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Andrea Giustina and William B Wehrenberg

The regulation of growth hormone (GH) secretion involves a complex neuroendocrine control system that includes the participation of several neurotransmitters and the feedback of hormonal and metabolic substrates. The final integration of these signals occurs in the hypothalamus, which controls GH secretion through two neuropeptides: GHRH, which stimulates GH secretion; and somatostatin, which inhibits it (1). The pattern of GH secretion in both rats and humans is pulsatile and sexually dimorphic (2). The role of GHRH and somatostatin in generating GH secretory pulses has been studied extensively in rats with the use of passive immunization techniques. These studies have demonstrated that GHRH regulates GH pulses and that somatostatin regulates baseline GH values. In humans, GH secretion is pulsatile in nature. The major secretory episode of GH occurs at night and is associated with rapid eye movement (REM) sleep. Additional episodes, however, are associated with exercise, stress or nutrient intake. Growth

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Andrea Giustina, Simonetta Bossoni, Corrado Bodini, Antonino Cimino, Giuseppe Pizzocolo, Maurizio Schettino and William B. Wehrenberg

Abstract.

We evaluated the effects of iv pretreatment with exogenous GH on the GH response to GHRH either alone or in combination with pyridostigmine in 14 Type I diabetic patients and 6 normal subjects. All the subjects received an iv bolus injection of biosynthetic human GH, 2 IU; 2 h later they received either a. pyridostigmine, 120 mg orally, or b. placebo, 2 tablets orally, followed 1 h later by iv injection of GHRH(1-29) NH2, 100 μg. In normal subjects the median GH peak after GH+GHRH was 1.8, range 1.2-6.9 μg/l. Pyridostigmine enhanced the GH response to GHRH in all subjects. The median GH peak after pyridostigmine+ GH+GHRH was 32.7, range 19.8-42.1 μg/l (p<0.001 vs GHRH alone). Seven diabetic subjects had median GH peaks after GH+GHRH >6.9 μg/l (the maximum GH peak after GH+GHRH in normal subjects) (group A: median GH peak 35.7, range 21.7-55 μg/l). The other diabetic subjects had GH peak lower than 6.9 μg/l (group B: median GH peak 4.4, range 2.1-6.5 μg/l). Pyridostigmine significantly increased the GH response to GHRH in group B patients (median GH peak 29.3, range 15.7-93.4 μg/l, p<0.001 vs GH+GHRH alone), but not in group A patients (median GH peak 39.9, range 21.9-64.9 μg/l). Group A diabetic patients were younger and had higher HbA1c and blood glucose levels than group B patients. In those diabetic patients with an exaggerated GH response to GH+GHRH, pyridostigmine failed to cause the increase in GH secretion observed in diabetic and control subjects with no responses to GH+GHRH. It can be suggested that elevated 24-h GH levels in some Type I diabetic patients may be due to decreased somatostatinergic tone which in turn causes altered autoregulation of GH secretion. We hypothesize that this finding is a consequence of a reset of the hypothalamic control of GH secretion caused by a chronically elevated blood glucose level in this subpopulation.

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Andrea Giustina, Mauro Doga, A Rosa Bussi, Massimo Licini and Maurizio Schettino

Galanin elicits growth hormone (GH) secretion in normal man but may cause a paradoxical fall of GH in acromegaly. The aim of our study was to investigate the effects of long-term treatment with bromocriptine on the galanin-induced GH decrease in acromegalic subjects. Six acromegalic patients (5F, 1M) chronically treated with bromocriptine underwent in randomized order: (i) iv infusion of 100 ml saline from 0 to 45 min and (ii) iv infusion of synthetic porcine galanin (0.5 mg in 100ml saline) from 0 to 45 min. In acromegalic patients, GH values fell from baseline (10.5±2.7 μg/1) to a mean nadir of 6.9±2.2 μg/1 after galanin infusion (57.8±9.4% vs basal levels). Saline infusion did not cause any change in circulating GH levels. The mean change in GH values with respect to baseline after galanin in these subjects significantly differed from that observed after saline from time 15 to 90 min. Serum prolactin levels were not significantly affected by galanin. Our results confirm that the dose of galanin capable of increasing plasma GH levels in normal subjects can decrease GH values in patients with acromegaly. Moreover, our data show that this paradoxical GH decrease induced by galanin can also be observed in patients chronically treated with bromocriptine. Therefore, the paradoxical decreasing effect of galanin on plasma GH levels in acromegaly seems not to be mediated via dopaminergic pathways.

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Andrea Giustina, Mauro Doga, Corrado Bodini, Angela Girelli, Fabio Legati, Simonetta Bossoni and Giuseppe Romanelli

Abstract

Glucocorticoids have been shown to inhibit GH secretion in normal man when administered in large amounts for several days. The aim of our study was 1. to investigate the acute effects of a single dose of glucocorticoids on GH secretion in normal man; 2. to look at the relationship between the increase in serum cortisol concentration and GH response to the stimuli. Six healthy volunteers received on three occasions in random order an iv injection of GHRH (1–29) NH2, 100 μg, alone or 60 min after oral administration of either 25 or 50 mg of cortisone acetate. Mean stimulated GH levels, GH peak and integrated GH concentration were significantly lower after GHRH plus cortisone 25 mg than after GHRH alone. Mean GH levels at 15 and 30 min after GHRH injection and the peak GH level showed a further decrease after GHRH plus cortisone 50 mg. We conclude that acute administration of pharmacological doses of glucocorticoids is able to inhibit GH response to GHRH, probably through enhancement of endogenous somatostatin release. Moreover, this pharmacological effect of glucocorticoids seems to be dose-dependent and thus directly related to serum cortisol concentrations.

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Andrea Giustina, Carlo Ferrari, Corrado Bodini, Maria Grazia Buffoli, Fabio Legati, Maurizio Schettino, Fausto Zuccato and William B. Wehrenberg

Abstract.

In vitro studies have demonstrated that thyroid hormones can enhance basal and stimulated growth hormone secretion by cultured pituitary cells. However, both in man and in the rat the effects of high thyroid hormone levels on GH secretion are unclear. The aim of our study was to test the GH response to human GHRH in hyperthyroid patients and to evaluate the effects on GH secretion of short- and long-term pharmacological decrease of circulating thyroid hormones. We examined 10 hyperthyroid patients with recent diagnosis of Graves' disease. Twelve healthy volunteers served as controls. All subjects received a bolus iv injection of GHRH(1-29)NH2, 100 μg. Hyperthyroid patients underwent a GHRH test one and three months after starting antithyroid therapy with methimazole, 10 mg/day po. GH levels at 15, 30, 45, 60 min and GH peak after stimulus were significantly lower in hyperthyroid patients than in normal subjects. The GH peak was also delayed in hyperthyroid patients. After one month of methimazole therapy, most of the hyperthyroid patients had thyroid hormone levels in the normal range, but they did not show significant changes in GH levels after GHRH, and the GH peak was again delayed. After three months of therapy with methimazole, the hyperthyroid patients did not show a further significant decrease in serum thyroid hormone levels. However, mean GH levels from 15 to 60 min were significantly increased compared with the control study. The GH peak after GHRH was also earlier than in the pretreatment study. In conclusion, the GH response to GHRH is inhibited and delayed by hyperthyroidism and returns to the normal pattern after long-term euthyroidism has been achieved with methimazole.

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Andrea Giustina, Anna Rosa Bussi, Fabio Legati, Simonetta Bossoni, Massimo Licini, Maurizio Schettino, Fausto Zuccato and William B Wehrenberg

Patients with hyperthyroidism have reduced spontaneous and stimulated growth hormone (GH) secretion. The aim of our study was to evaluate the effects of galanin, a novel neuropeptide which stimulates GH secretion in man, on the GH response to GHRH in patients with hyperthyroidism. Eight untreated hyperthyroid patients with Graves' disease (6F, 2M, aged 25–50 years) and six healthy volunteers (3F, 3M, aged 27–76 years) underwent from - 10 to 30 min in random order: (i) porcine galanin, iv, 500 μg in 100 ml saline; or (ii) saline, iv, 100 ml. A bolus of human GHRH(1-29)NH2, 100 μg, was injected iv at 0 min. Hyperthyroid patients showed blunted GH peaks after GHRH+saline (10.2±2.5 μg/l) compared to normal subjects (20.7±4.8 μg/l, p< 0.05). GH peaks after GHRH+ galanin were also significantly lower in hyperthyroid subjects (12.5±3 μg/l) compared to normal subjects (43.8±6 μg/l, p<0.05). That galanin is not able to reverse the blunted GH response to GHRH in hyperthyroidism suggests that hyperthyroxinemia may either increase the somatostatin release by the hypothalamus or directly affect the pituitary GH secretory capacity.

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Marilda Mormando, Luigi A Nasto, Antonio Bianchi, Gherardo Mazziotti, Antonella Giampietro, Enrico Pola, Alfredo Pontecorvi, Andrea Giustina and Laura De Marinis

Objective

Acromegaly is associated with an increased prevalence of vertebral fractures (VFs) in close relationship with GH hypersecretion. Two isoforms of the GH receptor (GHR) have been identified; the two isoforms differ or not by the expression of the protein fragment encoded by exon 3 of the GHR gene. Deletion of the exon 3 may influence the functional properties of the GHR and affect fracture risk in acromegalic patients.

Design

A cross-sectional study was designed to investigate the association between the d3-GHR isoform and the prevalence of VFs in patients with acromegaly.

Methods

In this study, 109 acromegalic patients were included (M/F, 48/61): 73 with controlled/cured acromegaly and 36 with active disease. GHR genotype was assessed in each patient. All patients were evaluated for VFs and bone mineral density at lumbar spine and hip. Serum IGF1 levels and bone metabolism markers were measured. A multivariate analysis was performed to establish risk factors for VFs in our population.

Results

d3-GHR carriers showed an increased prevalence of VFs when compared with patients expressing full-length GHR (35/55 vs 12/54; P<0.001). The association between GHR deletion and VFs was demonstrated both in patients with active disease and in those with controlled/cured disease. Out of 35 patients who were prospectively evaluated, 13 (37.1%) developed incident VFs. The incidence of VFs was significantly higher in patients for whom the GHR gene has been deleted when compared with those harboring the fl gene (P=0.04). In multivariate analysis, male sex (odds ratio (OR), 3.250; P=0.041), IGF1 levels (OR, 1.183; P=0.031), length of active diseases (OR, 1.038; P=0.001), and d3-GHR genotype (OR, 3.060; P=0.015) were all confirmed as risk factors of VFs in our population.

Conclusions

This study suggests for the first time that exon 3 deletion of GHR may predispose patients with active and controlled acromegaly to a higher risk of VFs.

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Maria Vittoria Davi', Luca Dalle Carbonare, Andrea Giustina, Marcello Ferrari, Anna Frigo, Vincenzo Lo Cascio and Giuseppe Francia

Background

Whether sleep apnoea syndrome (SAS) subsides after biochemical and clinical remission of acromegaly is controversial.

Objective

To assess the presence of SAS in a cohort of acromegalic patients, which included a subgroup with active disease and a subgroup in remission, and to evaluate clinical and biochemical independent predictors of SAS.

Design

Cross-sectional and longitudinal study.

Setting

Italian university department of internal medicine.

Patients

About 36 acromegalic patients: 18 active and 18 controlled.

Measurements

Polysomnography was performed in all patients and repeated in six with active acromegaly and SAS after achieving disease control. Echocardiographic parameters were also measured.

Results

The prevalence of SAS was 47% in the overall acromegalic population: 56% in the active group and 39% in the controlled one. In a multivariate analysis IGF1, male gender, age, body mass index, and disease duration were associated with SAS. Impaired glucose tolerance or diabetes was more prevalent in patients with SAS, particularly in the severe cases. Among the six patients of the longitudinal study, five showed improvement of SAS, but none recovered. No correlation was found between echocardiographic parameters and severity of SAS.

Conclusion

SAS can persist after recovery of acromegaly in several patients. Given the negative prognostic significance of this respiratory disorder, polysomnography should be included as routine procedure in the work-up of the acromegaly, even if in remission, being mandatory in those patients considered at high risk (elderly males, overweight, diabetic). Appropriate intensive treatment should be implemented to minimize the clinical impact of SAS in acromegaly.

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Stefania Bonadonna, Anna Burattin, Monica Nuzzo, Giovanna Bugari, Enrico Agabiti Rosei, Domenico Valle, Nicoletta Iori, John P Bilezikian, Johannes D Veldhuis and Andrea Giustina

Objective: Spontaneous parathyroid hormone (PTH) secretory dynamics include tonic and pulsatile components. It is not known how glucocorticoids might alter these secretory dynamics.

Design: The aim of our study was to evaluate spontaneous fluctuations in serum PTH levels in six adult male patients (aged 31–64 years) receiving chronic (>6 months) therapy with glucocorticoids (daily dosage >7.5 mg of prednisone or dose equivalent of other corticosteroid) as compared with a control group of 10 age- and sex-matched normal subjects.

Methods: Peripheral venous blood sampling was performed every 3 min for 6 h from 0900 to 1500 h. Plasma PTH release profiles were subjected to deconvolution analysis, a method that resolves measured hormone concentrations into secretion and clearance components, and to an approximate entropy (ApEn) estimate, that in turn provides an integrated measure of the serial regularity or orderliness of the release process.

Results: In the glucocorticoid-treated group, the PTH tonic secretory rate was reduced (4.3±0.74 vs 8.8±1.4 pg/ml per min in controls, P = 0.017). There was, however, an increase in the fractional pulsatile PTH secretion (42±8.2 vs 18.3±3.9 pg/ml per min, P = 0.006) in glucocorticoid-treated vs normal subjects. Mean overall PTH concentration, as well as mean integrated area, was similar among normal and glucocorticoid-treated subjects.

Conclusions: These results demonstrate, for the first time, that chronic glucocorticoid treatment induces a redistribution of spontaneous PTH secretory dynamics by reducing the amount released in tonic fashion and increasing the amount released as pulses.

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Andrea Giustina, Stefania Bonadonna, Giovanna Bugari, Annamaria Colao, Renato Cozzi, Salvatore Cannavo, Laura de Marinis, Ettore degli Uberti, Fausto Bogazzi, Gherardo Mazziotti, Francesco Minuto, Marcella Montini and Ezio Ghigo

Objective

In acromegaly, 25–50% of patients respond inadequately to conventional long-acting somatostatin analogue (SSA) therapy. Response may be improved by increasing SSA frequency or dose. This study evaluated the biochemical efficacy and safety of high-dose octreotide in patients with acromegaly.

Design

A 24-week prospective, multicentre, randomised, open-label trial conducted from 12 December 2005 to 23 October 2007 in patients with persistently uncontrolled acromegaly despite ≥6 month conventional SSA therapy.

Methods

Patients with ≥50% reduction in GH levels during previous SSA treatment were randomised to high-dose (60 mg/28 days) or high-frequency (30 mg/21 days) octreotide i.m. injection. Primary end-points were week 12 and 24 reduction in serum IGF1 and GH from baseline. Secondary end points included IGF1 normalisation and tumour shrinkage rates, and safety/tolerability evaluations.

Results

Significantly, more patients (10 out of 11) achieved week 24 IGF1 reduction in the high-dose than the high-frequency group (8 out of 15; P<0.05). In the high-dose group only, week-24 IGF1 values were significantly reduced (P=0.02) versus baseline. Normalisation of IGF1 occurred only with the high-dose regimen (4/11; P=0.02). Out of 14 patients experiencing adverse events, 5 reported drug-related gastrointestinal effects. No dose–response relationship was seen. Safety parameters were similar between treatment groups, apart from a slight decrease in HbA1c in the high-dose group only.

Conclusion

High-dose octreotide treatment is safe and effective (normalisation of IGF1 levels) in a subset of patients with active acromegaly inadequately controlled with long-term SSA. Individualised octreotide doses up to 60 mg/28 days may improve outcomes of SSA therapy.