Biomedical subjects

E Ghigo

Publications and source records attributed to E Ghigo.

At least 109 records · Page 6Linked to original sources

PubMed2001

Interleukin-10 stimulates Coxiella burnetii replication in human monocytes through tumor necrosis factor down-modulation: role in microbicidal defect of Q fever.

Coxiella burnetii, an obligate intracellular bacterium, is the agent of Q fever. The chronic form of the disease is associated with the overproduction of interleukin-10 and deficient C. burnetii killing by monocytes. We hypothesized that the replication of C. burnetii inside monocytes requires a macrophage-deactivating cytokine such as interleukin-10. In the absence of interleukin-10, C. burnetii survived but did not replicate in monocytes. C. burnetii replication (measured 15 days) was induced in interleukin-10-treated monocytes. This effect of interleukin-10 is specific since transforming growth factor beta1 had no effect on bacterial replication. C. burnetii replication involves the down-modulation of tumor necrosis factor (TNF) release. First, interleukin-10 suppressed C. burnetii-stimulated production of TNF. Second, the addition of recombinant TNF to interleukin-10-treated monocytes inhibited bacterial replication. Third, the incubation of infected monocytes with neutralizing anti-TNF antibodies favored C. burnetii replication. On the other hand, deficient C. burnetii killing by monocytes from patients with chronic Q fever involves interleukin-10. Indeed, C. burnetii replication was observed in monocytes from patients with Q fever endocarditis, but not in those from patients with acute Q fever. Bacterial replication was inhibited by neutralizing anti-interleukin-10 antibodies. As monocytes from patients with endocarditis overproduced interleukin-10, the defective bacterial killing is likely related to endogenous interleukin-10. These results suggest that interleukin-10 enables monocytes to support C. burnetii replication and to favor the development of chronic Q fever.

Antigens, CD↗

PubMed2001

Involvement of nitric oxide in the regulation of growth hormone secretion in dogs.

Nitric oxide (NO) is a highly reactive gas that has been suggested to function as a neurotransmitter in the neuroendocrine system. In this work, we have evaluated the role of NO pathways in growth hormone (GH) secretion by assessing the effect of L-arginine infusion, a precursor of NO formation, and L-NAME, a nitric oxide synthase (NOS) inhibitor. The experiments were carried out on 7 adult beagle dogs. A saline infusion was carried out on all the dogs as a control test. L-arginine (infusion i.v. 10 g in 100 ml of saline, from t = 0 to 30 min) and L-nitro-arginine-methyl ester, L-NAME (infusion of 300 microg/kg in 120 ml of saline, from t = -30 to 45 min) were administered alone and together with growth hormone-releasing hormone (GHRH) (i.v. bolus at 0 min, at a dose of 100 microg), the synthetic GH secretagogue GHRP-6 (i.v. bolus at 0 min, at a dose of 90 microg), and the 5-HT1D serotonin receptor agonist sumatriptan, SUM (s.c. injection at the dose of 3 mg). Plasma cGH was determined by RIA. Results were evaluated by one-way analysis of variance, followed by the Newman-Keuls test for multiple comparisons. L-arginine administration resulted in a slight increase in plasma cGH in comparison with saline controls. Combined administration of L-arginine and GHRH enhanced cGH release in comparison with GHRH alone. L-NAME alone did not modify baseline cGH levels, but completely suppressed the GH release induced by GHRH or GHRP-6. It also strongly reduced, but did not abolish the effect of the two peptides (GHRH plus GHRP-6) administered together. Finally, administration of the 5-HT1D agonist SUM induced a significant cGH secretion in all dogs, a response which was not modified when L-NAME was administered in combination with SUM. In conclusion, our data show that inhibition of NO blunts both GHRH or GHRP-6-induced cGH release, and are compatible with the hypothesis that it acts by decreasing hypothalamic somatostatin release.

Animals↗

PubMed2001

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↗

PubMed2001

Ghrelin-producing endocrine tumors of the stomach and intestine.

Ghrelin is a novel gastrointestinal hormone produced by about 20% of the rat and human gastric neuroendocrine cell population, which possesses strong GH-releasing activity, but also plays other central and peripheral roles, including influence on food intake, gastric motility, and acid secretion. The aim of the present study was to determine whether gastrointestinal endocrine hyperplastic and neoplastic lesions produce ghrelin, at both protein (immunohistochemistry) and mRNA (in situ hybridization and/or RT-PCR) levels, and express the GH secretagogue receptor mRNA by RT-PCR. Sixteen gastric and 20 intestinal carcinoids as well as normal gastrointestinal mucosa and atrophic gastritis-associated neuroendocrine cell hyperplasia were studied. The majority (12 of 16, 75%) of gastric carcinoids and only 5 of 18 (27%) of intestinal endocrine tumors were immunoreactive for ghrelin. In situ hybridization confirmed the immunohistochemical data, but also showed ghrelin mRNA in 1 gastric and 8 intestinal additional tumors. RT-PCR showed ghrelin mRNA in 14 of 14 cases, indicating a low level of ghrelin gene expression in all gastrointestinal endocrine tumors tested. Gastric neuroendocrine hyperplastic cells were also strongly positive for ghrelin. GH secretagogue receptor mRNA was absent in 3 gastric, but present in 7 of 11 intestinal carcinoids studied by RT-PCR. These findings demonstrate that most gastric carcinoids (and related neuroendocrine cell hyperplasias) and some intestinal carcinoids produce ghrelin. These hyperplastic/neoplastic conditions could represent the clinical model to clarify the existence and impact of ghrelin hypersecretion on endocrine and nonendocrine functions.

Adult↗

PubMed2001

Ghrelin, a natural GH secretagogue produced by the stomach, induces hyperglycemia and reduces insulin secretion in humans.

Ghrelin, a 28 amino acid gastric hormone is a natural ligand of the GH Secretagogue (GHS) receptor (GHS-R) and strongly stimulates GH secretion though, like synthetic GHS, it shows other endocrine and non-endocrine activities. Aim of the present study was to clarify whether ghrelin administration influences insulin and glucose levels in humans. To this goal, we compared the effects of ghrelin, hexarelin, a synthetic GHS, or placebo on insulin and glucose as well as on GH levels in 11 normal young volunteers (age [mean +/- SEM]: 28.5 +/- 3.1 yr; BMI: 22.2 +/- 0.9 Kg/m(2)). Ghrelin induced very marked increase in GH secretion (DeltaAUC(0-180): 5777.1 +/- 812.6 microg/l/h; p < 0.01) which was not modified by placebo. Placebo administration did not modify insulin and glucose levels. On the other hand, ghrelin administration induced a prompt increase in glucose levels (DeltaAUC(0-180): 1343.1 +/- 443.5 mg/dl/h; p < 0.01 vs. saline). Absolute glucose levels at +15' were already higher than those at baseline (93.9 +/- 7.1 mg/dl; p < 0.01) and persisted elevated up to 165' (90.3 +/- 5.8 mg/dl; p < 0.01 vs. 0'). Ghrelin administration was also followed by a decrease in serum insulin levels (DeltaAUC(0-180): -207.1 +/- 70.5 mU/l/h; p < 0.05 vs. saline). Absolute insulin levels were significantly reduced from 30' (11.4 +/- 0.9 mU/l, p < 0.1 vs. 0'), showed the nadir at +45' (10.0 +/- 0.6 mU/l, p < 0.01 vs. 0') and then persisted lower (p < 0.01) than baseline up to +105'. Hexarelin administration did not modify glucose and insulin levels despite its marked GH-releasing effect (DeltaAUC(0-180): 4156.8 +/- 1180.3 microg/l/h; p < 0.01 vs. saline) that was slightly lower (p < 0.05) than that of ghrelin. In conclusion, these findings show that, besides stimulating GH secretion, ghrelin is a gastric hormone possessing metabolic actions such as hyperglycemic effect and lowering effect on insulin secretion in humans, at least after acute administration.

Adult↗

PubMed2001

Endocrine activities of ghrelin, a natural growth hormone secretagogue (GHS), in humans: comparison and interactions with hexarelin, a nonnatural peptidyl GHS, and GH-releasing hormone.

An endogenous ligand for the GH secretagogue-receptor (GHS-receptor) has recently been isolated, from both the rat and the human stomach, and named ghrelin. It is a 28-amino-acid peptide showing a unique structure with an n-octanoyl ester at its third serine residue, which is essential for its potent stimulatory activity on somatotroph secretion. In fact, it has been demonstrated that ghrelin specifically stimulates GH secretion from both rat pituitary cells in culture and rats in vivo. The aim of the present study was to test the GH-releasing activity of ghrelin in humans and to compare it with that of GHRH and hexarelin (HEX), a nonnatural peptidyl GHS, which possesses strong GH-releasing activity but also significantly stimulates PRL, ACTH, and cortisol secretion. To clarify the mechanisms of action underlying the GH-releasing activity of ghrelin in humans, its interaction with GHRH and HEX was also studied. Seven normal young volunteers (7 men; 24-32 yr old; body mass index, 20-24 kg/m(2)) were studied. All subjects underwent the administration of ghrelin, HEX, and GHRH-29 (1.0 microg/kg i.v. at 0 min) as well as placebo (2 mL isotonic saline i.v. at 0 min). Six subjects also underwent the combined administration of ghrelin and GHRH or HEX. Blood samples were taken every 15 min from -15 up to +180 min. GH levels were assayed at each time point in all sessions; PRL, ACTH, cortisol, and aldosterone levels were also assayed after administration of ghrelin and/or HEX. Ghrelin administration induced a prompt and marked increase in circulating GH levels (Cmax, mean +/- SEM, 92.1 +/- 16.7 microg/L; area under the curve, 1894.9 +/- 347.8 microg/L.h). The GH response to ghrelin was clearly higher (P < 0.01) than the one recorded after GHRH (26.7 +/- 8.7 microg/L; 619.6 +/- 174.4 microg/L.h) and even significantly higher (P < 0.05) than after HEX (68.4 +/- 14.7 microg/L; 1546.9 +/- 380.0 microg/L x h). Ghrelin administration also induced an increase in PRL, ACTH, and cortisol levels; these responses were higher (P < 0.05) than those elicited by HEX. A significant increase in aldosterone levels was recorded after ghrelin but not after HEX. The endocrine responses to ghrelin were not modified by the coadministration of HEX. On the other hand, the coadministration of ghrelin and GHRH had a real synergistical effect (P < 0.05) on GH secretion (133.6 +/- 22.5 microg/L; 3374.3 +/- 617.3 microg/L x h). In conclusion, ghrelin, a natural ligand of GHS-receptor, exerts a strong stimulatory effect on GH secretion in humans, releasing more GH than GHRH and even more than a nonnatural GHS such as HEX. Ghrelin, as well as HEX, also stimulates lactotroph and corticotroph secretion. Ghrelin shows no interaction with HEX, whereas it has a synergistical effect with GHRH on GH secretion. Thus, ghrelin is a new hormone playing a major role in the control of somatotroph secretion in humans, and its effects are imitated by nonnatural GHS.

Adrenocorticotropic Hormone↗

PubMed2001

Relationship between the morphological evaluation of the pituitary and the growth hormone (GH) response to GH-releasing hormone Plus arginine in children and adults with congenital hypopituitarism.

The relationship between the hypothalamus-pituitary morphology and the somatotroph responsiveness to maximal provocative tests exploring the GH releasable pool is still unclear. We evaluated the GH-releasing effect of GHRH plus arginine (GHRH plus Arg) in 36 patients with congenital GH deficiency (GHD) according to their pituitary magnetic resonance imaging findings, consisting of anterior pituitary hypoplasia, stalk agenesis (neural and or vascular component), and posterior pituitary ectopia. Seventeen children (12 boys and 5 girls, aged 1--5.2 yr) were evaluated at the time of diagnosis of GHD (mean age, 3.6 +/- 1.4 yr), and 19 adults (13 males and 6 females, aged 15.9-28.6 yr) with childhood-onset GHD were reevaluated after completion of GH treatment (at least 6 months of withdrawal) at a mean age of 20.5 +/- 3.5 yr. Eleven children had isolated GHD, and 6 had multiple pituitary hormone deficiency (MPHD) whereas 7 adults had isolated GHD, and 12 had MPHD. A residual vascular component of the pituitary stalk was visualized in 7 children and 7 adults with isolated GHD, whereas magnetic resonance imaging showed complete pituitary stalk agenesis (both vascular and neural components) in 10 children and 10 adults, including 16 with MPHD (6 children) and 4 children with isolated GHD. In the children, the median peak GH response to GHRH plus Arg (7.6 microg/L; range, 2.4--40.2 microg/L) was significantly higher than that in the adults (1.8 microg/L; range, 0.8--37.4 microg/L; P = 0.0039); it was also significantly higher in the isolated GHD patients (18 microg/L; range, 3.3--40.2 microg/L) than in those with MPHD (1.9 microg/L; range, 0.8--7.6 microg/L; P = 0.00004). In the patients with residual vascular component of the pituitary stalk the median peak GH responses to GHRH plus Arg (19.1 microg/L; range, 1.6--40.2 microg/L) was significantly higher than that in patients with complete pituitary stalk agenesis (2.2 microg/L; range, 0.8--8.8 microg/L; P = 0.00005). There was a trend toward a decrease with age in peak GH response to GHRH plus ARG: Mean serum insulin-like growth factor I (IGF-I) levels were 36 +/- 7.1 microg/L in the children and 63.5 +/- 22.6 microg/L in the adults (P = 0.0001). The mean IGF-I level did not differ between the children with (35.7 +/- 4.8 microg/L) and those without (36.3 +/- 8.7 microg/L) the pituitary stalk; it was much higher in the adults with residual vascular pituitary stalk (81.1 +/- 17.7 microg/L) than in those with complete pituitary stalk agenesis (47.7 +/- 12.5 microg/L; P = 0.0002). The IGF-I level was 36.1 +/- 6.7 microg/L in the isolated GHD children and 36 +/- 8.6 microg/L in those with MPHD; levels were 82.1 +/- 19.4 and 52.7 +/- 16.8 microg/L respectively, in the adults (P = 0.003). In this study we have confirmed that the partial integrity of the hypothalamic pituitary connections is essential for GHRH plus Arg to express its GH-releasing activity and have shown that this provocative test is able to stimulate GH secretion to a greater extent in those patients with GHD, but with a residual vascular component of the pituitary stalk. This test is reliable in the diagnosis of congenital hypopituitarism in both children and adults when associated with complete pituitary stalk agenesis and MPHD. In younger children with congenital GHD but less severe impairment of the pituitary stalk the GH response to GHRH plus Arg may be within the normal range; deterioration of pituitary GH reserve with a GH response of less than 10 microg/L after 20 yr of age makes this test very sensitive in the diagnosis of adult GHD.

Adolescent↗

PubMed2001

Identification, characterization, and biological activity of specific receptors for natural (ghrelin) and synthetic growth hormone secretagogues and analogs in human breast carcinomas and cell lines.

The family of GH secretagogues (GHS) includes synthetic peptidyl (hexarelin) and nonpeptidyl (MK-0677) molecules possessing specific receptors in the pituitary and central nervous system as well as in peripheral tissues, including the heart and some endocrine organs. A gastric-derived peptide, named ghrelin, has recently been proposed as the natural ligand of the GHS receptors (GHS-Rs). The presence of specific GHS-Rs has now been investigated in nontumoral and neoplastic human breast tissue using a radioiodinated peptidyl GHS ([(125)I]-Tyr-Ala-hexarelin) as ligand. Specific binding sites for GHS were detected in membranes from several types of breast carcinomas, whereas a negligible binding was found in fibroadenomas and mammary parenchyma. The highest binding activity was found in well-differentiated (G1) invasive breast carcinomas and was progressively reduced in moderately (G2) to poorly (G3) differentiated tumors. [(125)I]-Tyr-Ala-hexarelin bound to tumor membranes was displaced by different unlabeled GHS such as hexarelin, Tyr-Ala-hexarelin, human ghrelin, and MK-0677 as well as by desoctanoyl-ghrelin and hexarelin derivative EP-80317, which are devoid of GH-releasing properties in vivo. In contrast, no competition was seen between radiolabeled Tyr-Ala-hexarelin and some peptides (CRF and insulin-like growth factor I) structurally and functionally unrelated to hexarelin or when GHRH and SRIF were tested in the displacement studies. The presence of specific GHS binding sites was also demonstrated in three different human breast carcinoma cell lines (MCF7, T47D, and MDA-MB231), in which, surprisingly, no messenger RNA for GHS-R1a was demonstrated by RT-PCR. In these cell lines, ghrelin (as well as hexarelin, MK-0677, EP-80317, and even desoctanoyl ghrelin) caused a significant inhibition of cell proliferation at concentrations close to their binding affinity. In conclusion, this study provides the first demonstration of specific GHS binding sites, other than GHS-R1, in breast cancer. These receptors probably mediate growth inhibitory effects on breast carcinoma cells in vitro.

Breast↗

PubMed2001

Mineralocorticoid receptor blockade by canrenoate increases both spontaneous and stimulated adrenal function in humans.

Animal studies indicate that mineralocorticoid receptors (MR) in the hippocampus play a major role in the glucocorticoid feedback control of the hypothalamo-pituitary-adrenal (HPA) axis. Specifically, MR mediate the proactive feedback of glucocorticoids in the maintenance of basal HPA activity. The stimulatory effect of intracerebroventricular and intrahippocampal MR blockade on the HPA axis in animals has been clearly shown, whereas the effect of systemic administration of mineralocorticoid antagonists in humans is still contradictory. To clarify this point, in seven normal young women (aged 25-32 yr; body mass index, 19.0-23.0 kg/m(2)) we studied the effects of canrenoate (CAN; 200 mg as iv bolus at 2000 h, followed by 200 mg infused in 500 mL saline over 4 h up to 2400 h) or placebo (saline, 1.0 mL as iv bolus at 2000 h, followed by 500 mL over 4 h up to 2400 h) on the spontaneous ACTH, cortisol, dehydroepiandrosterone (DHEA) and aldosterone secretion as well as on the ACTH, cortisol, and DHEA responses to human CRH (2.0 microg/kg as iv bolus at 2200 h) or arginine vasopressin (AVP; 0.17 U/kg as im bolus at 2200 h). Blood samples were taken every 15 min from 2000-2400 h. During placebo, spontaneous ACTH and cortisol levels showed progressive decreases (P < 0.05) from 2000-2400 h (baseline vs. nadir, mean +/- SEM, 2.0 +/- 0.3 vs. 1.4 +/- 0.2 pmol/L and 115.1 +/- 23.7 vs. 63.5 +/- 24.3 nmol/L), whereas DHEA and aldosterone levels did not change. CRH induced clear increases in ACTH, cortisol, and DHEA levels (peaks, mean +/- SEM, 7.1 +/- 1.1 vs. 1.6 +/- 0.2 pmol/L, 322.9 +/- 19.5 vs. 92.8 +/- 24.5 nmol/L, and 44.2 +/- 2.7 vs. 20.0 +/- 3.0 nmol/L; P < 0.05). Similarly, AVP elicited significant increases in ACTH, cortisol, and DHEA levels (3.8 +/- 0.3 vs. 1.5 +/- 0.1 pmol/L, 211.9 +/- 27.2 vs. 67.7 +/- 9.7 nmol/L, and 51.6 +/- 4.0 vs. 16.3 +/- 2.0 nmol/L; P < 0.05). During CAN treatment, ACTH, cortisol, and DHEA levels showed progressive rises, which begun at approximately 60 min and peaked between 2300 and 2400 h (ACTH, 3.4 +/- 0.4 vs. 1.1 +/- 0.3 pmol/L; cortisol, 314.5 +/- 49.6 vs. 123.3 +/- 13.2 nmol/L; DHEA, 52.0 +/- 8.8 vs. 21.0 +/- 2.3 nmol/L; P < 0.05 vs. baseline as well as vs. the same time points during placebo). Aldosterone secretion was not modified by CAN. The ACTH, cortisol, and DHEA responses to human CRH were enhanced by CAN (10.0 +/- 1.7 pmol/L, 462.2 +/- 36.9 nmol/L, and 66.3 +/- 8.8 nmol/L), although statistical significance (P < 0.05) was obtained for cortisol and DHEA only. Also the ACTH, cortisol and DHEA responses to AVP were amplified by CAN (8.0 +/- 2.6 pmol/L, 324.0 +/- 34.8 nmol/L, and 77.8 +/- 4.0 nmol/L); again, statistical significance (P < 0.05) was obtained for cortisol and DHEA only. In conclusion, our study shows that the blockade of MR by CAN significantly enhances the activity of the HPA axis in humans, indicating a physiological role for MR in its control. These results also suggest that the stimulatory effect of CAN on HPA axis is mediated by concomitant modulation of CRH and AVP release.

Adrenal Glands↗

PubMed2001

Somatostatin octapeptides (lanreotide, octreotide, vapreotide, and their analogs) share the growth hormone-releasing peptide receptor in the human pituitary gland.

The binding affinity of somatostatin-14 (SRIF), various SRIF derivatives, and some peptides belonging to the growth hormone-releasing peptide (GHRP) family to specific receptors for SRIF and GHRP in the human pituitary gland has been measured. GHRP receptors have been identified using [125I]Tyr-Ala-hexarelin, a peptide that thas been demonstrated to be a potent growth hormone (GH) releaser in humans. Tyr-Ala-hexarelin binding was displaced in a dose-dependent manner by different GHRPs (hexarelin, GHRP-2, and EP-51216). Surprisingly, some SRIF octapeptide derivatives such as vapreotide, lanreotide, octreotide, and their analogs were also able to displace the GHRP ligand. By contrast, no inhibition of Tyr-Ala-hexarelin binding was observed in the presence of SRIF or SRIF derivatives (SRIF H-2186, H-2485, and H-3382) that are known to have a weak SRIF-like activity. When [125I]Tyr1-SRIF-14 was used as a ligand, we observed displacement with SRIF and the octapeptide SRIF analogs but not with GHRPs and other SRIF derivatives. The results point to a sharing of the GHRP receptor with the octapeptide SRIF analogs, but not SRIF. Our data are consistent with the hypothesis that the putative natural GH secretagogue ligand may be a growth hormone release inhibiting factor that is different from SRIF and that is antagonized by GHRP.

Aged↗

PubMed2001

Growth hormone-releasing hormone and growth hormone secretagogue-receptor ligands: focus on reproductive system.

Growth hormone-releasing hormone (GHRH) and somatostatin are the most important hypothalamic neurohormones controlling growth hormone (GH) secretion. Several neurotransmitters and neuropeptides also play an important role in the control of GH secretion, mainly acting via modulation of GHRH and somatostatin. In the past two decades, particular attention has been given to a new family of substances showing a strong GH-releasing effect: GH secretagogues (GHSs). GHSs increase GH secretion in a dose- and age-related manner after iv and even oral administration. The endocrine effects of GHSs, are not fully specific for GH; they show, in fact, prolactin- (PRL), adenocorticotropic hormone- and cortisol-releasing effects. Specific GHS receptors are present in both the central nervous system and peripheral tissues, where they mediate several extraendocrine effects of GHSs. The isolation of these "orphan" receptors suggested the existence of an endogenous GHS-like ligand that could be represented by a recently discovered gastric peptide, named ghrelin. The interaction between GHSs and GHRH at the central level and in the pituitary gland, but not at peripheral level, has clearly been shown. Because GHRH and GHS receptors share the same localization in some peripheral tissues, they may have some interactions even at this level.

Adrenocorticotropic Hormone↗

PubMed2001

Biologic activities of growth hormone secretagogues in humans.

Growth hormone secretagogues (GHSs) are synthetic peptidyl and nonpeptidyl molecules with strong, dose-dependent, and reproducible growth hormone (GH)-releasing activity even after oral administration. GHSs release GH via actions on specific receptors (GHS-R) at the pituitary and, mainly, at the hypothalamic levels. GHSs likely act as functional somatostatin antagonists and meantime enhance the activity of GH-releasing hormone (GHRH)-secreting neurons. The GH-releasing effect of GHSs is independent of gender but undergoes marked age-related variations. Estrogens play a major role in enhancing the GH response to GHSs at puberty, which GHRH hypoactivity, somatostatinergic hyperactivity and impaired activity of the putative GHS-like ligand and receptors probably explain the reduced GH-releasing effect of GHSs in aging. The activity of GHSs is not fully specific for GH. Their slight prolactin-releasing activity probably comes from direct pituitary action. In physiological conditions, the ACTH-releasing activity of GHSs is dependent on central actions; a direct action on GHS-R in pituitary ACTH-secreting tumors likely explains the peculiar ACTH and cortisol hyperresponsiveness to GHSs in Cushing disease. GHSs have specific receptor subtypes in other central and peripheral endocrine and nonendocrine tissues mediating GH-independent biologic activities. GHSs influence sleep pattern, stimulate food intake, and have cardiovascular activities. GHs have specific binding in normal and neoplastic follicular derived human thyroid tissue and inhibit the proliferation of follicular-derived neoplastic cell lines. The discovery of ghrelin, a 28 amino acid peptide synthesized in the stomach but also in other tissues, has opened new fascinating perspectives of research in this field.

Age Factors↗

PubMed2001

Growth hormone-independent cardiotropic activities of growth hormone-releasing peptides in normal subjects, in patients with growth hormone deficiency, and in patients with idiopathic or ischemic dilated cardiomyopathy.

Growth hormone releasing peptides (GHRPs) are synthetic molecules endowed with potent neuroendocrine activities mediated by specific receptors in the pituitary and in the central nervous system. GHRPs receptors have been reported even in perpheral tissues, particularly in the myocardium, where they probably mediate growth hormone (GH)-independent activities. We studied in humans the cardiac effects of hexarelin administration in 7 normal adults, in 7 severe GH-deficient patients, and in 12 patients with severe dilated cardiomyopathy. Left ventricular ejection fraction (LVEF), mean blood pressure (MBP), heart rate (HR), and GH levels were evaluated at baseline and every 15 min up to 60 min after acute 2.0 microg/kg iv hexarelin administration. Basal LVEF in dilated cardiomyopathy was impaired and lower (p < 0.001) than in GH deficiency, in turn lower (p< 0.001) than in normal subjects. Hexarelin signficantly (p < 0.05) increased LVEF in normal and in GH-deficient subjects, but not in dilated cardiomyopathy, without significant variations in MBP and HR. Hexeralin significantly (p < 0.05) increased GH levels in normal subjects and in dilated cardiomyopathy but not in GH deficiency. These findings suggest that, in humans, the acute administration of hexarelin exerts a GH-independent positive inotropic effect likely mediated by specific GHRPs myocardial receptors.

Adult↗

PubMed2001

Hexarelin protects H9c2 cardiomyocytes from doxorubicin-induced cell death.

Growth hormone secretagogues (GHSs) are synthetic peptidyl and nonpeptidyl molecules that possess strong growth hormone-releasing activity acting on specific pituitary and hypothalamic receptor subtypes. Differently from nonpeptidyl GHSs, peptidyl molecules such as hexarelin, a hexapeptide, possess specific high-affinity binding sites in animal and human heart and, after prolonged treatment, protect rats in vivo from ischemia-induced myocardial damage. To verify the hypothesis that peptidyl GHSs protect heart cells from cell death, we have investigated the cellular effects of hexarelin on H9c2 cardiomyocytes, a fetal cardiomyocyte-derived cell line, and on Hend, an endothelial cell line derived from transformed murine heart endothelium. We show that (i)H9c2 cardiomyocytes show specific binding for 125I-Tyr-Ala-hexarelin, which is inhibited by peptidyl GHSs such as Tyr-Ala-hexarelin and hexarelin but not by the nonpeptidyl GHS MK-0677, (ii) hexarelin promotes survival of H9c2 cardiomyocytes induced to die by doxorubicin, and (iii) that hexarelin inhibits apoptosis, as measured by DNA fragmentation, induced in both H9c2 myocytes and endothelial cells. In conclusion, our findings show that peptidyl GHSs such as hexarelin act as survival factors for cardiomyocytes and endothelium-derived cells in culture. These findings suggest that the inhibitory activity of hexarelin on cardiomyocytes and endothelial cell death could explain, at least partially, its cardioprotective effect against ischemia recorded in rats in vivo.

Animals↗

PubMed2001

Growth hormone-releasing hormone combined with arginine or growth hormone secretagogues for the diagnosis of growth hormone deficiency in adults.

Insulin-induced hypoglycemia (ITT) is currently the "gold-standard" test for the diagnosis of adult growth hormone deficiency (GHD). ITT is often contraindicated, however, particularly in conditions that are also common in patients with suspected GHD. Used alone, GH-releasing hormone (GHRH) has no diagnostic value owing to within-subject variability and the inability to distinguish GHD from normal subjects. When combined with arginine, however, GHRH becomes a potent and reproducible test, which is unaffected by gender and aging, showing excellent specificity. The GHRH+ arginine (ARG) test distinguishes GHD patients from normal subjects and is at least as sensitive as ITT, provided that appropriate cutoff limits are considered. Its reliability for retesting GHD has also been demonstrated. The GHRH+ARG test can also be performed in a shorter procedure, resulting in potential for cost reduction. Synthetic GH secretagogues (GHSs) possess a strong and reproducible GH-releasing effect and synergize with GHRH. The combination of GHRH and a peptidyl GHS, such as hexarelin or GH-releasing peptide-6, has recently been shown as another reliable test for the diagnosis of adult GHD, again provided that the cutoff limit is appropriate to the potency of the test. Thus, GHRH combined with either arginine or GHS is a potential tool for the diagnosis of adult GHD.

Adult↗

PubMed2001

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↗

PubMed2001

Gender and gonadal influences on ghrelin mRNA levels in rat stomach.

OBJECTIVE: The recently isolated endogenous GH secretagogue, named ghrelin, is a gastric peptide of 28 amino acids with an n-octanoylation in the serine 3 that confers the biological activity to this factor. Ghrelin has been shown to directly stimulate GH release in vivo and in vitro and to be involved in the regulation of gastric acid secretion and motility. In the present work we have studied gender and gonadal dependency of ghrelin mRNA expression in rat stomach. DESIGN AND METHODS: We analysed ghrelin mRNA expression in rat stomach by Northern blot analysis. We also examined the effect of gonadal steroid deprivation on ghrelin mRNA expression. RESULTS AND CONCLUSIONS: The results obtained showed clearly that ghrelin gastric mRNA expression increased with age in young rats (up to 90 days old) but exhibited no significant sex difference at each age tested. Ghrelin mRNA levels were lowest at postnatal day 9, reaching a stable level of expression at day 40 in both female and male rats, although the increase in female rats appears much more gradual than that in males. Moreover, neither ovariectomy nor orchidectomy significantly modified ghrelin mRNA gastric levels in adult rats. In conclusion, these data indicate that ghrelin mRNA expression is associated with age and that a progressive increase is present from the perinatal period up to a stable level after puberty. Gonadal hormones did not alter ghrelin mRNA levels. Taken together, these data showed that ghrelin mRNA levels in young rats are age but not gender dependent, and are not influenced by gonadal steroids.

Aging↗

PubMed2001

Enhancement of the peripheral sensitivity to growth hormone in adults with GH deficiency.

OBJECTIVE: Adults with severe GH deficiency (GHD) need recombinant human growth hormone (rhGH) replacement to restore body composition, structure functions and metabolic abnormalities. The optimal rhGH dose for replacement has been progressively reduced to avoid side effects. The aim of the present study was to define the minimal rhGH dose able to increase both IGF-I and IGF binding protein (BP)-3 levels in GHD and to verify the possible change in GH sensitivity. DESIGN AND PATIENTS: To this goal, we studied the effect of 4-day treatment with 3 rhGH doses (1.25, 2.5 and 5.0 microg/kg/day) on IGF-I and IGFBP-3 levels in 25 panhypopituitary adults with severe GHD (12 males and 13 females, age: 44.5+/-3.0 years, body mass index (BMI): 27.0+/-0.9 kg/m(2)) and 21 normal young adult volunteers (NV, 12 males and 9 females, age: 30.5+/-2.0 years, BMI: 20.8+/-0.5 kg/m(2)). RESULTS: Basal IGF-I and IGFBP-3 levels in GHD were lower (P<0.001) than in NV. In NV the 1.25 microg/kg dose of rhGH did not modify IGF-I levels. The dose of 2.5 microg/kg rhGH significantly increased IGF-I levels in men (P<0.001) but not in women, while the 5.0 microg/kg dose increased IGF-I levels in both sexes (P<0.001). IGFBP-3 levels were not modified by any of the administered rhGH doses. In GHD patients, all rhGH doses increased IGF-I levels 12 h after both the first (P<0.01) and the fourth rhGH dose (P<0.001). At the end of treatment percentage increases in IGF-I were higher (P<0.001) in GHD patients than in NV. In contrast with NV, in GHD patients the IGF-I response to short-term stimulation with rhGH was independent of gender. Moreover, GHD patients showed increases in IGFBP-3 after the fourth administration of both 2.5 and 5.0 microg/kg rhGH. CONCLUSION: The results of the present study demonstrate that the minimal rhGH dose able to increase IGF-I and IGFBP-3 levels in GHD patients is lower than in normal subjects, at least after a very short treatment. This evidence suggests an enhanced peripheral GH sensitivity in GH deprivation.

Adult↗