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Jinous Samavat, Enrico Facchiano, Marcello Lucchese, Gianni Forti, Edoardo Mannucci, Mario Maggi and Michaela Luconi

Objective

Male obesity is often associated with reduced levels of circulating total (TT) and calculated free testosterone (cFT), with normal/reduced gonadotropins. Bariatric surgery often improves sex steroid and sex hormone-binding globulin (SHBG) levels. The aim of this study was to assess the effects of bariatric surgery on waist circumference (WC) and BMI, and on TT levels, in morbidly obese men, stratified, according to the gonadal state, in eugonadal and hypogonadal (TT<8 nmol/l) subjects.

Design

A cohort of morbidly obese patients (29 with hypogonadism (HG) and 26 without) undergoing bariatric surgery (37, 10, 6, and 2, with Roux-en-Y gastric bypass, laparoscopic adjustable gastric banding, biliopancreatic diversion and gastric sleeve, respectively) was studied at 6 and 12 months from the operation.

Methods

Anthropometric parameters (weight, BMI, WC) and sex hormones (gonadotropins, TT, cFT, estradiol (E2), SHBG) were assessed.

Results

WC was the only parameter significantly correlated with androgens, but not with E2, SHBG, and gonadotropins, at baseline. After surgery, a significant increase in TT, cFT, and SHBG, accompanied by a decrease in E2, was evident in the two groups. However, both TT and cFT, but not E2, SHBG, and gonadotropin variations, were significantly higher in the hypogonadal group at follow-up, with an overall 93% complete recovery from HG. Reduction in WC, but not BMI, was significantly greater in hypogonadal men (ΔWC=−29.4±21.6 vs −14.4±17.4 at 12 months, P=0.047).

Conclusions

Recovery from obesity-associated HG is one of the beneficial effects of bariatric surgery in morbidly obese men. The present findings suggest that the gonadal state is a predictor of WC decrease after bariatric surgery.

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Claudio Orlando, Salvatore Santoro, Carlo Calabrò, Gabriella B Vannelli and Gianni Forti

To obtain more information about testicular inhibin secretion in the prepubertal and pubertal human male, we measured the concentrations of immunoreactive inhibin with a heterologous radioimmunoassay in the spermatic and peripheral venous plasma of 5 prepubertal boys with unilateral undescended testis (Group I, PI), 3 prepubertal boys with inguinal hernia (Group II, P1), and 12 pubertal boys with left idiopathic varicocele. The latter subjects were divided, according to the degree of their pubertal development, in early pubertal (Group III, N = 5, P2) and mid-pubertal groups (Group IV, N=7, P3–4). In Group I, the mean (±sd) spermatic venous concentrations of inhibin (289.4±120.4 ml eq/l) were significantly higher than the corresponding mean peripheral venous concentrations (162.6±47.2; p<0.02) suggesting active testicular secretion of inhibin. In Group II, the spermaticperipheral inhibin gradient was not significant. In pubertal boys with idiopathic varicocele, the mean concentrations of spermatic inhibin were 1076.6±532.0 and 1023.4±274.5 in Groups III and IV, respectively. These levels were about five times higher than the corresponding peripheral concentrations (204.8±41.9 and 238.9±38.9; p<0.005 and p<0.001, respectively). When the data of all the boys were considered together the spermatic venous concentrations of inhibin were significantly correlated with those of peripheral venous FSH (r=0.4749, p<0.05). The spermatic venous inhibin concentrations and the spermatic/peripheral inhibin ratios were significantly correlated also with peripheral LH (r=0.5700 and 0.4766, p<0.01 and <0.05 respectively), spermatic testosterone (r = 0.6237 and 0.5893; p<0.05, respectively), and spermatic/peripheral testosterone ratios (r=0.7529 and 0.7313; p<0.01, respectively). Our results suggest: (a) the undescended testis of prepubertal boys secretes small but significant amounts of inhibin; (b) in pubertal boys with idiopathic varicocele the inhibin secretion of the testis of the affected side is more evident; (c) a contribution of Leydig cells to the testicular secretion of inhibin is likely.

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Mario Maggi, Maria Laura De Feo, Massimo Mannelli, Giuseppe Delitala and Gianni Forti

Abstract. We evaluated the gonadotrophin response to acute naloxone administration (10 mg iv) in 4 male patients with isolated hypogonadotrophic hypogonadism (age range 18.5–26 years) before and after pituitary priming with daily infusions of GnRH (25 μg/h for 4 h) for 4 days.

A blunted gonadotrophin response to acute GnRH administration (100 μg iv) and a lack of response to naloxone was observed before pituitary priming. After repeated infusions of GnRH, pituitary gonadotrophin responsiveness to GnRH was restored, whilst naloxone still did not affect gonadotrophin levels.

Our data suggest that in male isolated hypogonadotrophic hypogonadism 1) the lack of pituitary response to naloxone is not due to pituitary hyporesponsiveness to GnRH; 2) endogenous opioids do not exert any inhibitory influence on GnRH secreting neurons and thus are not involved in the pathogenesis of this disease.

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Giovanni Corona, Giulia Rastrelli, Matteo Monami, André Guay, Jaques Buvat, Alessandra Sforza, Gianni Forti, Edoardo Mannucci and Mario Maggi

Objective

To verify whether hypogonadism represents a risk factor for cardiovascular (CV) morbidity and mortality and to verify whether testosterone replacement therapy (TRT) improves CV parameters in subjects with known CV diseases (CVDs).

Design

Meta-analysis.

Methods

An extensive Medline search was performed using the following words ‘testosterone, CVD, and males’. The search was restricted to data from January 1, 1969, up to January 1, 2011.

Results

Of the 1178 retrieved articles, 70 were included in the study. Among cross-sectional studies, patients with CVD have significantly lower testosterone and higher 17-β estradiol (E2) levels. Conversely, no difference was observed for DHEAS. The association between low testosterone and high E2 levels with CVD was confirmed in a logistic regression model, after adjusting for age and body mass index (hazard ratio (HR)=0.763 (0.744–0.783) and HR=1.015 (1.014–1.017), respectively, for each increment of total testosterone and E2 levels; both P<0.0001). Longitudinal studies showed that baseline testosterone level was significantly lower among patients with incident overall- and CV-related mortality, in comparison with controls. Conversely, we did not observe any difference in the baseline testosterone and E2 levels between case and controls for incident CVD. Finally, TRT was positively associated with a significant increase in treadmill test duration and time to 1 mm ST segment depression.

Conclusions

Lower testosterone and higher E2 levels correlate with increased risk of CVD and CV mortality. TRT in hypogonadism moderates metabolic components associated with CV risk. Whether low testosterone is just an association with CV risk, or an actual cause–effect relationship, awaits further studies.

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Giovanni Corona, Giulia Rastrelli, Matteo Monami, Farid Saad, Michaela Luconi, Marcello Lucchese, Enrico Facchiano, Alessandra Sforza, Gianni Forti, Edoardo Mannucci and Mario Maggi

Objective

Few randomized clinical studies have evaluated the impact of diet and physical activity on testosterone levels in obese men with conflicting results. Conversely, studies on bariatric surgery in men generally have shown an increase in testosterone levels. The aim of this study is to perform a systematic review and meta-analysis of available trials on the effect of body weight loss on sex hormones levels.

Design

Meta-analysis.

Methods

An extensive Medline search was performed including the following words: ‘testosterone’, ‘diet’, ‘weight loss’, ‘bariatric surgery’, and ‘males’. The search was restricted to data from January 1, 1969 up to August 31, 2012.

Results

Out of 266 retrieved articles, 24 were included in the study. Of the latter, 22 evaluated the effect of diet or bariatric surgery, whereas two compared diet and bariatric surgery. Overall, both a low-calorie diet and bariatric surgery are associated with a significant (P<0.0001) increase in plasma sex hormone-binding globulin-bound and -unbound testosterone levels (total testosterone (TT)), with bariatric surgery being more effective in comparison with the low-calorie diet (TT increase: 8.73 (6.51–10.95) vs 2.87 (1.68–4.07) for bariatric surgery and the low-calorie diet, respectively; both P<0.0001 vs baseline). Androgen rise is greater in those patients who lose more weight as well as in younger, non-diabetic subjects with a greater degree of obesity. Body weight loss is also associated with a decrease in estradiol and an increase in gonadotropins levels. Multiple regression analysis shows that the degree of body weight loss is the best determinant of TT rise (B=2.50±0.98, P=0.029).

Conclusions

These data show that weight loss is associated with an increase in both bound and unbound testosterone levels. The normalization of sex hormones induced by body weight loss is a possible mechanism contributing to the beneficial effects of surgery in morbid obesity.

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David M Lee, Abdelouahid Tajar, Stephen R Pye, Steven Boonen, Dirk Vanderschueren, Roger Bouillon, Terence W O'Neill, Gyorgy Bartfai, Felipe F Casanueva, Joseph D Finn, Gianni Forti, Aleksander Giwercman, Thang S Han, Ilpo T Huhtaniemi, Krzysztof Kula, Michael E J Lean, Neil Pendleton, Margus Punab, Frederick C W Wu and the EMAS study group

Objective

Interrelationships between hormones of the hypothalamic–pituitary–testicular (HPT) axis, hypogonadism, vitamin D and seasonality remain poorly defined. We investigated whether HPT axis hormones and hypogonadism are associated with serum levels of 25-hydroxyvitamin D (25(OH)D) in men.

Design and methods

Cross-sectional survey of 3369 community-dwelling men aged 40–79 years in eight European centres. Testosterone (T), oestradiol (E2) and dihydrotestosterone were measured by gas chromatography–mass spectrometry; LH, FSH, sex hormone binding globulin (SHBG), 25(OH)D and parathyroid hormone by immunoassay. Free T was calculated from total T, SHBG and albumin. Gonadal status was categorised as eugonadal (normal T/LH), secondary (low T, low/normal LH), primary (low T, elevated LH) and compensated (normal T, elevated LH) hypogonadism. Associations of HPT axis hormones with 25(OH)D were examined using linear regression and hypogonadism with vitamin D using multinomial logistic regression.

Results

In univariate analyses, free T levels were lower (P=0.02) and E2 and LH levels were higher (P<0.05) in men with vitamin D deficiency (25(OH)D <50 nmol/l). 25(OH)D was positively associated with total and free T and negatively with E2 and LH in age- and centre-adjusted linear regressions. After adjusting for health and lifestyle factors, no significant associations were observed between 25(OH)D and individual hormones of the HPT axis. However, vitamin D deficiency was significantly associated with compensated (relative risk ratio (RRR)=1.52, P=0.03) and secondary hypogonadism (RRR=1.16, P=0.05). Seasonal variation was only observed for 25(OH)D (P<0.001).

Conclusions

Secondary and compensated hypogonadism were associated with vitamin D deficiency and the clinical significance of this relationship warrants further investigation.

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David M Lee, Martin K Rutter, Terence W O'Neill, Steven Boonen, Dirk Vanderschueren, Roger Bouillon, Gyorgy Bartfai, Felipe F Casanueva, Joseph D Finn, Gianni Forti, Aleksander Giwercman, Thang S Han, Ilpo T Huhtaniemi, Krzysztof Kula, Michael E J Lean, Neil Pendleton, Margus Punab, Alan J Silman, Frederick C W Wu and the European Male Ageing Study Group

Objectives

Low serum 25-hydroxyvitamin D (25(OH)D) and elevated parathyroid hormone (PTH) levels have been linked to insulin resistance, the metabolic syndrome (MetS) and its components. Data in healthy, community-dwelling Europeans are lacking, and previous studies have not excluded subjects receiving drug treatments that may distort the relationship between 25(OH)D/PTH and MetS. The aim of our analysis was to examine the association of 25(OH)D and PTH with Adult Treatment Panel III-defined MetS in middle-aged and older European men.

Design

This was a population-based, cross-sectional study of 3369 men aged 40–79 years enrolled in the European Male Ageing Study.

Results

After exclusion of subjects with missing data, 3069 men with a mean (±s.d.) age of 60±11 years were included in the analysis. Age-adjusted 25(OH)D levels were inversely associated with waist circumference, systolic blood pressure (BP), triglycerides, and glucose (all P<0.01). Age-adjusted PTH levels were only associated with waist and diastolic BP (both P<0.05). After adjusting for age, centre, season and lifestyle factors the odds for MetS decreased across increasing 25(OH)D quintiles (odds ratios 0.48 (95% confidence intervals 0.36–0.64) highest versus lowest quintile; P trend<0.001). This relationship was unchanged after adjustment for PTH, but was attenuated after additional adjustment for homoeostasis model assessment of insulin resistance (0.60 (0.47–0.78); P trend<0.001). There was no association between PTH and MetS.

Conclusions

Our results demonstrate an inverse relationship between 25(OH)D levels and MetS, which is independent of several confounders and PTH. The relationship is partly explained by insulin resistance. The clinical significance of these observations warrants further study.

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Thang S Han, Abdelouahid Tajar, Terence W O'Neill, Min Jiang, György Bartfai, Steven Boonen, Felipe Casanueva, Joseph D Finn, Gianni Forti, Aleksander Giwercman, Ilpo T Huhtaniemi, Krzysztof Kula, Neil Pendleton, Margus Punab, Alan J Silman, Dirk Vanderschueren, Michael E J Lean, Frederick C W Wu and the EMAS group

Background

Few published data link overweight and obesity with measures of quality of life (QoL) including sexual health in men.

Objective

To assess the association of overweight/obesity with impairment of physical and psychological QoL and sexual functions in men.

Design and setting

Cross-sectional, multicentre survey of 3369 community-dwelling men aged 40–79 (mean±s.d., 60±11) years randomly selected from eight European centres.

Outcomes

Adiposity was assessed by body mass index (BMI) and waist circumference (WC), QoL and functional impairments by physical and psychological function domains of the Short Form-36 questionnaire, Beck's Depression Inventory and the European Male Ageing Study sexual function questionnaire.

Results

Complete data on sexual activities and erectile function were available in 2734 (92%) and 3193 (95%) of the participants respectively. From the population studied, 814 men were obese (BMI ≥30 kg/m2) and 1171 had WC ≥102 cm, 25% of all men were unable to do vigorous activity and 2–13% reported depressive symptoms. Symptoms of sexual dysfunction ranged between 22% (low sexual desire) and 40% (infrequent morning erections) of the participants. Among obese men with both BMI ≥30 kg/m2 and WC ≥102 cm, at least one symptom of impaired physical, psychological and sexual function was reported by 41, 43 and 73% of the participants respectively. Compared with the reference group of non-obese men (BMI <30 kg/m2 and WC <102 cm), men with BMI ≥30 kg/m2 and WC ≥102 cm more frequently reported at least one symptom of impaired physical function (odds ratio (OR)=2.67; confidence interval (CI): 2.07–3.45, P<0.001), impaired psychological function (OR=1.48; CI: 1.14–1.90, P<0.01) and impaired sexual function (OR=1.45; CI: 1.14–1.85, P<0.01). These functional impairments were also more prevalent in men who had WC ≥102 cm even with BMI <30 kg/m2, but those with BMI ≥30 kg/m2 and WC <102 cm generally did not suffer from increased impaired physical or sexual health. Men with high BMI and WC were at even greater likelihood of having a composite of two or more or three or more symptoms compared with those with normal BMI and WC.

Conclusions

Men with high WC, including those who are ‘non-obese’ with BMI <30 kg/m2, have poor QoL with symptoms of impaired physical, psychological and sexual functions. Health promotion to improve QoL should focus on prevention of obesity and central fat accumulation.

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Ilpo T Huhtaniemi, Abdelouahid Tajar, David M Lee, Terence W O'Neill, Joseph D Finn, György Bartfai, Steven Boonen, Felipe F Casanueva, Aleksander Giwercman, Thang S Han, Krzysztof Kula, Fernand Labrie, Michael E J Lean, Neil Pendleton, Margus Punab, Alan J Silman, Dirk Vanderschueren, Gianni Forti, Frederick C W Wu and the EMAS Group

Background

The limitations of serum testosterone and estradiol (E2) measurements using non-extraction platform immunoassays (IAs) are widely recognized. Switching to more specific mass spectrometry (MS)-based methods has been advocated, but directly comparative data on the two methods are scarce.

Methods

We compared serum testosterone and E2 measurements in a large sample of middle-aged/elderly men using a common platform IA and a gas chromatography (GC)–MS method, in order to assess their limitations and advantages, and to diagnose male hypogonadism. Of subjects from the European Male Aging Study (n=3174; age 40–79 years), peripheral serum testosterone and E2 were analyzed using established commercial platform IAs (Roche Diagnostics E170) and in-house GC–MS methods.

Results

Over a broad concentration range, serum testosterone concentration measured by IA and MS showed high correlation (R=0.93, P<0.001), which was less robust in the hypogonadal range (<11 nmol/l; R=0.72, P<0.001). The IA/MS correlation was weaker in E2 measurements (R=0.32, P<0.001, at E2 <40.8 pmol/l, and R=0.74, P<0.001, at E2 >40.8 pmol/l). Using MS as the comparator method, IA ascertained low testosterone compatible with hypogonadism (<11 nmol/l), with 75% sensitivity and 96.3% specificity. The same parameters with IA for the detection of low E2 (<40.7 pmol/l) were 13.3 and 99.3%, and for high E2 (>120 pmol/l) 88.4 and 88.6%.

Conclusion

A validated platform IA is sufficient to detect subnormal testosterone concentrations in the diagnosis of male hypogonadism. The IA used for E2 measurements showed poor correlation with MS and may only be suitable for the detection of high E2 in men.

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Robert J A H Eendebak, Ilpo T Huhtaniemi, Stephen R Pye, Tomas Ahern, Terence W O’Neill, György Bartfai, Felipe F Casanueva, Mario Maggi, Gianni Forti, Robert D Alston, Aleksander Giwercman, Thang S Han, Krzysztof Kula, Michael E J Lean, Margus Punab, Neil Pendleton, Brian G Keevil, Dirk Vanderschueren, Martin K Rutter, Gindo Tampubolon, Royston Goodacre, Frederick C W Wu and for the EMAS Group

Context

The androgen receptor (AR) gene exon 1 CAG repeat length has been proposed to be a determinant of between-individual variations in androgen action in target tissues, which might regulate phenotypic differences of human ageing. However, findings on its phenotypic effects are inconclusive.

Objective

To assess whether the AR CAG repeat length is associated with longitudinal changes in endpoints that are influenced by testosterone (T) levels in middle-aged and elderly European men.

Design

Multinational European observational prospective cohort study.

Participants

A total of 1887 men (mean ± s.d. age: 63 ± 11 years; median follow up: 4.3 years) from centres of eight European countries comprised the analysis sample after exclusion of those with diagnosed diseases of the hypothalamic–pituitary–testicular (HPT) axis.

Main outcome measures

Longitudinal associations between the AR CAG repeat and changes in androgen-sensitive endpoints (ASEs) and medical conditions were assessed using regression analysis adjusting for age and centre. The AR CAG repeat length was treated as both a continuous and a categorical (6–20; 21–23; 24–39 repeats) predictor. Additional analysis investigated whether results were independent of baseline T or oestradiol (E2) levels.

Results

The AR CAG repeat, when used as a continuous or a categorical predictor, was not associated with longitudinal changes in ASEs or medical conditions after adjustments. These results were independent of T and E2 levels.

Conclusion

Within a 4-year time frame, variations in the AR CAG repeat do not contribute to the rate of phenotypic ageing, over and above, which might be associated with the age-related decline in T levels.