S. Grottoli

Obstructive sleep apnoea syndrome impairs insulin sensitivity independently of anthropometric variables

objectives Obstructive sleep apnoea syndrome (OSAS) is strongly associated with obesity and characterized by endocrine and metabolic changes including impairment of insulin sensitivity. The aim of this study was to further clarify the insulin dynamics and glucose metabolism in this condition.

Endocrine and metabolic responses to extreme altitude and physical exercise in climbers

CONTEXT Chronic hypoxia induces complex metabolic and endocrine adaptations. High-altitude (HA) exposure is a physiological model of hypoxia. OBJECTIVE To further investigate the endocrine and metabolic responses to extreme HA. METHODS We studied nine male elite climbers at sea level and at 5200 m after climbing Mt. Everest. RESULTS After 7 weeks at HA, body weight was reduced (P<0.05); regarding endocrine variables we observed: a) an increase of 2-h mean GH concentration (P<0.05) as well as of total IGF-I and IGF binding protein-3 levels (P<0.05 for both); b) a prolactin increase (P<0.05) coupled with testosterone decrease (P<0.01) and progesterone increase (P<0.05) without any change in estradiol levels: c) no change in cortisol, ACTH, and dehydroepiandrosterone sulfate (DHEAS) levels; d) an increase in free thyroxine (P<0.05) and free tri-iodothyronine (T(3)) decrease (P<0.05) but no change in TSH levels; e) a plasma glucose decrease (P<0.05) without any change in insulin levels; f) an increase in mean free fatty acid levels (P<0.05); g) despite body weight loss, leptin levels showed non-significant trend toward decrease, while ghrelin levels did not change at all. CONCLUSIONS The results of the present study in a unique experimental human model of maximal exposure to altitude and physical exercise demonstrate that extreme HA and strenuous physical exercise are coupled with specific endocrine adaptations. These include increased activity of the GH/IGF-I axis and a low T(3) syndrome but no change in ghrelin and leptin that was expected taking into account body weight decrease. These findings would contribute to better understanding human endocrine and metabolic physiology in hypoxic conditions.

Predictors of morbidity and mortality in acromegaly: an Italian survey

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.

Long-term treatment with cabergoline, a new long-lasting ergoline derivate, in idiopathic or tumorous hyperprolactinaemia and outcome of drug-induced pregnancy

Cabergoline (CAB), a new long-acting ergoline derivative, was shown to be very effective in reducing PRL levels in normal volunteers and in hyperprolactinemic patients. We evaluated the hormonal changes after discontinuation of long-term therapy with CAB as well as the safety of drug exposure during pregnancy both for mothers and babies. We therefore studied 48 patients (47 females and one male) with pathological hyperprolactinaemia (mean±SE, 117.2±15.2; median 73.2 µg/l), treated for 1–82 months (mean±SE, 28.3±3; median 18). After long-term treatment, CAB was withdrawn in 11 patients and PRL levels were persistently normal for almost 15 days and significantly lower (p <0.05) than basal at 30, 45, 60, 90, 120 days. Three patients had normal PRL levels still at 45 days after treatment discontinuation. Nine patients became pregnant after 1–37 months (mean 12.4) of therapy. In two patients the pregnancy was interrupted spontaneously in one case and voluntarily in the other. In all but one patients, after delivery or three-month breast feeding, PRL levels trended towards reduction. In two cases (one with microadenoma and one with idiopathic hyperprolactinaemia) PRL remained in the normal levels for 1–3 years after delivery. In conclusion CAB is able to inhibit plasma PRL levels for long time (up to 120 days) after withdrawal in patients with pathological hyperprolactinaemia treated with long-term therapy.

Efficacy of a slow-release formulation of lanreotide (Autogel® 120 mg) in patients with acromegaly previously treated with octreotide long acting release (LAR): an open, multicentre longitudinal study

Objective   Lanreotide Autogel® 120 mg (ATG120; Ipsen S.p.A, Milan, Italy) is a high‐dose, sustained‐release aqueous gel formulation, supplied in a prefilled syringe and given by deep subcutaneous injection. The aim of this study was to compare efficacy and tolerability of ATG120 given every 4–8 weeks with those of octreotide LAR (o‐LAR) given every 4 weeks.

Effects of glucose, free fatty acids or arginine load on the GH-releasing activity of ghrelin in humans

objective Ghrelin, a 28 amino acid peptide purified from the stomach and showing a unique structure with an n‐octanoyl ester in serine‐3 residue, is a natural ligand of the GH secretagogue (GHS) receptor (GHS‐R) and strongly stimulates GH secretion. In humans, ghrelin is more potent than growth hormone‐releasing hormone (GHRH) and non‐natural GHS such as hexarelin. Moreover, ghrelin shows a true synergism with GHRH, has no interaction with hexarelin and, similarly to non‐natural GHS, is partially refractory to the inhibitory effect of exogenous somatostatin (SS). Despite this evidence, the mechanisms underlying the GH‐releasing effect of ghrelin in humans have not been fully clarified.

Diagnostic reliability of a single IGF-I measurement in 237 adults with total anterior hypopituitarism and severe GH deficiency

objective Within an appropriate clinical context, GH deficiency (GHD) in adults must be demonstrated biochemically by a single provocative test. Insulin‐induced hypoglycaemia (ITT) and GH‐releasing hormone (GHRH) + arginine (ARG) are indicated as the tests of choice, provided that appropriate cut‐off limits are defined. Although IGF‐I is the best marker of GH secretory status, its measurement is not considered a reliable diagnostic tool. In fact, considerable overlap between GHD and normal subjects is present, at least when patients with suspected GHD are considered independently of the existence of other anterior pituitary defects. Considering the time and cost associated with provocative testing procedures, we aimed to re‐evaluate the diagnostic power of IGF‐I measurement.

Metabolic modulation of the growth hormone-releasing activity of hexarelin in man☆

Hexarelin (His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2) is a new potent synthetic growth hormone (GH)-releasing hexapeptide. The mechanism of action of hexarelin in man has never been evaluated. Hexarelin may act directly on specific pituitary receptors and indirectly on the hypothalamus. To elucidate its mechanism of action in man, we studied the interaction of hexarelin with glucose and free fatty acids (FFA), two metabolic factors known to inhibit both basal and GH-releasing hormone (GHRH) stimulated GH secretion. Glucose is thought to inhibit GH secretion via stimulation of endogenous somatostatin release, whereas FFA could also act directly on somatotrope cells. Therefore, we investigated the effect of oral glucose (100 g) and lipid-heparin infusion (250 mL of a 10% lipid solution + 2,500 U heparin) on the GH response to a maximal dose (2 micrograms/kg intravenously [IV]) of hexarelin or GHRH in six normal men. Hexarelin elicited a clear-cut GH response (mean +/- SEM; peak, 62.6 +/- 8.0 micrograms/L) that was higher (P < .01) than that observed after GHRH (peak, 19.8 +/- 2.4 micrograms/L). Although similar increases in plasma glucose were observed with the two peptides, oral glucose almost abolished the GH response to GHRH (peak, 5.6 +/- 0.9 micrograms/L, P < .01) while only blunting the somatotrope response to hexarelin (peak, 38.4 +/- 7.9 micrograms/L, P < .05). Similarly, lipid-heparin infusion nearly abolished the GH response to GHRH (peak, 4.9 +/- 1.0 micrograms/L, P < .01) while only blunting the somatotrope response to hexarelin (peak, 34.2 +/- 4.5 micrograms/L, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Relationships between dehydroepiandrosterone‐sulphate and anthropometric, metabolic and hormonal variables in a large cohort of obese women

The aim of the present study was to measure dehydroepiandrosterone‐sulphate (DHEA‐S) levels in obesity and assess the relationships between DHEA‐S and anthropometric, metabolic and hormonal variables.

Effects of acipimox, an antilipolytic drug, on the growth hormone (GH) response to GH-releasing hormone alone or combined with arginine in obesity.

Increased free fatty acid (FFA) levels of obese patients are likely involved in the pathogenesis of the growth hormone (GH) hyposecretion of obesity. To clarify their role, we studied the influence of inhibition of plasma FFA levels, induced by 500 mg oral acipimox (ACX), an antilipolytic drug, on the GH response to GH-releasing hormone (GHRH) alone or combined with arginine ([ARG] study A) in six normal women ([NS] aged 24 to 37 years; body mass index, 22.4 +/- 0.9 kg/m2) and six obese women ([OB] aged 21 to 40 years; body mass index 39.5 +/- 3.2 kg/m2). In a group of seven OB patients (aged 18 to 58 years; body mass index, 35.8 +/- 1.3 kg/m2), the effect of ACX on either GHRH- or GHRH+ARG-stimulated GH increase was also studied after a 4-day treatment with the same drug at 250 mg three times daily (study B). OB patients had baseline FFA levels higher than NS (0.77 +/- 0.06 v 0.44 +/- 0.09 mmol/L, P<.05). In study A, ACX reduced FFA levels to the same nadir in both groups (0.11 +/- 0.02 and 0.12 +/- 0.03 mmol/L, NS and OB subjects, respectively). In NS, ACX failed to significantly potentiate the GH response to either GHRH (1,371.9 +/- 425.2 v 1,001.8 +/- 229.0 micrograms/L x min) or GHRH+ARG (3558.4 +/- 1,513.7 v 3,045.9 +/- 441.8 micrograms/L x min), while in OB patients it increased the GH response to GHRH (797.6 +/- 277.3 v 353.8 +/- 136.7 micrograms/L x min, P<.01) and did not modify the response to ARG+GHRH (1,010.5 +/- 253.1 v 821.1 +/- 222.0 micrograms/L x min). In study B, ACX reduced FFA levels in OB patients (nadir, 0.09 +/- 0.04 mmol/L). This treatment strikingly increased the GH response to GHRH (1,734.0 +/- 725.4 v 271.5 +/- 112.8 micrograms/L x min, P<.01) and significantly potentiated that to ARG+GHRH (2,371.9 +/- 571.3 v 1,020.0 +/- 343.2 micrograms/L x min, P<.05). In conclusion, our present findings indicate that an acute reduction of plasma FFA levels in OB patients restores their somatotrope responsiveness, whereas it does not affect GH secretion in lean subjects. After prolonged treatment, ACX further improves GHRH-stimulated GH secretion in OB patients, suggesting that elevated FFA levels play a leading role in the GH hyposecretory state of obesity.