The future of the new selective estrogen receptor modulators

Selective estrogen receptor modulators (SERMs) are compounds that display mixed estrogen agonist/antagonist activity. Currently, four SERMs are licensed for clinical use: tamoxifen, toremifene, clomifene and raloxifene. The STAR and RUTH trials have provided useful data about the potential role of SERMs in the primary prevention of breast cancer and cardiovascular disease in postmenopausal women. New-generation SERMs, such as bazedoxifene, arzoxifene, lasofoxifene and ospemifene, are currently being evaluated. The aim is to find a SERM that conserves the skeleton and prevents breast cancer without increasing the risk of endometrial cancer and venous thromboembolism, and without inducing hot flushes. Technological advances in the study of estrogen receptor activation will provide key information for drug development.     

Calcium and vitamin D--for whom and when

The basis of 'nutritional' interventions for the prevention of postmenopausal osteoporosis and osteoporotic fracture is a large topic with much genetic and biochemical evidence, as well as the results of randomized controlled trials, to guide the investigator and clinician. The efficacy of treatment with calcium and vitamin D was once controversial, but with the advent of controlled clinical trials using bone mineral density as an endpoint it has become clear that calcium with or without vitamin D therapy can lead to reductions in the rate of bone loss in postmenopausal women of all ages. Furthermore, with certain caveats, calcium with vitamin D therapy in the older postmenopausal woman can lead to useful reductions in fracture rates and falls, especially in populations with reduced exposure to sunlight, which is potentially the majority of postmenopausal women in both developed and developing countries. However, estrogen, selective estrogen receptor modulators (SERMs) and bisphosphonates (especially when given in combination with calcium and vitamin D) are more efficacious in preventing fracture, particularly in postmenopausal patients with impaired bone structure.     

Primary prevention of coronary heart disease in women

The British Menopause Society Council is committed to provide up-to-date authoritative reviews to aid health professionals to inform and advise women about key issues in postreproductive health. Coronary heart disease (CHD) is a leading cause of death in women. Observational studies have consistently shown estrogen to help prevent CHD in postmenopausal women. The large randomized controlled Women's Health Initiative (WHI) trial did not confirm these observational findings. However, further analyses of the WHI study as well as the observational Nurses' Health Study have now found that the timing of onset of hormone replacement therapy (HRT) use is important and that estrogen may have a protective role in CHD in women aged 50-59 years. This consensus statement will examine the evidence regarding HRT and non-estrogen therapies (lipid lowering agents, aspirin, antihypertensives, antidiabetic medications, selective estrogen receptor modulators [SERMs]) as well as diet, lifestyle and smoking cessation in the primary prevention of CHD in women.     

Tissue-selective agents: selective estrogen receptor modulators and the tissue-selective estrogen complex

Menopause has been associated with vasomotor symptoms, vulvar-vaginal atrophy and osteoporosis. One of the goals in exploring the potential of selective estrogen receptor modulators (SERMs) was to determine if they could prevent fractures, reduce menopausal symptoms and treat vaginal atrophy, while being neutral or protective on the uterus, breast and cardiovascular system. However, no SERM to date has achieved this goal. More recently, the idea of pairing a SERM with estrogen(s), known as a tissue-selective estrogen complex (TSEC), has been studied in postmenopausal women. A TSEC combines the complementary tissue-selective activities of a SERM and estrogen(s), in an attempt to gain the benefits of each with better overall tolerability. The Selective estrogen Menopause And Response to Therapy (SMART) trials were multicentre, randomized, double-blind, placebo- and active-controlled phase 3 studies evaluating the safety and efficacy of the SERM, bazedoxifene (BZA) paired with conjugated estrogens (CEs) in healthy postmenopausal women. In the first SMART trial, BZA/CE protected the endometrium from estrogenic stimulation, relieved hot flushes and maintained bone mass, with rates of amenorrhea, breast pain and overall adverse events similar to those with placebo in more than 3400 women over two years. BZA 20 mg was the lowest effective dose of BZA in BZA/CE to protect the endometrium and maintain bone mass when paired with CE 0.625 mg and CE 0.45 mg. In SMART-2, these BZA/CE doses significantly reduced the frequency and severity of hot flushes over 12 weeks. Collectively, these data support the TSEC containing BZA/CE as a new paradigm for treating menopausal symptoms and preventing osteoporosis while protecting the endometrium from unopposed estrogenic stimulation.     

l-Arginine and tetrahydrobiopterin,but not sodium nitrite partially restored erectile dysfunction in aged rats

This paper gives an overview of our own studies and the literature on the biosynthesis and metabolism of estrogens in elderly men, the estrogen action in the male, and the clinical usefulness of estrogen therapy, including the phytoestrogens. Finally, the paper includes a short review of our knowledge of xenoestrogens and men's sexual health. A strong estrogen-deficient status is seen in male patients with mutations of the estrogen receptors or in cases of deviations of the aromatase gene. On the other hand, there are no clear age-dependent changes in estrogen secretion. But, in men with disorders of glucose metabolism and also of increased body mass index, the serum estrogen concentrations are significantly elevated. There are also strong positive correlations between serum estrogen levels and bone density, including prevalence of fractures and mood in men. New fields of interest are natural fatty esters of endogenous estrogens, e.g. lipoprotein-associated estrogens, and the role and clinical significance of tissue-specific, local estrogen biosynthesis (e.g. different promoters of the aromatase gene). Exogenous estrogen treatment is focused today on patients with normal testosterone and low levels of circulating estrogens documented on several occasions and with clinical symptoms of hormone deficiency; male-to-female transsexuals; and selected patients with prostate cancer. Some clinical studies show the benefits of estrogen treatment on some cardiovascular parameters and for treating selected signs of mental stress. An indirect estrogen replacement can occur if dehydroepiandrosterone is given orally to men. The clinical usefulness of dissociated estrogens, including non-feminizing estrogens and selective estrogen receptor modulators, is still an open question. The beneficial action of phytoestrogens in lowering the clinical symptoms of benign prostatic hyperplasia is well documented. Finally, the question about the definitive influence of so-called endocrine disruptors (xenoestrogens) on sexual functions in men is also discussed.     

Androgens, apoE, and Alzheimer's disease

Increasing evidence indicates that there are reductions in estrogen and androgen levels in aged men and women. These hormonal reductions might be risk factors for cognitive impairments and the development of Alzheimer's disease (AD). Aged people show improved cognition after treatments with sex steroids. Therefore, ongoing clinical AD trials have been designed to evaluate the potential benefits of estrogen therapy in women and testosterone therapy in men. Apolipoprotein E (apoE) plays an important role in the metabolism and redistribution of lipoproteins and cholesterol. The three major human apoE isoforms, apoE2, apoE3, and apoE4, differ in their effects on AD risk and pathology. Here I review various mechanisms proposed to mediate the differential effects of apoE isoforms on brain function and highlight the potential contribution of detrimental isoform-dependent effects of apoE on androgen- and androgen receptor (AR)-mediated pathways. I also discuss potential interactions of androgens with other AD-related factors.     

Bazedoxifene: a new selective estrogen receptor modulator for postmenopausal osteoporosis

An ongoing need for safe and effective pharmacological therapies exists for postmenopausal osteoporosis, which imposes a significant burden on both women and the health-care system. Bazedoxifene is a novel selective estrogen receptor modulator with a unique tissue-selectivity profile. In phase 3 clinical trials of nearly 10,000 postmenopausal women, bazedoxifene was shown to significantly reduce the risk of new vertebral fracture versus placebo, with favourable effects on bone mineral density, bone turnover markers and the lipid profile. Moreover, in a subgroup of women at increased risk of fracture, bazedoxifene significantly decreased non-vertebral fracture risk versus both placebo and raloxifene. Bazedoxifene has been shown to be safe and well tolerated, with no evidence of endometrial or breast stimulation. These data suggest that bazedoxifene may offer significant clinical benefit for postmenopausal women with or at risk of developing osteoporosis, which may subsequently lessen the medical and economic burden of this disease.     

Menopause and schizophrenia

We have come a long way from our understanding of the menopause as it was described in the 11th century by Trotula of Salerno, a female gynaecologist who said 'there are older women who give forth blood matter especially as menopause approaches them'. Yet very little is known about the impact menopause has on the mental health of women especially severe and enduring illnesses like schizophrenia. A lot of research has shown that estrogen acts as a protective factor due to its antidopaminergic properties, thus providing an explanation for the increase in risk of a new psychotic disorder during the menopause. This has further led to the hypothesis of hormone replacement therapy providing benefits in the management of these disorders in menopausal women. This review article highlights the importance of a clear understanding of this phase of life in patients suffering from or who present with a risk of developing schizophrenia.     

Examining Interactions of Marriage and Self-Efficacy Beliefs of Individuals with Rheumatoid Arthritis: A Conceptual Framework

The systemic and chronic nature of rheumatoid arthritis (RA) impacts functional and emotional health of the individuals including marital, family, and work responsibilities. Due to the costs and side effects of drugs, proponents of arthritis management advocate for examining psychosocial factors that improve the disease management of RA. In this paper, we propose that marital quality is associated with perceived self-efficacy among individuals with RA. We further hypothesize that this relationship is moderated by functional disability, pain levels, and the demographics of the individual. Based on the literature review we draw conclusions about the potential implications of marital quality on perceived self-efficacy. We also discuss practice and research implications of this association, including the development of educational initiatives.     

The Race and Class Privilege of Motherhood: TheNew York Times Presentations of Pregnant Drug‐Using Women1

Prior research has examined race and class bias embedded in media presentations of pregnant drug users; however, this past research is limited in identifying biases because it focuses on single substances—primarily crack cocaine. I build on this work by conducting a comparative analysis of more than 15 years worth of New York Times articles on three drugs (crack cocaine, alcohol, and tobacco) used during pregnancy. These three drugs have varying levels of deleterious effects on fetal development and infant health, as well as varying levels of use by poor and minority women. Because of this variation, I am able to assess whether media coverage of pregnant drug‐using women is proportional to the documented adverse consequences of specific drugs or, rather, whether media coverage is higher and more negative for poor and minority pregnant women regardless of the degree of adverse health consequences associated with the specific drug used. Through this analysis, I demonstrate that the prevalence and framing of news stories about pregnant drug‐using women has little to do with protecting the health of children. Rather, concern for children is a rhetorical tool used to define poor and minority women as bad mothers and blame them for contemporary changes in families.     

Lithium: underappreciated and underused?

Lithium is a remarkable drug with a fascinating history. Although less popular than other anticonvulsant and atypical antipsychotic mood-stabilizing drugs, lithium is beneficial in bipolar disorder and may be superior to other drugs for treatment-resistant depression and for reducing suicidal behaviors. Various studies have demonstrated that lithium has neuroprotective and neurotrophic cellular effects in the brain, suggesting it may be "brain healthy" for patients with mood disorders and useful for patients with other neurodegenerative disorders. In this article, I describe the history of lithium and review important aspects of its clinical use.     

Harnessing hormonal signaling for cardioprotection

Cardiovascular disease is the leading cause of death in women in the Western world and is predominant among the elderly. A large body of evidence suggests that hormonal signaling plays a critical role in the regulation of cardioprotective mechanisms, as premenopausal women are at significantly lower risk of heart disease compared with men, but the risk greatly increases with the onset of menopause. This association indicates that estrogen may protect the heart from cardiovascular disease. Whereas a number of analyses of the effects of hormone replacement therapy (HRT) on postmenopausal women supported the idea that estrogen is a cardioprotective factor, the findings of the more recent Women's Health Initiative (WHI) study suggested that HRT may actually increase the risk of cardiovascular events. These conflicting reports have left both patients and clinicians reluctant to continue using current HRT regimes. The WHI findings do not, however, negate the epidemiological link between menopause and increased cardiovascular risk. Hence, the identification of the specific actions of estrogen that promote cardioprotective pathways without enhancing deleterious vascular mechanisms may provide novel estrogen-based alternatives to current HRT strategies. In this Review, we outline the known actions of estrogen on the cardiovascular system, focusing on cardioprotective mechanisms that may be targeted for the development of new therapeutic approaches.     

Perceived discrimination and health: Paradigms and prospects

This article reviews recent research on the effects of perceived discrimination on subsequent mental and physical health. I argue that despite legal reforms banning discrimination since the civil rights era, discrimination persists, posing an ongoing health risk and maintaining social health inequalities. Couched within broader health trends, this covers ongoing challenges and new developments, particularly related to measurement, and promising directions. As the most commonly reported location of individual discrimination is at work, this review concludes by arguing for the significance of the workplace as a unique context ripe for further inquiry for scholars interested in health inequality.     

Interactive and higher-order effects of social influences on drug use.

The study of moderators and higher-order effects of social influences on drug use has many implications for theories of health behavior. In the present study, we investigated the longitudinal predictive effects of some of the prominent moderator variables that represent forms of susceptibility toward social influence in teenage drug use. We also studied the possibility that social influence may predict drug use in nonlinear (quadratic) forms, consistent with theories proposing that threshold or decelerating effects may occur in social influences on normatively sanctioned behaviors. Results showed that several of the interactive and quadratic predictive effects were significant. The findings supported the views that certain moderator variables act as buffers, which either protect the individual from social pressures to use drugs, or make the individual more susceptible to such pressures. In addition, two of the obtained quadratic effects of social influence lent support to the application of social impact theory to drug use. Overall, our findings suggest that interactive and nonlinear approaches to social influences on drug use provide a unique and viable theoretical perspective from which to construe this problem health behavior.     

Testosterone and body functions

Testosterone supplementation can help reduce many of the symptoms associated with androgen deficiency in the aging male by its effects on various parts of the body. Bone mineral density can decrease in the hypogonadal man and this may contribute to the increased fracture rate in the elderly. Testosterone therapy can improve bone mineral density and bone architecture by increasing bone formation and decreasing bone resorption – the possible benefits on fracture rate are unknown. Testosterone also improves body composition by reducing body fat mass and increasing lean body mass, and by increasing epidermal thickness, but its effects on muscle strength are still debated. In patients with diabetes and androgen deficiency, testosterone supplementation appears to reduce blood glucose and this could have important implications for cardiovascular risk reduction in patients with diabetes or the metabolic syndrome. The wide-ranging benefits of testosterone therapy in young and old men are clear and it appears that the route of administration (intramuscular, oral, or transdermal) does not alter this fact, but future work could illustrate even more profound effects of testosterone (e.g., in reducing cardiovascular risk) that could result in its recommended use in a wider range of patients.     

Health Consequences of Laws and Public Policies That Target,or Protect,Marginalized Populations

Laws and public policies that are seemingly unrelated to health, nevertheless, can have health consequences in populations that are targeted, or protected, by that legislation. In this paper, I first review research showing that systems of oppression, such as racism and sexism, can cause negative health outcomes. I next discuss mechanisms underlying the relationship between such systems of oppression and negative health effects. Last, I review research showing that laws and public policies can be seen as components of systems of oppression and, as such, are linked to health outcomes. Some policies and laws I include in my review are anti‐same‐sex marriage bills, punitive immigration laws, stop and frisk policies, and state‐level voter disenfranchisement policies. The link between health outcomes and laws and public policies has implications for the current political climate.     

Should St. Merciful Hospital Become CorpHealth,Inc.?: Ownership and Quality in U.S. Health Care Organizations

In this article, a review of empirical research on ownership and quality of care suggests the existence of a quality gap between for‐profit and nonprofit firms in some health sectors, depending on the prevailing type of financial payment for health care. Results of a theoretical model incorporating quality of care suggest that the nondistribution constraint is a simple and powerful explanation for a higher level of patient care quality at nonprofit health care facilities when reimbursement for health services is fixed prospectively. Analysis suggests that review of future conversions of health care facilities from nonprofit to for‐profit status should take into consideration the implied effects of the conversion on patient outcomes.