Heart And Estrogen/progestin Replacement Study Research Articles

From cardiovascular protection to cardiovascular risk: the metamorphosis of menopausal hormone therapy.

Over the last 70years, oestrogen therapy for the management of menopausal symptoms has undergone a metamorphosis from perceived cardiovascular protection to perceived cardiovascular risk. The former perception is based on the convincing evidence from the Nurses' Health Study cohorts and the epidemiological data surrounding early menopause. The latter, and later, perception is based on the disquieting results from two randomised controlled studies, the Heart and Estrogen/Progestin Replacement Study (HERS) and the Women's Health Initiative study (WHI). The reality is probably more nuanced than the conclusions presented by any of these studies. When face to face with a patient, the clinician must negotiate the appropriate decision pathway around the interaction between cardiovascular risk, cardiovascular disease, menopause, and oestrogen +/-progestogen-containing hormone therapy.

Menopause and menopausal hormone therapy in women: cardiovascular benefits and risks

The last decade has brought many challenges and uncertainties regarding the use of menopausal hormone therapy in women. Two early key studies, the Heart and Estrogen/Progestin Replacement Study (HERS) and the Women's Health Initiative (WHI) failed to prove beneficial effects of exogenous estrogen, and estrogen combined with progestin, in cardiovascular prevention. More recent studies, however, introduced the concept of a possible “window-of-opportunity” for hormonal therapy, in which menopausal hormone therapy is used early after the onset of menopause, and may lead to more favorable, cardio-protective outcomes. Despite the increasing wealth of clinical data, menopausal hormone therapy is not currently recommended for primary or secondary prevention of coronary heart disease in women. Further research is needed to understand the risk-benefit balance of menopausal hormone therapy.

Hormone replacement therapy and cardio-vascular disease

The results of large randomized trials such as the Women's Health Initiative (WHI), Heart and Estrogen / Progestin Replacement Study (HERS) or Estrogen Replacement and Atherosclerosis Study (ERAS) as well as the Million Women Study (MWS) which does not meet criteria RCT, concerning, among others the impact of HRT on breast cancer risk, thromboembolism, or the aging processes in the central nervous system caused the recent big confusion in the medical community , causing distrust about the safety and advisability of HRT in menopausal women. The paper presents an overview of the available, current literature on HRT. It was found that HRT should not be used in both primary and secondary prevention of coronary heart disease Great expectations was associated with an earlier initiation of therapy, before the advent of atherosclerosis - but there is currently no conclusive data about its role in the primary prevention of coronary disease. Oral HRT increases the risk of thromboembolic events - that is why you should prefer the form of a transdermal. HRT may increase the risk of ischemic stroke (but early initiation of therapy does not increase the risk of stroke) and should not be used in the primary prevention of stroke.

Routes of administration of hormone replacement therapy and cardiovascular effects in postmenopausal women

Earlier results of observational data showed beneficial effects with hormone therapy in women after menopause but the large clinical trials such as the Women’s Health Initiative (WHI), Heart and Estrogen/progestin Replacement Study (HERS) failed to demonstrate protective cardiovascular effects. However, re-analysis of WHI results recommended that the adverse outcomes maybe influenced by several factors such as age, time of initiation, dose, route of hormone therapy and pre-existing cardiovascular disease. In recent times, the use of hormone therapy in postmenopausal women is still limited to climacteric symptoms, probably due to insufficient data to support its use in chronic conditions such as cardiovascular disease. However, results from The Kronos Early Estrogen Prevention Study (KEEPS), has been expected to provide a definite answer to reduce cardiovascular disease with hormone therapy in postmenopausal women. Based on the results from recent studies, re-analysis of WHI results, and WHI /HERS reports, this article highlights the cardiovascular effects of hormone replacement therapy with different routes of administration in postmenopausal women.

Hormone replacement therapy in menopause

Although estrogen has been clinically available for more than six decades, women have been confused by different opinions regarding the risks and benefits of menopausal hormone therapy (HT), estrogen therapy (ET), and estrogen-progestin therapy (EPT). The publication of randomized controlled trials (RCTs), notably, the Heart and Estrogen/progestin Replacement Study (HERS) and Women's Health Initiative (WHI), has intensified the risk vs. benefit controversy. Millions of women are treated with HT for relief of menopausal symptoms, including vasomotor flushes and sweats, for which estrogen is uniquely and highly effective. Others may continue longer-term treatment in the hope that HT will help to prevent chronic disease. The preservation of bone mass with continuing estrogen therapy and reduction of subsequent risk of fracture is well established. Observational studies of the metabolic and vascular effects of estrogens have suggested a potential benefit in reducing the risk of vascular disease, but recently published randomized controlled trials demonstrated no evidence of benefit in women with established vascular disease or in apparently healthy women. The increased risks of breast cancer and thromboembolic disease have been confirmed in these trials, with evidence of increased risk of stroke. The absolute incidence of an adverse event is low, and the risk of stroke in an individual woman in a single year is very small, but with long-term use, the risks are cumulative over time. The risk-benefit balance needs to be individualized for each woman.

Menopausal Hormone Therapy and Cardiovascular Disease Risk: Utility of Biomarkers and Clinical Factors for Risk Stratification

Menopausal hormone therapy (HT) continues to have a clinical role in symptom management, but identifying women for whom benefits will outweigh the risks remains a challenge. Although hormone therapy (HT) is the most effective strategy for ameliorating vasomotor and other symptoms, randomized clinical trials show an unfavorable balance of benefits and risks for many women. However, closer examination of data from these trials suggests that it may be possible to classify women as better or worse candidates for HT by using individual risk stratification. Data from 2 landmark trials-the Women's Health Initiative (WHI) and the Heart and Estrogen/progestin Replacement Study (HERS)-suggest an important role for clinical characteristics, serum biomarkers, genomic markers, and gene-environment interactions in developing a personalized approach to the prediction of risk for cardiovascular disease (CVD) events for women while on HT. The available data suggest several characteristics of women who are optimal candidates for HT use: younger age (<60 years), recent onset of menopause (<10 years), favorable lipid profile (LDL cholesterol <130 mg/dL or LDL/HDL cholesterol ratio <2.5), absence of metabolic syndrome, and absence of factor V Leiden genotype. The identification of other characteristics is an area of active investigation. In addition, women at high risk for venous thromboembolism should avoid systemic HT or choose a transdermal rather than oral delivery route. Personalized medicine-i.e., the use of the specific biological profile of an individual to guide the choice of treatment-is highly relevant for clinical decision-making regarding HT and offers promise for improved treatment efficacy and safety.

Estrogen, vascular estrogen receptor and hormone therapy in postmenopausal vascular disease

Cardiovascular disease (CVD) is less common in premenopausal women than men of the same age or postmenopausal women, suggesting vascular benefits of estrogen. Estrogen activates estrogen receptors ERα, ERβ and GPR30 in endothelium and vascular smooth muscle (VSM), which trigger downstream signaling pathways and lead to genomic and non-genomic vascular effects such as vasodilation, decreased VSM contraction and growth and reduced vascular remodeling. However, randomized clinical trials (RCTs), such as the Women's Health Initiative (WHI) and Heart and Estrogen/progestin Replacement Study (HERS), have shown little vascular benefits and even adverse events with menopausal hormone therapy (MHT), likely due to factors related to the MHT used, ER profile, and RCT design. Some MHT forms, dose, combinations or route of administration may have inadequate vascular effects. Age-related changes in ER amount, distribution, integrity and post-ER signaling could alter the vascular response to MHT. The subject's age, preexisting CVD, and hormone environment could also reduce the effects of MHT. Further evaluation of natural and synthetic estrogens, phytoestrogens, and selective estrogen-receptor modulators (SERMs), and the design of appropriate MHT combinations, dose, route and ‘timing’ could improve the effectiveness of conventional MHT and provide alternative therapies in the peri-menopausal period. Targeting ER using specific ER agonists, localized MHT delivery, and activation of specific post-ER signaling pathways could counter age-related changes in ER. Examination of the hormone environment and conditions associated with hormone imbalance such as polycystic ovary syndrome may reveal the causes of abnormal hormone-receptor interactions. Consideration of these factors in new RCTs such as the Kronos Early Estrogen Prevention Study (KEEPS) could enhance the vascular benefits of estrogen in postmenopausal CVD.

Sex and gender differences in control of blood pressure.

In recent years, the interest in studying the impact of sex steroids and gender on the regulation of blood pressure and cardiovascular disease has been growing. Women are protected from most cardiovascular events compared with men until after menopause, and postmenopausal women are at increased risk of cardiovascular complications compared with premenopausal women. The pathophysiological mechanisms have not been elucidated, but are not likely to be as simple as the presence or absence of oestrogens, since hormone replacement therapy in elderly women in the Women's Health Initiative or HERS (Heart and Estrogen/progestin Replacement Study) did not provide primary or secondary prevention against cardiovascular events. Men are also thought to be at risk of cardiovascular disease at earlier ages than women, and these mechanisms too are not likely to be as simple as the presence of testosterone, since androgen levels fall in men with cardiovascular and other chronic diseases. In fact, many investigators now believe that it is the reduction in androgen levels that frequently accompanies chronic disease and may exacerbate cardiovascular disease in men. In the present review, the roles of sex steroids and gender in mediating or protecting against hypertension and cardiovascular disease will be discussed.

Fizjologia i choroby gruczołu piersiowego w różnych okresach życia kobiety (menopauza i ciąża)

Knowledge of physiology of the mammary gland help us understand pathological processes which can occur in this organ, for example carcinogenesis. The results of epidemiological studies indicate an increased incidence of breast cancer in women receiving sex steroids, but the data concerning this issue are not unequivocal. The results of WHI (Women Health Initiative) and HERS (Heart and Estrogen/Progestin Replacement Study) studies point out to an elevated risk of neoplasia in the mammary gland among women taking hormone replacement therapy, which evokes a great deal of concern, uncertainty and fear both among doctors and patients. This fear should be replaced by the algorithm of professional medical management and a suitable choice of therapy in relation to a woman’s age, genetic load, history of diseases and expected benefits. Directing a therapeutic option to the patient and supporting it with scientific data on HRT can convince women that the treatment will prevent, to a large extent, fractures, depression, Alzheimer’s disease, colon cancer, stroke and heart attack. The risk of possible breast cancer death is much lower than compared to the affliction caused by estrogen depletion during early menopause. In the following review we present data which deal with physiology of the mammary gland in different periods of the woman’s life, especially menopause. Moreover, the molecular mechanisms that may potentially play a role in neoplasia are discussed.

Placebo Adherence and Mortality in the Heart and Estrogen/Progestin Replacement Study

BackgroundAnalyses from double-blind randomized trials have reported lower mortality among participants who were more adherent to placebo compared with those who were less adherent. We explored this phenomenon by analyzing data from the placebo arm of the Heart and Estrogen/Progestin Replacement Study (HERS), a randomized, double-blind, placebo-controlled trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Our primary aim was to measure and explain the association between adherence to placebo and total mortality among the placebo-allocated participants in the HERS. Secondary aims included assessment of the association between placebo adherence and cause-specific morbidity and mortality. MethodsParticipants with “higher placebo adherence” were defined as having taken at least 75% of their placebo study medication during each individual's participation in the study, whereas those with “lower placebo adherence” took less than 75%. The primary outcome was in-study all-cause mortality. ResultsMore adherent participants had significantly lower total mortality compared with less adherent participants (hazard ratio, 0.52; 95% confidence interval, 0.29-0.93). Adjusting for available confounders did not change the magnitude or significance of the estimates. Analyses revealed that the association of higher adherence and mortality might be explained, in part, by time-dependent confounding. ConclusionsAnalyses of the HERS data support a strong association between adherence to placebo study medication and mortality. Although probably not due to simple confounding by healthy lifestyle factors, the underlying mechanism for the association remains unclear. Further analyses of this association are necessary to explain this observation.

HDL and CETP Inhibition: Will This DEFINE the Future?

The premature stopping of the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health) study due to futility has called into question the clinical value of high-density lipoprotein cholesterol (HDL-C) increases. The failure of estrogen therapy in the HERS (Heart and Estrogen/progestin Replacement Study) trial and the cholesteryl ester transfer protein (CETP) inhibitors torcetrapib (in the ILLUMINATE [Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events] trial) and, most recently, dalcetrapib in the dal-OUTCOMES trial has cast doubt on the "HDL-raising hypothesis" for providing additional benefits on top of statin therapy. The AIM-HIGH trial was designed to equalize low-density lipoprotein cholesterol (LDL-C) levels between the two treatment groups while the niacin arm would have a higher HDL-C. The study population included patients with low HDL-C and cardiovascular disease (CVD); because this population has a high residual risk for CVD on statin therapy, these patients were most likely to benefit from the niacin HDL-C-raising effect. These findings are disappointing because clinicians have used extended-release niacin to treat patients with low HDL-C because niacin has demonstrated benefit in earlier reported studies in conjunction with statins and other drugs, as observed in the Cholesterol Lowering Atherosclerosis Study (CLAS) and the HDL-Atherosclerosis Treatment Study (HATS). In the Coronary Drug Project, niacin alone was shown to reduce myocardial infarction, stroke, and the need for coronary bypass surgery. Niacin does not increase the number of HDL particles to the same extent it raises HDL-C. Niacin alters the composition of HDL, making the particle larger, which is similar to the effects of CETP inhibition on HDL. Both niacin and CETP inhibitors decrease the catabolism of HDL, thereby increasing the size of the HDL particle and raising HDL-C. Dalcetrapib, which does not decrease LDL-C while raising HDL-C, was recently discontinued from clinical development due to a interim analysis that determined that the study was futile. Anacetrapib, which markedly increases HDL-C while also significantly lowering LDL-C, remains in clinical development, with a large cardiovascular end point trial currently enrolling 30,000 high-risk patients. For now, the goal remains the achievement of LDL-C and non-HDL targets, and low HDL-c remains a significant independent risk factor, but there is insufficient evidence that raising HDL-C will provide a clinical benefit.

Vascular Effects of Estrogenic Menopausal Hormone Therapy

Cardiovascular disease (CVD) is more common in men and postmenopausal women (Post-MW) than premenopausal women (Pre-MW). Despite recent advances in preventive measures, the incidence of CVD in women has shown a rise that matched the increase in the Post-MW population. The increased incidence of CVD in Post-MW has been related to the decline in estrogen levels, and hence suggested vascular benefits of endogenous estrogen. Experimental studies have identified estrogen receptor ERα, ERβ and a novel estrogen binding membrane protein GPR30 (GPER) in blood vessels of humans and experimental animals. The interaction of estrogen with vascular ERs mediates both genomic and non-genomic effects. Estrogen promotes endothelium-dependent relaxation by increasing nitric oxide, prostacyclin, and hyperpolarizing factor. Estrogen also inhibits the mechanisms of vascular smooth muscle (VSM) contraction including [Ca2+]i, protein kinase C and Rho-kinase. Additional effects of estrogen on the vascular cytoskeleton, extracellular matrix, lipid profile and the vascular inflammatory response have been reported. In addition to the experimental evidence in animal models and vascular cells, initial observational studies in women using menopausal hormonal therapy (MHT) have suggested that estrogen may protect against CVD. However, randomized clinical trials (RCTs) such as the Heart and Estrogen/ progestin Replacement Study (HERS) and the Women's Health Initiative (WHI), which examined the effects of conjugated equine estrogens (CEE) in older women with established CVD (HERS) or without overt CVD (WHI), failed to demonstrate protective vascular effects of estrogen treatment. Despite the initial set-back from the results of MHT RCTs, growing evidence now supports the 'timing hypothesis', which suggests that MHT could increase the risk of CVD if started late after menopause, but may produce beneficial cardiovascular effects in younger women during the perimenopausal period. The choice of an appropriate MHT dose, route of administration, and estrogen/progestin combination could maximize the vascular benefits of MHT and minimize other adverse effects, especially if given within a reasonably short time after menopause to women that seek MHT for the relief of menopausal symptoms.

Healthy users, healthy adherers, and healthy behaviors?

In this issue of JBMR, Curtis colleagues (1) use data from the placebo group of a randomized, controlled osteoporosis trial to argue for a possible healthy adherer effect. Our understanding of this effect began when some randomized, controlled clinical trials in cardiovascular disease had cardiovascular outcomes that contradicted findings in prior observational studies. These findings highlighted the fact that several sources of bias can occur in observational studies. These biases can be related to patient behaviors, including both healthy user and healthy adherer effects. The best known examples of these biases have appeared in studies of cardiovascular disease. For example, a large observational study, the Nurses’ Health Study, showed decreased coronary heart disease in women taking hormonereplacement therapy (HRT) in 1985, a finding that was confirmed by other observational studies. However, more than 10 years later, two randomized, controlled clinical trials contradicted the observational findings: The Heart and Estrogen/ Progestin Replacement Study (HERS) showed no cardiovascular benefit from estrogen supplementation, and the Women’s Health Initiative showed increased incidence of cardiovascular events in women taking estrogen. How can we explain this divergence of results? First, we must identify and understand this divergence by understanding sources of bias. The first potential bias, the healthy user effect, occurs when patients who choose to receive one preventive service such as estrogen or a lipid-lowering agent also choose to receive other preventive services such as immunizations and screening tests. For example, patients who adhere to statins more frequently receive vaccinations and screening services. These same patients also may have less comorbidity and better functional status, increasing the likelihood of other healthy behaviors These patients also may be involved in fewer accidents, suggesting possible risk aversion. A second potential bias—the healthy adherer bias—was first demonstrated in 1980 when decreased mortality and fewer cardiovascular events were found in good adherers of placebo in a

Self-Reported Changes in Providers' Hormone Therapy Prescribing and Counseling Practices After the Women's Health Initiative

Prescribing and counseling practices in hormone therapy (HT) since publication of the Women's Health Initiative (WHI) trials have changed. Our objective was to compare changes by practice field and region. Between December 2005 and May 2006, we mailed surveys to 938 practitioners from two large integrated health systems in the Northeastern and Northwestern United States. We received 736 responses and excluded 144 who do not prescribe/counsel about HT, leaving 592. Data included prescriber characteristics, knowledge about HT trials, and self-reported HT counseling and prescribing changes. We compared provider characteristics and HT counseling and prescribing by region and practice field (obstetrician/gynecology [OB/GYN] or primary care). Respondents included 79 OB/GYNs and 513 primary care providers. OB/GYNs were more likely, than primary care providers to consider themselves experts regarding the Heart and Estrogen/progestin Replacement Study (HERS) and WHI trials (30.4% vs. 8.2%, p < 0.001). The majority (87%) were cautious about HT use, especially primary care providers (p < 0.01 compared to OB/GYNs). Respondents reported prescribing less oral unopposed estrogen (64%) and combination estrogen/progestin (81%) post-WHI. OB/GYNs were less likely to report decreases in oral unopposed estrogen use (p = 0.006). Use of lower-dose and transdermal products (low-dose estrogen, vaginal estrogen, estradiol vaginal ring) increased, especially by OB/GYNs. Our study highlights numerous HT prescribing and counseling differences between primary care and OB/GYN providers. Reasons for these differences are unknown but may be related to self-reported WHI/HERS knowledge. HT formulations used in the WHI trials are being replaced by low-dose and alternate formulations. Studies to support this practice are needed.

Impact of Sex Hormone Metabolism on the Vascular Effects of Menopausal Hormone Therapy in Cardiovascular Disease

Epidemiological studies have shown that cardiovascular disease (CVD) is less common in pre-menopausal women (Pre-MW) compared to men of the same age or post-menopausal women (Post-MW), suggesting cardiovascular benefits of estrogen. Estrogen receptors (ERs) have been identified in the vasculature, and experimental studies have demonstrated vasodilator effects of estrogen/ER on the endothelium, vascular smooth muscle (VSM) and extracellular matrix. Several natural and synthetic estrogenic preparations have been developed for relief of menopausal vasomotor symptoms. However, whether menopausal hormone therapy (MHT) is beneficial in postmenopausal CVD remains controversial. Despite reports of vascular benefits of MHT from observational and experimental studies, randomized clinical trials (RCTs), such as the Heart and Estrogen/progestin Replacement Study (HERS) and the Women's Health Initiative (WHI), have suggested that, contrary to expectations, MHT may increase the risk of CVD. These discrepancies could be due to agerelated changes in sex hormone synthesis and metabolism, which would influence the effective dose of MHT and the sex hormone environment in Post-MW. Age-related changes in the vascular ER subtype, structure, expression, distribution, and post-ER signaling pathways in the endothelium and VSM, along with factors related to the design of RCTs, preexisting CVD condition, and structural changes in the blood vessels architecture have also been suggested as possible causes of MHT failure in CVD. Careful examination of these factors should help in identifying the causes of the changes in the vascular effects of estrogen with age. The sex hormone metabolic pathways, the active versus inactive estrogen metabolites, and their effects on vascular function, the mitochondria, the inflammatory process and angiogenesis should be further examined. Also, the genomic and non-genomic effects of estrogenic compounds should be viewed as integrated rather than discrete responses. The complex interactions between these factors highlight the importance of careful design of MHT RCTs, and the need of a more customized approach for each individual patient in order to enhance the vascular benefits of MHT in postmenopausal CVD.

Submaximal exercise coronary artery flow increases in postmenopausal women without coronary artery disease after estrogen and atorvastatin

The aim of this study was to determine the effect of statins and hormone therapy on submaximal exercise-induced coronary artery blood flow in postmenopausal women without a history of coronary artery disease. Hormone therapy or statin therapy in early postmenopausal women without coronary artery disease has been shown to enhance arterial endothelial function; we hypothesized that these agents would improve submaximal exercise-induced coronary artery blood flow. Sixty-four postmenopausal women, aged 50 to 65 years without documented coronary artery disease, were randomized in a double-blind, crossover fashion to receive 8 weeks of hormone therapy versus placebo, with or without 80 mg/day of atorvastatin. Before receipt of any therapy and after each treatment period, each woman underwent measures of coronary artery blood flow at rest and stress. The combination of hormone therapy and atorvastatin increased submaximal exercise-induced coronary artery blood flow (P = 0.04). In the subgroups of women compliant with treatment, resting coronary artery blood flow increased in those receiving hormone therapy (P = 0.03) or statin therapy (P = 0.02). In postmenopausal women aged 50 to 65 years without documented coronary artery disease, resting and submaximal exercise-induced coronary artery blood flow improves after receipt of high-dose atorvastatin and conjugated estrogens therapy.

Effect of genistein therapy on plasma levels of asymmetric dimethylarginine in healthy postmenopausal women: a randomized, placebo-controlled study

The aim of this study was to investigate the effects of pure genistein therapy on asymmetric dimethylarginine in healthy postmenopausal women. Healthy postmenopausal women received pure genistein (n=21) or placebo (n=17) for 6 months, and no statistically significant effects on plasma asymmetric dimethylarginine levels were found with pure genistein treatment.

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Statin use is associated with lower risk of atrial fibrillation in women with coronary disease: the HERS trial

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