The IGF-I response to very low rhGH doses is preserved in human aging.
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Adult↗
Biomedical subjects
L Gianotti
Publications and source records attributed to L Gianotti.
IGF-1 levels in different conditions of low somatotrope secretion in adulthood: obesity in comparison with GH deficiency.
BACKGROUND: It is widely accepted that IGF-I synthesis and release depend on GH secretion as well as on the nutritional status and vary with age. Based on these premises, after the definition of normal IGF-I levels during lifespan, in a large population of normal subjects of both sexes, our aim was to verify IGF-I levels in large groups of adult patients with GH deficiency or obesity, a condition in which a reduced somatotrope secretion is well known. METHODS: To this goal, IGF-I levels were assayed after acid-ethanol extraction, in 326 normal subjects (NS, 98 men and 228 women, age 20-80 yrs, BMI 17.9-26.1 kg/m2), 54 patients with GH deficiency (GHD, 24 men and 30 women, age 20-80 yrs, BMI 18.2-27.1 kg/m2), and 195 patients with obesity (OB, 33 men and 162 women, age 17-71 yrs, BMI 27.7-64.9 kg/m2). In NS, IGF-I levels were similar in both sexes and showed a progressive decrease with age. No correlation was present between IGF-I and BMI in NS. Median IGF-I levels and the 3rd centile in NS when considered per decade were: III) 230 and 108.6; IV) 220 and 129.8; V) 150.5 and 72.4; VI) 163.0 and 62.4; VII) 110 and 41.6; VIII) 82 and 24.7 micrograms/l. In GHD, IGF-I levels were independent on sex and did not show reduction during lifespan. Mean IGF-I levels in GHD were lower than that in NS (64.5 +/- 5.9 vs 171.3 +/- 4.8 micrograms/l, p < 0.01) and did not correlate with age or BMI. Analyzing individual IGF-I levels, in GHD, in the III and IV decade 21/24 patients had IGF-I levels lower than 3rd centile while, up to the VIII decade, only 10/30 had IGF-I levels below normal limits. In OB, IGF-I levels were independent on sex but, like in NS, showed a progressive decrease with age and were independently, negatively correlated with BMI but not with WHR. Analyzing individual IGF-I levels, in OB, IGF-I levels were below 3rd centile in 10/77 patients in the III and IV decade and in only 8/108 patients up to the VIII decade. Mean IGF-I levels in the whole OB population (179.6 +/- 5.9 micrograms/l) were higher (p < 0.01) than those in GHD (64.5 +/- 5.9 micrograms/l) while only in the IV decade IGF-I levels in OB group were lower (p < 0.02) than those in NS (184.7 +/- 12.6 micrograms/l vs 224.0 +/- 9.2 micrograms/l). CONCLUSIONS: In conclusion, present data confirm that IGF-I levels depends on GH secretion as well as on nutritional status, being negatively and independently correlated with age and BMI. IGF-I assay is not a reliable test for the diagnosis of GH deficiency in adulthood though it gives good discrimination between GHD and normal subjects up to 40 yrs of age. In spite of low GH secretion, IGF-I levels are only slightly reduced in obesity, probably as consequence of hyperinsulinism.
Adult↗
Erythropoiesis after therapy with recombinant human erythropoietin: a dose-response study in anemic cancer surgery patients.
BACKGROUND AND OBJECTIVES: Preoperative treatment with 600 U/kg of recombinant human erythropoietin (r-HuEPO) effectively increases erythropoiesis in cancer patients. The aim of this study was to evaluate the erythropoietic response after different doses of r-HuEPO in order to find the minimum effective dose. MATERIALS AND METHODS: Twenty anemic sideropenic patients (hemoglobin </=110 g/l; serum iron <600 microg/l) with cancer of the gastrointestinal tract were randomly allocated to two groups: the first (n = 10) received 400 U/kg of r-Hu EPO divided in 4 doses (100 U/kg each, every 4 days); the second (n = 10) received 200 U/kg of r-HuEPO (50 U/kg each, every 4 days). Both groups were given intravenous iron gluconate (125 mg) every day for 15 days. RESULTS: After treatment, the serum iron level significantly rose in both groups. The production of new red blood cells was 176.3+/-90.8 ml in the 200 U/kg group and 268.4+/-79.4 ml in the 400 U/kg group (p = 0.036). The increase of hemoglobin was significantly higher in the 400 U/kg group (22.3+/-2.0 g/l) than in the 200 U/kg group (14.1+/-2.7 g/l) (p = 0.017). CONCLUSION: The r-HuEPO dose of 400 U/kg appears significantly more effective than the 200 U/kg to stimulate erythropoiesis in anemic sideropenic cancer patients.
Adenocarcinoma↗
Effects of beta-adrenergic agonists and antagonists on the growth hormone response to growth hormone-releasing hormone in anorexia nervosa.
BACKGROUND: In anorexia nervosa (AN), growth hormone (GH) hypersecretion and low insulin-like growth factor I (IGF-I) levels are present. It is unclear whether this is due to a peripheral GH resistance and a reduced IGF-I negative feedback on GH secretion or to a primary hypothalamic dysfunction. In AN, in contrast to normal subjects, cholinergic antagonists and agonists, whose action is somatostatin (SS)-mediated, have reduced and absent effects on the GH response to growth hormone-releasing hormone (GHRH). Since arginine, another substance acting via inhibition of SS, maintains its potentiating effect on GH secretion in AN, it has been hypothesized that somewhat specific alteration of the SS-mediated cholinergic influence may be present in this condition. To further clarify the neural control of AH secretion in AN, we evaluated the effects of beta-adrenergic agonists and antagonists, which are known to inhibit and increase, respectively, the GHRH-induced GH secretion in normal subjects. METHODS: We studied the effect of atenolol (ATE), a beta 1-adrenergic antagonist, and salbutamol (SALB), a beta 2-adrenergic agonist, on the GHRH-induced GH release in 10 patients with AN and in 10 normal age-matched women (NW). RESULTS: Basal GH levels were higher, whereas IGF-I were lower in AN than in NW. The GHRH-induced GH rise in AN was higher than that in NW. ATE significantly enhanced the GH response to GHRH in NW, but not in AN. The GH responses to GHRH after ATE pretreatment were similar in NW and in AN. The GH response to GHRH was inhibited by SALB in both NW and AN. The GH responses to GHRH after SALB pretreatment were similar in NW and AN. CONCLUSIONS: These data reveal an exaggerated somatotrope responsiveness to GHRH in AN that is not further increased by beta-adrenergic blockade, while is abolished by beta-adrenergic activation. This suggests that an impairment of beta-adrenergic influence on GH secretion is present in anorexia nervosa.
Adolescent↗
The activity of GH/IGF-I axis in anorexia nervosa and in obesity: a comparison with normal subjects and patients with hypopituitarism or critical illness.
GH/IGF-I axis activity changes have been reported both in anorexia nervosa (AN) and in obesity (OB). AN is characterized by GH hypersecretion and very low IGF-I levels as a result of undernutrition and acquired peripheral GH resistance. On the other hand OB is a GH hyposecretory state but IGF-I levels are generally preserved. The activity of GH/IGF-I axis in AN and OB has never been directly compared with that of other pathophysiological conditions such as hypopituitarism and critical illness in which a reduction of both GH and IGF-I secretion has been demonstrated. To this aim, we evaluated IGF-I levels and both basal and GHRH (1 microgram/kg) IV-induced GH secretion in 20 female patients with anorexia nervosa (mean age: 19.1 +/- 0.8 years) and in 15 female and 5 male patients with simple obesity (mean age: 39.0 +/- 3.0 years). We then compared the results with those of hypopituitaric patients with severe GH deficiency (GHD), including 10 female and 10 patients (mean age: 32.0 +/- 2.1 years), and with 4 female and 7 male patients with critical illness (CRI) following multiple trauma 72 hours after ICU admission (mean age: 59.2 +/- 1.2 years). Twenty-six normal subjects (NS) including 14 female and 12 male patients (mean age: 37.8 +/- 3.7 years) were studied as controls. Basal IGF-I levels in AN patients (93.5 +/- 11 micrograms/L) were lower (p < 0.001) than in the NS (201.7 +/- 13.5 micrograms/L) and OB (194.5 +/- 28.6 micrograms/L), which, in turn, were similar. IGF-I levels in AN patients were lower than in CRI patients (162.8 +/- 17.4 micrograms/L) and higher than in GHD patients (76.7 +/- 13.5 micrograms/L) but these differences did not attain statistical significance. Basal GH levels in AN patients (7.6 +/- 2.5 micrograms/L) were higher (p < 0.001) than in NS (1.8 +/- 0.3 micrograms/L), OB patients (1.1 +/- 0.5 micrograms/L), CRI patients (1.8 +/- 0.5 micrograms/L) and GHD patients (0.3 +/- 0.1 microgram/L), which were the lowest (p < 0.01). The GHRH-induced GH rise in AN patients (AUC: 2032.9 +/- 253.5 micrograms/L/h) was three fold higher (p < 0.001) than in NS (662.1 +/- 80.3 micrograms/L). On the other hand in OB (332.4 +/- 74.7 micrograms/L/h) the GH response to GHRH was similar to that in CRI (199.6 +/- 98.8 micrograms/L/h); both were clearly higher (p < 0.01) than in GHD patients (25.1 +/- 5.2 micrograms/L/h) but lower (p < 0.01) than in NS. These findings demonstrate that in AN patients, in spite of a clear increase of both basal and GHRH-induced GH secretion, IGF-I synthesis and release are as markedly impaired as in patients with panhypopituitarism and severe GHD. On the other hand in OB and in CRI, IGF-I synthesis and release are preserved despite marked impairment to GHRH-induced GH secretion. These results reinforce the major role of nutrition in conditioning the activity of GH/IGF-I axis in different patho-physiological states.
Adolescent↗
Low IGF-I levels are often uncoupled with elevated GH levels in catabolic conditions.
Increased GH together with decreased IGF-I levels pointing to peripheral GH insensitivity in critically ill patients have been reported by some but not by other authors. To clarify whether elevated GH levels are coupled with low IGF-I levels in all catabolic conditions, basal GH and IGF-I levels were evaluated in patients with sepsis (SEP, no.=13; age [mean+/-SE]=59.2+/-1.2 yr), trauma (TRA, no.=16; age=42.3+/-3.4 yr), major burn (BUR, no.=26; age=52.8+/-4.2 yr) and post-surgical patients (SUR, no.=11; age=55.0+/-4.7 yr) 72 hours after ICU admission or after cardiac surgery. GH and IGF-I levels were also evaluated in normal subjects (NS, no.=75; age=44.0+/-1.5 yr), in adult hypopituitaric patients with severe GH deficiency (GHD, no.=54; age=44.8+/-2.3 yr), in patients with liver cirrhosis (LC, no.=12; age=50.4+/-2.8 yr) and in patients with anorexia nervosa (AN, no.=19; age=18.7+/-0.8 yr). Basal IGF-I and GH levels in GHD were lower than in NS (68.6+/-6.4 vs 200.9+/-8.7 microg/l and 0.3+/-0.1 vs 1.4+/-0.2 microg/l; p<0.01). On the other hand, AN and LC showed IGF-I levels (70.4+/-9.1 and 52.4+/-10.5 microg/l) similar to those in GHD while GH levels (10.0+/-2.8 and 7.9+/-2.1 microg/l) were higher than those in NS (p<0.01). IGF-I levels in SEP (84.5+/-8.8 microg/l) were similar to those in GHD, AN and LC and lower than those in NS (p<0.01). IGF-I levels in BUR (105.2+/-10.9 microg/l) were lower than in NS (p<0.01) but higher than those in GHD, AN, LC and SEP (p<0.01). On the other hand, in TRA (162.8+/-17.4 microg/l) and SUR (135.0+/-20.7 microg/l) IGF-I levels were lower but not significantly different from those in NS and clearly higher than those in GHD, AN, LC, SEP and BUR. Basal GH levels in SEP (0.6+/-0.2 microg/l), TRA (1.8+/-0.5 microg/l), SUR (2.2+/-0.5 microg/l) and BUR (2.2+/-0.5 microg/l) were similar to those in NS, higher (p<0.05) than those in GHD and lower (p<0.01) than those in AN and LC. In conclusion, our data demonstrate that low IGF-I levels are not always coupled with elevated GH levels in all catabolic conditions. Differently from cirrhotic and anorectic patients, in burned and septic patients GH levels are not elevated in spite of very low IGF-I levels similar to those in panhypopituitaric GHD patients. These findings suggest that in some catabolic conditions peripheral GH insensitivity and somatotrope insufficiency could be concomitantly present.
Adolescent↗
Age-related variations in the neuroendocrine control, more than impaired receptor sensitivity, cause the reduction in the GH-releasing activity of GHRPs in human aging.
The mechanisms underlying the reduction in the GH-releasing activity of GHRPs in aging are still unclear. Aim of our study was to verify in man whether age-related impairment of the neurohormonal control of GH secretion and/or receptor alterations are involved in the reduced GH response to GHRPs in aging. To this goal, in 16 normal elderly subjects (E, 66-81 yr) and 12 young controls (Y, 24-28 yr) we studied the effects of 1.0, 2.0 and 3.0 micrograms/kg i.v. Hexarelin (HEX), a synthetic hexapeptide, or GHRH, as well as the interaction among HEX (2.0 micrograms/kg), GHRH (2.0 micrograms/kg) and arginine (ARG, 0.5 gr/kg) on GH secretion. In Y the GH response to increasing doses of HEX (1.0 vs. 2.0 vs. 3.0 micrograms/kg; AUC0;v-120 +/- SEM: 1728.4 +/- 406.4 vs. 2265.9 +/- 298.4 vs. 2934.3 +/- 482.2 micrograms/L/h, p < 0.05 for 1.0 vs. 2.0 micrograms/kg) and GHRH (649.6 +/- 111.4 vs. 792.2 +/- 117.6 vs. 1402.6 +/- 363.0 micrograms/L/h) showed a progressive increase. Two micrograms/kg HEX and 1 microgram/kg GHRH were the maximal effective doses. Similarly, in E the GH response to increasing doses of HEX (336.7 +/- 50.0 vs. 742.8 +/- 157.9 vs. 1205.1 +/- 178.1 micrograms/L/h, p < 0.05 for 1.0 vs. 2 micrograms/kg, p < 0.001 for 1.0 vs. 3.0 micrograms/kg and p < 0.03 for 2.0 vs. 3.0 micrograms/kg) and GHRH (183.8 +/- 27.3 vs. 260.9 +/- 17.3 vs. 356.1 +/- 46.3 micrograms/L/h, p < 0.005 for 1.0 vs. 3.0 micrograms/kg and p < 0.05 for 2.0 vs. 3.0 micrograms/kg) showed a progressive increase. In E the GH response to 3 micrograms/kg HEX or GHRH were clearly higher than those to 2 micrograms/kg. However, at each dose the GH responses to HEX or GHRH in E were lower (p < 0.05) than those in Y. In Y the GH response to HEX + GHRH was synergistical (4259.2 +/- 308.0 micrograms/L/h, p < 0.05). ARG strikingly potentiated the GHRH-induced GH rise (2640.8 +/- 273.6 micrograms/L/h, p < 0.01) but not the HEX-induced one (2371.7 +/- 387.2 micrograms/L/h) as well as the synergistical effect of HEX and GHRH (4009.1 +/- 360.8 micrograms/L/h). In E the GH response to HEX and GHRH was still synergistical (1947.7 +/- 306.0 micrograms/L/h, p < 0.05) but these responses were lower than those in young (p < 0.01). On the other hand, in E ARG restored the GH response to GHRH (1858.9 +/- 172.8 micrograms/L/h, p < 0.01) and even those to HEX (2069.5 +/- 528.7 micrograms/L/h, p < 0.01) and HEX + GHRH (4406.0 +/- 1079.2 micrograms/L/h, p < 0.05). Our present results indicate that the impairment of GHRP and GHRH receptor activity may have a role in the reduction of the somatotrope responsiveness in aging. However, the age-related reduction in the GH-releasing activity of GHRPs seems mainly dependent on age-related variations in the neural control, i.e. concomitant GHRH hypoactivity and somatostatinergic hyperactivity.
Adult↗
The IGF-I response to very low rhGH doses is preserved in human ageing.
OBJECTIVES: The activity of the GH/IGF-I axis varies during life and is clearly reduced in the elderly. In fact, GH, IGF-I and IGFBP-3 levels in older people are clearly reduced and similar to those observed in patients with GH deficiency. The declining activity of the GH/IGF-I axis with advancing age may contribute to changes in body composition, structure, function and metabolism. In fact, treatment with pharmacological doses of rhGH restored plasma IGF-I levels, increased lean body mass and muscle strength while decreased adipose tissue mass in healthy elderly subjects. At present it is unclear whether peripheral GH sensitivity is preserved in aging. To clarify this point, we aimed to verify the effect of both single dose and short term treatment with very low rhGH doses on the IGF-I levels in normal elderly subjects. Normal young adults were studied as controls. DESIGN: We studied the IGF-I response to rhGH administration after single (20 micrograms/kg s.c.) or repeated administrations (5 micrograms/kg s.c. for 4 days) in two groups of young and elderly subjects. SUBJECTS: Twenty-seven healthy elderly (ES, 14 F and 13 M, age mean +/- SEM: 69.4 +/- 1.3 years, BMI: 23.9 +/- 0.5 kg/m2) and 21 young adult subjects (YS, 12 F and 9 M, 29.8 +/- 1.2 years, 23.8 +/- 0.5 kg/m2) were studied, divided into two groups. MEASUREMENTS: Group 1: blood samples for IGF-I and IGFBP-3 assay were drawn basally and 12 h after rhGH administration (20 micrograms/kg). Group 2: blood samples for IGF-I, IGFBP-3, glucose and insulin assays were drawn basally, 12 h after the first and the last rhGH administration (5 micrograms/kg). Free T3 (fT3), free T4 (fT4) and TSH levels were also assayed basally and after the last rhGH administration; oestradiol and testosterone levels were measured basally. RESULTS: Basal IGF-I levels were lower in ES (whole group) than in YS (whole group) (123.1 +/- 8.9 vs. 230.4 +/- 16.1 micrograms/l, P < 0.001) while IGFBP-3 levels in the two groups were similar (2.7 +/- 0.2 vs. 3.1 +/- 0.2 mg/l). No sex-related differences in IGF-I and IGFBP-3 levels were recorded in either group. Group 1: the single administration of 20 micrograms/kg rhGH induced a significant (P < 0.001) IGF-I rise both in YS (318.0 +/- 25.3 vs. 256.0 +/- 21.6 micrograms/l) and ES (187.2 +/- 16.8 vs. 100.4 +/- 9.5 micrograms/l). IGF-I levels after rhGH in ES persisted lower than those in YS (P < 0.001), but the percentage IGF-I increase after rhGH was higher (P < 0.001) in ES (91.6 +/- 12.9%) than in YS (23.9 +/- 5.0%) subjects. Both in YS and ES IGFBP-3 levels were significantly increased to the same extent by 20 micrograms/kg rhGH (3.0 +/- 0.2 vs. 2.3 +/- 0.2 mg/l; 2.9 +/- 0.2 vs. 2.6 +/- 0.2 mg/l, P < 0.001 vs. baseline). Group 2: basal glucose, insulin, fT3, fT4 and TSH levels in YS and ES were similar; testosterone levels in aged and young men were similar while oestradiol levels in aged women were lower (P < 0.01) than in the young ones. IGF-I levels were significantly increased 12 h after the first administration of 5 micrograms/kg rhGH both in ES (166.6 +/- 15.7 vs. 138.3 +/- 12.1 micrograms/l, P < 0.03) and YS (272.2 +/- 16.1 vs. 230.4 +/- 16.1 micrograms/l, P < 0.001). Twelve hours after the last rhGH administration IGF-I levels were further increased (P < 0.001) both in ES (208.7 +/- 21.1 micrograms/l) and YS (301.7 +/- 17.6 micrograms/l). IGF-I levels in ES persisted lower than those in YS at each time point (P < 0.001); however, the percentage IGF-I increase after rhGH in ES and YS was similar (after the first administration: 22.4 +/- 5.1 vs. 21.7 +/- 5.1%; after the last administration: 52.9 +/- 9.5 vs. 39.5 +/- 9.9%). No significant variation in IGFBP-3, glucose, insulin, fT3, fT4 or TSH levels was recorded in either ES or YS. CONCLUSIONS: Our data demonstrate that IGF-I levels in aging are reduced but the peripheral sensitivity to rhGH is preserved. In fact, in aged subjects the percentage rhGH-induced IGF-I increase is similar or even highe
Adult↗
Artificial nutrition after major abdominal surgery: impact of route of administration and composition of the diet.
OBJECTIVE: To evaluate the impact of the route of administration of artificial nutrition and the composition of the diet on outcome. DESIGN: Prospective, randomized, clinical trial. SETTING: Department of surgery, university hospital. PATIENTS: One hundred sixty-six consecutive patients undergoing curative surgery for gastric or pancreatic cancer. INTERVENTIONS: At operation, the patients were randomized into three groups to receive: a) a standard enteral formula (control group; n = 55); b) the same enteral formula enriched with arginine, RNA, and omega-3 fatty acids (enriched group; n = 55); and c) total parenteral nutrition (TPN group; n = 56). The three regimens were isocaloric and isonitrogenous. Enteral nutrition was started within 12 hrs following surgery. The infusion rate was progressively increased to reach the nutritional goal (25 kcal/kg/day) on postoperative day 4. MEASUREMENTS AND MAIN RESULTS: Tolerance of enteral feeding, rate and severity of postoperative complications, and length of hospital stay were recorded. Early enteral infusion was well tolerated. Side effects were recorded in 22.7% of the patients, but only 6.3% did not reach the nutritional goal. The enriched group had a lower severity of infection than the parenteral group (4.0 vs. 8.6; p < .05). In subgroups of malnourished (n = 78) and homologous transfused patients (n = 42), the administration of the enriched formula significantly reduced both severity of infection and length of stay compared with the parenteral group (p < .05). Moreover, in transfused patients, the rate of septic complications was 20.0% in the enriched group, 38.4% in the control group, and 42.8% in the TPN group. CONCLUSIONS: Early enteral feeding is a suitable alternative to TPN after major abdominal surgery. The use of the enriched diet appears to be more beneficial in malnourished and transfused patients.
Adult↗
Effects of dexamethasone and alprazolam, a benzodiazepine, on the stimulatory effect of hexarelin, a synthetic GHRP, on ACTH, cortisol and GH secretion in humans.
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 microg/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 microg/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 microg/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 microg/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 microg/l) but abolished the HEX-induced ACTH and cortisol secretions (8.6 +/- 2.4 pg/ml, p < 0.05 and 111.0 +/- 6.0 microg/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 microg/l, p < 0.03) which was blunted by ALP (peak at 15 min: 21.5 +/- 5.5 microg/l, p < 0.05) while it was not modified by DEXA pretreatment (78.7 +/- 7.6 microg/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.
Adrenocorticotropic Hormone↗
IGF-I levels in different conditions of low somatotrope secretion in adulthood: obesity in comparison with GH deficiency.
BACKGROUND: It is widely accepted that IGF-I synthesis and release depend on GH secretion as well as on the nutritional status and vary with age. Based on these premises, after the definition of normal IGF-I levels during lifespan, in a large population of normal subjects of both sexes, our aim was to verify IGF-I levels in large groups of adult patients with GH deficiency or obesity, a condition in which a reduced somatotrope secretion is well known. METHODS: To this goal, IGF-I levels were assayed after acidethanol extraction, in 326 normal subjects (NS, 98 men and 228 women, age 20-80 yrs, BMI 17.9-26.1 kg/m2), 54 patients with GH deficiency (GHD), 24 men and 30 women, age 20-80 yrs, BMI 18.2-27.1 kg/m2), and 195 patients with obesity (OB, 33 men and 162 women, age 17-71 yrs, BMI 27.7-64.9 kg/m2). In NS, IGF-I levels were similar in both sexes and showed a progressive decrease with age. No correlation was present between IGF-I and BMI in NS. Median IGF-I levels and the 3rd centile in NS when considered per decade were: III) 230 and 108.6; IV) 220 and 129.8; V) 150.5 and 72.4; VI) 163.0 and 62.4; VII) 110 and 41.6; VIII) 82 and 24.7 microgram/l. In GHD, IGF-I levels were independent on sex and did not show reduction during lifespan. Mean IGF-I levels in GHD were lower than that in NS (64 +/- 5.9 vs 171.3 +/- 4.8 microgram/l, p < 0.01) and did not correlate with age or BMI. Analyzing individual IGF-I levels, in GHD, in the III and IV decade 21/24 patients had IGF-I levels lower than 3rd centile while, up to the VIII decade, only 10/30 had IGF-I levels below normal limits. In OB, IGF-I levels were independent on sex but, like in NS, showed a progressive decrease with age and were independently, negatively correlated with BMI but not with WHR. Analyzing individual IGF-I levels, in OB, IGF-I levels were below 3rd centile in 10/77 patients in the III and IV decade and in only 8/108 patients up to the VIII decade. Mean IGF-I levels in the whole OB population (179.6 +/- 5.9 microgram/l) were higher (p < 0.01) than those in GHD (64.5 +/- 5.9 microgram/l) while only in the IV decade IGF-I levels in OB group were lower (p < 0.02) than those in NS (184.7 +/- 12.6 microgram/l vs 224.0 +/- 9.2 microgram/l). CONCLUSIONS: In conclusion, present data confirm that IGF-I levels depends on GH secretion as well as on nutritional status, being negatively and independently correlated with age and BMI. IGF-I assay is not a reliable test for the diagnosis of GH deficiency in adulthood though it gives good discrimination between GHD and normal subjects up to 40 yrs of age. In spite of low GH secretion, IGF-I levels are only slightly reduced in obesity, probably as consequence of hyperinsulinism.
Adolescent↗
Effect of route of delivery and formulation of postoperative nutritional support in patients undergoing major operations for malignant neoplasms.
OBJECTIVE: To study the effect of the route of delivery and formulation of postoperative nutritional support on host defense, protein metabolism, infectious complications, and outcome. DESIGN: Prospective, randomized, clinical trial. SETTING: Department of Surgery at a university hospital. PATIENTS: Two hundred sixty candidates for pancreaticoduodenectomy or gastrectomy for cancer. INTERVENTIONS: Patients were randomly allocated into 3 groups during surgery. Starting 6 hours after operation, the first group received a standard enteral formula (standard group; n = 87); the second, the same enteral formula enriched with arginine, omega-3 fatty acids, and RNA (immunonutrition group; n = 87); and the third, total parenteral nutrition (parenteral group; n = 86). The 3 regimens were isocaloric and isonitrogenous. The nutritional goal was 105 kJ/kg per day. MAIN OUTCOME MEASURES: Immune response by phagocytosis ability of polymorphonuclear cells, interleukin (IL)-2 receptor levels, and delayed hypersensitivity response; protein synthesis by IL-6 and prealbumin; tolerance of enteral feeding; incidence of postoperative complications; and length of hospital stay. RESULTS: The immunonutrition group had a significantly better recovery of the immune parameters on postoperative day 8 compared with the other groups. Linear regression analysis showed an inverse correlation between IL-6 and preambulin levels (r = 0.766) only in the immunonutrition group. Only 11 patients (6.3%) in both enteral groups did not reach the nutritional goal. Postoperative infection rate was 14.9% (13/87) in the immunonutrition group, 22.9% (20/87) in the standard group, and 27.9% (24/86) in the parenteral group (P = .06). Mean +/- SD length of hospital stay was 16.1 +/- 6.2, 19.2 +/- 7.9, and 21.6 +/- 8.9 days in the immunonutrition, standard, and parenteral groups, respectively (P = .01 vs standard group; P = .004 vs parenteral group). CONCLUSIONS: Early postoperative enteral feeding is a valid alternative to parenteral feeding in patients undergoing major surgery. Immunonutrition enhances the host response, induces a switch from acute-phase to constitutive proteins, and improves outcome.
Aged↗
Radical oncologic surgery affects the circulatory levels of interleukin 10.
BACKGROUND AND OBJECTIVE: Interleukin 10 (IL-10) has been shown to be elevated in the plasma of cancer-bearing patients. The source of systemic IL-10 may be the tumor microenvironment. We therefore tried to evaluate if ablative surgery for gastrointestinal cancer could affect the levels of circulating IL-10. METHODS: Plasma IL-10 concentration was measured in 45 patients with adenocarcinoma of the gastrointestinal tract. Forty healthy subjects, 15 women undergoing hysterectomy for uterine fibroma, and 15 patients undergoing palliative operation for pancreatic cancer were used as control groups. Plasma IL-10 was assessed 1 day before surgery (baseline) and 1, 4, and 8 days after operation. RESULTS: The baseline concentration of IL-10 was significantly higher in cancer patients than in healthy subjects and in women with fibroma (8.6 ng/mL, 2.1 and 1.8 respectively; P = 0.015). After radical surgery, the IL-10 levels significantly dropped in cancer patients (from 8.6 ng/mL to 3.8; P = 0.024), whereas in subjects undergoing palliative operation, the concentration remained elevated (8.5 ng/mL baseline versus 7.9 on day + 1). CONCLUSIONS: The origin of circulating IL-10 may be the tumor microenvironment.
Adenocarcinoma↗
Effects of histaminergic antagonists on the GH-releasing activity of GHRH or hexarelin, a synthetic hexapeptide, in man.
The role of histamine in the neural control of GH secretion in man is still unclear, although a stimulatory influence has been hypothesized in man. To clarify this point, in 7 normal young women (23-28 yr) in their early follicular phase, we studied the effect of the histaminergic blockade by diphenhydramine (DPH, 80 mg os at -60 min) on the GH response to GHRH (2 micrograms/Hg iv) or Hexarelin (HEX, 2 micrograms/kg iv), a synthetic hexapeptide with strong GH-releasing effect. In 6 of the 7 women the effect of terfenadine (TRF, 120 mg os at -60 min), another H1-receptor antagonist, on the GH response to GHRH or HEX was also studied. As HEX has also PRL- and ACTH-releasing activity and histamine has been shown to have a stimulatory role in the neural control of these hormones, the effects of DPH or TRF on the HEX-induced PRL. ACTH and cortisol release were also studied. GHRH induced a GH rise (peak, mean +/- SEM: 35.4 +/- 6.5 vs 2.5 +/- 1.1 micrograms/l, p < 0.02, n = 7; 34.7 +/- 7.9 vs 3.9 +/- 1.5 micrograms/l, p < 0.02, n = 6) lower (p < 0.05) than that elicited by HEX (49.1 +/- 8.5 vs 3.9 +/- 1.0 micrograms/l, p < 0.01, n = 7; 48.7 +/- 8.9 vs 3.2 +/- 0.8 micrograms/l, p < 0.01, n = 6). DPH inhibited the GH response to both GHRH (AUC: 453.9 +/- 104.7 vs 1223.7 +/- 202.6 micrograms*min/l, p < 0.05) and HEX (922.0 +/- 215.4 vs 1636.4 +/- 267.5 micrograms*min/l, p < 0.05), although the HEX-induced GH rise persisted higher than that induced by GHRH (p < 0.05). TRF did not modify the GHRH-induced GH rise (950.5 +/- 369.2 mg*min/l vs 1115.3 +/- 255.6 micrograms*min/l) as well as the somatotrope responsiveness to HEX (1163.2 +/- 188.7 vs 1427.3 +/- 323.3 mg*min/l). HEX also significantly increased PRL (13.9 +/- 3.1 vs 6.5 +/- 0.8 micrograms/l, p < 0.03), ACTH (31.1 +/- 6.6 vs 16.6 +/- 2.9 pg/ml, p < 0.02) and cortisol (96.6 +/- 6.3 vs 82.2 +/- 6.2 micrograms/L, p < 0.05) levels. PRL, ACTH and cortisol responses to HEX were unaffected by DPH (536.5 +/- 85.6 vs 599.5 +/- 129.2 micrograms*min/l, 1068.5 +/- 306.0 vs 1282.8 +/- 222.0 pg*min/ml and 4277.4 +/- 588.4 vs 4738.3 +/- 355.3 micrograms*min/l, respectively) as well as by TRF (621.3 +/- 110.4 vs 530.3 +/- 131.4 micrograms*min/L, 972.4 +/- 189.6 vs 1060.2 +/- 224.7 pg*min/ml and 6203.8 +/- 1329.5 vs 5141.2 +/- 295.5 micrograms*min/l, respectively). In conclusion, our findings are against the hypothesis of a major role of H1-receptor-mediated histaminergic influence on GH secretion in humans. In fact, the H1-histaminergic blockade by TRF does not affect the GH response to GHRH or HEX; the inhibitory effect of DPH may probably be due to its intrinsic anticholinergic activity. Our data also confirm that Hexarelin releases more GH than GHRH and demonstrate that its effect on GH, PRL and ACTH release is not mediated by H1-receptors.
Administration, Oral↗
Mechanisms underlying the negative growth hormone (GH) autofeedback on the GH-releasing effect of hexarelin in man.
The growth hormone (GH) response to GH-releasing hormone (GHRH) is strongly inhibited by previous administration of recombinant human GH (rhGH), likely as a consequence of a somatostatin-mediated GH negative autofeedback. Hexarelin (HEX), a synthetic hexapeptide belonging to the GH-releasing peptide (GHRP) family, possesses a GH-releasing activity greater than that of GHRH both in animals and in man. The mechanism of action of GHRPs is yet to be completely clarified, although concomitant actions at the pituitary and hypothalamic level have been hypothesized. To further clarify the mechanisms of action underlying the GH-releasing activity of HEX, in six normal young volunteers we studied the effects of rhGH (2 U intravenously [IV]) on the GH response either to GHRH (2 microg/kg IV) or to HEX (2 microg/kg IV) alone or combined with GHRH and/or pyridostigmine ([PD], 120 mg orally). The GH-releasing effect of HEX was higher than that of GHRH (area under the curve [AUC], 2,200.8 +/- 256.9 v 792.2 +/- 117.6 microg/L/h, P < .001), whereas combined administration of the two substances induced a true synergistic effect, with GH release after HEX plus GHRH (4,259.2 +/- 308.0 microg/L/h) being higher (P < .02) than the arithmetic sum of the GH increases induced by each compound separately administered. After rhGH administration, the GH-releasing effect of HEX was blunted (1,468.9 +/- 193.7 microg/L/h, P < .04; inhibition of 32.1%), whereas that of GHRH was nearly abolished (102.0 +/- 7.8 microg/L/h, P < .02; inhibition of 86.1%). The GH response to combined administration of HEX and GHRH was also blunted by the previous rhGH bolus (3,070.6 +/- 481.8 microg/L/h, P < .02; inhibition of 26.7%). PD did not modify the GH-releasing effect of HEX either alone (2,456.8 +/- 317.5 microg/L/h) or combined with GHRH (4,009.1 +/- 360.8 microg/L/h). rhGH was again able to blunt the GH response to HEX combined with PD (1,619.3 +/- 237.9 microg/L/h, P < .02), but failed to modify the GH response to HEX combined with GHRH and PD (4,548.4 +/- 698.0 microg/L/h). In conclusion, these results demonstrate that rhGH administration only blunts the GH-releasing activity of HEX, but abolishes that of GHRH. The blunting effect of rhGH on the GH response to HEX is probably mediated by a concomitant reduction in the activity of GHRH-secreting neurons and an increase of somatostatinergic tone.
Adult↗
Low hexarelin dose and pyridostigmine have additive effect and potentiate to the same extent the GHRH-induced GH response in man.
OBJECTIVES: Hexarelin (HEX) is a synthetic hexapeptide belonging to the growth hormone-releasing peptide (GHRP) family. The exact mechanism underlying the strong GH-releasing activity of GHRPs is still unclear, though it has been shown that they act both at the pituitary and the hypothalamic level, where they have specific receptors. To clarify the influence of the cholinergic system on the GH-releasing activity of GHRPs in man, we investigated the effects of pyridostigmine, a cholinergic agonist which stimulates GH secretion by inhibiting somatostatin release, on the GH response to various HEX doses. DESIGN: We studied the GH release induced by various HEX doses (0.25, 0.5 and 2.0 micrograms/kg i.v.) and pyridostigmine (PD, 120 mg po), both alone and coadministered. The interactions between the lowest HEX dose or PD and the maximally effective GHRH dose (1.0 microgram/kg i.v.) were also studied. SUBJECTS: Six normal male volunteers, aged 24-30 years, were studied. MEASUREMENTS: Serum GH was measured in duplicate by immunoradiometric assay. RESULTS: The GH response to HEX administration was dose-dependent. In fact, the GH response to 0.25 microgram/kg HEX (AUC, mean +/- SEM: 816.4 (235.6 mU/l/120 min) was lower, although not significantly, than that to 0.5 microgram/kg HEX (2154.6 +/- 491.6 mU/l/120 min), which, in turn, was lower (p < 0.05) than that after 2.0 micrograms/kg HEX (4819.2 +/- 668.0 mU/l/120 min). The GH rise after GHRH (1299.2 +/- 222.8 mU/l/120 min) was lower (P < 0.05) than that after 2.0 micrograms/kg HEX, but not different from the responses to either 0.25 or 0.5 microgram/kg HEX. PD induced a significant GH rise (559.0 +/- 129.8 mU/l/120 min, P < 0.05 vs saline), similar to that after 0.25 microgram/kg HEX, and lower than those after both 0.5 and 2.0 micrograms/kg HEX (P < 0.05 and p < 0.01, respectively) and GHRH (p < 0.05). PD pretreatment enhanced the GH response to the lowest HEX dose (1961.4 +/- 253.8 mU/l/120 min, p < 0.05) in an additive way, but failed to modify the GH response to either 0.5 or 2.0 micrograms/kg HEX (2753.6 +/- 444.6 and 5179.0 +/- 770.8 mU/l/120 min, respectively). Notably, the GH response to 0.25 microgram/kg HEX + PD was still lower (P < 0.05) than that to 2.0 micrograms/kg HEX. PD pretreatment as well as 0.25 microgram/kg HEX truly potentiated the GH response to GHRH to the same extent (4926.6 +/- 912.8 mU/l/120 min, p < 0.05 and 5958.8 +/- 750.0 mU/l/120 min, p < 0.05 respectively). The GH responses to PD + GHRH and 0.25 microgram/kg HEX + GHRH were similar to that after 2.0 micrograms/kg HEX alone. CONCLUSIONS: Our results demonstrate that pyridostigmine is able to enhance the GH response only to a very low dose Hexarelin which, in turn, potentiates the GHRH-induced GH rise to the same extent as pyridostigmine. As there is evidence that GHRPs do not inhibit hypothalamic somatostatin release, these findings are consistent with the hypothesis that they act by antagonizing somatostatin activity and/or through unknown factors. On the other hand, though there is evidence showing that GHRH activity is needed for GHRP action, our findings indicate that GHRPs act, at least partially, independently of GHRH.
Adult↗
Adrenocorticotropin- and cortisol-releasing effect of hexarelin, a synthetic growth hormone-releasing peptide, in normal subjects and patients with Cushing's syndrome.
GH-releasing peptides (GHRPs) are synthetic, nonnatural molecules that strongly stimulate GH secretion, but also slightly increase PRL, ACTH, and cortisol levels in man. To investigate the mechanism underlying the ACTH- and cortisol-releasing activity of GHRPs in man, we compared the ACTH- and cortisol-releasing activity of Hexarelin (HEX; 2.0 micrograms/kg, iv), a hexapeptide belonging to the GHRP family, with that of human CRH (hCRH; 2.0 micrograms/kg, iv) in normal subjects (6 men and 6 women, 24-68 yr old) and patients with Cushing's syndrome (2 men and 15 women, 16-68 yr old). The GH response to HEX administration was also studied. In normal subjects, HEX administration significantly increased ACTH (peak us. baseline, mean +/- SD, 32.4 +/- 17.7 vs. 16.3 +/- 7.2 pg/mL; P < 0.005) and cortisol levels (135.9 +/- 51.0 vs. 110.0 +/- 31.6 micrograms/L; P < 0.01). The ACTH and cortisol responses to hCRH [35.7 +/- 13.2 vs. 17.1 +/- 7.7 pg/mL (P < 0.01) and 162.8 +/- 50.1 vs. 102.8 +/- 28.1 micrograms/L (P < 0.01), respectively] were similar to the responses to HEX. The stimulatory effect of HEX, but not that of hCRH, on both ACTH and cortisol secretion in Cushing's disease was clearly higher (P < 0.01) than that observed in normal subjects. In fact, in Cushing's disease both HEX and hCRH elicited a clear increase in ACTH levels [381.1 +/- 350.0 vs. 52.4 +/- 25.0 (P < 0.005) and 100.0 +/- 86.2 vs. 53.3 +/- 29.7 pg/mL (P < 0.01), respectively but the ACTH increase induced by HEX was about 7-fold greater (P < 0.02) than that induced by hCRH. Similarly, both HEX and hCRH elicited a significant increase in cortisol levels [366.9 +/- 189.5 vs. 189.7 +/- 86.3 micrograms/L (P < 0.005) and 209.9 +/- 125.4 vs. 167.2 +/- 96.3 micrograms/L (P < 0.02), respectively], but the cortisol increase induced by HEX was about 4-fold greater (P < 0.05) than that induced by hCRH. In patients with Cushing's syndrome due to adrenal adenoma or ectopic ACTH, no change in ACTH and cortisol levels was observed after either HEX or hCRH administration. The peak GH response to HEX in normal subjects was clearly higher (P < 0.03) than that in hypercortisolemic patients (45.8 +/- 20.5 vs. 22.4 +/- 21.1 micrograms/L). In conclusion, the ACTH- and cortisol-releasing activity of HEX is similar to that of hCRH in normal subjects, whereas it is dramatically enhanced in patients with Cushing's disease. This evidence indicates the importance of the ACTH-releasing activity of GHRPs and suggests that it could be at least partially independent of CRH-mediated mechanisms. As the stimulatory effect of HEX on ACTH and cortisol secretion is lost in patients with Cushing's syndrome due to adrenal adenoma or ectopic ACTH, these findings suggest the usefulness of GHRPs to investigate the activity of the hypothalamo-pituitary-adrenal axis in pathophysiological conditions and possibly to differentiate pituitary from ectopic ACTH-dependent Cushing's syndrome.
Adolescent↗
Oestrogen replacement does not restore the reduced GH-releasing activity of Hexarelin, a synthetic hexapeptide, in post-menopausal women.
Hexarelin (HEX), a synthetic hexapeptide, has a strong and reproducible GH-releasing activity in man after intravenous, subcutaneous, intranasal and oral administration. Its effect undergoes age-related variations, being reduced in elderly subjects. In spite of evidence in animals showing that the activity of GH-releasing peptides (GHRPs) is positively influenced by oestrogens, in young adults no sex-related difference has been found in the GH response to HEX or to other GHRPs. We aimed to clarify the influence of the menopause and oestrogens on the GH-releasing activity of HEX. We studied the GH response to the acute administration of the maximal effective dose of HEX (2 micrograms/kg i.v.) in 24 young women (YW, age: 27.3 +/- 0.5 years: body mass index (BMI): 20.7 +/- 0.3 kg/m2), 14 post-menopausal women (PW, age: 52.9 +/- 1.2 years: BMI: 23.2 +/- 0.9 kg/m2) and 14 aged women (AW, age: 68.9 +/- 1.5 years: BMI: 21.7 +/- 0.7 kg/m2). In 10 post-menopausal women the GH response to HEX was also studied after 3 months of transdermal oestradiol treatment (delivery 50 micrograms/die). Basal oestrogen and GH levels in PW were lower than those in YW (oestrogen: 4.8 +/- 3.6 vs 42.0 +/- 3.4 pg/ml (means +/- S.E.M.). P < 0.001: GH: 1.5 +/- 0.5 vs 2.9 +/- 0.6 micrograms/l, P < 0.02) and similar to those in AW (oestrogen: 1.3 +/- 0.4 pg/ml: GH: 0.9 +/- 0.2 microgram/l). IGF-l levels in PW were not different from those in YW (174.4 +/- 11.9 vs 195.5 +/- 14.9 micrograms/l) and higher than those in AW (109.8 +/- 15.8 micrograms/l, P < 0.01). The GH response to HEX in PW (areas under the curve +/- S.E.M.: 453.6 +/- 56.0 micrograms.min/l) was lower (P < 0.002) than that in YW (1630.4 +/- 259.7 micrograms.min/l) while it did not differ from that in AW (781.8 +/- 189.3 micrograms.min/l). In PW 3-month oestrogen administration increased oestradiol levels (38.3 +/- 5.9 vs 0.8 +/- 0.4 pg/ml, P < 0.001) making them similar to those recorded in YW, while it failed to modify both basal GH and IGF-l levels GH: 1.8 +/- 0.6 vs 1.5 +/- 0.7 micrograms/l: IGF-l: 164.6 +/- 14.3 vs 175.0 +/- 12.3 micrograms/l). Also the GH response to HEX was not modified by oestradiol treatment (518.4 +/- 125.6 vs 425.4 +/- 69.3 micrograms.min/l). In conclusion, present data confirm the strong GH-releasing effect of Hexarelin in humans and demonstrate that its activity is already reduced in post-menopausal women to an extent overlapping that in elderly women. Moreover, oestrogen treatment is not able to restore it. Thus, the lack of oestrogens does not seem to account for the reduced somatotraph responsiveness to GHRPs in the post-menopausal period.
Adult↗