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E Ghigo, E Arvat, G Rizzi, S Goffi, S Grottoli, M Mucci, MF Boghen and F Camanni

Ghigo E, Arvat E, Rizzi G, Goffi S, Grottoli S, Mucci M, Boghen MF, Camanni F. Growth hormonereleasing activity of growth hormone-releasing peptide-6 is maintained after short-term oral pretreatment with the hexapeptide in normal aging. Eur J Endocrinol 1994;131:499–503. ISSN 0804–4643

The reduced activity of the growth hormone (GH)–insulin-like growth factor I (IGF-I) axis in aging may contribute to changes in body composition. As this GH insufficiency is due to hypothalamic pathogenesis, the availability of GH-releasing peptides (GHRPs), such as GHRP-6 (His-d-Trp-Ala-Trp-d-Phe-Lys-NH2) which is active even after oral administration, might be useful to restore it. The aim of our study was to verify the effectiveness of oral administration of GHRP-6 in normal elderly subjects and to investigate whether its GH-releasing activity is maintained or vanishes after short-term oral treatment. Seven normal elderly women (aged 65–82 years) were studied. The effect of oral administration of 300 μg/kg GHRP-6 on GH secretion was investigated before and after 4 days of treatment with the hexapeptide given twice daily. The GH response to the maximal effective dose of GHRH (1 μg/kg iv) also was studied. Before treatment, oral administration of 300 μg/kg GHRP-6 elicited a clear GH rise (peak 10.7 ± 3.3 μg/l; AUC 353.1 ± 90.6 μg·l−1·h−1). which was significantly higher (p < 0.01) than that induced by intravenous GHRH (peak 5.1 ± 1.5 μg/l; AUC 106.5 ±43.9 μg · l−1·h−1). After 4 days of treatment with GHRP-6, the GH response to the hexapeptide was maintained, with a trend towards an increase (peak 16.8 ± 2.9 μg/l; AUC 499.8 ± 107.2 μg·l−1·h−1). The IGF-I levels were not increased significantly after treatment (77.1 ± 8.4 vs 84.1 ± 12.2 μg/l). In conclusion, our results demonstrate that, in aging, oral GHRP-6 administration elicits a GH response that is higher than the maximal effective dose of intravenous GHRH and that the effect of the hexapeptide does not vanish after short-term treatment. More prolonged treatment and/or more frequent administrations of GHRP-6 are likely needed to increase IGF-I levels.

F Camanni, Division of Endocrinology, Department of Pathophysiology, Ospedale Molinette, C.so Dogliotti 14, 10126 Torino, Italy

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G Aimaretti, C Baffoni, L DiVito, S Bellone, S Grottoli, M Maccario, E Arvat, F Camanni and E Ghigo

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.

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V Gasco, G Corneli, G Beccuti, F Prodam, S Rovere, J Bellone, S Grottoli, G Aimaretti and E Ghigo

GH deficiency (GHD) in adults has to be shown by a single provocative test, provided that it is validated. Insulin tolerance test (ITT) has been indicated as the test of choice; now also glucagon test is validated and represents an alternative. The GHRH plus arginine (ARG) test and testing with GHRH plus a GH secretagogue are equally reliable diagnostic tools, and are now considered as ‘golden’ standards as ITT. Childhood-onset (CO) GHD needs retesting in late adolescence or young adulthood; this is a major clinical challenge and raises questions about the most appropriate method and cut-off value. Appropriate re-evaluation of GH status is represented by simple measurement of IGF1 concentration off rhGH treatment. Clearly, low IGF1 levels are evidence of persistent severe GHD in subjects with genetic GHD or panhypopituitarism. However, normal IGF1 levels never rule out severe GHD and CO-GHD with normal IGF1 levels must undergo a provocative test. The appropriate GH cut-off limit is specific for each provocative test. As shown by the ROC curve analysis, in late adolescents and young adults, the lowest normal GH peak response to ITT is 6.1 μg/l while that to GHRH+ARG test is 19.0 μg/l. These cut-off limits, however, are just indicative as being variable as a function of the assay used. No other test is validated for retesting. As GHRH+ARG test mostly explores the GH-releasable pool, normal GH response would be verified by a second ITT in order to rule out subtle hypothalamic defect.

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M Maccario, F Tassone, C Gauna, SE Oleandri, G Aimaretti, M Procopio, S Grottoli, CD Pflaum, CJ Strasburger and E Ghigo

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.

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E Ghigo, E Arvat, L Gianotti, S Grottoli, G Rizzi, GP Ceda, MF Boghen, R Deghenghi and F Camanni

Ghigo E, Arvat E, Gianotti L, Grottoli S. Rizzi G, Ceda GP, Boghen MF, Deghenghi R, Camanni F. Shortterm administration of intranasal or oral Hexarelin, a synthetic hexapeptide. does not desensitize the growth hormone responsiveness in human aging. Eur J Endocrinol 1996;135:417–12. ISSN 0804–4643

The function of the growth hormone–insulin-like growth factor I (GH–IGF-I) axis is reduced in aging, although the secretory capacity of somatotrope cells is preserved. Previous studies have suggested that continuous administration of GH-releasing peptides (GHRPs) results in homologous desensitization to the GH-releasing effect of the peptides. In the present study we have studied whether healthy elderly subjects would remain responsive to short-term, intermittent treatment with Hexarelin (HEX), a GHRP, and whether this treatment would result in an increase in serum IGF-I. In study I, the effect of an 8-day treatment with intranasal administration of 1.25 mg (about 18 μg/kg) t.i.d. HEX on the acute GH response to the hexapeptide and on serum IGF-I, IGF binding protein 3 (IGFBP-3), prolactin and cortisol levels was studied in seven elderly subjects (four males and three females, aged 67–80 years). In study II, the same parameters were studied before and after a 15-day treatment with oral administration of 20 mg (about 300 μg/kg) t.i.d. HEX in seven elderly women (aged 63–80 years). The GH response to the intranasal HEX administration was not significantly higher than that induced by 1 μg/kg iv GHRH (229.4± 35.9 vs 145.8 ± 26.9 μg·1−1·h−1) and was maintained with a trend towards increase after an 8-day treatment with the peptide (342.5 ± 199.3 μg·1−1·h−1). On the other hand, HEX treatment did not significantly modify IGF-I (138.7 ± 11.1 vs 122.4 ± 14.1 μg/l) but increased IGFBP-3 levels (2.4 ± 0.2 vs 1.6 ± 0.2 mg/l, p < 0.02). The GH response to the oral HEX administration was also not significantly higher than that to iv GHRH (257.6 ± 72.0 vs 179.0 ±42.8 μg·1−1·h−1) and did not change after a 15-day treatment with the peptide (237.8±42.8 μg·1−1·h−1). Both IGF-I and IGFBP-3 levels were slightly but significantly increased by oral HEX treatment (156.0 ± 10.7 vs 141.6 ± 13.6 μg/l. p< 0.03, 3.4 ±0.2 vs 3.1 ± 0.2 mg/l, p < 0.03, respectively). Neither intranasal nor oral HEX treatment modified PRL or cortisol levels and did not induce any side effect. In conclusion, these results indicate that chronic but intermittent treatment with HEX, administered either by intranasal or oral route, does not desensitize the GH response to the peptide. Moreover, after HEX treatment a trend towards increase was shown for IGF-I and IGFBP-3 levels. Thus, our findings strengthen the hypothesis that prolonged treatment with HEX may restore the reduced GH release in aging.

F Camanni, Divisione di Endocrinologia. Ospedale Molinette. C. so Dogliotti 14, 10126 Torino. Italy

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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.

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H J Schneider, S Rovere, G Corneli, C G Croce, V Gasco, R Rudà, S Grottoli, G K Stalla, R Soffietti, E Ghigo and G Aimaretti

Objective: Hypopituitarism frequently follows pituitary neurosurgery (NS) and/or irradiation. However, the frequency of hypothalamic–pituitary dysfunction after NS of non-pituitary intracranial tumors is unclear. The aim of this study was to assess the presence of endocrine alterations in patients operated on for intracranial tumors.

Design: This is a retrospective study.

Methods: We studied 68 consecutive adult patients (28 female, 40 male, age 45.0 ± 1.8 years; body mass index (BMI): 26.5 ± 0.6) with intracranial tumors who underwent NS only (n = 17) or in combination with radiotherapy (RT) and/or chemotherapy (CT) (n = 51). In all subjects, basal endocrine parameters and the GH response to GHRH + arginine test (using BMI-dependent cut offs) were evaluated.

Results: In 20.6% of the patients, peripheral endocrinopathy related to CT and/or RT was present. Hypopituitarism was found in 38.2% of the patients. Total pituitary hormone, multiple pituitary hormone, and isolated pituitary hormone deficits were present in 16.2, 5.8, and 16.2% respectively. The most common pituitary deficits were, in decreasing order: LH/FSH 29.4%, GH 27.9%, ACTH 19.1%, TSH 17.7%, and diabetes insipidus 4.4%. Hyperprolactinemia was present in 13.2%. The prevalence of hypopituitarism was higher in patients who underwent NS only and with tumors located closely to the sella turcica, but a substantial proportion of patients with tumors not directly neighboring the sella also showed hypopituitarism.

Conclusions: Hypopituitarism frequently occurs after NS for intracranial tumors. Also, exposure of these patients to CT and/or RT is frequently associated with peripheral endocrinopathies. Thus, endocrine evaluation and follow-up of patients treated for intracranial tumors should be performed on a regular basis.

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M Arosio, G Reimondo, E Malchiodi, P Berchialla, A Borraccino, L De Marinis, R Pivonello, S Grottoli, M Losa, S Cannavò, F Minuto, M Montini, M Bondanelli, E De Menis, C Martini, G Angeletti, A Velardo, A Peri, M Faustini-Fustini, P Tita, F Pigliaru, G Borretta, C Scaroni, N Bazzoni, A Bianchi, M Appetecchia, F Cavagnini, G Lombardi, E Ghigo, P Beck-Peccoz, A Colao, M Terzolo and for the Italian Study Group of Acromegaly

Objective

To describe demographic and hormonal characteristics, comorbidities (diabetes mellitus and hypertension), therapeutic procedures and their effectiveness, as well as predictors of morbidity and mortality in a nationwide survey of Italian acromegalic patients.

Design

Retrospective multicenter epidemiological study endorsed by the Italian Society of Endocrinology and performed in 24 tertiary referral Italian centers. The mean follow-up time was 120 months.

Results

A total of 1512 patients, 41% male, mean age: 45±13 years, mean GH: 31±37 μg/l, IGF1: 744±318 ng/ml, were included. Diabetes mellitus was reported in 16% of cases and hypertension in 33%. Older age and higher IGF1 levels at diagnosis were significant predictors of diabetes and hypertension. At the last follow-up, 65% of patients had a controlled disease, of whom 55% were off medical therapy. Observed deaths were 61, with a standardized mortality ratio of 1.13 95% (confidence interval (CI): 0.87–1.46). Mortality was significantly higher in the patients with persistently active disease (1.93; 95% CI: 1.34–2.70). Main causes of death were vascular diseases and malignancies with similar prevalence. A multivariate analysis showed that older age, higher GH at the last follow-up, higher IGF1 levels at diagnosis, malignancy, and radiotherapy were independent predictors of mortality.

Conclusions

Pretreatment IGF1 levels are important predictors of morbidity and mortality in acromegaly. The full hormonal control of the disease, nowadays reached in the majority of patients with modern management, reduces greatly the disease-related mortality.