Hormone therapy and cardiovascular disease

As in other Western countries, cardiovascular disease (CVD) is the leading cause of death among women in Taiwan, exceeding the mortality from cervical or breast cancer. Women generally present with CVD after menopause and later than men, since menopause-related estrogen deficiency has been considered to be associated with an increased risk for CVD. Thus, coronary artery diseases and stroke are the two main contributors of mortality among postmenopausal women. Observational studies have reported a reduction in coronary artery disease risk after hormone therapy (HT) ranging from 31-44%. However, recent randomized controlled trials that evaluated the effect of HT on primary and secondary CVD prevention have questioned the efficacy of HT, despite confirming the lipid-lowering effect of estrogen. However, a cluster of factors are responsible for the genesis and progression of CVD. Until we further evaluate their specific actions and how these different factors interact, the issue related to HT and cardiovascular risk will remain unsettled. Since these studies have contributed to our understanding of the benefits and risks associated with HT, HT use should be individualized after consideration of the condition of each postmenopausal patient. Ideally, the efficacy of different preparations and dosages of HT in postmenopausal women who are at risk of CVD, before atheromatous lesions have developed, should be investigated.     

绝经期雌激素治疗与心血管健康

心血管疾病是妇女的首位死亡原因。其发生与众多危险因素有关。高血压是最重要、可纠正的危险因素。绝经后高血压和动脉粥样硬化性心血管疾病的患病率增高。现有证据提示绝经后早期启用雌激素治疗,对心血管系统有保护作用。妇科医生处理因绝经症状而就医的中年妇女时,应广泛关注妇女的整体健康,尤其是心血管健康。     

同型半胱氨酸在绝经后女性心血管疾病中的研究进展

绝经意味着女性卵巢功能衰竭,性激素水平改变导致女性出现一系列绝经相关症状,近期可出现血管舒缩症状如潮热、盗汗,神经精神症状等,远期危害可出现心血管疾病(cardiovascular disease,CVD)、骨质疏松、糖脂代谢紊乱、泌尿生殖道萎缩等全身各器官系统退行性病变.绝经后女性CVD发病风险升高,是中老年女性致死...     

Cardiovascular disease as a current threat of older women. Relation to estrogens

Cardiovascular disease (CVD) is the leading cause of death in women around the world. Cardiovascular disease risk increases after the menopause which may be related to metabolic and hormonal changes. The decline in ovarian function with menopause is associated with spontaneous increases in proinflammatory cytokines. Chronic inflammation is a major factor that drives the progression of atherosclerosis and atherothrombosis. Measurement of the inflammatory markers has been postulated as a method of determining increased risk of cardiovascular disease in apparently healthy older women. Endogenous estrogen appears to be cardioprotective and several observational epidemiological studies have suggested that hormone therapy reduces the risk of coronary events in healthy postmenopausal women. However, recent clinical studies failed to show such beneficial effect. Among the mechanism that may account for the effects of hormone therapy on cardiovascular disease is inflammation.     

Androgenkonzentrationen und kardiovaskuläre Risiken bei der Frau

Low testosterone concentrations in men are associated with a higher cardiovascular risk factor burden. Also in women, cardiovascular risk increases after menopause. The aim of this work was to analyze potential associations between androgen concentrations in women and cardiovascular risk factors, including clinical correlates and sleep, metabolic syndrome (MetS), type 2 diabetes mellitus (T2DM), as well as subclinical and clinical cardiovascular disease (CVD) and mortality. Data from 2000 women of the population-based, longitudinal Study of Health in Pomerania (SHIP) and multivariable regression models were analyzed. Cardiovascular risk factors including obesity, hypertension, dyslipidemia, and poor sleep quality were associated with androgen concentration. Furthermore, cross-sectional and long-term analyses yielded inverse associations between sex hormone-binding globulin (SHBG) and MetS as well as T2DM. No independent, significant associations between androgen concentrations and incidence of CVD, CVD mortality, or all-cause mortality were detected. In this epidemiological study, clinical correlates of androgens in women and associations between androgens and sleep were identified. Associations between androgens, subclinical CVD, and mortality confirmed the relative impact of cofactors. SHBG might represent a potential biomarker for cardiovascular risk factors, especially among postmenopausal women.     

Niedrigdosierte transdermale ?stradiol-Antiandrogen-Therapie

The vicious circle of increased body weight (BW), relative hyperandrogenemia (HA), dyslipidemia (DL), hypertension (H), insulin resistance (IR) and ultimately type 2 diabetes mellitus (DM) and severe cardiovascular disease (CVD) often affects postmenopausal women (PM). A total of 474 postmenopausal women on low-dose hormone replacement therapy (HRT) were compared to 1,073 premenopausal women receiving no therapy. An oral glucose tolerance test (OGTT) with measurement of insulin (I) and glucose (G) was carried out in women in five different body weight groups. Additionally, parameters of metabolism and other clinical chemistry measurements were carried out. Low-dose HRT can effectively halt this vicious circle. The increase in glucose levels in postmenopausal women is compensated by better insulin sensitivity. The production of insulin was not increased in comparison with premenopausal women and free insulin-like growth factor 1 (IGF-1) was even shown to decrease. The estrogen and androgen values in PM are comparable to that of premenopausal women in the early follicular phase. Controlled, low-dose HRT with bioidentical natural estrogen in combination with low dose antiandrogen can prevent the development of severe common diseases, such as IR and DM and is therefore an important method of primary prevention in postmenopausal women which should be made readily available.     

Aging, menopause, and free radicals

As women undergo menopause, circulating concentrations of estrogen decrease. The relative estrogen deprivation in postmenopausal women is associated with physiological changes and increased risk of several diseases, including cardiovascular disease. Studies in animals have shown that exogenous estrogen inhibits atherosclerosis, the underlying cause of cardiovascular disease. Ongoing clinical trials will soon provide data for the effect of exogenous estrogen on cardiovascular disease in postmenopausal women. Estrogen has a number of effects that could influence atherogenesis and cardiovascular disease. Estrogens have favorable effects on lipoproteins, but such effects can only account for part of the protection from cardiovascular disease that appears to be conferred by estrogen. Evidence suggests that estrogens can have both prooxidant and antioxidant effects. However, the available evidence suggests that in vivo physiological concentrations of estrogen may have a modest antioxidant activity, and prooxidant activity is unlikely. The antioxidant activity of estrogens and inhibition by estrogens of cellular processes that are thought to promote atherosclerosis are likely to be additional mechanism(s) by which estrogen inhibits atherosclerosis and cardiovascular disease, but more work is needed. Studies of some effects of estrogens on atherogenic processes in isolated cells need to be extended to the whole animal. The influence of estrogen receptors on inhibition of atherosclerosis by estrogen needs to be clarified. Future studies should be designed to investigate separately the estrogenic and antioxidant activities of estrogens and estrogen analogs. Investigations of the antioxidant activities of estrogens should include careful consideration of the interaction of estrogens with endogenous antioxidants and fatty acid saturation, and more attention should be paid to the potential for estrogens to inhibit intraarterial oxidation.     

Women and heart disease: missed opportunities

One woman dies of cardiovascular disease (CVD) every minute in the United States. CVD is the primary cause of mortality in US women, substantially affecting the lives of African American women compared to other ethnic groups. In a national survey conducted by the American Heart Association, 87% of women surveyed failed to cite heart disease as a major threat to their health. These misperceptions may lead women to underestimate their risk for CVD, resulting in a delay in seeking medical care, thus increasing their morbidity and mortality rates. Professional association guidelines and Internet resources for women and their health care providers are available to address the risk factors of smoking, diabetes mellitus, obesity, hypertension, hyperlipidemia, and physical inactivity. Unless women are informed and educated about these risk factors, they are unable to modify their lifestyles, be proactive in their health care, or reduce their cardiovascular risks.     

Cardiovascular disease and primary ovarian insufficiency

Cardiovascular disease (CVD) is the number-one killer of women. Women with primary ovarian insufficiency (POI) may be more burdened by cardiovascular disease, such as myocardial infarction and stroke, as compared with women with normal menopause. The increased burden may be mediated by a worsening of cardiovascular risk factors, such as lipids, corresponding with the loss of ovarian function. In contrast, the increased burden may be caused by factors that precede and potentially contribute to both CVD events and ovarian decline, such as X-chromosome abnormalities and smoking. Regardless of the cause, women with POI may serve as an important population to target for CVD screening and prevention strategies. These strategies should include the use of CVD risk stratification tools to identify women that may benefit from lifestyle modification and pharmacological therapy to prevent CVD. Sex steroid therapy for the sole purpose of CVD prevention in women with POI cannot be recommended, based on a lack of evidence.     

Physicians' Knowledge of Future Vascular Disease in Women with Preeclampsia

Objective. Preeclampsia, a hypertensive disorder of pregnancy, affects 5–8% of women. Large studies demonstrate a strong association between preeclampsia and future cardiovascular disease (CVD). Despite CVD being the leading cause of mortality for women, there has been little education for internal medicine physicians or obstetrician-gynecologists (ob-gyns) about this association; published guidelines do not include preeclampsia as a risk factor for future CVD. Therefore, women with a history of preeclampsia may not receive adequate risk-reduction counseling for CVD. It is unclear whether primary care physicians are aware of the association; thus, we sought to determine whether primary care providers at our institution were aware of preeclampsia's association with future CVD and whether they were providing appropriate counseling. Methods. An anonymous online survey was sent to all internists and (ob-gyns) at our hospital. Results. Although most internists (95%) and (ob-gyns) (70%) provide routine cardiovascular risk-reduction counseling, a substantial proportion of them were unaware of any health risk associated with a history of preeclampsia. Many internists were unsure or did not know whether preeclampsia is associated with ischemic heart disease (56%), stroke (48%), and decreased life expectancy (79%). The corresponding proportions for (ob-gyns) were 23, 38, and 77%, respectively. Only 9% of internists and 38% of obstetrician-gynecologists were providing cardiovascular risk-reduction counseling to women with a history of preeclampsia. Conclusion. There is limited knowledge of the association between preeclampsia and future CVD; this deficiency may limit the application of this risk factor to clinical care.     

Update on cardiovascular disease in post-menopausal women

Cardiovascular disease (CVD), and in particular coronary artery heart disease (CAHD), is the leading cause of morbidity and mortality in women. Until recently, most of our knowledge about the pathophysiology of CVD in women - and, subsequently, management guidelines - were based on studies conducted mostly in men. While similar mechanisms operate to induce CVD in women and men, gender-related differences exist in the anatomy and physiology of the myocardium, and sex hormones modify the course of disease in women. Women, more than men, have their initial manifestation of CAHD as angina pectoris; are likely to be referred for diagnostic tests at a more advanced stage of disease, and are less likely than men to have corrective invasive procedures. The overall morbidity and mortality following the initial ischaemic heart event is worse in women, and the case fatality rate is greater in women than in men. Also, the relative impact of impaired vasoreactivity of the coronary artery, increased viscosity of the blood and dysregulation of automaticity and arrhythmia, is greater in women than in men.The most effective means of decreasing the impact of CVD on women's health is by an active approach from childhood to proper principles of healthcare in order to modify the contribution of specific risk factors. The latter include obesity, abnormal plasma lipid profile, hypertension, diabetes mellitus, cigarette smoking, sedentary lifestyle, increased blood viscosity, augmented platelet aggregability, stress and autonomic imbalance. The use of lipid-lowering drugs has not been adequately studied in women but reports from studies conducted mostly in men do predict an advantage also to women. Oestrogen deficiency after spontaneous or medically induced menopause is an important risk factor for CVD and CAHD. Observational and mechanistic data suggest a role for oestrogen replacement after menopause for primary, and possibly secondary, prevention of CVD. However, two recent prospective trials suggest that treatment de novo with hormone replacement of older post-menopausal women after an acute coronary event may not confer cardiovascular protection and may increase the risk of thromboembolic disease. Results of ongoing long-term studies may determine the beneficial role of hormone replacement versus potential risks involved with this treatment.     

Women's cardiovascular health. An official position statement of the Association of Women's Health, Obstetric & Neonatal Nursing

The Association of Women's Health, Obstetric and Neonatal Nurses (AWHONN) maintains that nurses and other clinical professionals should include routine cardiovascular health screening,provide education, and promote awareness at health care visits for women across the lifespan.Advocacy for preventive measures should begin early, and adolescent girls and young women should be encouraged to adopt heart-healthy habits. For adult and senior women, nurses should work to increase patient awareness about risk factors,symptoms and treatment options associated with cardiovascular disease (CVD) and CVD risk.Efforts should extend to women of every age and health status.     

Comparative cardiovascular effects of different progestins in menopause.

Progesterone receptors are present in the arterial wall and it is, therefore, likely that the arterial effects of progestins are mediated through progesterone receptors as well as through down-regulation of the estradiol receptor. Progestin therapy affects arterial function, as it can stabilize arteries in a state of vasomotor instability, but may also induce vasoconstriction of estrogenized vessels. Thus, the cardiovascular effects of progestins may influence the cardioprotective effect of estrogens. There has been some concern that a combined estrogen-progestogen therapy may attenuate some of estrogen's beneficial effects on cardiovascular health. This is a reflection of the past epidemiologic studies which have used primarily unopposed estrogen. The PEPI trial is the only large-scale, long-term study to compare directly the effects of different combined hormone replacement therapy regimens upon plasma lipids in healthy women. This study has shown that the adjunctive clinical impact of different progestogens on the beneficial effect of estrogen replacement therapy is trivial. It has never been proved that in normocholesterolemic women, e.g., those included in the PEPI trial, the increase in HDL reduces cardiovascular mortality or morbidity. Based on the results of PEPI, hormone replacement therapy has positive effects on key heart disease risk factors and endometrial tissue, and the magnitude of those effects does not differ significantly across the hormone replacement therapy regimens used. At present there are only few and inconclusive data available on the vascular effect of progestins in menopausal women. Some studies found that progestins reduced the beneficial effect of estrogens, while others did not. Our group has recently shown that different estrogen-progestin treatments have different effects upon vascular reactivity and that a careful selection of the progestin to be added to estrogen is of capital importance to preserve, or even enhance the positive vascular effects of estrogens. Few epidemiological studies have investigated the effect of adding a progestin to estrogen therapy upon cardiovascular mortality and morbidity, and all have suggested that hormone replacement therapy may be more effective than estrogen replacement alone in reducing cardiovascular events in primary prevention. The results of the recently published Heart and Estrogen/progestin Replacement Study (HERS) have added some critical data on the effect of hormone replacement therapy for secondary prevention in women with coronary artery disease. The study, however, is affected by several important methodological and statistical problems, which make its interpretation difficult and its conclusions useless for clinical practice. The results of the study should be evaluated with caution by physicians who give advice on hormone replacement therapy, and no woman should be taken off hormone replacement therapy because of HERS. Of importance, the results of HERS should not be used to suggest alternative forms of treatment, especially the selective estrogen receptor modulators (SERMs), for cardiovascular protection in postmenopausal women.     

International Session Award. Non-invasive cutaneous cardiovascular dynamics (CVD) as a predictor of preterm delivery: a pilot study

AIM: To assess the clinical value of cardiovascular dynamics (CVD) pattern of 'positive cycling' in predicting true preterm labor. METHODS: Patients with a clinical diagnosis of preterm labor had CVD measurement with a non-invasive miniature pressure transducer applied to the fingertip concomitantly with uterine activity monitoring. Based on previous work by our group, the rapid ejection time (RET) reflects arterial compliance; an elevated RET is suggestive of vasoconstriction. Positive cycling is present when the RET shows elevation with uterine contractions and negative cycling is present when there are no changes in the RET with uterine contractions. RESULTS: Twenty-seven women had negative CVD cycling and nine had positive CVD cycling. There was no difference between the two groups in initial gestational age, cervical effacement or cervical dilation at testing. However, the mean interval from testing to delivery was 1.56 (SEM+/-0.29) days for positive cycling and 39 days (+/-5.25) for negative cycling (P < 0.001). CONCLUSION: Non-invasive cardiovascular patterns of positive cycling appear predictive of preterm delivery.     

Endocannabinoid type 1 receptor gene (CNR1) polymorphisms (rs806381, rs10485170, rs6454674, rs2023239) and cardiovascular risk factors in postmenopausal women

Introduction.?The risk of cardiovascular diseases (CVD) in women increases with menopausal stage. Obesity with metabolic disorders is the most important risk factor for CVD. The incidence of this phenotype of obesity increases in postmenopausal women. The endocannabinoid system plays an important role in regulation of several metabolic pathways. The aim of this work was to investigate whether genetic variations in the cannabinoid receptor gene (CNR1) can affect cardiovascular risk factors (e.g. fat distribution, obesity, fasting glucose, lipid profile, blood pressure, and free androgen and estrogen indexes) in postmenopausal women.

Methods.?The rs806381, rs10485170, rs6454674, and rs2023239 polymorphisms of the CNR1 gene were genotyped in 384 randomly selected postmenopausal Polish women (aged 50–60) using the minisequencing technique.

Results.?The rs806381, rs10485170, rs6454674, and rs2023239 polymorphisms were not significantly associated with anthropometric measures (waist circumference, carbohydrate and lipid metabolism, body mass index [BMI], total fat, glucose, insulin, fasting insulin resistance index [FIRI]). However, the rs2023239 polymorphism was associated with the free androgen index (p?=?0.03).

Discussion.?It seems that further genotyping of the endocannabinoid receptor gene cannot be used as a significant marker of predisposition to CVD in postmenopausal women, but it would be interesting to study this interrelation on a larger population of postmenopausal women.     

Erhöhte kardiovaskuläre Mortalität in der (späteren) Postmenopause

Cardiovascular diseases are the most common cause of mortality in the late postmenopause. The importance of estrogen deficiency is easy to recognize by the fact that the mortality increases exponentially after the menopause and particularly with rapid decreases in estrogen production, for example by bilateral oophorectomy. Besides age related alteration, the negative alterations in lipid and glucose metabolism, increase in hypertension, visceral fat, diabetes and metabolic syndrome are in correlation with the time span to the menopause and with this also to the estrogen deficiency. In contrast, estrogen treatment in the menopause has a positive effect on all these risk factors. More than 1,000 investigations indicate the cardiovascular preventive mechanisms of estrogen. However, in clinical studies a cardiovascular protection is only achieved if hormone substitution is initiated within 10 years after the menopause at the latest whereby the total mortality can be significantly reduced, in contrast to statins. Estrogen deficiency is therefore without a doubt the major cause of cardiovascular mortality in women in the late postmenopause.     

Raloxifene: A Review

women can now expect to live up to one-third of their lives in the post-menopausal state. This low estrogen state is a major risk factor for the development of osteoporosis and cardiovascular disease. The Osteoporosis Society of Canada currently recommends estrogen as the treatment of choice for preventing post-menopausal osteoporosis. Sustained unopposed estrogen use is associated with an increased risk of endometrial hyperplasia and endometrial cancer, necessitating the concomitant use of a progestin in those with an intact uterus. Recent large cohort studies suggest that estrogen and estrogen/progestin therapy may also be associated with an increased risk of breast cancer thus diminishing the beneficial effects of estrogen on overall mortality. Bisphosphonates are also available for the treatment and prevention of osteoporosis. They do not have the other beneficial effects that estrogen may provide. Selective estrogen receptor modulators (SERMs) represent a new therapeutic class of medications that have been developed to act as estrogen agonists in some tissues and estrogen antagonists in others. Raloxifene (Evista®) is a selective estrogen receptor modulator that, in pre-clinical and clinical studies, demonstrates estrogen agonist activity on bone and lipid metabolism, and shows estrogen antagonist activity on uterine and breast tissue. It is the first estrogen receptor active agent that has been shown in adequately powered, placebo-controlled, randomized clinical trials, to reduce the risk of new vertebral fractures in post-menopausal women with osteoporosis.     

Evidence for associations between common polymorphisms of estrogen receptor beta gene with homocysteine and nitric oxide.

BACKGROUND: Homocysteine and asymmetric dimethylarginine (ADMA) affect nitric oxide (NO) concentration, thereby contributing to cardiovascular disease (CVD). Both amino acids can be reduced in vivo by estrogen. Variation in the estrogen receptor (ER) may influence homocysteine and ADMA, yet no information is available on associations with single nucleotide polymorphisms in the estrogen receptor genes ERalpha (PvuII and XbaI) and ERbeta (1730G-->A and cx + 56 G-->A). OBJECTIVE: To find relationships between common polymorphisms associated with cardiovascular disease and cardiovascular risk factors homocysteine and ADMA. METHODS: In a cross-sectional study with healthy postmenopausal women (n = 89), homocysteine, ADMA, nitric oxide metabolites (NOx), plasma folate and ERalpha and beta polymorphisms ERalpha PvuII, ERalpha XbaI; ERbeta 1730G-->A (AluI), ERbeta cx + 56 G-->A (Tsp509I) were analyzed. RESULTS: Women who are homozygotic for ERbetacx + 56 G-->A A/A exhibited higher homocysteine (p = 0.012) and NOx (p = 0.056) levels than wildtype or heterozygotes. NOx concentration was also significantly affected by ERbeta 1730 G -->A polymorphism (p = 0.025). The ERbeta (p < 0.001) and ERalpha (p < 0.001) polymorphisms were in linkage disequilibrium. CONCLUSIONS: Women who are homozygotic for ERbetacx + 56 G-->A A/A may be at increased risk for cardiovascular disease due to higher homocysteine levels.     

The Framingham Study: historical insight on the impact of cardiovascular risk factors in men versus women

The Framingham Study has investigated the evolution of cardiovascular disease (CVD) over five decades in a general population sample of men and women. This study has provided valuable insight into the prevalence, incidence, prognosis, and predisposing risk factors for CVD in women compared to men. Women were found to outlive men and to experience fewer atherosclerotic CVD events, lagging behind men in incidence by 10-20 years. However, this gap in incidence closed with advancing age and in the elderly, CVD became the leading cause of death in women as well as men. Comparing the life-time risk of coronary heart disease (CHD) with that of breast cancer in the Framingham cohort indicated a threefold greater chance of having a CHD event (24-32%) than breast cancer (7-12.5%). Thus, CVD is not a minor problem in women, and vigorous preventive measures are warranted at all ages. There is a need for particular attention to glucose intolerance, abdominal obesity, and blood lipids, and a need for a great sense of urgency when hypertension is associated with diabetes or promotes left ventricular hypertrophy.     

Hormone therapy and cardiovascular disease: a systematic review and meta-analysis

BACKGROUND: Despite decades of evidence from observational studies, the use of hormone therapy for the prevention of cardiovascular disease (CVD) among postmenopausal women is controversial. The recent completion of several randomised clinical trials examining the effects of hormone therapy on CVD presents an opportunity to provide a more precise estimate of the cardiovascular risks of hormone therapy. OBJECTIVE: To summarise the effects of hormone therapy on CVD in postmenopausal women. SEARCH STRATEGY: MEDLINE, EMBASE, the Cochrane Library, DARE and CENTRAL were searched for clinical trials reporting mortality and/or CVD outcomes in association with hormone therapy. Bibliographies and editorials were also reviewed. All studies were reviewed and rated for quality independently by two reviewers. SELECTION CRITERIA: High quality, randomised placebo-controlled clinical trials of hormone therapy (duration greater than one year) in non-hospitalised postmenopausal women were included. DATA COLLECTION AND ANALYSIS: Summary relative risks were estimated for all-cause mortality, coronary heart disease (CHD) mortality, non-fatal acute myocardial infarction (AMI) and all stroke. MAIN RESULTS: Seven randomised clinical trials met the inclusion criteria. The use of hormone therapy had no significant effect on all-cause mortality, non-fatal AMI or CHD mortality, with relative risks of 1.02 [95% confidence interval (CI) 0.93-1.13], 1.00 (0.88-1.14) and 0.99 (0.82-1.21), respectively. For all stroke, the summary relative risk was 1.29 (1.13-1.48). AUTHOR'S CONCLUSIONS: This systematic review, incorporating the latest available trial data, shows that hormone therapy does not significantly change the risk of all-cause morality, CHD death or non-fatal AMI but increases the risk of stroke in postmenopausal women.