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Massimo Mannelli, Mario Maggi, Maria Laura De Feo, Silvana Cuomo, Giuseppe Delitala, Giorgio Giusti and Mario Serio

Abstract. To evaluate a possible role for endogenous opiates in modulating sympathetic-adrenal function in humans, we measured plasma epinephrine and norepinephrine (radioenzymatic method), blood pressure and heart rate in 8 normal men (aged 24–33 years) before and after placebo or different doses (0.4, 4.8, 10 mg) of naloxone. In 6 subjects plasma insulin and glucagon levels were also measured by radioimmunoassay after placebo and 10 mg naloxone.

Naloxone had no significant effect upon blood pressure, heart rate, plasma insulin, glucagon or norepinephrine. Placebo, 0.4 and 4.8 mg naloxone caused no significant change in peripheral levels of epinephrine while 10 mg produced an increase in epinephrine concentrations 15 min after iv injection (186 ± 23 vs 99 ± 9 pmol/l, P < 0.01).

Since naloxone did not modify plasma levels of insulin and glucagon, an indirect effect of naloxone on adrenal medullary secretion seems to be excluded.

These results are in agreement with in vitro experimental data obtained in animals and suggest that endogenous opiates also have a role in modulating adrenal medullary secretion in man.

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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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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, Vito A Giagulli, Elisa Maseroli, Linda Vignozzi, Antonio Aversa, Michael Zitzmann, Farid Saad, Edoardo Mannucci and Mario Maggi

Objective

The role of testosterone (T) in regulating body composition is conflicting. Thus, our goal is to meta-analyse the effects of T supplementation (TS) on body composition and metabolic outcomes.

Methods

All randomized controlled trials (RCTs) comparing the effect of TS on different endpoints were considered.

Results

Overall, 59 trials were included in the study enrolling 3029 and 2049 patients in TS and control groups respectively. TS was associated with any significant modification in body weight, waist circumference and BMI. Conversely, TS was associated with a significant reduction in fat and with an increase in lean mass as well as with a reduction of fasting glycaemia and insulin resistance. The effect on fasting glycaemia was even higher in younger individuals and in those with metabolic diseases. When only RCTs enrolling hypogonadal (total T <12 mol/l) subjects were considered, a reduction of total cholesterol as well as triglyceride (TGs) levels were also detected. Conversely, an improvement in HDL cholesterol levels as well as in both systolic and diastolic blood pressure was not observed.

Conclusion

Our data suggest that TS is able to improve body composition and glycometabolic profile particularly in younger subjects and in those with metabolic disturbances. Specifically designed studies are urgently needed to confirm this point.

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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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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.

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Marco Bonomi, Valeria Vezzoli, Csilla Krausz, Fabiana Guizzardi, Silvia Vezzani, Manuela Simoni, Ivan Bassi, Paolo Duminuco, Natascia Di Iorgi, Claudia Giavoli, Alessandro Pizzocaro, Gianni Russo, Mirella Moro, Letizia Fatti, Alberto Ferlin, Laura Mazzanti, Maria Chiara Zatelli, Salvo Cannavò, Andrea M Isidori, Angela Ida Pincelli, Flavia Prodam, Antonio Mancini, Paolo Limone, Maria Laura Tanda, Rossella Gaudino, Mariacarolina Salerno, Pregnolato Francesca, Mohamad Maghnie, Mario Maggi, Luca Persani and Italian Network on Central Hypogonadism

Objective

Isolated hypogonadotropic hypogonadism (IHH) is a rare disorder with pubertal delay, normal (normoosmic-IHH, nIHH) or defective sense of smell (Kallmann syndrome, KS). Other reproductive and non-reproductive anomalies might be present although information on their frequency are scanty, particularly according to the age of presentation.

Design

Observational cohort study carried out between January 2008 and June 2016 within a national network of academic or general hospitals.

Methods

We performed a detailed phenotyping of 503 IHH patients with: (1) manifestations of hypogonadism with low sex steroid hormone and low/normal gonadotropins; (2) absence of expansive hypothalamic/pituitary lesions or multiple pituitary hormone defects. Cohort was divided on IHH onset (PPO, pre-pubertal onset or AO, adult onset) and olfactory function: PPO-nIHH (n = 275), KS (n = 184), AO-nIHH (n = 36) and AO-doIHH (AO-IHH with defective olfaction, n = 8).

Results

90% of patients were classified as PPO and 10% as AO. Typical midline and olfactory defects, bimanual synkinesis and familiarity for pubertal delay were also found among the AO-IHH. Mean age at diagnosis was significantly earlier and more frequently associated with congenital hypogonadism stigmata in patients with Kallmann’s syndrome (KS). Synkinesis, renal and male genital tract anomalies were enriched in KS. Overweight/obesity are significantly associated with AO-IHH rather than PPO-IHH.

Conclusions

Patients with KS are more prone to develop a severe and complex phenotype than nIHH. The presence of typical extra-gonadal defects and familiarity for PPO-IHH among the AO-IHH patients indicates a common predisposition with variable clinical expression. Overall, these findings improve the understanding of IHH and may have a positive impact on the management of patients and their families.