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Spontaneous regression of cancer is a rare phenomenon seldom described in patients with hepatocellular carcinoma. A case of spontaneous regression of hepatocellular carcinoma is reported and compared with the reports published in the English literature. A 52-yr-old man presented with biopsy-proven hepatocellular carcinoma, which was considered to be unrespectable at initial laparotomy. The tumor subsequently regressed without specific treatment, as assessed radiologically and by normalization of a previously elevated α-fetoprotein level. At repeat laparotomy 14 months after initial diagnosis, intraoperative ultrasound failed to disclose a hepatic mass, and multiple biopsies stowed no evidence of malignancy. To date, only nine case reports of apparently spontaneous regression of hepatocellular carcinoma have been published in the English literature. Clinical characteristics discriminating these patients from less fortunate patients with hepatocellular carcinoma could not be identified. The mechanisms underlying this intriguing phenomenon remain unknown. [ABSTRACT FROM AUTHOR]

Purpose: Suppression of ovarian function and aromatase inhibition (AI) increases disease-free survival in premenopausal women with estrogen receptor (ER)-positive early-stage breast cancer but accelerates bone loss. We therefore hypothesized that suppressing bone remodeling using denosumab (DMAB) would prevent bone loss in these women., Methods: In a 12-month double-blind randomized trial, 68 women with ER-positive early-stage breast cancer commencing ovarian function suppression and AI were randomly assigned to 60 mg DMAB (n = 34) or placebo (PBO; n = 34) once every 6 months (at 0 and 6 months). Volumetric bone mineral density (BMD), microarchitecture, and estimated bone strength of the distal tibia and distal radius were measured using high-resolution peripheral quantitative computed tomography, and spine and hip BMD were measured using dual-energy X-ray absorptiometry at 0, 6, and 12 months. The primary end point and treatment effect was the mean adjusted between group difference (MAD; [95% CI]) in distal tibial total volumetric BMD over 12 months, with a single P value tested over all time points. The study is registered with the Australian New Zealand Clinical Trials Registry (anzctr.org.au; identifier: ACTRN12616001051437)., Results: Intention-to-treat analysis included all 68 randomly assigned women. Over 12 months, compared with PBO, DMAB prevented the decrease in distal tibial total BMD (MAD, 20.8 mg HA/cm 3 [95% CI, 17.3 to 24.2]), cortical BMD (42.9 mg HA/cm 3 [95% CI, 32.1 to 53.9]), trabecular BMD (3.32 mg HA/cm 3 [95% CI, 1.45 to 5.20], P = .004), estimated stiffness (11.6 kN/m [95% CI, 7.6 to 15.6]), and failure load (563 N [95% CI, 388 to 736]). Findings were similar at the distal radius. Decreases in BMD at the lumbar spine (MAD, 0.13 g/cm 2 [95% CI, 0.11 to 0.15]), total hip (0.08 g/cm 2 [95% CI, 0.07 to 0.09], and femoral neck (0.06 g/cm 2 [95% CI, 0.05 to 0.07]) were also prevented. All P < .001 unless otherwise noted., Conclusion: Treatment with DMAB at commencement of estradiol suppression therapy preserves BMD, bone microarchitecture, and estimated strength, and is likely to increase fracture-free survival.

Radioiodine treatment (RIT) has a high success rate in both the treatment of hyperthyroidism and improving the quality of life (QoL) of symptomatic patients. In asymptomatic patients with subclinical hyperthyroidism thyroid related QoL outcomes are less well known., Methods: Study aim was to evaluate thyroid-related QoL in patients with subclinical hyperthyroidism mostly due to toxic nodular goitre undergoing RIT, compared to a control group of euthyroid subjects. Study design was monocentric, prospective, controlled. Fifty control subjects were enrolled and 51 RIT patients. Most subjects were examined at least twice at an interval of 6 months, with visits immediately before and 6 months after treatment in the RIT group. QoL was estimated with the ThyPRO questionnaire, using its composite scale as primary outcome. Treatment effect was the mean adjusted difference (MAD) between groups over time, using repeated? measures mixed? effects models., Results: TSH concentrations were lower in the RIT group prior to treatment and recovered thereafter slightly above the level of the control group. Correspondingly, QoL improved significantly after 6 months from a worse level in the RIT group, compared to controls (MAD -10.3 [95% CI -14.9, -5.7], p<0.001). QoL improvements were strong for general items, but less pronounced for the hyperthyroid domain. Compared to controls, thyroid volume, thyroid functional capacity (SPINA-GT) and deiodinase activity (SPINA-GD) were significantly reduced in the RIT group., Conclusion: Patients with subclinical hyperthyroidism improve both biochemically and in their QoL after RIT, compared to controls. QoL assessment should have a wider role in clinical practice to complement biochemical tests and help with treatment decisions., Competing Interests: JWD is co-owner of the intellectual property rights for the patent "System and Method for Deriving Parameters for Homeostatic Feedback Control of an Individual" (Singapore Institute for Clinical Sciences, Biomedical Sciences Institutes, Application Number 201208940-5, WIPO number WO/2014/088516). All other authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported., (Thieme. All rights reserved.)

Endocrine regulation in the hypothalamic-pituitary-thyroid (HPT) axis is orchestrated by physiological circuits which integrate multiple internal and external influences. Essentially, it provides either of the two responses to overt biological challenges: to defend the homeostatic range of a target hormone or adapt it to changing environmental conditions. Under certain conditions, such flexibility may exceed the capability of a simple feedback control loop, rather requiring more intricate networks of communication between the system's components. A new minimal mathematical model, in the form of a parametrized nonlinear dynamical system, is here formulated as a proof-of-concept to elucidate the principles of the HPT axis regulation. In particular, it allows uncovering mechanisms for the homeostasis of the key biologically active hormone free triiodothyronine (FT3). One mechanism supports the preservation of FT3 homeostasis, whilst the other is responsible for the adaptation of the homeostatic state to a new level. Together these allow optimum resilience in stressful situations. Preservation of FT3 homeostasis, despite changes in FT4 and TSH levels, is found to be an achievable system goal by joining elements of top-down and bottom-up regulation in a cascade of targeted feedforward and feedback loops. Simultaneously, the model accounts for the combination of properties regarded as essential to endocrine regulation, namely sensitivity, the anticipation of an adverse event, robustness, and adaptation. The model therefore offers fundamental theoretical insights into the effective system control of the HPT axis., Competing Interests: JD is co-owner of the intellectual property rights for the patent “System and Method for Deriving Parameters for Homeostatic Feedback Control of an Individual” (Singapore Institute for Clinical Sciences, Biomedical Sciences Institutes, Application Number 201208940-5, WIPO number WO/2014/088516). All remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hoermann, Pekker, Midgley, Larisch and Dietrich.)

Background: Current hyponatraemia guidelines are divided on the use of tolvaptan in hospitalised patients with moderate to severe hyponatraemia, due to an uncertain risk-benefit ratio. We will conduct a randomised trial to test the hypothesis that early use of tolvaptan improves the rate of serum sodium correction and clinical outcomes compared with current standard first-line therapy, restriction of fluid intake, without increasing the risk of serum sodium overcorrection., Methods: We will enrol hospitalised patients with euvolaemic or hypervolaemic hyponatraemia and serum sodium of 115-130 mmol/L at Austin Health, a tertiary care centre in Melbourne, Australia. Participants will be randomised 1:1 to receive either tolvaptan (initial dose 7.5 mg) or fluid restriction (initial limit 1000 ml per 24 h), with titration of therapy based on serum sodium response according to a pre-determined protocol over a 72-h intervention period. The primary endpoint will be the between-group change in serum sodium over time, from study day 1 to day 4. Secondary endpoints include serum sodium increment in the first 24 and 48 h, proportion of participants with normalised serum sodium, length of hospital stay, requirement for serum sodium re-lowering with intravenous dextrose or desmopressin, cognitive and functional measures (Confusion Assessment Method Short form, Timed Up and Go test, hyponatraemia symptom questionnaire), 30-day readmission rate, treatment satisfaction score and serum sodium 30 days after discharge. The trial will be overseen by an independent Data Safety Monitoring Board. Serum sodium will be monitored every 6-12 h throughout the study period, with pre-specified thresholds for commencing intravenous 5% dextrose if serum sodium rise targets are exceeded., Discussion: We seek to inform future international guidelines with high-quality data regarding the utility and safety of tolvaptan compared to standard therapy fluid restriction in patients with moderate-severe hyponatraemia in hospital. If tolvaptan use in this patient group is endorsed by our findings, we will have established an evidence-based framework for tolvaptan initiation and monitoring to guide its use., Trial Registration: Australia and New Zealand Clinical Trials Registry ACTRN12619001683123 . Registered on December 2 2019., (© 2022. The Author(s).)

Objective: Indirect evidence suggests that the effects of testosterone on fat mass in men are dependent on aromatization to estradiol (E2). However, no controlled study has assessed the effects of E2 in the absence of testosterone., Design: Six-month randomized, placebo-controlled trial with the hypothesis that men randomized to E2 would reduce their fat mass., Methods: Seventy-eight participants receiving androgen deprivation therapy for prostate cancer were randomized to 0.9 mg of 0.1% E2 gel per day, or matched placebo. Dual x-ray absorptiometry body composition was measured at baseline, month 3, and month 6. The primary outcome was total fat mass., Results: Serum E2 increased in the estradiol group over 6 months compared to placebo, and mean-adjusted difference (MAD) was 207 pmol/L (95% CI: 123-292), P < 0.001. E2 treatment changed total fat mass, MAD 1007 g (95% CI: 124-1891), but not significantly, so P = 0.09. There were other consistent non-significant trends toward increased proportional fat mass, MAD 0.8% (95% CI: 0.0-1.6), P= 0.15; gynoid fat, MAD 147 g (95% CI: 2-293), P = 0.08; visceral fat, 53 g (95% CI: 1-105) P = 0.13; and subcutaneous fat, MAD 65 g (95% CI: 5-125), P = 0.11. Android fat increased, MAD 164 g (95% CI: 41-286), P = 0.04., Conclusion: Contrary to our hypothesis, we provide suggestive evidence that E2 acting in the absence of testosterone, may increase total and regional fat mass in men. Given the premature closure of clinical trials due to the COVID pandemic, this potentially important observation should encourage additional studies to confirm or refute whether E2 promotes fat expansion in the absence of testosterone.

Purpose: The aim of this study was to determine early weight loss-associated changes in subcutaneous abdominal white adipose tissue (WAT) gene expression in obese men with lowered serum testosterone by RNA next-generation sequencing., Methods: Fourteen men, mean age (IQR) 51.6 years (43.4-54.5), BMI 38.3 kg/m 2 (34.6-40.8) and total testosterone 8.4 nmol/L (7.5-9.5) provided subcutaneous WAT samples at baseline and after 2 weeks of a very low energy diet., Results: Body weight loss was similar in participants receiving testosterone (n = 6), -5.27 kg [95% CI -6.17; -4.26], and placebo (n = 8), -4.57 kg [95% CI -6.10; -3.55], p = 0.86. In placebo-treated men, of the 14,410 genes expressed in subcutaneous WAT, four genes, Angiopoietin-like 4, Semaphorin 3 G, Neuropilin 2 and Angiopoietin 4, were upregulated (adjusted false discovery rate P < 0.05). In an exploratory analysis comparing men receiving testosterone and placebo, the most-upregulated gene in the testosterone group (exploratory p < 0.0005) was the neuropeptide y receptor 2., Conclusions: In obese men, dieting is associated with upregulation of WAT-expressed Angiopoietin-like 4, a secreted protein that regulates lipid metabolism, Semaphorin 3 G, a proposed adipocyte differentiation factor and secreted adipokine, and its receptor Neuropilin 2, as well as Angiopoietin 4, a vascular integrity factor. In an exploratory analysis, testosterone was associated with the upregulation of neuropeptide y receptor 2, a receptor involved in appetite regulation. Further studies are needed to confirm these observations and their potential biological implications., Trial Registration: clinicaltrials.gov, Identifier NCT01616732, Registration date: June 8, 2012.

The aim of this study was to determine whether testicular volume is correlated with clinical and biochemical markers of hypothalamic-pituitary-testicular (HPT) axis function. This was a cross-sectional substudy of a larger randomized controlled trial including obese men, body mass index (BMI) ≥30 kg m -2 , with a total testosterone level <12 nmol l -1 . Testicular volume was measured by orchidometer, testosterone by liquid chromatography/tandem mass spectrometry, and body composition by dual-energy X-ray absorptiometry. Men completed the Aging Males' Symptoms (AMS) score, International Index of Erectile Function-5 (IIEF-5), physical function, and handgrip dynamometer testing. Eighty-nine men participated with a median (interquartile range [IQR]) age of 53.1 (47.6, 59.2) years, BMI of 37.0 (34.6, 40.5) kg m -2 , and a total testosterone of 7.0 (6.1, 7.9) nmol l -1 . Median testicular volume was 18 (IQR: 10, 20) ml. Testicular volume was negatively correlated with BMI (τ = -0.1952, P = 0.010) and total fat mass (τ = -0.2115, P = 0.005) independent of age and testosterone. When BMI, testosterone, sex hormone-binding globulin (SHBG), and luteinizing hormone (LH) were present in a multivariable model, only BMI (-0.38 ml change in testicular volume per 1 kg m -2 BMI; 95% CI: -0.74, -0.02; P = 0.04) and LH (-0.92 ml change in testicular volume per 1 IU l -1 LH; 95% CI: -1.75, -0.095; P = 0.03) remained independent significant predictors of testicular volume. Testicular volume was positively correlated with IIEF-5 (τ = 0.2092, P = 0.021), but not related to handgrip strength, physical function tests, or AMS. In obese men, testicular volume is inversely and independently associated with measures of adiposity, but not with most clinical or biochemical markers of HPT axis action. From a clinical perspective, this suggests that obesity might compromise the reliability of reduced testicular volume as a sign of androgen deficiency in men., Competing Interests: None

Background: Interventions such as testosterone treatment may change body composition and metabolic outcomes without substantial changes in weight and BMI., Objectives: Using testosterone treatment as a paradigm, we hypothesized that a body shape index (ABSI) reflects body composition changes more accurately than traditional markers, such as weight, BMI and waist circumference., Intervention: Secondary analysis of a 56-week RCT in 100 dieting obese men with low-normal testosterone receiving testosterone treatment or placebo, and subsequent off-treatment follow-up., Results: At the end of the trial period, ABSI-unlike weight, BMI or waist circumference-had significantly decreased in the treatment group, compared with placebo (mean adjusted difference -0.18 [95% CI: -0.32, -0.05] × 10 -2 m 11/6 kg -2/3 , overall P<0.001). Changes in ABSI during the active trial phase correlated with changes in fat mass (tau = 0.18, P = 0.02), and not with lean mass (tau = -0.11, P = 0.14), BMI (tau = 0.10, P = 0.17), or visceral fat (tau = 0.07, P = 0.37). ABSI baseline values were positively correlated with waist circumference (tau = 0.21, P = 0.002) and visceral fat (tau = 0.18, P = 0.009), correlated inversely with lean mass (tau = -0.21, P = 0.002), and were uncorrelated with BMI (tau = -0.10, P = 0.15) and fat mass (tau = 0.01, P = 0.83). Two years after cessation of treatment, ABSI again reflected body composition as the between-group differences in all parameters did not persist., Conclusions: A readily obtainable anthropomorphic measure, ABSI reflects the differential loss of fat mass mediated by testosterone in dieting obese men more closely than BMI or waist circumference. It may serve as a clinically useful marker to monitor body composition changes, particularly in response to interventions.

Background: In the treatment for hypothyroidism, a historically symptom-orientated approach has given way to reliance on a single biochemical parameter, thyroid stimulating hormone (TSH)., Main Body: The historical developments and motivation leading to that decision and its potential implications are explored from pathophysiological, clinical and statistical viewpoints. An increasing frequency of hypothyroid-like complaints is noted in patients in the wake of this directional shift, together with relaxation of treatment targets. Recent prospective and retrospective studies suggested a changing pattern in patient complaints associated with recent guideline-led low-dose policies. A resulting dramatic rise has ensued in patients, expressing in various ways dissatisfaction with the standard treatment. Contributing factors may include raised problem awareness, overlap of thyroid-related complaints with numerous non-specific symptoms, and apparent deficiencies in the diagnostic process itself. Assuming that maintaining TSH anywhere within its broad reference limits may achieve a satisfactory outcome is challenged. The interrelationship between TSH, free thyroxine (FT4) and free triiodothyronine (FT3) is patient specific and highly individual. Population-based statistical analysis is therefore subject to amalgamation problems (Simpson's paradox, collider stratification bias). This invalidates group-averaged and range-bound approaches, rather demanding a subject-related statistical approach. Randomised clinical trial (RCT) outcomes may be equally distorted by intra-class clustering. Analytical distinction between an averaged versus typical outcome becomes clinically relevant, because doctors and patients are more interested in the latter. It follows that population-based diagnostic cut-offs for TSH may not be an appropriate treatment target. Studies relating TSH and thyroid hormone concentrations to adverse effects such as osteoporosis and atrial fibrillation invite similar caveats, as measuring TSH within the euthyroid range cannot substitute for FT4 and FT3 concentrations in the risk assessment. Direct markers of thyroid tissue effects and thyroid-specific quality of life instruments are required, but need methodological improvement., Conclusion: It appears that we are witnessing a consequential historic shift in the treatment of thyroid disease, driven by over-reliance on a single laboratory parameter TSH. The focus on biochemistry rather than patient symptom relief should be re-assessed. A joint consideration together with a more personalized approach may be required to address the recent surge in patient complaint rates.

To assess the effect of testosterone treatment on bone remodelling and density in dieting obese men, 100 obese men aged 53 years (interquartile range 47-60) with a total testosterone level <12 nmol/L receiving 10 weeks of a very low energy diet (VLED) followed by 46 weeks of weight maintenance were randomly assigned at baseline to 56 weeks of intramuscular testosterone undecanoate (n = 49, cases) or matching placebo (n = 51, controls). Pre-specified outcomes were between-group differences (mean adjusted difference, MAD) in serum c-telopeptide (CTx), N-terminal propeptide of type 1 procollagen (P1NP) and bone mineral density (BMD). At trial end, CTx was significantly reduced in men receiving testosterone compared to placebo, MAD -66 ng/L (95% CI -113, -18), p = 0.018, and this was apparent already after the 10 week VLED phase, MAD -63 ng/L (95% CI -108, -18), p = 0.018. P1NP was marginally increased after VLED, MAD +4.2 ug/L (95% CI -0.01, +8.4), p = 0.05 but lower at study end, MAD -5.6 ug/L (95% CI -10.1, -1.1), p = 0.03. No significant changes in sclerostin, lumbar spine BMD or femoral BMD were seen. We conclude that in obese men with low testosterone levels undergoing weight loss, bone remodelling markers are modulated in a way that may have favourable effects on bone mass.

Despite significant progress in assay technology, diagnosis of functional thyroid disorders may still be a challenge, as illustrated by the vague upper limit of the reference range for serum thyrotropin ( TSH ). Diagnostical problems also apply to subjects affected by syndrome T, i.e., those 10% of hypothyroid patients who continue to suffer from poor quality of life despite normal TSH concentrations under substitution therapy with levothyroxine ( L - T 4 ). In this paper, we extend a mathematical model of the pituitary-thyroid feedback loop in order to improve the understanding of thyroid hormone homeostasis. In particular, we incorporate a TSH - T 3 -shunt inside the thyroid, whose existence has recently been demonstrated in several clinical studies. The resulting extended model shows good accordance with various clinical observations, such as a circadian rhythm in free peripheral triiodothyronine ( FT 3 ). Furthermore, we perform a sensitivity analysis of the derived model, revealing the dependence of TSH and hormone concentrations on different system parameters. The results have implications for clinical interpretation of thyroid tests, e.g., in the differential diagnosis of subclinical hypothyroidism.

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., (© 2017 John Wiley & Sons Ltd.)

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/m 2 ) 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/m 2 (-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/m 2 (-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., (© 2017 John Wiley & Sons Ltd.)

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., (© 2016 John Wiley & Sons Ltd.)

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/s 2 (-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., (© 2016 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.)

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 cm(2)/m(2) (ref. > 52.4 cm(2)/m(2)). 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., (© 2015 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

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., (© 2015 John Wiley & Sons Ltd.)

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., (© 2014 John Wiley & Sons Ltd.)

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-proBNP. 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-proBNP 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., (© 2014 John Wiley & Sons Ltd.)

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 pm, 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 pm, 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 pm 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., (© 2014 John Wiley & Sons Ltd.)

Objective: The objective of the study was to assess the effect of T treatment on constitutional and sexual symptoms in men with type 2 diabetes (T2D)., Design: This was a randomized double-blind, parallel, placebo-controlled trial., Setting: The study was conducted at a tertiary referral center., Patients: Men aged 35-70 years with T2D, a hemoglobin A1c less than 8.5%, and a total T level less than 12.0 nmol/L (346 ng/dL) with mild to moderate aging male symptoms and erectile dysfunction., Intervention: Eighty-eight participants were randomly assigned to 40 weeks of im T undecanoate (n = 45) or matching placebo (n = 43)., Main Outcome Measures: Constitutional symptoms using the aging male symptoms (AMS) score, sexual desire (question 17 AMS score), and erectile function (International Index of Erectile Function-5)., Results: T treatment did not substantially improve aging male symptoms [mean adjusted difference (MAD) in change over 40 weeks across the T and placebo groups in AMS total score, -0.9 (95% confidence interval [CI] -4.1, 2.2), P = .67] or sexual desire [MAD in question 17 AMS, -0.3 (95% CI -0.8, 0.2), P = .17]. Although compared with placebo, erectile function in men assigned to T was reduced [MAD in International Index of Erectile Function abridged version 5, -2.0 (95% CI -3.4, -0.6), P < .02], there was no significant difference between baseline and 40-week International Index of Erectile Function abridged version 5 scores if both groups were analyzed separately. At baseline, symptoms were worse in men with depression and microvascular complications but did not correlate with T levels., Conclusions: In this trial, T treatment did not substantially improve constitutional or sexual symptoms in obese, aging men with T2D with mild to moderate symptoms and modest reduction in T levels typical for the vast majority of such men.