Biomedical subjects

E Arvat

Publications and source records attributed to E Arvat.

At least 109 records · Page 6Linked to original sources

PubMed1998

Specific receptors for synthetic GH secretagogues in the human brain and pituitary gland.

In vitro studies have been performed to demonstrate and characterize specific binding sites for synthetic GH secretagogues (sGHS) on membranes from pituitary gland and different human brain regions. A binding assay for sGHS was established using a peptidyl sGHS (Tyr-Ala-hexarelin) which had been radioiodinated to high specific activity at the Tyr residue. Specific binding sites for 125I-labelled Tyr-Ala-hexarelin were detected mainly in membranes isolated from pituitary gland and hypothalamus, but they were also present in other brain areas such as choroid plexus, cerebral cortex, hippocampus and medulla oblongata with no sex-related differences. In contrast, negligible binding was found in the thalamus, striatum, substantia nigra, cerebellum and corpus callosum. The binding of 125I-labelled Tyr-Ala-hexarelin to membrane-binding sites is a saturable and reversible process, depending on incubation time and pH of the buffer. Scatchard analysis of the binding revealed a finite number of binding sites in the hypothalamus and pituitary gland with a dissociation constant (Kd) of (1.5 +/- 0.3) x 10(-9) and (2.1 +/- 0.4) x 10(-9) mol/l respectively. Receptor activity is sensitive to trypsin and phospholipase C digestion, suggesting that protein and phospholipids are essential for the binding of 125I-labelled Tyr-Ala-hexarelin. The binding of 125I-labelled Tyr-Ala-hexarelin to pituitary and hypothalamic membranes was displaced in a dose-dependent manner by different unlabelled synthetic peptidyl (Tyr-Ala-hexarelin, GHRP2, hexarelin, GHRP6) and non-peptidyl (MK 0677) sGHS. An inhibition of the specific binding was also observed when binding was performed in the presence of [D-Arg1-D-Phe5-D-Trp7,9-Leu11]-substance P, a substance P antagonist that has been found to inhibit GH release in response to sGHS. In contrast, no competition was observed in the presence of other neuropeptides (GHRH, somatostatin, galanin or Met-enkephalin) which have a known influence on GH release. In conclusion, the present data demonstrate that sGHS have specific receptors in human brain and pituitary gland and reinforce the hypothesis that these compounds could be the synthetic counterpart of an endogenous GH secretagogue involved in the neuroendocrine control of GH secretion and possibly in other central activities.

Adult↗

PubMed1998

Orally active growth hormone secretagogues: state of the art and clinical perspectives.

Growth hormone secretagogues (GHS) are synthetic, non-natural peptidyl and nonpeptidyl molecules with potent stimulatory effect on somatotrope secretion. They have no structural homology with growth hormone-releasing hormone (GHRH) and act via a specific receptor, which has now been cloned and is present at both the pituitary and hypothalamic level. This evidence strongly suggests the existence of a still unknown natural GHS-like ligand. Several data favour the hypothesis that GHS could counteract somatostatinergic activity at both the pituitary and hypothalamic level and/or, at least partially, via a GHRH-mediated mechanism. However, the possibility that they act via an unknown hypothalamic factor remains open. GH-releasing peptide-6 (GHRP-6) is the first hexapeptide studied extensively in humans. More recently, peptidyl superanalogues GHRP-1, GHRP-2 and hexarelin, and nonpeptidyl mimetics, such as the spiroindoline derivative MK-677, have been synthesized and their effects have been studied in humans. The GH-releasing activity of GHS is marked, dose related and reproducible after intravenous, subcutaneous, intranasal and even oral administration. The effect of GHS is partially desensitized but prolonged, intermittent oral administration increases insulin-like growth factor I (IGF-I) levels. The GH-releasing effect of GHS undergoes age-related variations; it increases from birth to puberty, remains similar in adulthood and decreases with ageing. The effect of GHS on GH release is synergistic with that of GHRH, while it is only partially refractory to inhibitory influences, which nearly abolish the effect of GHRH. GHS maintain their GH-releasing activity in some somatotrope hypersecretory states such as acromegaly, anorexia nervosa, hyperthyroidism and critical illness. The GH response to GHS has been reported clear although reduced in GH deficiency, obesity and hypothyroidism, while it is strongly reduced in patients with pituitary stalk disconnection or Cushing's syndrome. In short children, elderly subjects, critically ill patients and even in adult patients with GH deficiency an increase of IGF-I has been shown after GHS treatment. These data indicate that treatment with orally active GHS in humans enhances the activity of the GH-IGF-I axis and could be clinically useful.

Administration, Oral↗

PubMed1998

GH response to GHRH combined with pyridostigmine or arginine in different conditions of low somatotrope secretion in adulthood: obesity and Cushing's syndrome in comparison with hypopituitarism.

BACKGROUND: Diagnosing GH deficiency in adults is difficult due to the age-related variations of GH/IGF-I axis and the influence of nutrition. Nowadays, GH replacement is allowed for patients with GH peak to provocative stimuli < 3 micrograms/L. Somatotrope insufficiency is present in hypopituitarism but also in obesity and hypercortisolism. However, to evaluate GH insufficiency in adults is difficult due to variations of GH and IGF-I levels as function of age and nutrition status. METHODS: We aimed to verify the GH response to GHRH (1 microgram/kg i.v.) combined with pyridostigmine (PD, 120 mg p.o.) or arginine (ARG, 0.5 g/kg i.v.), in 26 hypopituitaric patients (GHD), in 11 obese women (OB), in 8 women with Cushing's syndrome (CS), and in 72 control subjects (NS). RESULTS: IGF-l levels in GHD were lower than those in OB (p < 0.01) and in CS (p < 0.01) which, in turn, were lower to those in NS (p < 0.02). In NS, the GH peak responses to GHRH + PD and GHRH + ARG were similar and the minimum normal GH peak was 16.5 micrograms/L. GHD had GH responses similar, lower than those in NS (p < 0.01) and always below the normal limit. However, only 12/20 and 8/14 had peaks < 3 micrograms/L; conventionally, below this limit severe GH deficiency is shown and rhGH replacement is allowed. In OB, the GH responses to GHRH + PD and GHRH + ARG were similar, lower (p < 0.01) and higher (p < 0.01) than those in NS and GHD, respectively. Six out of 11 OB had GH peaks below the normal limits but nobody < 3 micrograms/L. In CS the GH response to GHRH + PD was lower than that to GHRH + ARG (p < 0.01); both these responses were lower than those in NS (p < 0.01) and even in OB (p < 0.01) but higher than those in GHD (p < 0.01). All and 7/8 CS had GH peaks lower than normal limits after PD + GHRH and ARG + GHRH, respectively while 6/8 showed GH peak < 3 micrograms/L after PD + GHRH but only 1 after ARG + GHRH. CONCLUSIONS: Present data demonstrate that the maximal somatotrope secretory capacity is reduced in OB and even more in CS. From a diagnostic point of view, PD + GHRH and ARG + GHRH tests distinguish OB from severe GHD. As hypercortisolism impairs the activity of cholinesterase inhibitors, only ARG + GHRH, but not PD + GHRH is a reliable test to explore the maximal somatotrope secretory capacity in CS. Notably, even with the ARG + GHRH test, in CS the maximal somatotrope secretory capacity is sometimes so reduced as to overlap with that of severe GHD.

Adult↗

PubMed1997

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↗

PubMed1997

Reduction of the somatotrope responsiveness to GHRH and Hexarelin but not to arginine plus GHRH in hyperprolactinemic patients.

Aim of the present study was to verify the maximal secretory capacity of somatotrope cells in patients with pathological hyperprolactinemia (HPRL) comparing it with that in normal age-matched women (NW). To this goal in 12 HPRL normal weight patients (age 28.6 +/- 2.6 yr, BMI 23.1 +/- 1.1 kg/m2) and 8 NW (27.2 +/- 0.8 yr, 22.8 +/- 0.8 kg/m2) we studied the GH response to GHRH (1 microgram/kg i.v.), GHRH plus arginine (ARG, 0.5 g/kg i.v.), an amino acid probably acting at the hypothalamic level inhibiting somatostatin release, and Hexarelin (HEX, 2 micrograms/kg i.v.), a synthetic hexapeptide belonging to GHRP family, which acts concomitantly at the pituitary and the hypothalamic level. IGF-I levels in HPRL were similar to those in NW (179.2 +/- 16.5 micrograms/l and 218.5 +/- 30.8 micrograms/l). In NW the GH response to GHRH (AUC: 1299.5 +/- 186.9 micrograms 90 min/l) was lower (p < 0.02) than those to GHRH + ARG (5252.7 +/- 846.3 micrograms 90 min/l) and HEX 3216.6 +/- 462.3 micrograms 90 min/l) which, in turn, were similar. In HPRL the GH response to GHRH (894.7 +/- 242.4 micrograms 90 min/l) was lower (p < 0.03) than that to HEX (1586.5 +/- 251.3 micrograms 90 min/l) and both were lower (p < 0.03) than that to GHRH + ARG (4468.8 +/- 941.7 micrograms 90 min/l). In HPRL the GH responses to GHRH and HEX were lower than those that in NW (p < 0.03) while that to GHRH + ARG was similar in both groups. These results demonstrate that the somatotrope responsiveness to GHRH and HEX is clearly reduced in patients with pathological hyperprolactinemia. On the other hand, in this condition the GH response to GHRH + ARG is normal. As arginine likely acts via inhibition of hypothalamic somatostatin release, these findings show that the maximal secretory capacity of somatotrope cells in hyperprolactinemia is preserved and indicate that partial refractoriness of somatotrope cells to GHRH and HEX could be due to somatostatinergic hyperactivity.

Adenoma↗

PubMed1997

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↗

PubMed1997

Effects of GHRP-2 and hexarelin, two synthetic GH-releasing peptides, on GH, prolactin, ACTH and cortisol levels in man. Comparison with the effects of GHRH, TRH and hCRH.

GHRP-2 (D-Ala-D-beta Nal-Trp-D-Phe-Lys-NH2) and Hexarelin (HEX) (His-D-2-methylTrp-Ala-Trp-DPhe-Lys-NH2) are synthetic, non-natural super-analogs of GHRP-6 endowed with potent stimulatory effect on GH secretion and slight stimulatory effect on PRL, ACTH and cortisol levels. Their GH-releasing activity ahs never been compared each other and their effects on PRL, ACTH and cortisol have never been compared with that of other stimuli. To clarify these points, in 6 normal young adults (22-27 yr) we studied the GH, PRL, ACTH and cortisol responses to 1 and 2 micrograms/kg i.v. GHRP-2 and HEX comparing them with that after 1 micrograms/kg i.v. GHRH and 400 micrograms i.v. TRH + 2 micrograms/kg i.v. hCRH. The Gh responses to 2 micrograms/kg i.v. GHRP-2 or HEX, compared with those to 1 microgram/kg GHRH, were also studied in 6 normal elderly subjects (66-73 yr). In young adults 1 microgram/kg i.v. GHRP-2 and HEX induced a similar, strong GH response, which was higher (p < 0.05) than that to GHRH. The administration of 2.0 micrograms/kg i.v. GHRP-2 and HEX again elicited a similar GH response, which was higher (p < 0.05) than that after the 1.0 microgram/kg dose. In elderly subjects, the GH those in young subjects. In young adults, the PRL responses to all doses of GHRP-2 or HEX were similar and lower (p < 0.01) responses were similar to those to hCRH. In conclusion, our results demonstrate that, in man, GHRP-2 and HEX have similar, 2 and HEX is not fully specific, as they induce similar increases in PRL, ACTH and cortisol levels. The PRL-releasing activity of GHRPs is lower than that of TRH while their ACTH/cortisol-releasing activity is similar to that of hCRH.

Adrenocorticotropic Hormone↗

PubMed1997

Maximal secretory capacity of somatotrope cells in obesity: comparison with GH deficiency.

OBJECTIVE: To evaluate the maximal secretory capacity of somatotrope cells in obesity and to compare it with that in hypopituitaric patients with GH deficiency. DESIGN: Stimulation with GHRH. (1 microgram/kg i.v.), combined with arginine (ARG, 0.5 g/kg i.v.), which strongly potentiates the GH response to the neurohormone, likely inhibiting hypothalamic somatostatin. The reproducibility of the GH response to GHRH + ARG was evaluated in a second session. SUBJECTS: Forty-five patients with simple obesity (OB 11 male and 34 female, age 40.5 +/- 1.8 y, BMI 38.8 +/- 1.1 kg/m2), 49 patients with hypopituitarism (GHD, 23 male and 26 female, 43.6 +/- 2.4 y, 24.7 +/- 0.7 kg/m2) and 44 normal young volunteers (NS, 25 male and 19 female, 33.8 +/- 1.0 y, 21.6 +/- 0.3 kg/m2) were studied. MEASUREMENTS: GH levels were assayed by IRMA method, basally at -60 and 0 min, and than every 15 min up to +120 min. Basal IGF-I levels were assayed by RIA method, after acid-ethanol extraction. RESULTS: IGF-I levels in OB were lower (P < 0.005) than those in NS but higher (P < 0.005) than those in GHD. Mean peak GH response to GHRH + ARG in OB was clearly lower than that in NS (P < 0.005) and higher (P < 0.005) than that in GHD. Sixty-percent OB and 100% GHD showed peak GH responses lower than the minimum normal limit in NS (16.5 micrograms/l) while 4% OB and only 53% GHD with GH responses lower than 3 micrograms/l, the limit under which GH replacement therapy of severe deficiency is allowed. Good intraindividual reproducibility of the GH response to GHRH + arginine test was present in all groups (OB: r = 0.78, P < 0.0001; GHD: r = 0.57, P < 0.003; NS: r = 0.74, P < 0.0001;. CONCLUSIONS: The maximal secretory capacity of somatotrope cells is clearly less than normal in the obese but still more than is seen in GHD subjects. However, in about 50% of obese patients, the pituitary GH releasable pool overlaps with that of hypopituitaric patients with GH deficiency. Thus, even when the maximal secretory capacity of somatotrope cells is evaluated by a potent and reproducible provocative tests such as GHRH + arginine, overweight has to be taken in a great account as the cause of severely impaired GH response in patients with suspected GH deficiency.

Adult↗

PubMed1997

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↗

PubMed1997

Repeated administration of growth hormone-releasing hormone with or without previous administration of pyridostigmine in insulin-dependent diabetes mellitus.

In insulin dependent diabetes mellitus (IDDM) either elevated growth hormone (GH) levels or abnormal responses to specific as well as unspecific stimuli have been reported. As hyperglycemia is known to blunt GH response to various stimuli, a normal GH response to GHRH in presence of hyperglycemia should also be considered inappropriate. To investigate the mechanism underlying this inappropriate GH response, in 9 patients with IDDM, selected for normal GH response to GHRH, we studied the GH response to two consecutive GHRH boluses (1 microgram/kg), the second of which preceded 30 min before by pyridostigmine (120 mg p.o.). Seven age matched normal volunteers were evaluated as control group. Basal plasma glucose and serum GH levels were significantly higher in patients with IDDM than in normal subjects (184.4 +/- 9.6 vs 86.2 +/- 4.4 mg/dl, p < 0.01 and 2.4 +/- 1.0 vs 1.0 +/- 0.4 microgram/l, p < 0.01 respectively). Both in normal subjects and in patients with IDDM the GH response to the second consecutive GHRH administration was lower than that of the first GHRH bolus (delta AUC: 82.5 +/- 28.3 vs 401.1 +/- 131.2 micrograms/l/h, p < 0.05 and 77.2 +/- 30.4 vs 336.8 +/- 60.0 p < 0.02, respectively). Pyridostigmine was able to restore the blunted GH responsiveness to the second GHRH administration in both groups, but this response was found higher in normal than in diabetic subjects (delta AUC: 1250.8 +/- 136.2 vs 527.5 +/- 147.6, p < 0.01). Since the GH-releasing effect of PD is likely to be mediated by the inhibition of hypothalamic somatostatin release, our results suggest that there is also an impaired somatostatin tone in hyperglycemic type 1 diabetic patients with normal GH response to GHRH.

Adult↗

PubMed1997

Age-related growth hormone-releasing activity of growth hormone secretagogues in humans.

Growth hormone-releasing peptides (GHRPs) are synthetic molecules with strong, dose-related and reproducible growth hormone (GH)-releasing activity in humans. GHRPs act at both the pituitary and the hypothalamic level, where specific receptors have been located. In adults, GHRPs release more GH than does GH-releasing hormone (GHRP), whilst their co-administration has a synergistic effect, indicating that they have, at least partially, different mechanisms of action. However, normal activity of GHRH-secreting neurones is needed to achieve the full GH-releasing effect of GHRPs. In contrast to GHRH, the GH-releasing activity of GHRPs is not further increased by substances acting via inhibition of hypothalamic somatostatin, and is only blunted by substances that stimulate hypothalamic somatostatin release. Even free fatty acids and exogenous somatostatin, which act directly on somatotrophs, do no more than blunt the effect of GHRPs. Thus, the GH-releasing activity of GHRPs is partially refractory to inhibitory influences, GHRPs act, at least in part, by antagonism of somatostatin activity, both at the pituitary and the hypothalamic level. The GH-releasing effect of GHRPs is not dependent on gender, but undergoes age-related variations. Gonadal steroids seem to influence the activity of GHRPs only in childhood. The reduced GH response to GHRPs in the elderly is probably due mainly to concomitant GHRH hypoactivity and somatostatinergic hyperactivity. A preserved GH-releasing effect of GHRPs has been reported in acromegaly, anorexia nervosa, hyperthyroidism and in critically ill patients. GHRPs have also been found to increase GH release in children with idiopathic short stature, in GH deficiency and in obese patients, in whom there is a well-known reduction of somatotroph function. The GH response to GHRPs is markedly reduced in hypothyroidism and Cushing's syndrome.

Aging↗

PubMed1997

Hexarelin, a synthetic growth-hormone releasing peptide, shows no interaction with corticotropin-releasing hormone and vasopressin on adrenocorticotropin and cortisol secretion in humans.

Hexarelin (HEX) is a synthetic growth-hormone-releasing peptide (GHRP) which acts via specific receptors at both the pituitary and the hypothalamic level to stimulate GH release both in animals and in man. Like other GHRPs, HEX possesses also significant prolactin- and adrenocorticotropin (ACTH) cortisol-releasing activity, but the mechanisms underlying these effects are even less clear. To clarify the mechanisms by which HEX stimulates the pituitary-adrenal axis in man, in 7 healthy young volunteers we studied the effects of HEX (2.0 microg/kg i.v.) and/or human corticotropin-releasing hormone (hCRH; 2.0 microg/kg i.v.) and/or arginine vasopressin (AVP; 0.17 U/kg i.m.) on ACTH and cortisol secretion. The GH responses to HEX alone and combined with hCRH and/or AVP were also studied. HEX increased ACTH and cortisol secretion (peak, mean +/- SEM: 26.3 +/- 5.1 vs. 15.8 +/- 3.1 pg/ml and 145.0 +/- 11.4 vs. 131.7 +/- 11.7 microg/l, p < 0.01, respectively) to levels overlapping with those induced by AVP (27.9 +/- 6.1 vs. 13.1 +/- 3.5 pg/ml and 167.6 +/- 16.2 vs. 113.3 +/- 9.4 microg/l, p < 0.01, respectively) and similar to those elicited by hCRH (28.1 +/- 4.6 vs. 17.4 +/- 3.1 pg/ml and 182.7 +/- 22.8 vs. 114.8 +/- 12.3 microg/l, p < 0.02, respectively). The ACTH but not the cortisol response to hCRH was higher (p < 0.02) than those to HEX when evaluated as area under the curve. The co-administration of HEX and AVP had no significant interaction on ACTH and cortisol peak levels (40.7 micro 5.3 pg/ml and 168.8 +/- 13.5 microg/l, respectively). On the other hand, the co-administration of HEX and hCRH had a less than additive effect on ACTH and cortisol secretion (53.3 +/- 11.2 pg/ml and 204.0 +/- 13.7 microg/l, respectively). CRH and AVP had a true synergistic effect on ACTH (104.9 +/- 14.2 pg/ml, p < 0.01) and an additive effect on cortisol secretion (281.3 +/- 10.8 microg/l, p < 0.02). HEX did not modify the effect of CRH + AVP on both ACTH (135.5 +/- 22.0 pg/ml) and cortisol secretion (261.1 +/- 13.2 microg/l). The GH response to HEX (55.7 +/- 19.8 vs. 2.7 +/- 1.9 microg/l, p < 0.005) was unaffected by the administration of CRH alone (53.5 +/- 21.0 microg/l) and/or AVP co-administration (60.2 +/- 21.2 and 45.9 +/- 10.6 microg/l, respectively). In conclusion, the results of this study demonstrate that GHRPs, beside their well-known GH-releasing activity, possess a remarkable ACTH-releasing activity, overlapping with that of AVP and similar to that of hCRH, two neurohormones which are known to play the major role in the control of the pituitary-adrenal axis. It is noteworthy that HEX shows no synergistic effect with either AVP or hCRH which, on the other hand, truly synergize. This evidence suggests the hypothesis that the ACTH-releasing activity of GHRPs could be, at least partially, independent of both CRH- and AVP-mediated actions in humans.

Adrenocorticotropic Hormone↗

PubMed1997

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↗

PubMed1997

Growth hormone-releasing peptides.

Growth hormone-releasing peptides (GHRPs) are synthetic, non-natural peptides endowed with potent stimulatory effects on somatotrope secretion in animals and humans. They have no structural homology with GHRH and act via specific receptors present either at the pituitary or the hypothalamic level both in animals and in humans. The GHRP receptor has recently been cloned and, interestingly, it does not show sequence homology with other G-protein-coupled receptors known so far. This evidence strongly suggests the existence of a natural GHRP-like ligand which, however, has not yet been found. The mechanisms underlying the GHRP effect are still unclear. At present, several data favor the hypothesis that GHRPs could act by counteracting somatostatinergic activity both at the pituitary and the hypothalamic level and/or, at least partially, via a GHRH-mediated mechanism. However, the possibility that GHRPs act via an unknown hypothalamic factor (U factor) is still open. GHRP-6 was the first hexapeptide to be extensively studied in humans. More recently, a heptapeptide, GHRP-1, and two other hexapeptides, GHRP-2 and Hexarelin, have been synthesized and are now available for human studies. Moreover, non-peptidyl GHRP mimetics have been developed which act via GHRP receptors and their effects have been clearly demonstrated in animals and in humans in vivo. Among non-peptidyl GHRPs, MK-0677 seems the most interesting molecule. The GH-releasing activity of GHRPs is marked and dose-related after intravenous, subcutaneous, intranasal and even oral administration. The effect of GHRPs is reproducible and undergoes partial desensitization, more during continuous infusion, less during intermittent administration: in fact, prolonged administration of GHRPs increases IGF-1 levels both in animals and in humans. The GH-releasing effect of GHRPs does not depend on sex but undergoes age-related variations. It increases from birth to puberty, persists at a similar level in adulthood and decreases thereafter. By the sixth decade of life, the activity of GHRPs is reduced but it is still marked and higher than that of GHRH. The GH-releasing activity of GHRPs is synergistic with that of GHRH, is not affected by opioid receptor antagonists, such as naloxone, and is only blunted by inhibitory influences, including neurotransmitters, glucose, free fatty acids, gluco corticoids, recombinant human GH and even exogenous somatostatin, which are known to almost abolish the effect of GHRH. GHRPs maintain their GH-releasing effect in somatotrope hypersecretory states such as in acromegaly, anorexia nervosa and hyperthyroidism. On the other hand, their good GH-releasing activity has been shown in some but not in other somatotrope hyposecretory states. In fact, reduced GH responses after GHRP administration have been reported in idiopathic GH deficiency as well as in idiopathic short stature, in obesity and in hypothyroidism, while in patients with pituitary stalk disconnection or Cushing's syndrome the somatotrope responsiveness to GHRPs is almost absent. In short children an increase in height velocity has also been reported during chronic GHRP treatment. Thus, based on their marked GH-releasing effect even after oral administration, GHRPs offer their own clinical usefulness for treatment of some GH hyposecretory states.

Animals↗

PubMed1997

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↗

PubMed1997

The GH, prolactin, ACTH and cortisol responses to Hexarelin, a synthetic hexapeptide, undergo different age-related variations.

Hexarelin (HEX) is a synthetic growth hormone-releasing peptide (GHRP) which acts on specific receptors at both the pituitary and the hypothalamic level to stimulate GH release in an age-dependent manner. Like other GHRPs, HEX possesses also prolactin (PRL) and ACTH/cortisol-releasing activity. similar to that of human corticotropin-releasing hormone (hCRH). The mechanisms underlying the stimulatory effect of GHRPs on lactotrope and corticotrope secretion are even less clear and the influence of age on these endocrine activities of GHRPs is unknown. To clarify this point we studied the GH, PRL, ACTH and cortisol responses to the maximal effective dose of HEX (2.0 micrograms/kg i.v.) in: 12 prepubertal children (Pre-C, 8 male, 4 female, age 5.8-12.1 years); 12 pubertal normal short children (Pub-C, 5 male, 7 female, age 9.7-15.5 years, pubertal stage II-IV); 20 normal young adults (Young, 6 males, 14 females, age 23-32 years); and in 16 normal elderly people (Elderly, 5 male, 11 female, age 66-81 years). The GH response to HEX was clear in Pre-C (0-120 min area under curve, mean +/- S.E.M. 769.5 +/- 122.2 micrograms*min/l) but strikingly increased (P < 0.001) in Pub-C (1960.2 +/- 283.5 micrograms*min/l). The HEX-induced GH rise in Young (1829.7 +/- 243.1 micrograms*min/l) persisted similar to that in Pub-C, but decreased in Elderly (951.1 +/- 232.9 micrograms*min/I, P < 0.005); the latter was, in turn, similar to that in Pre-C. HEX induced a significant PRL increase which, however, showed no age-related variations, being similar in Pre-C (512.1 +/- 88.0 micrograms*min/l), Pub-C (584.0 +/- 106.0 micrograms*min/l), Young (554.9 +/- 56.0 micrograms*min/l) and Elderly (523.9 +/- 59.6 micrograms*min/l). The ACTH-releasing activity of HEX was present in Pre-C (1356.6 +/- 204.9 pg*min/ml) and was clearly enhanced (P < 0.02) in Pub-C (2253.5 +/- 242.8 pg*min/ml). The ACTH rise after HEX in Young (1258.1 +/- 141.2pg*min/ml) was lower (P < 0.02) than that in Pub-C and similar to that in Pre-C, while the ACTH response to HEX in Elderly (1786.5 +/- 340.1 pg*min/ml) showed a further trend toward increase, being similar to that in Pub-C. On the other hand, the cortisol response to HEX showed no significant age-related variations, being not different in Pre-C (7747.2 +/- 1031.6 micrograms*min/l), Pub-C (6106.0 +/- 862.9 micrograms*min/l), Young (6827.5 +/- 509.6 micrograms*min/I) and Elderly (7950.6 +/- 658.3 micrograms*min/l). In conclusion, our present data demonstrate that in humans the GH- and ACTH-releasing activities of HEX undergo different age-related variations, while its PRL-releasing activity is not dependent on age. These finding suggest that actions at different levels and/or on different receptor subtypes mediate the different age-related hormonal effects of GHRPs.

Adolescent↗

PubMed1996

Influence of beta-adrenergic agonists and antagonists on the GH-releasing effect of Hexarelin in man.

Beta-adrenergic receptors mediate the inhibitory influence of cathecolamines on GH secretion, probably via the stimulation of hypothalamic somatostatin release. Accordingly, beta-adrenergic agonists and antagonists inhibit and increase, respectively, the GH response to many stimuli, including GHRH, in man. Aim of the present study was to verify the effect, if any, of beta-adrenergic drugs on the GH response to Hexarelin, a synthetic GH-releasing hexapeptide. Interestingly, the GH-releasing effect of Hexarelin has been reported to be partially refractory to neuroendocrine manipulations known to strongly enhance or abolish the GHRH-induced GH release. In 6 normal male volunteers (aged 22-27 yr) we studied the interaction of the maximally effective iv dose of Hexarelin (HEX, 2 micrograms/kg iv at 0 min) with atenolol (100 mg po at -60 min) or salbutamol (0.08 mg/kg po at -60 min), which are beta-adrenergic antagonist and agonist, respectively. HEX induced a marked GH rise (AUC, mean +/- SE: 4573.2 +/- 588.8 micrograms.min/L), which was unchanged by atenolol (4706.2 +/- 928.2 micrograms.min/L) but blunted by salbutamol (2792.8 +/- 618.0 micrograms.min/L, p < 0.03). In conclusion, present data show that, in man, the GH-releasing effect of Hexarelin is not enhanced by beta-adrenergic blockade while is only blunted by the activation of beta receptors. According to other data, these results indicate that the potent GH-releasing activity of Hexarelin is, at least partially, refractory to beta-adrenergic-mediated manipulations of somatostatinergic activity.

Adrenergic beta-Agonists↗

PubMed1996

Galanin positively modulates prolactin secretion in normal women.

It is widely accepted that, in man, galanin, a neuropeptide, has a clear GH-releasing effect while its stimulatory influence on PRL secretion is matter of debate. To clarify this point, in 6 normal young women (23-35 yr) in their early follicular phase, we studied the effect of galanin (pGAL, 80 pmol/kg. min infused i.v. over 60 min) on both basal and arginine (ARG, 0.5 g/kg i.v. in 30 min), TRH (400 micrograms i.v. as a bolus at 0 min) or metoclopramide (MCP, 10 mg i.v. as a bolus at 0 min)-stimulated PRL secretion. GAL infusion failed to significantly increase basal PRL levels (peak vs baseline: 12.2 +/- 3.6 vs 8.7 +/- 1.2 micrograms/L) but counteracted the spontaneous PRL decrease observed during saline infusion (AUC: 1216.6 +/- 282.1 vs 672.0 +/- 94.5 micrograms.min/L; p < 0.05). GAL infusion clearly enhanced the PRL response to TRH (AUC: 5806.3 +/- 743.0 vs 3952.1 +/- 423.9 micrograms.min/L, p < 0.05) and ARG (AUC: 3676.8 +/- 382.6 vs 2638.9 +/- 287.0 micrograms.min/L, p < 0.05), respectively. On the other hand, GAL failed to modify the MCP-induced PRL response (AUC: 15409.5 +/- 2085.3 vs 14,787.9 +/- 2045.5 micrograms.min/L). The PRL response to MCP was higher than that to TRH (p < 0.01) which, in turn, was higher than that to ARG (p < 0.01). During GAL infusion, the PRL response to TRH or ARG remained lower (p < 0.01) than that after MCP administration. Thus, in conclusion, present data demonstrate that in normal women galanin enhances the PRL response to ARG and TRH but fails to modify that induced by dopamine receptor blockade with metoclopramide. Based on evidence that the inhibition of central dopaminergic activity inhibits the lactotrope responsiveness to dopaminergic antagonists or TRH, it is unlikely that galanin influences PRL secretion via inhibition of dopaminergic tone.

Adult↗