ContextLow testosterone (T) levels are often found in obese men with impaired glucose tolerance (IGT) and overt type 2 diabetes (T2DM); however, the mechanisms underlying this condition and its correct therapy are still under debate.ObjectiveTo evaluate the effectiveness of clomiphene citrate (CC) in increasing endogenous T levels in obese men with low serum T and with IGT or T2DM treated with metformin (MET).DesignCross-over, randomized, double-blind, placebo-controlled study.Methods24 obese men, aged 47.3 ±. 6.3 (range 35–55 years), with low T level (≤3 ng/mL) and naïve diagnosis of IGT or T2DM were included. Subjects were randomized to CC 25 mg/day or placebo (Plac) with MET 2 g/day for 3 months. After a 6-week wash-out period, subjects were moved to the alternative arm for additional 3 months. Clinical evaluation and blood exams performed prior to and at the end of treatment.ResultsOf 24 randomized, 21 were evaluable, classified as IGT (n = 11) or T2DM (n = 10). Compared to baseline levels, T levels increased significantly after 3 months of CC treatment (3.03±0.80 to 5.99±1.67 ng/mL P<0.001) but not after the Plac treatment (2.87±0.78 to 3.09±0.84 ng/mL P<0.001 between the treatments). T changes were similar in IGT and T2DM subjects. Gonadotropins as well raised significantly after CC treatment (LH 3.83±1.45 to 8.53±6.40 mU/mL; FSH 4.84±1.67 to 10.15±5.08 mU/mL P<0.001 respectively), whereas no changes for LH (3.51±1.59 to 3.63±1.39 mU/mL) but a smooth increased for FSH (4.61±2.49 to 5.39±2.65 mU/mL; P = 0.004) were shown after Plac treatment (LH P = 0.001 and FSH P = 0.002 between treatments). Furthermore, fasting glucose (106.8±23.2 to 101.1±25.7 mg/dL; P = 0.004), insulin (19.3±12.1 to 15.6±10.1 μU/mL; P = 0.010) and HOMA-IR (4.94±2.89 to 3.69±2.12; P = 0.001) decreased significantly during the CC treatment period, whereas no significant changes were observed in any of these parameters in the Plac treatment.ConclusionsA low dose of CC therapy was able to significantly increase serum T levels in all participants with mild modifications of clinical and metabolic parameters.Trial registrationEudraCT 2011-000439-10

Background: Functional hypogonadism is a common disorder among patients with obesity and type 2 diabetes mellitus and could be managed by first treating the underlying causes.Objective: The present study was undertaken to investigate the contribution of body weight and glycemic control to the reversibility of hypogonadism to eugonadism in a real-life setting. Materials and methods:Adult obese male patients with uncontrolled type 2 diabetes mellitus, complaining of mild to moderate erectile dysfunction and suspected of functional hypogonadism evaluated at our institution from 2015 to 2017, were retrospectively included. The gonadal status 3 and 12 months after the glucose-lowering medication prescription was assessed.Results: Seventy-one consecutive patients were enrolled, with 24 (34%) of them achieving total testosterone ≥300 ng/dL (10.4 nM/L) at the end of the study. When they were stratified according to HbA1c and body weight loss, a direct correlation was found for the latter only. Particularly, 94% of patients achieving a body weight loss >10% presented with total testosterone ≥300 ng/dL. An inverse correlation was found for HbA1c, with no higher prevalence of total testosterone ≥300 ng/dL in patients with HbA1c <6.5%. Discussion:The findings are strengthened by the rigorous study design. However, a limited number of patients and glucose-lowering medications could be included. Conclusions:The present study supports the hypothesis that in obese patients with uncontrolled type 2 diabetes mellitus losing weight may have a greater impact on androgens compared to improving glycemic control. Further prospective studies are needed to corroborate this finding. K E Y W O R D Sfunctional hypogonadism, erectile dysfunction, type 2 diabetes mellitus, obesity | 655 GIAGULLI et AL.

Given the lack of clarity regarding the value of varicocele correction in improving male fertility, we examined whether divergent results in this regard could be attributed to selection of patients, especially with regard to the duration of their infertility or to the length of patients' androgen receptor CAG repeats. In a prospective study, involving all varicocele patients consulted consecutively for infertility, we compared the pregnancy rate (PR) over 1 year produced by patients who opted not to have varicocele correction after extensive information concerning fertility prospects (N = 185), with that by patients who had varicocele correction (N = 137). In the second study involving another smaller group of varicocele subjects (N = 72), we investigated whether CAG repeat length in the androgen receptor gene had any influence on fertility of varicocele-corrected patients. Overall, the PR in corrected and uncorrected varicocele groups did not differ significantly, but when subjects with infertility beyond 2 years were considered, varicocele-corrected subjects had a significantly greater PR than uncorrected varicocele patients (p = 0.025). Together with infertility duration, spermatozoa progressive motility appears the most important predictor of fertility, whereas neither grade of varicocele nor age of the couple (within the age limits of this study) influenced the outcome. Similarly, CAG repeat length did not affect the outcome of varicocele correction. These data suggest that varicocele correction at 1 year of infertility does not result in a significantly higher PR than that achieved by men with uncorrected varicocele. In view of the high spontaneous PR in subjects with an infertility of less than 2 years, varicocele correction aimed at restoring fertility appears to be most appropriate for men whose infertility extends beyond 2 years.

Purpose This study examined whether the AR-CAG repeat length might affect clinical characteristics (testis volume) seminal parameters (sperm count and its mobility) along with hormonal serum profile [FSH, LH, Testosterone (T) and Inhibin B (InhB)] both in idiopathic male infertility (IM) and in infertility due to a previous condition of cryptorchidism (CryM) or to Y chromosome long arm microdeletions (YM). Design Observational study without intervention(s).Patients One hundred and ten IM patients [90 idiopathic olizoospermic males (IOM) and 20 idiopathic azoospermic males (IAM)], 19 CryM male and 10 YM patients were included. Sixty-one age-matched healthy men who had fathered within 3 years were involved representing the control group (FM). Results AR-CAG repeats stretch was significantly longer in IOM (p<0.05), CryM (p<0.05) and YM (p<0.001) than FM. When the AR-CAG repeat tracts were subdivided in three subgroups according to the length of CAG repeats tract assessed in fertile subjects (the one with the middle (n 19-21) belonging to the 25 and 75 % inter-quartile, the ends belonging to the <25 % interquartile and >75 % inter-quartile, respectively), there was a statistically significant difference of distribution of AR-CAG tract length among fertile and different groups of infertile men (p= <0.0005; chi-square test). Moreover, the subgroup of AR-CAG repeat stretch with 22-28 triplets was associated with lower levels of InhB both in idiopathic oligozoospermic (Scheffe, Bonferroni and Dunett tests p = < 0.01) and azoospermic men (Scheffe, Bonferroni and Dunett test p=<0.05), while, when FM and men with idiopathic infertility were gathered in a single group, both the subgroup of AR-CAG tract with 15-18 repeats and the one with 22-28 repeats are associated with lower testis volume, reduced sperm count and serum InhB levels. Conclusions Our study showed that the outliers of AR-CAG repeat length seem to influence the function of AR, affecting testis volume and Sertoli cell function and consequently sperm production in both fertile and idiopathic infertile men.Keywords CAG repeat length polymorphism . Idiopathic male infertility . Y chromosome long arm microdeletions . Sertoli cell . Leydig cell . Inhibin B and testosteroneCapsule No concrete evidence about the pathogenetic role of androgen receptor (AR) CAG repeat length polymorphism in infertile men has been obtained so far. This study aims to search it, measuring AR-CAG polymorphism both in fertile and in infertile men with idiopathic infertility or with well-known causes of infertility (i.e. cryptorchidism and Ychromosomal microdeletions). The shortest tract as well as the longest one of AR-CAG repeat polymorphism may negatively affect the spermatogenesis in fertile and infertile men.

Background: Clomiphene citrate (CC) has been shown to restore the hypothalamicpituitary-gonadal (HPG) axis by increasing testosterone (T) levels to physiological levels in patients with dysmetabolic conditions such as obesity, metabolic syndrome and type 2 diabetes mellitus (T2DM). However, the data are unclear regarding the effects on Sertoli cell (SC) function. Aim:To study SC function by assessing Inhibin B (IB) and anti-Mullerian hormone (AMH) levels at baseline and after 3 months of CC treatment. Materials and methods:This is an ancillary study of a cross-over, randomised, doubleblind, placebo-controlled trial performed to evaluate androgen response to CC treatment in dysmetabolic obese subjects with low T levels treated with metformin. We evaluated SC function by assessing IB and AMH levels at baseline and after 3 months of each treatment in ten dysmetabolic obese subjects with low T levels. In all subjects, the influence of the clinical characteristics, metabolic and hormonal baseline parameters on SC and Leydig (LC) function, evaluated respectively with AMH, IB, follicle-stimulating hormone (FSH) and T levels, was tested.Results: No significant changes were observed for IB and AMH concentrations after each treatment period. Whereas T and oestradiol (E2) levels were shown to be significantly higher in the CC plus metformin phase (CC/Met) only. No clinical, metabolic or hormonal parameters showed significant effects on serum AMH at baseline or after treatments. However, baseline T, dihydrotestosterone (DHT) and E2 positively affected IB levels during CC/Met therapy (P = .003, P = .038 and P = .049, respectively). Baseline leptin and FSH had a negative (P = 031) and positive (P = .048) respectively role on T levels during CC/Met, as they were statistically significant compared to the placebo period (Plac/Met). Conclusion:Unlike the LC activity, CC was unable to influence SC function, as shown by the lack of IB and AMH serum modifications, thus suggesting an intrinsic nonreversible defect of SC cells in patients with dysmetabolic conditions. K E Y W O R D SAMH, Inhibin B, obesity, testosterone | 39 PELUSI Et aL.

Prepuberal-onset (PRHH) and postpuberal-onset (PSHH) Hypogonadotropic Hypogondism (HH) refer to a heterogeneous group of patients, showing a broad spectrum of clinical signs and symptoms of androgen deficiency in consideration of the different possible aetiologies and the age at onset. These patients, though, required Gonadotropin treatment (GnTh) by means of administration of both the β Human Chorionic Gonodadotropin (β HCG) and the Follicle Stimulating Hormone (FSH) to obtain mature sperms in the ejaculate aiming to reach fertility levels. However, the response to GnTh is always unpredictable concerning either the effectiveness or the duration of the therapy. Consequently, different studies have been carried out to identify clinical (i.e. cryptorchidism, gynecomastia, testis size, etc) and biochemical markers [serum Testosterone (T) and Inhibin B (IB)] that can be useful to predict the effectiveness of GnTh. Given that the actions of T, even those directed at inducing and maintaining spermatogenesis, are mediated by its interaction with the Androgen Receptor (AR), we measured the AR CAG repeat polymorphism in men with HH, in order to examine whether the CAG polymorphism extensions could co-regulate the GnTh effectiveness. Twenty-three HH subjects were subdivided according to the age at onset (pre- and postpubertal) and treated with the same scheme and doses of GnTh, extending the period of treatment up to 30 months. Thirty-five healthy and fertile men served as a control group (CG). Twelve HH subjects (3 PRHH and 9 PSHH), who reached complete spermatogenesis within 12 months, showed the length of AR CAG repeat number [20 (19-23) = median (interquartile range 25th - 75th percentile)] not statistically different from our CG [20 (19-22)], while CAG repeat number [23 (20-25)] of 11 HH patients (9 PRHH and 2 PSHH) who obtained mature sperms in their ejaculate beyond a year to within 30 months, was significantly higher. Our results suggest that the length of AR CAG repeat polymorphism might affect the response to GnTh in men suffering from HH, in particular in those patients with prepubertal-onset hypogonadism.

Introduction. The prevalence of erectile dysfunction (ED) increases along with the burden of chronic diseases. This retrospective study aimed to assess the prevalence and severity of ED according to the levels of chronic comorbidities.Material and Methods. Two hundred twenty-two outpatients referred to the Outpatients Clinic of Endocrinology and Metabolic Disease of Conversano Hospital (Italy) with ED complaints from January 2018 to December 2019 were retrospectively eligible for this cross-sectional study. The ED severity and comorbidities burden were assessed by the 5-item International Index of Erectile Function questionnaire (IIEF-5) and Charlson comorbidity index (CCI). A modified index (mCCI) was developed to integrate other common risk factors for ED and was compared to the original tool. The primary outcome was to assess the prevalence of ED according to the severity of CCI. The secondary outcomes included the correlation between 1) IIEF-5 and total testosterone (TT); 2) CCI and TT; 3) IIEF-5 and CCI. Finally, the performance of the CCI and mCCI were compared.Results. The overall prevalence of ED increased along with the CCI score: 45% (5 on 11) for CCI=0; 95% (19 on 20) for CCI=1; 91% (29 on 32) for CCI=2; 99% (158 on 160) for CCI≥3 (p<.0001) Moreover, IIEF-5 score was directly correlated with TT levels (r=0.67; p<.0001). CCI correlated with both TT levels and IIEF-5 score (r=-0.34 and -0.44; p<.0001, respectively). Finally, a lower IIEF-5 score was significantly and independently associated with higher age and CCI as well as lower TT and SHBG. Compared to the CCI, an equal performance was also found with the mCCI.Discussion. Our results showed that CCI and mCCI are reliable tools to assess the presence and severity of ED among outpatients referred to the endocrine center. However, some limitations should be considered, including the number of participants, which appeared underpowered; the single-center experience; possible underestimation of CCI referred to a diagnostic delay of included comorbidities; arbitrary assignment of burden-points to hypertension dyslipidemia and cigarette smoking.Conclusion. The present study found that CCI, a validated tool to assess the burden of comorbidities, correlates with both the prevalence and severity of ED. This confirms that ED is a reliable proxy of overall male health, but further studies are needed to confirm this potential application.

Background: The prevalence of erectile dysfunction (ED) rises with the number and severity of chronic diseases. Study aims. This cross-sectional study assessed the frequency and severity of ED in patients with multiple chronic conditions. Study aims: This cross-sectional study assessed the frequency and severity of ED in patients with multiple chronic conditions. Methods: The 5-item International Index of Erectile Function questionnaire (IIEF-5) to diagnose and classify ED. The Charlson Comorbidity Index (CCI) was used to assess the burden of chronic comorbidity. The primary outcome was to assess the ED frequency according to CCI severity. The secondary outcomes included the assessment of correlation between 1) IIEF-5 and total testosterone (TT), 2) CCI and TT, 3) IIEF-5 and CCI. Lastly, the CCI and modified CCI (mCCI) performance were compared with each other. Results: The overall frequency of ED increased along with the CCI score severity: 45% for CCI=0; 95% for CCI=1; 91% for CCI=2; 99% for CCI≥3 (p<.0001). CCI correlated negatively with TT levels and IIEF-5 score (r=-0.34 and -0.44; p<.0001). Compared to the CCI, a novel proposed mCCI performs well. Discussion: The frequency and severity of ED are relevant in outpatients with sexual complaints and those with chronic comorbidities. Despite limitations, mCCI may be considered a reliable tool to assess the overall burden of multiple chronic conditions in patients with comorbidities. Conclusion: ED is a reliable proxy of overall male health. Further studies are needed to confirm this potential application.