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Dolores Collado Escobar, Lucia M. Vicentini, Ezio Ghigo, Enrica Ciccarelli, Luciana Usellini, Carlo Capella and Daniela Cocchi

Abstract. It has been reported that rat growth hormone releasing factor (rat GRF-43), similarly to the two human GRFs (GRF-40 and 44) stimulates adenylate cyclase activity in pituitary cells. Controversial findings have been presented by two different groups on the action of GRF on phosphoinositides (PI) metabolism, a phenomenon linked to Ca++ – mediated intracellular mechanisms. In the work to be reported, we evaluated the accumulation of inositol phosphates induced by GRF exposure in primary cultures of rat and human pituitary cells. Addition of rat GRF-43 to rat pituitary cells at doses up to 1 μm had no effect on inositol phosphates accumulation, while already at a dose as low as 0.05 nm it increased growth hormone secretion in the incubation medium significantly. In the same cell system, TRH, a known activator of PI breakdown, significantly increased [3H]inositol phosphates. In primary cultures of human somatotrophs from acromegalic subjects as in rats, addition of hpGRF-40 and also of TRH did not elicit any modification in the accumulation of [3H]inositol phosphates. Consistent with in vivo findings, both peptides induced a significant release of GH in the medium. Our results show that the GH releasing effect of GRF does not involve the hydrolysis of phosphatidylinositol in normal rat as well as in tumoral human somatotrophs. In addition it appears that the anomalous response of TRH on adenomatous cells from acromegalic patients is differently mediated in respect to the action of the tripeptide on normal lactotrophs and thyrotrophs.

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Enrico Mazza, Stefania Goffi, Paolo Barchi, Emanuela Arvat, Jaele Bellone, Paolo Limone, Ezio Ghigo and Franco Camanni

Mazza E, Goffi S, Barchi P, Arvat E, Bellone J, Limone P, Ghigo E, Camanni F. Enhanced adrenocorticotrophic hormone and cortisol responses to corticotrophin-releasing hormone in central idiopathic diabetes insipidus. Eur J Endocrinol 1994;130:121–4. ISSN 0804–4643

It is well known that arginine vasopressin (AVP) exerts a stimulatory effect on adrenocorticotrophic hormone (ACTH) secretion. Moreover, there is consistent evidence that the hypothalamic AVP-secreting neurons are involved in the neuroregulation of ACTH secretion. With the aim to throw further light on the interaction between AVP and corticotrophin-releasing hormone (CRH) in the neuroregulation of ACTH secretion, in this study we compared the ACTH and cortisol responses to human CRH (100 μg iv as a bolus) in 18 normal subjects (15 females and three males, age 22–35 years) and seven patients with central isolated diabetes insipidus (six females and one male, age 16–40 years). Two patients were newly diagnosed and five had discontinued substitution therapy with desamino-D-AVP 24 h before testing. All had free access to water before and during the test period. The ACTH and cortisol responses to CRH were higher in subjects with diabetes insipidus than in controls, either when evaluated as peak values (ACTH, mean±sem: 17.0±1.2 vs 7.7±0.7 pmol/l, p=0.0003; cortisol: 611.3±59.4 vs 450.7±21.2 nmol/l, p=0.01) or area under curve values (ACTH: 672.5±75.7 vs 364.0±33.6 pmol·1−1·h−1. p=0.002; cortisol: 29158.0±2937.0 vs 23236.7±1052.1 nmol·l−1 · h−1, p=0.03). These results show that patients with diabetes insipidus have an exaggerated pituitary-adrenal response to CRH. This may be due to the fact that in diabetes insipidus AVP secretion from parvocellular neurons of the paraventricular nucleus in the hypophysial portal system is not impaired. Alternatively, AVP secretion may be defective in both magnocellular and parvocellular hypothalamic AVP-secreting neurons. In this case, it could be hypothesized that adjustment is made to the feedback regulatory mechanisms of the hypothalamic–pituitary–adrenal axis, so that the CRH–ACTH axis assumes a main role with respect to the AVP–ACTH axis.

Franco Camanni, Divisione di Endocrinologia, Ospedale Molinette, corso Dogliotti 14, 10126 Torino. Italy

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Sergio Bernasconi, Cecilia Volta, Antonella Cozzini, Mariangela Ziveri, Lucia Ghizzoni, Costantino Panza and Ezio Ghigo

To determine whether differences in the neuroendocrine control of GH are present between children and adult subjects, the GH response to GHRH (1 μg/kg) (group 1), insulin-induced hypoglycemia (0.1 U/kg iv) (group 2), clonidine (150 μg/m2 po) (group 3) and iv arginine (0.5 g/kg in 30 min) (group 4) after GHRH pretreatment (1 μg/kg) was studied in 26 short-stature normal children (mean age 10.2 years). The results were compared with historical data in adults. No differences were present among mean peak GH levels after the first and second stimuli in groups 1, 2 and 3, while in group 4 the GH response to arginine administration was lower than that obtained after the initial GHRH (0.43±0.04 vs 0.9±0.13 nmol/l). Moreover, comparing the GH peak values following the second stimulus, it appears that the greatest GH responses were elicited by GHRH (1.31±0.23 nmol/l) and clonidine (1.11±0.22 nmol/l), while the lowest was elicited by arginine (0.43±0.04 nmol/l). In adults, sequential GHRH administration leads to inhibition of the response of the somatotropes, probably mediated by an increase in hypothalamic somatostatin. Our results confirm that after GHRH prestimulation GHRH elicits a significant GH response suggesting that activation of the somatostatinergic tone is less effective in children. This hypothesis also explains the low GH response to arginine which acts selectively through somatostatin inhibition.

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Ezio Ghigo, Gianluca Aimaretti, Laura Gianotti, Jaele Bellone, Emanuela Arvat and Franco Camanni

Ghigo E, Aimaretti G, Gianotti L, Bellone J, Arvat E, Camanni F. New approach to the diagnosis of growth hormone deficiency in adults. Eur J Endocrinol 1996;134:352–6. ISSN 0804–4643

Pyridostigmine (PD), a muscarinic cholinergic agonist, and arginine (ARG) clearly increase the growth hormone (GH) response to growth hormone-releasing hormone (GHRH) in man. The current study was undertaken to investigate the value and safety of PD + GHRH and ARG + GHRH tests as well as the measurement of serum insulin-like growth factor I (IGF-I) in diagnosing GH deficiency in adults. Fifty-four patients considered GH deficient from extensive organic or idiopathic pituitary disease and 326 healthy adults were studied. The IGF-I concentrations were lower than the 3rd percentile of normal values in only 31 of the 54 (57.4%) patients with hypopituitarism. However, the IGF-I levels in hypopituitary patients and in normal subjects overlapped more frequently between 41 and 60 years (50%) and between 61 and 80 years (92.3%) as opposed to between 20 and 40 years (8.6%). In contrast to the IGF-I measurement, the ranges of peak GH responses to PD + GHRH and ARG + GHRH tests were clearly differentiated between the hypopituitary (0.2–6.8 and 0.1–9.5 μg/l, respectively) and normal subjects 17.7–114 and 16.1–119 μg/l, respectively). However, the PD + GHRH test was reliable only in subjects of 20–40 years of age. In conclusion, IGF-I measurement had no value in the diagnosis of GH deficiency in adults aged over 40 years, but is reliable enough when young adults of 20–40 years of age are considered. Both PD + GHRH and ARG + GHRH testing should be considered more reliable biochemical measurements of GH deficiency. In contrast to the PD + GHRH test, the ARG + GHRH test is reliable throughout the adult lifespan and appears to be the most appropriate for patient compliance and safety.

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

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Aart Jan van der Lely, Peter Jönsson, Patrick Wilton, Ann-Charlotte Åkerblad, José Cara and Ezio Ghigo

Objective

To investigate the characteristics of patients who need more or less pegvisomant (PEGV) to normalize serum IGF-I.

Design

ACROSTUDY is a global noninterventional safety surveillance study of long-term treatment outcomes in patients treated with PEGV. As of June, 2014, ACROSTUDY included data on 2016 patients. All patients treated for at least 6weeks at a dose above 30mg/day and who had two consecutive normal serum IGF-I values were included in the ‘high’-dose group (H; n=56; mean daily dose 44±12.5; median dose 40, 35–60 (10–90%)). Patients with two consecutive normal IGF-I values and who never received a PEGV dose above 10mg/day were included in the ‘low’-dose group (L; n=368; mean daily dose 7.5±2.5; median dose 8.6, 4.3–10 (10–90%)).

Results

Patients in the H group were significantly younger (median 47 vs 52years) and had a significantly higher BMI (median 31.8 vs 26.5kg/m2). They had more diabetes (55% vs 21%), sleep apnea (25% vs 14 %) and more hypertension (61% vs 43%). The incidence of (serious) adverse events was low and was not different between the groups.

Conclusions

Patients who need more PEGV to normalize IGF-I have more aggressive disease, as they are younger, have higher baseline IGF-I levels, more hypertension, more sleep apnea and diabetes and are more overweight. A better understanding of this dose-efficacy relationship of PEGV might avoid inappropriate dosing and prevent serum IGF-I levels from remaining unnecessarily uncontrolled.

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Valentina Gasco, Flavia Prodam, Silvia Grottoli, Paolo Marzullo, Salvatore Longobardi, Ezio Ghigo and Gianluca Aimaretti

Recombinant human GH has been licensed for use in adult patients with GH deficiency (GHD) for over 15 years. Early weight- and surface area-based dosing regimens were effective but resulted in supraphysiological levels of IGF1 and increased incidence of side effects. Current practice has moved towards individualised regimens, starting with low GH doses and gradually titrating the dose according to the level of serum IGF1 to achieve an optimal dose. Here we present the evidence supporting the dosing recommendations of current guidelines and consider factors affecting dose responsiveness and parameters of treatment response. The published data discussed here lend support for the use of low GH dosing regimens in adult GHD. The range of doses defined as ‘low dose’ in the studies discussed here (∼1–4 mg/week) is in accordance with those recommended in current guidelines and encompasses the dose range recommended by product labels.

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Simona Bo, Anna Castiglione, Ezio Ghigo, Luigi Gentile, Marilena Durazzo, Paolo Cavallo-Perin and Giovannino Ciccone

Objective

Available data about mortality of type 2 diabetic patients treated with different sulphonylureas are scarce and contradictory.

Design

We evaluated the associations between all-cause and cause-specific mortality and treatments with different sulphonylureas in a retrospective cohort of type 2 diabetic patients from a diabetes clinic.

Methods

All 1277 patients treated with sulphonylureas during 1996–1997 were enrolled: 159 patients were treated with tolbutamide, 977 glibenclamide and 141 gliclazide. The baseline data (centralised laboratory parameters, anthropometric data and presence of chronic complications) were abstracted from the clinical records. Information on vital status was collected from demographic files after 14-year follow-up. Adjusted hazard ratios (HR) were estimated with Cox (all-cause mortality) or Fine and Gray models (cause-specific mortality), including several potential confounders.

Results

Five hundred and fifty-six patients died during the follow-up: 262 from cardiovascular causes, 158 from cancer and 136 from other causes. When compared with the glibenclamide users, the gliclazide and tolbutamide users showed a significantly lower cancer mortality (HR=0.30; 95% CI 0.16–0.55, and HR=0.48; 95% CI 0.29–0.79 respectively). These results were strongly confirmed in the 555 patients on sulphonylurea monotherapy. None of the patients who were treated with gliclazide monotherapy died from cancer during the follow-up, and the patients on tolbutamide treatment exhibited a lower cancer mortality than the glibenclamide users (HR=0.40; 95% CI 0.22–0.71). Data did not change after stratification for the duration of sulphonylurea treatment from diabetes diagnosis to the study enrolment.

Conclusions

Cancer mortality was markedly reduced in the patients on gliclazide and tolbutamide treatment. These results suggest additional benefits for these drugs beyond their blood glucose-lowering effect and strongly advocate for further investigation.

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Roberta Giordano, Marcella Balbo, Andreea Picu, Lorenza Bonelli, Rita Berardelli, Alberto Falorni, Ezio Ghigo and Emanuela Arvat

Objective: In autoimmune polyglandular syndrome types 1, 2, and 4 primary adrenal insufficiency is present, but its diagnosis is often late. We investigated the function of the hypothalamic–pituitary–adrenal axis in a group of patients with autoimmune diseases (AP) without any symptoms and signs of hypoadrenalism.

Design: In 10 AP and 12 normal subjects (NS), we studied cortisol (F), aldosterone (A), and DHEA responses to 0.06 μg adrenocorticotropin (ACTH) (1–24) followed by 250 μg, ACTH and F responses to human corticotropin-releasing hormone (hCRH; 100 μg) and insulin tolerance test (ITT) (0.1 UI/kg).

Results: Basal F, A, DHEA, as well as urinary free cortisol and plasma renin activity levels in AP and NS were similar, whereas ACTH levels in AP were higher (P<0.05) than in NS. NS showed F, A, and DHEA response to both consecutive ACTH doses. In AP, the F, A, and DHEA responses to 250 μg ACTH were similar to those in NS, whereas the 0.06 μg ACTH dose did not elicit any significant response. The ACTH responses to hCRH and ITT in AP were higher (P<0.05) than in NS. The F response to hCRH in AP was lower (P<0.05) than in NS, whereas the F response to ITT in AP did not significantly differ from NS.

Conclusions: Enhancement of both basal and stimulated corticotrope secretion coupled with reduced adrenal sensitivity to low ACTH dose is present in AP patients without symptoms and signs of hypoadrenalism. This functional picture suggests that normal adrenal secretion is maintained due to corticotrope hyperfunction, suggesting the existence of some subclinical primary hypoadrenalism.

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Rita Berardelli, Ioannis Karamouzis, Elisa Marinazzo, Elisa Prats, Andreea Picu, Roberta Giordano, Ezio Ghigo and Emanuela Arvat

Context

Mineralocorticoid receptors (MRs) in the hippocampus display an important role in the control of the hypothalamic–pituitary–adrenal (HPA) axis, mediating the proactive feedback of glucocorticoids, which maintains the basal HPA activity. The systemic administration of MR antagonists enhances spontaneous and CRH-stimulated ACTH, cortisol, and DHEA secretion, while the effects of chronic treatment with MR antagonists are scanty. Our study was performed in order to clarify this point.

Design

ACTH, cortisol, and DHEA levels were studied during the infusion of placebo, canrenoate, a MR antagonist (CAN, 200 mg i.v. bolus at 1600 h followed by 200 mg infused over 4 h), and human CRH (hCRH; 2.0 μg/kg i.v. bolus at 1800 h) before and during the last week of 28-day treatment with CAN (200 mg/day p.o.) in eight young women.

Results

Pre-treatment sessions: CAN and hCRH administration increased ACTH, cortisol, and DHEA levels versus placebo (P<0.05). Post-treatment sessions: during placebo infusion, cortisol and DHEA were significantly amplified versus pre-treatment session (P<0.05), while ACTH levels were not modified; CAN infusion, differently from pre-treatment session, was not able to significantly increase ACTH, cortisol, and DHEA levels; ACTH, cortisol, and DHEA responses to hCRH were amplified with respect to pre-treatment session, although statistical significance was obtained for cortisol and DHEA only.

Conclusions

MR blockade by acute CAN administration significantly enhances the HPA activity in the afternoon, during the quiescent phase of the circadian rhythm. At the same period, prolonged treatment with CAN amplifies both spontaneous and CRH-stimulated activities of the HPA axis, while it blunts the HPA responsiveness to a further MR-mediated stimulation.

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Ferdinando Massara, Ezio Ghigo, Pia Molinatti, Enrico Mazza, Vittorio Locatelli, Eugenio E. Müller and Franco Camanni

Abstract. It is known that in normal subjects repeated administrations of the growth hormone-releasing factor (GRF) induces a state of partial refractoriness of the somatotropes to GRF. Studies were conducted to verify whether the cholinergic system plays a role in the mechanism(s) underlying the reduced GH responsiveness to the neuropeptide. In five healthy men, the GH response to three consecutive injections of GRF (50 μg iv), administered at 2 h intervals, was considerably blunted after the second and third GRF bolus. Administration of the inhibitor of cholinesterase, pyridostigmine bromide (120 mg orally) 30 min before the second GRF bolus, not only restored but greatly potentiated the GH responsiveness to the second GRF bolus. The GH response to the third GRF bolus was not apparently influenced by pre-treatment with pyridostigmine. These data reinforce the view that cholinergic neurotransmission plays an important role in the control of GH secretion in human.