Biomedical subjects

E Arvat

Publications and source records attributed to E Arvat.

At least 127 records · Page 7Linked to original sources

PubMed1996

Hexarelin, a synthetic growth hormone releasing peptide, stimulates prolactin secretion in acromegalic but not in hyperprolactinaemic patients.

OBJECTIVE: In man, new synthetic peptides such as hexarelin have been shown to have a potent and dose dependent GH releasing activity. Furthermore, a significant PRL releasing activity has also been demonstrated, but this has been investigated in less detail. We have therefore evaluated the effect of hexarelin on PRL and GH secretion in patients with active acromegaly or pathological hyperprolactinaemia. DESIGN: Hexarelin (2 micrograms/kg i.v.), a modified derivative of GHRP-6 of the following structure: His-2-Me-D-Trp-Ala-Trp-D-Phe-Lys-NH2, or placebo, was administered in random order on two separate occasions. PATIENTS: Eight patients with active acromegaly (ACRO, 6 F and 2 M, mean age 61.7 years, range 56-73), 6 with macroadenomas and 2 without radiological signs of tumour, and 6 female patients with pathological hyperprolactinaemia (HPRL, mean age 31.2 years, range 18-47) 5 with microadenomas and 1 with empty sella, were studied. Fourteen normal subjects (NS, 8 F and 6 M, 27.1 years, 24-30) were studied as controls. MEASUREMENTS: GH and PRL levels were evaluated every 15 minutes for 2 hours after hexarelin or placebo. Both hormones were measured using commercial IRMA kits. Basal IGF-I was measured in all subjects using an RIA following acid-ethanol extraction. RESULTS: Hexarelin induced a significant increase in PRL levels in NS (median, range, delta peak HEX vs placebo: 150 (-14-402) vs 10 (-34-24) mU/l; delta AUC HEX vs placebo: 7710 (2,100-3 2540) vs 30 (-2,566-2,040) mU min/l, P < 0.01) and in ACRO (190 (-10-496) vs 6 (-100-34) mU/l; 10,170 (-5,310-51,436) vs -82 (-6,030-1,410) mU min/l, P < 0.02), but not in HPRL (10 (-180-80) vs 50 (-100-240) mU/l; -600 (-16,996-10,140) vs -1,950 (-8,540-14,160) mU min/l). Hexarelin also induced a lower increase of GH in HPRL (60 (30-82) vs 1.8 (-0.2-2.2) mU/l; 2,853 (1,477.6-4,372.6 vs 91.6 (-160.6-174) mU min/l, P < 0.05) than in NS (90.8 (50.6-181) vs 0.8 (-1.2-6.8) mU/l; 6642 (2,004-13,252.6 vs 42 (456-900) mU min/l, P < 0.01) or in ACRO (117.2 (21.2-420.6 vs 3.8 (-2.2-18) mU/l; 6645 (1,554-22,138.6 vs 334.6 (-324-1,065) mU min/l, P < 0.02). CONCLUSIONS: Our data show that the PRL releasing effect of hexarelin is preserved in acromegaly but lost in pathological hyperprolactinaemia. In contrast with acromegaly, the GH releasing effect of hexarelin is also blunted in hyperprolactinaemic patients. These data demonstrate that patients with pathological hyperprolactinaemia are partially refractory to the activity of hexarelin.

Acromegaly↗

PubMed1996

New approach to the diagnosis of growth hormone deficiency in adults.

Pyridostigmine (PD), a muscarinic cholinergic agonist, and arginine (ARG) clearly increase the growth hormone (GH) response to growth hormone-releasing hormone (GHRH) in man. The current study was undertaken to investigate the value and safety of PD + GHRH and ARG + GHRH tests as well as the measurement of serum insulin-like growth factor I (IGF-I) in diagnosing GH deficiency in adults. Fifty-four patients considered GH deficient from extensive organic or idiopathic pituitary disease and 326 healthy adults were studied. The IGF-I concentrations were lower than the 3rd percentile of normal values in only 31 of the 54 (57.4%) patients with hypopituitarism. However, the IGF-I levels in hypopituitary patients and in normal subjects overlapped more frequently between 41 and 60 years (50%) and between 61 and 80 years (92.3%) as opposed to between 20 and 40 years (8.6%). In contrast to the IGF-I measurement, the ranges of peak GH responses to PD + GHRH and ARG + GHRH tests were clearly differentiated between the hypopituitary (0.2-6.8 and 0.1-9.5 microg/l, respectively) and normal (17.7-114 and 16.1-119 microg/l, respectively). However, the PD + GHRH test was reliable only in subjects of 20-40 years of age. In conclusion, IGF-I measurement had no value in the diagnosis of GH deficiency in adults aged over 40 years, but is reliable enough when young adults of 20-40 years of age are considered. Both PD + GHRH and ARG + GHRH testing should be considered more reliable biochemical measurements of GH deficiency. In contrast to the PD + GHRH test, the ARG + GHRH test is reliable throughout the adult lifespan and appears to be the most appropriate for patient compliance and safety.

Adult↗

PubMed1996

Short-term administration of intranasal or oral Hexarelin, a synthetic hexapeptide, does not desensitize the growth hormone responsiveness in human aging.

The function of the growth hormone-insulin-like growth factor I (GH-IGF-I) axis is reduced in aging, although the secretory capacity of somatotrope cells is preserved. Previous studies have suggested that continuous administration of GH-releasing peptides (GHRPs) results in homologous desensitization to the GH-releasing effect of the peptides. In the present study we have studied whether healthy elderly subjects would remain responsive to short-term, intermittent treatment with Hexarelin (HEX), a GHRP, and whether this treatment would result in an increase in serum IGF-I. In study I, the effect of an 8-day treatment with intranasal administration of 1.25 mg (about 18 micrograms/kg) t.i.d. HEX on the acute GH response to the hexapeptide and on serum IGF-I, IGF binding protein 3 (IGFBP-3), prolactin and cortisol levels was studied in seven elderly subjects (four males and three females, aged 67-80 years). In study II, the same parameters were studied before and after a 15-day treatment with oral administration of 20 mg (about 300 micrograms/kg) t.i.d. HEX in seven elderly women (aged 63-80 years). The GH response to the intranasal HEX administration was not significantly higher than that induced by 1 microgram/kg iv GHRH (229.4 +/- 35.9 vs 145.8 +/- 26.9 micrograms.l-1.h-1) and was maintained with a trend towards increase after an 8-day treatment with the peptide (342.5 +/- 199.3 micrograms.l-1.h-1). On the other hand, HEX treatment did not significantly modify IGF-I (138.7 +/- 11.1 vs 122.4 +/- 14.1 micrograms/l) but increased IGFBP-3 levels (2.4 +/- 0.2 vs 1.6 +/- 0.2 mg/l, p < 0.02). The GH response to the oral HEX administration was also not significantly higher than that to iv GHRH (257.6 +/- 72.0 vs 179.0 +/- 42.8 micrograms.l-1.h-1) and did not change after a 15-day treatment with the peptide (237.8 +/- 42.8 micrograms.l-1.h-1). Both IGF-I and IGFBP-3 levels were slightly but significantly increased by oral HEX treatment (156.0 +/- 10.7 vs 141.6 +/- 13.6 micrograms/l, p < 0.03, 3.4 +/- 0.2 vs 3.1 +/- 0.2 mg/l, p < 0.03, respectively). Neither intranasal nor oral HEX treatment modified PRL or cortisol levels and did not induce any side effect. In conclusion, these results indicate that chronic but intermittent treatment with HEX, administered either by intranasal or oral route, does not desensitize the GH response to the peptide. Moreover, after HEX treatment a trend towards increase was shown for IGF-I and IGFBP-3 levels. Thus, our findings strengthen the hypothesis that prolonged treatment with HEX may restore the reduced GH release in aging.

Administration, Intranasal↗

PubMed1996

Acute administration of recombinant human growth hormone inhibits the somatotrope responsiveness to growth hormone-releasing hormone in childhood.

In adulthood the growth hormone (GH) response to growth hormone-releasing hormone (GHRH) is inhibited by previous acute administration of either GH or GHRH and it is restored by substances that inhibit hypothalamic somatostatin release. Because in children the GH response to GHRH is not affected by previous neurohormone administration, it has been suggested that in childhood a GH increase is not able to trigger the somatostatin-mediated negative GH autofeedback mechanism. To verify this hypothesis, in 25 children (8 girls and 17 boys; 15 prepubertal and 10 in pubertal stages II-IV) with familial short stature (normal height velocity and insulin-like growth factor I levels) we studied the effect of acute i.v. administration of different recombinant human GH doses (group 1, N = 5, 0.06 U/kg; group 2, N = 6, 0.01 U/kg; group 3, N = 7, 0.005 U/kg at - 150 min) or saline on the GH response to GHRH (1 microgram/kg i.v. at 0 min). In another group (N = 7), we studied the effect of 0.005 U/kg iv recombinant human GH or saline on the GH response to GHRH combined with arginine (0.5 g/kg i.v. over 30 min), which likely inhibits hypothalamic somatostatin release. Serum GH increases after recombinant human GH were dose-dependent (GH peak, mean +/- SEM, 171.7 +/- 24.4, 33.3 +/- 3.9 and 21.8 +/- 5.1 micrograms/l, respectively). The administration of recombinant human GH strongly inhibited the GHRH-induced GH rise in all groups (group 1, 7.1 +/- 1.7 vs 23.1 +/- 7.6 micrograms/l, p < 0.05; group 2, 9.5 +/- 2.8 vs 26.9 +/- 8.5 micrograms/l, p < 0.05; group 3, 9.1 +/- 2.7 vs 34.8 +/- 7.2 micrograms/l, p < 0.02). The GH response to arginine + GHRH (56.9 +/- 13.3 micrograms/l) was higher than that to GHRH alone recorded in group 1 (p < 0.005), group 2 (p < 0.01) and group 3 (p < 0.01), while exogenous recombinant human GH failed to inhibit it (45.0 +/- 9.4 micrograms/l). Our results demonstrate that in childhood, as well as in adulthood, recombinant human GH administration inhibits the somatotrope responsiveness to GHRH. This inhibitory effect is likely to be mediated by hypothalamic somatostatin release.

Arginine↗

PubMed1996

Reproducibility of the growth hormone response to stimulation with growth hormone-releasing hormone plus arginine during lifespan.

The reliability and reproducibility of provocative stimuli of growth hormone (GH) secretion in the diagnosis of GH deficiency are still controversial both in childhood and in adulthood. The combined administration of GH-releasing hormone (GHRH) and arginine (ARG), which likely acts via inhibition of hypothalamic somatostatin release, is one of the most potent stimuli known so far and has been proposed recently as the best test to explore the maximal somatotrope capacity of somatotrope cells. However, it is well known that, usually, provocative stimuli of GH secretion suffer from poor reproducibility and that of the GHRH + ARG test has still to be verified. We aimed to verify the between- and within-subject variability of the GH response to the GHRH + ARG test in normal subjects during their lifespan as well as in hypopituitaric patients with GH deficiency (GHD). In 10 normal children (C: six male and four female, age 12.3 +/- 0.9 years, body mass index (BMI) = 16.6 +/- 0.7 kg/m2, pubertal stages I-III), 18 normal young adults (Y: ten male and eight female, age 31.1 +/- 1.3 years, BMI = 21.4 +/- 0.4 kg/m2), 12 normal elderly subjects (E: two male and ten female, age 74.4 +/- 1.8 years, BMI= 22.6 +/- 0.6 kg/m2) and 15 panhypopituitaric GH-deficient patients (GHD: nine male and six female, age 40.9 +/- 4.1 years, BMI= 22.7 +/- 1.0 kg/m2), we studied the inter- and intra-individual variability of the GH response to GHRH (1 microg/kg i.v.) + ARG (0.5 g/kg i.v.) in two different sessions at least 3 days apart. The GH responses to GHRH + ARG in C (1st vs 2nd session: 61.6 +/- 8.1 vs 66.5 +/- 9.4 microg/l), Y (70.4 +/- 10.1 vs 76.2 10.7 microg/l) and E (57.9 14.8 vs 52.1 +/- 8.0 microg/l) were similar and reproducible in all groups. The somatotrope responsiveness to GHRH + ARG also showed a limited within-subject variability (r = 0.71, 0.90 and 0.89 and p < 0.02, 0.0005 and 0.0005 for C, Y and E, respectively). Similarly in GHD, the GH response to the GHRH + ARG test showed a good inter- (1st vs 2nd session: 2.3 +/- 0.5 vs 2.2 +/- 0.6 microg/l) and intra-individual reproducibility (r = 0.70, p < 0.005). The GHRH + ARG-induced GH responses in GHD were markedly lower (p < 0.0005) than those in age-matched controls and no overlap was found between GH peak responses in GHD and normal subjects. In normal subjects, the GH response to GHRH + ARG is very marked, independent of age and shows limited inter- and intra-individual variability. The GH response to the GHRH + ARG test is strikingly reduced in panhypopituitaric patients with GHD, in whom the low somatotrope responsiveness is reproducible. Thus, these findings strengthen the hypothesis that GHRH + ARG should be considered the most reliable test to evaluate the maximal secretory capacity of somatotrope cells and to distinguish normal subjects from GHD patients in adulthood.

Adult↗

PubMed1996

Somatotrope responsiveness to Hexarelin, a synthetic hexapeptide, is refractory to the inhibitory effect of glucose in obesity.

Both spontaneous and stimulated growth hormone (GH) secretion is reduced in obesity, in which state insensitivity to the inhibitory effect of hyperglycemia also has been reported. To further investigate this point, in eight male obese (OB) patients (27-49 years old; body mass index = 39.5 +/- 1.7 kg/m2) we studied the effect of oral glucose load (100 g) on the GH response to Hexarelin (HEX, 2 micrograms/kg iv), a synthetic hexapeptide belonging to the GH-releasing peptide family, which has been reported to be able to induce a marked GH rise even in obese patients. As a control group, six male age-matched normal subjects (NS) were studied (26-35 years old; body mass index = 22.3 +/- 1.5 kg/m2). In all subjects the GH response to growth hormone-releasing hormone (GHRH, 1 microgram/kg iv) was also studied. Basal GH and insulin-like growth factor I (IGF-I) levels in OB and NS were similar (0.3 +/- 0.1 vs 0.5 +/- 1.0 microgram/l and 166.7 +/- 12.3 vs 145.4 +/- 6.9 micrograms/l, respectively). Hexarelin induced a clear GH rise in OB (peak: 20.0 +/- 2.9 micrograms/l; AUC: 1193.0 +/- 213.7 micrograms.l-1.120 min-1) but this response was clearly lower (p < 0.0002) than that observed in NS (62.6 +/- 7.3 micrograms/l, 4587.5 +/- 614.9 micrograms.l-1.120 min-1). The GHRH-induced GH rise was lower (p < 0.002) in OB (4.4 +/- 1.2 micrograms/l, 331.0 +/- 95.9 micrograms.l-1.120 min-1) than that in NS (20.2 +/- 1.9 micrograms/l, 1281.0 +/- 157.5 micrograms.l-1 .120 min-1) and both were lower (p < 0.05) than those induced by HEX. In NS, glucose significantly blunted the GH response to HEX (38.4 +/- 7.2 micrograms/l, 2236.5 +/- 514.8 micrograms.l-1.120 min-1, p < 0.05) but failed to modify it in OB (19.4 +/- 2.7 micrograms/l, 934.5 +/- 151.3 micrograms.l-1. 120 min-1). Plasma glucose peaks after oral glucose load in OB and NS were similar (164.5 +/- 9.7 vs 145.8 +/- 4.6 mg/dl). In conclusion, the present data demonstrate that, in contrast to normal subjects, in obese patients HEX has a reduced GH-releasing effect that is not inhibited by glucose. In OB patients as well as in normal subjects HEX releases more GH than GHRH. These findings strengthen the evidence that GH secretion in obesity is refractory either to stimulatory inputs or to the inhibitory effect of hyperglycemia.

Administration, Oral↗

PubMed1996

Human aging and the GH-IGF-I axis.

The activity of the GH-IGF-I axis undergoes an age-related reduction and in the elderly both spontaneous GH secretion and IGF-I levels are frequently low overlapping with those usually recorded in GH deficient patients. Hypoactivity of the GH-IGF-I axis could explain age-related changes in body composition, function and metabolism, as also indicated by evidence that treatment with rhGH reverses these alterations. The mechanisms underlying the hypoactivity of the GH-IGF-I axis in the aged likely include changes in nutrition and lifestyle, e.g. reduction of physical exercise. However, alterations of neurohormonal hypothalamic control of GH secretion, including reduced activity of GHRH-secreting neurons and somatostatinergic hyper-activity, seem to play a major role. The exaggerated somatostatinergic hyperactivity could be due, in turn, to the impairment of cholinergic activity found in the aging brain. Age-related variations in the activity of other neurotransmitters, such as catecholamines, amino acids, e.g. arginine, neuropeptides, e.g. galanin and/or a putative natural GHRP-like ligand, could play a key role in causing the reduced activity of the GH-IGF-I axis. It is still unclear whether it is of benefit to restore GH secretion in aging. As the pituitary GH releasable pool is preserved in the elderly, it would be more appropriate to increase GH by GH secretagogues such as the new synthetic GH-releasing peptides (GHRPs) or non-peptidyl GHRP mimetics which are active even with oral administration.

Aging↗

PubMed1995

Interaction of salbutamol and galanin on both basal and growth hormone releasing hormone-stimulated growth hormone secretion in humans.

Beta adrenergic receptors mediate the inhibitory influence of catecholamines on GH secretion in man, likely via stimulation of hypothalamic somatostatin release. To further clarify the role of beta adrenergic receptors in the neural control of GH secretion, in 7 normal females (age 21-27 yr) we studied the interaction of salbutamol (SAL 0.08 mg/kg orally), a beta 2-adrenergic agonist, with GHRH (1 microgram/kg i.v.) and/or galanin (GAL 15 micrograms/kg i.v.), a neuropeptide endowed with a GH-releasing effect which is likely mediated by concomitant stimulation of GHRH- and inhibition of somatostatin-secreting neurons. SAL inhibited the GH response to GHRH (AUC: 282.6 +/- 102.7 vs 1083.6 +/- 176.5 micrograms/l/h, p < 0.05) and, although not significantly, that to GAL (263.9 +/- 103.7 vs 418.4 +/- 70.4 micrograms/l/h). GAL enhanced the GHRH-induced GH rise (2129.5 +/- 362.2 micrograms/l/h, p < 0.05) but SAL pretreatment inhibited this effect (1249.8 +/- 257.1 micrograms/l/h, p < 0.02) so that the GH response to the combined administration of GHRH, GAL and SAL overlapped with that to the neurohormone alone. In conclusion, our results show that the inhibitory influence of beta adrenergic activation on GH secretion overrides the stimulatory one of galanin. They strengthen the view that in man beta-adrenergic receptors and galanin modulate GH secretion having opposite influences aimed to balance the function of the GH-IGF-I axis.

Adrenergic alpha-Agonists↗

PubMed1995

Metabolic modulation of the growth hormone-releasing activity of hexarelin in man.

Hexarelin (His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2) is a new potent synthetic growth hormone (GH)-releasing hexapeptide. The mechanism of action of hexarelin in man has never been evaluated. Hexarelin may act directly on specific pituitary receptors and indirectly on the hypothalamus. To elucidate its mechanism of action in man, we studied the interaction of hexarelin with glucose and free fatty acids (FFA), two metabolic factors known to inhibit both basal and GH-releasing hormone (GHRH) stimulated GH secretion. Glucose is thought to inhibit GH secretion via stimulation of endogenous somatostatin release, whereas FFA could also act directly on somatotrope cells. Therefore, we investigated the effect of oral glucose (100 g) and lipid-heparin infusion (250 mL of a 10% lipid solution + 2,500 U heparin) on the GH response to a maximal dose (2 micrograms/kg intravenously [IV]) of hexarelin or GHRH in six normal men. Hexarelin elicited a clear-cut GH response (mean +/- SEM; peak, 62.6 +/- 8.0 micrograms/L) that was higher (P < .01) than that observed after GHRH (peak, 19.8 +/- 2.4 micrograms/L). Although similar increases in plasma glucose were observed with the two peptides, oral glucose almost abolished the GH response to GHRH (peak, 5.6 +/- 0.9 micrograms/L, P < .01) while only blunting the somatotrope response to hexarelin (peak, 38.4 +/- 7.9 micrograms/L, P < .05). Similarly, lipid-heparin infusion nearly abolished the GH response to GHRH (peak, 4.9 +/- 1.0 micrograms/L, P < .01) while only blunting the somatotrope response to hexarelin (peak, 34.2 +/- 4.5 micrograms/L, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1995

Modulation of growth hormone-releasing activity of hexarelin in man.

Hexarelin (His-D-2-methyl-Trp-Ala-Trp-D-Phe-Lys-NH2) is a new synthetic growth hormone (GH)-releasing hexapeptide. The mechanism of action of hexarelin in man is not fully elucidated. As for other GH-releasing peptides, an action on both the pituitary gland and the hypothalamus has been hypothesized. In the present study, we evaluated the modulation of GH-releasing activity of hexarelin in man. In a first experiment conducted on 6 healthy male volunteers, we studied the interaction of the maximally effective intravenous dose of hexarelin (2 micrograms/kg i.v.) with GH-releasing hormone (GHRH, 2 micrograms/kg i.v.) and somatostatin (2 micrograms/kg/h i.v.). In a second experiment involving another 6 male subjects, we evaluated the interaction of hexarelin with neuroactive substances, such as pirenzepine (0.6 mg/kg i.v.), pyridostigmine (120 mg p.o.) and arginine (0.5 g/kg i.v.), thought to modulate endogenous somatostatin secretion. Hexarelin induced a higher increase in GH levels as compared to GHRH (integrated output calculated as area under the curve AUC0-120 4,693 +/- 691 vs. 1,494 +/- 102 micrograms.min/l, p < 0.01). Coadministration of hexarelin and GHRH produced a higher GH response than hexarelin alone (AUC0-120 7,395 +/- 450 micrograms.min/l, p < 0.05). Somatostatin abolished the GH response to GHRH (AUC0-120 363 +/- 89 micrograms.min/l, p < 0.01), while it only blunted that to hexarelin (AUC0-120 1,314 +/- 297 micrograms.min/l, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1995

Effect of galanin on basal and stimulated secretion of prolactin, gonadotropins, thyrotropin, adrenocorticotropin and cortisol in humans.

Galanin enhances both baseline and growth hormone-releasing hormone (GHRH)-induced GH secretion both in animals and in man. Although galanin has a clear influence on the secretion of other anterior pituitary hormones in animals, in man it increases prolactin (PRL) slightly but does not affect spontaneous thyrotropin (TSH), luteinizing hormone (LH), follicle-stimulating hormone (FSH) or adrenocorticotropin (ACTH) secretion. The aim of our study was to verify the effect of galanin on basal and releasing hormone-stimulated release of gonadotropins, PRL, TSH, ACTH and cortisol secretion. As GH release has been shown to be inhibited by corticotropin-releasing hormone (CRH), we also studied the effect of CRH on galanin-stimulated GH increase. The effect of porcine galanin (15 micrograms/kg iv infused in 60 min) alone and in combination with thyrotropin-releasing hormone (TRH, 200 micrograms iv bolus), CRH (100 micrograms iv bolus) and gonadotropin-releasing hormone (GnRH, 100 micrograms iv bolus) on GH, PRL, TSH, ACTH, cortisol, FSH and LH secretion in seven normal young women (aged 25-30 years) was studied. Galanin infusion caused an increase in serum GH levels (p < 0.02) but failed to modify significantly the spontaneous PRL, LH, FSH, TSH, ACTH and cortisol secretion. The combined administration of TRH, GnRH and CRH caused a significant increase in PRL (p < 0.02), LH (p < 0.02), FSH (p < 0.02), TSH (p < 0.02), ACTH (p < 0.02) and cortisol (p < 0.05), but not in GH levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗

PubMed1995

Involvement of brain catecholamines and acetylcholine in growth hormone hypersecretory states. Pathophysiological, diagnostic and therapeutic implications.

Secretion of growth hormone (GH) is excessive in acromegaly, but also in a number of other pathological states such as anorexia nervosa, insulin-dependent diabetes mellitus (IDDM), liver cirrhosis, depression, renal failure and GH-insensitivity syndrome. Abnormalities in the neuroendocrine control of GH secretion and/or a state of insensitivity to GH contribute to hypersecretion of GH in these states, with the possible exception of acromegaly, which appears to be a primary pituitary disease. GH hypersecretion may also occur in neonates or adolescents with tall stature, thus reflecting particular physiological or paraphysiological conditions. In the cohort of brain neurotransmitters, catecholamines and acetylcholine reportedly play a major role in the control of neurosecretory GH-releasing hormone (GHRH) and somatostatin (SS)-producing neurons, and hence GH secretion. Activation of alpha 2-adrenoceptors or of muscarinic cholinergic receptors in the hypothalamus stimulates GH release, probably through stimulation of GHRH and inhibition of SS release, respectively. Activation of dopamine receptors likewise stimulates GH release, while activation of beta-receptors inhibits GH release through stimulation of hypothalamic SS function. This review discusses the involvement of brain catecholamines and acetylcholine in GH hypersecretory states, including anorexia nervosa, acromegaly, IDDM, liver cirrhosis, depression, renal failure and GH insensitivity syndrome, with a view to providing a fuller understanding of their pathophysiology and, whenever possible, diagnostic and therapeutic implications.

Acetylcholine↗

PubMed1994

Arginine but not pyridostigmine, a cholinesterase inhibitor, enhances the GHRH-induced GH rise in patients with anorexia nervosa.

Pirenzepine, a muscarinic antagonist probably acting via stimulation of hypothalamic somatostatin release, abolishes the growth hormone releasing hormone (GHRH)-stimulated growth hormone (GH) rise in normal subjects but only blunts it in patients with anorexia nervosa (AN). This finding suggested the existence in AN of an alteration of cholinergic system and/or somatostatinergic tone. To further investigate these mechanisms, in 11 AN women patients (age 18.8 +/- 0.9 years; BMI 13.4 +/- 0.4) we studied the GH response alone (1 microgram/Kg IV as a bolus at 0 min) and combined with pyridostigmine (PD, 120 mg orally, 60 min before GHRH administration), a cholinesterase inhibitor, or arginine (ARG 30 g infused over 30 min starting at 0 min), two compounds probably acting via inhibition of hypothalamic somatostatin (SS) release. The GH response to GHRH preceded by a previous (120 min before) neurohormone administration also was studied. All these tests also were performed in 20 normal age-matched women (age 22.0 +/- 1.8 yrs; BMI20.1 +/- 2.4). Basal serum GH levels were higher in AN patients than in normal volunteers (NV) (10.3 +/- 3.4 versus 2.8 +/- 0.3 microgram/L; p < 0.001), whereas plasma IGF-I levels were lower in AN patients than in NV (43.3 +/- 10.6 versus 172.4 +/- 13.9 micrograms/L; p < 0.00001). In AN patients, GHRH administration induced a GH rise higher, though not significantly, than that in NV [delta area under the curve (AUC) 1173.6 +/- 167.6 versus 834.6 +/- 188.1 micrograms/L/h]. The GH response to the second of two consecutive GHRH boluses was lower (p < 0.01) than that of the first one either in AN patients or in NV (67.6 +/- 27.4 and 53.1 +/- 25.7 micrograms/L/h, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1994

Effects of direct and indirect acetylcholine receptor agonists on growth hormone secretion in humans.

Cholinergic pathways in the central nervous system positively influence growth hormone (GH) secretion. In fact pyridostigmine, a cholinesterase inhibitor, enhances both basal and GH-releasing hormone (GHRH)-induced GH secretion while, conversely, pirenzepine, an antagonist of muscarinic M1 receptors, inhibits the GH response to GHRH and to other physiological and pharmacological stimuli. The effect of the cholinergic system on GH secretion probably takes place via inhibition of the release of endogenous somatostatin. In this study in 36 normal adults (26 males and 10 females, age 22-35 years) we compared the effects of three cholinesterase inhibitors (pyridostigmine, 120 mg p.o., n = 19; neostigmine, 10 micrograms/kg i.v., n = 6; physostigmine, 12.5 micrograms/kg i.v., n = 6) and bethanechol, a direct muscarinic receptor agonist that is mainly active on muscarinic M3 receptors (25 micrograms/kg i.v., n = 5), on both basal and GHRH (1 microgram/kg i.v.)-stimulated GH secretion. Pyridostigmine, neostigmine and physostigmine induced a significant GH increase (peak vs. basal levels, mean +/- S.E.: 10.4 +/- 1.6 vs. 0.6 +/- 0.2 micrograms/l, P = 0.0001; 13.3 +/- 1.2 vs. 0.5 +/- 1.1 micrograms/l, P = 0.004; and 14.9 +/- 3.1 vs. 2.7 +/- 1.1 micrograms/l, P = 0.025;, respectively). These drugs also induced a similar potentiation of the GH response to GHRH (peak: 48.3 +/- 5.6 vs. 16.2 +/- 2.2 micrograms/l, P = 0.0001; 49.2 +/- 2.2 vs. 19.9 +/- 5.1 micrograms/l, P = 0.006; and 76.9 +/- 12.4 vs. 18.1 +/- 5.3 micrograms/l, P = 0.001, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1994

Arginine enhances the growth hormone-releasing activity of a synthetic hexapeptide (GHRP-6) in elderly but not in young subjects after oral administration.

In man the GH-releasing hexapeptide His-DTrp-Ala-Trp-DPhe-Lys-NH2 (GHRP-6) has been shown to be active even after oral administration. On the other hand, it has been shown that arginine (ARG) totally restores the reduced somatotropic responsiveness to GHRH observed in aging. Based on the foregoing, in this study we verified the GH-releasing activity of oral GHRP-6 (300 micrograms/kg) in normal aging and the possible enhancing effect of 8 g oral ARG on the GH-releasing effect of GHRP-6. Eight young (age 24-32 yr) and 8 elderly (age 66-85 yr) subjects were studied. In all the GH response to GHRH (1 microgram/kg iv) was also studied. Both IGF-I levels and the GH response to iv GHRH were lower in elderly than in young subjects (mean +/- SE, IGF-I: 65.1 +/- 9.1 vs 142.9 +/- 9.4 micrograms/L, p < 0.0001; GH peak: 5.4 +/- 1.0 vs 13.6 +/- 0.8 micrograms/L, p < 0.0001). Oral GHRP-6 administration induced a GH rise in elderly which was lower, though not significantly, than that in young subjects (GH peak: 9.9 +/- 2.0 vs 16.2 +/- 5.4 micrograms/L). Oral ARG administration enhanced the GHRP-6-induced GH rise in elderly (GH peak: 22.1 +/- 3.3 micrograms/L, p < 0.01 vs GHRP-6 alone) while failed to modify it in young subjects (GH peak: 13.5 +/- 3.4 micrograms/L). The GH response to oral ARG+GHRP-6 in elderly was higher than that to all stimuli in young adults (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1994

Interaction of salbutamol with pyridostigmine and arginine on both basal and GHRH-stimulated GH secretion in humans.

OBJECTIVE: It is well known that acetylcholine and arginine stimulate GH secretion while activation of beta-adrenergic receptors inhibits GH secretion in man. We aimed therefore to ascertain whether or not the inhibitory influence of beta-adrenergic receptors on GH secretion would over-ride the stimulatory one of acetylcholine and arginine. DESIGN: We studied the interaction of salbutamol, a beta 2-adrenergic agonist (SAL, 0.08 mg/kg orally) with pyridostigmine, a cholinesterase inhibitor (PD, 120 mg orally), or arginine (0.5 g/kg i.v.) on both basal and GHRH (1 microgram/kg i.v.)-stimulated GH secretion. SUBJECTS: Fourteen healthy male volunteers, aged 20-35 years, were studied. MEASUREMENTS: Serum GH was measured in duplicate by immunoradiometric assay. RESULTS: In study A, SAL inhibited the GH response both to GHRH (P < 0.01) and ARG (P < 0.002). ARG enhanced the GHRH-induced GH rise (P < 0.01) but its effect was abolished (P < 0.02) by SAL pretreatment. In study B, SAL inhibited the GH response both to GHRH (P < 0.01) and PD (P < 0.02). PD enhanced the GH response to GHRH (P < 0.001) but its effect was abolished (P < 0.05) by SAL pretreatment. In both studies, the GH response to GHRH alone was similar to that to the neurohormone when combined with ARG + SAL or PD + SAL. CONCLUSION: Our results show that beta 2-adrenergic activation by salbutamol is able to inhibit not only the GH rise induced by GHRH, arginine and pyridostigmine, but even the potentiating effect of both arginine and pyridostigmine on the GH response to GHRH. They indicate that catecholamines, acetylcholine and arginine play a major role in GH secretion having opposite influences aimed to balance the function of the hypothalamus-GH-IGF-I axis in man.

Adult↗

PubMed1994

Growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, after intravenous, subcutaneous, intranasal, and oral administration in man.

We evaluated the GH-releasing activity of hexarelin, a new synthetic hexapeptide, after i.v. (1 and 2 micrograms/kg), sc (1.5 and 3 micrograms/kg), intranasal (20 micrograms/kg), and oral (po; 20 and 40 mg) administration to 12 healthy young volunteers. Reference treatments were i.v. saline and GH-releasing hormone (GHRH; 1 microgram/kg). GH release (mean +/- SEM) after the i.v. dose of 1 microgram/kg hexarelin [area under the curve (AUC), 3175 +/- 506 micrograms/min.L] was about 2 times higher than that induced by 1 microgram/kg GHRH (AUC, 1544 +/- 161 micrograms/min.L; P < 0.001). Hexarelin (2 micrograms/kg, i.v.) elicited a further increase in GH levels (AUC, 4422 +/- 626 micrograms/min.L) compared to the 1 microgram/kg dose. The GH response to 2 micrograms/kg hexarelin, i.v., was very reproducible (AUC, 4016 +/- 563 vs. 3959 +/- 803 micrograms/min.L). The sc administration of hexarelin produced a dose-dependent GH response (AUC, 3180 +/- 392 and 4459 +/- 566 micrograms.min.L with 1.5 and 3 micrograms/kg, respectively). Intranasal administration of 20 micrograms/kg hexarelin induced GH release (AUC, 2642 +/- 452 micrograms/min.L) similar to that caused by 1 microgram/kg, i.v. Twenty and 40 mg hexarelin, po, produced a dose-related increase in GH levels (AUC, 2278 +/- 442 and 4079 +/- 514 micrograms/min.L). Biological bioavailabilities were 77.0 +/- 10.5%, 4.8 +/- 0.9%, and 0.3 +/- 0.1% for the sc, intranasal, and po routes, respectively. This study shows that the GH response to hexarelin administered by the i.v. route has a limited variability and is superior to the response to GHRH. The GH-releasing activity appeared to be dose dependent. Thus, hexarelin could be clinically useful to stimulate GH secretion in humans.

Administration, Intranasal↗

PubMed1994

Arginine and growth hormone-releasing hormone restore the blunted growth hormone-releasing activity of hexarelin in elderly subjects.

Although both spontaneous and stimulated GH secretion undergo an age-related decline, the secretory capacity of somatotrope cells is preserved in human aging. In the present study we compared the GH responses to hexarelin, GHRH, and the combined administration of hexarelin and GHRH or arginine in young and elderly subjects. Thirteen young (24- to 30-yr-old) and 16 elderly (65- to 84-yr-old) normal males were divided into 2 groups. The first group (7 young and 8 elderly subjects) received the following as single iv injections during 3 different treatment sessions: hexarelin (2 micrograms/kg), GHRH (2 micrograms/kg), or hexarelin (2 micrograms/kg) plus GHRH (2 micrograms/kg). The second group (6 young and 8 elderly subjects) was administered single iv injections of hexarelin (2 micrograms/kg) or hexarelin (2 micrograms/kg) plus arginine (0.5 g/kg) during 2 different treatment sessions. In both groups basal IGF-I levels in the elderly were lower than those in young subjects (114.5 +/- 18.7 vs. 211.5 +/- 19.1 micrograms/L; P < 0.001). In the first group the GH response to hexarelin was greater in young compared to elderly subjects (area under the curve from 0-120 = 4849 +/- 601 vs. 2112 +/- 683 micrograms.min/L; P < 0.001). GHRH elicited a lower GH response than that induced by hexarelin in both young (1455 +/- 102 micrograms/h.L; P < 0.02) and elderly subjects (563 +/- 87 micrograms/min.L; P < 0.02). GHRH potentiated the somatotrope response to hexarelin in both young (7725 +/- 503 micrograms/min.L; P < 0.02) and elderly subjects (3895 +/- 612 micrograms/min.L; P < 0.02), but to a lesser extent in the latter (P < 0.001). In the second group, the GH response induced by hexarelin was also higher in young subjects than in elderly subjects (4819 +/- 668 vs. 1649 +/- 459 micrograms/min.L; P < 0.001). The GH response to hexarelin was potentiated by arginine in elderly (4139 +/- 1057 micrograms/min. L; P < 0.001), but not in young subjects (4743 +/- 774 micrograms/min.L). This study shows that the maximal effective dose of hexarelin releases more GH than the maximal effective dose of GHRH in both normal young and elderly subjects. The effect of hexarelin on GH secretion is age dependent, and the GH response to the combined administration of hexarelin and GHRH was significantly higher in young subjects compared to elderly subjects. Arginine does not potentiate the GH response to hexarelin in young subjects, whereas it significantly enhances it in elderly subjects.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗