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STUDY QUESTION: Are early signs of metabolic disorder in late adolescence associated with features of impaired testicular function many years before the majority seek parenthood? SUMMARY ANSWER: Adolescents with features of metabolic disorder at 17 years, or insulin resistance (IR) at 20 years of age, show impaired testicular function and altered hormone levels compared to those without metabolic disorder. WHAT IS KNOWN ALREADY: Controversial evidence suggests a recent decline in sperm production potentially linked to environmental influences, but its cause remains unclear. Concomitant increases in obesity and diabetes suggest that lifestyle factors may contribute to this decline in testicular function. Although obesity has been associated with adverse testicular function in some studies, it remains unclear whether poor testicular function merely reflects, or causes, poor metabolic health. If metabolic disorder were present in adolescence, prior to the onset of obesity, this may suggest that metabolic disorder maybe a precursor of impaired testicular function. STUDY DESIGN, SIZE, DURATION: The Western Australian Pregnancy Cohort (Raine) Study is a longitudinal study of children born in 1989-1991 who have undergone detailed physical assessments since birth (1454 male infants born). At 17 years of age, 490 boys underwent a hepatic ultrasound examination, serum cytokine assessment (n = 520) and a metabolic assessment (n = 544). A further metabolic assessment was performed at 20 years (n = 608). Testicular assessment was performed at 20 years; 609 had reproductive hormones measured, 404 underwent a testicular ultrasound and 365 produced a semen sample. PARTICIPANTS/MATERIALS, SETTING, METHODS: Testicular volume was estimated by ultrasonography, and semen analysis was performed according to World Health Organization guidelines. Concentrations of LH, FSH and inhibin B (inhB) in serum were measured by immunoassay and total testosterone by liquid chromatography-mass spectro

Study question: In a population of men within a birth cohort, are features of an adverse cardiometabolic profile in late adolecence associated with impaired testicular function at 20 years of age? Summary answer: Despite the majority of men being only 20 years old, with a normal BMI, features of cardiometabolic disorder were associated with signs of testicular impairment. What is known already: An adverse cardiometabolic profile in adulthood has been reported to be associated with impaired testicular function; however no data exists from younger men. Hence it is unclear whether the metabolic disorder predates the adverse testicular function, or whether it is the lower serum testosterone concentration that predisposes the man to metabolic disorder in later life. Study design, size, duration: The Raine Study recruited 2900 women in pregnancy and retained the 2868 children born to form the Raine Study cohort. At 17 years of age males underwent a liver ultrasound for fatty liver (n = 490), and serum cytokines were measured (n = 520). At 20 years, measures included blood biochemistry (n = 618), a DEXA scan (n = 634), and a testicular assessment performed; semen sample (n = 365), testicular ultrasound (n = 404) and serum testosterone, LH, FSH and inhibin B concentrations were assayed (n = 620). Participants/materials, setting, methods: Fasting bloods were analysed for serum IL-18 by ELISA, tumor necrosis factor receptors (TNFR1 & 2) by cytometric bead array, and liver enzymes, insulin, glucose, lipids, high sensitivity CRP (hsCRP) and uric acid. Homeostasis model assessment (HOMA) was calculated and insulin resistance (IR) was defined by a HOMA>4. DEXA measurement was performed for lean and total fat mass. A cluster analysis was used to derive high-risk groups with features consistent with the metabolic syndrome. Main results and the role of chance: Participants that had testicular assess-ment were similar clinically to those that declined participation. The prevalence of

© 2017 Bisphenol A (BPA) is a ubiquitous chemical suspected to possess oestrogenic hormonal activities. Male population studies suggest a negative impact on testicular function. As Sertoli cell proliferation occurs during fetal or early postnatal life, it is speculated that oestrogenic environmental exposures may influence mature testicular function. Among 705 Western Australian Pregnancy Cohort (Raine) Study men aged 20–22 years, 404 underwent testicular ultrasound examination (149 had maternal serum available), and/or 365 provided semen (136 had maternal serum) and/or 609 serum samples for sex steroids, gonadotrophins and inhibin B analysis (244 had maternal serum). Maternal serum collected at 18 and 34 weeks' gestation was pooled and assayed for concentrations of total BPA (free plus conjugated) as an estimate of antenatal exposure. Testicular volume was calculated by ultrasonography, and semen analysis performed. Serum LH, FSH and inhibin B were measured by immunoassay; testosterone, oestradiol, oestrone andBPA were measured by liquid chromatography-mass spectrometry. BPA levels were detectable in most (89%) maternal serum samples. After adjustment for maternal smoking, abstinence and varicocele, sperm concentration and motility were significantly correlated to maternal serum BPA (r = 0.18; P = 0.04 for both). No other associations of maternal serum BPA with testicular function were observed.

Aims: To investigate associations of sarcopenic obesity with incident falls and fractures among Australian community-dwelling older men. Method(s): 1486 CHAMP participants (mean +/- SD age: 76.6 +/- 5.3 y) with complete baseline data for whole-body DXA (appendicular lean mass [ALM] and body fat percentage), hand grip strength (HGS) and gait speed were included. Participants were contacted every 4 months following baseline for mean 6.1+/-2.1 y to ascertain incident falls and fractures (confirmed by radiographic reports). Sarcopenia was defined by both the European Working Group on Sarcopenia (EWGSOP) and Foundation for the National Institutes of Health (FNIH) algorithms. Obesity was defined as body fat >=30 %. Univariable and multivariable binary logistic regression, negative binomial regression and survival analyses determined associations of sarcopenic obesity with incident falls and fracture adjusting for age, living alone, smoking status, physical activity, psychotropic and corticosteroid use, self-reported chronic pain and health, number of comorbidities, and serum 25OHD, haemoglobin and albumin levels. Result(s): 51 % of men reported at least one fall and 26 % reported multiple falls. Sarcopenic obese men according to the EWGSOP definition had over two-fold higher likelihood of being a faller (odds ratio: 2.05; 95%CI: 1.24, 3.39) or multiple faller (2.46; 1.51, 4.01) compared to non-sarcopenic non-obese, but FNIH-defined sarcopenic obesity was not associated with falls or multiple falls (both P>0.05). Similarly, the highest rates for falls were observed for EWGSOP-defined sarcopenic obese (incidence rate ratio 2.49; 95%CI: 1.89, 3.29 compared to non-sarcopenic non-obese) but, according to the FNIH definition, the highest rate of falls was observed for sarcopenic non-obese men (1.38; 1.08, 1.77). 152 (10 %) participants sustained a fracture during follow-up. There was a shorter time to first fracture for men with EWGSOP-defined sarcopenic obesity (mean: 7.6; 95%

© 2017, Springer Science+Business Media New York. Advancing age is associated with increased cancer incidence, but the role of sex hormones as risk predictors for common cancers in older men remains uncertain. This study was performed to assess associations of testosterone (T), dihydrotestosterone (DHT) and estradiol (E2), with incident prostate, lung and colorectal cancer in community-dwelling older men. Plasma T, DHT and E2 were assayed using liquid chromatography-mass spectrometry between 2001 and 2004 in 3690 men. Cancer outcomes until 20 June 2013 were ascertained using data linkage. Analyses were performed using proportional hazards competing-risks models, and adjustments were made for potential confounding factors including smoking status. Results are expressed as subhazard ratios (SHR). There were 348, 107 and 137 cases of prostate, lung and colorectal cancers respectively during a median of 9.1-year follow-up. Mean T was comparable in current and non-smokers, whilst mean DHT was lower in ex- and current smokers compared to non-smokers. After adjusting for confounders including smoking, higher T or DHT was associated with an increased incidence of lung cancer (SHR = 1.30, 95% CI 1.06–1.60; p = 0.012 per 1 SD increase in T and SHR = 1.29, 95% CI 1.08–1.54; p = 0.004 for DHT). Sex hormones were not associated with prostate or colorectal cancer. In older men, higher T or DHT predict increased incidence of lung cancer over the next decade. Sex hormones are not associated with incident prostate or colorectal cancer. Further studies are warranted to determine if similar associations of sex hormones with lung cancer are present in other populations and to investigate potential underlying mechanisms.

Context: In mice, undercarboxylated osteocalcin (ucOC) modulates insulin secretion and sensitivity and increases testosterone (T) secretion from Leydig cells, but human data are lacking. We hypothesized that ucOC is associated with diabetes risk and modulates sex hormone concentrations in older men, distinct from other bone turnover markers. Participants: Participants were community-dwelling men aged 70 to 89 years resident in Perth, Western Australia. Main Outcome Measures: Serum total osteocalcin (TOC), N-terminal propeptide of type I collagen (P1NP), and collagen type I C-terminal cross-linked telopeptide (CTX) were measured by immunoassay, and ucOC by hydroxyapatite binding. Plasma total T, DHT, and estradiol (E2) were assayed by mass spectrometry.Results: Excluding men with osteoporosis or conditions affecting sex hormones or on bisphosphonates, glucocorticoids, or warfarin, 2966 men were included. In multivariate analyses, higher ucOC was associated with reduced diabetes risk (odds ratio [OR] per 1 SD increase = 0.55, P < .001). Similar results were seen for TOC (OR = 0.60, P < .001), P1NP (OR = 0.64, P < .001), and CTX (OR = 0.60, P < .001) but not ucOC/TOC. When all 4 markers were included in the fully adjusted model, higher ucOC (OR = 0.56, P < .001) and CTX (OR = 0.76, P = .008) remained associated with reduced diabetes risk. E2 was inversely associated with ucOC (coefficient −0.04, P = .031), TOC (−0.05, P = .001) and CTX (−0.04, P = .016); and positively with ucOC/TOC (0.05, P = .002). DHT was inversely associated with ucOC/TOC (−0.04, P = .040). T was not associated with bone turnover. Conclusions: Higher bone remodeling rates are associated with reduced diabetes risk in older men. Higher ucOC is both a marker of bone remodeling and an independent predictor of reduced diabetes risk. E2 is inversely associated with bone turnover markers. We found no evidence ucOC modulates circulating T in older men.

© 2015 The Author(s) Published by the Royal Society. All rights reserved. Prenatal testosterone may have a powerful masculinizing effect on postnatal physical characteristics. However, no study has directly tested this hypothesis. Here, we report a 20-year follow-up study that measured testosterone concentrations from the umbilical cord blood of 97 male and 86 female newborns, and procured three-dimensional facial images on these participants in adulthood (range: 21-24 years). Twenty-three Euclidean and geodesic distances were measured from the facial images and an algorithm identified a set of six distances that most effectively distinguished adult males from females. From these distances, a 'gender score' was calculated for each face, indicating the degree of masculinity or femininity. Higher cord testosterone levels were associated with masculinized facial features when males and females were analysed together (n = 183; r = —0.59), as well as when males (n = 86; r = —0.55) and females (n = 97; r = —0.48) were examined separately (p-values < 0.001). The relationships remained significant and substantial after adjusting for potentially confounding variables. Adult circulating testosterone concentrations were available for males but showed no statistically significant relationship with gendered facial morphology (n = 85, r = 0.01, p = 0.93). This study provides the first direct evidence of a link between prenatal testosterone exposure and human facial structure.

Context: Older men have lower T levels, but whether differences in circulating T or its metabolites dihydrotestosterone (DHT) or estradiol (E2) contribute to cardiovascular disease remains controversial. Objective: We tested the hypothesis that plasma T, DHT, and E2 are differentially associated with the incidence of myocardial infarction (MI) and stroke in older men. Participants and Methods: Plasma total T, DHT, and E2 were assayed using liquid chromatography-mass spectrometry in early-morning samples from 3690 community-dwelling men aged 70–89 years. Outcomes of the first hospital admission or death due to MI or stroke were ascertained by data linkage. Results: Mean follow-up was 6.6 years. Incident MI occurred in 344, stroke in 300, and neither in 3046 men. In a multivariate analysis adjusting for age and other risk factors, T, DHT, and E2 were not associated with incident MI [fully adjusted hazard ratio (HR) for T in quartile (Q) 4 vs Q1: 0.92, 95% confidence interval (CI) 0.66–1.28; DHT: 0.83, 95% CI 0.59–1.15; E2: 0.84, 95% CI 0.62–1.15]. Higher T or DHT was associated with a lower incidence of stroke (T: Q4: Q1 fully adjusted HR 0.56, 95% CI 0.39–0.81, P = .002; DHT: 0.57, 95% CI 0.40–0.81, P = .002). E2 was not associated with stroke (HR 0.76, 95% CI 0.54–1.08, P = .123). Conclusions: Higher plasma T or DHT is a biomarker for reduced risk of stroke but not MI. Androgen exposure may influence outcomes after rather than the incidence of MI, whereas androgens but not E2 are independent predictors of stroke risk. Randomized clinical trials are needed to clarify the impact of modifying T or DHT on the risk of stroke in aging men.

Context: Testosterone (T) levels decline with age and lower T has been associated with increased mortality in aging men. However, the associations of its metabolites, dihydrotestosterone (DHT) and estradiol (E2), with mortality are poorly defined. Objective: We assessed associations of T, DHT, and E2 with all-cause and ischemic heart disease (IHD) mortality in older men. Participants: Participants were community-dwelling men aged 70 to 89 years who were residing in Perth, Western Australia. Main Outcome Measures: Plasma total T, DHT, and E2 were assayed using liquid chromatographytandem mass spectrometry in early morning samples collected in 2001 to 2004 from 3690 men. Deaths to December 2010 were ascertained by data linkage. Results: There were 974 deaths (26.4%), including 325 of IHD. Men who died had lower baseline T (12.8 ± 5.1 vs 13.2 ± 4.8 nmol/L [mean ± SD], P = .013), DHT (1.4 ± 0.7 vs 1.5 ± 0.7 nmol/L, P = .002), and E2 (71.6 ± 29.3 vs 74.0 ± 29.0 pmol/L, P = .022). After allowance for other risk factors, T and DHT were associated with all-cause mortality (T: quartile [Q] Q2:Q1, adjusted hazard ratio [HR] = 0.82, P = .033; Q3:Q1, HR = 0.78, P = .010; Q4:Q1, HR = 0.86, P > .05; DHT: Q3:Q1, HR = 0.76, P = .003; Q4:Q1, HR=0.84, P > .05). Higher DHT was associated with lower IHD mortality (Q3:Q1, HR = 0.58, P = .002; Q4:Q1, HR = 0.69, P = .026). E2 was not associated with either all-cause or IHD mortality. Conclusions: Optimal androgen levels are abiomarker for survival because older men with midrange levels of T and DHT had the lowest death rates from any cause, whereas those with higher DHT had lower IHD mortality. Further investigations of the biological basis for these associations including randomized trials of T supplementation are needed. (J Clin Endocrinol Metab 99: E9-E18, 2014). © Copyright 2014 by The Endocrine Society.

Objective In men, testosterone (T) levels decline with age, and lower T predicts all-cause and cardiovascular mortality. However, the associations of T and its metabolites, dihydrotestosterone (DHT) and estradiol (E2), with symptomatic peripheral arterial disease remain unclear. We assessed associations of T, DHT and E2 with lower limb intermittent claudication in older men. Design Cross-sectional study. Participants Community-dwelling men aged 70-89 years resident in Perth, Western Australia. Measurements Intermittent claudication was ascertained by the Edinburgh Claudication Questionnaire. Early morning, plasma T, DHT and E2 were assayed using liquid chromatography-tandem mass spectrometry. Results There were 268 men with intermittent claudication and 2435 without claudication or any leg pain. Men with nonspecific leg pain (n = 986) were excluded. After adjusting for age, smoking, BMI, waist/hip ratio, hypertension, dyslipidaemia, diabetes, creatinine and prevalent cardiovascular disease (CVD), higher T was associated with reduced risk of having claudication (per 1 SD increase, odds ratio [OR] = 0·80, 95% confidence interval [CI] = 0·69-0·94, P = 0·006; quartiles, Q4/Q1, OR = 0·54, 95% CI = 0·36-0·81). Higher DHT was associated with reduced risk of having claudication (per 1 SD increase, OR = 0·86, 95% CI = 0·73-1·00, P = 0·048; Q4/Q1, OR = 0·64, 95% CI = 0·43-0·95). E2 was not associated with claudication (per 1 SD increase, OR = 0·96, 95% CI = 0·83-1·11, P = 0·565; Q4/Q1, OR = 0·88, 95% CI = 0·60-1·29). Conclusions Lower T or DHT levels, but not E2, are associated with symptoms of intermittent claudication in older men. Reduced exposure to androgens may represent a causal factor or biomarker for symptomatic peripheral arterial disease. Further studies are needed to examine underlying mechanisms and evaluate therapeutic options in ageing men. © 2013 John Wiley & Sons Ltd.

Increased risk of schizophrenia in adolescent males indicates that a link between the development of dopamine-related psychopathology and testosterone-driven brain changes may exist. However, contradictions as to whether testosterone increases or decreases dopamine neurotransmission are found and most studies address this in adult animals. Testosterone-dependent actions in neurons are direct via activation of androgen receptors (AR) or indirect by conversion to 17â-estradiol and activation of estrogen receptors (ER). How midbrain dopamine neurons respond to sex steroids depends on the presence of sex steroid receptor(s) and the level of steroid conversion enzymes (aromatase and 5á-reductase). We investigated whether gonadectomy and sex steroid replacement could influence dopamine levels by changing tyrosine hydroxylase (TH) protein and mRNA and/or dopamine breakdown enzyme mRNA levels [catechol-O-methyl transferase (COMT) and monoamine oxygenase (MAO) A and B] in the adolescent male rat substantia nigra. We hypothesized that adolescent testosterone would regulate sex steroid signaling through regulation of ER and AR mRNAs and through modulation of aromatase and 5á-reductase mRNA levels.

GH treatment in adults with GH deficiency has numerous beneficial effects, but most studies have been small. We report the results of an Australian multicenter, randomized, double-blind, placebo-controlled trial of the effects of recombinant human GH treatment in adults with GH deficiency. GH deficiency was defined as a peak serum GH of <5 mU/liter in response to insulin-induced hypoglycemia. Patients were randomly assigned to receive either GH (0.125 U/kg per week for 1 month and 0.25 U/kg per week for 5 months) or placebo. After 6 months, all patients received GH. The primary end points were biochemical responses, body composition, quality of life, and safety. One hundred sixty-six patients (72 females and 91 males) with a mean age of 40 +/- 1 yr (+/-SEM; range 17-67 yr) were recruited. Serum insulin-like growth factor-I (IGF-I) increased from a standard deviation score of -2.64 +/- 0.27 (range -8.8 to +3.82; n = 78) to +1.08 +/- 2.87 (range -7.21 to +6.42) at 6 months in the GH/GH group; 38% of the whole group were above the age- specific reference range following treatment [17.6% and 68.9% with subnormal (<2 SD) or normal (+/-2 SD) pretreatment levels, respectively]. Fasting total cholesterol (P = 0.042) and low-density lipoprotein cholesterol (P = 0.006) decreased over the first 6 months. Fat-free mass increased in the first 6 months whether measured by bioelectrical impedance (P < 0.001) or dual energy x-ray absorptiometry (DEXA; P < 0.001). Total-body water increased in the first 6 months whether measured by bioelectrical impedance (P < 0.001) or deuterium dilution (P = 0.002). Fat mass measured by DEXA (P < 0.001), skinfold thicknesses (P < 0.001), and waist/hip ratio (P = 0.001) decreased in the first 6 months. Most changes in body composition were complete by 3 months of treatment and maintained to 12 months. Whole-body bone mineral density (BMD) (by DEXA) was unaffected by GH treatment. Self-reported quality of life was considered good before treatment, a

Evidence about the association between treatment with high-risk medicines and frailty in older individuals is limited. We investigated the relationship between high-risk prescribing and frailty at baseline, as well as 2-year incident frailty, in 1,662 men 70 years of age. High-risk prescribing was defined as polypharmacy (5 medicines), hyperpolypharmacy (10 medicines), and by the Drug Burden Index (DBI), a dose-normalized measure of anticholinergic and sedative medicines. At baseline, frail participants had adjusted odds ratios (ORs) of 2.55 (95% confidence interval, CI: 1.69-3.84) for polypharmacy, 5.80 (95% CI: 2.90-11.61) for hyperpolypharmacy, and 2.33 (95% CI: 1.58-3.45) for DBI exposure, as compared with robust participants. Of the 1,242 men who were robust at baseline, 6.2% developed frailty over two years. Adjusted ORs of incident frailty were 2.45 (95% CI: 1.42-4.23) for polypharmacy, 2.50 (95% CI: 0.76-8.26) for hyperpolypharmacy, and 2.14 (95% CI: 1.25-3.64) for DBI exposure. High-risk prescribing may contribute to frailty in community-dwelling older men.

Background: Adolescence is characterized by marked psychosocial, behavioural and biological changes and represents a critical life transition through which adult health and well-being are established. Substantial research confirms the role of psycho-social and environmental influences on this transition, but objective research examining the role of puberty hormones, testosterone in males and oestradiol in females (as biomarkers of puberty) on adolescent events is lacking. Neither has the tempo of puberty, the time from onset to completion of puberty within an individual been studied, nor the interaction between age of onset and tempo. This study has been designed to provide evidence on the relationship between reproductive hormones and the tempo of their rise to adult levels, and adolescent behaviour, health and wellbeing. Methods/Design The ARCHER study is a multidisciplinary, prospective, longitudinal cohort study in 400 adolescents to be conducted in two centres in regional Australia in the State of New South Wales. The overall aim is to determine how changes over time in puberty hormones independently affect the study endpoints which describe universal and risk behaviours, mental health and physical status in adolescents. Recruitment will commence in school grades 5, 6 and 7 (10–12 years of age). Data collection includes participant and parent questionnaires, anthropometry, blood and urine collection and geocoding. Data analysis will include testing the reliability and validity of the chosen measures of puberty for subsequent statistical modeling to assess the impact over time of tempo and onset of puberty (and their interaction) and mean-level repeated measures analyses to explore for significant upward and downward shifts on target outcomes as a function of main effects. Discussion The strengths of this study include enrollment starting in the earliest stages of puberty, the use of frequent urine samples in addition to annual blood samples to measure puberty h

Context: Testosterone (T) levels decline with increasing age. Controversy exists over the threshold for classifying T as low vs. normal in older men. The relevance of assessing dihydrotestosterone (DHT) and estradiol (E2) remains unclear. Objective: We assessed the associations of T, DHT, and E2 in men aged 70 yr or older and established reference ranges for these in healthy older men. Participants: Community-dwelling men aged 70-89 yr residing in Perth, Western Australia, Australia, participated in the study. Main Outcome Measures: Plasma T, DHT, and E2 were assayed using liquid chromatography-tandem mass spectrometry in early morning samples from 3690 men. Results: Increasing age, higher body mass index and waist to hip ratio, dyslipidemia, diabetes, and higher LH were independently associated with lower levels of T and DHT. Increasing age, diabetes, and higher LH were associated with lower E2. In a reference group of 394 men aged 76.1 ± 3.2 yr reporting excellent or very good health with no history of smoking, diabetes, cardiovascular disease, cancer, depression, or dementia, the 2.5th percentile for T was 6.4 nmol/liter (184 ng/dl); DHT, 0.49 nmol/liter; and E2, 28 pmol/liter. Applying these cutoffs to all 3690 men, those with low T or DHT had an increased odds ratio for frailty, diabetes, and cardiovascular disease. Men with both low T and DHT had a higher odds ratio for these outcomes. Conclusions: The 2.5th percentile in a reference group of healthy older men provides age-appropriate thresholds for defining low T, DHT, and E2. Additional studies are needed to test their potential applicability and clinical utility in older men. Copyright © 2012 by The Endocrine Society.