty societies endorse the use of menopausal hormone therapy in recent menopausal women who have no contraindications. Additional research is needed regarding hormone therapy during the perimenopausal phase when endogenous estrogen is declining.
With the exception of the footnote1 which is sourced in the American College of Obstetrics and Gynecology literature, all information in this article is directly from the article by, Khoudary PHD, MPH, FAHA et al, “The Menopause Transition and Cardiovascular Disease Risk: Implications for Timing of Early Prevention”
A Scientific Statement from the American Heart Association, Circulation,
Nov 30, 2020; 142e506-e532
More information about heart disease can be found the American Heart Association website.
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