In addition to the increased risk of CVD, which comes with postmenopausal changes in sex hormone levels, menopause is also associated with a higher incidence of cardiac risk factors including diabetes, hypertension, obesity, dyslipidemia, and other co-morbidities. The lipid profile is adversely affected during menopause; total cholesterol, LDL, and triglycerides are increased while HDL is decreased. Insulin and glucose metabolism is impaired, as evidenced by increased insulin resistance in postmenopausal women. Postmenopausal women tend to have more abdominal obesity due to body fat redistribution, which is associated with alterations in the lipid profile and glucose metabolism. These women are predisposed to the metabolic syndrome, which can be defined as having central obesity, impaired fasting glucose, hyperlipidemia, and elevated blood pressure [21]. The pro-coagulant effects of estrogen can become predominant as fibrinogen, factor VII activity, antithrombin III, and plasminogen activator inhibitor-1 (PAI-1) are increased after menopause [21] (Table 16.2).

The Framingham study provides supporting evidence for the association between postmenopausal status and CHD. An analysis of a cohort of 2,873 women followed for 24 years revealed the incidence of cardiovascular disease in age matched men under 60 years was twice that of same age women. Among postmenopausal women up to the age of 55 years, cardiovascular disease was twice that of premenopausal women, with 70 cardiovascular events occurring in postmenopausal women compared to 20 events in premenopausal women. When analyzing the risk of stroke, MI, and congestive heart failure (CHF), however, the number of events was smaller. Premenopausal and postmenopausal women experienced 9 and 39 events respectively, a difference that does not meet statistical significance [23]. In the Nurses Health study, a prospective cohort of 35,616 healthy, naturally postmenopausal women, a younger age at menopause was associated with a higher risk of CHD [24].

These adverse effects on the cardiovascular system may be seen sooner in women who smoke and thus undergo natural menopause at an earlier age [2]. Women who smoke typically reach menopause 2 years earlier than non-smokers [25].

Women with polycystic ovary syndrome (PCOS) are predisposed to CHD and may suffer from adverse cardiovascular events, given the associated endocrine and metabolic abnormalities such as insulin resistance, glucose intolerance, lipid abnormalities, hypertension, and increased levels of plasminogen activator inhibitor [26]. In premenopausal women with coronary risk factors undergoing coronary angiography for suspected myocardial ischemia, disruption of the ovulatory cycle characterized by hypoestrogenemia of hypothalamic origin, was also associated with angiographic coronary artery disease [27].

The risk of CHD differs in women undergoing menopause prematurely by bilateral oophorectomy. Several studies have shown increased CHD risk among females who underwent surgical menopause. Women who underwent bilateral oophorectomy and did not use estrogen replacement therapy were found to be at increased risk of CHD when compared to age-matched controls in the Nurses’ Health Study (risk ratio 2.2) [28]. In a study by Rosenberg et al., the relative risk of developing a myocardial infarction increased with decreasing age at bilateral oophorectomy [29].

The Multi-ethnic Study of Atherosclerosis (MESA), a multicenter, longitudinal cohort study involving 3,213 men and 3,601 women, found that early menopause was a strong predictor of CHD and stroke (twofold increased risk), regardless of traditional CVD risk factors in the population-based sample of multiethnic US women [30].

Lifestyle modification with a focus on risk factor reduction should be the first step in the prevention of CHD [21]. Women should be encouraged to stop smoking. The risk of CHD is two to four times greater in women who smoke [2, 31]. Diet should be modified to include less saturated fat intake. Weight should be controlled through both diet and physical activity. In women with established hypertension, appropriate antihypertensive therapy should be given [21, 32].

In the past, hormone therapy (HT) was believed to be beneficial for women’s hearts and was routinely prescribed for CHD prevention in the postmenopausal years. In the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial, a randomized clinical trial published in 1995, postmenopausal women, ages 45–64 years, receiving either estrogen alone or in combination with a progestin, were observed to have a reduction in LDL, increased HDL levels, and lower fibrinogen levels. Unopposed estrogen has been most effective at increasing HDL cholesterol (HDL-C), however it is associated with endometrial hyperplasia, thus limiting its use to women without a uterus. A conjugated equine estrogen (CEE) with cyclic micronized progesterone (MP) used in women with a uterus still showed a favorable effect on HDL-C without the risk of endometrial hyperplasia [33]. To explain the risks and benefits of HT, the mechanisms of action should be considered.

Most women will live a third of their life after menopause, therefore it is important to be aware of the symptoms and available treatment options associated with estrogen loss [2]. Hormone therapy (HT) utilizes estrogen, with or without the addition of progestin. Estrogen can be given continuously in the form of tablets, skin patches, gels, subcutaneous implants, or intranasal sprays. Both natural estrogens and synthetic derivatives are available for HT. Systemic estrogen therapy (ET) has been proven to be the most effective treatment for vasomotor symptoms. Growing observational evidence is showing that transdermal ET may be associated with less risk of deep vein thrombosis, stroke, and MI [39, 40]. Transdermal preparations of estradiol also have the advantage of avoiding first pass hepatic effect, and thus may provide potential benefit to women with hypothyroidism or low libido. In women with a uterus, combination estrogen and progestin is necessary to avoid adverse effects of unopposed estrogen on the endometrium that can lead to endometrial cancer. Therefore, estrogen is typically combined with a progestin and is referred to as estrogen plus progestin therapy (EPT). Treatment may be cyclic, with daily estrogen and 12–14 days of progestin each month, or continuous-combined with both daily estrogen and low dose progestin [38].

Menopausal hormone therapy continues to have a clinical role in the management of vasomotor symptoms. For healthy women younger than 60 years and within 10 years of menopause, HT seems to be associated with low cardiovascular risk. If started on HT, women should use the lowest effective dose for the shortest duration of time to achieve treatment goals of relieving debilitating hot flashes and night sweats. Studies have shown that, for many women, low doses relieve vasomotor symptoms as effectively as standard doses. The need for continuing therapy should be assessed at least annually [38].

Contraindications of HT include breast or endometrial cancer, cardiovascular disease, thromboembolic disorders, and active liver or gallbladder disease. In women with contraindications to HT, alternatives to treat bothersome night sweats and hot flashes include lifestyle modifications (i.e. reducing body temperature, maintaining a healthy weight, smoking cessation, relaxation techniques, and acupuncture), non-prescription medications including vitamin E, soy products, and non-hormonal prescription medications, which include clonidine, paroxetine, venlafaxine, and gabapentin [38].

Given multiple potentially beneficial effects of estrogens on the cardiovascular system, there was a lot of expectation for the protective effects of postmenopausal hormone therapy for CVD prevention in women [17]. Due to the compelling evidence of cardioprotection by estrogen, the Coronary Drug Project, a randomized clinical trial funded in 1965 by the National Heart Institute, was designed to examine the benefits of estrogen in men who were at high risk of a heart attack [41]. Since optimal doses of estrogen for men were not known, men received a high dose of 2.5 mg of estrogen daily. Prevention of heart attacks was not seen, and the study was stopped early due to higher mortality among men receiving estrogen therapy.

Although the Coronary Drug Project had been terminated early, postmenopausal women in general practice continued to be treated with estrogen based on epidemiologic studies showing reduced rates of CHD among users of estrogen therapy [15].

The HERS study [44], published in 1998, was the first large-scale randomized clinical outcome trial to evaluate the effects of HT on secondary prevention of CHD in 2,763 postmenopausal women. Participants, with a mean age of 66.7 years and documented existing coronary artery disease, were randomly assigned to take either placebo or combination hormone therapy (noncyclic conjugated equine estrogens [CEE] 0.625 mg + medroxyprogesterone acetate 2.5 mg) and followed for 4.1 years. There was no difference in the primary outcome of nonfatal myocardial infarction (MI) and coronary death between the hormone and placebo arms. A post-hoc time trend analysis of the data showed a significant time trend suggesting an excess of coronary events among hormone-treated women during the first year after the randomization (hazard ratio 1.52), with a trend toward fewer events at 3–5 years of follow up.

Given the decreased risk of coronary events at 3–5 years of follow-up in the HERS study, women were followed for an additional 2.7 years in an open-label, event surveillance study, HERS II. In HERS II, women remained on their original drug assignments. At the end of the study, hormone therapy failed to reveal a decreased risk of coronary events in women with established CHD, even after adjusting for potential confounders such as aspirin therapy, statin use, smoking, etc [47, 48].

The results from the Estrogen Replacement and Atherosclerosis (ERA) trial were reported in 2000. ERA was a randomized angiographic end-point trial comparing the effects of estrogen therapy (ET) and combination hormone therapy (HT) to placebo in postmenopausal women with pre-existing coronary artery disease. The trial also failed to show a benefit in women receiving ET and HT on the progression of atherosclerosis. This lack of benefit occurred despite the fact that women receiving HT in this study had a significant increase in HDL cholesterol and a decrease in LDL cholesterol [45].

The conclusion from these studies was that there was no long-term difference between women receiving HT and those receiving placebo and that postmenopausal hormone therapy should not be used for the sole purpose of secondary prevention of CHD in women with a history of established coronary artery disease [19, 49]. Since women enrolled in HERS and ERA had established coronary artery disease, the results of these studies may not directly apply to the use of hormone therapy in healthy postmenopausal women [50].

For many years, hormone therapy was thought to play a role in the primary prevention of CHD in “healthy” women. In order to study this hypothesis, a large, randomized trial, the Women’s Health Initiative (WHI), was designed to compare HT with placebo in postmenopausal women [5]. The WHI included 16,608 healthy women, ages 50–79 years, with an intact uterus and no pre-existing coronary artery disease. Subjects were randomized to receive either conjugated equine estrogen (0.625 mg/day) with medroxyprogesterone acetate (2.5 mg/day) or placebo. The trial had several different arms, including an estrogen plus progestin arm (EPT) and an estrogen-only arm (ET) for women post hysterectomy (~10,739 women). In May 2002, after a mean follow up of 5.2 years, the study was stopped prematurely due to a 26 % increased risk of invasive breast cancer and excessive CVD events in the EPT group during the first year and nearly a 30 % increased risk of coronary events, mainly nonfatal myocardial infarctions. A 41 % increased risk of stroke and a doubled risk of venous thromboembolism was also seen [49]. Controversy erupted when investigators felt compelled to send letters to women participating in the trial stating that those in the EPT group had experienced an increased risk of breast cancer, heart attacks, strokes, and blood clots during the early portion of the trial. At the same time, however, investigators stated that only 1 % of study participants had experienced adverse events and that the data was very preliminary. They pointed out the early detriment seen with HT in the HERS trial disappeared after the first year.

The estrogen only arm of the study, however, showed no significant effect of HT on CVD risk. Overall CVD risk was estimated to be increased by eight cases per 10,000 women per year in the combined therapy group while the risk was estimated to be decreased by three cases per 10,000 women per year in the estrogen only group [35]. Women in the ET arm of the WHI also demonstrated no increased risk of breast cancer. The WHI trial was actually terminated early (in 2002) after finding a small but significant increase in cardiovascular events and other adverse outcomes in the hormone therapy group. The early termination of the WHI trial created much controversy regarding the role of HT and its effects on cardiovascular health in women. The trial changed the practice of prescribing HT for postmenopausal women. Many women had their hormone therapy discontinued at that time.

The aforementioned trials showed that menopausal hormone therapy did not prevent incidence or recurrence of CVD in women and increased their risk of stroke. Taken together, the cumulative data of HERS, ERA, and WHI supported the concept that HT should not be used in the prevention of cardiovascular disease and redirected focus on established preventative lifestyle and medical therapies such as smoking cessation, heart healthy diet, physical activity, weight management, as well as control of hypertension and hypercholesterolemia [47].