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Introduction: The proportion of patients with low GH response to provocative tests increases with the number of other pituitary hormone deficiencies, reason why in panhypopituitary patients GH stimulation tests may be unnecessary to diagnose GH deficiency (GHD) Purpose: To re-evaluate the diagnostic cut-offs of GH response to GHRH + arginine (ARG) test related to BMI, considering the patients’ pituitary function as the gold standard for the diagnosis of GHD. Methods: The GH responses to GHRH + ARG were studied in 358 patients with history of hypothalamic-pituitary disease. GHD was defined by the presence of at least 3 other pituitary deficits (n = 223), while a preserved somatotropic function was defined by the lack of other pituitary deficits and an IGF-I SDS ≥ 0 (n = 135). The cut-off with the best sensitivity (SE) and specificity (SP), was identified for each BMI category using the ROC curve analysis. To avoid over-diagnosis of GHD we subsequently searched for the cut-offs with a SP ≥ 95%. Results: The best GH cut-off was 8.0 μg/l (SE 95%, SP 100%) in lean, 7.0 μg/l (SE 97.3%, SP 82.8%) in overweight, and 2.8 μg/l (SE 84.3%, SP 91.7%) in obese subjects. The cut-off with a SP ≥ 95% was 2.6 μg/l (SE 68.5%, SP 96.6%) in overweight and 1.75 μg/l (SE 70.0%, SP 97.2%) in obese subjects. Conclusions: This is the first study that evaluates the diagnostic cut-offs of GH response to GHRH + ARG related to BMI using a clinical definition of GHD as gold standard. Our results suggest that with this new approach, the GHRH + ARG cut-offs should be revised to avoid GHD over-diagnosis.

Purpose: Patients with secondary adrenal insufficiency (SAI) have an increased morbidity and an impaired health-related quality of life (HRQoL), which seems to primarily depend on the sub-optimal replacement of hypoadrenalism with standard glucocorticoid (GC) therapy, and on the inadequate correction of other associated pituitary deficiencies. A dual-release hydrocortisone (DR-HC) formulation has shown to exert positive effects on morbidity and HRQoL, mainly in patients with primary adrenal insufficiency. We assessed the variations of anthropometric and metabolic parameters and HRQoL in patients with SAI after switching from cortisone acetate (CA) or hydrocortisone (HC) to DR-HC. Methods: Twenty-one patients (17 M, 4 F) treated with CA (n= 16; 25 mg/day twice a day) or HC (n= 5; 20 mg/day three times a day), were evaluated for waist circumference, BMI, fasting glucose, HbA1c, insulin, HOMA-IR index, serum lipids, electrolytes, blood pressure and HRQoL at baseline, at 3, 6 and 12 months after switching from CA/HC to DR-HC. Results: The study showed a significant reduction of waist circumference and BMI (p= 0.04, for both), after 3 and 6months of DR-HC treatment, respectively. No significant changes were observed for fasting glucose, insulin, HOMA-IR index, HbA1c, total cholesterol, triglycerides, LDL cholesterol, electrolytes, and blood pressure. However, HDL cholesterol significantly decreased (p= 0.003). An improvement of AddiQoL total score was observed during DR-HC treatment (p= 0.01), mainly for the category “emotions”. No predictors resulted for these changes. Conclusion: DR-HC treatment provides some benefits in patients with SAI, reducing central adiposity and improving HRQoL; however, worsening of HDL cholesterol is observed during treatment with DR-HC.

Background: When evaluating a patient for central adrenal insufficiency (CAI), there is a wide range of morning cortisol values for which no definite conclusion on hypothalamus–pituitary–adrenal (HPA) axis function can be drawn; in these cases, a stimulation test is required. Aim of this study was to develop an integrated model for CAI prediction when morning cortisol is in the grey zone, here defined as 40.0–160.0 μg/L. Methods: Overall, 119 patients with history of sellar tumour which underwent insulin tolerance test (ITT) for the evaluation of HPA axis were enrolled. Supervised regression techniques were used for model development. Results: An integrated predictive model was developed and internally validated, and showed a significantly better diagnostic performance than morning cortisol alone (AUC 0.811 vs 0.699, p= 0.003). A novel predictive score (CAI-score) was retrieved, on a 5.5-point scale, by considering morning cortisol (0 points if 130.1–160.0 μg/L, 1 point if 100.1–130.0 μg/L, 1.5 points if 70.1–100.0 μg/L, 2.5 points if 40.0–70.0 μg/L), other pituitary deficits (2 points if ≥ 3 deficits), and sex (1 point if male). A diagnostic algorithm integrating CAI-score and ITT was finally proposed, with an overall accuracy of 99%, and the possibility to avoid the execution of stimulation tests in 25% of patients. Conclusions: This was the first study that proposed an integrated score for the prediction of CAI when morning cortisol is in the grey zone. This score might be helpful to reduce the number of patients who need a stimulation test for the assessment of HPA axis function.

Purpose: Uncertainties exist about the predictors of the severity of the clinical picture of GH deficiency (GHD) syndrome. Aim of the study was to evaluate, in adult patients with GHD, the predictors of the development of hypercholesterolemia, hypertension, diabetes mellitus, and osteoporosis. Methods: We retrospectively studied 327 adult patients (age 47.1 ± 17.1 years) with untreated severe GHD (mean follow-up 110.9 ± 56.8 months). GHD was defined by GHRH + arginine test using BMI cut-offs. The possible development of hypercholesterolemia, hypertension, diabetes mellitus, and osteoporosis was investigated by Kaplan–Meier survival analysis. For each clinical outcome, either a univariate or multivariate analysis according to the Cox proportional-hazards model was performed to identify those factors that were associated with the development of the event. Results: GH secretion parameters were not associated with the outcomes. Hypercholesterolemia was positively and negatively predicted by a BMI ≥ 30 kg/m2(HR 2.50, p0.00) and the dose of l-thyroxine possibly in place (HR 0.98, p0.02), respectively. Hypertension was positively predicted by a BMI ≥ 30 kg/m2(HR 2.64, p 0.00) and IGF-I SDS values (HR 2.26, p0.00). Diabetes mellitus was positively predicted by hypertension (HR 11.76, p0.01). Osteoporosis was positively and negatively predicted by hypercholesterolemia (HR 3.25, p0.01) and hypertension (HR 0.21, p0.00), respectively. Conclusions: The severity of the impairment of GH secretion does not predict the development of the clinical picture of GHD syndrome: untreated adult GHD does not increase the development of metabolic risk factors in hypopituitaric patients.

Background/Objectives:Food-induced thermogenesis is generally reported to be higher in the morning, although contrasting results exist because of differences in experimental settings related to the preceding fasting, exercise, sleeping and dieting. To definitively answer to this issue, we compared the calorimetric and metabolic responses to identical meals consumed at 0800 hours and at 2000 hours by healthy volunteers, after standardized diet, physical activity, duration of fast and resting.Subjects/Methods:Twenty subjects (age range 20–35 years, body mass index=19–26 kg m−2) were enrolled to a randomized cross-over trial. They randomly received the same standard meal in the morning and, 7 days after, in the evening, or vice versa. A 30-min basal calorimetry was performed; a further 60-min calorimetry was done 120-min after the beginning of the meal. Blood samples were drawn every 30-min for 180-min. General linear models, adjusted for period and carry-over, were used to evaluate the ‘morning effect’, that is, the difference of morning delta (after-meal minus fasting values) minus evening delta (after-meal minus fasting values) of the variables.Results:Fasting resting metabolic rate (RMR) did not change from morning to evening; after-meal RMR values were significantly higher after the morning meal (1916; 95% confidence interval (CI)=1792, 2041 vs 1756; 1648, 1863 kcal; P<0.001). RMR was significantly increased after the morning meal (90.5; 95% CI=40.4, 140.6 kcal; P<0.001), whereas differences in areas-under-the-curve for glucose (−1800; −2564,−1036 mg dl−1× h, P<0.001), log-insulin (−0.19; −0.30,−0.07 μU ml−1× h; P=0.001) and fatty free acid concentrations (−16.1;−30.0,−2.09 mmol l−1× h; P=0.024) were significantly lower. Delayed and larger increases in glucose and insulin concentrations were found after the evening meals.Conclusions:The same meal consumed in the evening determined a lower RMR, and increased glycemic/insulinemic responses, suggesting circadian variations in the energy expenditure and metabolic pattern of healthy individuals. The timing of meals should probably be considered when nutritional recommendations are given.

The management of choice of non-functioning pituitary adenomas (NFPAs) remains debulking surgery when symptomatic. However, patient series systematically reporting the NFPAs outcome that were not treated either surgically, medically or with radiotherapy during long follow-up thereby giving an indication of their natural history are limited. Aim of the present study was to evaluate the natural course of presumed NFPAs, the outcome of confirmed NFPAs during a long follow-up period. Between 1993 and 2013, 84 patients with presumed NFPA were studied retrospectively. Patients were enrolled based on the following criteria: imaging suggestive of pituitary adenoma, absence of any biochemical/clinical evidence of hormonal excess, exclusion of prolactinomas and at least one sequential imaging during the follow-up. Repeated assessment of the pituitary function, visual fields and imaging was performed at regular intervals. The follow-up duration was evaluated from the first and last imaging dates. In group F (follow-up without surgery, 33 patients), the macroadenomas showed a 15 % probability of tumor growth and reduction. Similar tumor size alterations were observed also for the microadenomas. In group S (surgery, 51 patients), both residual tumors (>1 and <1 cm) following initial surgical resection remain mainly stable until the last imaging. Based on the given lack of approved medical treatment and the possible risks of surgical intervention in presence of significant comorbidities, our study proposes a conservative approach with a careful follow-up in patients with NFPAs without visual or neurological abnormalities.

Cardiometabolic disorders have been associated with primary hyperparathyroidism (PHPT), while the relationship of cardiovascular risk score (CRS) and metabolic syndrome (MS) with different clinical presentation of PHPT remains undefined. Our aim was to evaluate CRS, MS and its components in PHPT looking for their correlation to different clinical forms. In 68 consecutive PHPT patients and 68 matched controls, CRS, MS and its components were assessed to perform an observational case–control study at an ambulatory referral center for Bone Metabolism Diseases. Patients were stratified in symptomatic and asymptomatic PHPT; these latter were divided in high-risk and low-risk subgroups for end-organ damage. An increased proportion of PHPT patients had intermediate-high CRS and MS (mean, 95 % Confidence Interval (CI) 51.5 %, 39.6–63.3 and 20.6 %, 11.0–30.2, respectively, p< 0.02 vs. controls). Intermediate-high CRS was prevalent both in symptomatic and low-risk asymptomatic PHPT while MS resulted prevalent in low-risk asymptomatic but not in symptomatic PHPT. Type 2 DM, IFG, mixed dyslipidemia, hypertriglyceridemia, HDL-hypocholesterolemia, and LDL-hypercholesterolemia predominated in low-risk asymptomatic, while only LDL-hypercholesterolemia prevailed also in symptomatic PHPT. In patients and controls without cardiometabolic risk factors, HOMA-IR index was significantly increased in PHPT vs. controls (p< 0.03) and associated to total calcium (R= 0.73; p< 0.001). By multivariate analysis low-risk asymptomatic PHPT predicted MS after adjusting for age, sex, and BMI. Our data show an increased frequency of intermediate-high CRS both in symptomatic and low-risk asymptomatic PHPT while MS prevails in low-risk asymptomatic PHPT, supporting the potential for cardiovascular morbidity and mortality also in this form.

Aims:Primary hyperparathyroidism (pHPT) is characterized by an increased frequency of glucose tolerance abnormalities associated with insulin resistance. Few studies evaluated the prevalence of metabolic syndrome (MetS) in pHPT and whether there are differences between asymptomatic pHPT patients and symptomatic ones. Thus, we sought to investigate the prevalence of MetS in pHPT patients in comparison to the prevalence of MetS in Italian population. Subjects and methods:We conducted a retrospective chart review of 294 pHPT patients, of these 154 [age (mean±SD) 58.7±13.3 yr, body mass index 25.6±4.8 kg/m2; serum calcium (11.3±1.2 mg/dl) 2.8±0.3 mmol/l; PTH 234.8±224.3 ng/l] met the inclusion criteria. A modified National Cholesterol Educational Program (NCEP)/Adult Treatment Panel III (ATP III) definition of the MetS was used. Prevalence of MetS was compared with that reported for the Italian population (Progetto Cuore Study). Results:The prevalence of the MetS (34/154, 22.1%) was similar to that reported in the general Italian population. Asymptomatic pHPT patients were older (62.1±12.7 vs56.4±13.2 yr, p<0.008) and showed higher prevalence of MetS than symptomatic ones (30.2% vs16.5%, p<0.045). Moreover the prevalence of nephrolitiasis or overt bone disease was not different between patients MetS+pHPT compared to MetS-pHPT, whereas femoral bone mineral density (BMD) was higher in MetS+pHPT (p<0.003). In the logistic regression model age and femoral BMD were independent predictors of MetS. Conclusions:The prevalence of MetS in pHPT is not increased in comparison to the general population, thus, its diagnosis is not an appropriate tool to identify the additional cardiovascular risk related to pHPT. Difference in age affects the increased prevalence of MetS in asymptomatic pHPT patients.

Insulin and IGF binding protein (IGFBP)-1 are linked by negative association. Somatostatin (SS) reduces insulin secretion by acting on pancreatic β-cell and also by decreasing GH secretion. SS analogues in acromegaly reduce total IGF-I levels inhibiting GH hypersecretion, but they also reduce free IGF-I bioactivity increasing IGFBP-1 levels by inducing insulin decrease. In 13 acromegalic patients we studied GH, IGF system, insulin, and glucagon levels at baseline and at 7 days, 1 and 6 months under treatment with slow release (SR)-lanreotide (LAN) (60 mg im monthly). The hormonal and metabolic response to arginine (ARG) (0.5 g/kg iv in 30 min) was also studied at each time point. LAN decreased GH, total IGF-I, and IGFBP-3 levels at each time point. Insulin and glucagon levels were reduced, while IGFBP-1 and free IGF-I levels were increased by LAN at day 7 and after 1 month only. LAN did not modify the GH, insulin, glucagon, glucose, and IGFBP-1 responses to ARG. At each time point ARG-induced insulin increase was coupled to increase in glucagon and IGFBP-1 levels. This study shows that acromegalic patients under chronic treatment with LAN display: a) inhibition of GH and total IGF-I levels, not coupled to persistent decrease in free IGF-I levels; b) persistent decrease in IGFBP-3 but transient decrease and increase in insulin and IGFBP-1, respectively; c) unchanged hormonal and metabolic response to ARG. Our findings also show that ARG stimulates IGFBP-1 despite marked increase in insulin secretion; this escape from the negative relationship linking insulin and IGFBP-1 would likely reflect the ARG-induced glucagon increase.

Obstructive sleep apnea syndrome (OSAS) is a serious, prevalent condition that has significant mortality and morbidity when untreated. It is strongly associated with obesity and is characterized by changes in the serum levels or secretory patterns of several hormones. In particular, obese patients with OSAS show a peculiar reduction of both spontaneous and stimulated GH secretion coupled with reduced IGF-I concentrations and impaired peripheral sensitivity to GH. These endocrine abnormalities are more marked than those observed in non-apneic obese subjects, and are likely to be due to the effects of hypoxia and sleep fragmentation on hormone secretory pattern. The GH/IGF-I axis activity disruption can be responsible, at least in part, for metabolic alterations, which are common in OSAS and increase the risk of cardiovascular events as well as mortality. Effective assessment and management of OSAS may correct endocrine changes, improve quality of life, and prevent associated morbidity or death.

Hippocampal mineralocorticoid receptors (MR) play a major role in the control of hypothalamus-pituitary-adrenal (HPA) axis. The functional profile of HPA axis and the impact of MR blockade under chronic exposure to mineralocorticoid excess are unknown. To clarify this issue, ACTH, cortisol, and aldosterone secretions were studied in 6 patients with primary hyperaldosteronism (HA) and 8 controls (IMS) during placebo, placebo+human CRH (hCRH) (2 μg/kg iv bolus at 22:00 h), potassium canrenoate (CAN, 200 mg iv bolus at 20:00 h followed by 200 mg infused over 4 h) or CAN+hCRH. During placebo, both aldosterone and ACTH levels were higher (p<0.01) in HA than in NS, while cortisol levels were not significantly different. Both HA and NS showed significant ACTH and cortisol responses to hCRH (p<0.004), although the hormonal responses in HA were higher (p<0.02) than in NS. CAN infusion did not modify aldosterone levels in both HA and NS. Under CAN infusion, ACTH showed progressive rise in NS (p<0.05) but not in HA, while cortisol levels showed a significant (p<0.05) but less marked and delayed increase in HA compared to NS. CAN enhanced hCRH-induced ACTH and cortisol responses in NS (p<0.05), but not in HA. In conclusion, in humans primary hyperaldosteronism is associated with deranged function of the HPA axis. In fact, hyperaldosteronemic patients show basal and hCRH-stimulated HPA hyperactivity that is, at least partially, refractory to further stimulation by mineralocorticoid blockade with canrenoate. Whether this hormonal alteration can influence the clinical feature of hypertensive patients with primary hyperaldosteronism needs to be clarified.

The increasing prevalence of obesity has triggered intense research on its pharmacotherapy. Besides central neuroendocrine pathways, many peripheral endocrino-metabolic signals have been investigated, but only few are probably of some utility in weight loss. This review reports about ghrelin and other gastrointestinal peptides involved in hunger and satiety.

Background Function and structure of peritoneal membrane (PM) are impaired on peritoneal dialysis (PD). Peritoneal sclerosis is a common finding in peritoneal biopsies (PB) of PD patients. The aim of this study was to examine the impact of peritoneal sclerosis on peritoneal function and clinical parameters in PD patients submitted to peritoneal biopsy.Methods A PB was performed on 31 PD patients during catheter removal due to malfunction or after drop-out from treatment. For each patient PM transport was evaluated by the last peritoneal equilibration test before PB. Each daily glucose load was calculated. Tissue was formalin-embedded and stained for histological and immunohistochemical studies.Results Patients with submesothelial sclerosis and those with impairment of submesothelial basement membrane and subendothelial vascular membrane were submitted to a larger daily glucose load. Peritoneal sclerosis > 50 microns was more frequent in high transporters, who were exposed to larger daily glucose load compared to medium-high transporters. Mesothelial loss is correlated to peritoneal sclerosis and vascular injuries.Conclusions Peritoneal sclerosis is not constant in PD patients: it is related to the loss of mesothelium integrity, to the daily glucose load of PD treatment and to vascular injuries, but apparently not to the presence of inflammatory infiltrate. It remains a matter of debate how much the peritoneal sclerosis modifies the function of PM and how new more biocompatible PD solutions could reduce PM injury.

Human ageing is associated to a declining activity of the GH/IGF-I axis and to several changes in body composition, function and metabolism which show strict similarities with those of younger adults with pathological GH deficiency. The age-related changes of the GH/IGF-I axis activity are mainly dependent on age-related variations in the hypothalamic control of somatotroph function, which is also affected by changes in peripheral hormones and metabolic input. The term “somatopause” indicates the potential link between the age-related decline in GH and IGF-I levels and changes in body composition, structural functions and metabolism which characterise ageing. Physical exercise is an important environmental regulator of the GH/IGF-I axis activity. Increased physical fitness and regular training increase GH production in adults, while the GH response to aerobic or resistance exercise is reduced with age. In older subjects regular exercise has the potential to improve overall fitness and quality of life and is also associated to decreased morbidity and increased longevity. Similar effects are seen following GH therapy in adult deficiency. This assumption led to clinical trials focusing on rhGH and/or rhIGF-I as potential anabolic drug interventions in elderly subjects. To restore the activity of GH/IGF-I axis with anabolic, anti-ageing purposes, attention has been also paid to GH-releasing molecules such as GHRH, orally active synthetic GH-secretagogues (GHS) and, more recently, to the endogenous natural GHS, ghrelin, which exerts several important biological actions, including the regulation of metabolic balance and orexigenic effects. At present, however, there is no definite evidence that “frail” elderly subjects really benefit from restoring GH and IGF-I levels within the young adult range by treatment with rhGH, rhIGF-I, GHRH or GHS. In this article the alteration of the GH/IGF-I axis activity during ageing is revised taking into account the role of physical activity as a regulator of the axis function and considering the effects of the restoration of GH and IGF-I circulating levels on body composition and physical performance. 2003, Editrice Kurtis

Reduction in both spontaneous and stimulated GH secretion in obesity has been clearly demonstrated. Mild hyperactivity of hypothalamus-pituitary-adrenal (HPA) axis has been also reported. Glucagon, at least after im administration, induces clear increase in either GH or ACTH and F levels but its effect on somatotroph and corticotroph secretion in obesity has never been studied. In 7 patients with abdominal obesity (OB, aged 24–42 yr, BMI: 29.1–43.9 kg/m2, waist/hip ratio [WHR]: 0.86–1.00) we studied the GH, ACTH and F responses to the im administration of glucagon (0.017 mg/kg at 0 min). The results in OB were compared with those in a group of 6 age-matched controls normal subjects (Ns aged 26–32 yr, BMI 19.7–22.5 kg/m2). In Ns glucagon administration induced clear increase in GH (peak vsbaseline, mean±SE: 11.6±3.4 vs3.3±0.7 μg/l, p<0.02), and ACTH (52.9±15.2 vs19.0±1.5 pg/ml, p<0.02) levels which peaked at +150 and +165 min, respectively. Increase in F levels (222.3±23.8 vs158.3±7.0 ng/ml, p<0.05) was also recorded but peaked at +180 min. In OB glucagon administration induced GH response (7.4±2.3 vs0.8±0.6 μg/l) lower (p<0.05) than that recorded in Ns; when the GH responses were evaluated by co-variance analysis, a significant difference between the 2 groups was recorded in term of peaks but not of AUCs. On the other hand, the ACTH response to glucagon in OB was higher than that in Ns (11452.6±2447.7 vs4892.2±719.4 pg/ml·min, p<0.05). The F response to glucagon in OB and Ns was, however, similar (24057.9± 4109.1 vs29835.9±1566.0 ng/ml·min). In conclusion, this study demonstrates that in obese patients the im administration of glucagon elicits blunted GH response but exaggerated ACTH increase which is uncoupled with the adrenal response. These findings agree with the existence of concomitant GH insufficiency and altered corticotroph function in obesity.

OBJECTIVE: To extend the insights on the action of GH secretagogues (GHS) on pituitary function, we studied the impact of intermittent daily s.c. administration of a peptidyl GHS, hexarelin (HEX), on 24-h GH, PRL, ACTH and cortisol release in healthy volunteers. DESIGN: We investigated the impact of two or three times daily s.c. administration of a short-acting peptidyl GHS, the hexapeptide HEX (1.5 microg/kg) on 24-h GH, PRL, ACTH and cortisol secretion (sampling every 20 min) in six normal young men. To monitor possible down-regulation, the effect of 1 microg/kg i.v. HEX at the end of each 24-h sampling period was studied. METHODS: Multi-parameter deconvolution analysis was used to quantitate pulsatile GH, PRL, ACTH and cortisol secretion and estimate the corresponding hormone half-lives. Complementary to deconvolution analysis, approximate entropy was used as a scale- and model-independent statistic to quantify the serial orderliness or pattern regularity of hormone measurements. RESULTS: Mean and integrated (24-h) serum GH concentrations were increased from baseline values to the same extent by two and three HEX injections. Both HEX schedules equally increased GH secretory burst mass (but not burst frequency), mean daily GH production rate, GH half-life and irregularity of GH release patterns. No change occurred in the secretion of IGF-I, PRL, ACTH and cortisol. Intravenous HEX at the end of each spontaneous 24-h profile induced a significant rise in GH, PRL, ACTH and cortisol. Prior HEX administration blunted the GH response, abolished that of ACTH and cortisol and did not modify the PRL increase. CONCLUSIONS: The study showed that two or three daily s.c. injections of HEX augmented 24-h GH secretion equally, amplifying selectively GH secretory pulse mass without altering lactotroph and corticotroph secretion. IGF-I levels were not modified by these 1-day HEX treatment schedules.

OBJECTIVE: Adults with severe GH deficiency (GHD) need recombinant human growth hormone (rhGH) replacement to restore body composition, structure functions and metabolic abnormalities. The optimal rhGH dose for replacement has been progressively reduced to avoid side effects. The aim of the present study was to define the minimal rhGH dose able to increase both IGF-I and IGF binding protein (BP)-3 levels in GHD and to verify the possible change in GH sensitivity. DESIGN AND PATIENTS: To this goal, we studied the effect of 4-day treatment with 3 rhGH doses (1.25, 2.5 and 5.0 microg/kg/day) on IGF-I and IGFBP-3 levels in 25 panhypopituitary adults with severe GHD (12 males and 13 females, age: 44.5+/-3.0 years, body mass index (BMI): 27.0+/-0.9 kg/m(2)) and 21 normal young adult volunteers (NV, 12 males and 9 females, age: 30.5+/-2.0 years, BMI: 20.8+/-0.5 kg/m(2)). RESULTS: Basal IGF-I and IGFBP-3 levels in GHD were lower (P<0.001) than in NV. In NV the 1.25 microg/kg dose of rhGH did not modify IGF-I levels. The dose of 2.5 microg/kg rhGH significantly increased IGF-I levels in men (P<0.001) but not in women, while the 5.0 microg/kg dose increased IGF-I levels in both sexes (P<0.001). IGFBP-3 levels were not modified by any of the administered rhGH doses. In GHD patients, all rhGH doses increased IGF-I levels 12 h after both the first (P<0.01) and the fourth rhGH dose (P<0.001). At the end of treatment percentage increases in IGF-I were higher (P<0.001) in GHD patients than in NV. In contrast with NV, in GHD patients the IGF-I response to short-term stimulation with rhGH was independent of gender. Moreover, GHD patients showed increases in IGFBP-3 after the fourth administration of both 2.5 and 5.0 microg/kg rhGH. CONCLUSION: The results of the present study demonstrate that the minimal rhGH dose able to increase IGF-I and IGFBP-3 levels in GHD patients is lower than in normal subjects, at least after a very short treatment. This evidence suggests an enhanced peripheral GH sensitivity in GH deprivation.

OBJECTIVE: To verify the hypothesis of an increased sensitivity to GH in obesity (OB) and Cushing's syndrome (CS). DESIGN: We studied the effects of short-term administration of low-dose rhGH on circulating IGF-I levels in patients with simple OB or CS and in normal subjects (NS). METHODS: Nineteen women with abdominal OB aged (mean +/- s.e.m.) 38.2+/-3.1 years, body mass index 40.7+/-2.5 kg/m(2), waist to hip ratio 0.86+/-0.02, ten with CS (50.4+/-4.2 years, 29.7 +/- 3.3 kg/m(2)) and 11 NS (35.0+/-3.6 years, 20.5+/-0.5 kg/m(2)) underwent s.c. administration of 5 microg/kg per day rhGH at 2200 h for four days. Serum IGF-I, IGF-binding protein-3 (IGFBP-3), GH-binding protein (GHBP), insulin and glucose levels were determined at baseline and 12 h after the first and the last rhGH administration. RESULTS: Basal IGF-I levels in NS (239.3+/-22.9 microg/l) were similar to those in OB (181.5+/-13.7 microg/l) and CS (229.0+/-29.1 microg/l). Basal IGFBP-3, GHBP and glucose levels in NS, OB and CS were similar while insulin levels in NS were lower (P<0.01) than those in OB and CS. In NS, the low rhGH dose induced a sustained rise of IGF-I levels (279.0+/-19.5 microg/l, P<0.001), a non-significant IGFBP-3 increase and no change in GHBP, insulin and glucose levels. In OB and CS, the IGF-I response to rhGH showed progressive increase (246.2+/-17.2 and 311.0+/-30.4 microg/l respectively, P<0.01 vs baseline). Adjusting by ANCOVA for basal values, rhGH-induced IGF-I levels in CS (299.4 microg/l) were higher than in OB (279.1 microg/l, P<0.01), which, in turn, were higher (P<0.05) than in NS (257.7 microg/l). In OB, but not in CS, IGFBP-3 and insulin levels showed slight but significant (P<0.05) increases during rhGH treatment, which did not modify glucose levels in any group; thus, in the OB patient group a significant fall in glucose/insulin ratio was observed. CONCLUSIONS: Short-term treatment with low-dose rhGH has enhanced stimulatory effect on IGF-I levels in OB and, particularly, in hypercortisolemic patients. These findings support the hypothesis that hyperinsulinism and hypercortisolism enhance the sensitivity to GH in humans.

An inhibitory influence of insulin-like growth factor-I (IGF-I) on hypothalamus-pituitary-adrenal (HPA) axis has been hypothesized. In fact, it has been reported that the rhGH (recombinant human GH)-induced IGF-I increase inhibits both cortisol and GH response to MK-0677, a non-peptidyl GH secretagogue in animals. The aim of this study was to further clarify the inhibitory role, if any, of IGF-I on corticotroph function. We studied the effect of rhIGF-I (recombinant human IGF-I; 20 μg/kg sc at −180 min) or placebo on the ACTH and cortisol responses to hCRH (human CRH; 2.0 μg/kg iv at 0 min) or hexarelin (HEX; 2.0 μg/kg iv at 0 min), a peptidyl GHS, in normal young women. The effect of rhIGF-I on the GH response to HEX was also studied. The subjects were six normal young women [age: 26–35 yr; body mass index (BMI): 19–23 kg/m2] in their early follicular phase. The results showed that after sc rhIGF-I administration, circulating IGF-I levels increased approximately 77%, peaking at −60 min and persisting similar up to +120 min. The mean ACTH, cortisol and GH concentrations did not change from −180 to 0 min when evaluated after both placebo or rhIGF-I. CRH and HEX induced similar ACTH (peak vsbaseline, mean±SE: 47.5±10.9 vs 21.3±3.0 pg/ml and 30.3±6.9 vs 19.2±3.8 pg/ml, respectively; p<0.04) and cortisol responses (177.5±5.4 vs109.3±10.3 μg/l and 149.4±12.3 vs 119.8±16.4 μg/l, respectively, p<0.04). RhIGF-I pre-treatment did not modify the ACTH and cortisol responses to hCRH (46.0±13.8 pg/ml and 181.1±16.9 μg/l, respectively) as well as those to HEX (28.8±5.0 pg/ml and 144.1±16.2 μg/l, respectively). On the other hand, the GH response to HEX was clearly reduced by rhIGF-I (23.9±4.7 vs64.7±14.8 μg/l, p<0.05). Our findings show that rhIGF-I-induced increase of circulating IGF-I levels exerts negative feedback action on somatotroph secretion, while it does not modify the corticotroph and the adrenal responsiveness to CRH or hexarelin.

OBJECTIVE: Glucagon administration stimulates both somatotroph and corticotroph secretion in humans, although this happens only if glucagon is administered by the intramuscular route and not by the intravenous route. On the other hand, GH secretagogues (GHS) strongly stimulate GH and also possess ACTH-releasing activity. DESIGN AND METHODS: To clarify the mechanisms underlying the stimulatory effects of both glucagon and GHS on somatotroph and corticotroph secretion, we studied the GH, ACTH and cortisol responses to glucagon (GLU, 0.017 mg/kg i.m.) and Hexarelin, a peptidyl GHS (HEX, 2.0 microg/kg i.v.) given alone or in combination in 6 normal young volunteers (females, aged 26-32 years, body mass index 19.7-22.5 kg/m). RESULTS: GLU administration elicited a clear increase in GH (peak vs baseline, mean+/-S.E.M.: 11.6+/-3.4 vs 3. 3+/-0.7 microg/l, P<0.02), ACTH (11.6+/-3.3 vs 4.1+/-0.3 pmol/l, P<0. 02) and cortisol (613.5+/-65.6 vs 436.9+/-19.3 nmol/l, P<0.05) levels. HEX induced a marked increase in GH levels (55.7+/-19.8 vs 3. 7+/-1.9 microg/l, P<0.005) and also significant ACTH (5.7+/-1.1 vs 3. 4+/-0.6 pmol/l, P<0.01) and cortisol (400.2+/-31.4 vs 363.4+/-32.2 nmol/l, P<0.05) responses. The GH area under the curve (AUC) after HEX was clearly higher than after GLU (1637.3+/-494.0 vs 479.1+/-115. 7 microg/l/120 min, P<0.04) while HEX and GLU coadministration had a true synergistic effect on GH release (3243.8+/-687.5 microg/l/120 min, P<0.02). The ACTH and cortisol AUCs after HEX were lower (P<0. 02) than those after GLU (208.3+/-41.3 vs 426.3+/-80.9 pmol/l/120 min and 18 874.5+/-1626.1 vs 28 338.5+/-2430.7 nmol/l/120 min respectively). The combined administration of HEX and GLU had an effect which was less than additive on both ACTH (564.02+/-76.5 pmol/l/120 min) and cortisol (35 424.6+/-5548.1 nmol/l/120 min) secretion. CONCLUSIONS: These results show that the intramuscular administration of glucagon releases less GH but more ACTH and cortisol than Hexarelin. The combined administration of glucagon and Hexarelin has a true synergistic effect on somatotroph secretion but a less than additive effect on corticotroph secretion; these findings suggest that these stimuli act via different mechanisms to stimulate somatotrophs while they could have a common action on the hypothalamo-pituitary-adrenal axis.

OBJECTIVE: It is known that glucagon administration elicits ACTH and cortisol responses in humans, although this effect takes place after intramuscular or subcutaneous but not after the intravenous route of administration. The mechanisms underlying this stimulatory effect on corticotroph secretion are unknown but they are unrelated to glucose variations and stress-mediated actions. DESIGN AND METHODS: To throw further light on the stimulatory effect of i.m. glucagon on the pituitary-adrenal axis, using six normal young female volunteers (26-32 years, body mass index 19.7-22.5 kg/m(2)) we studied the interaction between glucagon (GLU; 0.017 mg/kg i.m.) and human corticotropin-releasing hormone (hCRH; 2.0 microg/kg i.v.) or vasopressin (AVP; 0.17 U/kg i.m.). The interactions between hCRH and AVP on the hypothalamo-pituitary-adrenal (HPA) axis and the GH response to GLU alone or combined with hCRH or AVP were also studied. RESULTS: GLU i.m. administration elicited a clear increase in ACTH (peak vs baseline, means+/-s.e.m.: 11.6+/-3.3 vs 4.2+/-0.3 pmol/l, P<0.05), cortisol (613.5+/-65.6 vs 436.9+/-19.3 nmol/l, P<0.05) and GH levels (11.6+/-3.4 vs 3.3+/-0.7 microg/l, P<0.05). The ACTH response to GLU (area under the curve: 426.4+/-80.9 pmol/l per 120 min) was higher than that to AVP (206.3+/-38.8 pmol/l per 120 min, P<0.02) and that to hCRH (299.8+/-39.8 pmol/l per 120 min) although this latter difference did not attain statistical significance. The GLU-induced cortisol response (28336.9+/-2430.7 nmol/l per 120 min) was similar to those after hCRH (24099.2+/-2075.2 nmol/l per 120 min) and AVP (21808.7+/-1948.2 nmol/l per 120 min). GLU and hCRH had an additive effect on ACTH (964.9+/-106.6 pmol/l per 120 min, P<0.02) and a less than additive effect on cortisol levels (35542.5+/-2720. 2 nmol/l per 120 min). Similarly, GLU and AVP had an additive effect on ACTH (825.6+/-139.6 pmol/l per 120 min, P<0.02) and an effect less than additive on cortisol levels (33059.2+/-1965.3 nmol/l per 120 min). The effects of GLU co-administered with hCRH or AVP were similar to those of the combined administration of hCRH and AVP on ACTH (906. 0+/-152.7 pmol/l per 120 min) and cortisol (34383.5+/-1669.2 nmol/l per 120min) levels. The GH response to GLU was not modified by hCRH or AVP. CONCLUSIONS: These results show that i.m. glucagon administration is a provocative stimulus of ACTH and cortisol secretion, at least as potent as hCRH and AVP. The ACTH-releasing effect of i.m. glucagon is not mediated by selective CRH or AVP stimulation but the possibility that both neurohormones play a role could be hypothesized.

Classical provocative stimuli of GH secretion such as insulin-induced hypoglycaemia, arginine, clonidine, glucagon and levodopa have been widely used in clinical practice for approximately 30 years. On the other hand, in the last 10 years new potent stimuli of GH secretion have been proposed, but an extensive comparison with the classical ones has rarely been performed, at least in adults. In order to compare the GH-releasing activity of old and new provocative stimuli of GH secretion, and to define the normative values of the GH response, in 178 normal adults (95 males, 83 females; age range: 20-50 years, all within +/-15% of their ideal body weight), we studied the GH response to: insulin-induced hypoglycaemia (ITT, 0.1IU/kg i.v.), arginine (ARG, 0.5g/kg i.v.), clonidine (CLO, 300 microg/kg p.o.), glucagon (GLU, 1mg i.m.), pyridostigmine (PD, 120mg p.o.), galanin (GAL, 80pmol/kg per min), GH-releasing hormone (GHRH, 1 microg/kg i.v.), GHRH+ARG, GHRH+PD, hexarelin, a GH-releasing protein (HEX, 2 microg/kg i.v.) and GHRH+HEX (0.25 microg/kg i.v.). The mean (+/-s.e.m.) peak GH response to ITT (21.8+/-2.8, range: 3.0-84.0 microg/l) was similar to those to ARG (18.0+/-1.6, range: 2.9-39.5 microg/l) or GLU (20. 5+/-2.2, range: 10.6-36.9 microg/l) which, in turn, were higher (P<0. 001) than those to CLO (8.2+/-1.6, range: 0.3-21.5 microg/l), PD (9. 6+/-1.1, range: 2.2-33.0 microg/l) and GAL (9.3+/-1.1, range: 3.9-18. 3 microg/l). The GH response to GHRH (19.1+/-1.5, range: 2.7-55.0 microg/l) was similar to those after ITT, ARG or GLU but clearly lower than those after GHRH+ARG (65.9+/-5.5, range: 13.8-171.0 microg/l) and GHRH+PD (50.2+/-4.6, range: 17.7-134.5 microg/l) which, in turn, were similar. The GH response to HEX (55.3+/-5.5, range: 13.9-163.5 microg/l) was similar to those after GHRH+ARG and GHRH+PD but lower (P<0.001) than that after GHRH+HEX (86.0+/-4.3, range: 49. 0-125.0 microg/l) which was the most potent stimulus of GH secretion. In this adult population the third centile limits of peak GH response to various stimuli were the following: ITT: 5.3; ARG: 2.9; CLO: 1.5; GLU: 7.6; PD: 2.2; GAL: 4.0; GHRH: 5.0; GHRH+ARG: 17.8; GHRH+PD: 17.9; HEX: 21.6; GHRH+HEX: 57.1. These results confirm that, among classical provocative tests of GH secretion, ITT followed by ARG and GLU are the most potent ones and possess clear limits of normality. GHRH+ARG or PD and HEX are strong stimuli of GH secretion which, however, is maximally stimulated by a combination of GHRH and a low dose of HEX. It is recommended that each test is used with appropriate cut-off limits.

Both IGF-I and DHEA-S undergo an age-related decrease and their decrease could be involved in age-related changes in body composition, structure functions and metabolism. On the other hand, it is well known that mean IGF-I levels are clearly reduced in hypopituitaric patients with GH deficiency (GHD) while data about dehydroepiandrosterone sulfate (DHEA-S) levels in hypopituitarism are scanty. We evaluated DHEA-S and IGF-I levels and their relationship in 90 patients with panhypopituitarism (HYPOPIT) with severe GHD [49 women and 41 men; age, mean±SE: 47.9±1.49 yr, range: 20-80 yr; BMI: 26.4±0.6 kg/m2; 21 with childhood-onset (CO) and 69 with adult-onset (AO) HYPOPIT]. DHEA-S and IGF-I levels were also evaluated in 24 HYPOPIT with GHD after 3-month recombinant human GH (rhGH) replacement. Data in HYPOPIT were compared with those in a large group of healthy controls (NS, 233 women and 103 men, aged 20–80 yr; all subjects were within ±15% of their ideal body weight). In NS both DHEA-S levels and IGF-I were gender-independent while showed a strong, inverse correlation with age (r=-0.6; p<0.001 and r=-0.56; p<0.0001, respectively). Nevertheless, no relationship was found between DHEA-S and IGF-I levels in NS. In HYPOPIT, age-adjusted mean DHEA-S and IGF-I levels were clearly lower than those in NS (2.3±0.4 vs 16.0±0.7 µg/l, p<0.005; 71.1±4.5 vs 170±4.7 µg/l, p<0.005). IGF-I levels in CO-HYPOPIT were lower (p<0.01) than those in AO-HYPOPIT (49.6±4.8 vs 77.0±5.4 µg/l), while DHEA-S levels were similar in both subgroups (2.6±0.7 vs 2.3±0.4 µg/l). In HYPOPIT both DHEA-S and IGF-I were independent of age and gender while there was a trend toward a positive association between each other (r=0.45; p<0.003). Analyzing individual levels in HYPOPIT with respect to age-adjusted normal ranges, IGF-I levels were below normal in 84, 62 and 0% between 20–40, 40–60 and 60–80 yr, respectively. On the other hand, DHEA-S levels were below normal in 84, 86 and 67% between 20–40, 40–60 and 60–80, respectively. In HYPOPIT rhGH treatment strikingly increased IGF-I levels (150±3.2 vs 85.3±4.1 µg/l, p<0.005) while did not modify DHEA-S levels (1.7±0.2 vs 1.6±0.2 µg/l). In conclusion, our results demonstrate that DHEA-S and IGF-I are negatively and independently associated to age in physiological conditions but not in hypopituitaric patients in whom both are strikingly reduced. Both DHEA-S and IGF-I levels in HYPOPIT show some overlap with those in normal subjects; thus the assay of these parameters is not diagnostic for hypopituitarism. DHEA-S reduction in HYPOPIT does not depend on IGF-I as indicated also by evidence that GH replacement restores IGF-I but does not modify DHEA-S levels.

The GH response to provocative stimuli in obese is often as low as in panhypopituitaric patients with severe GHD; however, IGF-I levels are normal or slightly reduced. In 53 patients with simple obesity (11 M and 42 F, age: 40.3±1.6 yr, BMI: 39.1±1.0 Kg/m2), we evaluated the GH response to GHRH (1 µg/kg iv)+arginine (ARG, 0.5 g/kg iv), and total IGF-I levels. The mean (±SE) GH peak after GHRH+ARG was markedly lower (74% reduction, p<0.0001) in obese (16.8±2.0 µg/l) than in normal subjects (62.7±4.3 µg/l). IGF-I levels in obese patients (134.0±7.6 µg/l) were lower (33% reduction, p<0.001) than in normal subjects (200.8±5.7 µg/l). Taking into account the 3rdcentile limit of normal response, the GH response to GHRH+ARG was reduced in 62.3% (33/53) of the obese patients, and 21.2% (7/33) of them had low IGF-I levels. Assuming the 1stcentile limit, it was reduced in 33.9% (18/53) obese subjects, and 22% (4/18) of them had low IGF-I levels. Considering 3.0 µg/L as arbitrary cut-off, the GH response was reduced in 5.7% (3/53) of the obese patients, and still one of them had low IGF-I levels. Our findings: a) confirm that the secretory capacity of somatotroph cells is often deeply impaired in obesity; b) demonstrate that IGF-I assay generally rules out severe impairment of GH/IGF-I axis in obese patients with marked reduction of the GH secretion; c) indicate that the percentage of obese patients with concomitant reduction of GH secretion and IGF-I levels is not negligible. Thus, IGF-I assay should be routinely performed in obese patients; those presenting with low IGF-I levels should undergo further evaluation of their hypothalamo-pituitary function and morphology, particularly in the presence of empty sella.

Sex and age are the major determinants of serum levels of dehydroepiandrosterone sulfate (DHEA-S): they are about twice in men than in women and show a progressive reduction from the end of the puberty to aging in both sexes. It has been reported that DHEA-S levels are also negatively influenced by insulin. Moreover, DHEA-S levels reduction has been associated to increased risk for cardiovascular disease, which connotes hyperinsulinemic states, such as obesity. We have evaluated serum levels of DHEA-S and insulin as function of age and body mass index (BMI) in 376 adult women (age 18.1–89.6 yrs, median 42.2; BMI 15.7–57.8 kg/m2, median 32.7) by multiple regression and piecewise regression analysis. Insulin levels positively associated to BMI (p=0.000002) and DHEA-S levels negatively associated with age (p=0.000001). Considering the whole population, DHEA-S levels were related positively with BMI (p=0.0013) independently of age. DHEA-S were also directly related to insulin levels independently of age (p=0.042), but this association disappeared after correction for BMI. Piecewise regression analysis did not reveal a threshold level for the increase of BMI (p=0.0004). Interestingly, DHEA-S levels and BMI were positively associated before but not after menopause. Taking into account only obese population, (no.=143, age 18.7w–67.3 yrs, mean 39.0, median 39.4) DHEA-S levels were again related negatively with age and positively with BMI, while were unrelated with waist to hip ratio (p=0.391). Our data show that increasing body mass and insulin secretion is not associated to DHEA-S reduction in women. This evidence suggests that DHEA-S is unlikely implicated in the pathogenesis of cardiovascular disease in obese women.

Abdominal obesity is connoted by hyperinsulinism and insulin insensitivity, a trend toward glucose intolerance, hypoactivity of GH/IGF-I axis and alterations of hypothalamo-pituitary-adrenal (HPA) axis. It has been hypothesized that treatment with metformin (MET) and dexfenfluramine (DEX) could counteract those endocrine- metabolic alterations. Thus, we studied the effects of 3-month treatment with MET or DEX on anthropometric (BMI, WHR, FM and FFM), metabolic (basal and OGTT-induced glucose) and hormonal variables (IGF-I, DHEA-S, androstendione, testosterone, fT3, fT4, TSH, basal and OGTT-induced insulin) as well as on blood pressure in 28 normotensive patients with abdominal obesity (OB, 3 M, 25 F; 47.5±1.5 yr [mean±SE], BMI 35.4±1.1 kg/m2, WHR 0.98±0.04 and 0.86±0.07, in M and F, respectively). All patients were on balanced hypocaloric diet (1400 Kcal/day). Patients were randomly assigned to treatment with MET (no.=10, 500 mg twice daily po) or DEX (no.=10, 15 mg thrice daily po) or placebo (no.=8). Before treatment all groups had similar anthropometric, metabolic and hormonal values. After 3-month treatment with MET, DEX or placebo, weight, BMI and WHR reductions were similar in all groups (p<0.05 vsbaseline in either group). In each group FFM/FM ratio showed non significant trend toward increase. No significant variations in metabolic and endocrine variables were recorded in each group after 1 and 3-month treatment. However, glucose tolerance, OGTT-induced insulin response, glucose/ insulin ratio showed a similar trend toward improvement in all groups, while IGF-I, 24 h urinary cortisol, DHEA-S, androstendione, testosterone, thyroid hormone and TSH levels did not show any variation. Significant (p<0.02) and similar reductions of DBP, but not of SBP, levels were found in all groups. In conclusion, our findings demonstrate that, at least after 3-month treatment, metformin and dexfenfluramine do not modify the effects of diet on anthropometric, metabolic and hormonal parameters as well as on blood pressure in patients with abdominal obesity.

Primary pigmented micronodular disease is a peculiar form of ACTH-indepen-dent Cushing’s syndrome characterized by the familial occurrence, the frequent association with malformations and the pathological adrenocortical picture consisting in micronod-ules with cellular deposition of lipofuscinic pigment. We describe here a case occurring in a 14-year-old girl.

Dopaminergic system seems to influence the regulation of insulin secretion, although in man conflicting data are reported. Furthermore, bromocriptine (BRC), a dopaminergic agonist, has been recently found to inhibit the seasonally occurring hyperinsulinemia and the increase in body weight in the hamster. On this basis, we investigated the effect of BRC on spontaneous and stimulated insulin secretion in human obesity. Six obese (BMI: 33.2±1.6 Kg/m2) underwent the administration of: 1) arginine (ARG, 0.5 g/Kg iv in 30 min), 2) BRC (2.5 mg po), 3) ARG + BRC. In each test plasma glucose and serum insulin, growth hormone (GH) and prolactin levels were determined. BRC did not significantly reduce spontaneous and ARG-induced insulin release. Baseline and stimulated glucose levels were also unchanged. BRC determined an increase in GH levels (3.7±1.3 vs0.5±0.3 μg/l, p<0.05), but failed to modify the somatotrope responsiveness to ARG. On the other hand, both spontaneous and stimulated PRL secretion were reduced by BRC (2.5±0.4 vs6.7±1.1 μg/l, p<0.05 and 0.8±1.9 vs11.0±2.1 μg/l, p<0.05, respectively). Our results show that in obese patients the acute activation of dopaminergic receptors by bromocriptine fails to modify both basal and ARG-induced insulin release, while inhibits spontaneous and stimulated PRL secretion. Our data also show that the low GH response to arginine in obesity is not improved by the coadministration of bromocriptine, in agreement with the hypothesis that both substances act by the same mechanism, i.e. inhibition of endogenous somatostatin release.

Parasympathetic nervous system is known to affect insulin secretion in animal and man and there is evidence that it is involved in the outcome of spontaneous and stimulated insulin hypersecretion observed in animal obesity. In human obesity, there are contradictory data. We studied the effect of 150 mg orally administered pirenzepine (PNZ), a muscarinic receptor antagonist, on the insulin response to glucose (75 g po or 0.33 g/kg i.b.w. iv) or arginine (0.5 g/kg infused in 30 min) in 18 obese subjects normotolerant to glucose. PNZ did not modify basal serum insulin and the hormone response to either intravenous glucose (AUC: 5221.6±1177.6 vs5309.8±1534.8 mU/L.min) or arginine load (4257.9±832.7 vs3952.8±549.3 mU/L.min). Calculated as AUC the insulin response to oral glucose load was unaffected by PNZ (6601.5±1218.6 vs8614.3±1095.2 mU/L-min). Actually, the insulin rises at +30 min after oral glucose load was significantly blunted by PNZ (37.0±3.4 vs81.6±16.9 mU/L; p<0.03). However, after statistical evaluation by ANCOVA assuming basal insulin and +30 min glucose levels as covariates, this significance disappeared. Our present data do not agree with the hypothesis that the cholinergic system plays a role in the exaggerated insulin secretion of obesity. Nevertheless, these findings confirm that acetylcholine positively influences insulin secretion in humans, likely viaindirect mechanisms.

Arginine has well-known stimulatory effects on GH, PRL and insulin secretion in man but the mechanisms underlying these effects are still unclear. More recently, it has been demonstrated that arginine is the precursor of nitric oxide (NO) which mediates its vasodilatator effect. Thus, it has been hypothesized that NO could also mediate the hormonal effects of arginine. To clarify this point, in seven normal young volunteers (7 normal male subjects, age 26–35 yr) we compared the effects of arginine hydrochloride (ARG, 0.5 g/kg iv over 30 min) on GH, PRL, insulin and glucose levels as well as on blood pressure, with those of isosorbide dinitrate (ISDN, 5 mg po) and molsidomine (MOLS, 4 mg po), two NO donors which possess well-known vasodilatatory effects. ARG infusion elicited a clear-cut GH increase (peak vsbaseline 17.6±4.7 vs2.7±0.8 (g/L, p<0.01), PRL (20.6±2.8 vs6.9±0.5 (g/L, p<0.01) and insulin levels (31.4±5.7 vs4.5±2.1 (U/L, p<0.01) while induced a biphasic variation of plasma glucose levels with early increase (p<0.01), followed by late decrease below basal values (p<0.01). On the other hand, blood pressure was decreased by ARG (nadir vsbaseline; systolic: 103±6 vs112±3, p<0.02 and diastolic 61 ±4 vs72±2 mmHg, p<0.02, respectively). ISDN and MOLS did not modify basal GH, PRL and insulin as well as glucose levels while induced a clear reduction in blood pressure (ISDN: nadir vsbaseline; systolic: 94±4 vs112±2, p<0.02; diastolic 69±3 vs80±2, p<0.02; MOLS: systolic: 94±3 vs113±2 p<0.02; diastolic 63±4 vs72±2, p<0.02). The lowering effect of both ISDN and MOLS on both systolic and diastolic blood pressure levels was higher than that induced by ARG. The effect of the latter was, in turn, significantly different from that of placebo on diastolic levels only. In conclusion, our present date are against the hypothesis that NO mediates the stimulatory effects of arginine on GH, PRL and insulin secretion. On the other hand, our findings agree with the hypothesis that ARG has NO-mediated vasodilatatory effect able to decrease blood pressure in man.

Beta adrenergic receptors mediate the inhibitory influence of catecholamines on GH secretion in man, likely via stimulation of hypothalamic somatostatin release. To further clarify the role of β adrenergic receptors in the neural control of GH secretion, in 7 normal females (age 21–27 yr) we studied the interaction of salbutamol (SAL 0.08 mg/kg orally), a β2-adrenergic agonist, with GHRH (1 μg/kg iv) and/or galanin (GAL 15 μg/kg iv), a neuropeptide endowed with a GH-releasing effect which is likely mediated by concomitant stimulation of GHRH- and inhibition of somatostatin-secreting neurons. SAL inhibited the GH response to GHRH (AUC: 282.6 ±102.7 vs 1083.6 ±176.5 μg/l/h, p< 0.05) and, although not significantly, that to GAL (263.9 ±103.7 vs 418.4 ±70.4 μg/l/h). GAL enhanced the GHRH-induced GH rise (2129.5 ±362.2 μg/l/h, p< 0.05) but SAL pretreatment inhibited this effect (1249.8 ±257.1 μg/l/h, p<0.02) so that the GH response to the combined administration of GHRH, GAL and SAL overlapped with that to the neurohormone alone. In conclusion, our results show that the inhibitory influence of β adrenergic activation on GH secretion overrides the stimulatory one of galanin. They strenghten the view that in man β-adrenergic receptors and galanin modulate GH secretion having opposite influences aimed to balance the function of the GH-IGF-I axis.

In obesity there is a clear reduction of both spontaneous and stimulated GH secretion. Furthermore, in obese patients the somatotrope responsiveness to provocative stimulation is selectively refractory to the inhibitory effect of glucose load. It has been hypothesized that hyperinsulinism of obese patients could play a role in the pathogenesis of these alterations. Aim of the present study was to verify the GH response to GHRH and the ability of glucose load to inhibit it in patients with essential hypertension in whom hyperinsulinism and insulin resistance are frequently present. To this goal, 7 patients with essential hypertension (HP, age, mean±SE: 29.6±2.4 yr, 3 females and 4 males, BMI: 21.7±1.2 kg/m2), 7 obese (OB, 4 females and 3 males, 31.9±4.1 yr, 35.6±2.0 kg/m2) and 7 normal subjects (NS, 4 females and 3 males, 28.3±3.9 yr, 21.0±1.6 kg/m2) underwent the following tests: GHRH (1 pg/kg iv at time 0) alone and preceded by oral glucose load (OGTT, 100 g po at — 45 min). Basal insulin levels were similar in HP and OB (11.3±0.5 and 12.7±2.2 µU/ml, respectively); these, in turn, were higher (p<0.005) than those in NS (6.8±0.8 µU/ml). Basal plasma glucose levels in HP were similar to those in OB and NS (80.3±3.6, 86.9±6.7 and 84.4±1.7 mg/dl, respectively). In HP and OB and NS basal GH (1.0±0.5, 1.0±0.6 and 0.3±0.1 εg/l, respectively) and IGF-I levels (132.6±14.8, 137.3±13.2 and 138.8±12.2 εg/l, respectively) were similar. In HP the GH response to GHRH (AUC: 1058.8±347.8 εg/l/min) was similar to that observed in NS (959.0±167.8 εg/l/min) and higher than that in OB (344.8±67.2 εg/l/min, p<0.01). OGTT clearly blunted (p<0.01) the GHRH-induced GH response in HP as well as in NS (401.8±104.4 and 521.6±76.6 (g/l/min, respectively) but not in OB (387.4±78.8 (g/l/min). The OGTT-induced insulin levels in HP did not differ from those of OB, both being higher (p<0.05) than those recorded in NS. Glucose levels after OGTT were similar in the three groups. In conclusion, this study demonstrates that, like in normal subjects but differently from in obese patients the GH response to GHRH is normal in patients with essential hypertension and it is normally inhibited by oral glucose load even when these patients show high insulin levels. Thus, it is unlikely that the low somatotrope secretion and its refractoriness to inhibition by glucose load in obesity is due to hyperinsulinism.

It is widely accepted that abdominal obesity presents with exaggerated insulin secretion, insulin resistance and a trend toward glucose intolerance. Hypertension is frequently associated to abdominal obesity, and hyperinsulinism could play a role in its pathogenesis. Some studies reported that Ca-antagonists positively influence insulin sensitivity and glucose tolerance in obese patients with normal or elevated blood pressure. However, other studies reported worsening of metabolic balance during treatment with Ca-antagonists in hypertensive non-insulin-dependent diabetes mellitus (NIDDM) patients and in normal subjects. We studied 19 patients with abdominal obesity, mild hypertension and insulin resistance on balanced, mild hypocaloric diet (1400 Kcal), to verify the effects of the Ca-antagonist nifedipine on both basal and oral glucose tolerance test (OGTT)-induced glucose and insulin levels as well as on IGF-I basal and DHEA-S levels and fat mass (FM). To achieve this goal, 10 hypertensive obese subjects (HOB-NIFE, 3 males, 7 females, mean age±SD 44.6±1.7 yr; body mass index (BMI) 37.1±2.5 Kg/m2, WHR 0.95±0.02) received 3-month treatment with nifedipine (Adalat Crono 30 Bayer, 1 tab daily) while other 9 hypertensive obese (HOB, 3 males, 6 females, 42±2.4 yr, BMI 35.8±1.8 Kg/m2, WHR 0.91±0.03) were studied during diet only. The same parameters were studied also in 8 normotensive obese patients (OB: 3 males, 5 females, 48.1±2.1 yr, BMI 35.8±2.4 Kg/m2, WHR 0.90±0.03) on the same balanced hypocaloric diet. Basal systolic (SBP) and diastolic (DBP) blood pressure levels in HOB-NIFE and HOB were similar. At baseline, all groups had similar basal and OGTT-induced glucose, insulin and glucose insulin ratio (GIR) levels as well as IGF-I and DHEA-S levels. After 3 months BMI fell to the same extent in all groups (p<0.05 vsbaseline) while WHR and FFM/FM ratio did not change. SBP and DBP decreased HOB-NIFE (p<0.02) but also during diet alone in both HOB and OB, though to a lesser extent (p<0.05). Both basal and OGTT-stimulated glucose and insulin levels as well as IGF-I and DHEA-S levels were not modified in HOB-NIFE as well as in HOB and OB. In conclusion, our data indicate that nifedipine treatment does not modify glucose tolerance as well as insulin secretion and sensitivity, IGF-I and DHEA-S levels in hypertensive abdominal obese patients. Thus, nifedipine treatment has no detrimental effects on endocrine-metabolic balance in hypertensive obese patients.

Abstract: In patients who have not undergone transplantation, Guillain-Barr� syndrome (GBS) is typically preceded by an acute infection often sustained by Campylobacter jejuni. Thus far, in renal transplant recipients, only eight cases of GBS have been reported. In seven patients GBS was attributed to cytomegalovirus infection and in the eighth patient to cyclosporin A neurotoxicity. We report here the case of a GBS in a renal transplant recipient following C. jejuni bacteremia. The infection quickly disappeared after erythromycin and methronidazole therapy. GBS progressively evolved into a paraparesis within 1 week. After reaching a plateau phase, the clinical status improved and the patient was able to walk unassisted after 3 weeks. At his last check-up, 54 months later, the patient was doing well with a functioning graft and only minimal weakness of the lower limbs.

Aim of this study was to verify whether arginine (ARG), which likely inhibits hypothalamic somatostatin release, has an enhancing effect on the GHRH-induced GH rise, even when administered orally at low dose. To this goal we studied the effects of 4 g orally administered ARG, either hydrochloride (ARG-H) or aspartate (ARG-A), on both basal and GHRH (1 μg/Kg iv) -stimulated GH secretion in 31 children with familial short stature (11 males and 20 females, aged 5.5–13.8 yr, pubertal stage l–lll, and compared the results with those of iv infusion of 0.5 g/kg ARG-H. Oral ARG-H (Group A,n=11) induced a significant increase of basal GH levels (4.2±1.3 vs 1.0±0.4 μg/L, p<0.02) and enhanced the GH response to GHRH (41.1±8.6 vs 25.3±6.7 μg/L, p<0.02). Oral ARG-A (Group B, n=10) induced a slight, but not statistically significant increase in serum GH levels (3.4±1.5 vs 1.0±0.3 μg/L) and enhanced the GHRH-induced GH rise (49.7±9.8 vs 26.1±8.4 μg/L, p<0.05).Intravenous ARG-H (Group C, n=10) stimulated basal GH levels (6.2±1.2 vs 1.2±0.3 μg/L, p<0.005) and increased the GHRH-induced GH rise (46.7±5.0 vs 17.1 ± 2.3 μg/L, p<0.005). This response was similar to those after oral ARG-H or ARG-A plus GHRH. No variation was observed in PRL levels after oral ARG (either ARG-H or ARG-A) and/or GHRH. These results show that a low dose of orally administered ARG is able to enhance the GHRH-induced GH rise with the same extent of a high dose iv administered ARG in normal short children. The potential usefulness of oral ARG combined with GHRH to restore GH secretion in hypothalamic GH deficiency might be envisaged.

In order to verify the true GH-releasing effect of glucagon and to explain the mechanism underlying this effect, we studied the effect of glucagon (GLU, 1 mg) administered either iv or im on both basal and GHRH (1 μg/kg)- induced GH rise in 48 normal short children and adolescents. Moreover, the in vitroeffect of GLU on rat anterior pituitary cells was studied. Intravenous administration of GLU induced no significant GH rise. On the other hand, im GLU administration induced a clearcut GH increase (mean ± SE GH peak after GLU vs placebo = 25.7±3.9 vs 10.1±3.6 μg/L, p<0.01). Intravenous administration of GLU failed to modify the GHRH-induced GH rise either when coadministered with the neurohormone (35.2±4.1 vs 34.1±6.0 μg/L) or when given 60 min earlier (20.2±5.8 vs 21.1±8.3 μg/L). Differently from iv GLU, im GLU strikingly potentiated the GH response to GHRH given 90 min later (57.5±6.3 vs 24.7±9.1 μ/L, p<0.01). Mean plasma glucose levels increased 30 min after GLU, administered either iv or im, and returned to basal levels 60 min later. GH secretion from dispersed rat pituitary cells was unaffected by incubation with GLU (10−10-10−4mol/L). Incubation of the cells with 10−7mol/L GHRH induced instead a clear-cut stimulation of GH release. In conclusion, our data demonstrate that glucagon persehas not GH-releasing activity as indicated by its uneffectiveness to release GH in vitroand after intravenous administration. The mechanisms underlying the GH increase which follows intramuscular administration of glucagon are not clear.

In this study, we retrospectively analyzed the effects of treatment in 19 patients with membranous lupus nephritis (MLN) and nephrotic syndrome. Eight patients were treated with corticosteroids alone, and the other 11 patients received methylprednisolone and chlorambucil alternated every other month for 6 months. At presentation, sex, age, duration of renal disease before renal biopsy, plasma creatinine, and arterial hypertension were similar in the two study groups. Of the eight patients treated with corticosteroids alone, three showed complete remission and one partial remission of the nephrotic syndrome. During the follow-up (mean, 114+/-63 months), seven of these eight patients developed one or more renal flare-ups. Of the 11 patients treated with methylprednisolone and chlorambucil, seven had complete remission, and the other four had partial remission of the nephrotic syndrome. During the follow-up (mean, 83+/-59 months), only one patient had renal flare-up. At the end of the follow-up, all patients were alive, but three patients in the group treated with corticosteroids alone had developed a doubling of plasma creatinine, and another patient had persistent nephrotic syndrome. Two other patients were in complete remission, one patient was in partial remission, and the last patient had nonnephrotic proteinuria. In the group of patients treated with methylprednisolone and chlorambucil, one patient developed extracapillary glomerulonephritis and eventually entered end-stage renal failure 24 years after the clinical onset of renal disease. Seven patients were in complete remission, and three patients were in partial remission at the last follow-up visit. This retrospective study suggests that methylprednisolone and chlorambucil may induce a more stable remission of nephrotic syndrome and may better protect renal function in the long term in comparison with corticosteroids alone. However, these results must be confirmed by a prospective controlled trial. (Am J Kidney Dis 1998 Apr;31(4):681-6)

In all industrial countries, the number of elderly patients who need dialysis has increased in recent years. In the present study, we retrospectively analyzed two different age groups of nondiabetic peritoneal dialysis patients treated at the same unit by the same team of physicians and nurses with the same protocols. However, our purpose was to study possible differences in technique and survival rates, causes of dropout, complications, hospitalization rate, and everyday needs between the two groups. The results of 63 consecutive nondiabetic patients older than 70 years treated with continuous ambulatory peritoneal dialysis (CAPD) were compared with those of 86 nondiabetic patients aged 40 to 60 years treated during the same period. Patient survival was significantly worse in the elderly patients, but the observed to expected survival ratio with respect to age was similar. Technique survival was comparable in the two groups. Total hospitalization was 5,501 days (32 d/yr) in the elderly patients and 4,511 days (18 d/yr; P < 0.05) in the younger group. The peritonitis rate was 0.52 episodes/patient-year in the elderly patients and 0.37 episodes/patient-year in the younger patients (P < 0.002). The exit site infection rate was similar in the two groups (0.30 episodes/yr v0.29 episodes/yr). Other complications related to CAPD did not differ between the elderly and younger patients. Rehabilitation and biochemical data after 1 year of CAPD were similar in the two groups of patients. After 1 year of treatment, 12% of the younger patients and 43% of the elderly patients (P < 0.005) needed a partner for dialysis. Twenty-nine of 39 (74%) of the elderly patients and 30 of 53 (57%) of the younger patients considered their lifestyle acceptable after 1 year of dialysis. Thirty-four of 39 (87%) of the elderly patients and 32 of 53 (60%) of the younger patients (P < 0.02) rated their physical and social state after rehabilitation as better or comparable to that they had before terminal uremia. (Am J Kidney Dis 1998 Mar;31(3):479-90)

Within an appropriate clinical context, growth hormone deficiency (GHD) in adults must be demonstrated biochemically. The assays of insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) e do no do not establish the diagnosis of adult GHD. Similarly, the evaluation of spontaneous growth hormone (GH) secretion over 24 h has no diagnostic value in adulthood even when an ultra-sensitive GH assay is used. The diagnosis of adult GHD is established by provocative testing of GH secretion, and insulin-induced hypoglycaemia using the insulin tolerance test (ITT) is indicated as the test of choice. Alternative provocative tests of GH secretion have been proposed and have to be used with appropriate cut-off limits. Testing with GH releasing hormone (GHRH) alone has no diagnostic value, but when GHRH is given in combination with arginine or pyridostigmine it becomes the most potent and reproducible provocative test to evaluate the maximal secretory capacity of somatotrope cells. The potentiating effect of arginine on the GHRH-induced GH response is fully preserved while the stimulatory effect of GHRH + pyridostigmine is reduced in ageing. The GHRH + arginine test is well tolerated and reproducibly distinguishes between normal and GHD adult and elderly subjects. Thus, the GHRH + arginine test is the most promising alternative to the ITT provided that cut-off limits appropriate to its potent stimulatory effect are considered.