Benefits Of Menopausal Hormone Therapy Research Articles

The menopausal transition period and cardiovascular risk.

The menopausal transition period spans, on average, 2-8 years before the final menstrual period and is associated with an increase in clinical and subclinical cardiovascular risk. In this Review, we discuss the metabolic and cardiovascular changes that occur during the menopausal transition period and the role of ovarian ageing, chronological ageing and other ageing-related risk factors in mediating these changes. Disentangling the relative contributions of chronological and reproductive ageing to cardiovascular risk is challenging, but data from longitudinal studies in women transitioning from premenopause to post-menopause have provided valuable insights. We also discuss evidence on how cardiovascular risk is altered by premature or early menopause, surgical menopause, and vasomotor and other menopausal symptoms. Whether targeted interventions can slow the progression of atherosclerosis and subclinical disease during the menopausal transition, thus delaying or preventing the onset of cardiovascular events, remains to be determined. Furthermore, we consider the recommended strategies for cardiovascular risk reduction in women undergoing menopausal transition using the framework of the American Heart Association's Life's Essential 8 key measures for improving and maintaining cardiovascular health, and discuss the cardiovascular risks and benefits of menopausal hormone therapy. Finally, we also discuss novel therapies that might benefit this population in reducing cardiovascular risk.

Menopausal symptoms and hormone therapy in women with multiple sclerosis: A baseline-controlled study

BackgroundDepression, sleep disturbances, and cognitive difficulties impair the quality of life in people with multiple sclerosis (MS). Similar symptoms are also frequent during the menopausal transition. In clinical practice, it is important to consider the multifactorial causes of these overlapping symptoms and the potential benefits of menopausal hormone therapy (MHT). The objective of this study was to evaluate vasomotor symptoms (VMS), mood, sleep, and cognition of menopausal women with and without MS at baseline and during one year of MHT. MethodsIn this prospective baseline-controlled study, peri- and early postmenopausal participants with (n=14) and without (n=13) MS received MHT containing 1 or 2 mg of estradiol and cyclical 10 mg dydrogesterone for one year. VMS frequency, depressive symptoms (measured by Beck Depression Inventory), insomnia severity (Insomnia Severity Index), and cognitive performance (Paced Auditory Serial Addition Test; PASAT, Symbol Digit Modalities Test; SDMT) were evaluated at baseline and at 3 and 12 months of treatment. Differences in the outcome measures between groups at baseline were assessed using the Mann-Whitney U test. Changes during follow-up compared to baseline within groups were evaluated by Wilcoxon Signed Ranks Test. P < 0.05 was considered for statistical significance. MS activity was monitored by clinical assessment and brain MRI at baseline and at 12 months. ResultsDepressive symptoms were more common in MS group, while vasomotor and insomnia symptoms were equally common. During follow-up with MHT, VMS frequency decreased in both groups. Depressive symptoms decreased at 3 months (p = 0.031 with MS; p = 0.024 without MS) and the reduction was sustained at 12 months (p = 0.017; p = 0.042, respectively). Alleviation in insomnia symptoms was seen in participants without MS at 3 months (p = 0.029) and in those participants with MS suffering insomnia at baseline (p = 0.016 at 3 months; p = 0.047 at 12 months). Both groups improved their performance in PASAT, but no significant change was observed in SDMT. MS activity at baseline was mainly stable, and no increase in activity was detected during MHT. ConclusionImprovements in vasomotor, depressive, and insomnia symptoms observed during one year of MHT are encouraging and suggest that larger placebo-controlled studies of MHT in women with MS are warranted. Cognitive implications were inconclusive because the findings in PASAT likely result from practice effect. MHT did not show any adverse effect on MS activity and increasing safety data will hopefully facilitate patient recruitment for future studies.

Trends in Prescribing Menopausal Hormone Therapy and Bisphosphonates in Australia and Manitoba, Canada and Adherence to Recommendations.

Background: Recommendations for using menopausal hormone therapy (MHT) and bisphosphonates for postmenopausal osteoporosis management have changed over time. After the release of the Women's Health Initiative (WHI) trial results in 2002, new evidence on risks and benefits of MHT became available, and newer guidelines generally specify that MHT should not be prescribed for prevention of chronic disease, including osteoporosis. This raises the question of whether bisphosphonate prescribing changed over time to compensate for the decrease in MHT use. Materials and Methods: We examined trends in dispensed prescriptions in Australia (national) and Canada (province of Manitoba) in relation to prescribing recommendations. Administrative data were used to describe dispensing patterns and changes for persons of all ages from 1996 to 2008, and for women aged 50 to ≥80 years from 2003 to 2008 in Australia and 1996 to 2008 in Canada. Results: In both geographic settings, MHT dispensing increased 1996-2001, peaked in 2001, and declined substantially thereafter (67% reduction in MHT prescriptions for Australia; 64% reduction for Manitoba, Canada to 2008). From 2003 to 2008, the number of MHT prescriptions declined among all age groups in both settings, with the highest declines among women in their 50s. Concurrently, bisphosphonate dispensing increased until 2005 (2001-2005: 260% increase in the number of prescriptions in Australia; 125% increase in Manitoba) and stabilized thereafter, in both settings. Annual bisphosphonate dispensing rates increased 4.1-10.9% for women in their 70s and 80s in Australia and Manitoba during the period studied. Conclusions: Based on dispensed prescriptions data, more recent guidelines for MHT and bisphosphonates use for postmenopausal osteoporosis, which were updated during the study period (and are still consistent with the current guidelines), appear to have been broadly adhered to in both settings.

The Metabolic Benefits of Menopausal Hormone Therapy Are Not Mediated by Improved Nutritional Habits. The OsteoLaus Cohort.

Menopause alters body composition by increasing fat mass. Menopausal hormone therapy (MHT) is associated with decreased total and visceral adiposity. It is unclear whether MHT favorably affects energy intake. We aimed to assess in the OsteoLaus cohort whether total energy intake (TEI) and/or diet quality (macro- and micronutrients, dietary patterns, dietary scores, dietary recommendations)—evaluated by a validated food frequency questionnaire—differ in 839 postmenopausal women classified as current, past or never MHT users. There was no difference between groups regarding TEI or consumption of macronutrients. After multivariable adjustment, MHT users were less likely to adhere to the unhealthy pattern ‘fat and sugar: Current vs. never users [OR (95% CI): 0.48 (0.28–0.82)]; past vs. never users [OR (95% CI): 0.47 (0.27–0.78)]. Past users exhibited a better performance in the revised score for Mediterranean diet than never users (5.00 ± 0.12 vs. 4.63 ± 0.08, p < 0.04). Differences regarding compliance with dietary recommendations were no longer significant after adjustment for covariates. Overall, these results argue against a major role of TEI and diet quality as possible mediators of the MHT metabolic benefits. Future research on this relationship should focus on other potential targets of MHT, such as resting energy expenditure and physical activity.

Risks and benefits of menopausal hormone therapy

Risks and benefits of menopausal hormone therapy

Aging, the menopausal transition, and hormone replenishment therapy: retrieval of confidence and compliance.

The negative health consequences of age and the postmenopausal hypoestrogenic state and their clinical management are described in this paper. While some dysfunctional elements are irreversibly entrained, others can be modified by an updated menopausal hormone therapy (MHT) strategy reflecting revision and reassessment of the initial Women's Health Initiative (WHI) reports. However, until that positive outcome is realized, menopausal women and their healthcare providers must re-establish willingness to utilize these effective strategies. This reluctance is fueled by persistent mistaken application of WHI results that reflect the bundled risk and benefits of MHT in asymptomatic women aged 50-79 (average age 63), as opposed to women in their 40s and 50s who initiate therapy because of vasomotor symptoms. The absolute risk of adverse outcomes is much lower and the benefits dramatically higher in these younger women. In addition, newer FDA-approved formulations, lower dosage regimens, and transdermal delivery methodologies offer wider choice of approaches and promise even greater safety. The positive and negative lessons of the WHI have been learned and can be applied effectively.

What the Women's Health Initiative has taught us about menopausal hormone therapy.

Our understanding of the complex relationship between menopausal hormone therapy (MHT) and cardiovascular disease (CVD) risk has been informed by detailed analyses in the Women's Health Initiative (WHI), the largest randomized, placebo-controlled trial evaluating MHT in postmenopausal women. Although the WHI demonstrated increased risk of CVD events with MHT in the overall cohort, subsequent secondary analyses demonstrated that these risks were influenced by the woman's age and time since menopause, with lower absolute risks and hazard ratios for younger than older women. As MHT is the most effective treatment for the vasomotor symptoms of menopause, it is important to understand its risks and how to conduct risk stratification for symptomatic women. In addition to reviewing the WHI findings, studies pre- and post-WHI are reviewed to describe the relationship between MHT and CVD risk in menopausal women. The absolute risks of adverse cardiovascular events for MHT initiated in women close to menopause are low, and all-cause mortality effects are neutral or even favorable for younger menopausal women. The WHI has advanced and refined our understanding of the relationship between MHT and CVD risk. Although MHT should not be used for CVD prevention, absolute risks of CVD are low when MHT is started close to menopause in healthy women and hazard ratios tend to be lower for younger than older women. For women in early menopause and without contraindications to treatment, the benefits of MHT are likely to outweigh the risks when used for menopausal symptom management.

Perimenopausal women's attitude toward the transition and decisions about menopausal hormone therapy (MHT): Study of influencing factors using The Health Belief Model (HBM)

Introduction: Discrepancies between age-dependent benefits of Menopausal Hormone Therapy (MHT) for control of menopause symptoms and the information reaching women concerned have been subject of recurrent debate. Apparently women are mostly misinformed and deprived of appropriate treatments. The present study used the Health Belief Model (HBM) to explore factors influencing health behaviour e.g. perceived susceptibility, severity, risk and benefits, barriers and need for medication.

Use of cardiovascular age for assessing risks and benefits of menopausal hormone therapy.

The Women's Health Initiative studies and others have suggested that menopausal hormone therapy may enhance the risk of new cardiovascular (CV) events in older women and diminish the development of coronary atherosclerosis in younger women. The underlying mechanisms to explain these findings are encapsulated in the term "Timing Hypothesis." Extensive pathophysiologic studies have provided mechanistic evidence for the dichotomous effects of estrogen on coronary artery vasculature. Early in the atherosclerotic disease process, estrogen exerts protective effects on the endothelium and retards plaque formation. Late in the process, estrogen causes plaque erosion or rupture with subsequent thrombosis and acute coronary events. Analysis of the Timing Hypothesis in women examined in the Women's Health Initiative primarily used chronologic age to assess divergent effects of estrogen. The complexity of the data underlying coronary pathophysiology has resulted in controversy whether MHT can be used in older women or those with prior CV disease. In a debate of this issue at a recent International Menopause Society meeting, the concept of using CV age rather than chronologic age was discussed as a practical method of resolving this issue and facilitating therapeutic decisions in older women. This "Personal Perspective" will review the concepts underlying CV age, describe how it is determined, provide support for its utility, and propose future studies using this parameter.

The Benefit of Menopausal Hormone Therapy on Bone Density and Microarchitecture Persists After its Withdrawal.

Menopausal hormone therapy (MHT) favorably affects bone mineral density (BMD). Whether MHT also affects bone microarchitecture, as assessed by trabecular bone score (TBS), has never been evaluated. Our objective was to assess the effect of MHT on TBS and BMD before and after its withdrawal. This was a cross-sectional study. This study included the general community. Data were collected from the OsteoLaus cohort (1500 women aged 50-80 years). After exclusion of women with bone-modulating treatments, 1279 women were categorized according to MHT status into current (CU), past (PU), and never (NU) users. Spine TBS and BMD at lumbar spine, femoral neck, and total hip were assessed by dual X-ray absorptiometry. Age- and body mass index-adjusted analysis showed higher TBS values in CU vs PU or NU (1.31 ± 0.01, 1.29 ± 0.01, and 1.27 ± 0.01, respectively; P < .001). All BMD values were significantly higher in CU vs PU or NU. Compared to NU, PU exhibited higher lumbar spine (0.94 ± 0.01 vs 0.91 ± 0.01 g/cm2; P = .017) and total hip (0.86 ± 0.01 vs 0.84 ± 0.01 g/cm2; P = .026) BMD and a trend for higher TBS (P = .066). The 10-year loss of TBS and BMD at lumbar spine and total hip was significantly lower for both CU and PU vs NU. MHT duration had no effect on bone parameters. In PU, the residual effect on TBS and BMD was significantly more prominent in early discontinuers (<2 years). MHT is associated with bone microarchitecture preservation, as assessed by TBS. The effect of MHT on TBS and BMD persists at least 2 years after withdrawal.

MENOPAUSAL HORMONE THERAPY BENEFITS AND DIFFERENT FORMS.

Declining of ovarian hormone production can seriously disturb the quality of woman's life, with physical and emotional consequences and to potentiate the development of additional health risks such as cardiovascular diseases and osteoporosis which are already present in women of older age. Benefits of Menopausal Hormone Therapy. Menopausal hormone therapy ameliorates the quality of life by resolving the atrophic symptoms and vasomotor problems, protecting from the osteoporosis, maintaining the skin and connective tissue turgor, as well as by improving libido, mood and depression during the menopausal transition. Forms of Menopausal Hormone Therapy. There are several possibilities to treat menopausal problems: estrogen, combination of estrogen and progestogen, androgens, selective estrogen receptor modulators, tissue selective estrogen complex, tibolon and alternatives. Initiating, Monitoring and Discontinuing Menopausal Hormone Therapy. Menopausal hormone therapy should be started when the problems due to menopausal symptoms appear. It is important to have on mind that the effects of hormones depend on age and actual condition of the woman's organism. The goal is effective treatment at the lowest dose and during the shortest interval needed for symptom control. The therapy must be reevaluated every year and potential risks must be discussed as well. Menopausal hormone therapy ameliorates the quality of woman's life in perimenopause. Type, doses and duration of the menopausal hormone therapy should be individualized.

Confronting the challenges of the menopausal transition.

Canada’s Generation X is now entering the menopausal transition and pursuing effective therapy for bothersome vasomotor symptoms. They do so at a time when confusion about the safe and appropriate use of menopausal hormone therapy (MHT) has never been greater. Misplaced fears among women and their health care providers about MHT have, in many circumstances, led them to abandon this most effective therapy. This review discusses the physiology of the menopausal transition, the nature of symptoms related to withdrawal of ovarian estrogen production, and the potential benefits and risks of MHT. It is now clear that for most recently menopausal women the benefits of MHT outweigh the risks. The rationale for choosing different dosages, formulations, and regimens is reviewed.

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.

Risks and benefits of menopausal hormone therapy in postmenopausal Chinese women

The aim of this study was to assess risks and benefits of conjugated equine estrogens (CEE) and medroxyprogesterone acetate (MPA) in postmenopausal Chinese women. A retrospective cohort study was undertaken using the Taiwan National Health Insurance Research Database, a population-based healthcare claims dataset. Eligible women aged 50 to 79 years were classified as exposed to CEE 0.625 mg/day with MPA 5.0 mg/day (estrogen [E] + progestin [P], n = 4,712) or CEE 0.625 mg/day only (E-only, n = 1,208) and were age-matched to unexposed women (n = 10,125). Follow-up was complete in 96% of the participants. The primary outcomes were coronary heart disease (CHD) and invasive breast cancer. The global index summarized risks of primary outcomes, stroke, pulmonary embolism, colon and endometrial cancers, hip fractures, and death. Time-to-event analyses were performed. Median durations of exposure in the E + P and E-only groups were 6.9 and 9 months, respectively. Median follow-up was 110 months. Hazard ratios (95% CI) for E + P exposure were as follows: myocardial infarction, 0.78 (0.51-1.19); CHD death, 1.21 (0.53-2.70); breast cancer, 1.48 (1.20-1.83); global index, 0.79 (0.72-0.87). Hazard ratios for E-only exposure were as follows: myocardial infarction, 0.76 (0.35-1.68); CHD death, 0.57 (0.11-2.80); breast cancer, 1.44 (0.99-2.10); global index, 1.09 (0.92-1.28). Per 10,000 person-years, there were 12 excess breast cancer cases with E + P exposure; there were 39 fewer global index events with E + P exposure. Adjusting for age, statin and aspirin use, hypercholesterolemia, diabetes, and hypertension did not significantly change estimates. In postmenopausal Chinese women, CEE with or without MPA was not associated with increased rates of CHD, but CEE with MPA may be associated with a higher breast cancer rate. E + P exposure conferred lower global index event rates.

Mechanisms of estrogen protection in diabetes and metabolic disease.

Until menopause, women are largely protected against several metabolic disorders, implicating a role for sex hormones. Adiposity and insulin resistance are fundamental features in the pathogenesis of type 2 diabetes mellitus. Emerging data suggest that sex-steroid hormones and adipocyte-derived hormones and cytokines could be associated with type 2 diabetes risk and that some of these novel markers can exhibit a sexual dimorphism with regard to this risk. Evidence suggests that the female hormone, 17β-estradiol protects insulin production and prevents diabetes. Although 17β-estradiol acts primarily via two distinct estrogen receptors (ERs), ERα and ERβ, it appears that ERα protects β-cell survival, whereas ERβ reduces ERα function and provokes β-cell apoptosis. Accordingly, use of menopausal hormone therapy has been shown to reduce diabetes incidence and weight gain. Recent findings that benefits of menopausal hormone therapy might not outweigh the risks in some women do not negate the importance of identifying mechanisms by which 17β-estradiol attenuates the development and progression of metabolic disease. This could lay the ground to the design of pharmacological treatments for the prevention of menopause-associated metabolic disorders that are safer and more efficacious than current hormone-based regimens.

Determinants of Female Reproductive Senescence: Differential Roles for the Ovary and the Neuroendocrine Axis

Aging in women is a complex process that begins with the transition into reproductive senescence and evolves to impact not just women's procreative potential but also multiple health-related parameters including longevity. Although somatic aging is an equal opportunity nemesis, certain disease states correlate highly with ovarian failure and the menopause, such as osteoporosis, diabetes, cardiovascular disease, and compromised cognitive function. Epidemiological studies suggest that a delayed natural menopause confers longevity and decelerates the appearance of many of the debilitating morbidities associated with the menopause. However, recent randomized clinical trials assessing the benefits of menopausal hormone therapy during the postmenopause clearly suggest that attenuation of the negative consequences of reproductive aging involves much more than a simple add back of ovarian steroids in the postmenopause. Conflicts between observations in epidemiological studies and in randomized clinical trials give good reason for continued innovative research focused on identifying the mechanisms that bring about the transition from peak reproductive potential to female reproductive quiescence. This article provides a brief update on our current understanding of the physiological and cellular mechanisms that precipitate and/or commit women to transit into reproductive senescence.

Potential Approaches to Enhance the Effects of Estrogen on Senescent Blood Vessels and Postmenopausal Cardiovascular Disease

Cardiovascular disease (CVD) is more common in postmenopausal than premenopausal women, suggesting vascular protective effects of estrogen. Vascular estrogen receptors ERalpha, ERbeta and a transmembrane estrogen-binding protein GPR30 have been described. Also, experimental studies have demonstrated vasodilator effects of estrogen on the endothelium, vascular smooth muscle and extracellular matrix. However, randomized clinical trials have not supported vascular benefits of menopausal hormone therapy (MHT), possibly due to the subjects' advanced age and age-related changes in estrogen synthesis and metabolic pathways, the vascular ERs number, distribution and integrity, and the post-ER vascular signaling pathways. Current MHT includes natural estrogens such as conjugated equine estrogen, as well as synthetic and semi-synthetic estrogens. New estrogenic formulations and hormone combinations have been developed. Phytoestrogens is being promoted as an alternative MHT. Specific ER modulators (SERMs), and selective agonists for ERalpha such as PPT, ERbeta such as DPN, and GPR30 such as G1 are being evaluated. In order to enhance the vascular effectiveness of MHT, its type, dose, route of administration and timing may need to be customized depending on the subject's age and pre-existing CVD. Also, the potential interaction of estrogen with progesterone and testosterone on vascular function may need to be considered in order to maximize the vascular benefits of MHT on senescent blood vessels and postmenopausal CVD.

Vascular Sex Hormone Receptors and their Specific Modulators in the Management of Postmenopausal Cardiovascular Disease

Cardiovascular disease (CVD) is more common in men and postmenopausal women than premenopausal women, suggesting vascular benefits of female sex hormones. Studies on the vasculature have identified estrogen receptors ERα, ERβ and a novel estrogen binding membrane protein GPR30, that mediate genomic and/or non-genomic effects. Estrogen promotes endothelium-dependent relaxation by inducing the production/activity of nitric oxide, prostacyclin, and hyperpolarizing factor, and inhibits the mechanisms of vascular smooth muscle contraction including [Ca(2+)](i), protein kinase C, Rho kinase and mitogen-activated protein kinase. Additional effects of estrogen on the cytoskeleton, matrix metalloproteinases and inflammatory factors contribute to vascular remodeling. However, the experimental evidence did not translate into vascular benefits of menopausal hormone therapy (MHT), and the HERS, HERS-II and WHI clinical trials demonstrated adverse cardiovascular events. The discrepancy has been partly related to delayed MHT and potential changes in the vascular ER amount, integrity, affinity, and downstream signaling pathways due to the subjects' age and preexisting CVD. The adverse vascular effects of MHT also highlighted the need of specific modulators of vascular sex hormone receptors. The effectiveness of MHT can be improved by delineating the differences in phramcokinetics and pharmacodynamics of natural, synthetic, and conjugated equine estrogens. Estriol, "hormone bioidenticals" and phytoestrogens are potential estradiol substitutes. The benefits of low dose MHT, and transdermal or vaginal estrogens over oral preparations are being evaluated. Specific ER modulators (SERMs) and ER agonists are being developed to maximize the effects on vascular ERs. Also, the effects of estrogen are being examined in the context of the whole body hormonal environment and the levels of progesterone and androgens. Thus, the experimental vascular benefits of estrogen can be translated to the outcome of MHT in postmenopausal CVD, as more specific modulators of sex hormone receptors become available and are used at the right dose, route of administration and timing, depending on the subject's age and preexisting cardiovascular condition.

Estrogenic Compounds, Estrogen Receptors and Vascular Cell Signaling in the Aging Blood Vessels

The cardiovascular benefits of menopausal hormone therapy (MHT) remain controversial. The earlier clinical observations that cardiovascular disease (CVD) was less common in MHT users compared to non-users suggested cardiovascular benefits of MHT. Also, experimental studies have identified estrogen receptors ERalpha, ERbeta and GPR30, which mediate genomic or non-genomic effects in vascular endothelium, smooth muscle, and extracellular matrix (ECM). However, data from randomized clinical trials (RCTs), most notably the Women's Health Initiative (WHI) study, have challenged the cardiovascular benefits and highlighted adverse cardiovascular events with MHT. The discrepancies have been attributed to the design of RCTs, the subjects' advanced age and preexisting CVD, and the form of estrogen used. The discrepancies may also stem from age-related changes in vascular ER amount, distribution, integrity, and post-receptor signaling pathways as well as structural changes in the vasculature. Age-related changes in other sex hormones such as testosterone may also alter the hormonal environment and influence the cardiovascular effects of estrogen. Investigating the chemical properties, structure-activity relationship and pharmacology of natural and synthetic estrogens should improve the effectiveness of conventional MHT. Further characterization of phytoestrogens, selective estrogen-receptor modulators (SERMs), and specific ER agonists may provide substitutes to conventional MHT. Conditions with excess or low estrogen levels such as polycystic ovary syndrome (PCOS) and Turner syndrome may provide insight into the development and regulation of ER and the mechanisms of aberrant estrogen-ER interactions. The lessons learned from previous RCTs have led to more directed studies such as the Kronos Early Estrogen Prevention Study (KEEPS). Careful design of experimental models and RCTs, coupled with the development of specific ER modulators, hold the promise of improving the actions of estrogen in the aging blood vessels and thereby enhancing the efficacy and safety of MHT in postmenopausal CVD.

Hormone Therapy of Premature Ovarian Failure

Ovarian hormones play an important role in women’s health, providing the most reliable and convenient means of contraception and of relieving menopausal symptoms.1,2 Hormone therapy also has other benefits, eg, regulation of menstrual irregularities and relief of dysmenorrhea in menstruating women and prevention of vulvovaginal atrophy and osteoporosis/fractures in postmenopausal women. In addition, natural estrogens, principally 17β-estradiol, and natural progesterone (but not synthetic progestins) have biological effects that protect the vasculature from oxidative and inflammatory injury and prevent cardiovascular disease.3 These functions have been adduced by some to account for the 10- to 15-year delay in presentation of clinical cardiovascular disease and events in women compared with men. In contrast to the unquestioned benefits of endogenous ovarian hormones, hormone therapy of women with ovarian failure, whether naturally occurring or surgically induced, continues to be a topic of active debate in the scientific and popular literature. Although observational studies have shown substantial (≈50% reduction in coronary heart disease) benefit of menopausal hormone therapy (also referred to as “menopausal hormone replacement therapy” or “hormone replacement therapy”) in women who choose to take them (usually beginning treatment in the perimenopausal or early postmenopausal period), randomized, controlled trials have not confirmed a cardioprotective effect and have even shown evidence of harm. Accordingly, current guidelines do not recommend use of menopausal hormone therapy for the prevention or treatment of cardiovascular disease in women. Important limitations of the available randomized, controlled trials are that they typically enrolled women who were >60 years of age and, thus, were ≥10 years postmenopause and that they typically used nonphysiological hormone preparations, eg, conjugated equine estrogen and the synthetic progestin medroxyprogesterone …