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.     

Metabolic syndrome and the menopause

The metabolic syndrome consists of a combination of risk factors that include abdominal obesity, atherogenic dyslipidaemia, hypertension and insulin resistance. It increases the risk of cardiovascular disease and type 2 diabetes. The increased risk of cardiovascular disease is higher in women than in men. The first manifestation of metabolic syndrome may occur in pregnancy presenting as gestational diabetes or preeclampsia. Both conditions are associated with increased insulin resistance. Also metabolic syndrome is more common in polycystic ovarian syndrome. It has been suggested that there is a metabolic syndrome resulting from the menopause due to estrogen deficiency, as many of the risk factors are more prevalent in postmenopausal women. Also estrogen replacement improves insulin sensitivity and reduces the risk of diabetes. The key elements in managing the metabolic syndrome are weight reduction, increasing physical activity and diet modification. If blood pressure, lipid and glycaemic control are not achieved through these interventions then pharmacological therapy will be required.     

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.     

Testosterone and the breast

Although women have been treated with testosterone (T) for female sexual dysfunction since the 1950s, the role of T in normal female physiology is not yet fully defined. One of the major safety concerns of androgen therapy is whether androgens have a stimulatory effect on the breast that could lead to breast carcinomas. The proposed mechanisms for such stimulation include local estrogen production from the aromatase enzyme complex present in the breast tissue or by the direct stimulation of the androgen receptor. Predominant data from in vitro studies have shown that androgens actually have apoptotic and antiproliferative effects and not stimulatory effects. Animal models have shown similar results to in vitro studies, finding that androgens inhibit breast cancer growth. Prospective and retrospective epidemiological analyses have shown mixed outcomes, with no clear consensus regarding androgen use and breast cancer risk. Hyperandrogenism in patients with polycystic ovarian syndrome with elevated levels of endogenous T is not associated with an increased risk of breast cancer and may, in fact, be protective. Another human model with excess of T is female-to-male transgenderism, in which genotypic women are treated with large doses of exogenous T with no increased risk. High-dose androgen therapy also has been effective in treating patients with advanced breast cancer. Thus, the preponderance of data suggests that T use in females is not associated with an increased risk of breast carcinoma.     

Homocysteine, menopause and cardiovascular disease

A high plasma concentration of total homocysteine (tHcy) and a deficiency of vitamins related to its metabolism, such as vitamin B12 and folate, have been associated with cardiovascular disease. Postmenopausal women have higher concentrations than age-matched premenopausal women, and plasma concentrations of homocysteine in postmenopausal women taking hormone replacement therapy are significantly lower than they are in those who do not take estrogen supplements. Because of the possible mixed effects of HRT on cardiovascular events, surrogate end-points must be evaluated with caution. While measuring homocysteine levels is relatively simple, evidence from well designed trials is awaited before population screening can be advocated. Also, the benefits of reducing homocysteine levels with folic acid and vitamin B6 and B12 supplements are highly debated.     

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.     

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.     

The disconnection between policy practices and women's lived experiences: combining work and life in the UK and the Netherlands

Combining work and family life is central to women's participation in the labour market. Work–life balance has been a key objective of UK and Dutch policy since the 1990s, but policies created at the national level do not always connect with the day to day experiences of women juggling caring and domestic responsibilities with paid work. Using qualitative data from a European Social Fund Objective 3 project the paper explores women's lived realities of combining work and family life in the UK in comparison to the Netherlands as a possible ‘best practices’ model. We argue that women in both countries experience work–life balance as an ongoing process, continually negotiating the boundaries of work and family, and that there needs to be a more sophisticated appreciation of the differing needs of working parents. Whilst policy initiatives can be effective in helping women to reconcile dual roles, many women in both the UK and the Netherlands still resolve these issues at the individual or personal level and feel that policy has not impacted on their lives in any tangible way.     

Health-related quality of life in old age: preliminary report on the male perspective

Health-related quality of life is a key element of successful aging. With life expectancy increasing, postmenopausal estrogen/gestagen replacement therapy has been under discussion for some time with the aim of achieving a higher quality of life in old age. For a long time, the relevance of hormonal aging was only discussed with reference to women; however, more recent work deals with concepts that affect both sexes. According to recent studies, numerous symptoms and complaints which may impair quality of life, can be attributed to hormonal changes in old age in both women and men. The majority of age-related complaints, such as a decline in physical performance, decreased sexual activity and a deterioration of general well-being, are strongly reminiscent of the symptoms of classical pituitary disorders in adulthood. Since the early 1990s, scientific studies have also been investigating the influence of hormone 'replacement' in elderly men, using, for example, growth hormones. However, until now there has been no suitable measure for assessing the quality of life specifically in elderly men. In a research project aimed at developing a questionnaire (the VITA? questionnaire), roughly equal numbers of elderly men and women were asked about their subjective health and quality of life. It was found that men assessed their health-related quality of life very positively in a number of different dimensions of the questionnaire. In the present article the individual aspects of the quality of life of men are described and examples of gender-related differences are presented and discussed.     

Functional foods for cardiovascular disease in women

Cardiovascular disease (CVD) is the leading cause of death in women. Functional food consumption can play an important role in the prevention and treatment of CVD. The purpose of this review is to establish recommendations for the intake of functional food ingredients in a healthy diet, such as soy proteins and isoflavone, omega-3 fatty acids (FAs) from fish oils (FOs) including eicosapentaenoic acid (EPA) and docoshexaenoic acid (DHA) and plant sterols-(PS) enriched foods - for prevention and treatment of CVD in postmenopausal women. First, controversial results exist on CVD risk factors after intake of soy protein and isoflavone that indicates that further clinical studies need to be done to better understand their role in maintaining and improving cholesterol levels. However, since soy contains polyunsaturated fats, replacing some higher fat meat protein sources with soy products may contribute to cardiovascular health. Secondly, FOs, including EPA and DHA, have shown promising effects for lowering triglyceride levels. In addition, emerging research appears to show that omega-3 FAs may have additional health effects with improved arterial health and a reduction in oxidative stress in postmenopausal women. Thirdly, foods and beverages supplemented with PS may reduce cholesterol; therefore, are a worthy addition to interventions aimed at lowering heart disease risk in women. Overall, incorporating functional foods into a healthy diet may be beneficial in helping to reduce lipids levels and thus the risk of CVD.     

Not Such Strange Bedfellows After All

Abstract

The irritable bowel syndrome (IBS) is best defined as abdominal pain of greater than three months duration, with or without a change in bowel habits. Barium studies, sedimentation rate, and the lactose tolerance test are usually within normal limits. The underlying physiology includes a predominance of 3 cycles/minute basal electrical rhythm (BER). The abdominal pain is poorly localized and usually intermittent, without a clear relationship to medication. Differential diagnosis should include inflammatory bowel disease, infectious colitis or gastroenteritis, lactose intolerance, gallbladder disease, peptic ulcer disease, pelvic inflammatory disease, ovarian cysts and tumors, and endometriosis. A sedimentation rate is an important part of the diagnostic workup which may or may not include barium studies. Anticholinergics have been shown to alter the abnormal BER of irritable bowel syndrome and have proven to be of use in treating this syndrome. Dietary counseling should include advising the patient to eat slowly and at regular hours, and heat applied to the abdomen in the form of a hot water bag has been useful. “Overprogrammed” individuals with irritable bowel syndrome should be advised to modify their activities as this type of stress may give rise to the symptoms.

“Effect of Estrogen/Progestin Potency on Lipid/Lipoprotein Cholesterol,” PATRICIA WAHL, CAROLYN WALDEN, ROBERT KNOPP, JOANNE HOOVER, ROBERT WALLACE, GERARDO HEISS, and BASH RIFKIND. We studied 374 women taking oral contraceptives, 284 women taking estrogen preparations after menopause, and 1086 women taking no hormones, to determine the relation of plasma lipids and lipoprotein cholesterol concentrations to various types of estrogen/progestin formulations. Premenopausal women using oral contraceptives containing a relatively low dose of estrogen combined with a medium or high dose of progestin (Norlestrin, Ovral, or Demulen) had a 24 per cent higher median concentration of low-density-lipoprotein cholesterol than did those not using hormones (P < 0.05). Women using oral contraceptives that are high in estrogen and low in progestin (Envoid or Oracon) had significantly higher concentrations of high-density-lipoprotein cholesterol than did nonusers; those using Ovral, a low-estrogen and high-progestin formulation, had significantly lower levels of high-density-lipoprotein cholesterol. In postmenopausal women the use of estrogen was associated with concentrations of low-density-lipoprotein cholesterol that were 11 to 19 per cent below the levels in postmenopausal women who did not use hormones. The effects of estrogen-progestin balance on low-density and high-density lipoproteins may underlie the increased incidence of stroke and myocardial infarction in women of childbearing age who take oral contraceptives. (New England Journal of Medicine 1983;308:862–7.)     

Mental health around and after the menopause

The menopause is a time in a woman's life when it is recognized that biological and social changes can impact upon mental wellbeing. Several studies have investigated the relationship between menopause and psychological symptoms, especially depression, with mixed results. In part, this is due to a considerable overlap between depressive symptoms and those due to declining estrogen levels, causing challenges in assessment. However it appears that vulnerable women are at a higher risk of succumbing to depression during menopausal transition. Antidepressants remain the mainstay of treating depressive symptoms, with little conclusive evidence for hormone replacement therapy. Memory problems during menopause are a common complaint, but there is no demonstrated link to subsequent dementia. This paper also reviews considerations of diagnosis and treatment of postmenopausal depression.     

An intersectional perspective on Muslim women's issues and experiences in employment

Drawing on a qualitative study of second‐generation Pakistani heritage Muslim women in employment in the UK, this article uses and develops an intersectional perspective to explain the interconnected and overlapping factors, such as gender, ethnicity and religion that affect these women at work. It also considers individual strategies and resources these women use to address any obstacles in the way of their employment and careers. The article uses the notions of inequality regimes and intersectionality to explain inequality in the workplace and the complex challenges facing Muslim female employees. The results show that these women continue to face a myriad of challenges in the UK workplace, and that a unilateral focus on gender does not sufficiently explain the work‐related experiences of second‐generation Muslim women in the UK. Therefore, it is important to take into account gender's intersection with ethnicity and religion.     

The use of selective estrogen receptor modulators on bone health in men

Selective estrogen receptor modulators (SERMs) represent a class of drugs that act as agonist or antagonist for estrogen receptor in a tissue-specific manner. The SERMs drugs are initially used for the prevention and treatment of osteoporosis in postmenopausal women. Bone health in prostate cancer patients has become a significant concern, whereby patients undergo androgen deprivation therapy is often associated with deleterious effects on bone. Previous preclinical and epidemiological findings showed that estrogens play a dominant role in improving bone health as compared to testosterone in men. Therefore, this evidence-based review aims to assess the available evidence derived from animal and human studies on the effects of SERMs on the male skeletal system. The effects of SERMs on bone mineral density (BMD)/content (BMC), bone histomorphometry, bone turnover, bone strength and fracture risk have been summarized in this review.     

Potential strategies to avoid progestogen-induced premenstrual disorders

Non-hormonal approaches to premenstrual syndrome (PMS) treatment such as selective serotonin reuptake inhibitors are by no means effective for all women and frequently we must resort to endocrine therapy. During many of the hormonal approaches, PMS-like symptoms can be introduced or re-introduced during the necessary cyclical or continuous progestogen component of the therapy. This is seen with combined oral contraception, progestogen only contraception, progestogen therapy for heavy menstrual bleeding and endometriosis, sequential hormone replacement therapy and any therapeutic strategy for premenstrual syndrome where it is necessary to provide endometrial protection, including estrogen suppression of ovulation or add-back during gonadotrophin releasing hormone suppression. The link to progestogen is very often missed by health professionals. When the pattern of symptoms mimics the cyclicity of PMS, it is termed progestogen-induced premenstrual disorder. The need to use progestogen to protect the endometrium from the proliferative actions of estrogen can pose insurmountable difficulties in managing premenstrual disorders. In the absence of any really useful evidence, nearly all practice in this area depends on clinician experience. We cannot afford to wait for adequate research evidence to be produced - it never will - and so we must rely on empirical findings, clinical experience, theoretical strategies and common sense.     

Understanding the self-organization of occupational sex segregation with mobility networks

Decades after the beginning of the gender revolution, most women and men still work in sex-typed occupations. This is a primary driver of the gender wage gap. Most research describing the patterns of occupational sex segregation focuses on supposedly innate job characteristics that match gender stereotypical abilities and preferences, such as the use of mathematical skills or social skills, on income and status differences between occupations, and on organizational job characteristics, for example, the need to work long hours. However, beyond such occupational attributes, sex segregation is hypothesized to exhibit emergent patterns that are linked to the interdependent job mobility of women and men, in particular, men selectively leaving feminizing occupations. Developing new tools inspired by statistical network research, and using representative, longitudinal data that contain detailed occupational mobility from the UK between 2000 and 2008, this replacement mechanism is analyzed. It is shown that 19–28% of observed sex segregation is linked to this emergent phenomenon in a statistical model that disentangles the various predictors of the allocation of women and men to different occupations. This makes it the most important predictor of segregation in contrast to concurrently modelled explanations based on occupational characteristics.Data and materials availabilityThe BHPS data and the LFS data are available from the UK Data Service (https://www.ukdataservice.ac.uk/). The O*NET data is available from the O*NET homepage (https://www.onetcenter.org/). Software implemented in the environment R and code for data analysis are available upon request from the authors.     

Use of unopposed systemic estrogen therapy in non-hysterectomized women: a population-based study in the UK

A population study of 28 general practices in Oxfordshire, UK found that 0.028% of 17,712 non-hysterectomized women aged 45-60 years were using systemic unopposed estrogen. This is significantly lower than that reported in the Million Women Study.     

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.     

Estrogen treatment affects brain functioning after menopause

Sex hormones have powerful neuromodulatory effects on functional brain organization and cognitive functioning. This paper reviews findings from studies investigating the influence of sex hormones in postmenopausal women with and without hormone therapy (HT). Functional brain organization was investigated using different behavioural tasks in postmenopausal women using either estrogen therapy or combined estrogen plus gestagen therapy and age- and IQ-matched postmenopausal women not taking HT. The results revealed HT-related modulations in specific aspects of functional brain organization including functional cerebral asymmetries and interhemispheric interaction. In contrast to younger women during the menstrual cycle, however, it seems that HT, and especially estrogen therapy, after menopause affects intrahemispheric processing rather than interhemispheric interaction. This might be explained by a faster and more pronounced age-related decline in intrahemispheric relative to interhemispheric functioning, which might be associated with higher sensitivity to HT. Taken together, the findings suggest that the female brain retains its plasticity even after reproductive age and remains susceptible to the effects of sex hormones throughout the lifetime, which might help to discover new clinical approaches in the hormonal treatment of neurological and psychiatric disorders.     

Systemic lupus erythematosus and hormone replacement therapy

The indications for hormone replacement therapy (HRT) in postmenopausal women is the treatment of climacteric symptoms and the prevention of osteoporosis. Women with systemic lupus erythematosus (SLE) are more likely to have a premature menopause, osteoporosis and cardiovascular disease. HRT can induce SLE flares and cardiovascular or venous thromboembolic events. Therefore it should not be used in women with active disease or those with antiphospholipid (aPL) antibodies. In general, it should be used only for patients without active disease, a history of thrombosis or aPL antibodies. Non-oral administration of estrogen is recommended because of its lesser effect on coagulation. With regard to the progestogen, progesterone or pregnane derivatives are preferred. Otherwise, non-estrogen-based strategies should be used.