Current perspectives on the benefits of HRT in menopausal women

AIMS: Women in the West can now expect to live one third of their life in a postmenopausal state, and consequently in a state of estrogen deficiency. This can have a number of consequences, and many women suffer vasomotor symptoms during the climacteric. Estrogen deficiency can also result in changes to the skin, hair, urogenital, cardiovascular and skeletal systems. This article reviews some of the main actions of replacement estrogen in postmenopausal women, and discusses the major benefits of estrogen replacement therapy (ERT) and hormone replacement therapy (HRT). REVIEW: HRT is well documented to reduce vasomotor symptoms in women suffering from estrogen deficiency, and can have beneficial effects on the skin and the prevention of skin aging. HRT has beneficial effects on urogenitary function including reductions in urinary incontinence and vaginal atrophy. HRT is used as a first-line treatment to prevent or reverse the development of postmenopausal osteoporosis and can reduce the risk of fractures if taken for 5-10 years from the menopause. In epidemiological studies, ERT was associated with a reduction in the risk of coronary heart disease. Estrogens seem to affect the cardiovascular system directly and indirectly such as reducing some of the coronary risk factors. In recent years, estrogen has been linked to beneficial effects in the CNS including an association with a reduction in the risk of developing Alzheimer's Disease. Despite these benefits, HRT compliance remains low, and physicians need to address this if patients are to gain the benefits.     

Metabolic and vascular effect of progestins in post-menopausal women. Implications for cardioprotection

Estrogen therapy causes changes in a variety of cardiovascular risk factors, including insulin resistance, lipoprotein profile, haemostasis, coronary atherosclerosis and vascular reactive, that suggest a potential cardioprotective effect in postmenopausal women. With respect to the role of adjunctive progestins, currently available data suggest that the cardiovascular effects may differ depending on the type, dosage and route of administration of the progestin. Androgenic progestins antagonise the favourable cardiovascular effect of estrogens, whilst non-androgenic progestins do not impair, or may even enhance, the beneficial effect of estrogens. Therefore, less androgenic progestins would appear to be the agent of choice for combined hormone therapy in postmenopausal women with cardiovascular risk factors.     

Postmenopausal hormone therapy: new questions and the case for new clinical trials

Observational studies suggest that postmenopausal hormone therapy (HT) prevents coronary heart disease, whereas randomized clinical trials have not confirmed a cardioprotective effect. Although observational studies may have overestimated the coronary benefit conferred by postmenopausal hormone use, there are other plausible explanations for the apparent discrepancy between previous results and the less favorable findings from clinical trials such as the large Women's Health Initiative. There is now a critical mass of data to support the hypothesis that age or time since menopause may importantly influence the benefit-risk ratio associated with HT, especially with respect to cardiovascular outcomes, and that the method of administration, dose, and formulation of exogenous hormones may also be relevant. Although the weight of the evidence indicates that older women and those with subclinical or overt coronary heart disease should not take HT, estrogen remains the most effective treatment currently available for vasomotor symptoms, and its effects on the development of coronary disease in newly postmenopausal women remain unclear. Moreover, effects of HT on quality of life and cognitive function in recently postmenopausal women merit further study. These unresolved clinical issues provide the rationale for the design of the Kronos Early Estrogen Prevention Study, a 5-year randomized trial that will evaluate the effectiveness of low-dose oral estrogen and transdermal estradiol in preventing progression of atherosclerosis in recently postmenopausal women.     

Hormone replacement therapy and risk for coronary heart disease. Data from the CORA-study--a case-control study on women with incident coronary heart disease

BACKGROUND: Hormone replacement therapy (HRT) has been suggested to prevent cardiovascular disease, while some intervention studies have shed doubt on this concept. Thus, uncertainty remains whether current HRT use is beneficial as to cardiovascular disease or may even be harmful. OBJECTIVES: This research investigates the association of hormone replacement therapy, risk factors and lifestyle characteristics with the manifestation of coronary heart disease in current HRT users versus never users. DESIGN: The coronary risk factors for atherosclerosis in women study (CORA-study) provide clinical and biochemical parameters and data on lifestyle in 200 consecutive pre- and postmenopausal women with incident coronary heart disease compared to 255 age-matched population-based controls, of which 87.9% were postmenopausal. RESULTS: Significantly more controls than cases used currently HRT for a median of 9.5 years (32.9% versus 20.2%), while 50.0% of cases and 42.5% of controls had never used HRT (p<0.02). Compared to women who never used HRT, current users ate less meat and sausage, had a significantly lower BMI and waist-to-hip ratio and a lower prevalence of hypertension, insulin resistance and diabetes. However, current users among cases were often smokers and smoked significantly more cigarettes than never users. In a multivariate analysis the risk of current HRT users for coronary artery disease was 57% lower than the risk of never users (odds ratio 0.428, CI 0.206-0.860, p<0.02). Adjustment for conventional and dietary risk factors revealed neither current HRT use, nor HRT use combined with smoking as independent risk factors. CONCLUSIONS: These data from the CORA-study are not compatible with an adverse impact of hormone replacement therapy on cardiovascular disease, rather support the notion of beneficial effects of HRT on weight, central adiposity, insulin sensitivity and blood pressure. Yet, the data do not support the presumption of a general healthy user effect in women on HRT either. Rather, in some women adverse lifestyle habits, especially intense smoking, appear to counteract possible beneficial effects of HRT.     

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.     

Association of cardiovascular risk factors with intima-media thickness of the carotid arteries in early postmenopausal women

OBJECTIVE: The aim of this study was to examine the association between carotid intima-media thickness (IMT) and coronary heart diseases (CHD) risk factors in a large population of peri- and postmenopausal women. DESIGN: Participants in this study were 906 healthy peri- and postmenopausal women from southwestern France, 45 to 65 years old with no history of cardiovascular disease and no utilization of estrogen/hormone therapy. Women were classified either as perimenopausal (n = 240) or post-menopausal (n = 666) according both to the regularity of menses and to serum follicle-stimulating hormone and estradiol values. All women answered a questionnaire, which included 72 questions, related to the identification of familial and personal cardiovascular risk factors. Biological measurements were performed to evaluate their lipid-lipoprotein profiles and fasting glucose levels, ultrasonography was used to measure IMT and total body scanners by DXA were performed to determine the percentage of body fat. RESULTS: Multiple regression analyses were used to examine the ability of each variable to explain IMT values. Mean IMT of the right carotid artery was 0.520 (+/- 0.07) mm. Of the 906 women, 9% were currently taking lipid-lowering drugs, 12.8% and less than 2% were being treated for hypertension and diabetes, respectively. Additionally, 124 women were found to have current hypertension, 10% had a familial history of CHD, and 18% were regular smokers. In multiple regression analyses, only increasing age (P < 0.001) and systolic and diastolic blood pressure (P < 0.001) were independently and significantly associated with IMT. CONCLUSIONS: These results show that only a few risk factors were associated with IMT in this population of healthy peri- and postmenopausal women. These results might be related to the fact that this study was conducted in an area of France well known for having the lowest rates of CHD in women, which is further supported by the thinner IMT found in this population as compared with a higher-risk population. Therefore, these results might not be relevant for CHD in older or high-risk women.     

Different mechanisms for benefit and risk of coronary heart disease and stroke in early postmenopausal women: a hypothetical explanation

In younger postmenopausal women, estrogen is thought to be protective against coronary heart disease. The mechanism for this effect is likely to be an inhibition of the development of atherosclerosis. However, in older postmenopausal women with established atherosclerosis, the initiation of estrogen therapy may cause coronary artery plaque instability and rupture, resulting in coronary thrombosis and myocardial infarction. Compared with these findings of coronary disease prevention in younger women, estrogen therapy has been linked to an increased risk of ischemic stroke in both younger and older postmenopausal women, although the risk is small and the event rate in younger women is considered to be rare. Here, we provide an argument that the mechanism for stroke risk in younger women is not based on atherosclerotic disease, as occurs in older women for both coronary disease and stroke, but is related to thrombosis. Susceptibility for stroke is increased in women, and various factors leading to thrombosis may explain this risk. This notion is supported by data that estrogen regimens that decrease the risk of venous thrombosis (lower oral doses and transdermal therapy) may not be associated with an increase in ischemic stroke risk.     

强化降脂治疗的临床应用和意义

针对心血管高危人群我们应进行强化降脂治疗,使低密度脂蛋白-胆固醇(LDL-C)降至2.6 mmol/L或<1.8 mmol/L。这种治疗措施能阻断或逆转动脉粥样硬化病变进展,有助于防治急性冠脉综合征。提倡强化降脂治疗,能使更多的冠心病及其高危者受益。     

雌激素防治骨质疏松症的研究进展

１９４１年Ａｌｂｒｉｇｈｔ首先提出绝经与骨质疏松之间的关系，５０多年来，大量的临床与实验研究证实，雌激素缺乏是绝经后骨质疏松的重要发病因素。低雌激素状态或绝经后补充雌激素，可以预防雌激素低下引起的骨丢失，并对绝经后的多种改变有防治作用，例如绝经后症状...     

A woman's journey through the reproductive, transitional and postmenopausal periods of life: impact on cardiovascular and musculo-skeletal risk and the role of estrogen replacement

Sex hormones are fundamental for female development and they are important physiologically to maintain the health and normal functioning of several organs such as the brain, heart and bone. It is now clear that the hormonal changes that occur during a woman's life, particularly her estrogen status, can modulate disease activity. This is especially true for cardiovascular and musculo-skeletal diseases, which are two leading causes of morbidity and mortality in women. With the general aging of the population they represent a serious and growing public health concern.Estrogen synthesis and blood levels fluctuate during a woman's life and in this review three broad periods will be considered: reproductive phase, transition and postmenopausal phase. Generally speaking, women in the reproductive phase of their life are at low risk of cardiovascular and musculo-skeletal disorders. However, the onset of menopause and the loss of ovarian function is associated with a significant increase in the prevalence of diseases such as coronary heart disease, osteoarthritis and osteoporosis. The prevalence of these debilitating diseases continues to increase through the postmenopausal period. Estrogen replacement is an obvious treatment approach to counter the problems associated with the loss of ovarian function and subsequent estrogen deficiency. Overall, oral and transdermal estrogen replacement are similarly effective in relieving menopausal symptoms and disorders that manifest during this period of a woman's life. Transdermal estrogen may be preferable in older women because of its lower thrombogenic potential.In this journey through a woman's life current best evidence relating to cardiovascular and musculo-skeletal risk will be reviewed in line with well documented management strategies.     

Risk factors for coronary heart disease: a study in inner London.

A survey was carried out among 281 men and women aged between 30 and 64 years randomly selected from five general practices located in the inner London borough of Tower Hamlets, to determine the prevalence of risk factors for coronary heart disease. Smoking and obesity were both more pronounced in Tower Hamlets than in comparable national studies: 51% of men and 44% of women were smokers and 57% of these were smoking 20 or more cigarettes per day. A body mass index of 30 or more was present in 18% of men and 10% of women and a body mass index of 25 or more in 71% of men and 49% of women. Two or more risk factors for coronary heart disease (smoking and/or hypertension and/or raised cholesterol levels) were present in 25% of men and 22% of women. For every person known by their general practitioner to have established cardiovascular disease, there were an additional two people also at risk on the basis of multiple risk factors. In this inner city population the prevalence of cardiovascular risk, for women as well as men, has major resource and organizational implications for primary care. A strategy for change requires action based on graded multiple risks for both men and women.     

Postmenopausal estrogen therapy and cardiovascular disease. Ten-year follow-up from the nurses' health study

BACKGROUND. The effect of postmenopausal estrogen therapy on the risk of cardiovascular disease remains controversial. Our 1985 report in the Journal, based on four years of follow-up, suggested that estrogen therapy reduced the risk of coronary heart disease, but a report published simultaneously from the Framingham Study suggested that the risk was increased. In addition, studies of the effect of estrogens on stroke have yielded conflicting results. METHODS. We followed 48,470 postmenopausal women, 30 to 63 years old, who were participants in the Nurses' Health Study, and who did not have a history of cancer or cardiovascular disease at base line. During up to 10 years of follow-up (337,854 person-years), we documented 224 strokes, 405 cases of major coronary disease (nonfatal myocardial infarctions or deaths from coronary causes), and 1263 deaths from all causes. RESULTS. After adjustment for age and other risk factors, the overall relative risk of major coronary disease in women currently taking estrogen was 0.56 (95 percent confidence interval, 0.40 to 0.80); the risk was significantly reduced among women with either natural or surgical menopause. We observed no effect of the duration of estrogen use independent of age. The findings were similar in analyses limited to women who had recently visited their physicians (relative risk, 0.45; 95 percent confidence interval, 0.31 to 0.66) and in a low-risk group that excluded women reporting current cigarette smoking, diabetes, hypertension, hypercholesterolemia, or a Quetelet index above the 90th percentile (relative risk, 0.53; 95 percent confidence interval, 0.31 to 0.91). The relative risk for current and former users of estrogen as compared with those who had never used it was 0.89 (95 percent confidence interval, 0.78 to 1.00) for total mortality and 0.72 (95 percent confidence interval, 0.55 to 0.95) for mortality from cardiovascular disease. The relative risk of stroke when current users were compared with those who had never used estrogen was 0.97 (95 percent confidence interval, 0.65 to 1.45), with no marked differences according to type of stroke. CONCLUSIONS. Current estrogen use is associated with a reduction in the incidence of coronary heart disease as well as in mortality from cardiovascular disease, but it is not associated with any change in the risk of stroke.     

Readiness for lifestyle advice: self-assessments of coronary risk prior to screening in the British family heart study. Family Heart Study Group.

BACKGROUND. Where health professionals and patients hold similar views of a problem, health outcomes may be better. AIM. The aims of this paper were to document how attenders at primary care cardiovascular screening clinics perceived their risks of coronary heart disease prior to screening; the degree of similarity between perceived level of risk and an epidemiologically derived risk score; and the relative importance assigned to individual risk factors by subjects compared with those assigned by the risk score. METHOD: These issues were investigated in 3725 middle aged men and women who accepted an invitation to attend health screening as part of the British family heart study. RESULTS. Overall, there was a tendency for subjects to be optimistic (37%) rather than pessimistic (21%) when judging their risk of coronary heart disease. Nevertheless, there were strong significant associations between perceived risk and the levels of individual risk factors, particularly personal and family medical history and body mass index. There was also a strong association with the overall risk score though a large minority (31%) held views of their risk of coronary heart disease that were quite different from those based upon the epidemiologically derived index of risk. Respondents accorded greater importance to smoking and parental death from coronary heart disease and less importance to cholesterol level and blood pressure than did the risk score. CONCLUSION. Possible explanations for the observed disagreement are over-optimism or the relative importance given to individual risk factors. The relationships between patients' perceptions of risk and the epidemiological indices likely to be espoused by health professionals are important in understanding the difficulties in communication that might arise in offering lifestyle advice after screening for cardiovascular risk.     

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.     

Peripheral arterial disease in women

Peripheral arterial disease (PAD) is chronic arterial occlusive disease of the lower extremities caused by atherosclerosis whose prevalence increases with age. Only one-half of women with PAD are symptomatic. Symptomatic and asymptomatic women with PAD are at increased risk for all-cause mortality, cardiovascular mortality, and mortality from coronary artery disease. Modifiable risk factors that predispose women to PAD include active cigarette smoking, passive smoking, diabetes mellitus, hypertension, dyslipidemia, increased plasma homocysteine levels and hypothyroidism. With regard to management, women who smoke should be encouraged to quit and referred to a smoking cessation program. Hypertension, diabetes mellitus, dyslipidemia, and hypothyroidism require treatment. Statins reduce the incidence of intermittent claudication and improve exercise duration until the onset of intermittent claudication in women with PAD and hypercholesterolemia. Anti-platelet drugs such as aspirin or especially clopidogrel, angiotensin-converting enzyme inhibitors and statins should be given to all women with PAD. Beta blockers are recommended if coronary artery disease is present. Exercise rehabilitation programs and cilostazol increase exercise time until intermittent claudication develops. Chelation therapy should be avoided as it is ineffective. Indications for lower extremity percutaneous transluminal angioplasty or bypass surgery in women are (1) incapacitating claudication interfering with work or lifestyle; and (2) limb salvage in women with limb-threatening ischemia as manifested by rest pain, non-healing ulcers, and/or infection or gangrene. Future research includes investigation of mechanisms underlying why women have a higher risk of graft failure and major amputation.     

Clinical commentary: Reaching new targets in monotherapy and combination therapy

Cardiovascular disease remains the most common cause of death in the United States. There has, however, been a decline in the age-adjusted death rate for coronary heart disease. This decline may be due, in part, to more aggressive treatment guidelines for treating cardiovascular risk factors, such as hypertension, diabetes, and dyslipidemia. The 2004 update to the National Cholesterol Education Program guidelines have recommended lower low-density lipoprotein cholesterol goals in high-risk patients. Based on the new targets for low-density lipoprotein cholesterol, clinicians will need more efficacious lipid-lowering therapies and improved options for combination therapy. Statin and statin-based combinations have been the mainstays of therapy during the last several years, and as statin utilization increases in the United States, more high-risk patients become exposed to potential statin intolerance. This commentary reviews statin-sparing combinations and use of cholesterol-absorption inhibitors.     

The C677T methylenetetrahydrofolate reductase polymorphism influences the homocysteine-lowering effect of hormone replacement therapy.

Elevated homocysteine is an independent risk factor for cardiovascular disease and has been associated with a common C677T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene. Estrogen use has been shown to reduce homocysteine concentrations, suggesting that this might contribute to the cardiovascular benefit of hormone replacement therapy. We examined 90 postmenopausal women to determine if MTHFR genotype affected the response of homocysteine to hormone replacement therapy. Women with the TT genotype did not show decreased homocysteine in response to hormone replacement therapy as demonstrated for women with the CC genotype and may receive decreased cardiovascular benefits from hormone replacement therapy.     

The cost-effectiveness of lipid lowering in patients with ischaemic heart disease: an intervention and evaluation in primary care.

BACKGROUND: There has been a major revolution in the recommended treatment of hyperlipidaemia in patients with ischaemic heart disease following the publication of the Scandinavian Simvastatin Survival Study. This was the first major study to demonstrate that lipid-lowering drugs reduced mortality and morbidity in patients with ischaemic heart disease. AIM: To evaluate the feasibility and cost-effectiveness of screening and treating hyperlipidaemia in patients with ischaemic heart disease in primary care. METHOD: A study conducted in a rural dispensing training practice on the border of Nottinghamshire and Lincolnshire involving 327 patients with ischaemic heart disease who were registered with the practice on 1 January 1996. RESULTS: Eighty per cent of patients with ischaemic heart disease were considered eligible for screening and 80% of those attended for screening. The majority of patients who were screened had hyperlipidaemia that persisted after dietary advice. Despite lipid-lowering drugs, few patients had serum lipid concentrations in the target range at the end of six months. The costs of identifying and treating 83 patients with lipid-lowering drugs over five years is estimated at 105,318 Pounds at 1996 prices, or 94,257 Pounds assuming a 6% discount rate per annum. Two-thirds of this is owing to the cost of lipid-lowering drugs. The discounted cost per coronary event prevented would be 17,138 Pounds (95% CI = 12,568 Pounds-26,183 Pounds). The discounted cost per coronary death prevented would be 32,502 Pounds (95% CI = 23,564 Pounds-55,445 Pounds). There were no important adverse effects of lipid-lowering drugs on quality of life or mood. CONCLUSION: Such a programme is feasible and acceptable within primary care, although the ongoing cost implications need to be considered against the costs and benefits of other interventions.     

A clinical trial of estrogen-replacement therapy after ischemic stroke.

BACKGROUND: Observational studies have suggested that estrogen-replacement therapy may reduce a woman's risk of stroke and death. METHODS: We conducted a randomized, double-blind, placebo-controlled trial of estrogen therapy (1 mg of estradiol-17beta per day) in 664 postmenopausal women (mean age, 71 years) who had recently had an ischemic stroke or transient ischemic attack. Women were recruited from 21 hospitals in the United States and were followed for the occurrence of stroke or death. RESULTS: During a mean follow-up period of 2.8 years, there were 99 strokes or deaths among the women in the estradiol group, and 93 among those in the placebo group (relative risk in the estradiol group, 1.1; 95 percent confidence interval, 0.8 to 1.4). Estrogen therapy did not reduce the risk of death alone (relative risk, 1.2; 95 percent confidence interval, 0.8 to 1.8) or the risk of nonfatal stroke (relative risk, 1.0; 95 percent confidence interval, 0.7 to 1.4). The women who were randomly assigned to receive estrogen therapy had a higher risk of fatal stroke (relative risk, 2.9; 95 percent confidence interval, 0.9 to 9.0), and their nonfatal strokes were associated with slightly worse neurologic and functional deficits. CONCLUSIONS: Estradiol does not reduce mortality orthe recurrence of stroke in postmenopausal women with cerebrovascular disease. This therapy should not be prescribed for the secondary prevention of cerebrovascular disease.