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.     

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.     

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.     

Testosterone,testosterone therapy and prostate cancer

Abstract

With prostate cancer not observed in eunuchs and total androgen suppression by castration an effective first-line treatment for advanced prostate cancer, the dramatic regression seen in tumour symptoms after castration, lead to the theory that high levels of circulating androgens were a risk factor for prostate cancer. This theory however, ignored the effects testosterone variations within a physiologic range could have on early tumour events and since the early 2000s, clinical evidence discounting testosterone as a linear mechanistic cause of prostate cancer growth mounted, with alternative mechanistic hypotheses such as the saturation model being proposed. Together with a growing understanding of the negative health effects and decreased quality of life in men with testosterone deficiency or hypogonadism, a paradigm shift away from testosterone as a prostate cancer inducer occurred allowing clinicians to use testosterone therapy as potential treatment for men with difficult and symptomatic hypogonadism that had been previously treated for prostate cancer. In this review we contextualise the idea of testosterone as a risk factor for prostate cancer inducement and compile the most current literature with regards to the influence of testosterone and testosterone therapy in prostate cancer.     

Male breast cancer

Male breast cancer (MBC) is a rare disease. However, as global populace ages, there is a trend to MBC increasing. Although aetiology is still unclear, constitutional, environmental, hormonal (abnormalities in estrogen/androgen balance) and genetic (positive family history, Klinefelter syndrome, mutations in BRCA1 and specially BRCA2) risk factors are already known. Clinic manifestation is painless hard and fixed nodule in the subareolar region in 75% of cases, with nipple commitment earlier than in women. Breast cancer has similar prognostic factors in males and females, among which axillary adenopathy (present in 40–55% cases) is the most important one. Although mammography, ultrasonography and scintigraphy can be useful tools in diagnosis; clinical assessment, along with a confirmatory biopsy, remains the main step in the evaluation of men with breast lesions. Infiltrating ductal carcinoma is the most frequent histological type. The established standard of care is modified radical mastectomy followed by tamoxifen for endocrine-responsive positive disease, although other options are being explored. While similarities between breast cancer in males and females exist, it is not appropriate to extrapolate data from female disease to the treatment of male. There is a need for specific multi-institutional trials to better understanding of clinicopathologic features and establishment of optimal therapy for this disease.     

Testosterone metabolism,dose–response relationships and receptor polymorphisms: selected pharmacological/toxicological considerations on benefits versus risks of testosterone therapy in men

In this review selected toxicological problems related to testosterone therapy in hypogonadal men are discussed. Applying ‘classical’ pharmacological/toxicological findings (e.g. animal studies on short- and long-term toxicity) to clinical situations is not very helpful. Molecular biological knowledge and especially evaluation of epidemiological studies, as well as intervention studies, on testosterone therapy in hypogonadal men are more useful. Potential risks include overdosage for lifestyle reasons, e.g. excessive muscle building and reduction of visceral obesity, when erythrocytosis occurs concomitantly. Modern galenic formulations of testosterone administration (e.g. transdermal gel, suitable testosterone esters for intramuscular application and newer oral preparations) avoid supraphysiological serum concentrations, therefore significantly reducing the toxicological risk. A hypothetical model of the toxicological risks of testosterone therapy is given that is based on the influence of testosterone metabolism (aromatization vs. reduction) of the respective parameter/target chosen. Finally, the great influence of polymorphisms of the androgen receptor on the assessment of toxicological risk and on the individualization of androgen therapy is shown. Already existing national, continental and international guidelines or recommendations for the testosterone therapy should be harmonized.     

The relationship between plasma androgens (dehydroepiandrosterone sulfate and testosterone), insulin,coagulation and fibrinolytic factors in men with coronary arteriosclerosis

Thrombosis plays an important role in the pathogenesis of myocardial infarction and stroke. It is known that a decrease in estradiol plasma concentration in postmenopausal women results in an increase in fibrinogen, plasminogen activator inhibitor (PAI) and tissue-type plasminogen activator (tPA) concentrations, whereas estradiol replacement therapy decreases the plasma concentrations of these factors. In men, the risk of developing myocardial infarction is higher than in premenopausal women. However, the role of male sex hormones in the pathogenesis of arteriosclerosis, although the subject of many studies, has not yet been elucidated. The aim of this study was to determine the plasma levels of and correlation between androgens, insulin, coagulation and fibrinolytic factors in men with coronary arteriosclerosis with and without a history of myocardial infarction. The study was carried out in a group of 109 non-obese men, aged 28-60 years, with coronary artery disease demonstrated by coronary angiography. In this group, 64 men had a history of one myocardial infarction and ten reported two or more such episodes. The control group consisted of 14 volunteers, who were healthy men aged 39-63 years with normal body weight. In men with coronary arteriosclerosis, the plasma levels of dehydroepiandrosterone sulfate (DHEAS) and testosterone were lower, whilst insulin, fibrinogen, PAI, PAI activity and lipoprotein(a) were higher in comparison with the group of healthy controls. We found that, in men with coronary arteriosclerosis, those with the highest incidence of infarction demonstrated the most advanced hyper-insulinism, had lower levels of DHEAS and testosterone, the highest fibrinogen plasma concentrations, as well as PAI-1, tPA and PAI activity. A positive correlation between insulin, PAI-1, tPA and fibrinogen has been shown. In conclusion, low androgen and high insulin concentrations, high PAI-1 and PAI activity, high tPA and fibrinogen concentration may be prognostic indicators of myocardial infarction in men with arteriosclerosis.     

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.     

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.     

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.     

Continued Pursuit of Happily Ever After: Low Barriers to Divorce and Happiness

Throughout the 1970s, a “no-fault revolution” swept through the United States, reducing the legal and economic barriers to divorce. Previous studies have found that these legal changes did at least temporarily increase divorces, and may have been, on average, detrimental to women’s economic well-being. It has also been suggested that reducing the barriers to divorce redistributed power to spouses with better predicted outcomes on the remarriage market. In keeping with this theory, the current study examined men and women ages 25–50 as they transitioned to low-barriers to divorce regimes. My data show that reductions in the barriers to divorce were associated with reductions in women’s happiness, particularly among older women and women with children. Conversely, older men and men with children (these women’s potential partners) reported on average higher happiness after low barriers to divorce. These relationships were found even for individuals who remained married, suggesting that this redistribution of happiness was in part the result of a change in bargaining power within marriages.     

Gender, social status, and emotional reliance

Past research has suggested the potential importance of considering emotional reliance, a dimension of interpersonal dependence, when addressing social and developmental risk factors for depression. Based on a probability sample of 1,393 adults aged 18-55 residing in Toronto, Canada, this paper addresses gender differences in emotional reliance and the relevance of emotional reliance in explaining the gender-depression association. We also explore link-ages between emotional reliance and status factors. Findings indicate that emotional reliance is significantly related to depression and that women report greater reliance than men, independent of social status factors like marital and parental status, education, income, and occupational prestige. Moreover, the positive association between emotional reliance and depression is greater for women. Several social status factors modify the relationship between gender and emotional reliance. Both education and occupational prestige reduce reliance, and are particularly beneficial in this regard for women. Marriage, on the other hand, increases emotional reliance, especially for men. We offer interpretations of this pattern of findings.     

Gender‐Related Effects of Information Technology Implementation

In investigating gender‐related effects of information technology implementation the contextual factors (e.g. job design, implementation management, external workload) need to be taken into account. In the Vienna Implementation Studies the effects of technology implementation on users' stress levels and satisfaction were investigated in longitudinal research designs. In our previous study, the 1st Vienna Implementation Study, negative effects of the technology implementations were shown in more women than men. It was argued that women due to their lower qualified jobs and due to the lack of participation, also experienced more negative consequences. In the 2nd Vienna Implementation Study effects of ‘continuous’ implementation of information technology on 212 clerical workers (n women: 142; n men: 70) were investigated. No gender‐related effects of information technology implementation were found, nor did women and men differ in job characteristics and in participation in the implementation process. It can be concluded from the two studies that potential differences between women and men are caused by differences in the contextual factors of job design and participation. Further, it emerged from our studies that women — at least in the field of clerical jobs — have benefited from the introduction of technology.     

Predictors of HIV Sexual Risk Behavior Among Men Who Have Sex with Men,Men Who Have Sex with Men and Women,and Transgender Women

ABSTRACT

Men who have sex with men, men who have sex with men and women, and transgender women are at high risk for HIV infection. This study seeks to clarify which known HIV risk factors (partner type, sex location, serodiscordance, multiple sex partners, substance use during sex) contribute to engagement in high-risk (unprotected receptive anal) sex in each population. Data collected from June 2005 through June 2008 indicate all three populations display different HIV sexual risk profiles. The data suggest that HIV-prevention interventions should be individually tailored to address the specific needs of these three highly vulnerable and impacted populations.     

Briefly Noted

Researchers have found that mirtazapine, in addition to counseling for substance use, reduced methamphetamine use and some HIV risk behaviors in cisgender men and transgender women who have sex with men. Mirtazapine, an antidepressant also known as Remeron, showed benefits after treatment ended, even if patients didn't always take their medication or took less than they were supposed to. The study follows a previous study of mirtazapine finding reductions in methamphetamine use and sexual risk behaviors among men who have sex with men. “Effects of mirtazapine for methamphetamine use disorder among cisgender men and transgender women who have sex with men: A placebo‐controlled randomized clinical trial” was published in JAMA Psychiatry online last week by Phillip Coffin, M.D. and colleagues. The RCT took place over a course of 24 weeks from 2013 to 2017 in San Francisco. Main outcomes measured were urine tests for methamphetamine and sexual risk behaviors, with sleep, methamphetamine craving, dependence severity, and adverse events also assessed. Sexual risk behaviors included number of sexual partners, and frequency of condomless anal sex. Participants assigned to mirtazapine also had reductions in depressive symptoms.     

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.