How does menopause affect cardiovascular health?

Updated: Jun 06, 2018
  • Author: PonJola Coney, MD; Chief Editor: Richard Scott Lucidi, MD, FACOG  more...
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Coronary artery disease (CAD) is the leading cause of morbidity and mortality in men and postmenopausal women. Menopause increases the risk for women still further, independent of age. Before menopause, the risk of CAD for women lags behind the risk for men by approximately 10 years; after menopause, it catches up. As a result, mortality from CAD is increasing in women. The Framingham study was pivotal in showing the relation between menopause and increased cardiovascular mortality. [38]

The Women’s Health Initiative (WHI) was a randomized, controlled trial that addressed the issue of whether postmenopausal women should take hormone therapy or estrogen therapy for prevention of CAD [39, 40] ; more than 27,000 healthy women participated in the trial. The investigators concluded that hormone therapy and estrogen therapy are not indicated for the prevention of CAD.

Emerging analyses of WHI data from the Estrogen-Alone Trial—a double-blind, placebo-controlled, randomized clinical trial evaluating the effects of conjugated equine estrogens (CEE) on chronic disease incidence among postmenopausal women with prior hysterectomy and after a mean of 7.1 years of follow-up—suggested that treatment effects differ by age. [6] Compared with older women, younger women receiving CEE had a lower risk of CAD.

Greater safety and possible benefit for women in their 50s, with potential harm for older women, were observed with respect to coronary heart disease, total myocardial infarction, colorectal cancer, total mortality, and the global index of chronic diseases. [6] Although immediate use of hormone or estrogen therapy in the early postmenopausal time may reduce the risk of CAD, the WHI clearly shows that women more than 9 years post menopause should not be started on hormone therapy or estrogen therapy for CAD prevention.

Initiating hormone therapy or estrogen therapy in the immediate perimenopausal or postmenopausal period is believed to be beneficial because significant atherosclerotic changes have not yet occurred. Once 9 years have passed since menopause, the arterial damage seems to have commenced.

Studies are ongoing to prove these theories in humans and primate models. Studies of hormones and atherosclerotic arterial plaques in ovariectomized monkeys show promise in this regard. [41, 42] Further evidence in support of estrogen’s protective effects when it is used within a few years of menopause came from the subanalysis by Manson et al in 2007, which showed that there was less coronary artery calcification in women taking oral CEE than in those taking placebo. [43]

Data from the National Heart, Lung, and Blood Institute (NHLBI)-sponsored Women’s Ischemia Syndrome Evaluation suggested that by using the quantitative measurements of the timing and type of menopause and hormone therapy use, earlier initiation was associated with less angiographic CAD in women with natural, but not surgical, menopause. [44]

The beneficial effect of estrogen on cardiovascular mortality is due to many factors. One mechanism appears to be estrogen’s effects on lipid metabolism, which includes reducing low-density lipoprotein (LDL) and increasing high-density lipoprotein (HDL). Studies have suggested that the best predictors of CAD in men and women are different [45] and that triglycerides, HDL, and lipoprotein(a) may be more significant in women. [46]

Women with elevated lipoprotein(a) levels should be treated more aggressively, and the treatment considered should include estrogen therapy, as well as a statin. A positive relation between estrogen therapy and reduction of primary cardiovascular risk has been demonstrated in several studies, and the risk reduction in women who are taking estrogen therapy may be similar to the risk reduction in those who are receiving specific lipid-lowering therapy. [47]

In view of the WHI data, however, neither hormone therapy nor estrogen therapy should be given for CAD at this time. The primary indication for hormone therapy or estrogen therapy is symptomatic relief of vasomotor symptoms.

The Heart and Estrogen/Progestin Replacement (HERS) Study, [48, 49, 50] a study of 2763 postmenopausal women with known CAD, compared the effect of continuous combined hormone therapy versus that of placebo over an average of 4.2 years; no beneficial reduction of CAD event rates was initially observed in the hormone therapy groups.

In fact, the initial adverse event rate was higher in the treatment arm than in the placebo arm, offsetting a later reduction in risk in the hormone therapy group. [48, 49, 50] An 11% reduction in LDL and a 10% increase in HDL were apparent in the treatment group. These observations together suggest that the protective effects of estrogen on cardiovascular morbidity result from many mechanisms and not solely from lowering of lipids and that estrogen alone is inadequate for secondary prevention of CAD.

The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial, compared various CAD risk factors as predictors of outcomes in 875 healthy postmenopausal women who received various hormone therapy regimens by randomizing the participants to receive either placebo or 1 of 5 estrogen/progestin regimens. [51]

All treatment groups showed an overall improvement in HDL and LDL levels in comparison with the placebo group. [51] The improvement in HDL level was better in the group that received unopposed estrogen than in the other treatment groups; however, individuals using unopposed estrogen also had the highest rate of endometrial hyperplasia.

The Nurses’ Health Study demonstrated an approximately 11% risk reduction for primary cardiovascular disease in postmenopausal women who used hormone therapy compared with women who had never used hormone therapy, irrespective of the duration of use. [52] The risk reduction did not appear to be dose-dependent. However, these data have been eclipsed by those reported by the WHI.

The greatest beneficial effect of estrogen appears to be on endothelial function. Women undergoing angioplasty appear to be protected against restenosis by estrogen therapy. [53] Progression of early atherosclerosis, as measured by carotid intimal thickness, was greater over time in postmenopausal women who smoked than in women who smoked and were on estrogen therapy. [54]

Monkey studies have shown that coronary vasculature has a favorable response to CEEs. [55, 56] These findings continue to be investigated in further human studies, in the breakdown of age groups in the WHI data, and in animal studies. [42, 55, 57]

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