Large divergence in testosterone concentrations between men and women: Frame of reference for elite athletes in sex-specific competition in sports, a narrative review.

OBJECTIVE: The purpose of this narrative review was to summarize available data on testosterone levels in normal, healthy adult males and females, to provide a physiologic reference framework to evaluate testosterone levels reported in males and females with conditions that elevate androgens, such as disorders of sex development (DSD), and to determine the separation or overlap of testosterone levels between normal and affected males and females. METHODS: A literature review was conducted for published papers, from peer reviewed journals, reporting testosterone levels in healthy males and females, males with 46XY DSD, and females with hyperandrogenism due to polycystic ovary syndrome (PCOS). Papers were selected that had adequate characterization of participants, and description of the methodology for measurement of serum testosterone and reporting of results. RESULTS: In the healthy, normal males and females, there was a clear bimodal distribution of testosterone levels, with the lower end of the male range being four- to fivefold higher than the upper end of the female range(males 8.8-30.9 nmol/L, females 0.4-2.0 nmol/L). Individuals with 46XY DSD, specifically those with 5-alpha reductase deficiency, type 2 and androgen insensitivity syndrome testosterone levels that were within normal male range. Females with PCOS or congenital adrenal hyperplasia were above the normal female range but still below the normal male range. CONCLUSIONS: Existing studies strongly support a bimodal distribution of serum testosterone levels in females compared to males. These data should be considered in the discussion of female competition eligibility in individuals with possible DSD or hyperandrogenism.

Safety, pharmacokinetics and pharmacological effects of the selective androgen receptor modulator, GSK2881078, in healthy men and postmenopausal women.

AIM: Selective androgen receptor modulators (SARMs) induce anabolic effects on muscle without the adverse effects of androgenic steroids. In this first-in-human study, we report the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of the SARM GSK2881078. METHODS: In Part A, healthy young men (n = 10) received a single dose of study drug (0 mg, 0.05 mg, 0.1 mg, 0.2 mg GSK2881078 or matching-placebo). In Part B, repeat-dose cohorts in men (n = 65) were 0.05 mg, 0.2 mg then 0.08 mg, 0.24 mg, 0.48 mg, 0.75 mg, or placebo; in women (n = 24) they were 0.24 mg, 0.35 mg, or placebo (7 days for 0.5 mg, 14 days for other doses). RESULTS: PK analysis showed dose-proportional increases in exposure and a long >100-h half-life. No significant effects on vital signs, electrocardiograms, cardiac telemetry or standard clinical laboratory studies were observed. A dose-response effect was observed on lowering both high-density lipoprotein and sex hormone-binding globulin. In females at 0.35 mg, differences from placebo were -0.518 (95% confidence interval: -0.703, -0.334) mmol l-1 and -39.1 (-48.5, -29.7) nmol l-1 , respectively. Women showed greater sensitivity to these parameters at lower doses than men. Drug-related adverse events (AEs) were mild. One woman developed a drug rash and was withdrawn. Two men had elevated creatine phosphokinase after physical exertion during follow-up. A serious AE occurred in a subject on placebo. CONCLUSIONS: These data demonstrate pharmacodynamic effects with acceptable tolerability and support further clinical evaluation of this SARM.

Association between low muscle mass, functional limitations and hospitalisation in heart failure: NHANES 1999-2004.

BACKGROUND/OBJECTIVES: Muscle mass decreases with age, and heart failure (HF) patients may experience greater reductions due to pathophysiological processes associated with this disease. Reduced muscle mass may predispose HF patients to functional limitations and increased morbidity and mortality. This study estimated the associations between HF, low muscle mass (LMM), functional limitations and hospitalisation, as well as the combined effect of HF and LMM on these outcomes in a nationally representative sample. DESIGN: A cross-sectional survey. SETTING: the National Health and Nutrition Examination Survey 1999-2004. SUBJECTS: A total of 402 HF (weighted 3,994,205) and 7,061 non-HF participants (weighted 91,058,850), ≥45 years with dual-energy X-ray absorptiometry measurements. METHODS: the 20th percentile of the sex-specific distribution of lean appendicular mass residuals from linear regression with height and fat mass as predictors, served as the LMM cut-point. Logistic regression provided adjusted odds ratios (OR) and 95% confidence intervals (CI) for the association of HF and LMM with functional limitations and hospitalisation. RESULTS: There were statistically significant adjusted associations between HF and limitations in household chores, walking one-fourth of a mile and hospitalisation (OR (95% CI): 2.5 (1.7 -3.8), 1.9 (1.2 -3.0) and 1.6 (1.1 -2.4), respectively). LMM was significantly associated with limitations in household chores and walking one-fourth of a mile (OR (95% CI): 1.5 (1.2, 1.9) and 1.4 (1.2, 1.7), respectively). Interaction between HF and LMM was noted for the associations with functional limitations. CONCLUSIONS: This hypothesis-generating study found a synergistic interaction between HF and LMM; the presence of LMM increased the negative effects of HF. HF patients may experience increased disease burden due to LMM.

Longitudinal changes in high-density lipoprotein cholesterol and cardiovascular events in older adults.

OBJECTIVE: While low high-density lipoprotein cholesterol (HDL-C) is associated with increased risk of cardiovascular (CV) events, there are limited data evaluating the association of longitudinal change in HDL-C with CV event risk in older populations. The aim of this study was to examine the association between within-subject changes in HDL-C levels and CV events in an older population. DESIGN: Observational cohort study. PATIENTS: 1293 men and 1422 women age ≥50 years, with ≥2 consecutive HDL measurements, and no prior CVD as part of Framingham Offspring Study. MEASUREMENTS: A clinical CV event was defined as the first occurrence of any of the following: coronary heart disease (coronary death, myocardial infarction, coronary insufficiency and angina), cerebrovascular event, peripheral artery disease or heart failure. RESULTS: Median total follow-up time across subjects was 9·6 years. Change in HDL-C was evaluated as between-exam (approximately 3·5 years) percentage change in HDL-C, categorized as ≥10% decrease, <10% change (stable) and ≥10% increase. Crude and adjusted sex-specific Cox hazards regression models with change in HDL-C as a time-dependent covariate quantified the association with CV events. Mean baseline age of the analysis sample was 53 years. There were 233 and 111 CV events among men and women, respectively. Change in HDL-C was not significantly associated with CVD incidence in men or women, without or with adjustment for confounders including baseline HDL-C or use of relevant medications. CONCLUSION: In conclusion, relatively short-term (3·5 years) changes in HDL-C levels do not affect CV events in men and women.

Oral testosterone with and without concomitant inhibition of 5α-reductase by dutasteride in hypogonadal men for 28 days.

PURPOSE: Co-administration of the 5α-reductase inhibitor dutasteride increases the oral testosterone bioavailability in men with experimentally induced hypogonadism. We examined oral testosterone with and without dutasteride administration in hypogonadal men for 28 days. MATERIALS AND METHODS: We randomly assigned 43 hypogonadal men to twice daily oral doses of 150, 250 or 400 mg testosterone with 0.25 mg dutasteride, 400 mg testosterone alone or 0.25 mg dutasteride alone for 28 days in a multicenter study. Subjects underwent pharmacokinetic profiling of serum hormones on days 1 and 28. A total of 32 men completed all study procedures. RESULTS: Serum testosterone increased in all groups on testosterone compared with that in the dutasteride only group. At the 400 mg dose the combination of testosterone and dutasteride resulted in average testosterone concentrations that were 2.7 and 4.6 times higher than in the testosterone only group on days 1 and 28, respectively (p <0.01). On day 28 average testosterone was 20% to 30% lower in all groups on testosterone and dutasteride, and 50% lower in the testosterone only group compared with day 1. Serum dihydrotestosterone was suppressed in all groups on dutasteride and increased in the testosterone only group. CONCLUSIONS: Oral testosterone administration resulted in a therapeutic serum testosterone concentration in hypogonadal men. Dutasteride improved the oral bioavailability of testosterone while suppressing dihydrotestosterone. Compared with day 1, testosterone was decreased after 28 days of administration. Additional study is warranted of oral testosterone with dutasteride for testosterone deficiency.

Physical function and health-related quality-of-life in a population-based sample.

BACKGROUND. It is of interest to understand whether impaired physical function is associated with health-related quality-of-life (HRQOL). We examined upper and lower body physical function and its relationship with two domains of HRQOL among men. METHODS. We conducted a population-based observational study of musculoskeletal health among Boston, MA residents, the Boston Area Community Health/Bone Survey. Participants were 1219 randomly-selected Black, Hispanic, and White males (30-79 years). Upper body function was measured using hand grip strength, while lower body function was measured by combining a timed walk and a chair stand test. HRQOL was measured using the physical (PCS-12) and mental health (MCS-12) component scores of the SF-12. Multivariate linear regression models were used to estimate the association between poor function and HRQOL. RESULTS. There was a significant association of poor upper body physical function with the MCS-12 (ß coefficient: -4.12, p = 0.003) but not the PCS-12 (ß coefficient: 0.79, p = 0.30) compared to those without poor function. Those with poor lower body physical function had significantly lower PCS-12 scores (ß: -2.95, p = 0.007), compared to those without poor function, but an association was not observed for MCS-12 scores. CONCLUSIONS. Domains of physical function were not consistently related to domains of HRQOL.

Association of sex hormones and C-reactive protein levels in men.

OBJECTIVES: The age-associated decline in sex hormone levels in men is paralleled by an increase in cardiovascular disease and associated risk factors including low grade chronic inflammation. The objective of this analysis was to investigate the association between sex hormone levels and C-reactive protein (CRP) in a population-based sample of men. DESIGN: Population-based, cross-sectional observational survey. PARTICIPANTS: A multistage stratified design was used to recruit a random sample of 2301 racially and ethnically diverse men age 30-79 years. Blood samples were obtained on 1899 men. Analyses were conducted on 1559 men with complete data on CRP and sex hormone levels. MEASUREMENTS: High-sensitivity CRP levels. The association between CRP and sex hormone levels was assessed using multiple linear regression models. RESULTS: An inverse association was observed, in both bivariate and multivariate analyses, between CRP and total testosterone, free testosterone and SHBG levels. These associations remained statistically significant after adjusting for age, body mass index, comorbid conditions and lifestyle factors. A positive trend between oestradiol (total and free) and CRP levels was not statistically significant. CONCLUSIONS: A robust, inverse dose-response correlation between testosterone and SHBG levels with CRP levels provides further evidence of a potential role of androgens in inflammatory processes.

Lean mass, muscle strength, and physical function in a diverse population of men: a population-based cross-sectional study.

BACKGROUND: Age-related declines in lean body mass appear to be more rapid in men than in women but our understanding of muscle mass and function among different subgroups of men and their changes with age is quite limited. The objective of this analysis is to examine racial/ethnic differences and racial/ethnic group-specific cross-sectional age differences in measures of muscle mass, muscle strength, and physical function among men. METHODS: Data were obtained from the Boston Area Community Health/Bone (BACH/Bone) Survey, a population-based, cross-sectional, observational survey. Subjects included 1,157 black, Hispanic, and white randomly-selected Boston men ages 30-79 y. Lean mass was assessed by dual-energy x-ray absorptiometry. Upper extremity (grip) strength was assessed with a hand dynamometer and lower extremity physical function was derived from walk and chair stand tests. Upper extremity strength and lower extremity physical function were also indexed by lean mass and lean mass was indexed by the square of height. RESULTS: Mean age of the sample was 47.5 y. Substantial cross-sectional age differences in grip strength and physical function were consistent across race/ethnicity. Racial/ethnic differences, with and without adjustment for covariates, were evident in all outcomes except grip strength. Racial differences in lean mass did not translate into parallel differences in physical function. For instance, multivariate modeling (with adjustments for age, height, fat mass, self-rated health and physical activity) indicated that whereas total body lean mass was 2.43 kg (approximately 5%) higher in black compared with white men, black men had a physical function score that was approximately 20% lower than white men. CONCLUSIONS: In spite of lower levels of lean mass, the higher levels of physical function observed among white compared with non-white men in this study appear to be broadly consistent with known racial/ethnic differences in outcomes.

Myosteatosis in the Context of Skeletal Muscle Function Deficit: An Interdisciplinary Workshop at the National Institute on Aging.

Skeletal muscle fat infiltration (known as myosteatosis) is an ectopic fat depot that increases with aging and is recognized to negatively correlate with muscle mass, strength, and mobility and disrupt metabolism (insulin resistance, diabetes). An interdisciplinary workshop convened by the National Institute on Aging Division of Geriatrics and Clinical Gerontology on September 2018, discussed myosteatosis in the context of skeletal muscle function deficit (SMFD). Its purpose was to gain a better understanding of the roles of myosteatosis in aging muscles and metabolic disease, particularly its potential determinants and clinical consequences, and ways of properly assessing it. Special attention was given to functional status and standardization of measures of body composition (including the value of D3-creatine dilution method) and imaging approaches [including ways to better use dual-energy X-ray absorptiometry (DXA) through the shape and appearance modeling] to assess lean mass, sarcopenia, and myosteatosis. The workshop convened innovative new areas of scientific relevance to light such as the effect of circadian rhythms and clock disruption in skeletal muscle structure, function, metabolism, and potential contribution to increased myosteatosis. A muscle-bone interaction perspective compared mechanisms associated with myosteatosis and bone marrow adiposity. Potential preventive and therapeutic approaches highlighted ongoing work on physical activity, myostatin treatment, and calorie restriction. Myosteatosis' impact on cancer survivors raised new possibilities to identify its role and to engage in cross-disciplinary collaboration. A wide range of research opportunities and challenges in planning for the most appropriate study design, interpretation, and translation of findings into clinical practice were discussed and are presented here.

Menopause-specific questionnaire assessment in US population-based study shows negative impact on health-related quality of life.

OBJECTIVE: To use the Menopause-Specific Quality of Life Questionnaire (MENQOL) to assess the impact of menopausal symptoms on health-related quality of life in a large US population-based study. METHODS: Participants were recruited from the US population through random-digit-dialing and probability sampling. Analyses included 2703 postmenopausal women 40-65 years old in our Menopause Epidemiology Study. Respondents answered a 30-min questionnaire, including the MENQOL. RESULTS: Scores for each domain were: vasomotor: 3.2+/-2.2; psycho-social: 3.3+/-1.8; physical: 3.5+/-1.5; sexual: 2.9+/-2.1. There were significant differences in the MENQOL scores by age, smoking, exercise, education, employment status and BMI. Women aged 60-65 years (p<0.0001), with a bachelor's degree or higher level of education (p<0.0001), who exercised at least 3 days a week (p<0.0001), who had never smoked (p<0.0001), with a body mass index < or =25kg/m(2) (p<0.0001), and who had significantly lower scores indicating better quality of life. Hot flashes affected work (46.0%), social activities (44.4%), leisure activities (47.6%), sleep (82.0%), mood (68.6%), concentration (69.0%), sexual activity (40.9%), total energy level (63.3%) and overall quality of life (69.3%). CONCLUSION: Symptoms experienced during menopause and socio-demographic characteristics affect the quality of life in postmenopausal women. Hot flashes impact the daily activities of most postmenopausal women, especially those with more frequent/severe symptoms. Treatments that safely and effectively treat these symptoms could improve quality of life among postmenopausal women.

Correlates of low testosterone and symptomatic androgen deficiency in a population-based sample.

CONTEXT: Risk factors for low testosterone and symptomatic androgen deficiency (AD) may be modifiable. OBJECTIVE: Our objective was to examine demographic, anthropometric, and medical correlates of low testosterone and symptomatic AD. DESIGN: Data were used from the Boston Area Community Health Survey, an epidemiological study conducted from 2002-2005. SETTING: Data were obtained from a community-based random sample of racially and ethnically diverse men. PATIENTS OR OTHER PARTICIPANTS: Data were available for 1822 men. MAIN OUTCOME MEASURES: Multivariate logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations of covariates with 1) low testosterone and 2) symptomatic AD. The operational definition of low testosterone was serum total testosterone less than 300 ng/dl and free testosterone less than 5 ng/dl; symptomatic AD was defined as the additional presence of symptoms: any of low libido, erectile dysfunction, or osteoporosis or two or more of sleep disturbance, depressed mood, lethargy, or diminished physical performance. RESULTS: Factors associated with low testosterone included age (OR = 1.36; 95% CI= 1.11-1.66, per decade), low per-capita income ($6000 or less per household member vs. more than $30,000; OR = 2.86; 95% CI = 1.39-5.87), and waist circumference (per 10-cm increase; OR = 1.75; 95% CI = 1.45-2.12). Only age (OR = 1.36; 95% CI = 1.04-1.77), waist circumference (OR = 1.88; 95% CI = 1.44-2.47), and health status (OR = 0.21; 95% CI = 0.05-0.92, excellent vs. fair/poor) were associated with our construct of symptomatic AD. Of all variables, waist circumference was the most important contributor in both models. CONCLUSIONS: Waist circumference is a potentially modifiable risk factor for low testosterone and symptomatic AD. Manifestation of symptoms may be a consequence of generally poor health status.

The effect of 5alpha-reductase inhibition with dutasteride and finasteride on bone mineral density, serum lipoproteins, hemoglobin, prostate specific antigen and sexual function in healthy young men.

PURPOSE: Dutasteride and finasteride are 5alpha-reductase inhibitors that dramatically decrease serum levels of dihydrotestosterone. Because androgens affect bone, lipids, hematopoiesis, prostate and sexual function, we determined the impact of 5alpha-reductase inhibitors on these end points. MATERIALS AND METHODS: We conducted a randomized, double-blinded, placebo controlled trial of 99 men 18 to 55 years old randomly assigned to receive 0.5 mg dutasteride (33), 5 mg finasteride (34) or placebo (32) daily for 1 year. Bone mineral density was measured at baseline, after 1 year of treatment and 6 months after drug discontinuation. In addition, markers of bone turnover, fasting serum lipoprotein concentrations, hemoglobin and prostate specific antigen were measured at baseline, after 26 and 52 weeks of treatment, and again 24 weeks after drug discontinuation. Sexual function was assessed at these points by a validated questionnaire. RESULTS: Significant suppression of circulating dihydrotestosterone levels with the administration of dutasteride or finasteride did not significantly affect bone mineral density or markers of bone metabolism. Similarly serum lipoproteins and hemoglobin were unaffected. Serum prostate specific antigen and self-assessed sexual function decreased slightly during treatment with both 5alpha-reductase inhibitors but returned to baseline during followup. CONCLUSIONS: Profound suppression of circulating serum dihydrotestosterone induced by 5alpha-reductase inhibitors during 1 year does not adversely impact bone, serum lipoproteins or hemoglobin, and has a minimal, reversible effect on serum prostate specific antigen and sexual function in normal men. Circulating dihydrotestosterone does not appear to have a clinically significant role in modulating bone mass, hematopoiesis or lipid metabolism in normal men.

Nanomilled oral testosterone plus dutasteride effectively normalizes serum testosterone in normal men with induced hypogonadism.

Oral androgen development has been hampered by the rapid metabolism of orally administered testosterone (T) and low bioavailibility. The addition of the 5alpha-reductase inhibitor dutasteride (D) to oral T in oil dramatically improves concentrations of serum T. In this study we evaluate the absorption of oral T+D, comparing nanomilled T (NmT+D) vs T dissolved in oil (Capmul; CpT+D), as nanomilling might offer a simpler, more practical means of oral T administration, given the limited solubility of T in oil. Twelve healthy men were administered leuprolide on Day -14 to suppress endogenous T biosynthesis and were pretreated with D to block 5alpha-reductase. Once hypogonadal, subjects were sequentially administered 200- and 400-mg doses of CpT+D and NmT+D in the fasted and fed states. Serum T and dihydrotestosterone (DHT) were measured: before dose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours after each dose. Two weeks after leuprolide administration, T levels were below the normal range. A 400-mg dose of either formulation of oral T+D increased mean serum T above the lower limit of the normal range for 8-10 hours. Food had a minimal effect on the pharmacokinetic parameters of the NmT+D formulation but decreased the maximum observed concentration after dosing (C(max)) for CpT+D. Serum DHT remained below the normal range throughout the study period with both formulations. No significant changes in liver function tests or other adverse events were observed. A 400-mg dose of either oral T+D formulation normalized serum T for 8-10 hours and suppressed DHT. NmT allows for tablet formulation, and its pharmacokinetics were not affected by food, demonstrating the feasibility of oral nanomilled T as a promising and practical twice-daily therapy for the treatment of male hypogonadism.

Predictivity of Nonclinical Male Reproductive Findings for Human Effects.

BACKGROUND: Testing of pharmaceutical products for reproductive toxicity in male laboratory animals is required for registration. METHODS: We evaluated whether the results of studies showing male reproductive toxicity in experimental animals was predictive of reproductive effects in men participating in clinical trials. We surveyed companies for information on pharmaceutical candidates that had shown male reproductive toxicity in nonclinical studies for which there was information on male reproductive effects in clinical trials. RESULTS: Among 12 pharmaceutical candidates submitted by five companies, only one compound that had shown male reproductive toxicity in experimental animals also demonstrated reproductive toxicity in men. CONCLUSION: In this sample of compounds, nonclinical studies appeared to over-predict reproductive toxicity in men. We identified possible reasons for the apparent lack of predictivity of the experimental animal studies. Birth Defects Research 110:17-26, 2018. © 2017 Wiley Periodicals, Inc.

Creatine ( methyl-d3) dilution in urine for estimation of total body skeletal muscle mass: accuracy and variability vs. MRI and DXA.

A noninvasive method to estimate muscle mass based on creatine ( methyl-d3) (D3-creatine) dilution using fasting morning urine was evaluated for accuracy and variability over a 3- to 4-mo period. Healthy older (67- to 80-yr-old) subjects ( n = 14) with muscle wasting secondary to aging and four patients with chronic disease (58-76 yr old) fasted overnight and then received an oral 30-mg dose of D3-creatine at 8 AM ( day 1). Urine was collected during 4 h of continued fasting and then at consecutive 4- to 8-h intervals through day 5. Assessment was repeated 3-4 mo later in 13 healthy subjects and 1 patient with congestive heart failure. Deuterated and unlabeled creatine and creatinine were measured using liquid chromatography-tandem mass spectrometry. Total body creatine pool size and muscle mass were calculated from D3-creatinine enrichment in urine. Muscle mass was also measured by whole body MRI and 24-h urine creatinine, and lean body mass (LBM) was measured by dual-energy X-ray absorptiometry (DXA). D3-creatinine urinary enrichment from day 5 provided muscle mass estimates that correlated with MRI for all subjects ( r = 0.88, P < 0.0001), with less bias [difference from MRI = -3.00 ± 2.75 (SD) kg] than total LBM assessment by DXA, which overestimated muscle mass vs. MRI (+22.5 ± 3.7 kg). However, intraindividual variability was high with the D3-creatine dilution method, with intrasubject SD for estimated muscle mass of 2.5 kg vs. MRI (0.5 kg) and DXA (0.8 kg). This study supports further clinical validation of the D3-creatine method for estimating muscle mass. NEW & NOTEWORTHY Measurement of creatine ( methyl-d3) (D3-creatine) and D3-creatinine excretion in fasted morning urine samples may be a simple, less costly alternative to MRI or dual-energy X-ray absorptiometry (DXA) to calculate total body muscle mass. The D3-creatine enrichment method provides estimates of muscle mass that correlate well with MRI, and with less bias than DXA. However, intraindividual variability is high with the D3-creatine method. Studies to refine the spot urine sample method for estimation of muscle mass may be warranted.

GSK2881078, a SARM, Produces Dose-Dependent Increases in Lean Mass in Healthy Older Men and Women.

Context: GlaxoSmithKline (GSK) 2881078 is a nonsteroidal, selective androgen receptor modulator (SARM) under investigation by GSK for treatment of reduced mobility and other functional limitation in men and women with muscle weakness associated with chronic and acute illnesses. Objective: This was a phase 1b study intended to explore across a dose range the pharmacokinetics (PK)-pharmacodynamics relationship and further safety and tolerability data for GSK2881078. This study also evaluated effects of CYP3A4 inhibition on PK of GSK2881078. Methods: This was a randomized, placebo-controlled, parallel-group, repeat-dose, dose-escalation study in healthy older males and postmenopausal females. A total of three cohorts of males and three cohorts of females were studied. Dosing at each dose level was twice daily for the first 3 days followed by once daily for up to 53 days. Repeated dual-energy X-ray absorptiometry and MRI cross-sectional thigh scans were performed. The effect of CYP3A4 inhibition on GSK2881078 PK was evaluated in a separate cohort. Results: GSK2881078 was generally well tolerated and no serious adverse events were reported. Compared with placebo, there was greater lean mass accrual with all dose levels of GSK2881078. Females exhibited a greater response at lower doses than did males. Transient elevations of alanine aminotransferase were observed. The effect of CYP3A4 inhibition on GKS2881078 PK was unlikely to be of clinical significance. Conclusions: GSK2881078 yielded dose-dependent increases in lean mass with evidence of enhanced sensitivity in women. The compound was well tolerated.

Correction to: HIF prolyl hydroxylase inhibition protects skeletal muscle from eccentric contraction induced injury.

Following publication of the original article [1], the authors flagged that there is a discrepancy with the Availability of data and materials statement on page 12 of the article.

HIF prolyl hydroxylase inhibition protects skeletal muscle from eccentric contraction-induced injury.

BACKGROUND: In muscular dystrophy and old age, skeletal muscle repair is compromised leading to fibrosis and fatty tissue accumulation. Therefore, therapies that protect skeletal muscle or enhance repair would be valuable medical treatments. Hypoxia-inducible factors (HIFs) regulate gene transcription under conditions of low oxygen, and HIF target genes EPO and VEGF have been associated with muscle protection and repair. We tested the importance of HIF activation following skeletal muscle injury, in both a murine model and human volunteers, using prolyl hydroxylase inhibitors that stabilize and activate HIF. METHODS: Using a mouse eccentric limb injury model, we characterized the protective effects of prolyl hydroxylase inhibitor, GSK1120360A. We then extended these studies to examine the impact of EPO modulation and infiltrating immune cell populations on muscle protection. Finally, we extended this study with an experimental medicine approach using eccentric arm exercise in untrained volunteers to measure the muscle-protective effects of a clinical prolyl hydroxylase inhibitor, daprodustat. RESULTS: GSK1120360A dramatically prevented functional deficits and histological damage, while accelerating recovery after eccentric limb injury in mice. Surprisingly, this effect was independent of EPO, but required myeloid HIF1α-mediated iNOS activity. Treatment of healthy human volunteers with high-dose daprodustat reduced accumulation of circulating damage markers following eccentric arm exercise, although we did not observe any diminution of functional deficits with compound treatment. CONCLUSION: The results of these experiments highlight a novel skeletal muscle protective effect of prolyl hydroxylase inhibition via HIF-mediated expression of iNOS in macrophages. Partial recapitulation of these findings in healthy volunteers suggests elements of consistent pharmacology compared to responses in mice although there are clear differences between these two systems.

Prevalence of symptomatic androgen deficiency in men.

CONTEXT: Despite recognition that androgen deficiency in men should be defined according to biochemical and clinical criteria, most prevalence estimates are based on low testosterone levels alone. OBJECTIVE: The objective of this study was to examine the association between symptoms of androgen deficiency and low total and calculated free testosterone levels and estimate the prevalence of symptomatic androgen deficiency in men. DESIGN: This study was a population-based, observational survey. PARTICIPANTS: A total of 1,475 Black, Hispanic, and white men, between the ages of 30-79 yr, with complete data on testosterone, SHBG, and symptoms of androgen deficiency, and who are not taking medications that impact sex steroid levels were randomly selected from the Boston Area Community Health Survey. OUTCOME: Outcomes were measured as symptomatic androgen deficiency, defined as low total (<300 ng/dl) and free (<5 ng/dl) testosterone plus presence of low libido, erectile dysfunction, osteoporosis or fracture, or two or more of following symptoms: sleep disturbance, depressed mood, lethargy, or diminished physical performance. RESULTS: Mean age of the sample was 47.3 +/- 12.5 yr. Approximately 24% of subjects had total testosterone less than 300 ng/dl, and 11% of subjects had free testosterone less than 5 ng/dl. Prevalence of symptoms were as follows: low libido (12%), erectile dysfunction (16%), osteoporosis/fracture (1%), and two or more of the nonspecific symptoms (20%). Low testosterone levels were associated with symptoms, but many men with low testosterone levels were asymptomatic (e.g. in men 50+ yr, 47.6%). Crude prevalence of symptomatic androgen deficiency was 5.6% (95% confidence interval: 3.6%, 8.6%), and was not significantly related to race and ethnic group. Prevalence was low in men less than 70 yr (3.1-7.0%) and increased markedly with age to 18.4% among 70 yr olds. Projection of these estimates to the year 2025 suggests that there will be as many as 6.5 million American men ages 30-79 yr with symptomatic androgen deficiency, an increase of 38% from 2000 population estimates. CONCLUSIONS: Prevalence of symptomatic androgen deficiency in men 30 and 79 yr of age is 5.6% and increases substantially with age. The aging of the U.S. male population will cause a large increase in the burden of symptomatic androgen deficiency. Future work should address the clinical significance of low testosterone levels in asymptomatic men.

The effect of 5alpha-reductase inhibition with dutasteride and finasteride on semen parameters and serum hormones in healthy men.

CONTEXT: Dutasteride and finasteride are 5alpha-reductase inhibitors (5ARIs) that dramatically reduce serum levels of dihydrotestosterone (DHT). OBJECTIVE: Because androgens are essential for fertility, we sought to determine the impact of 5ARI administration on serum testosterone (T), DHT, and spermatogenesis. DESIGN, SETTING, SUBJECTS, AND INTERVENTION: We conducted a randomized, double-blinded, placebo-controlled trial in 99 healthy men randomly assigned to receive dutasteride (D; 0.5 mg) (n = 33), finasteride (F; 5 mg) (n = 34), or placebo (n = 32) once daily for 1 yr. MAIN OUTCOME MEASURES: Blood and semen samples were collected at baseline and 26 and 52 wk of treatment and 24 wk after treatment and were assessed for T, DHT, and semen parameters. RESULTS: D and F significantly (P < 0.001) suppressed serum DHT, compared with placebo (D, 94%; F, 73%) and transiently increased serum T. In both treatment groups, total sperm count, compared with baseline, was significantly decreased at 26 wk (D, -28.6%; F, -34.3%) but not at 52 wk (D, -24.9%; F, -16.2%) or the 24-wk follow-up (D, -23.3%; F, -6.2%). At 52 wk, semen volume was decreased (D, -29.7%; F, -14.5%, significantly for D) as was sperm concentration (D, -3.2%; [corrected] F, -7.4%, neither significant). There was a significant reduction of -6 to 12% in sperm motility during treatment with both D and F and at follow-up. Neither treatment had any effect on sperm morphology. CONCLUSIONS: This study demonstrates that the decrease in DHT induced by 5ARIs is associated with mild decreases in semen parameters that appear reversible after discontinuation.