Testing pituitary function in aging individuals.
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Aged↗
Biomedical subjects
Silvia Grottoli
Publications and source records attributed to Silvia Grottoli.
IGFs and IGFBPs in adult growth hormone deficiency.
In the current guidelines for the diagnosis of adult GH deficiency (GHD) it is stated that, within the appropriate clinical context, it has to be shown by provocative tests only. But the diagnostic value of measuring IGF-I levels has been recently revisited. It has been confirmed that normal IGF-I levels do not rule out severe GHD in adults. However, it has also been emphasized that very low IGF-I levels in patients highly suspected for GHD (and without malnutrition, liver disease or hypothyroidism) could be considered definite evidence for severe GHD. This assumption particularly applies to patients with childhood-onset, severe GHD or with multiple hypopituitarism acquired in adulthood. The value of measuring IGF-I levels for monitoring the efficacy and the adequacy of rhGH replacement remains definitely accepted.
Adult↗
The cut-off limits of the GH response to GH-releasing hormone-arginine test related to body mass index.
OBJECTIVE: The diagnosis of growth hormone (GH) deficiency (GHD) in adults is based on a reduced peak GH response to provocative tests, such as the insulin tolerance test (ITT) and the GH-releasing hormone-arginine (GHRH-ARG) test. However, the cut-off limits of peak GH response in lean subjects are not reliable in obese patients; this is noteworthy since adult GHD is often associated with obesity. Aim of this study was to evaluate the diagnostic cut-off limits of peak GH response to the GHRH-ARG test in overweight and obese as well as in lean population. DESIGN AND METHODS: The GH responses to the GHRH-ARG test were studied in 322 patients with organic hypothalamic-pituitary disease and in 318 control subjects. Patients were subdivided into two groups on the basis of the number of pituitary hormone deficits, except for GH deficiency: (a) patients with total pituitary hormone deficit (TPHD) and (b) patients without or with no more than two pituitary hormone deficits (PHD). Both patients and control subjects were divided into three subgroups according to body mass index (BMI): lean (BMI <25 kg/m(2)), overweight (BMI > or = 25 and <30 kg/m(2)) and obese (BMI > or =30 kg/m(2)). TPHD patients were assumed to be GH deficient, whereas PHD patients may include subjects with either normal or impaired GH secretion. The statistical analysis was carried out by the Receiver-Operating Characteristic curve analysis (Medcalc 7.2). The diagnostic cut-off points were calculated for lean, overweight and obese subjects to provide optimal separation of GH-deficient patients and control subjects according to two criteria: (1) a balance between high sensitivity and high specificity; (2) to provide the highest pair of sensitivity/specificity values for GH deficiency. RESULTS: In the lean population the best pair of values, with highest sensitivity as 98.7% and highest specificity as 83.7%, was found using a peak GH cut-off point of 11.5 mug/l. In the overweight population the best pair of values, 96.7 and 75.5%, respectively, was found using a peak GH cut-off point of 8.0 mug/l. In the obese population the best pair of values, 93.5 and 78.3%, respectively, was found using a peak GH cut-off point of 4.2 mug/l. Applying the above mentioned cut-off points, among PHD patients we found that 80 subjects (72%) were GHD whereas 31 (28%) had normal GH secretion. CONCLUSIONS: In conclusion the GHRH-ARG test is a reliable tool for the diagnosis of adult GH deficiency in lean, overweight and obese patients, provided that specific BMI-related cut-off limits are assumed.
Adult↗
Insulin-like growth factor I levels and the diagnosis of adult growth hormone deficiency.
The current guidelines state that, within the appropriate clinical context, the diagnosis of adult growth hormone (GH) deficiency must be made biochemically using provocative tests. Measurement of insulin-like growth factor I (IGF-I) and binding protein 3 (IGFBP-3) levels cannot always distinguish between healthy and GH-deficient individuals. In particular, IGFBP-3 as a marker of GH status is clearly less sensitive than IGF-I and there is general agreement that its measurement does not provide useful diagnostic information. However, the diagnostic value of measuring IGF-I levels has been revisited recently. It has been confirmed that normal IGF-I levels do not rule out severe GH deficiency (GHD) in adults, in whom the diagnosis has therefore to be based on the demonstration of severe impairment of the peak GH response to provocative tests. It has also been emphasized that very low IGF-I levels in patients with high suspicion of GHD could be considered to be definite evidence for severe GHD. This assumption particularly applies to patients with childhood-onset, severe GHD or with multiple hypopituitary deficiencies acquired in adulthood. In addition, the use of IGF-I levels to monitor the efficacy and adequacy of recombinant human GH replacement remains widely accepted.
Adult↗
Alprazolam (a benzodiazepine activating GABA receptor) reduces the neuroendocrine responses to insulin-induced hypoglycaemia in humans.
OBJECTIVE: Alprazolam (ALP), a benzodiazepine-activating GABAergic receptor, possesses clear centrally mediated inhibitory effects on ACTH and cortisol secretion that could reflect an inhibitory influence on CRH- and/or AVP-secreting neurones. An inhibitory effect of ALP on catecholamine release has also been shown while its effect on GH secretion is unclear. To further clarify the neuroendocrine actions of ALP, we studied the ALP effects on the neurohormonal responses to hypoglycaemia in a group of normal subjects. DESIGN: In eight normal subjects [four women and four men, 22-34 years old, body mass index (BMI) 20-25 kg/m2] the ACTH, cortisol, GH, adrenaline (A) and noradrenaline (NA) responses to insulin-induced hypoglycaemia [ITT, 0.1 UI/kg regular insulin intravenously (i.v.) at 0 min] preceded by placebo or ALP (0.02 mg/kg orally at -90 min) were studied in two sessions at least 10 days apart. MEASUREMENTS: Blood samples were taken basely at -90 and 0 min and every 15 min up to +120 min. ACTH, cortisol, GH, A and NA level were assayed at each time point in both sessions. RESULTS: All subjects experienced hypoglycaemia (plasma glucose levels below 2.2 mmol/l). After placebo ITT induced clear-cut increases in ACTH (peak vs. baseline, mean +/- SEM: 27.9 +/- 3.9 vs. 7.1 +/- 1.5 pmol/l), cortisol (438.1 +/- 32.0 vs. 237.7 +/- 19.3 nmol/l) and GH (38.1 +/- 9.7 vs. 5.7 +/- 2.0 micro g/l) levels (P < 0.05). Marked increase in A (6627.2 +/- 116.7 vs. 263.7 +/- 71.4 pmol/l) and NA (3.8 +/- 1.5 vs. 1.6 +/- 1.0 nmol/l) levels were also recorded (P < 0.05). Pretreatment with ALP significantly inhibited the ACTH peak response to ITT (17.8 +/- 5.0 pmol/l, P < 0.05), while the cortisol response showed a non significant reduction (342.1 +/- 38.7 nmol/l). ALP also significantly reduced the GH (21.7 +/- 4.7 micro g/l, P < 0.02) and A (3828.0 +/- 1400.7 pmol/l, P < 0.02) responses to ITT. On the contrary, ALP lowered basal NA levels (P < 0.05) but did not significantly affect its response to ITT (2.2 +/- 1.2 nmol/l). Glucose changes induced by ITT were not modified by ALP. CONCLUSIONS: This study shows that GABAergic activation by alprazolam significantly inhibits the neuroendocrine and adrenomedullary responses to hypoglycaemia.
Adrenocorticotropic Hormone↗
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. DESIGN, PATIENTS AND MEASUREMENTS: We studied 30 obese patients with OSAS [OSA, 21 males, 9 females; age, mean +/- SEM: 53.1 +/- 1.7 years; body mass index (BMI): 38.6 +/- 1.1 kg/m2; waist-to-hip ratio (WHR): 0.99 +/- 0.07; Apnoea/Hypopnoea Index (AHI): 40.5 +/- 5.8 events/h of sleep] by means of overnight polysomnography and oral glucose tolerance testing. Mathematical models were used to assess: (i) whole-body insulin sensitivity index (ISI composite); (ii) hepatic ISI; (iii) the first phase of insulin secretion (DeltaI30'-0'/DeltaG30'-0'). Results were compared with those in 27 weight-matched patients with simple obesity (OB, 12 males, 15 females; age: 48.1 +/- 2.8 years, BMI: 38.5 +/- 1.4 kg/m2, WHR: 0.94 +/- 0.09; AHI: 2.15 +/- 0.5 events/h of sleep) and with 20 normal subjects (NS, 15 females; 5 males, age: 40.4 +/- 2.9 years; BMI: 22.2 +/- 0.6 kg/m2). RESULTS: ISI composite value was significantly lower in OSAS (1.71 +/- 1.41) than in OB (3.08 +/- 0.27) and in NS (6.1 +/- 0.4) even after age-, BMI- and WHR-adjustment. Similarly, hepatic ISI was significantly different among the three groups (OB = 0.25 +/- 0.02, OSAS = 0.16 +/- 0.014 and NS = 0.55 +/- 0.04). Sex did not affect ISI indices. Insulin secretion estimates were not significantly different among the three groups. DISCUSSION: Obese patients with obstructive sleep apnoea syndrome are more insulin resistant than patients with simple obesity independently of the degree and distribution of adiposity. The worsening in insulin sensitivity in obstructive sleep apnoea syndrome patients could reflect the hypoxic state and would account for the increased vascular risk in this condition.
Analysis of Variance↗
Lanreotide 60 mg, a new long-acting formulation: effectiveness in the chronic treatment of acromegaly.
Lanreotide (LAN) 60 mg (LAN60), a new long-acting formulation of LAN alleged to suppress GH/IGF-I hypersecretion for 28 d in acromegalic patients, was administered in a prospective open multicenter study to 92 patients with active acromegaly (61 women and 31 men, aged 20-79 yr). LAN60 was given as adjuvant treatment (AT) in 62 patients; the other 30 patients [primary treatment (PT)] were de novo (n = 20) or previously treated only by pharmacotherapy (n = 10). After wash-out from previous treatments, LAN60 was started im every 28 d for 3 injections; the dose was then individually tailored, aiming at lowering GH to less than 2.5 micro g/liter and IGF-I to the normal range. After a median follow-up of 24 months (range, 6-48 months), IGF-I normalized in 65% of patients, decreasing from 199 +/- 8% (expressed as a percentage of the upper limit of normal range; mean +/- SE) to 87 +/- 4% (P < 0.0001). GH fell to less than 2.5 microg/liter in 63% of patients and to less than 1 microg/liter in 25%, decreasing from 20 +/- 3 to 3 +/- 0.4 microg/liter (P < 0.0001). A progressive increase in the rate of IGF-I normalization was observed (from 49% at 1 yr to 77% at 3 yr). The rate of GH/IGF-I normalization was 72% at 36 months by Kaplan-Meier analysis. No tachyphylaxis was observed throughout the study. Shortening the interval between injections to 21 d improved GH/IGF-I suppression. PT and AT patients achieved similar final GH/IGF-I levels and rates of normalization. Tumor shrank in 39% of assessable patients and in 50% of PT. Plasma glucose levels did not change, and high density lipoprotein cholesterol increased (by 19.3 +/- 5.1%; P = 0.0215). Gallstones appeared or worsened in 13% of patients. LAN60 is a new, very effective and long-lasting formulation for the treatment of acromegaly. The persistence of a powerful suppression of GH/IGF-I levels, the progressive increase in the rate of IGF-I normalization, and the similarity in the efficacy achieved in PT and AT patients point to a role for LAN60 in the primary treatment of acromegaly.
Acromegaly↗
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. SUBJECTS: To this aim we enrolled six normal young volunteers [age (mean +/- SEM) 28.9 +/- 3.1 year; body mass index 22.3 +/- 1.0 kg/m2). DESIGN AND MEASUREMENTS: In all subjects we studied the effects of glucose (OGTT, 100 g oral glucose at -45 min) or free fatty acids (FFA) load [lipid-heparin emulsion, Li-He, Intralipid 10% 250 ml + heparin 2500 U i.v. from -30 to +120 min] as well as of arginine (ARG, 0.5 g/kg infused from 0 to +30 min) on the GH response to human ghrelin (1.0 micro g/kg i.v. at 0 min) administration. These results were compared with those obtained by studying the effects of OGTT, Li-He and ARG on the GH response to GHRH-29 (1.0 micro g/kg i.v. at 0 min). RESULTS: The GH response to ghrelin (auc 5452.4 +/- 991.3 micro g/l/h) was higher (P < 0.05) than that after GHRH (1519.4 +/- 93.3 micro g/l/h). The GH response to GHRH was inhibited by OGTT (450.7 +/- 81.1 micro g/l/h, P < 0.05) and almost abolished by Li-He (230.0 +/- 63.6 micro g/l/h, P < 0.05) while was markedly potentiated by ARG (2520.4 +/- 425.8 micro g/l/h, P < 0.05). The GH response to GHRH + ARG, however, was lower (P < 0.05) than that to ghrelin alone. The GH response to ghrelin was blunted by OGTT (2153.1 +/- 781.9 micro g/l/h, P < 0.05) as well as by Li-He (3158.8 +/- 426.7 micro g/l/h, P < 0.05) but these responses remained higher (P < 0.05) than that to GHRH alone. On the other hand, ARG did not modify the GH response to ghrelin (6324.3 +/- 1275.5 micro g/l/h). For GH 1 micro g/l = 2 mU/l. CONCLUSIONS: In humans, ghrelin exerts a strong stimulatory effect on GH secretion which is partially refractory to the inhibitory effect of both glucose and FFA load and is not enhanced by ARG. These factors almost abolish and potentiate, respectively, the GH response to GHRH, at least partially, via modulation of hypothalamic SS release. Thus, our findings agree with the hypothesis that ghrelin as well as non-natural GHS acts, at least partially, by antagonizing SS activity.
Adult↗
Endocrine activities of cortistatin-14 and its interaction with GHRH and ghrelin in humans.
Cortistatin (CST)-14, a neuropeptide with high homology with somatostatin (SS)-14, binds all sst subtypes but, unlike SS, also ghrelin's receptor. In six normal adults, we studied the effects of CST-14 or SS-14 administration (2.0 micro g/kg/h iv) on: 1) GH and insulin secretion; 2) the GH response to GHRH (1.0 microg/kg i.v.); and 3) the GH, prolactin (PRL), ACTH, cortisol, insulin, and glucose responses to ghrelin (1.0 microg/kg i.v.). CST-14 inhibited GH and insulin secretion (P < 0.01) to the same extent of SS-14. The GH response to GHRH was similarly inhibited (P < 0.01) by either CST-14 or SS-14. Ghrelin released more GH than GHRH (P < 0.01); these responses were similarly inhibited (P < 0.05) by either CST-14 or SS-14, that made ghrelin-induced GH rise similar to that after GHRH alone. Neither CST-14 nor SS-14 modified PRL, ACTH, or cortisol responses to ghrelin. The inhibitory effect of CST-14 and SS-14 on insulin was unaffected by ghrelin that, in turn, reduced insulin secretion per se (P < 0.01). Ghrelin increased glucose levels (P < 0.05); CST-14 and SS-14 did not modify this effect. Thus, CST-14 inhibits both basal and stimulated GH secretion in humans to the same extent of SS-14. The GH-releasing activity of ghrelin seems partially resistant to CST-14 as well as SS-14. CST-14 and SS-14 do not affect PRL and ACTH secretion but, like ghrelin, inhibit insulin secretion; the ghrelin-induced inhibition is not additive with that of CST-14 or SS-14, suggesting a common mechanism of action on beta cell secretion.
Adrenocorticotropic Hormone↗