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Sergliflozin, the active entity of sergliflozin etabonate, is a selective inhibitor of sodium-dependent glucose cotransporter 2 (SGLT2). The pharmacokinetics and pharmacodynamics of sergliflozin were evaluated following single oral dose administration of sergliflozin etabonate (5-500 mg) in healthy volunteers (n = 22) and patients with type 2 diabetes mellitus (n = 8). The prodrug was rapidly and extensively converted to sergliflozin; the latter displayed linear kinetics, reached maximum plasma concentrations at approximately 30 to 45 minutes postdose (t(max)), and had a plasma elimination half-life (t(1/2)) of ~0.5 to 1 hour. Both prodrug and active entity showed low glomerular filtration and/or extensive renal tubular reabsorption, with <0.5% of the administered dose being recovered in the urine. In both populations, sergliflozin etabonate produced a dose-related glucosuria under fasting conditions and following glucose loading but did not appreciably affect urinary electrolyte excretion or fluid balance. The magnitude and duration of the glucosuric effect closely paralleled plasma sergliflozin concentrations. Sergliflozin did not significantly affect fasting plasma glucose levels but produced transient attenuation of the plasma glucose AUC following glucose challenge. Single doses of sergliflozin etabonate 5 to 500 mg were well tolerated, and there were no clinically significant adverse laboratory findings. [ABSTRACT FROM AUTHOR]

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 D 3 -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., (Copyright © 2020 Correa-de-Araujo, Addison, Miljkovic, Goodpaster, Bergman, Clark, Elena, Esser, Ferrucci, Harris-Love, Kritchevsky, Lorbergs, Shepherd, Shulman and Rosen.)

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., (© 2018 John Wiley & Sons Ltd.)

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.

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.

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.

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., (© 2017 Wiley Periodicals, Inc.)

A noninvasive method to estimate muscle mass based on creatine ( methyl-d 3 ) (D 3 -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 D 3 -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 D 3 -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). D 3 -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 D 3 -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 D 3 -creatine method for estimating muscle mass. NEW & NOTEWORTHY Measurement of creatine ( methyl-d 3 ) (D 3 -creatine) and D 3 -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 D 3 -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 D 3 -creatine method. Studies to refine the spot urine sample method for estimation of muscle mass may be warranted.

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., (© 2017 The British Pharmacological Society.)

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., (© The Author 2015. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Current methods for clinical estimation of total body skeletal muscle mass have significant limitations. We tested the hypothesis that creatine (methyl-d3) dilution (D3-creatine) measured by enrichment of urine D3-creatinine reveals total body creatine pool size, providing an accurate estimate of total body skeletal muscle mass. Healthy subjects with different muscle masses [n = 35: 20 men (19-30 yr, 70-84 yr), 15 postmenopausal women (51-62 yr, 70-84 yr)] were housed for 5 days. Optimal tracer dose was explored with single oral doses of 30, 60, or 100 mg D3-creatine given on day 1. Serial plasma samples were collected for D3-creatine pharmacokinetics. All urine was collected through day 5. Creatine and creatinine (deuterated and unlabeled) were measured by liquid chromatography mass spectrometry. Total body creatine pool size and muscle mass were calculated from D3-creatinine enrichment in urine. Muscle mass was also measured by magnetic resonance imaging (MRI), dual-energy x-ray absorptiometry (DXA), and traditional 24-h urine creatinine. D3-creatine was rapidly absorbed and cleared with variable urinary excretion. Isotopic steady-state of D3-creatinine enrichment in the urine was achieved by 30.7 ± 11.2 h. Mean steady-state enrichment in urine provided muscle mass estimates that correlated well with MRI estimates for all subjects (r = 0.868, P < 0.0001), with less bias compared with lean body mass assessment by DXA, which overestimated muscle mass compared with MRI. The dilution of an oral D3-creatine dose determined by urine D3-creatinine enrichment provides an estimate of total body muscle mass strongly correlated with estimates from serial MRI with less bias than total lean body mass assessment by DXA., (Copyright © 2014 the American Physiological Society.)

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., (© 2013 John Wiley & Sons Ltd.)

Background: We recently validated in cross-sectional studies a new method to determine total body creatine pool size and skeletal muscle mass based on D 3 -creatine dilution from an oral dose and detection of urinary creatinine enrichment by isotope ratio mass spectrometry (IRMS). Routine clinical use of the method in aging and disease will require repeated application of the method, with a more widely available technology than IRMS, to enable determination of change in skeletal muscle mass in longitudinal studies. We therefore adapted the method to liquid chromatography-tandem mass spectrometry (LC-MS/MS) technology, and sought to establish proof of concept for the repeated application of the method in a longitudinal study. Because the turnover of creatine is slow, it was also critical to determine the impact of background enrichment from an initial dose of oral D 3 -creatine on subsequent, longitudinal measurements of change in muscle mass., Methods: Rats were given an oral tracer dose of D 3 -creatine (1.0 mg/kg body weight) at 10 and 17 weeks of age. LC-MS/MS was used to determine urinary D 3 -creatine, and urinary D 3 -creatinine enrichment, at time intervals after D 3 -creatine administration. Total body creatine pool size was calculated from urinary D 3 -creatinine enrichment at isotopic steady state 72 h after administration of D 3 -creatine tracer., Results: At 10 weeks of age, rat lean body mass (LBM) measured by quantitative magnetic resonance correlated with creatine pool size (r = 0.92, P = 0.0002). Over the next 7 weeks, the decline in urinary D 3 -creatinine enrichment was slow and linear, with a rate constant of 2.73 ± 0.06 %/day. Subtracting background urinary D 3 -creatinine enrichment from the elevated enrichment following a second dose of D 3 -creatine at 17 weeks permitted repeat calculations of creatine pool size. As at 10 weeks, 17-week LBM correlated with creatine pool size (r = 0.98, P <0.0001). In addition, the change in creatine pool size was correlated with the change in LBM during the 7 weeks of rat growth between measurements (r = 0.96, P <0.0001)., Conclusion: The LC-MS/MS-based D 3 -creatine dilution method can be applied repeatedly to measure total body creatine skeletal muscle mass change in longitudinal study.

Oral administration of testosterone has potential use for the treatment of hypogonadism. We have recently demonstrated that a novel formulation of oral testosterone transiently normalized serum testosterone in a single-dose pharmacokinetic study. In this report, we present the steady-state pharmacokinetics of this formulation. Twelve healthy young men were rendered hypogonadal with the gonadotropin-releasing hormone antagonist acyline (300 μg/kg subcutaneously) and administered 300 mg of oral testosterone 3 times daily for 9 days. Serum testosterone, dihydrotestosterone (DHT), estradiol, and sex hormone-binding globulin (SHBG) were measured before and 1, 2, 4, 5, 6, 8, 10, 11, 12, 14, 16, and 24 hours on the first and ninth day of dosing. Before testosterone administration, all men had serum testosterone under 75 ng/dL. Over day 1, the 24-hour average (geometric mean [%CV]) serum total testosterone was 378 (45) ng/dL. This decreased to 315 (41) ng/dL after 9 days of continuous treatment (P = .1 compared with day 1). The 24-hour average serum SHBG was 27 (46) nmol/L on day 1 and was significantly reduced to 19 (47) nmol/L by day 9 (P < .01). As a result, the calculated free testosterone values were similar between day 1 and day 9: 8.7 (43) and 8.3 (37) ng/dL, respectively. DHT was in the reference range and estradiol was slightly below on day 9. Oral testosterone (300 mg) dosed 3 times daily normalized serum testosterone in men with experimentally induced hypogonadism after 9 days of dosing and significantly suppressed SHBG. This formulation of oral testosterone may have efficacy for the treatment of testosterone deficiency.

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 (β coefficient: -4.12, p = 0.003) but not the PCS-12 (β 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 (β: -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.

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., (Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Oral administration of testosterone might be useful for the treatment of testosterone deficiency. However, current "immediate-release" formulations of oral testosterone exhibit suboptimal pharmacokinetics, with supraphysiologic peaks of testosterone and its metabolite, dihydrotestosterone (DHT), immediately after dosing. To dampen these peaks, we have developed 2 novel modified-release formulations of oral testosterone designed to slow absorption from the gut and improve hormone delivery. We studied these testosterone formulations in 16 normal young men enrolled in a 2-arm, open-label clinical trial. Three hundred-mg and 600-mg doses of immediate-release and modified fast-release or slow-release formulations were administered sequentially to 8 normal men rendered hypogonadal by the administration of the gonadotropin-releasing hormone antagonist acyline. Blood for measurement of serum testosterone, DHT, and estradiol was obtained before and 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours after each dose. A second group of 8 men was studied with the coadministration of 1 mg of the 5α-reductase inhibitor finasteride daily throughout the treatment period. Serum testosterone was increased with all formulations of oral testosterone. The modified slow-release formulation significantly delayed the postdose peaks of serum testosterone and reduced peak concentrations of serum DHT compared with the immediate-release formulation. The addition of finasteride further increased serum testosterone and decreased serum DHT. We conclude that the oral modified slow-release testosterone formulation exhibits superior pharmacokinetics compared with immediate-release oral testosterone both alone and in combination with finasteride. This formulation might have efficacy for the treatment of testosterone deficiency.

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.

Context: The CAG repeat polymorphism in the androgen receptor, denoted (CAG)n, is thought to (inversely) index androgen sensitivity. We hypothesized that (CAG)n would exhibit a modifying influence on the association between circulating total and calculated free testosterone (TT and FT) and physical frailty in aging men., Objective: The objective of the study was to establish the influence of (CAG)n on the relation between circulating TT, FT, LH, SHBG, and frailty., Design: This was a prospective cohort study of health and endocrine functioning in randomly selected men, with a baseline (T1: 1987-89) and two follow-up (T2: 1995-1997; T3: 2002-2004) visits., Setting: This was an observational study of men residing in greater Boston, MA., Participants: A total of 624 subjects aged 50-86 yr were retained., Main Outcome Measures: The frailty phenotype was measured at T3. Components included weight loss, exhaustion, low physical activity, weakness, and slowness. Subjects exhibiting two of these five components were considered to be in an intermediate state, and those exhibiting three or more were considered frail., Results: (CAG)n was positively associated with TT and FT. Multivariable regression analyses revealed no influence of CAG on longitudinal within-subject changes in hormone levels or cross-sectional (T3) associations between hormone concentrations and the prevalence of intermediate frailty or frailty. Models incorporating subjects' history of hormone decline produced similar negative results., Conclusions: This population-based study does not support the hypothesis that interindividual differences in (CAG)n can account for a lack of association between circulating androgens and the frailty phenotype. Longitudinal analyses are needed to confirm these conclusions.

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.

Context: Although previous studies have indicated associations between circulating testosterone (T) or estradiol (E2) concentrations and bone mineral density, the relationship between gonadal steroids and skeletal geometry is not well defined., Objective: Our objective was to uncover the relation between circulating T or E2 and proximal femur geometry in a diverse sample of men., Design: We used data on 808 men enrolled in the Boston Area Community Health/Bone Study. Serum concentrations of total and calculated free T and E2 were obtained via early-morning blood sampling. The geometry of the proximal femur at three sites (the narrow neck, intertrochanter, and shaft) was obtained using the Hip Structural Analysis technology. Analyses adjusted for subjects' age, height, total body lean mass and fat mass, and level of physical activity were performed., Setting: In-home interviews accompanied by subject visits to the General Clinical Research Center at Boston University School of Medicine were performed., Study Participants: A randomly selected cohort of men living in Boston, MA (ages 30-79 yr) was included in the study., Interventions: These were not applicable., Main Outcome Measures: Bone mineral density and bone outer diameter, cross-sectional area (measuring bone material), and section modulus (an index of bending strength) were calculated., Results: In age-adjusted models, E2 was positively associated with hip strength parameters, whereas T was not. Adjustment for age and other parameters resulted in substantial reductions in, but not complete elimination of, associations between E2 and hip strength parameters., Conclusion: Circulating E2 is strongly associated with proximal femur strength, an association that is partially mediated by body composition.

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.

Objectives: To examine the association between aging and physical function in men by testing a theoretically based model of aging, hormones, body composition, strength, and physical function with data obtained from men enrolled in the Boston Area Community Health/Bone (BACH/Bone) Survey., Design: Cross-sectional, observational survey., Setting: Population-based., Participants: Eight hundred ten black, Hispanic, and white randomly selected men from the Boston area aged 30 to 79., Measurements: Testosterone, estradiol, sex hormone-binding globulin, lean and fat mass, grip strength, and summated index of physical function (derived from walk and chair stand tests)., Results: Measures of grip strength and physical function declined strongly with age. For instance, 10 years of aging was associated with a 0.49-point difference (scale 0-7) in physical function. Age differences in total testosterone and estradiol concentrations were smaller than age differences in their free fractions. Weak or nonsignificant age-adjusted correlations were observed between hormones and measures of physical function, although path analysis revealed a positive association between testosterone and appendicular lean mass and a strong negative association between testosterone and total fat mass. Lean and fat mass, in turn, were strongly associated with grip strength and physical function, indicating the possibility that testosterone influences physical function via indirect associations with body composition., Conclusion: The age-related decline in serum testosterone concentration in men has a weak association with physical strength and functional outcomes through its associations with lean and fat mass.

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.

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.

Objectives: To describe the onset, progression, and remission of symptomatic androgen deficiency (SAD) using longitudinal data from the Massachusetts Male Aging Study (MMAS)., Design: A prospective, population-based study of men living in Boston, Massachusetts. Data were collected in three waves: T1 (1987/89), T2 (1995/97), T3 (2002/04). Onset, progression, and remission were defined in terms of transitions in SAD status from one wave to the next., Setting: In-person, in-home interviews., Participants: Seven hundred sixty-six community-dwelling men aged 40 to 70 at baseline (T1) contributed data from T1 to T2 and 391 from T2 to T3., Measurements: SAD was defined in terms of serum total and free testosterone (T) levels and symptoms associated with low circulating androgens. Total T and sex hormone-binding globulin (SHBG) were measured using radioimmunoassay. Free T was calculated from total T and SHBG measurements., Results: At T2 or T3, the likelihood of SAD was markedly greater for subjects who had exhibited SAD at the previous wave (odds ratio=3.8, 95% confidence interval=1.9-7.4), overall 55% of subjects who exhibited SAD experienced remission by the next study wave. The probability of SAD was greater with older age and greater body mass index. Multivariate models demonstrated that the likelihood of remission was at least 50% for most subpopulations., Conclusion: Over approximately 15 years of follow-up, SAD did not represent a stable health state. The likelihood of SAD would remit exceeded the likelihood that it would not, particularly among younger and leaner men.

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.

Objective: To describe characteristics of vasomotor symptoms, specifically daily frequency and severity, among women 40-65 years old in the United States (US)., Design: A survey was completed by a nationally representative sample of 4402 US women aged 40-65 years old. A questionnaire focusing on menopausal symptoms was administered online in April 2005., Results: The prevalence of vasomotor symptoms was 79% in peri- and 65% in postmenopausal women. Women with daily vasomotor symptoms had an average of 2.5 very mild/mild, 2.6 moderate, 2.5 severe, and 1.4 very severe daytime hot flushes in a typical day. Women with night sweats every night had an average of 2.4 moderate, 3.2 severe, and 2.7 very severe night sweats in a typical night. Overall, 9% of peri- and 7% of postmenopausal women reported 7+ moderate to very severe vasomotor symptoms in a typical day. Although some women reported that symptoms were worse in the evening and in the summer, many women reported they were consistent, both throughout the day and throughout the seasons of the year., Conclusions: The Menopause Epidemiology Study builds upon existing literature by providing data on daily frequency and severity of vasomotor symptoms. There are many women with frequent and severe vasomotor symptoms who may benefit from treatment.

Objectives: A population-based study was used to describe healthcare seeking behavior for menopausal symptoms and treatment among women 40-65 years old in the United States., Methods: Participants were recruited into the Menopause Epidemiology Study from the KnowledgePanel(SM), which is selected by random digit dialing and probability sampling from the US population. From this source, 6201 women 40-65 years old were contacted and 4402 women participated. From the 3135 peri- and postmenopausal women, detailed information was obtained on menopausal symptoms, healthcare seeking, medication usage, and symptom relief from the medication., Results: Many women (60%) reported seeking health care for their menopausal symptoms. More than half of these women sought health care in the past 12 months. Vasomotor symptoms were the most frequently reported menopause symptoms across all races/ethnicities, and the most common symptoms discussed with a health care professional. One-third of the women (34%) used only hormone therapies, 12% used complementary and/or alternative medicines, and 16% used both for treatment of menopausal symptoms., Conclusions: This study has shown that a large number of women consult healthcare providers for menopausal symptoms, indicating these symptoms are bothersome. Yet, in the United States, there is considerable variation in the symptomatology, healthcare seeking, and use of therapies for menopausal symptoms across cultures. To alleviate these symptoms women have tried alternative treatments as well as hormone therapies, yet many women did not get complete relief of specific symptoms.

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.

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.

Management of secondary hyperparathyroidism is challenging with traditional therapy. The calcimimetic cinacalcet HCl acts on the calcium-sensing receptor to increase its sensitivity to calcium, thereby reducing parathyroid hormone (PTH) secretion. This phase 3, multicenter, randomized, placebo-controlled, double-blind study evaluated the efficacy and safety of cinacalcet in hemodialysis (HD) and peritoneal dialysis (PD) patients with PTH > or =300 pg/ml despite traditional therapy. A total of 395 patients received once-daily oral cinacalcet (260 HD, 34 PD) or placebo (89 HD, 12 PD) titrated from 30 to 180 mg to achieve a target intact PTH (iPTH) level of < or =250 pg/ml. During a 10-wk efficacy assessment phase, cinacalcet was more effective than control for PTH reduction outcomes, including proportion of patients with mean iPTH levels < or =300 pg/ml (46 versus 9%), proportion of patients with > or =30% reduction in iPTH from baseline (65 versus 13%), and proportion of patients with > or =20, > or =40, or > or =50% reduction from baseline. Cinacalcet had comparable efficacy in HD and PD patients; 50% of PD patients achieved a mean iPTH < or =300 pg/ml. Cinacalcet also significantly reduced serum calcium, phosphorus, and Ca x P levels compared with control treatment. The most common side effects, nausea and vomiting, were usually mild to moderate in severity and transient. Once-daily oral cinacalcet was effective in rapidly and safely reducing PTH, Ca x P, calcium, and phosphorus levels in patients who received HD or PD. Cinacalcet offers a new therapeutic option for controlling secondary hyperparathyroidism in patients with chronic kidney disease on dialysis.

Dihydrotestosterone (DHT) is the primary metabolite of testosterone in the prostate and skin. Testosterone is converted to DHT by 5alpha-reductase, which exists in two isoenzyme forms (types 1 and 2). DHT is associated with development of benign prostatic hyperplasia (BPH), and reduction in its level with 5alpha-reductase inhibitors improves the symptoms associated with BPH and reduces the risk of acute urinary retention and prostate surgery. A selective inhibitor of the type 2 isoenzyme (finasteride) has been shown to decrease serum DHT by about 70%. We hypothesized that inhibition of both isoenzymes with the dual inhibitor dutasteride would more effectively suppress serum DHT levels than selective inhibition of only the type 2 isoenzyme. A total of 399 patients with BPH were randomized to receive once-daily dosing for 24 wk of dutasteride (0.01, 0.05, 0.5, 2.5, or 5.0 mg), 5 mg finasteride, or placebo. The mean percent decrease in DHT was 98.4 +/- 1.2% with 5.0 mg dutasteride and 94.7 +/- 3.3% with 0.5 mg dutasteride, significantly lower (P < 0.001) and with less variability than the 70.8 +/- 18.3% suppression observed with 5 mg finasteride. Mean testosterone levels increased but remained in the normal range for all treatment groups. Dutasteride appeared to be well tolerated with an adverse event profile similar to placebo.

Adult GH deficiency (AGHD) is characterized by an altered body composition, an atherogenic lipid profile, decreased exercise capacity, and diminished quality of life. We performed a randomized, double-blind, placebo-controlled, multicenter study in 166 subjects with AGHD to assess the effects of GH on these outcomes. GH was initiated at 0.0125 mg/kg.d, increased to 0.025 mg/kg.d as tolerated, or decreased to 0.00625 mg/kg.d for 12 months. Primary measures of efficacy included body composition, strength and endurance, and quality of life. Additional parameters included serum IGF-I concentrations, serum lipids, and bone mineral density. After 12 months, 79% of subjects remained on GH 0.0125 mg/kg.d, whereas 21% received 0.00625 mg/kg.d. GH-treated men and women demonstrated significant decreases in total body and trunk fat and increases in lean body mass over baseline. In GH-treated men, mean IGF-I SD scores exceeded age-adjusted normal ranges, whereas similar doses produced a smaller response in women. GH treatment was associated with significant improvements in total cholesterol and low-density lipoprotein (P < 0.05 for all). No significant treatment effects were observed in strength and endurance, quality of life, or bone mineral density. GH treatment was generally well tolerated. Subjects with AGHD should receive individualized GH therapy to maintain IGF-I between the mean value and +2 SD and improve body composition and cardiovascular risk factors.

Objective: To heighten the awareness of treating physicians of the potential for serious and fatal thromboembolic complications after inferior petrosal sinus sampling in patients with Cushing's syndrome., Methods: We retrospectively reviewed inpatient and outpatient medical records for a 12-year period to identify patients with Cushing's syndrome who had thromboembolic complications after inferior petrosal sinus sampling at a single institution. Case reports of affected patients are presented., Results: Of 34 patients with corticotropin-dependent Cushing's syndrome who underwent inferior petrosal sinus sampling, 2 had deep venous thrombosis. One of these patients succumbed to pulmonary thromboembolism., Conclusion: Serious and potentially fatal thromboembolic disorders may complicate inferior petrosal sinus sampling. Prospective studies should be undertaken to determine the true incidence of deep venous thrombosis after this procedure in patients with Cushing's syndrome.

Cancer of the prostate is the leading cancer among American men, yet few risk factors have been established. Hair growth and development are influenced by androgens, and it has long been suspected that prostate cancer also is responsive to these hormones. A blinded, case-control study was undertaken to determine if hair patterning is associated with risk of prostate cancer, as well as specific hormonal profiles. The study accrued 315 male subjects who were stratified with regard to age, race, and case-control status (159 prostate cancer cases/156 controls). Hair-patterning classification and serum levels of total and free testosterone (T), sex hormone binding globulin, and dihydrotestosterone (DHT) were performed. Data indicate that hair patterning did not differ between prostate cancer cases and controls; however, significant hormonal differences were detected between the two groups. Free T was greater among cases than in controls (16.4 +/- 6.1 vs. 14.9 +/- 4.8 pg/ml, P = 0.02). Conversely, DHT-related ratios were greater among controls (P = 0.03 for DHT/T and P = 0.01 for DHT/free T). Several strong associations also were found between hormone levels and hair patterning. Men with vertex and frontal baldness had higher levels of free T (16.5 +/- 5.5 and 16.2 +/- 8.0 pg/ml, respectively) when compared to men with either little or no hair loss (14.8 +/- 4.7 pg/ml) (P = 0.01). Data suggest that increased levels of free T may be a risk factor for prostatic carcinoma. In addition, although no differences in hair patterning were detected between cases and controls within this older population, further research (i.e., prospective trials or case-control studies among younger men) may be necessary to determine if hair patterning serves as a viable biomarker for this disease, especially given the strong association between free T levels and baldness.

In summary, the history and physical examination provide a valuable overview of a patient's condition and clues as to the causes. Typically, the most important features are evidence of gynecomastia, completeness of genital development and virilization, testicular size and consistency, and condition of the prostate gland. Preliminary laboratory evaluation is usually done at the conclusion of the initial evaluation and generally includes a total or free testosterone level, a semen analysis, urinalysis, and screening profiles for blood count, liver and renal function, and serum electrolytes. A more detailed hormonal evaluation would include gonadotropins, luteinizing hormone and follicle-stimulating hormone, prolactin, estradiol, and possibly thyroid studies. With this information complete, the astute clinician can develop a working diagnosis and plan for further evaluation or referral to a specialist.

Massively obese males often show symptoms of hypogonadism, but the mechanism for this is unclear. Increased endogenous opioid inhibition of the hypothalamic GnRH pulse generator resulting in insufficient stimulation of the pituitary gonadotroph has been proposed as a possible mechanism. If this hypothesis is correct, obese males should be more sensitive to the LH-elevating effects of the opiate antagonist, naloxone, than men of normal weight and gonadal status. This study investigated the etiology of obesity-related hypogonadism by examining luteinizing hormone (LH) and follicle stimulating hormone (FSH) responses to gonadotropin-releasing hormone (GnRH) and to infusions of saline or naloxone. Subjects were five obese (201 +/- 14% IBW) and five normal weight (control) (97 +/- 4% IBW) males. Before treatment, obese males had significantly (p < 0.05) lower testosterone levels than control subjects (307 +/- 72 vs. 597 +/- 49 ng/dl), whereas estradiol, androstenedione, and dehydroepiandrosterone levels were not different between the two groups. Both groups showed equivalent elevations in LH (fourfold to sixfold) in response to GnRH stimulation, but obese patients had significantly lower basal (p < 0.05) and GnRH-stimulated (p < 0.01) FSH levels. Infusions of naloxone (but not saline) led to significant (p < 0.01) increases in LH above preinfusion baseline levels (20.5 +/- 2.8% in obese and 28.6 +/- 6.3% in controls). In control subjects, integrated LH levels during naloxone infusion were not significantly elevated above those found during saline infusion, while obese subjects exhibited a 43% augmentation of integrated LH (31.0 +/- 5.3 ng/ml during naloxone vs. 21.7 +/- 1.8 ng/ml during saline, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The results of transsphenoidal adenomectomy for growth hormone (GH)-secreting pituitary adenomas in acromegaly performed over a 17-year period were analyzed retrospectively to determine which preoperative factors significantly influenced the long-term surgical outcome. These variables were then used to develop a logistic regression model to determine the probability of surgical failure. The series consisted of 103 patients. Long-term follow-up study (mean duration 102 +/- 64 months) was performed to derive outcome analysis and determinants of failure. Surgical control was defined as a long-term postoperative serum basal GH level of less than 5 micrograms/liter, a long-term postoperative serum somatomedin C (SM-C) level of less than 2.2 U/ml, and a favorable clinical response. Eighteen (17.5%) patients did not meet these criteria. The overall control rate by the GH criteria was 81.3% and by the SM-C criteria 76.2%. By multivariate logistic regression analysis, tumor stage was the strongest predictor of outcome (p < 0.05). The preoperative GH level, tumor grade, and preoperative SM-C level were significant univariate predictors (p < 0.05). There were statistically significant differences in mean preoperative GH and SM-C levels (p < 0.05, t-test) and tumor stage (p < 0.05, chi-squared test) between patients whose acromegaly was controlled by surgery and those whose acromegaly was not. Furthermore, estimates were derived of the probability of surgical failure based on preoperative GH level, preoperative SM-C level, and tumor grade and stage. The authors believe these findings will enhance clinical decision-making for neurosurgeons considering transsphenoidal microsurgery in patients with acromegaly.

UDP-glucuronyl transferase (UDPGT) activity was determined for androgens in tissue minces and microsomal fractions from the liver and extrahepatic tissues (kidney, skin, prostate, and preputial glands) of the male rat. Liver microsomes showed the highest UDPGT activity with each of the androgens tested (Vmax = 7, 3, and 10 nmol/minute/mg protein for testosterone, androsterone, and androstanediol, respectively). UDPGT activity (Vmax) for androstanediol in the liver was 10(2)-fold higher than in the kidney and 10(3)-fold higher than in the skin and prostate. UDPGT activity for androgens was not detected in microsomes from preputial glands. Furthermore, no body site distribution was found for androgen UDPGT activity in skin microsomes. The Michaelis-Menten constant (Km) for UDPGT in liver microsomes was 20.4, 12.2, and 2.2 microM, respectively, for testosterone, androstanediol, and androsterone. Kidney microsomes showed a Km of 19.4 and 26.9 microM, respectively, for androstanediol and androsterone. The Km for testosterone was very high in the kidney (138 microM), suggesting that it was a poor substrate. In microsomes from the skin and prostate, the Km was very high (range 43-162 microM) for all three androgen substrates, suggesting that these androgens were not the preferred substrates for UDPGT in these tissues. These results indicate that the liver was the main site of androgen UDPGT activity and the skin and prostate formed little, if any, androgen glucuronides. These results suggest that androstanediol glucuronide was formed primarily in the liver and may not be a reliable marker of peripheral androgen metabolism.

A case of fatal disseminated fungal infection due to Conidiobolus coronatus in a patient with a renal transplant is described. This organism, known to cause localized infections in otherwise healthy individuals in the tropics, is now recognized as a cause of fatal infection in immunosuppressed hosts. Histologically, localized infections are characterized by lack of vessel invasion and the presence of an eosinophilic sleeve around fungal elements, called the Splendore-Hoeppli phenomenon. The histologic findings in the present case were more typical of mucormycosis, and the correct diagnosis was established only after the organism was isolated and identified in culture.

Plasma lipid, lipoprotein and apolipoprotein levels are known to decrease after major surgery. Coronary artery bypass surgery additionally involves use of extracorporeal circulation by use of a cardiopulmonary bypass pump, which necessitates hemodilution due to saline dextrose infusion to prime the pump. To investigate changes in lipids, lipoproteins and apolipoproteins as well as changes in C-reactive protein and albumin we conducted a study on 22 patients undergoing cardiac surgery involving cardiopulmonary bypass. Timed arterial blood samples were taken before, during and after cardiopulmonary bypass. At the onset and during cardiopulmonary bypass a rapid and significant fall was observed in all lipids and lipoproteins except lipoprotein(a) with recovery to near basal levels by 72 h for cholesterol, triglycerides, high density lipoprotein cholesterol and albumin, while apolipoproteins AI and B remained below basal levels during the postoperative period up to 72 h. In contrast, lipoprotein(a) levels increased at the onset, doubled during cardiopulmonary bypass and remained elevated postoperatively. On the other hand, C-reactive protein levels fell at the onset and during cardiopulmonary bypass but they became markedly elevated postoperatively. When results were corrected for hemodilution, the response patterns remained unchanged. As lipoprotein(a) is both atherogenic and thrombogenic, its elevation during cardiopulmonary bypass may be clinically important.

The ability of insulin to decrease urinary sodium excretion has been recognized for more than 30 years. While most investigators agree that this occurs predominantly through increased tubular sodium reabsorption, the nephron segments at which insulin exerts this effect in vivo remain controversial. Additionally, little information is available in mammalian systems on the mechanism of the insulin response or its relation to other hormonal systems important in the regulation of tubular sodium transport. Data from amphibian transporting epithelia suggest a potential for interactions between insulin and several other peptide hormones in the regulation of sodium transport. The following discussion attempts to review our knowledge of the effects of insulin on renal sodium reabsorption and describes new data suggesting that insulin's antinatriuretic response is dependent on antidiuretic hormone but independent of the angiotensin and prostaglandin systems.

Ten patients were studied before and after autologous adrenal medullary transplantation to the central nervous system for Parkinson's disease to determine if the presence of new catecholamine-producing tissue near the hypothalamus would alter hypothalamic or pituitary function, mineralocorticoid levels, or catecholamine production. No clinically apparent ill effects occurred. Changes in endocrine function were largely short-term and transient: at 7-10 days after surgery, urinary catecholamine levels were significantly increased, PRL levels were significantly elevated despite markedly increased serum dopamine levels, and gonadal steroid levels (estradiol and testosterone) were significantly lower despite unchanged basal and stimulated levels of gonadotropins. Dehydroepiandrosterone sulfate was significantly reduced at 7-10 days after surgery and remained low at 3-6 months. Other changes at 3-6 months after surgery included increased stimulated corticotropin levels and reduced serum aldosterone response to upright posture. The changes at 7-10 days were probably due to stress or unilateral adrenalectomy or both; the changes at 3-6 months were likely due to unilateral adrenalectomy. We conclude that unilateral adrenalectomy and autologous adrenal medullary transplantation to the central nervous system does not produce clinically important changes in endocrine function; however, possible adverse consequences of long-term reduction of dehydroepiandrosterone sulfate levels cannot be excluded.

This study explores the possibility of improving endocrinologic testing during petrosal sinus catheterization by determining both beta-endorphin and corticotropin (ACTH). We studied 14 patients with Cushing's disease, two with adrenal tumor, and three with ectopic tumors secreting ACTH. In patients with Cushing's disease, beta-endorphin concentrations paralleled those of ACTH in all basal plasma samples collected either from petrosal sinuses or peripheral veins. Individual responses of beta-endorphin and ACTH to corticotropin releasing hormone (CRH) were closely related to the presence of a corticotroph adenoma. In such patients, a consistently higher concentration of beta-endorphin over ACTH was observed in all samples collected either from petrosal sinuses or peripheral veins; the ratios were unchanged after the administration of CRH. In patients with ectopic ACTH secretion, the mean ratio of beta-endorphin over ACTH (with both values expressed in pmol/L) was significantly higher (3.5) than that of patients with Cushing's disease (2.9) or Cushing's syndrome due to adrenal tumor (2.7).