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Summary: Background: Cancer-induced muscle wasting begins early in the course of a patient's malignant disease, resulting in declining physical function and other detrimental clinical consequences. This randomised, double-blind, placebo-controlled phase 2 trial assessed the efficacy and safety of enobosarm, a selective androgen receptor modulator, in patients with cancer. Methods: We enrolled male (>45 years) and female (postmenopausal) patients with cancer who were not obese and who had at least 2% weight loss in the previous 6 months. Participants were randomly assigned (1:1:1 ratio, by computer generated list, block size three, stratified by cancer type) to receive once-daily oral enobosarm 1 mg, 3 mg, or placebo for up to 113 days at US and Argentinian oncology clinics. The sponsor, study personnel, and participants were masked to assignment. The primary endpoint was change in total lean body mass from baseline, assessed by dual-energy x-ray absorptiometry. Efficacy analyses were done only in patients who had a baseline and an on-treatment assessment in the protocol-specified window of within 10 days before baseline or first study drug, and within 10 days of day 113 or end of study (evaluable efficacy population). Adverse events and other safety measurements were assessed in the intention-to-treat (safety) population. This trial is registered with ClinicalTrials.gov, number NCT00467844. Findings: Enrolment started on July 3, 2007, and the last patient completed the trial on Aug 1, 2008. 159 patients were analysed for safety (placebo, n=52; enobosarm 1 mg, n=53; enobosarm 3 mg, n=54). The evaluable efficacy population included 100 participants (placebo, n=34; enobosarm 1 mg, n=32; enobosarm 3 mg, n=34). Compared with baseline, significant increases in total lean body mass by day 113 or end of study were noted in both enobosarm groups (enobosarm 1 mg median 1·5 kg, range −2·1 to 12·6, p=0·0012; enodosarm 3 mg 1·0 kg, −4·8 to 11·5, p=0·046). Change in total lean body mass within the placebo group (median 0·02 kg, range −5·8 to 6·7) was not significant (p=0·88). The most common serious adverse events were malignant neoplasm progression (eight of 52 [15%] with placebo vs five of 53 [9%] with enobosarm 1 mg vs seven of 54 [13%] with enobosarm 3 mg), pneumonia (two [4%] vs two [4%] vs three [6%]), and febrile neutropenia (three [6%vs one [2%] vs none). None of these events were deemed related to study drug. Interpretation: Cancer cachexia is an unmet medical need and our data suggest that use of enobosarm might lead to improvements in lean body mass, without the toxic effects associated with androgens and progestational agents. Funding: GTx. [ABSTRACT FROM AUTHOR]

Abstract: Background: Low testosterone (T) has been associated with insulin resistance and diabetes mellitus (DM) among men in population-based studies. These studies included racially diverse men, but did not target for inclusion individuals with opiate use, Hepatitis C Virus (HCV) infection, or Human Immunodeficiency Virus (HIV) infection, which disproportionately affect inner-city populations and may alter the relationship between T and DM. Methods: The association between free T (FT) and abnormal glucose metabolism was studied among male participants in the Study of HIV, Injection Drug Use, Nutrition, and Endocrinology (SHINE). Logistic regression was used to examine the relationship between log FT and both insulin resistance and prediabetes/DM. Results: Of 175 men, 43 (24.6%) had low levels of FT (< 52 pg/ml). There were more men in the low FT group on methadone maintenance (39.5% vs. 15.2%, P =0.001), but there was no difference in FT by HIV or HCV status. Overall, 23 men (13.1%) had prediabetes/DM, which was unrelated to FT (odds ratio (OR) of prediabetes/DM for each log increase in FT=0.56, 95% Confidence Interval (CI)=0.13–2.41). FT was also not related to insulin resistance. Conclusions: The prevalence of hypogonadism was high in this inner-city cohort and was associated with methadone use. However, low FT was not related to insulin resistance or prediabetes/DM. Continued work to identify diabetes risk factors among inner-city populations will help determine targets for intervention to reduce diabetes incidence. Treatment trials of testosterone to reduce diabetes among hypogonadal men may be of particular relevance to opiate users, many of whom are hypogonadal. [Copyright &y& Elsevier]

Age-related hormonal decline is gradual and less recognized in men than in women. Symptoms are oftentimes ignored and non-specific. Fatigue, lack of concentration, mood swings, decreased sexual desire, erectile dysfunction, infertility, hair loss, reduced muscle and bone mass, and weight gain are a few of the symptoms of male hypogonadism. This disorder is linked to reduction in quality of life, and poorer health outcomes as it may increase the risk for cardiovascular disease, diabetes mellitus, metabolic syndrome, Alzheimer's disease and premature death. Different modalities of testosterone replacement therapy have evolved over 70 years, and sales continue to grow. Each preparation is differentiated by route of delivery, ease of use, cost and pharmacokinetics. Topical/transdermal testosterone replacement therapy, including patches and gels, are the most modern formulations on the market. These are more expensive treatments, but yield more physiological concentrations of testosterone. Restoration of testosterone levels to the eugonadal range reverses signs and symptoms of hypogonadism, except for infertility, and may alleviate co-morbidities associated with hypogonadism. Patient understanding of and compliance with both treatment and monitoring are of utmost importance to achieve clinical success with maximum benefit and minimum risk. The aim of our review is to summarize the indications, contraindications, benefits and risks of testosterone replacement therapy as they relate to transdermal administration. Further, we compare the various testosterone preparations, focusing on the newest topical/transdermal routes of administration that are currently available. [ABSTRACT FROM AUTHOR]

Summary Background Physiologic processes during ageing leading to multi-morbidity and diseases that increase risk of premature death may be influenced by ageing-associated changes in endogenous hormone production. Objective To evaluate the decline in sex steroid hormone levels across age and estimate the number of US men 40+ years old who may have low hormone levels. Design We measured serum testosterone, oestradiol and sex hormone binding globulin by immunoassay in 1351 men 20+ years old in Third National Health and Nutrition Examination Survey. We estimated free hormones by mass action. Results Free testosterone declined most rapidly with age (a 2% decline in geometric mean concentration occurred after ageing 1·3 years), followed by total testosterone (2·4 years), free oestradiol (4·1 years) and total oestradiol (8·1 years). These hormone changes with age translated into 25·0% and 30·2% of men 70+ years old having low total (which we defined as <10·4 n [ABSTRACT FROM AUTHOR]

Background: Skeletal muscle (SM) mass decreases with advanced age and with disease in HIV infection. It is unknown whether age-related muscle loss is accelerated in the current era of antiretroviral therapy and which factors might contribute to muscle loss among HIV-infected adults. We hypothesized that muscle mass would be lower and decline faster in HIV-infected adults than in similar-aged controls.Methods: Whole-body (1)H-magnetic resonance imaging was used to quantify regional and total SM in 399 HIV-infected and 204 control men and women at baseline and 5 years later. Multivariable regression identified associated factors.Results: At baseline and Year 5, total SM was lower in HIV-infected than control men. HIV-infected women were similar to control women at both time points. After adjusting for demographics, lifestyle factors, and total adipose tissue, HIV infection was associated with lower Year 5 SM in men and higher SM in women compared with controls. Average overall 5-year change in total SM was small and age related, but rate of change was similar in HIV-infected and control men and women. CD4 count and efavirenz use in HIV-infected participants were associated with increasing SM, whereas age and stavudine use were associated with decreasing SM.Conclusions: Muscle mass was lower in HIV-infected men compared with controls, whereas HIV-infected women had slightly higher SM than control women after multivariable adjustment. We found evidence against substantially faster SM decline in HIV infected versus similar-aged controls. SM gain was associated with increasing CD4 count, whereas stavudine use may contribute to SM loss. [ABSTRACT FROM AUTHOR]

Bone mineral density (BMD) is an important factor linked to bone health. Little is known of the prevalence of low BMD and its associated risk factors in an urban underserved population. Between 2001 and 2004, we recruited 338 subjects who completed drug use and medical history questionnaires, underwent hormonal measurements, and underwent whole-body dual-energy X-ray absorptiometry (DXA) for evaluation of BMD and body composition. Of these, 132 subjects had site-specific DXA (lumbar spine and hip) performed. Osteoporosis was defined as a T-score of -2.5 or less for men 50 years of age and older and postmenopausal women and a Z-score of -2.0 or less in men younger than 50 years of age and premenopausal women at either the lumbar spine, total hip, or femoral neck, according to National Osteoporosis Foundation (NOF) guidelines. The cohort consisted of mostly African-American, middle-aged people with a high prevalence of illicit drug use, 50% HIV, and 39% hepatitis C. Osteoporosis was identified in 22% of subjects (24 men, 5 women), with the majority of cases (90%) attributable to osteoporosis at the lumbar spine. Osteoporosis was more common in men than in women. Lower whole-body BMD among women was associated with multiple risk factors, but only with lower lean mass among men. Osteoporosis was highly prevalent in men, mainly at the spine. The risk factors for bone loss in this population need to be further clarified. Screening men for osteoporosis starting at age 50 might be warranted in this population given the multiple risk factors and the unexpectedly high prevalence of low BMD. © 2011 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Purpose: Low cholesterol levels and statin drugs may protect against prostate cancer with a worse prognosis. Their protective mechanism is unknown, but has been hypothesized to be related to cholesterol's role as a sex steroid hormone precursor. We evaluated whether serum testosterone and estradiol differ by cholesterol or cholesterol-lowering drug use.Materials and Methods: Testosterone and estradiol were measured for 1,457 male participants in the Third National Health and Nutrition Examination Survey. We estimated multivariable-adjusted geometric mean hormone concentration by quintiles of cholesterol concentration and by cholesterol-lowering drugs use.Results: Across quintiles of cholesterol, testosterone level did not differ (mean, 95% confidence interval (CI); Q1: 5.25, 5.02-5.49, Q5: 5.05, 4.76-5.37 ng/ml; p-trend = 0.32), whereas estradiol levels were lower (Q1: 38.7, 36.9-40.5; Q5: 33.1, 31.8-34.5 pg/ml; p-trend < 0.0001). Neither testosterone (no: 5.12, 4.94-5.30, yes: 4.91, 4.33-5.57 ng/ml, p = 0.57) nor estradiol (no: 35.9, 34.8-37.1; yes: 33.9, 29.4-39.2 pg/ml; p = 0.39) differed by cholesterol-lowering drugs use.Conclusion: Testosterone did not differ by cholesterol or cholesterol-lowering drug use. Estradiol was lower in men with higher cholesterol, but did not differ by cholesterol-lowering drug use. Our results suggest that the lower risk of advanced prostate cancer among statin users is not readily explained by a cholesterol-mediated effect of statins on sex hormone levels. [ABSTRACT FROM AUTHOR]

Purpose: The profound hypogonadism due to androgen deprivation therapy for prostate cancer results in complications such as sexual dysfunction, poor quality of life, vasomotor symptoms and altered cognition. Since estrogen is associated with cardiovascular risks, phytoestrogens are being increasingly evaluated as a potential treatment for these adverse effects. We evaluated the effects of high dose isoflavones, equivalent to that consumed by Asian populations, on the aforementioned consequences of androgen deprivation therapy. Materials and Methods: A total of 33 men undergoing androgen deprivation therapy for prostate cancer were enrolled in this randomized, double-blind, placebo controlled, 12-week pilot trial. Participants were randomly assigned to receive 20 gm soy protein containing 160 mg total isoflavones (17) vs taste matched placebo, that is 20 gm whole milk protein (16). The study was performed at a tertiary care center in the United States. Results: At baseline the groups were well matched in demographic parameters, sleep quality, cognition and overall quality of life. However, men in the isoflavone group had a higher baseline prevalence of hot flashes and poor intercourse satisfaction compared to those on placebo. At 12 weeks there were no significant differences between the 2 groups in any outcome measure. Conclusions: This pilot study of high dose isoflavones in androgen deprived men showed no significant improvement in cognition, vasomotor symptoms or any other aspect of quality of life measures compared to placebo. Future studies should use variable doses of isoflavones for a longer period before ruling out beneficial isoflavone effects in this population. [Copyright &y& Elsevier]