SUMMARYNormal testicular physiology results from the integrated function of the tubular and interstitial compartments. Serum markers of interstitial tissue function are testosterone and insulin-like factor 3 (INSL3), whereas tubular function can be assessed by sperm count, morphology and motility, and serum anti-Mü llerian hormone (AMH) and inhibin B. The classical definition of male hypogonadism refers to testicular failure associated with androgen deficiency, without considering potential deficiencies in germ and Sertoli cells. Furthermore, the classical definition does not consider the fact that low basal serum testosterone cannot be equated to hypogonadism in childhood, because Leydig cells are normally quiescent. A broader clinical definition of hypogonadism that could be applied to male patients in different periods of life requires a comprehensive consideration of the physiology of the hypothalamic-pituitary-testicular axis and its disturbances along development. Here we propose an extended classification of male hypogonadism based on the pathophysiology of the hypothalamic-pituitary-testicular axis in different periods of life. The clinical and biochemical features of male hypogonadism vary according to the following: (i) the level of the hypothalamic-pituitary-testicular axis primarily affected: central, primary or combined; (ii) the testicular cell population initially impaired: whole testis dysfunction or dissociated testicular dysfunction, and: (iii) the period of life when the gonadal function begins to fail: foetal-onset or postnatal-onset. The evaluation of basal testicular function in infancy and childhood relies mainly on the assessment of Sertoli cell markers (AMH and inhibin B). Hypergonadotropism should not be considered a sine qua non condition for the diagnosis of primary hypogonadism in childhood. Finally, the lack of elevation of gonadotropins in adolescents or adults with primary gonadal failure is indicative of a combined hypogonadism involving the gonads and the hypothalamic-pituitary axis.

The aim of the study was to establish the characteristics of presentation of 94 patients with Kinelfelter's syndrome (KS) referred to the endocrinologist at different ages. The diagnosis of KS was more frequent in the age group between 11 and 20 years (46.8%). Most of the patients (83.7%) showed the classic 47,XXY karyotype and 7.1% showed a 47,XXY/46,XY mosaicism. Half of the patients younger than 18 years presented mild neurodevelopmental disorders. The most frequent clinical findings were cryptorchidism in prepubertal patients, and small testes, cryptorchidism, and gynecomastia in pubertal patients. FSH, LH, AMH, and inhibin B levels were normal in prepubertal patients and became abnormal from midpuberty. Most adults were referred for small testes, infertility, and gynecomastia; 43.6% had sexual dysfunction. Testosterone levels were low in 45%. Mean stature was above the 50th percentile, and 62.5% had BMI ≥25.0 kg/m2. In conclusion, the diagnosis of Klinefelter syndrome seems to be made earlier nowadays probably because pediatricians are more aware that boys and adolescents with neuro-developmental disorders and cryptorchidism are at increased risk. The increasing use of prenatal diagnosis has also decreased the mean age at diagnosis and allowed to get insight into the evolution of previously undiagnosed cases, which probably represent the mildest forms. In adults average height and weight are slightly higher than those in the normal population. Bone mineral density is mildly affected, more at the spine than at the femoral neck level, in less than half of cases.

Erection depends largely on the release of nitric oxide (NO) by vascular endothelial cells. Insulin resistance (IR) is a metabolic abnormality that produces endothelial dysfunction characterized by decreased synthesis and release of NO. The aim of this paper is to evaluate the effect of treatment with metformin on the response to sildenafil in patients with erectile dysfunction (ED) and IR enrolled in a prospective, randomized, controlled, double-blind placebo study. We included 30 male patients with ED, IR, and poor response to sildenafil. Exclusion criteria included pharmacologic, anatomic, or endocrine ED; diabetes; prostatic surgery; or chronic illnesses. Erectile function was rated according to the International Index of Erectile Function 5 (IIEF-5); IR was measured by homeostasis model assessment (HOMA; IR 5 HOMA $ 3). Patients were randomized to receive metformin (n 5 17) or placebo (n 5 13). After treatment with metformin, patients with ED showed a significant increase in IIEF-5 score and a significant decrease in HOMA, both occurring at month 2 (IIEF-5: 17.0 6 6.0 vs 14.3 6 3.9, P 5 .01; HOMA: 3.9 6 1.6 vs 5.5 6 2.4, P 5 .01) to 4 of treatment (IIEF-5: 19.8 6 3.8 vs 14.3 6 3.9, P 5 .005; HOMA: 4.5 6 1.9 vs 5.5 6 2.4, P 5 .04), with no changes in these parameters in patients with ED receiving placebo. Patients treated with metformin had more adverse events than those who received placebo: 61.5% compared with 7.7%, P 5 .03, respectively. Adverse events were mild, mainly gastrointestinal, and did not cause discontinuation of treatment. Treatment with metformin in patients with ED and poor response to sildenafil reduced the IR and improved erectile function.

Objectives To evaluate the characteristics of presentation, biochemical profile, and etiology of gynecomastia in adults. Methods Medical records of 237 men aged 18-85 years with gynecomastia were evaluated. Results Highest prevalence of gynecomastia was observed between 21 and 30 years (n = 74; 31.2%). The most common presenting complaints were aesthetic concerns (62.8%) and breast pain (51.2%). 25.3% of the subjects had a history of pubertal gynecomastia. 56.5% had bilateral gynecomastia. 39.9% were overweight and 22.8% were obese. The etiology could not be identified in 45.1% of the cases; the most frequent identified causes were anabolic steroids consumption (13.9%), hypogonadism (11.1%), and use of pharmaceutical drugs (7.8%). Patients with bilateral gynecomastia had a longer history of disease, higher BMI, and lower testosterone levels. Conclusions Patients with gynecomastia presented more often with aesthetic concerns and secondarily with breast pain. The most frequent final diagnosis was idiopathic gynecomastia, whereas the most frequent identified etiologies were anabolic steroids consumption, hypogonadism, and use of pharmaceutical drugs. Despite the low frequency of etiologies such as thyroid dysfunction or adrenal carcinoma, we emphasize the importance of a thorough assessment of the patient, as gynecomastia may be the tip of the iceberg for the diagnosis of treatable diseases.

SUMMARYMen with type 2 diabetes mellitus (DM2) have lower testosterone levels and a higher prevalence of hypogonadism. It still remains unclear the mechanism by which there is a relationship between hypogonadism and DM2. The objective was to evaluate the hypothalamic-pituitary-gonadal axis at different levels in eugonadal patients with DM2. Fourteen patients with DM2 (DM2 group) and 15 subjects without DM2 (normal glucose tolerance test) as control group (CG) were included. We assessed: (i) fasting glucose, insulin, Homeostasis Model Assessment (HOMA); (ii) luteinizing hormone (LH) pulsatility through blood collections every 10 min for 4 h; (iii) gonadotropin-releasing hormone (GnRH) test: basal LH and 30, 60 and 90 min after 100 lg of i.v. GnRH; (iv) human chorionic gonadotropin (hCG) test: basal total testosterone (TT), bioavailable testosterone (BT), free testosterone (FT), estradiol (E2), bioavailable E2 (BE2) and sex hormone-binding globulin (SHBG) and 72 h post 5000 IU of i.m. hCG. There were no differences in age, body mass index and waist circumference between groups. Glucose was higher in the DM2 group vs. CG: 131.1 AE 25.5 vs. 99.1 AE 13.6 mg/ dL, p = 0.0005. There were no difference in basal insulin, HOMA, TT, BT, FT, E2, BE2, SHBG and LH levels between groups. The DM2 group had lower LH pulse frequency vs. CG: 0.8 AE 0.8 vs. 1.5 AE 0.5 pulses, p = 0.009. Differences in LH pulse amplitude were not found. A negative correlation was found between the number of LH pulses and glucose, r: À0.39, p = 0.03. There were no differences in the response of LH to GnRH between groups nor in the response of sexual steroids and SHBG to hCG. Patients with DM2 showed lower hypothalamic pulse frequency without changes in the pituitary response to GnRH nor testicular response to hCG. Glucose levels negatively correlated with the number of LH pulses which suggests a negative effect of hyperglycaemia in the hypothalamic secretion of GnRH.