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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

Epidemiological studies consistently demonstrate that lowered serum testosterone is not only common in men with established Type 2 diabetes, but also predicts future diabetic risks and increased mortality. Preclinical studies report plausible mechanisms by which low testosterone could mediate dysglycaemia. Exogenous testosterone treatment consistently reduces fat mass, increases muscle mass and improves insulin resistance in some studies, but the majority of currently available randomized controlled trials (RCTs) do not report a consistent glycaemic benefit. In men with diabetes, testosterone treatment effects on androgen deficiency-like clinical features are inconsistent, and effects on sexual dysfunction may be attenuated compared with men without diabetes. The long-term risks of testosterone treatment in older men without medical disease of the hypothalamic-pituitary-testicular axis are not known. Current RCTs are not definitive, owing to their small size, short duration and enrolment of men with mostly relatively good baseline glycaemic control not specifically selected for the presence of androgen deficiency symptoms. Although large, well-designed clinical trials are needed, given the benefit-risk ratio of testosterone treatment is not well understood, routine serum testosterone testing or testosterone treatment of asymptomatic men with Type 2 diabetes is currently not recommended. Carefully selected, symptomatic men with low testosterone who are informed of the lack of high-level evidence regarding the long-term benefits and risks of this approach may be offered a trial of testosterone treatment in combination with lifestyle measures, weight loss and optimization of comorbidities., (© 2019 Diabetes UK.)

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: Low circulating testosterone is associated with an increased risk of developing type 2 diabetes (T2DM) in overweight men with impaired glucose tolerance (IGT)., Aims: To determine in a multi-centre, double-blinded placebo-controlled randomized trial whether testosterone treatment combined with lifestyle intervention (Weight Watchers) relative to lifestyle intervention alone reduces T2DM incidence and improves glucose tolerance at 2 years., Study Population: Overweight or obese men aged 50-74 years with a serum testosterone of ≤14 nmol/L and IGT or newly diagnosed T2DM established by an oral glucose tolerance test (OGTT)., Setting, Drug and Protocol: Six Australian capital city-based tertiary care centres. Participants were randomized 1:1 and injected with testosterone undecanoate (1000 mg/4 mL) or vehicle (4 mL castor oil), at baseline, 6 weeks and 3-monthly thereafter. PRIMARY ENDPOINTS: (a) Proportion of participants with 2-hour OGTT ≥11.1 mmol/L at 2 years, and (b) a difference at 2 years ≥0.6 mmol/L in the mean 2-hour OGTT glucose between treatments., Secondary Endpoints: Fasting insulin, HbA1c, body composition, maximal handgrip strength; sexual function and lower urinary tract symptoms; serum sex steroids and sex hormone binding globulin; mood and psychosocial function; adherence to lifestyle intervention; and healthcare utilization and costs., Safety: Overseen by an Independent Data Safety Monitoring Committee. Haematocrit, lipids and prostate-specific antigen (PSA) are assessed 6-monthly and information relating to haematological, urological and cardiovascular adverse events from each clinic visit. SUB-STUDIES: (a) Changes in bone density and micro-architecture, (b) motivation and behaviour, (c) telomere length, (d) extended treatment up to 4 years, and (e) hypothalamo-pituitary testicular axis recovery at treatment end., (© 2018 John Wiley & Sons Ltd.)

Obesity, increasing in prevalence globally, is the clinical condition most strongly associated with lowered testosterone concentrations in men and presents as one of the strongest predictors of receiving testosterone treatment. While low circulating total testosterone concentrations in modest obesity primarily reflect reduced concentrations of sex hormone binding globulin, more marked obesity can lead to genuine hypothalamic-pituitary-testicular axis (HPT) suppression. HPT axis suppression is likely mediated via pro-inflammatory cytokine and dysregulated leptin signalling and aggravated by associated comorbidities. Whether oestradiol-mediated negative hypothalamic-pituitary feedback plays a pathogenic role requires further study. Although the obesity-hypogonadism relationship is bidirectional, the effects of obesity on testosterone concentrations are more substantial than the effects of testosterone on adiposity. In markedly obese men submitted to bariatric surgery, substantial weight loss is very effective in reactivating the HPT axis. In contrast, lifestyle measures are less effective in reducing weight and generally only associated with modest increases in circulating testosterone. In randomized controlled clinical trials (RCTs), testosterone treatment does not reduce body weight, but modestly reduces fat mass and increases muscle mass. Short-term studies have shown that testosterone treatment in carefully selected obese men may have modest benefits on symptoms of androgen deficiency and body composition even additive to diet alone. However, longer term, larger RCTs designed for patient-important outcomes and potential risks are required. Until such trials are available, testosterone treatment cannot be routinely recommended for men with obesity-associated nonclassical hypogonadism. Lifestyle measures or where indicated bariatric surgery to achieve weight loss, and optimization of comorbidities remain first line., (© 2018 John Wiley & Sons Ltd.)

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.

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.)

Context: Middle-aged and older men (≥50 years), especially those who are obese and suffer from comorbidities, not uncommonly present with clinical features consistent with androgen deficiency and modestly reduced testosterone levels. Commonly, such men do not demonstrate anatomical hypothalamic-pituitary-testicular axis pathology but have functional hypogonadism that is potentially reversible., Evidence Acquisition: Literature review from 1970 to October 2016., Evidence Synthesis: Although definitive randomized controlled trials are lacking, evidence suggests that in such men, lifestyle measures to achieve weight loss and optimization of comorbidities, including discontinuation of offending medications, lead to clinical improvement and a modest increase in testosterone. Also, androgen deficiency-like symptoms and end-organ deficits respond to targeted treatments (such as phosphodiesterase-5 inhibitors for erectile dysfunction) without evidence that hypogonadal men are refractory. Unfortunately, lifestyle interventions remain difficult and may be insufficient even if successful. Testosterone therapy should be considered primarily for men who have significant clinical features of androgen deficiency and unequivocally low testosterone levels. Testosterone should be initiated either concomitantly with a trial of lifestyle measures, or after such a trial fails, after a tailored diagnostic work-up, exclusion of contraindications, and appropriate counseling., Conclusions: There is modest evidence that functional hypogonadism responds to lifestyle measures and optimization of comorbidities. If achievable, these interventions may have demonstrable health benefits beyond the potential for increasing testosterone levels. Therefore, treatment of underlying causes of functional hypogonadism and of symptoms should be used either as an initial or adjunctive approach to testosterone therapy.

Background: Obese men commonly have reductions in circulating testosterone and report symptoms consistent with androgen deficiency. We hypothesized that testosterone treatment improves constitutional and sexual symptoms over and above the effects of weight loss alone., Methods: We conducted a pre-specified analysis of a randomized double-blind, placebo-controlled trial at a tertiary referral center. About 100 obese men (body mass index (BMI)⩾30 kg m - 2 ) with a repeated total testosterone level ⩽12 nmol l -1 and a median age of 53 years (interquartile range 47-60) 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 the between-group differences in Aging Male Symptoms scale (AMS) and international index of erectile function (IIEF-5) questionnaires., Results: Eighty-two men completed the study. At study end, cases showed significant symptomatic improvement in AMS score, compared with controls, and improvement was more marked in men with more severe baseline symptoms (mean adjusted difference (MAD) per unit of change in AMS score -0.34 (95% confidence interval (CI) -0.65, -0.02), P=0.04). This corresponds to improvements of 11% and 20% from baseline scores of 40 and 60, respectively, with higher scores denoting more severe symptoms. Men with erectile dysfunction (IIEF-5⩽20) had improved erectile function with testosterone treatment. Cases and controls lost the same weight after VLED (testosterone -12.0 kg; placebo -13.5 kg, P=0.40) and maintained this at study end (testosterone -11.4 kg; placebo -10.9 kg, P=0.80). The improvement in AMS following VLED was not different between the groups (-0.05 (95% CI -0.28, 0.17), P=0.65)., Conclusions: In otherwise healthy obese men with mild to moderate symptoms and modest reductions in testosterone levels, testosterone treatment improved androgen deficiency symptoms over and above the improvement associated with weight loss alone, and more severely symptomatic men achieved a greater benefit.

Background: Whether testosterone treatment has benefits on body composition over and above caloric restriction in men is unknown. We hypothesised that testosterone treatment augments diet-induced loss of fat mass and prevents loss of muscle mass., Methods: We conducted a randomised double-blind, parallel, placebo controlled trial at a tertiary referral centre. A total of 100 obese men (body mass index ≥ 30 kg/m 2 ) with a total testosterone level of or below 12 nmol/L and a median age of 53 years (interquartile range 47-60) 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 10-weekly intramuscular testosterone undecanoate (n = 49, cases) or matching placebo (n = 51, controls). The main outcome measures were the between-group difference in fat and lean mass by dual-energy X-ray absorptiometry, and visceral fat area (computed tomography)., Results: A total of 82 men completed the study. At study end, compared to controls, cases had greater reductions in fat mass, with a mean adjusted between-group difference (MAD) of -2.9 kg (-5.7 to -0.2; P = 0.04), and in visceral fat (MAD -2678 mm 2 ; -5180 to -176; P = 0.04). Although both groups lost the same lean mass following VLED (cases -3.9 kg (-5.3 to -2.6); controls -4.8 kg (-6.2 to -3.5), P = 0.36), cases regained lean mass (3.3 kg (1.9 to 4.7), P < 0.001) during weight maintenance, in contrast to controls (0.8 kg (-0.7 to 2.3), P = 0.29) so that, at study end, cases had an attenuated reduction in lean mass compared to controls (MAD 3.4 kg (1.3 to 5.5), P = 0.002)., Conclusions: While dieting men receiving placebo lost both fat and lean mass, the weight loss with testosterone treatment was almost exclusively due to loss of body fat., Trial Registration: clinicaltrials.gov, identifier NCT01616732 , registration date: June 8, 2012.

Quantification of abdominal visceral adipose tissue (VAT) is important to understand obesity-related comorbidities. We hypothesized that dual X-ray absorptiometry (DXA) measurements of VAT would correlate with traditional gold standards of magnetic resonance imaging (MRI) and computed tomography (CT) in older men. Deming regression and Bland-Altman plots were used to assess the agreement between VAT measured simultaneously by DXA and MRI (n=95) in a cohort of older males participating in a randomized trial of testosterone replacement for diabetes. We also correlated DXA with single-slice CT (n=102) in a cohort of older males undergoing testosterone deprivation for prostate cancer. Lunar Prodigy DXA scanners using enCORE software was used to measure VAT. DXA VAT volume strongly correlated with MRI VAT volume (r=0.90, P<0.0001) and CT VAT area (r=0.83, P<0.0001). As DXA assesses VAT volume in a smaller compartment than MRI, Bland-Altman analysis demonstrated DXA systematically underestimated VAT by an approximately 30% proportional bias. DXA VAT volume measured by Lunar Prodigy DXA scanners correlate well with gold standard MRI and CT quantification methods, and provides a low radiation, efficient, cost-effective option. Future clinical studies examining the effects of interventions on body composition and regional fat distribution may find DXA an appropriate volumetric method to quantify VAT.

With increasing modernization and urbanization of Asia, much of the future focus of the obesity epidemic will be in the Asian region. Low testosterone levels are frequently encountered in obese men who do not otherwise have a recognizable hypothalamic-pituitary-testicular (HPT) axis pathology. Moderate obesity predominantly decreases total testosterone due to insulin resistance-associated reductions in sex hormone binding globulin. More severe obesity is additionally associated with reductions in free testosterone levels due to suppression of the HPT axis. Low testosterone by itself leads to increasing adiposity, creating a self-perpetuating cycle of metabolic complications. Obesity-associated hypotestosteronemia is a functional, non-permanent state, which can be reversible, but this requires substantial weight loss. While testosterone treatment can lead to moderate reductions in fat mass, obesity by itself, in the absence of symptomatic androgen defi ciency, is not an established indication for testosterone therapy. Testosterone therapy may lead to a worsening of untreated sleep apnea and compromise fertility. Whether testosterone therapy augments diet- and exercise-induced weight loss requires evaluation in adequately designed randomized controlled clinical trials.

Although men with type 2 diabetes (T2D) frequently have lowered testosterone levels, it is not well established whether this is ascribable to the diabetic state per se, or because of other factors, such as obesity. Our objective was to determine the prevalence and correlates of low testosterone in middle-aged men with diabetes. We conducted a cross-sectional study in 240 men including 80 men with type 1 diabetes (T1D), 80 men with T2D and 80 men without diabetes. Prevalence of a total testosterone ≤8 nmol/L was low, occurring in none of the men with T1D, 6.2% of men with T2D and 2.5% of men without diabetes. Men with T1D had higher testosterone levels compared with men without diabetes (p < 0.001), even after adjustment for body mass index (BMI) and age (p < 0.02). While men with T2D had lower testosterone compared with controls (p = 0.03), this was no longer significant when BMI and age were taken into account (p = 0.16). In the entire cohort, TT remained inversely associated with BMI independent of age, sex hormone-binding globulin and diabetic status (p = 0.01), whereas calculated free testosterone (cFT) was independently and inversely associated with age (p < 0.001), but not with BMI (p = 0.47). These results suggest that marked reductions in circulating testosterone are uncommon in middle-aged men with diabetes. Increasing BMI and age are dominant drivers of lowered total and cFT, respectively, independent of the presence or absence of diabetes., (© 2013 American Society of Andrology and European Academy of Andrology.)

In recent years, obesity has been identified as a risk factor for the development of breast cancer in postmenopausal women, and it has been associated with a poor outcome. Many factors appear to be important in the mechanism of this increased risk, including estrogen, estrogen receptors, and the adipokines leptin and adiponectin. Estrogen, a potent mitogen for mammary cells, has long been implicated in the development of mammary tumors. Because adipose-associated aromatase activity increases the conversion of androgen to estrogen, mammary adipose tissue is thought to be an important source of local estrogen production. Leptin, which increases in the circulation in proportion to body fat stores, has been demonstrated in vitro to promote breast cancer cell growth. Animal models have also identified leptin as an important factor for the development of mammary tumors. In contrast to leptin, serum adiponectin concentrations are inversely related to body fat stores, and the addition of adiponectin to human breast cancer cells reduces cell proliferation and enhances apoptosis. This review explores the relationship between these factors and the development of mammary cancer in humans and mouse models.

Background: Obesity and dysglycemia (comprising insulin resistance, the metabolic syndrome and type 2 diabetes), that is diabesity, are associated with reduced circulating testosterone and, in some men, clinical features consistent with androgen deficiency. Objective: To review the metabolic impact of late‐onset hypogonadism. Methods: Comprehensive literature search with emphasis on recent publications. Results: Obesity is one of the strongest modifiable risk factors for late‐onset hypogonadism, and coexisting diabetes leads to further hypothalamic‐pituitary‐testicular axis suppression. The hypothalamic‐pituitary‐testicular axis suppression is functional and hence potentially reversible, and occurs predominantly at the level of the hypothalamus. While definitive mechanistic data are lacking, the evidence suggests that hypothalamic‐pituitary‐testicular axis suppression is mediated by dysregulation of pro‐inflammatory cytokines leading to hypothalamic inflammation. Dysregulation of central leptin and insulin signaling may also contribute. In contrast, recent data challenge the paradigm that estradiol excess is a major contributor to hypothalamic‐pituitary‐testicular axis suppression. Instead, relative estradiol signaling deficiency may contribute to metabolic dysregulation in men with diabesity. While weight loss and optimization of comorbidities can reverse functional hypothalamic‐pituitary‐testicular axis suppression, testosterone treatment leads to metabolically favorable changes in body composition and to improvements in insulin resistance. Discussion: The relationship between diabesity and late‐onset hypogonadism is bidirectional. Preliminary evidence suggests that, in carefully selected men, lifestyle measures and testosterone treatment may have additive effects. Conclusions: While recent research has provided new insights into mechanistic and clinical aspects of diabesity‐associated late‐onset hypogonadism, more evidence from well‐designed large trials is needed to guide the optimal clinical approach to such men. [ABSTRACT FROM AUTHOR]