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.     

Physical activity and hormone-replacement therapy: interactive effects on cognition?

The purpose of this study was to examine the interactive effects of hormone-replacement therapy (HRT) and physical activity (PA) on the cognitive performance of older women. Postmenopausal women (n = 101) were recruited to complete a PA questionnaire, provide demographic information, and perform the digit-symbol substitution task (DSST) and the trail-making tests (TMT). Regression analyses were conducted for participants with complete data for each cognitive test (DSST n = 62; TMT n = 69). For both tasks, results indicated that PA and education were positively related and age was negatively related to cognitive performance. The interaction of HRT with PA did not add to the predicted variance of either measure of cognitive performance. This was true even after limiting the HRT users to women using unopposed estrogen. It is concluded that the beneficial relationship between PA and these two measures of cognitive performance in postmenopausal women exists irrespective of HRT use.     

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.)     

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.     

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.     

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.     

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.     

Pheromonal influences on sociosexual behavior in postmenopausal women

To determine whether a putative human sex‐attractant pheromone increases specific sociosexual behaviors of postmenopausal women, we tested a chemically synthesized formula derived from research with underarm secretions from heterosexually active, fertile women that was recently tested on young women. Participants (n = 44, mean age = 57 years) were postmenopausal women who volunteered for a double‐blind placebo‐controlled study designed “to test an odorless pheromone, added to your preferred fragrance, to learn if it might increase the romance in your life.” During the experimental 6‐week period, a significantly greater proportion of participants using the pheromone formula (40.9%) than placebo (13.6%) recorded an increase over their own weekly average baseline frequency of petting, kissing, and affection (p = .02). More pheromone (68.2%) than placebo (40.9%) users experienced an increase in at least one of the four intimate sociosexual behaviors (p = .04). Sexual motivation frequency, as expressed in masturbation, was not increased in pheromone users. These results suggest that the pheromone formulation worn with perfume for a period of 6 weeks has sex‐attractant effects for postmenopausal women.     

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.     

Biological factors in human sexuality

This paper considers a number of key concepts relevant to biological determinants of human sexuality, including sexual differentiation, brain mechanisms involved in sexual response, the role of sex hormones, and the sexual effects of drugs. The paper concludes with consideration of how little is known about the interaction between biology and culture in shaping human sexuality, and the need for research in this area.     

Menopause and sexual desire: the role of testosterone

The present short review underlines the role of testosterone (T) in the motivational and satisfaction components of women's sexuality and critically discusses the strategies to treat hypoactive sexual desire disorder (HSDD), a condition of low desire associated with personal and/or interpersonal difficulties, which is more common in surgical menopausal women. There are multiple ways androgens target the brain regions (hypothalamic, limbic and cortical) involved in sexual function and behaviour. Even though circulating available androgens have been implicated in several domains of sexual response, they seem to be related weakly to symptoms, such as low sexual desire, poor sexual arousal, orgasm and diminished well-being in postmenopausal women. The possibilities of treating low sexual desire/HSDD are multifaceted and should include the combination of pharmacological treatments able to maximize biological signals driving the sexual response, and individualized psychosocial therapies in order to overcome personal and relational difficulties. Transdermal T has been shown to be effective at a dose of 300 μg/day both in surgically and naturally menopausal women replaced with estrogen or not, without any relevant side-effects. However, the decision to treat postmenopausal women with HSDD with T is mainly based on clinical judgement, after informed consent regarding the unknown long-term risks.     

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.     

Dysfunctional sexual beliefs as vulnerability factors to sexual dysfunction

The differences on sexual beliefs presented by men and women with sexual dysfunction and their sexually functional counterparts were investigated. A total of 488 participants (160 females and 232 males without sexual problems and 47 females and 49 males with a DSM-IV diagnosis of sexual dysfunction) answered the Sexual Dysfunctional Beliefs Questionnaire. Findings showed that, although effects have only reached statistical significance for the female group, both dysfunctional men and women endorsed more sexual dysfunctional beliefs than functional. Women presented significantly more age related beliefs (after menopause women loose their sexual desire, as women age, the pleasure they get from sex decreases) and body image beliefs (women who are not physically attractive cannot be sexually satisfied). Additionally, sexually dysfunctional males presented higher scores (not statistically significant) on 'macho' belief (a real man has sexual intercourse very often) and the beliefs about women satisfaction (the quality of the erection is what most satisfies women). Overall, findings support the idea that sexual beliefs may play a role as vulnerability factors for sexual dysfunction.     

Dehydroepiandrosterone (DHEA) and the menopause: an update

Since we last reviewed this topic in 2001, considerably more information about dehydroepiandrosterone (DHEA) has accrued, but this has not necessarily left us any wiser about the use of this steroid in postmenopausal women. There is no further evidence that DHEA supplementation is likely to be useful in the prevention of cardiovascular disease or cognitive impairment, or in the promotion of wellbeing. Evidence has, however, accumulated for beneficial effects of DHEA on osteoporosis, both in postmenopausal women and in patients receiving long-term glucocorticoid therapy. What is also emerging is a link between low DHEA levels and cardiovascular risk, and between high DHEA levels and breast cancer risk. In fact, the benefits and adverse effects of DHEA administration in postmenopausal women increasingly resemble those of conventional hormone replacement therapy. Overall, we conclude that DHEA is not currently to be recommended for therapeutic use in the majority of postmenopausal women. However, DHEA supplementation may be of benefit in two specific groups of women: those with the lowest circulating levels of DHEA; and those for whom osteoporosis is a particular problem.     

Infant Sex Moderates the Effects of Maternal Pre‐ and Postnatal Stress on Executive Functioning at 8 Months of Age

Previous studies report that early life stress, including maternal pre‐ and postnatal stress, has adverse effects on cognitive development and that these associations might be sex‐specific. However, no studies exist on early life stress and infant executive functioning (EF). The aim of this study was to examine the relationship between maternal pre‐ and postnatal stress and infant EF, and whether these associations are moderated by infant sex. Maternal prenatal depressive, general anxiety, and pregnancy‐specific anxiety symptoms were measured three times, and postnatal depressive and general anxiety symptoms were measured 6 months postpartum. Infant EF was assessed with a modified A‐not‐B task 8 months postpartum (N = 214). Maternal postnatal general anxiety predicted poorer EF in girls in comparison with boys. Moreover, there was a trend toward an interaction between prenatal anxiety and infant sex such that prenatal anxiety predicted infant EF differently in girls and in boys. No association was found between depressive symptoms or pregnancy‐specific anxiety symptoms and infant EF. These findings suggest that maternal anxiety may have sex‐specific effects on early EF and that pre‐ and postnatal stress may differently affect infant EF/cognitive development. The implications of these findings and important future directions are discussed.     

Management of premature menopause

There has been some confusion among women and health professionals since the publication of the Women's Health Initiative and Million Women studies about the management of premature ovarian failure (POF). Both studies were undertaken in women aged 50 and over, and cannot be extrapolated to their younger counterparts, who would normally be producing their endogenous estrogen, since they have functioning ovaries. Estrogen-based replacement therapy is the main stay of treatment for women with POF and is recommended at least until the average age of natural menopause (52 years in the UK). This view is endorsed by regulatory bodies such as the Committee on Safety of Medicines (now the Commission on Human Medicines) in the UK. No evidence shows that estrogen replacement increases the risk of breast cancer to a level greater than that found in normally menstruating women, and women with POF do not need to start mammographic screening early unless other risk factors are present, such as family history.     

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.     

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.