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F Cella, G Giordano and R Cordera

OBJECTIVE: To investigate in normal-weight premenopausal women the relationship between circulating leptin and serum gonadotropins and gonadal steroids, during both spontaneous and pharmacologically induced menstrual cycles. DESIGN: Clinical longitudinal study. METHODS: Two groups of age-matched, normal-weight premenopausal volunteer women (groups I and II) were enrolled in this study. Women in group I were free of any hormonal treatment, while women in group II were taking a triphasic estrogen--progestin contraceptive preparation. Blood samples were collected daily in both groups after an overnight fast throughout a complete menstrual cycle. RESULTS: In the spontaneously cycling women, serum leptin concentration positively correlated with estradiol (P<0.03) and progesterone (P<0. 05) and was higher in the luteal than in the follicular phase (P<0. 05). However, a significant (P<0.03) short-lasting increase in circulating leptin was present in the late follicular phase of all subjects. In the women using hormonal contraception serum leptin remained unchanged throughout the cycle, along with constantly low values of circulating luteinizing hormone and follicle-stimulating hormone. CONCLUSIONS: In normal-weight premenopausal women serum leptin concentrations differ during the menstrual cycle in line with changes in gonadotropin and gonadal steroid concentrations, increasing in the luteal phase of the cycle after a peri-ovulatory peak. These findings suggest a permissive role for leptin with regard to the functioning of the corpus luteum.

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G Bona, R Paracchini, M Giordano and P Momigliano-Richiardi

Growth hormone (GH) is a multifunctional hormone produced in the anterior pituitary that promotes postnatal growth of skeletal and soft tissues. GH secretion and release are complex phenomena depending on several intrinsic and extrinsic factors modulating the release of two hypothalamic hormones, GH releasing hormone and somatostatin. Any genetic or acquired disorder that impairs GH secretion or action causes a pathological phenotype characterized by harmonic short stature with isolated GH deficiency (IGHD) or combined pituitary hormone deficiency (CPHD). In this article we report current knowledge about the genetic basis of IGHD and CPHD.

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M. Giusti, R. Torre, P. Cavagnaro, R. Attanasio, L. Traverso and G. Giordano

Abstract. Measurement of integrated concentration of GH by means of continuous withdrawal sampling is a method of evaluating physiological hormonal secretion. Integrated concentration of GH was evaluated in 5 subjects with idiopathic hypogonadal hypogonadism (range 19–27 years) and in a 17-year-old male with idiopathic delay of puberty (5 males, 1 female) before and 30–240 days after the start of pulsatile GnRH administration. Gonadotropins and testosterone or 17β-estradiol were restored, whereas 24-h integrated concentration of GH (before therapy 5.4 ± 1.3 IU/l; during GnRH 8.1 ± 2.0 IU/l; P< 0.05) was increased by GnRH therapy. However, no correlation was found between GH levels and sex steroid concentrations during GnRH pulsatile administration. These data further confirm that a physiological increase in gonadotropins and sex steroids can modulate GH synthesis and/or release.

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R Giordano, E Marinazzo, R Berardelli, A Picu, M Maccario, E Ghigo and E Arvat

Objective

To evaluate long-term morphological, functional, and clinical outcome in adrenal incidentalomas.

Design and methods

A total of 118 patients (77 F and 47 M; age 62.3±1.0 years) with adrenal incidentalomas were evaluated at baseline and followed-up for median 3 years (range 1–10 years) by clinical, biochemical, hormonal, and morphological evaluation. Among them, six patients with diagnosis of subclinical Cushing's syndrome (SCS) underwent surgery.

Results

At entry, 86% (n=102) of tumors were nonfunctioning (NF) and 14% (n=16) showed SCS. Comparing NF with SCS patients, a significantly higher percentage of dyslipidemia was found in the group of SCS patients (50 vs 23%, P=0.033). During follow-up, adrenal function remained normal in all NF patients, none of them developed subclinical or overt endocrine disease. The cumulative risk of mass enlargement was globally low (25%), but progressive up to 8 years. SCS was confirmed in all patients, and none of them shifted to overt Cushing's syndrome. The cumulative risk of developing metabolic–cardiovascular abnormalities was globally low (22%), but progressive up to 8 years and new diseases were recorded in the group of NF patients only (three patients with dyslipidemia, four with impaired fasting glucose/impaired glucose tolerance, and three with diabetes mellitus). SCS patients who underwent surgery did not show any significant clinical improvement.

Conclusions

The risk of mass enlargement, hormonal, and metabolic impairment over time is globally low. Conservative management seems to be appropriate, but further prospective studies are needed to establish the long-term outcome of such patients, especially for metabolic status, cardiovascular risk profile and their relationship with endocrine function.

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D. Bessarione, F. Perfumo, M. Giusti, F. Ginevri, G. Mazzocchi, R. Gusmano and G. Giordano

Abstract. The uraemic syndrome is characterized by several endocrinological disturbances. This study was undertaken in order to evaluate the GH response to growth hormone-releasing hormone (GRH) in children with chronic renal failure (CRF) and to compare the results with those observed after insulin hypoglycaemia. Twenty-two children with CRF, 10 undergoing continuous ambulatory peritoneal dialysis (CAPD) and 12 on conservative treatment (CT), age ranges 2–15 years, were studied and the data were compared with those from 14 children with normal renal function and normal hormonal behaviour, affected by short stature (NC), and those form 13 healthy adult volunteers (NA). The GRH test (1 μg/kg body weight, iv) was carried out in 8 CAPD, 8 CT, 9 NC and 10 NA subjects. The blood samples were taken every 30 min for 3 h in CAPD and CT and for 2 h in NC and NA starting at 09.00 h. The following hormones were measured: GH, LH, FSH, Prl, TSH and cortisol (F). The insulin test (0.1 U/kg body weight, iv) was carried out in 5 CAPD, 5 CT, 10 NC and 9 NA on blood samples taken every 30 min for 2 h, measuring GH and glycaemia. No adverse effects were observed after the infusion of GRH.

GRH administration induced a prompt response in all subjects, but GH plasma levels were significantly higher in uraemic children than in adults (peak value of 43.5 ± 8.2, 45.0 ± 8.4, 27.8 ± 6.0; 13.5 ± 2.6 μg/ml in CAPD, CT, NC and NA, respectively). The secretory areas were significantly narrower in NC (P < 0.05) and NA (P < 0.01) than in CAPD, and in NA than in CT (P < 0.01). The GH response to insulin did not differ in the 4 groups. The secretory area in CAPD and CT was wider after GRH than after insulin. The GH peak value of CAPD and NC was significantly higher after GRH than following insulin. No significant variation in TSH, LH and FSH was observed after the infusion of the neuropeptide, whereas Prl and F showed a reduction. The behaviour of Prl and F in NA and NC was similar after placebo and GRH.

Our data show: a) There is a greater response of GH to GRH in children than in adults; b) compared with the insulin test, GRH stimulation seems to be a reliable means of evaluating GH secretion both in normal and uraemic children owing to the absence of qualitatively different responses and to the freedom from the adverse effects or risks which follow insulin infusion; c) GRH administration does not induce any significant variation on other hypophyseal hormones and the reduction of Prl and F seems to follow the normal sleep-wake and circadian behaviour.

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E Arvat, B Maccagno, J Ramunni, M Maccario, R Giordano, F Broglio, F Camanni and E Ghigo

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.

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M C Amato, A Magistro, G Gambino, R Vesco and C Giordano

Objective

On the basis of the known diabetes risk in polycystic ovary syndrome (PCOS), recent guidelines of the Endocrine Society recommend the use of an oral glucose tolerance test (OGTT) to screen for impaired glucose tolerance (IGT) and type 2 diabetes (T2DM) in all women with PCOS. However, given the high prevalence of PCOS, OGTT would have a high cost–benefit ratio. In this study, we identified, through a receiver operating characteristic analysis, simple predictive markers of the composite endpoint (impaired fasting glucose (IFG) or IGT or IFG+IGT or T2DM) in women with PCOS according to the Rotterdam criteria.

Design

We conducted a cross-sectional study of 241 women with PCOS in a university hospital setting.

Methods

Clinical, anthropometric, and metabolic (including OGTT) parameters were evaluated. The homeostasis model assessment of insulin resistance (HOMA2-IR), the Matsuda index of insulin sensitivity, and the oral dispositional index and visceral adiposity index (VAI) were determined.

Results

Out of 241 women included in this study, 28 (11.6%) had an IFG, 13 (5.4%) had IGT, four (1.7%) had IFG+IGT, and four (1.7%) had T2DM. Among the anthropometric variables examined, the VAI had a significantly higher C-statistic compared with BMI (0.760 (95% CI: 0.70–0.81) vs 0.613 (95% CI: 0.54–0.67); P=0.014) and waist circumference (0.760 (95% CI: 0.70–0.81) vs 0.619 (95% CI: 0.55–0.68); P=0.028). Among all the hormonal and metabolic serum variables examined, DHEAS showed the highest C-statistic (0.720 (95% CI: 0.65–0.77); P<0.001).

Conclusions

In addition to fasting glucose, the VAI and DHEAS may be considered useful tools for prescreening in all women with PCOS without the classical risk factors for diabetes.

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C Pinducciu, G Borgonovo, A Arezzo, GC Torre, G Giordano and R Cordera

DNA point mutations of the TSH receptor and of the alpha subunit of the stimulatory GTP-binding protein (Gs alpha) have been suggested as major causes of hyperfunctioning thyroid adenomas. However, significant differences in the prevalence of these mutations (from 0.3 to 84%) have been found in different populations. The present study was designed to evaluate further the presence of mutations in discrete fragments of cDNA encoding critical regions of the TSH receptor and of the Gs alpha involved in signal transduction and cAMP production. Genomic DNA extracted from 15 thyroid adenomas and surrounding quiescent thyroid tissues was used as a template to amplify four DNA fragments of TSH receptor and one DNA fragment of Gs alpha. TSH receptor and Gs alpha DNAs were analyzed by a number of techniques. We did not detect any mutations (new or previously described) in our patients. These results confirm that the causes of solitary toxic adenomas are protean, and only some of them may be somatic DNA point mutations. Since the clinical features of solitary toxic adenoma are homogeneous, it could be important to establish the specific molecular defect underlying each case, in order to follow up the patients and to assess their clinical evolution.

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E Arvat, B Maccagno, J Ramunni, R Giordano, F Broglio, L Gianotti, M Maccario, F Camanni and E Ghigo

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.

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R Giordano, A Picu, L Bonelli, F Broglio, F Prodam, S Grottoli, G Muccioli, E Ghigo and E Arvat

Object: Somatostatin (SS) is known to inhibit GH and insulin, while its effect on corticotrope secretion is controversial: inhibition of ACTH secretion by agonists activating somatostatinergic receptors (sst)-2 and sst-5 was reported in vitro. Cortistatin (CST) not only binds all sst receptor subtypes but also possesses central actions that are not shared by SS.

Design: In nine patients with Cushing’s disease (CD), ACTH, cortisol, GH, insulin, and glucose levels were studied during 120-min i.v. infusion of SS-14 (2.0 μg/kg per h), CST-17 (2.0 μg/kg per h) or saline.

Results: Both SS or CST significantly affected the hypothalamic–pituitary–adrenal axis. Cortisol was decreased to the same extent by either SS or CST (P < 0.05). Both SS and CST decreased ACTH, although statistical difference was reached only during CST (P < 0.05). Analyzing the individual responses as Δareas under curve (ΔAUCs), a clear and consensual inhibition of ACTH and cortisol under either SS or CST was recorded in five out of nine patients. Both SS or CST inhibited (P < 0.05) insulin, that even showed a rebound (P < 0.01) at the end of infusion. GH was not modified by either peptide.

Conclusion: SS and CST often display similar inhibitory effects on the HPA axis in CD. The activation of sst receptors by both peptides is followed in almost 50% of patients by a remarkable inhibition of ACTH and cortisol hypersecretion. These findings reinforce the view that sst receptors are involved in the control of the secretory activity of tumoral corticotropic cells.