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Summary: Background: Sarcopenia is associated with adverse outcomes in cirrhosis. Branched‐chain amino acids (BCAA) target several pathways that lead to muscle loss in this population. Aims: We aimed to evaluate the impact of BCAA supplementation on sarcopenia measures in patients with cirrhosis. Methods: We conducted a 12‐month double‐blinded, randomised, controlled trial of BCAA supplementation (30 g daily) compared to an equicaloric, equi‐nitrogenous whey protein in volunteers with cirrhosis and reduced muscle strength. The primary endpoint was an increase in grip strength and upper limb lean mass measured on DEXA. Mean‐adjusted differences (MAD, 95% CI) between groups at 6 and 12 months are reported as treatment effect using a linear mixed model for repeated measures. Results: A total of 150 volunteers entered the trial (74 BCAA, 76 control), with a median age of 58 years [IQR 48; 63] and MELD of 14 [12; 17]. At 12 months, 57% in the BCAA arm and 61% in the control arm met the primary endpoint (p = 0.80). No significant between‐group difference was found in grip strength (MAD ‐0.15 kg [−0.37; 0.06], p = 0.29) or upper limb lean mass (1.7 kg [−0.2; 3.6], p = 0.22) at 12 months. No significant differences in other body composition parameters, physical performance, frailty, rates of hospitalisation or mortality were found between the BCAA and the control group. Fatigue improved across the entire cohort, without significant between‐group differences. 15% of volunteers reported side effects, with distaste higher in the BCAA arm (p = 0.045). Conclusion: BCAA supplementation did not improve measures of muscle strength, mass or performance or physical frailty compared to a whey protein supplement in a randomised controlled setting. ACTRN12618000802202. [ABSTRACT FROM AUTHOR]

Objective: Aromatase inhibitor (AI) therapy provides oncological benefits in postmenopausal women with oestrogen receptor‐positive breast cancer. However, AI treatment has been associated with increased cardiovascular risk. In nonbreast cancer populations, experimentally induced low oestrogen states and natural transition to menopause have been associated with increases in visceral adipose tissue (VAT), a known surrogate marker for cardiometabolic risk. Given that AI treatment blocks oestradiol production, we hypothesized that AI treatment would increase VAT. Methods: We conducted a prospective 12‐month cohort study of 52 postmenopausal women newly initiating AI treatment (median age: 64.5 years) and 52 women with breast pathology not requiring endocrine therapy (median age: 63.5 years). VAT area and other body composition parameters were measured at baseline, 6 months and 12 months using dual X‐ray absorptiometry. Other risk markers of cardiometabolic health were also assessed. Results: In women initiating AI treatment, there was no statistically significant difference in VAT area after 12 months when compared to controls, with a mean adjusted difference of −5.00 cm2 (−16.9, 6.91), p =.55. Moreover, changes in total fat mass, lean mass, subcutaneous adipose tissue area, hepatic steatosis and measures in endothelial function were also not statistically different between groups after 12 months. Findings were similar after adjustments for activity levels and coronavirus disease 2019 lockdown duration. Conclusions: These data provide reassurance that over the initial 12 months of AI therapy, AI treatment is not associated with metabolically adverse changes in body composition, hepatic steatosis or vascular reactivity. The impact of extended AI therapy on cardiometabolic health requires further study. [ABSTRACT FROM AUTHOR]

Objective: Roles for estradiol in modulating cognition in men remain uncertain. We assessed the isolated effects of estradiol on cognition in men in the absence of testosterone. Design: Randomized trial of transdermal estradiol 0.9 mg daily, or matched placebo, for 6 months, hypothesizing that estradiol would improve verbal learning, verbal memory, and spatial problem solving over time. Patients: Men receiving androgen deprivation therapy (ADT) for prostate cancer. Measurements: Cognition was assessed by a tablet‐based cognitive battery (Cogstate) at baseline, Month 1, Month 3, and Month 6. Anxiety and depression symptoms were assessed using the Hospital Anxiety and Depression Scale. Results: Seventy‐eight participants were randomized. Baseline mean scores were 21.0 (standard deviation [SD] 4.1) for the International Shopping List test (ISL), assessing verbal learning and memory (higher scores better), and 60.4 (SD 19.5) for the Groton Maze Learning test (GML), assessing spatial problem solving (lower scores better). There was no significant difference in performance over time for the estradiol group versus the placebo group for the ISL, mean adjusted difference (MAD) 0.7 (95% confidence interval [CI] −1.2 to 2.5), p =.36, or the GML, MAD −3.2 (95% CI −12.0 to 5.6), p = 0.53. There was no significant difference between groups over time in performance in any other cognitive domain, or on depression or anxiety scores. Conclusions: We found no major effects of estradiol on cognition in men with castrate testosterone concentrations. Although the cognitive effects of ADT are debated, this study suggests that any such effects are unlikely to be prevented by the administration of estradiol. [ABSTRACT FROM AUTHOR]

Androgen deprivation therapy (ADT) given to men with prostate cancer causes rapid and severe sex steroid deficiency, leading to increased bone remodeling and accelerated bone loss. To examine the effects of a single dose of zoledronic acid on bone microarchitecture, we conducted a 2‐year randomized placebo controlled trial in 76 men, mean age (interquartile range [IQR]) 67.8 years (63.8 to 73.9) with non‐metastatic prostate cancer commencing adjuvant ADT; 39 were randomized to zoledronic acid and 37 to matching placebo. Bone microarchitecture was measured using high‐resolution peripheral quantitative computed tomography (HR‐pQCT). Using a mixed model, mean adjusted differences (MAD; 95% confidence interval [95% CI]) between the groups are reported as the treatment effect at several time points. Over 24 months, zoledronic acid showed no appreciable treatment effect on the primary outcomes for total volumetric bone mineral density (vBMD); radius (6.7 mg HA/cm3 [−2.0 to 15.4], p = 0.21) and tibia (1.9 mg HA/cm3 [−3.3 to 7.0], p = 0.87). Similarly, there were no between‐group differences in other measures of microarchitecture, with the exception of a modest effect of zoledronic acid over placebo in total cortical vBMD at the radius over 12 months (17.3 mgHA/cm3 [5.1 to 29.5]). In contrast, zoledronic acid showed a treatment effect over 24 months on areal bone mineral density (aBMD) by dual‐energy X‐ray absorptiometry (DXA) at all sites, including lumbar spine (0.10 g/cm2 [0.07 to 0.13]), p < 0.001), and total hip (0.04 g/cm2 [0.03 to 0.05], p < 0.001). Bone remodeling markers were initially suppressed in the treatment group then increased but remained lower relative to placebo (MADs at 24 months CTX −176 ng/L [−275 to –76], p < 0.001; P1NP –18 mg/L [−32 to –5], p < 0.001). These findings suggest that a single dose of zoledronic acid over 2 years is ineffective in preventing the unbalanced bone remodeling and severe microstructural deterioration associated with ADT therapy. © 2020 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Summary: Context: Calorie restriction and overtraining are increasingly seen in young men who suffer from increasing societal pressure to attain a perceived ideal male body image. The resulting energy deficit can lead to multiple endocrine consequences, including suppression of the male gonadal axis. Design: We reviewed the literature, including two unpublished cases. Results: We identified 23 cases, aged median (range) 20 years (16‐33), with a body mass index of 15.9 kg/m2 (12.5‐20.5). Total testosterone was 3.0 nmol/L (0.6‐21.3), and luteinizing hormone (LH) 1.2 mIU/L (<0.2‐7.5), with 91% of cases demonstrating hypogonadotropic hypogonadism. Associated findings included evidence of growth hormone resistance (increased growth hormone in 57% and low insulin‐like growth factor‐1 in 71%), hypercortisolaemia (50%) and a nonthyroidal illness picture (67%). In cases with longitudinal measurements following weight regain, serum testosterone (n = 14) increased from median [interquartile range] 3.2 nmol/L [1.9‐5.1] to 14.3 nmol/L [9.3‐21.2] (P < 0.001), and LH (n = 8) from 1.2 IU/L [0.8‐1.8] to 3.5 IU/L [3.3‐4.3] (P = 0.008). Conclusions: Hypogonadotropic hypogonadism can occur in the context of energy deprivation in young otherwise healthy men and may be underrecognized. The evidence suggests that gonadal axis suppression and associated hormonal abnormalities represent an adaptive response to increased physiological stress and total body energy deficit. The pathophysiology likely involves hypothalamic suppression due to dysregulation of leptin, ghrelin and pro‐inflammatory cytokines. The gonadal axis suppression is functional, because it can be reversible with weight gain. Treatment should focus on reversing the existing energy deficit to achieve a healthy body weight, including psychiatric input where required. [ABSTRACT FROM AUTHOR]

Introduction: Reduced muscle area on CT scan is an independent predictor of mortality in cirrhosis. We examine for the first time the relationship between dual energy x‐ray absorptiometry (DEXA) lean mass parameters on outcomes in cirrhotic men awaiting liver transplantation. Materials and Methods: We retrospectively reviewed DEXA scans performed during transplant assessment between 2001 and 2016. Baseline data including the presence of ascites and MELD score were recorded. DEXA lean mass measures were adjusted for height. The primary outcome was 12‐month wait‐list mortality. Results: Four hundred twenty men with median age 55.4 years [interquartile range 49.2; 59.4] and MELD 16 [12; 20] were studied. Median follow‐up was 58.5 [28.8; 109] months. 12‐month wait‐list mortality was 12.4%. Appendicular lean mass was inversely associated with mortality (HR 0.78 [0.62; 0.98], P = 0.03). Lean mass of arms (HR 0.37 [0.16; 0.83], P  = 0.02) rather than legs (HR 0.77 [0.58; 1.03], P  = 0.08) was responsible for this association. Upper limb lean mass showed a significant interaction with MELD score in predicting wait‐list mortality, particularly within 4 months. Total lean mass was not associated with mortality but increased in conjunction with increasing ascites (OR for ascites 1.20 [1.15; 1.25], P < 0.001 for each unit increase in MELD). Conclusion: Upper limb lean mass by DEXA is strongly associated with mortality in men awaiting liver transplantation. The superiority of upper limb lean mass probably relates to confounding of lower limb measures by fluid retention. This DEXA parameter represents a novel and reproducible measure of sarcopenia in cirrhosis. [ABSTRACT FROM AUTHOR]

Abstract: Background: Thyroid feedback regulation and equilibria between thyroid hormones differ in the presence or absence of a functioning thyroid remnant. Materials and Methods: This study examines the relationship between the sensitivity of TSH feedback and thyroid capacity in untreated patients with thyroid autoimmune disease (n = 86) and healthy controls (n = 271). Functional capacity was estimated at maximum TSH stimulation, and pituitary TSH response was FT4‐standardised with two established indices, the TSH index and the thyrotroph thyroid hormone resistance index. Results: The two indices correlated inversely with thyroid volume and functional thyroid capacity. Relationships were shifted upwards in patients with thyroid autoimmune disease. This positioned patients with thyroid autoimmune disease predominantly at the lower capacity range and upper part of TSH index. The relationship was modulated by serum FT3 concentrations, shifting 0.19 [95%CI: 0.12, 0.26] mIU/L per pmol FT3 increase. FT3 correlated with TSH index in total group ( τ = 0.09, P = 0.009) and both subgroups. FT3 levels were maintained despite a substantial capacity loss by progressively increasing conversion rates of T3 from T4, only collapsing at capacities below <1.5 pmol/s. Conclusion: Functional thyroid capacity and preferential T3 generation are essential elements in adjusting the sensitivity of hypothalamic‐pituitary‐thyroid feedback control and balancing system equilibria. This suggests that the indirect regulatory role of glandular T3 co‐secretion exceeds its quantitative contribution to the thyroid hormone pool. Implications for clinical practice extend to the diagnostic use of TSH in patients with impaired thyroid reserve. [ABSTRACT FROM AUTHOR]

Background Testosterone treatment in obese dieting men augments the diet-associated loss of fat mass, but protects against loss of lean mass. We assessed whether body composition changes are maintained following withdrawal of testosterone treatment. Methods We conducted a prespecified double-blind randomized placebo-controlled observational follow-up study of a randomized controlled trial ( RCT). Participants were men with baseline obesity (body mass index >30 kg/m2) and a repeated total testosterone level <12 nmol/L, previously enrolled in a 56-week testosterone treatment trial combined with a weight loss programme. Main outcome measures were mean adjusted differences ( MAD) (95% confidence interval), in body composition between testosterone- and placebo-treated men at the end of the observation period. Results Of the 100 randomized men, 82 completed the RCT and 64 the subsequent observational study. Median [ IQR] observation time after completion of the RCT was 82 weeks [74; 90] in men previously receiving testosterone (cases) and 81 weeks [67;91] in men previously receiving placebo (controls), P=.51. At the end of the RCT, while losing similar amounts of weight, cases had, compared to controls, lost more fat mass, MAD −2.9 kg (−5.7, −0.2), P=.04, but had lost less lean mass MAD 3.4 kg (1.3, 5.5), P=.002. At the end of the observation period, the former between-group differences in fat mass, MAD −0.8 kg (−3.6, 2.0), P=1.0, in lean mass, MAD −1.3 kg (−3.0, 0.5), P=.39, and in appendicular lean mass, MAD −0.1 kg/m2 (−0.3, 0.1), P=.45, were no longer apparent. During observation, cases lost more lean mass, MAD −3.7 kg (−5.5, −1.9), P=.0005, and appendicular lean mass, MAD −0.5 kg/m2 (−0.8, −0.3), P<.0001 compared to controls. Conclusions The favourable effects of testosterone on body composition in men subjected to a concomitant weight loss programme were not maintained at 82 weeks after testosterone treatment cessation. [ABSTRACT FROM AUTHOR]

Objective Recent evidence suggests that androgens either directly or via aromatisation to oestradiol may regulate telomere length, hence providing a mechanism whereby reproductive steroids are linked to biological ageing in men. Using men with prostate cancer initiating androgen deprivation therapy ( ADT), we tested the hypothesis that severe sex steroid deprivation would accelerate telomere shortening. Design We conducted a secondary analysis of a 2-year prospective controlled study among 65 men with nonmetastatic prostate cancer newly commencing adjuvant ADT (n=40) and age- and radiotherapy-matched prostate cancer controls (n=25). Methods We measured leucocyte telomere length ( LTL) expressed as telomeric/single copy control gene (T/S) ratio at baseline, 6, 12 and 24 months. Generalized linear models determined the mean adjusted difference ( MAD) (95% confidence interval) between groups during follow-up. Results Compared to controls over 24 months, men receiving ADT had no change in LTL, MAD for T/S ratio (0.105 [−0.004; 0.213], P=.235). Conclusions Using men with prostate cancer receiving ADT as a model we found no evidence that prolonged and profound sex steroid deprivation is associated with accelerated telomere shortening. Larger studies will be required to confirm or refute these findings. [ABSTRACT FROM AUTHOR]

Objective While androgen deprivation therapy (ADT) has been associated with decreased quality of life (QoL), controlled prospective studies are lacking. We aimed to assess QoL during ADT using two validated questionnaires and determine contributing factors. Design Prospective controlled study. Patients Sixty-three men with nonmetastatic prostate cancer newly commencing ADT ( n = 34) and age- and radiotherapy-matched prostate cancer controls ( n = 29). Measurements QoL was measured by Short-Form 12 version 2 survey (SF-12) and Aging Males' Symptoms (AMS) score at 0, 6 and 12 months. Generalized linear models determined the mean adjusted difference (MAD) (95% confidence interval) between groups during follow-up. Results Compared to controls over 12 months, men receiving ADT had decreased SF-12 physical component score [MAD −3·61 (−6·94, −0·29), P = 0·013] reflecting worsening QoL but no change in the mental component ( P = 0·74). Total AMS score increased [MAD 9·35 (5·65, 13·07), P < 0·001], reflecting worse QoL. Both SF-12 and AMS changes were greater than reported minimum clinically important differences. AMS sub-domains showed increased somatic [MAD 3·96 (1·94, 5·99), P < 0·001] and sexual [MAD 3·80 (2·16, 5·44), P < 0·001] components but not psychological ( P = 0·19). Decrements were related to an increase in hot flushes ( P = 0·016) but not haemoglobin decrease ( P = 0·46). Conclusions Within 12 months, ADT is associated with clinically significant decreased QoL, particularly physical and sexual aspects, independent of the confounding effects of a cancer diagnosis or radiotherapy. As QoL is a crucial aspect of prostate cancer treatment, addressing hot flushes, sexual dysfunction and exercise may potentially improve outcomes for men undergoing ADT. [ABSTRACT FROM AUTHOR]

Background Although muscle mass declines with testosterone deficiency in men, previous studies of muscle function have not demonstrated consistent deficits, likely due to relatively insensitive methodology. Our objective was to determine the effects of testosterone deprivation on the biomechanical function of individual lower-limb muscles. Methods We conducted a 12-month prospective, observational case-control study of 34 men newly commencing androgen deprivation treatment (ADT) for prostate cancer and 29 age-matched prostate cancer controls. Participants were assessed at 0, 6, and 12 months while walking in a biomechanics laboratory. We combined video-based motion capture and ground reaction force data with computerized musculoskeletal modelling to assess the following primary outcomes: (i) peak joint torques at the hip, knee and ankle, and corresponding individual muscle forces; (ii) individual muscle contributions to acceleration of the body's centre of mass; and (iii) walking speed, stride length, and step width. A linear mixed model was used to compare mean differences between groups. Results Compared with controls over 12 months, men receiving ADT had a mean reduction in total testosterone level from 14.1 to 0.4 nmol/L, and demonstrated more marked decreases in peak hip flexor torque by 14% [mean difference −0.11 N/kg (−0.19, −0.03), P = 0.01] and peak knee extensor torque by 16% [−0.11 N/kg (−0.20, −0.02), P = 0.02] of the initial mean value. Correspondingly, iliopsoas force decreased by 14% ( P = 0.006), and quadriceps force decreased by 11%, although this narrowly missed statistical significance ( P = 0.07). Soleus decreased contribution to forward acceleration of the body's centre of mass by 17% [mean difference −0.17 m/s2 (−0.29, −0.05), P < 0.01]. No significant changes between groups were observed in other joint torques or individual muscle contributions to acceleration of the body. Step width increased by 18% [mean adjusted difference 1.4 cm (0.6, 27.4), P = 0.042] in the ADT group compared with controls, with no change in stride length or walking speed. Conclusions Testosterone deprivation selectively decreases lower-limb muscle function, predominantly affecting muscles that support body weight, accelerate the body forwards during walking, and mediate balance. Future exercise and pro-myogenic interventional studies to mitigate ADT-associated sarcopenia should target these deficits. [ABSTRACT FROM AUTHOR]

Background & Aims Circulating testosterone is usually reduced in men with cirrhosis, but there has not been a comprehensive analysis of androgen status or circulating oestrogens. Little is known about associations between circulating sex steroids with aspects of health in this population. Methods We report data from men with cirrhosis and low serum testosterone (<12 nmol/L or calculated free testosterone <230 pmol/L). Comprehensive circulating sex steroid profiles were measured by liquid chromatography-mass spectrometry and compared with age-matched controls. Relationships between sex hormone levels, severity of liver disease, biochemistry and clinical outcomes were assessed. Results Serum oestrone and oestradiol were significantly elevated in men with cirrhosis compared with controls (median, 869.1 pmol/L vs. 133.8 pmol/L and 166.7 pmol/L vs. 84.6 pmol/L respectively). Serum oestrone correlated with MELD score (correlation +0.306, P < 0.001) and inversely correlated with serum sodium (correlation −0.208, P = 0.004) and haemoglobin (correlation −0.177, P = 0.012). No such correlations were observed for oestradiol. Serum testosterone levels inversely correlated with MELD score (correlation −0.294, P < 0.001) and positively with handgrip strength (correlation +0.242, P < 0.001), physical activity (correlation +0.276, P = 0.012), haemoglobin (correlation +0.282, P < 0.001) and serum sodium (+0.344, P < 0.001). Dihydrotestosterone inversely correlated with MELD score (correlation −0.225, P = 0.002) and shared similar significant relationships to testosterone. Conclusion Low serum androgens and elevated serum oestrone (but not oestradiol) are associated with higher MELD and individual adverse health outcomes in cirrhotic cohort of men selected for low testosterone. Serum oestrone may be a novel marker of ill health in this population. Whether low androgens are markers or mediators of ill health requires further investigation. [ABSTRACT FROM AUTHOR]

Background and Aim Both sarcopenia and low serum testosterone have been associated with increased mortality in men with cirrhosis. It is not known how these variables interact. Methods We conducted a retrospective longitudinal cohort study of 145 men referred for liver transplant evaluation between 2005 and 2012. Baseline demographics included hormone profile and model of end-stage liver disease (MELD) score. Baseline computerized tomography was reformatted to calculate skeletal muscle area at L4 using validated, Tomovision software-based methodology. The primary outcome was time to death or liver transplantation. Results Median testosterone was low at 6.2 nmol/L (ref. 10-27.6 nmol/L) as was muscle mass at 48.0 cm2/m2 (ref. > 52.4 cm2/m2). Muscle mass correlated with both serum testosterone (tau = 0.132, P = 0.019) and MELD score (tau = −0.155, P = 0.007). In separate multivariable models, both sarcopenia (hazard ratio [HR] 1.05, P = 0.04) and low testosterone (HR 1.08, P = 0.01) were significantly associated with mortality independent of MELD score. When the variables MELD score, muscle area, and testosterone were entered into a single model, low testosterone but not sarcopenia remained significantly predictive of mortality (HR 1.07, P = 0.02, and HR 1.04, P = 0.09, respectively). Conclusion Low testosterone and sarcopenia are both associated with increased mortality in men with advanced liver disease and may identify patients at high risk of mortality that would be missed by the MELD score alone. Low testosterone appears to be a better predictor of mortality than sarcopenia and is a simpler test to improve the prognostic value of the MELD score. Interventional trials are required to determine whether low testosterone and sarcopenia are markers or mediators of mortality in this population. [ABSTRACT FROM AUTHOR]

Objective To assess the effect of testosterone treatment on cardiac biomarkers in men with type 2 diabetes (T2D). Design Randomized double-blind, parallel, placebo-controlled trial. Patients Men aged 35-70 years with T2D and a total testosterone level ≤12.0 nmol/l (346 ng/dl) at high risk of cardiovascular events, median 10-year United Kingdom Prospective Diabetes Study (UKPDS) coronary heart disease (CHD) risk 21% (IQR 16%, 27%). Eighty-eight participants were randomly assigned to 40 weeks of intramuscular testosterone undecanoate (n = 45) or matching placebo (n = 43). Main Outcome Measures N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT). Result Testosterone treatment reduced NT-proBNP (mean adjusted difference (MAD) in change over 40 weeks across the testosterone and placebo groups, -17.9 ng/l [95% CI -32.4, -3.5], P = 0.047), but did not change hs-cTnT (MAD, 0.41 ng/l (95% CI -0.56, 1.39), P = 0.62). Six men, three in each group experienced an adverse cardiac event, displaying already higher baseline NT-proBNP (P < 0.01) and hs-cTnT levels (P = 0.01). At baseline, 10-year UKPDS CHD risk was associated positively with NT-proBNP (τ = 0.21, P = 0.004) and hs-cTnT (τ = 0.23, P = 0.003) and inversely with testosterone (total testosterone τ = -0.18, P = 0.02, calculated free testosterone τ = -0.19, P = 0.01), but there was no significant association between testosterone and cardiac biomarkers (P > 0.05). Conclusions In this trial of men with T2D and high cardiovascular risk, testosterone treatment reduced NT-proBNP and did not change hs-cTnT. Further studies should determine whether men with increased cardiac biomarkers prior to testosterone therapy are at higher risk of testosterone treatment-associated adverse cardiac events. [ABSTRACT FROM AUTHOR]

Context The effects of testosterone treatment on glucose metabolism and other outcomes in men with type 2 diabetes (T2D) and/or the metabolic syndrome are controversial. Objective To perform a systematic review and meta-analysis of placebo-controlled double-blind randomized controlled clinical trials ( RCT) of testosterone treatment in men with T2D and/or the metabolic syndrome. Data sources A systematic search of RCTs was conducted using Medline, Embase and the Cochrane Register of controlled trials from inception to July 2014 followed by a manual review of the literature. Study selection Eligible studies were published placebo-controlled double-blind RCTs published in English. Data extraction Two reviewers independently selected studies, determined study quality and extracted outcome and descriptive data. Data synthesis Of the 112 identified studies, seven RCTs including 833 men were eligible for the meta-analysis. In studies using a simple linear equation to calculate the homeostatic model assessment of insulin resistance ( HOMA1), testosterone treatment modestly improved insulin resistance, compared to placebo, pooled mean difference ( MD) −1·58 [−2·25, −0·91], P < 0·001. The treatment effect was nonsignificant for RCTs using a more stringent computer-based equation ( HOMA2), MD −0·19 [−0·86, 0·49], P = 0·58). Testosterone treatment did not improve glycaemic (HbA1c) control, MD −0·15 [−0·39, 0·10], P = 0·25, or constitutional symptoms, Aging Male Symptom score, MD −2·49 [−5·81, 0·83], P = 0·14). Conclusions This meta-analysis does not support the routine use of testosterone treatment in men with T2D and/or the metabolic syndrome without classical hypogonadism. Additional studies are needed to determine whether hormonal interventions are warranted in selected men with T2D and/or the metabolic syndrome. [ABSTRACT FROM AUTHOR]

Objective Our objective was to characterize and evaluate prognostic implications of circulating sex steroids in patients at different stages of chronic kidney disease ( CKD). Design Prospective observational cohort study. Patients We prospectively recruited patients with CKD III- IV, undergoing chronic dialysis and kidney transplant recipients ( KTR) from a single centre in 2003-2004. Measurements Two stored samples taken 3 months apart were analysed for sex hormones using liquid chromatography/tandem mass spectrometry, and the mean of the two was used for analysis. We also measured novel biomarkers troponin T and NT-pro BNP. Patients were followed until death, transplant or 30 June 2013, and survival analysis performed. Results In males, but not in females, both testosterone ( P = 0·003) as well as oestradiol ( P < 0·02) levels were lowest in dialysis patients and highest in KTR. Over a median follow up of 8·5 years (interquartile range 3·8-9·2), 52 men (36%) died and 24 (17%) received a kidney transplant. In Cox proportional hazards regression up to 9·6 years, an increase in total testosterone of 1 nmol/l was associated with a 9·8% (95% confidence interval 3·1-16·3) decrease in mortality independent of age, body mass index, stage of renal disease and circulating levels of NT-pro BNP or troponin T. By contrast, sex steroid levels were not associated with mortality in females. Conclusions Testosterone levels differ across stages of kidney disease and low testosterone levels predict mortality in males, independent of established and novel predictors of mortality. [ABSTRACT FROM AUTHOR]

Objective We examined the interrelationships of pituitary thyrotropin ( TSH) with circulating thyroid hormones to determine whether they were expressed either invariably or conditionally and distinctively related to influences such as levothyroxine ( L- T4) treatment. Design and methods This prospective study employing 1912 consecutive patients analyses the interacting equilibria of TSH and free triiodothyronine ( FT3) and free thyroxine ( FT4) in the circulation. Results The complex interrelations between FT3, FT4 and TSH were modulated by age, body mass, thyroid volume, antibody status and L- T4 treatment. By group comparison and confirmation by more individual TSH-related regression, FT3 levels were significantly lower in L- T4-treated vs untreated nonhypothyroid autoimmune thyroiditis (median 4·6 vs 4·9 p m, P < 0·001), despite lower TSH (1·49 vs 2·93 mU/l, P < 0·001) and higher FT4 levels (16·8 vs 13·8 p m, P < 0·001) in the treated group. Compared with disease-free controls, the FT3- TSH relationship was significantly displaced in treated patients with carcinoma, with median TSH of 0·21 vs 1·63 ( P < 0·001) at a comparable FT3 of 5·0 p m in the groups. Disparities were reflected by calculated deiodinase activity and remained significant even after accounting for confounding influences in a multivariable model. Conclusions TSH, FT4 and FT3 each have their individual, but also interlocking roles to play in defining the overall patterns of thyroidal expression, regulation and metabolic activity. Equilibria typical of the healthy state are not invariant, but profoundly altered, for example, by L- T4 treatment. Consequently, this suggests the revisitation of strategies for treatment optimization. [ABSTRACT FROM AUTHOR]

Objective To examine the prevalence and prognostic implications of low serum testosterone levels in men with chronic liver disease. Design We conducted an observational study at a tertiary referral centre. Patients and measurements Baseline serum testosterone was measured in 171 men presenting to the Victorian Liver Transplant Unit for liver transplant evaluation. Patients were followed up to liver transplant or death. Results Sixty-one per cent of men had a low total testosterone level (TT, <10 n m), and 90% of men had a low calculated free testosterone level ( cFT, <230 p m). During the available observation time (median 8 months, interquartile range 4-14 months), 56 men (33%) died and 63 (37%) received a liver transplant. Fifty-two (30%) survived without a transplant. Median time to death was 8 months (range 2-13) and to liver transplant was 8 months (4-14). Baseline low TT and cFT levels both ( P < 0·0001) predicted mortality. Moreover, in a Cox proportional hazard model, both low total ( P = 0·02) and free testosterone ( P = 0·007) levels remained predictive of death independently of established prognostic factors, such as the model for end-stage liver disease (MELD) score and serum sodium levels. A decrease in TT by 1 n m and in cFT by 10 p m was associated with an 8% increase in mortality. Conclusions Low testosterone levels are common in men with severe liver disease and predict mortality independent of MELD, the standard score used to prioritize the allocation of liver transplants. [ABSTRACT FROM AUTHOR]

Posterior retroperitoneoscopic adrenalectomy is one of the new endoscopic methods in endocrine surgery. In a prospective clinical study 142 posterior retroperitoneoscopic adrenalectomies (72 right, 70 left) were performed in 130 patients (52 males, 78 females, age 49.1 ± 14.9 years). Indications were primary adrenal tumors (unilateral, n= 118; bilateral, n= 2), adrenal metastases ( n= 2), and bilateral ACTH-dependent hyperplasias ( n= 10). Tumor size ranged from 0.5 to 7.0 cm (mean 2.7 ± 1.4 cm). Partial adrenalectomies were performed in 39 patients. Conversion to open posterior adrenalectomy was necessary in five patients and seven procedures (5%). Intraoperative and postoperative complications were minor and occurred in 5% and 13%, respectively. Mortality was zero. Operating time was 101 ± 39 minutes (range 35–285 minutes) and depended on tumor type (pheochromocytoma versus others; p < 0.01), tumor size (< 3 vs. ≥ 3 cm; p < 0.05), gender ( p < 0.05), and extent of resection (partial versus complete, p < 0.05. Twenty-three adrenalectomies (17%) were performed within 1 hour or less. Blood loss was 54 ± 72 ml. Consumption of analgesics was low (mean 6 mg piritramide postoperatively). Median duration of hospitalization was 3 days. Posterior retroperitoneoscopic adrenalectomy is a safe method that has become a standard procedure in endocrine surgery. [ABSTRACT FROM AUTHOR]

Background: Defined by thyroid‐pituitary feedback control, clinical diagnosis of hypothyroidism and hyperthyroidism has become synonymous with TSH measurement. We combined in silico analysis and in vivo data to explore the central influences on thyroidal T3 production. Materials & methods: A system of five coupled first‐order nonlinear parameterised ordinary differential equations (ODEs) is used to model the feedback control of TSH and TRH by thyroid hormones together with the feedforward control of thyroidal T3 secretion and enzymatic T4‐T3 conversion. Dependencies of the stable equilibrium solutions of this ODE system, that is the homeostasis of the underlying physiological process, on the system parameters were investigated whether they accounted for clinical observations. Results: During the modelled transition to hypothyroidism, central control imposed an increasing influence in maintaining serum FT3 levels, compared to peripheral conversion efficiency. Numerical continuation analysis revealed dependencies of T3 production on different elements of TSH feedforward control. While T4‐T3 conversion provided the main T3 source in euthyroidism, this was overtaken by increasing glandular T3 secretion when thyroid reserve declined. The computational results were in good agreement with data from untreated patients with autoimmune thyroiditis. Conclusions: Dependencies revealed in the expression of control differ in thyroid health and disease, using a physiologically based mathematical model of combined feedback‐feedforward control of the hypothalamic‐pituitary‐thyroid regulation. Strong T3‐protective mechanisms of the control system emerge with declining thyroid function, when glandular T3 secretion becomes increasingly influential over conversion efficiency. This has wide‐ranging implications for the utility of TSH in clinical decision‐making. [ABSTRACT FROM AUTHOR]