OBJECTIVE: To compare insulin-like growth factor-I (IGF-I) concentrations in obese and normal subjects, and evaluate the possible relationships between IGF-I concentrations and demographic, anthropometric, metabolic and hormonal variables in obese patients. SUBJECTS AND METHODS: 286 obese outpatients (OB, 234 female and 52 male; age 18 ± 71 y, body mass index (BMI) b 27 kgam 2 ) were recruited. MEASUREMENTS: BMI, waist-to-hip ratio (WHR), serum basal and oral glucose tolerance test (OGTT)-stimulated glucose and insulin concentrations, IGF-I, basal growth hormone (GH), prolactin (PRL), androgens, thyrotropin (TSH), free triiodothyronine (fT 3 ), free thyroxine (fT 4 ), free fatty acids (FFA), triglycerides, total and high density lipoprotein (HDL)-cholesterol, 24h-urinary cortisol levels and blood pressure (BP) values were measured. IGF-I concentrations were also evaluated in a large population of 326 age-matched controls (controls, 228 women, 98 men; age 20 ± 86 y, BMI`25 kgam 2 ). RESULTS: IGF-I concentrations were lower in OB than in controls (age-adjusted mean: 21.6 vs 23.6 nmolaL, P`0.03). However, individual IGF-I concentrations in OB were within the age-adjusted normal range. In both groups, IGF-I concentrations were gender-independent, and showed a simple negative correlation with age (r À0.47). In OB, univariate analysis also shows that IGF-I concentrations were negatively correlated with BMI (r À0.33), but not WHR, with both basal (r À0.16) and OGTT-stimulated glucose levels (r À0.17), as well as FFA levels (r À0.19), and with both diastolic and systolic BP (both r À0.17). In OB women, IGF-I concentrations positively correlated with PRL (r 0.31), testosterone (r 0.30), androstenedione (r 0.30), and dehydroepiandrosterone-sulfate (DHEAS) concentrations (r 0.41). No correlation was found with other variables. The multiple regression analysis showed that IGF-I concentrations were inversely and independently related to age and BMI only. CONCLUSIONS: In obesity, IGF-I concentrations are slightly reduced, but generally within the age-adjusted normal range. IGF-I concentrations in obesity show independent and negative relationships with age and BMI, but are not associated with fat distribution, insulin secretion, glucose tolerance, BP or risk indices for cardiovascular disease (CVD).

Free fatty acid (FFA) administration stimulates the hypothalamic-pituitary-adrenal (HPA) axis in rats, suggesting that the HPA axis and lipolysis may be linked by a positive-feedback loop. To clarify the influence of FFA on the HPA axis in humans, we studied the effect of lipid load on both basal and stimulated ACTH and cortisol secretion in normal subjects. In six young female volunteers [(mean +/- SEM) age, 24.4 +/- 2.1 yr; body mass index, 23.1 +/- 1.2 kg/m(2)), ACTH, cortisol, FFA, glucose, and insulin levels were measured every 30 min for 330 min during the following procedures: 1) i.v. saline infusion (from 0 to 330 min); 2) i.v. FFA infusion (Intralipid 10%, from 0 to 210 min) followed by saline infusion (from 210 to 330 min); 3) human CRH (hCRH) administration (2 microg/kg i.v. at 90 min) during saline infusion (from 0 to 330 min); and 4) hCRH administration during FFA infusion (Intralipid 10%, from 0 to 210 min, followed by saline infusion from 210 to 330 min). During saline infusion, ACTH and cortisol levels progressively declined. Lipid-heparin emulsion (LHE) infusion strikingly increased circulating FFA levels and, simultaneously, amplified the ACTH and cortisol decrease (P < 0.05). After LHE withdrawal, FFA decrease was associated with an increase (P < 0.05) in ACTH and cortisol levels (restored to baseline values within 60 min). The ACTH and cortisol responses to hCRH, however, were unaffected by LHE that, concomitantly, induced an increase (P < 0.05) in glucose but not in insulin levels. This study shows that an LHE-induced increase in FFA levels has an inhibitory effect on spontaneous ACTH and cortisol secretion in humans. Lipid load, however, does not affect the ACTH and cortisol responses to hCRH; this evidence would indicate that the negative influence of FFA on the HPA axis in humans takes place at the suprapituitary level.

Patients with anorexia nervosa (AN) may develop multiple endocrine abnormalities, including amenorrhea, hyperactivity of the hypothalamus-pituitary-adrenal axis, hypothyroidism and particular changes in the activity of the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis. Exaggerated GH secretion and reduced IGF-I levels are usually found in AN, as well as in conditions of malnutrition and malabsorption, insulin-dependent diabetes mellitus, liver cirrhosis and catabolic states. In AN, GH hypersecretion at least partially reflects malnutrition-induced peripheral GH resistance, which leads to reduced IGF-I synthesis and release; this implies an impairment of the negative IGF-I feedback action on GH secretion. On the other hand, primary alterations in the neural control of GH secretion cannot be ruled out. The neuroendocrine alterations include enhanced somatotroph responsiveness to growth hormone releasing hormone (GHRH) and impaired GH response to most central nervous system-mediated stimuli. Particular resistance to cholinergic manipulation has also been demonstrated, thus suggesting a somewhat specific alteration in the somatostatin (SS)-mediated cholinergic influence on GH secretion. Moreover, paradoxical GH responses to glucose load, thyrotropin releasing hormone (TRH) and luteinizing hormone releasing hormone (LHRH) have also been reported. The effect of reduced leptin levels on GH hypersecretion in AN is still unclear, but ghrelin (the gastric hormone that is a natural ligand of the GH secretagogue receptor and strongly stimulates somatotroph secretion) is thought to play a major role. Regardless of the supposed central and peripheral alterations, it has to be emphasised that the activity of the GH/IGF-I axis in AN is generally restored by nutritional and stable weight gain. It therefore reflects an impaired nutritional state and cannot be considered a primary hallmark of the disease.

Hexarelin (HEX) is a synthetic GHRP which acts on specific receptors at both the pituitary and the hypothalamic level to stimulate GH release both in animals and in humans. Like other GHRPs, HEX possesses also acute ACTH and cortisol-releasing activity similar to that of hCRH. The mechanisms underlying the stimulatory effect of GHRPs on hypothalamo-pituitary-adrenal (HPA) axis are still unclear, although a CNS-mediated action has been demonstrated. In 6 normal healthy young women (26–34 years) we studied the effects on ACTH and cortisol secretion of HEX (2.0 µg/kg i.v. at 0 min) alone and preceded by dexamethasone (DEXA, 1 mg p.o. at 23.00 h on the previous night) or alprazolam (ALP, 0.02 mg/kg p.o. at –90 min), a benzodiazepine which binds to GABA receptors and possesses CRH-mediated inhibitory activity on HPA axis. ACTH and cortisol secretion after saline administration as well as the GH response to HEX alone and preceded by DEXA or ALP were also studied. HEX administration elicited an increase in ACTH (peak vs. baseline, mean ± SEM: 28.0 ± 6.7 vs. 11.7 ± 2.2 pg/ml, p < 0.05) and cortisol secretion (162.6 ± 15.0 vs. 137.7 ± 12.6 µg/l, p < 0.05). DEXA pretreatment strongly inhibited basal ACTH (3.2 ± 0.7 pg/ml, p < 0.01) and cortisol levels (11.3 ± 2.5 µg/l, p < 0.001) and abolished the ACTH and cortisol responses to HEX (3.6 ± 0.9 pg/ml, p < 0.01 and 10.7 ± 2.0 µg/l, p < 0.001), respectively. On the other hand, ALP pretreatment did not significantly modify basal ACTH (7.9 ± 2.0 pg/ml) and cortisol levels (127.6 ± 14.5 µg/l) but abolished the HEX-induced ACTH and cortisol secretions (8.6 ± 2.4 pg/ml, p < 0.05 and 111.0 ± 6.0 µg/l, p < 0.05), respectively. ACTH and cortisol levels after HEX when preceded by ALP overlapped with those recorded during saline. HEX induced a clear GH response (peak at 15 min vs. baseline: 65.5 ± 20.5 vs. 2.2 ± 0.7 µg/l, p < 0.03) which was blunted by ALP (peak at 15 min: 21.5 ± 5.5 µg/l, p < 0.05) while it was not modified by DEXA pretreatment (78.7 ± 7.6 µg/l). In conclusion, our present data demonstrate that the ACTH- and cortisol-releasing effect of HEX is abolished by either dexamethasone or alprazolam, a benzodiazepine, which is even able to blunt the GH-releasing activity of the hexapeptide. These findings suggest that, in physiological conditions, the stimulatory effect of GHRPs on HPA axis is sensitive to the negative glucocorticoid feedback and could be mediated by GABAergic mechanisms; the latter seem also involved in the GH-releasing activity of GHRPs.

The present results show that dehydroepiandrosterone-sulphate levels are not reduced in obesity, being slightly increased, particularly in young adulthood. Dehydroepiandrosterone-sulphate levels are positively and independently associated with androgen, 24-h urinary cortisol and IGF-I levels but do not seem associated with insulin levels or cardiovascular risk indices.