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S Grottoli

Publications and source records attributed to S Grottoli.

At least 37 records · Page 2Linked to original sources

Neuroendocrine and metabolic determinants of the adaptation of GH/IGF-I axis to obesity.

Obese patients show marked impairment in spontaneous secretion as well as in the somatotroph responsiveness to all provocative stimuli. GH insufficiency in obese patients has been reported reversible after long-term diet and marked weight loss but somatotroph secretion is not restored by fasting. Among potential neuroendocrine causes, GHRH hypoactivity has been shown but it is likely that alterations in the influence of ghrelin, the gastric-derived natural ligand of the GHS-R, and or of the NPY/leptin interplay could have a role. Among metabolic alterations, the chronic elevation of FFA levels and hyperinsulinism probably have a key role in causing GH insufficiency in obesity. Despite marked GH insufficiency, total IGF-I levels are basically preserved while free IGF-I levels are even increased thus questioning real hypoactivity of GH/IGF-I axis in obesity. Peripheral GH hypersensitivity due to increased GH receptor status, hyperinsulinism and reduced IGFBP-I levels likely explain almost normal total IGF-I and increased free IGF-I levels which, in turn, probably exert an increased negative feedback action on somatotroph cells.

Adaptation, Physiological↗

Effects of 36 hour fasting on GH/IGF-I axis and metabolic parameters in patients with simple obesity. Comparison with normal subjects and hypopituitary patients with severe GH deficiency.

OBJECTIVE: Reduction of growth hormone (GH) secretion in obesity probably reflects neuroendocrine and metabolic abnormalities. Even short-term fasting stimulates GH secretion and distinguishes normal from hypopituitary subjects with growth hormone deficiency (GHD). Marked weight loss improves GH secretion in obesity but the effect of fasting is controversial. We studied the effects of a 36 h fasting on the GH/IGF-I axis and metabolic parameters in obesity. SUBJECTS: We studied nine obese patients (OB; three male and six female; age, 29.2+/-4.8; range, 18-59 y; body mass index (BMI), 43.4+/-2.7 kg/m(2); WHR, 0.9+/-0.1). Fifteen normal subjects (NS; eight male and seven female 28.9+/-0.6, 25-35 y; 21.6+/-0.4 kg/m(2)) and 10 adult hypopituitary patients with severe GH deficiency (GHD; seven male and three female; 37.6+/-2.3, 29-50 y; 24.5+/-1.0 kg/m(2); GH peak<3 microg/l after ITT and/or<9 microg/l after GHRH+arginine) served as control groups. STUDY DESIGN: We studied the effects of 36 h fasting on 8 h diurnal mean GH, insulin and glucose concentrations (mGHc, mINSc and mGLUc; assay every 30 min from 8.00 am to 4.00 pm) as well as on IGF-I, IGFBP-3, ALS, IGFBP-1, GHBP and free fatty acid (FFA) levels. RESULTS: Before fasting, basal IGF-I and ALS levels in OB were similar to those in NS and both were higher (P<0.001) than those in GHD. IGFBP-3 levels in OB were lower (P<0.01) than in NS but higher (P<0.02) than in GHD. GHBP levels in OB and GHD were similar and both were higher (P<0.01) than in NS. Glucose levels were similar in all groups. FFA levels in OB were higher (P<0.01) than in NS but similar to those in GHD. IGFBP-1 in OB were lower (P<0.05) than in NS and GHD which, in turn, were similar. On the other hand, mINSc in OB was higher (P<0.01) than that in NS and GHD which, in turn, were similar. The mGHc in OB was similar to that in NS but only the latter was higher (P<0.05) than in GHD. The individual mGHc in the three groups overlapped. After fasting, IGF-I levels in GHD were unchanged while they decreased in OB (P=NS) as well as in NS (P<0.01). IGFBP-3 and ALS levels did not change. GHBP levels in OB and GHD were unchanged while they increased in NS (P<0.01). Glucose and FFA levels were reduced and increased, respectively, in all groups (P<0.02 and P<0.01). IGFBP-1 increased while mINSc decreased in all groups (P<0.02 and P<0.01); in OB they persisted lower and higher (P<0.01) respectively, than in NS and GHD. Fasting significantly increased mGHc in NS (P<0.001) but not in OB as well as in GHD. Individual mGHc in OB showed persistent overlap with GHD. CONCLUSIONS: Short-term fasting does not increase GH secretion in obesity and does not distinguish somatotroph function in obese from that in severe GHD adults. Short-term fasting in obesity has attenuated effects on insulin and IGFBP-1 secretion while it normally increases free fatty acids in spite of any change in GH secretion.

Adolescent↗

Elderly subjects show severe impairment of dehydroepiandrosterone sulphate and reduced sensitivity of cortisol and aldosterone response to the stimulatory effect of ACTH(1-24).

OBJECTIVE: Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis in ageing has been reported both in humans and in animals and may be involved in age-related changes in body composition, structure functions and metabolism, as well as in brain ageing. Despite the supposed HPA hyperactivity and its refractoriness to negative glucocorticoid feedback, low levels of dehydroepiandrosterone (DHEA) and its sulphate have been clearly demonstrated in human ageing and may suggest another cause of age-related changes in structure function and metabolism. Thus, our aim was to verify the adrenal responsiveness to various ACTH doses in normal elderly subjects. DESIGN: We studied cortisol (F), aldosterone (A) and DHEA responses to the sequential administration of very low, low and supramaximal ACTH1-24 doses (0.06 microg or 0.5 microg followed by 250 microg ACTH1-24 i.v. at 0 and +60 minutes) in healthy elderly subjects (ES) [six females and two males, aged 63-75 years, body mass index (BMI) 22-26 kg/m2]. The results in ES were compared with those recorded in healthy young subjects (YS) (six females and six males, aged 22-34 years, BMI 20-25 kg/m2). RESULTS: Basal DHEA levels in ES were lower (P < 0.05) than in YS, while F and A levels were similar in both groups. DHEA, F and A responses to ACTH were dose-dependent in both groups. In ES, however, DHEA levels showed no response to the 0.06 microg dose, a modest increase after 0.5 microg and a clearer rise after 250 microg ACTH; at any dose, the DHEA response in ES was clearly lower than in YS (P < 0.04). The F responses to 0.5 microg and 250 microg ACTH in ES were similar to those in YS; whereas, in ES, 0.06 microg ACTH elicited a non significant F increase which was significantly lower than in YS (P < 0.05). Similarly, the A responses to the highest ACTH doses were similar in both groups but, in ES, 0.06 microg ACTH elicited no increase in A secretion, which was clearly lower than in YS (P < 0.03). CONCLUSIONS: Normal elderly subjects show severe reduction of DHEA response to a wide range of ACTH doses, in agreement with peculiar impairment of the activity of the adrenal reticularis zone in ageing. In contrast to young adults, elderly subjects also show no cortisol and aldosterone response to a very low ACTH dose. This evidence indicates a reduced sensitivity to ACTH in the fasciculata and glomerulosa zones of the adrenal gland in ageing.

Adult↗

Effects of recombinant human insulin-like growth factor I administration on the growth hormone (gh) response to GH-releasing hormone in obesity.

Circulating GH levels are reduced in obesity due to true reduction of the 24-h GH production rate. GH insufficiency in obesity might reflect neuroendocrine abnormalities and/or alterations in peripheral hormones and metabolic factors. The somatotroph response to provocative stimuli including GHRH is markedly blunted in obese patients. However, the somatotroph responsiveness to GHRH in obesity shows also peculiar refractoriness to the inhibitory effect of glucose load. In this present study we aimed at verifying the effect of low dose rhIGF-I (20 microgram/kg, sc, at 0 min) on the GH response to GHRH (1 microgram/kg, iv, at 180 min) in obesity. With this goal in mind, six obese women with abdominal adiposity [OB; age (mean +/- SEM), 32.3 +/- 4.4 yr; body mass index, 32.8 +/- 2.3 kg/m(2)] were studied. The effects of recombinant human insulin-like growth factor I (rhIGF-I) administration on circulating total IGF-I, insulin, and glucose levels were also evaluated. The results in OB were compared with those recorded in age-matched lean women (NW; age, 28.3 +/- 1.2 yr; body mass index, 20.1 +/- 0.5 kg/m(2)), in whom the inhibitory effect of rhIGF-I had already been shown. Basal IGF-I levels in OB were similar to those in NW (199.7 +/- 33.3 vs. 274.4 +/- 25.3 microgram/L). The mean GH concentration over 3 h (from 0-180 min) in OB was lower than that in NW (0.9 +/- 0.4 vs. 2.6 +/- 0.8 microgram/L; P = NS). Administration of GHRH induced a GH response in OB lower than that in NW (area under the curve from 180-270 min, 576.5 +/- 137.5 vs. 1315.9 +/- 189.9 microgram/L.min; P < 0.02). Administration of rhIGF-I increased circulating IGF-I levels in both groups to the same percent extent (326.8 +/- 28.3 and 420.3 +/- 26.5 microgram/L in OB and NW, respectively). rhIGF-I administration inhibited the GH response to GHRH in OB (240.1 +/- 99.6 microgram/L; P < 0.05) as well as in NW (730.2 +/- 288.1 microgram/L; P < 0.05), although it failed to lower the mean GH concentration over 3 h in either OB or NW. After rhIGF-I the GH response to GHRH in OB was slight and was still lower (P < 0.05) than that in NW; in fact, the percent decreases were similar in both groups (44.21 +/- 14.06 and 48.21 +/- 13.95 microgram/L, in OB and NW, respectively). The mean insulin (107.1 +/- 21.9 and 36.8 +/- 7.2 pmol/L), but not glucose (4.0 +/- 0.3 and 4.1 +/- 0.1 mmol/L), levels calculated over 270 min, were higher (P = 0.005) in OB than in NW; rhIGF-I administration did not modify insulin and glucose levels in either group. Our study shows that the sc administration of a low rhIGF-I dose inhibits the somatotroph responsiveness to GHRH in obese as well as in normal subjects, indicating that somatotroph sensitivity to the inhibitory effect of rhIGF-I is preserved in obesity.

Abdomen↗

Effects of short-term administration of low-dose rhGH on IGF-I levels in obesity and Cushing's syndrome: indirect evaluation of sensitivity to GH.

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.

Adult↗

The GH/IGF-I axis in obesity: influence of neuro-endocrine and metabolic factors.

In this review we propose an integrated neuro-endocrine-metabolic point of view on the alterations (adaptations?) of GH/IGF-1 axis in obesity, summarizing the evidence from the literature, particularly focusing the data on humans and adding where possible results from our studies in this field. It is well-known that GH secretion is deeply impaired in overweight patients: we reviewed the multiple mechanisms underlying this issue, considering either central (CNS-related, such as impairment of GHRH tone or increased somatostatin release) or peripheral (ie metabolic: insulin, free fatty acids, glucose) factors. A central point of the debate about GH insufficiency in obesity is if it represents a simple adaptive phenomenon or reflects a true impairment of the axis activity. Evaluation of IGF-I levels and generation in obesity was the mean used to address this question: a bulk of evidence on IGF-I balance in human obesity has been provided, but the matter is still uncertain and unsolved.

Blood Glucose↗

Alprazolam, a benzodiazepine, blunts but does not abolish the ACTH and cortisol response to hexarelin, a GHRP, in obese patients.

GH secretagogues (GHS) act on specific receptors at the pituitary and hypothalamic level and possess potent GH-releasing activity but also stimulate prolactin (PRL), ACTH and cortisol (F) secretion. However, hyperactivity of the HPA axis in obesity has been reported. The objective of this study was to clarify the endocrine activity of GHS in obesity. In nine obese patients (obese OB), 9 F, age, (34.8 +/- 3.7 y, body mass index (BMI), 35.0 +/- 2.2 kg/m2; WHR, 0.9 +/- 0.02), 14 controls (normal subjects, NS), 14 F, 30.4 +/- 0.9 y, 20.0 +/- 0.4 kg/m2), we studied the ACTH, F and GH responses to hexarelin (HEX, 2.0 microg/kg), a peptidyl GHS, alone and preceded by alprazolam (ALP, 0.02 mg/kg), and a benzodiazepine which has an inhibitory effect on corticotroph secretion. The HEX-induced ACTH response in OB was higher than that in n.s., but this difference did not attain statistical significance. In n.s. the HEX-induced ACTH response was abolished by ALP (P < 0.03) which, however, only blunted that in OB (P < 0.02). The GH response to HEX in OB was lower (P < 0.02) than that in n.s.. ALP blunted the GH response to HEX in n.s. (P < 0.03) while it did not modify that in OB. The GABAergic activation by alprazolam abolishes the ACTH response to hexarelin in normal subjects, while it only blunts that in obese subjects. Moreover, alprazolam blunts the GH response to hexarelin in normal but not in obese subjects. Thus, obese patients show partial refractoriness to the inhibitory effect of alprazolam on both corticotroph and somatotroph function.

Adrenocorticotropic Hormone↗

Adrenal responsiveness to high, low and very low ACTH 1-24 doses in obesity.

OBJECTIVE: To investigate adrenal activity in visceral obesity in which adrenal hyperactivity has been hypothesized. This could reflect hypothalamus-pituitary alterations leading to slight hyperfunction of the adrenal. Primary adrenal hypersensitivity to ACTH drive in obesity has also been suggested. However, it has also been reported that dehydroepiondrosterone (DHEA) levels in obesity are reduced and it has been hypothesized that this could play a role in the increased cardiovascular risk in obese patients. SUBJECTS: We have studied seven obese women with visceral adiposity (OB, age: 33.6+/-3.3 years, BMI: 33.8+/-1.3 kg/m2, WHR: 0.88+/-0.01). The results in OB were compared with those recorded in a group of age-matched normal women (NS, age: 30+/-1.3 years, BMI: 19.9+/-0.4 kg/m2, WHR: 0.76+/-0.02). METHODS: We have studied the cortisol (F), aldosterone (A) and DHEA responses to ACTH 1-24 administered at low (LD, 0.5 microg/m2) or very low (VLD, 0.125 microg/m2) dose followed by a second challenge with supramaximal dose (HD, 250 microg). RESULTS: Basal F, A and DHEA levels in OB were similar to those in NS. The peak F responses to ACTH were dose-related in both groups. At each dose the F peaks in OB (VLD: 495.6+/-43.9 nmol/l, HD: 722.3+/-67.7 nmol/l; LD: 519.2+/-46.0 nmol/l, HD: 729.6+/-44.7 nmol/l) were similar to those in NS (VLD: 556.7+/-45.9 nmol/l, HD: 704.8+/-20.7 nmol/l; LD: 511.8+/-22.8 nmol/l, HD: 726.7+/-26.5 nmol/l). The peak A responses to ACTH were dose-related in both groups. At each dose, the A peaks in OB (VLD: 0.55+/-0.03 pmol/l, HD: 0.79+/-0.09 pmol/l; LD: 0.63+/-0.04 pmol/l, HD: 0.78+/-0.09 pmol/l) were similar to those in NS (VLD: 0.8+/-0.10 pmol/l, HD: 0.86+/-0.09 pmol/l; LD: 0.8+/-0.10 pmol/l, HD: 0.95+/-0.12 pmol/l). The peak DHEA responses to ACTH were dose-related in both groups. At each dose the DHEA peaks in OB (VLD: 58.6+/-13.3 nmol/l, HD: 61.9+/-13.1 nmol/l; LD: 55.18+/-6.4 nmol/l, HD: 72.3+/-9.8 nmol/l) were similar to those in NS (VLD: 54.3+/-8.2 nmol/l, HD: 57.8+/-8.2 nmol/l; LD: 42.2+/-3.7 nmol/l, HD: 56.9+/-4.3 nmol/l). CONCLUSIONS: This study shows that the cortisol, aldosterone and dehydroepiondrosterone responses to high, low and very low ACTH doses in obese women overlap with those in age-matched lean controls; these findings suggest normal sensitivity of the different zones of the adrenal cortex to ACTH in obesity.

Adolescent↗

Short-term fasting abolishes the sex-related difference in GH and leptin secretion in humans.

We studied growth hormone (GH) and leptin secretion in eight male (age 29.3 +/- 1.2 yr, body mass index 22.2 +/- 0.5 kg/m(2)) and seven female normal subjects (28.0 +/- 0.8 yr, 20.1 +/- 0.7 kg/m(2)) before and after 36 h of fasting. In the fed state, 8-h mean GH and leptin concentrations were higher in females (P < 0.05 and P < 0. 0001, respectively). Fasting increased GH and decreased leptin in both sexes. There was significant interaction between gender and fasting (P < 0.05 for GH and P < 0.005 for leptin). Females showed a slighter increase in GH but a more marked decrease in leptin, so that there was no significant gender-related difference in GH and leptin after fasting. Fasting did not modify insulin-like growth factor (IGF) I, IGF binding protein (IGFBP)-3, acid-labile subunit, or GH binding protein; increased IGFBP-1 and free fatty acids (P < 0.0001) but decreased glucose (P < 0.001) and insulin levels (P < 0.05). In males, insulin levels were higher (P < 0.05) in the fed state and underwent deeper reduction after fasting (interaction P < 0.03). In conclusion, GH and leptin secretions are higher in women than in men in the fed but not in the fasting condition, which abolishes these gender-related differences in humans.

Adult↗

Arginine counteracts the inhibitory effect of recombinant human insulin-like growth factor I on the somatotroph responsiveness to growth hormone-releasing hormone in humans.

Insulin-like growth factor I (IGF-I) exerts a negative feedback effect on GH secretion via either direct actions at the pituitary level or indirect ones at the hypothalamic level, through stimulation of somatostatin (SS) and/or inhibition of GHRH release. In fact, recombinant human IGF-I (rhIGF-I) in humans inhibits spontaneous GH secretion as well as the GH response to GHRH and even more to GH/GH-releasing peptides, whose main action is on the hypothalamus, antagonizing SS and enhancing GHRH activity. The aim of the present study was to further clarify in humans the mechanisms underlying IGF-I-induced inhibition of somatotroph secretion. In six normal young volunteers (all women; mean +/- SEM: age, 28.3+/-1.2 yr; body mass index, 21.3+/-1.2 kg/m2) we studied the GH response to GHRH (1 microg/kg, iv, at 0 min), both alone and combined with arginine (ARG; 0.5 g/kg, iv, from 0-30 min), which probably acts via inhibition of hypothalamic SS release, after pretreatment with rhIGF-I (20 microg/kg, sc, at -180 min) or placebo. rhIGF-I increased circulating IGF-I levels (peak at -60 vs. -180 min: 54.9+/-3.9 vs. 35.9+/-3.3 mmol/L; P < 0.05) to a reproducible extent, and these levels remained stable and within the normal range until 90 min. The mean GH concentration over 3 h (from -180 to 0 min) before ARG and/or GHRH was not modified by placebo or rhIGF-I. After placebo, the GH response to GHRH (peak, 23.6+/-2.9 microg/L) was strikingly enhanced (P < 0.05) by ARG coadministration (69.6+/-9.9 microg/L). rhIGF-I blunted the GH response to GHRH (13.1+/-4.5 microg/L; P < 0.05), whereas that to GHRH plus ARG was not modified (59.5+/-8.9 microg/L), although it occurred with some delay. Mean glucose and insulin concentrations were not modified by either placebo or rhIGF-I. In conclusion, ARG counteracts the inhibitory effect of rhIGF-I on somatotroph responsiveness to GHRH in humans. These findings suggest that the acute inhibitory effect of rhIGF-I on the GH response to GHRH takes place on the hypothalamus, possibly via enhancement of SS release, and that ARG overrides this action.

Adult↗

Comparisons among old and new provocative tests of GH secretion in 178 normal adults.

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.

Adult↗

Assessment of GH/IGF-I axis in obesity by evaluation of IGF-I levels and the GH response to GHRH+arginine test.

The GH response to provocative stimuli in obese is often as low as in panhypopituitaric patients with severe GHD; however, IGF-I levels are normal or slightly reduced. In 53 patients with simple obesity (11 M and 42 F, age: 40.3+/-1.6 yr, BMI: 39.1+/-1.0 Kg/m2), we evaluated the GH response to GHRH (1 microg/kg iv)+arginine (ARG, 0.5 g/kg iv), and total IGF-I levels. The mean (+/-SE) GH peak after GHRH+ARG was markedly lower (74% reduction, p<0.0001) in obese (16.8+/-2.0 microg/l) than in normal subjects (62.7+/-4.3 microg/l). IGF-I levels in obese patients (134.0+/-7.6 microg/l) were lower (33% reduction, p<0.001) than in normal subjects (200.8+/-5.7 microg/l). Taking into account the 3rd centile limit of normal response, the GH response to GHRH+ARG was reduced in 62.3% (33/53) of the obese patients, and 21.2% (7/33) of them had low IGF-I levels. Assuming the 1st centile limit, it was reduced in 33.9% (18/53) obese subjects, and 22% (4/18) of them had low IGF-I levels. Considering 3.0 microg/L as arbitrary cut-off, the GH response was reduced in 5.7% (3/53) of the obese patients, and still one of them had low IGF-I levels. Our findings: a) confirm that the secretory capacity of somatotroph cells is often deeply impaired in obesity; b) demonstrate that IGF-I assay generally rules out severe impairment of GH/IGF-I axis in obese patients with marked reduction of the GH secretion; c) indicate that the percentage of obese patients with concomitant reduction of GH secretion and IGF-I levels is not negligible. Thus, IGF-I assay should be routinely performed in obese patients; those presenting with low IGF-I levels should undergo further evaluation of their hypothalamo-pituitary function and morphology, particularly in the presence of empty sella.

Adult↗

Three-month treatment with metformin or dexfenfluramine does not modify the effects of diet on anthropometric and endocrine-metabolic parameters in abdominal obesity.

Abdominal obesity is connoted by hyperinsulinism and insulin insensitivity, a trend toward glucose intolerance, hypoactivity of GH/IGF-I axis and alterations of hypothalamo-pituitary-adrenal (HPA) axis. It has been hypothesized that treatment with metformin (MET) and dexfenfluramine (DEX) could counteract those endocrine-metabolic alterations. Thus, we studied the effects of 3-month treatment with MET or DEX on anthropometric (BMI, WHR, FM and FFM), metabolic (basal and OGTT-induced glucose) and hormonal variables (IGF-I, DHEA-S, androstendione, testosterone, fT3, fT4, TSH, basal and OGTT-induced insulin) as well as on blood pressure in 28 normotensive patients with abdominal obesity (OB, 3 M, 25 F; 47.5+/-1.5 yr [mean+/-SE], BMI 35.4+/-1.1 kg/m2, WHR 0.98+/-0.04 and 0.86+/-0.07, in M and F, respectively). All patients were on balanced hypocaloric diet (1400 Kcal/day). Patients were randomly assigned to treatment with MET (no.=10, 500 mg twice daily po) or DEX (no.=10, 15 mg thrice daily po) or placebo (no.=8). Before treatment all groups had similar anthropometric, metabolic and hormonal values. After 3-month treatment with MET, DEX or placebo, weight, BMI and WHR reductions were similar in all groups (p<0.05 vs baseline in either group). In each group FFM/FM ratio showed non significant trend toward increase. No significant variations in metabolic and endocrine variables were recorded in each group after 1 and 3-month treatment. However, glucose tolerance, OGTT-induced insulin response, glucose/insulin ratio showed a similar trend toward improvement in all groups, while IGF-I, 24 h urinary cortisol, DHEA-S, androstendione, testosterone, thyroid hormone and TSH levels did not show any variation. Significant (p<0.02) and similar reductions of DBP, but not of SBP, levels were found in all groups. In conclusion, our findings demonstrate that, at least after 3-month treatment, metformin and dexfenfluramine do not modify the effects of diet on anthropometric, metabolic and hormonal parameters as well as on blood pressure in patients with abdominal obesity.

Abdomen↗