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.

The mechanisms involved in the preprandial rise and postprandial fall of circulating ghrelin levels are as yet unknown. Many hormonal and metabolic responses to nutrient intake begin during the cephalic or preabsorptive phase and are mostly mediated by the autonomous nervous system. The aim of the present study was to investigate the effects of the cephalic phase on ghrelin response to feeding in human subjects. The modified sham feeding (MSF), a well established technique in which nutrients are smelled, chewed, and tasted, but not swallowed, was used. Sixteen healthy volunteers (seven men and nine women; mean age ± sd: 31 ± 8 yr; body mass index, 22 ± 3 kg/m²) were studied after overnight fasting. Seven of them received a standardized mixed meal, and nine underwent MSF. Blood samples for ghrelin, insulin, and glucose were taken at time −30, 0, 15, 30, 45, 60, 120 min during both tests. Pancreatic polypeptide determinations were evaluated at all times as markers of vagal activity only during MSF. Ghrelin levels significantly increased from time −30 to 0 min before the two tests, then significantly decreased: after the real feeding from 933 ± 479 pg/ml (277 ± 142 pmol/liter) to 455 ± 185 pg/ml (135 ± 55 pmol/liter; P < 0.05), and after the sham feeding from 917 ± 313 pg/ml (272 ± 93 pmol/liter) to 519 ± 261 pg/ml (154 ± 77 pmol/liter; P < 0.05). There were no significant differences between the patterns of the responses as evaluated by ANOVA (P = 0.863). As expected after MSF, plasma pancreatic polypeptide concentrations promptly increased from 58 ± 29 pg/ml (14 ± 7 pmol/liter) to 113 ± 38 pg/ml (27 ± 9 pmol/liter) at 15 min (P < 0.01). Both insulin and glucose levels increased during the actual mixed meal, whereas they were not significantly modified by MSF. In conclusion, circulating ghrelin concentrations are decreased by sham feeding as they are by real feeding in humans. These findings underline the importance of the cephalic response to nutrient intake, i.e. the role of vagal activity, in the control of ghrelin secretion.

The aim of the study was to evaluate the hypothalamus-pituitary-adrenal (HPA) axis in patients (nine males, three females; mean age ± sem 51 ± 2 yr) with adult-onset GH deficiency (GHD) due to surgically treated pituitary tumors with preserved HPA function and without evidence of tumor recurrence before and during recombinant human (rh) GH replacement therapy (duration 31 ± 6 months). HPA function was assessed by urinary free cortisol and morning serum cortisol levels as well as cortisol responses to 1 μg ACTH test (n = 7 patients) or insulin tolerance test (n = 5 patients) before and during rhGH therapy, the cut-off for the diagnosis of hypoadrenalism being a cortisol peak less than 18 μg/dl (<500 nmol/liter) after stimulatory tests. Serum cortisol and urinary free cortisol levels were significantly lower on therapy than before [7.6 ± 0.8 vs. 11.5 ± 0.9 μg/dl (208 ± 22 vs. 317 ± 24 nmol/liter), P < 0.01, and 19.6 ± 2.5 vs. 32.2 ± 3.2 μg per 24 h (54 ± 7 vs. 89 ± 9 nmol per 24 h), P < 0.05, respectively], whereas no change in cortisol-binding globulin levels was observed. Cortisol peak after either ACTH test or insulin tolerance test was lower on rhGH therapy than before [15.9 ± 1.5 vs. 20.2 ± 1.1 μg/dl (437 ± 43 vs. 557 ± 31), P = 0.01, and 13.1 ± 2.6 vs. 20.4 ± 1.4 μg/dl (362 ± 71 vs. 564 ± 37 nmol/liter), P = 0.03, respectively]. Accordingly, central hypoadrenalism was detected in nine of 11 patients. In conclusion, low GH and IGF-I levels, likely enhancing the conversion of cortisone to cortisol, may mask a condition of central hypoadrenalism. Therefore, the reassessment of HPA function in GHD patients during rhGH therapy is mandatory.

Context: The effects of chronic therapy with long-acting somatostatin analogs (SSTa) on metabolic and cardiovascular parameters have been partially elucidated in acromegalic patients. Objective: The objective of this study was to compare the long-term effects of SSTa treatment and successful surgery on GH/IGF-I secretion and cardiovascular risk parameters in acromegaly. Design, Patients, and Intervention: This was a retrospective study of 36 acromegalic patients treated with SSTa and evaluated after a median of 66 months and of 33 sex-, age-, and body mass index-matched cured patients evaluated after a similar period of remission, all from the Institute of Endocrine Sciences (Milan, Italy). Main Outcome Measures: The main outcome measures were fasting and post-oral load glucose homeostasis, hemoglobin A_1c, insulin sensitivity and secretion by several indexes, lipid profile, and blood pressure. Results: Fasting and areas under the glucose response curve rose in patients controlled (n = 29) and not controlled (n = 7) by SSTa, becoming higher than those in cured subjects. A 1% hemoglobin A_1c increase was observed in all nondiabetic SSTa patients, but not in cured subjects. Basal insulin secretion and resistance, evaluated by homeostasis model assessment, decreased in all SSTa patients, whereas oral glucose tolerance test-derived insulin secretion and resistance, evaluated by insulinogenic index and oral glucose tolerance test-derived insulin secretion, improved only in SSTa-treated controlled patients. Triglycerides did not change during SSTa, whereas high-density lipoprotein cholesterol increased in SSTa-treated controlled patients. At the last visit, the contemporary presence of at least three cardiovascular risk factors was more frequent in patients treated with SSTa than in cured subjects. Conclusions: SSTa therapy induces long-lasting disease control and improvement of insulin sensitivity and high-density lipoprotein cholesterol levels in responsive patients. The progressive glucose homeostasis alterations, observed independently from the degree of cure, suggest the need for glucose homeostasis and peripheral vascular complications monitoring during chronic SSTa treatment.