EMAS position statement: Managing the menopause in the context of coronary heart disease

Introduction

Cardiovascular disease (CVD) including coronary heart disease (CHD) and stroke is the most common cause of female death. Premenopausal CHD is very rare but when women enter the menopause the incidence of CHD increases markedly. CHD presents 10 years later in women than in men. The reason is still unclear but the protective effects of estrogens have been suggested.

Aims

To formulate a position statement on the management of menopause women in the context of coronary heart disease.

Materials and methods

Literature review and consensus of expert opinion.

Results and conclusions

Based on long term randomized placebo-controlled studies hormone therapy (HT) is not recommended for the primary or secondary prevention of CHD in postmenopausal women. In most countries the only indication for HT is the treatment of menopausal symptoms. Women with known CHD or with many coronary risk factors seeking HT because of troublesome climacteric symptoms should be evaluated for their individual baseline risk of developing breast cancer, venous thromboembolism and CHD recurrence. The same applies to non hormone therapy-based treatments where long term clinical studies are lacking. Risks should be weighed against expected benefit from symptom relief and improved quality of life. The lowest effective estrogen dose should be used during the shortest possible time. Transdermal administration is preferred if risk factors for VTE exist. Different progestogens might differ in their cardiovascular effects. Observational studies suggest that micronized progesterone or dydrogesterone may have a better risk profile than other progestogens with regard to thrombotic risk.     

Rationale for use of lower estrogen doses for postmenopausal hormone therapy

In placebo-controlled clinical trials low dose estrogens have been shown to reduce hot flashes an average of 65%. Low dosage is effective in preventing bone loss in early menopause and both low and ultralow estrogen dosages can prevent bone loss among women many years beyond menopause. Epidemiological studies indicate less risk of cardiovascular disease and venous thromboembolism in women who use low dose estrogens compared to standard dose. Low dosages of estrogens are less likely to produce unacceptable side effects, such as vaginal bleeding or breast tenderness. When prescribing low dosage estrogen, one can safely use less progestogen, either less daily dosage or less frequent cycles. Older women on ultralow estrogen may not require regular progestogen because the endometrium is not stimulated. In conclusion, there is a strong rationale for use of lower estrogen dosage in HT. Low dosage estrogen can relieve vasomotor symptoms and can prevent postmenopausal bone loss. Women taking low dosages of estrogens are less likely to have unacceptable side effects, such as vaginal bleeding or breast tenderness. Moreover, the potential harm caused by standard dosages of estrogen with progestin, including coronary heart disease, venous thromboembolism, stroke, and breast cancer may be mitigated by use of lower estrogen doses that do not require daily or monthly progestin opposition.     

Postmenopausal hormone therapy in clinical perspective

Although many of the risks and benefits of postmenopausal hormone therapy are known, only recently has the magnitude of these effects and their perspective to other therapies become more fully understood. Careful review of randomized controlled trials indicates that the risks of postmenopausal hormone therapy including breast cancer, stroke and venous thromboembolism are similar to other commonly used agents. Overall, these risks are rare (less than 1 event per 1,000 women) and even rarer when initiated in women less than 60 years of age or within 10 years of menopause. In addition, the literature indicates similar benefit of postmenopausal hormone therapy, in women who initiate hormone therapy in close proximity to menopause, to other medications used for the primary prevention of coronory heart disease in women.     

Coronary heart disease in menopausal women: implications of primary and secondary prevention trials of hormones

In direct contrast to the observational studies, both primary and secondary prevention trials of female reproductive hormones have found no benefit for coronary heart disease (CHD). Basic science studies have elucidated several mechanisms by which estrogen may improve coronary arterial physiology and prevent pathology, but have also found mechanisms by which estrogen might increase coagulation or inflammation, or might trigger coronary events in advanced lesions. Animal studies suggest that hormones may retard early atherosclerosis, while both animal studies and human angiographic trials are conclusive that hormones do not retard progression of raised lesions. Hormone use in the primary prevention observational studies would mostly have started at the age of menopause, in women whose arteries on average would be closer to normal than those of women in the clinical trials. One hypothesis worthy of further study is that estrogen may have a beneficial effect in normal or near-normal arteries, but the opposite effect in the presence of established atherosclerosis. However, at the average age of menopause, a substantial proportion of women has raised lesions, and a smaller proportion already has advanced lesions. Also, the apparent benefit of hormone use was found in secondary prevention observational studies, i.e., in women with compromised arteries. It is likely that uncorrected biases in the observational studies lead to an overestimation of any benefit of hormone use. On the other hand, endogenous estradiol may be responsible for the later onset of coronary disease in women compared to men; if so, then the appropriate test of the estrogen hypothesis would employ transdermal estradiol in a young population of menopausal women. Hormones are not indicated for the prevention of CHD, particularly in the light of the increased risk for stroke and venous thrombosis. Their use for other indications (menopausal symptoms, osteoporosis) needs to be tempered by the risk for cardiovascular disease (CVD).     

Hormone therapy and coronary artery calcification in asymptomatic postmenopausal women: the Rancho Bernardo Study

OBJECTIVE: To determine (1) whether past or current hormone therapy (HT) in postmenopausal women is associated with subclinical coronary artery plaque burden, (2) whether any association is independent of age, body size, blood pressure, lipids, fasting plasma glucose, cigarette smoking, leisure time physical activity, alcohol intake, use of lipid-lowering medications, and socioeconomic status, and (3) whether any association varies by duration of HT or by the use of combined versus unopposed HT. DESIGN: An observational study, with HT validated and coronary heart disease risk factors determined between 1997 and 1999 in a research clinic, and coronary artery calcium score (CACS) evaluated by electron beam computed tomography in 2001 through 2002. Participants were 204 community-dwelling postmenopausal women from the Rancho Bernardo cohort aged 55 to 78 years with no history of heart disease. RESULTS: The odds of severe CACS in current estrogen users (n = 127) was 0.40 (95% CI 0.19, 0.82), controlling for all covariates. Past users (n = 40) had intermediate odds (multiply adjusted OR = 0.66, 95% CI = 0.28, 1.58). In subgroup analyses, age-adjusted associations did not differ between the 68 women using unopposed estrogen versus the 59 using an estrogen-progestin regimen. Women who had used HT for at least 10 years (n = 86) had significantly less (P = 0.01) plaque burden than shorter term users (n = 41). CONCLUSIONS: Both the strong association and the duration of use effect independent of lifestyle and social class suggest an antiatherogenic effect of postmenopausal estrogen. Only a clinical trial can completely exclude confounding by social class, lifestyle, and unmeasured covariates.     

Rise and fall of hormone therapy in postmenopausal women with cardiovascular disease

Whereas observational data for postmenopausal women using hormone therapy (HT) have shown a protective effect against cardiovascular disease, prospective, randomized trials have demonstrated a harmful effect on the vascular system.This study describes the effects of HT on lipids, hemostatic parameters, inflammation, and the vascular wall. Reasons for the different results of observational and experimental studies of HT are postulated. The timing of hormonal supplementation seems crucial. Used chronically, HT has no harmful effects; however, first-time use of HT after a recent cardiovascular event results in an early increase in adverse cardiovascular events. In most observational studies, women started HT for postmenopausal symptoms, whereas in experimental studies, women started HT 10 to 20 years or longer after menopause. Cumulative evidence supports the hypothesis that HT has more effect in maintaining vascular health than in alleviating endothelial dysfunction. HT has not proven beneficial in the long term in women at risk of a cardiovascular event. The interval between menopause and the start of HT plays a crucial role in the effectiveness of HT in the vascular system.     

HRT as secondary prevention of cardiovascular disease

Objective: To review the evidence of the efficacy of postmenopausal hormone replacement therapy (HRT) in secondary prevention of coronary artery disease or stroke. Results: Although a number of rather large and prolonged non-randomized observational studies have produced convincing and consistent evidence of the efficacy of HRT in the prevention of recurrence of cardiac events, the first randomized, placebo controlled trial (RCT) on heart disease and estrogen replacement study (HERS) reported no benefit of conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA) in secondary prevention of cardiac events in women with established coronary artery disease. This was supported by RCT reporting no effect of CEE or CEE + MPA on the progress of coronary sclerosis. Similarly, some nonrandomized observational studies have evaluated the risk of recurrent stroke in regard to the use of HRT, and the data are conflicting reporting a reduced or increased risk of recurrence for HRT users. One RCT has shown that low-dose estrogen treatment can only slow down the progression of carotid arteriosclerosis in high-risk postmenopausal women, whereas two other RCTs have shown no benefit (or risk) of using HRT for secondary prevention of ischemic stroke or progression of carotid atherosclerosis. Conclusion: The evidence accumutaed so far shows that HRT has no place in secondary prevention of coronary or carotic artery disease. Its use in these patients must be based on solid nonvascular indications and expected benefits from these causes.     

Estrogen replacement therapy and gallbladder disease in postmenopausal women

OBJECTIVE: To examine the role of estrogen replacement therapy on the development of gallbladder disease in postmenopausal women. DESIGN: Systematic review of the English literature was conducted. All studies that addressed the association between hormone replacement therapy and gallbladder disease published from 1970 to the present were reviewed. RESULTS: Seven observational studies, two clinical trials, two case series, and one nonrandomized and three randomized investigations were reviewed. The results of each study were reported and analyzed. CONCLUSIONS: Estrogen replacement therapy in postmenopausal women increased the chances for gallstone formation.     

EMAS position statement: Managing menopausal women with a personal or family history of VTE

Introduction

Venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE), is a serious cardiovascular event whose incidence rises with increasing age.

Aims

To formulate a position statement on the management of the menopause in women with a personal or family history of VTE.

Material and methods

Literature review and consensus of expert opinion.

Results and conclusions

Randomized controlled trials have shown an increased risk of VTE in oral hormone therapy (HT) users. There are no randomized trial data on the effect of transdermal estrogen on VTE. Recent observational studies and meta-analyses suggest that transdermal estrogen does not increase VTE risk. These clinical observations are supported by experimental data showing that transdermal estrogen has a minimal effect on hepatic metabolism of hemostatic proteins as the portal circulation is bypassed. A personal or family history of VTE, especially in individuals with a prothrombotic mutation, is a strong contraindication to oral HT but transdermal estrogen can be considered after careful individual evaluation of the benefits and risks. Transdermal estrogen should be also the first choice in overweight/obese women requiring HT. Observational studies suggest that micronized progesterone and dydrogesterone might have a better risk profile than other progestins with regard to VTE risk. Although these findings should be confirmed by randomized clinical trials, they strongly suggest that both the route of estrogen administration and the type of progestin may be important determinants of the overall benefit-risk profile of HT.     

Health behaviors and other characteristics of women on hormone therapy: results from the Third National Health and Nutrition Examination Survey, 1988-1994

OBJECTIVE: To examine the prevalence of hormone therapy (HT) use and compare demographic characteristics, health behaviors, and health indicators between current HT users and never-users in a nationally representative sample of postmenopausal women. DESIGN: The Third National Health and Nutrition Examination Survey was a cross-sectional survey conducted between 1988 and 1994, including 3,673 postmenopausal women aged 40 years and older. RESULTS: Overall, 419 (11.4%) of the women reported current HT use, 857 (23.3%) reported past use, and 2,397 (65.3%) were never-users. Non-Hispanic black women and women aged 70 years or older were less likely to be current users. Higher socioeconomic status (education and income) and surgical menopause were associated with increased odds of current hormone use. After adjusting for the above variables, women who reported being inactive during leisure time and obese women (body mass index >or= 30) were less likely to be current users. Women who had 5 to 29 alcoholic drinks per month, perceived their health status as "good," took a multiple vitamin, were aware of having high blood cholesterol, and had a clinic for regular medical care were more likely to be current users. Smoking habits were not significantly different between the groups. CONCLUSIONS: Current HT users have different demographic profiles and may lead healthier lives than never-users. This is important to take into account when studying the effects of HT, and it may partly explain differences in findings regarding the health effects of HT use in observational studies compared with randomized clinical trials.     

Controversies about HRT--lessons from monkey models

Lessons from monkey models contribute significantly to a better understanding of the controversies in reconciling the differences in postmenopausal hormone treatment outcomes between observational and randomized trial data. Monkey studies brought attention to premenopausal estrogen deficiency with resulting premature coronary artery atherosclerosis. Recently, those monkey studies were confirmed for premenopausal women in the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE) Study. Monkey studies have provided convincing evidence for the primary prevention of coronary artery atherosclerosis when estrogens are administered soon after the development of estrogen deficiency. Equally convincing are the data from monkey studies indicating the total loss of these estrogens beneficial effects if treatment is delayed for a period equal to six postmenopausal years for women. An attempt has been made using the monkey model to identify the hormone treatment regimen most effective in preventing the progression of coronary artery atherosclerosis. By a substantial margin, the most effective approach is that of using estrogen containing oral contraceptive during the perimenopausal transition, followed directly by hormone replacement therapy postmenopausally. Because of similarities between human and nonhuman breast, monkeys have had a major role in clarifying controversies surrounding the breast cancer risk of estrogen only versus estrogen plus progestin therapies. The results of monkey studies suggest little or no effects of estrogen only treatment; whereas, estrogen+progestin clearly increases breast cancer risk.     

Recent reversal of trends in hormone therapy use in a European population

OBJECTIVE: The impact of the Women's Health Initiative (WHI) randomized trial results published in July 2002 indicating that hormone therapy (HT) is potentially harmful for the heart and the mammary gland of naturally postmenopausal women was assessed for the first time in a European population. DESIGN: This study continuously monitored HT use from 1994 through 2003 in a population-based random sample of 5,758 women aged 35 to 74 years residing in Geneva (city and canton), Switzerland, yielding 1,938 naturally postmenopausal women with an intact uterus and 206 artificially postmenopausal women. Women in the former subgroup weighed substantially less than their WHI trial counterparts but were not otherwise at lower risk for cardiovascular disease. RESULTS: Among the naturally postmenopausal women with an intact uterus, current HT use increased from 29% to 46% (P < 0.0001) through July 2002 and then decreased abruptly to 31% in 2003. Current HT use remained stable (range, 38%-46%; trend P = 0.92) among the artificially postmenopausal women. CONCLUSIONS: Successive annual increases from 1994 through 2001 in the prevalence of current HT use by postmenopausal women living in Geneva were dramatically reversed to the level in 1994 just after the results of the WHI trial were published, but only for naturally postmenopausal women with an intact uterus. Approximately one in three of the latter women who stopped using HT may also have lost its beneficial effects on bone health.     

The effect of hormone therapy on the risk for age-related maculopathy in postmenopausal women

OBJECTIVE: To evaluate the effect of postmenopausal hormone therapy (HT) as well as the use of oral contraceptives and lifetime endogenous hormone exposure on the risk for age-related maculopathy (ARM) in postmenopausal women. DESIGN: This was a cross-sectional, controlled study. A total of 102 women from 60 to 80 years of age who were receiving HT and 100 controls underwent a detailed clinical funduscopic evaluation and stereoscopic fundus photography for the presence and grading of ARM. All participants completed a standardized questionnaire regarding vascular risk factors, HT, and lifetime exogenous and endogenous estrogen and progesterone exposure. Statistical analysis was performed using Student's t test, chi2 test, and a multivariate logistic regression model. RESULTS: The HT and the non-HT groups did not differ in terms of early (11% v 15%), late (6% v 6%), or wet (2% v 2%) ARM prevalence rates. Women with ARM were significantly older than controls (69 v 66 years; P = 0.001, 95% CI = 0.008 - 0.027) and were more likely to have ischemic heart disease (21% v 9%; OR = 2.86, P = 0.03, 95% CI = 0.020 - 0.360). Lifetime exogenous and endogenous hormone exposures and other cardiovascular risk factors were not significantly different among women with ARM as compared with controls. CONCLUSION: Postmenopausal HT may not affect the risk for either early or late ARM in women aged 60 to 80 years. The risk for both entities is not necessarily affected by either exogenous or endogenous lifetime hormone exposure. A history of ischemic heart disease may be associated with an increased risk for ARM.     

Effects of estrogen and opioid blockade on blood pressure reactivity to stress in postmenopausal women

Estrogen may influence coronary heart disease risk in women through the effects of endogenous opioids on autonomic control of blood pressure. In a randomized, placebo-controlled trial, we examined the combined effects of estrogen and the opioid antagonist, naltrexone, on blood pressure responses to psychological stress in 42 postmenopausal women. After 3 months of estrogen or estrogen plus progestin (hormone replacement therapy; n = 27) or placebo replacement, participants completed a mental arithmetic task after administration of .7 mg/kg oral naltrexone or placebo. Systolic blood pressure (SBP), diastolic blood pressure, mean arterial pressure and heart rate (HR) were measured at rest and during the arithmetic stressor. Stress produced significant increases in circulatory measures regardless of estrogen condition or opioid blockade (p’s < .001). Interestingly, there was an estrogen by naltrexone interaction on SBP reactivity scores [F(1,38) = 4.36, p < .05], where women on estrogen with intact opioid receptors showed the largest SBP responses to stress, compared with all other conditions. This is consistent with some studies of premenopausal women, suggesting that estrogens may alter opioid function during stress. The interaction between estrogen and endogenous opioids may explain sex differences in opioid effects on stress reactivity in younger premenopausal women.     

B-type natriuretic peptide after hormone therapy in postmenopausal women with chest pain and normal coronary angiogram

OBJECTIVES: Coronary heart disease is relatively uncommon in premenopausal women but shows a sharp increase after menopause. The decline of endogenous ovarian hormones is commonly assumed to be a major component of this phenomenon. The effects of estrogens on the vasculature have been investigated extensively in previous studies. However, the effects of estrogens on myocardial function have not been evaluated in humans. We sought to examine the effects of hormone therapy (HT) on myocardial function and cardiac natriuretic peptides in postmenopausal women with chest pain and a normal coronary angiogram. DESIGN: Transdermal HT (estradiol: 0.72 mg/2 d) was administered to 15 postmenopausal women with chest pain and a normal coronary angiogram (mean age, 53 y) for 12 weeks, and oral HT (conjugated equine estrogens: 0.625 mg/d) was administered to another 15 postmenopausal women (mean age, 54 y) for 12 weeks. Echocardiography or cardiac catheterization showed no cardiac dysfunction in any woman at baseline. Cardiac function was evaluated by echocardiography, and plasma B-type natriuretic peptide was measured every 4 weeks. RESULTS: B-type natriuretic peptide levels increased after transdermal HT (baseline: 13.1 +/- 3.1, 4 wk: 22.1 +/- 2.9, 8 wk: 33.2 +/- 3.1, 12 wk: 38.4 +/- 3.3 pg/mL; P < 0.01 vs baseline). The levels were also augmented after oral HT (baseline: 14.1 +/- 3.8, 4 wk: 23.2 +/- 3.3, 8 wk: 35.6 +/- 3.9, 12 wk: 39.6 +/- 3.5 pg/mL; P < 0.01 vs baseline). Serial echocardiography showed no changes in ventricular function in either treatment group. At baseline the serum estradiol levels in the transdermal group were comparable with those in the oral group. CONCLUSIONS: The estradiol levels after HT increased in both groups, but there was no significant difference between the two groups. B-type natriuretic peptide levels increased without cardiac dysfunction, and the chest symptoms were relieved in some participants after HT. Thus, estrogen supplementation augments natriuretic peptide levels without harmful effects on ventricular function.     

Potential age-dependent effects of estrogen on neural injury

In 2000, approximately 10 million women were receiving hormone replacement therapy (HRT) for alleviation of menopausal symptoms. A number of prior animal studies suggested that HRT may be neuroprotective and cardioprotective. Then, in 2003, reports from the Women's Health Initiative (WHI) indicated that long-term estrogen/progestin supplementation led to increased incidence of stroke. A second branch of the WHI in women with prior hysterectomy found an even stronger correlation between estrogen supplementation alone and stroke incidence. Follow-up analyses of the data, as well as data from other smaller clinical trials, have also demonstrated increased stroke severity in women receiving HRT or estrogen alone. This review examines the studies indicating that estrogen is neuroprotectant in animal models and explores potential reasons why this may not be true in postmenopausal women. Specifically, age-related differences in estrogen receptors and estrogenic actions in the brain are discussed, with the conclusion that animal models of disease must closely mimic human disease to produce clinically relevant results.     

Concurrent administration of sustained-release bezafibrate may counteract the increased thrombotic risk associated with oral estrogen therapy.

Although hormone replacement therapy (HRT) can have many favorable effects on serum lipids and on vascular endothelium that presumably mediate the decreased risk for heart attack and stroke associated with HRT in observational epidemiology, oral estrogen also has various pro-coagulant effects: increases in serum triglycerides and factor VII activity, decreases in serum antithrombin III and protein S. This may explain the increased risk for venous thromboembolism observed with HRT and oral contraceptives, as well as the temporary increase in coronary risk noted when women with preexisting coronary disease initiate HRT. The well-tolerated hypolipidemic agent bezafibrate has anticoagulant actions that are diametrically opposed to the procoagulant effects of oral estrogen: namely, reductions in serum triglycerides and factor VII activity, and an increase in antithrombin III. However, bezafibrate could be expected to complement the protective effects of oral estrogen on serum lipids and on serum IGF-I activity. Thus, there is reason to believe that concurrent bezafibrate administration would minimize any thrombotic risk associated with HRT or oral contraception, while amplifying the health benefits of oral estrogen, and would make it more feasible to administer these therapies in women at increased vascular risk. These predictions require confirmation in controlled clinical studies. Certain natural hypolipidemic agents may also have potential as adjuvants to oral estrogen, but their effects on hemostasis require further investigation.