S. G. Cella

Reduced growth hormone response to growth hormone-releasing hormone in children with simple obesity: evidence for somatomedin-C mediated inhibition.

We have evaluated the plasma GH response to a single injection of 1μg/kg of GH‐releasing hormone (GHRH)‐40 in 15 obese children and 15 age‐matched control children. Most of the obese children showed a subnormal plasma GH response to GHRH and the mean plasma GH integrated area (IC‐GH) following stimulation was significantly smaller in obese than control children. Plasma somatomedin‐C (SM‐C) levels were significantly higher in obese than control children, and were negatively correlated with the peak plasma GH levels (r=−0.616, P<001) and the IC‐GH (r=−0.554, P<0.02) after GHRH. Non‐esterified fatty acids (NEFA) and fasting plasma insulin levels were also elevated in obese children, but did not correlate with the extent of plasma GH response to GHRH. These data confirm previous observations on the refractoriness of obese children to release GH after GHRH, and imply that it may be due to the feedback inhibition operated by the elevated plasma levels of SM‐C.

Prolactin-lowering and -releasing drugs. Mechanisms of action and therapeutic applications.

SummaryDrugs whose systemic and/or central administration induce suppression or stimulation of prolactin secretion are reviewed. The most commonly used prolactin-lowering drugs include: (a) direct acting dopamine receptor agonists (e.g. dopamine, apomorphine and the ergot derivatives); (b) indirect-acting dopamine agonists (e.g. amphetamine, nomifensine, methylphenidate, amineptine); (c) drugs which impair serotoninergic neurotransmission (e.g. the neurotoxin 5,7-dihydroxytryptamine and the serotonin receptor antagonists methysergide and metergoline); (d) γ-aminobutyric acid [GABA]-mimetic drugs (e.g. GABA, muscimol, ethanolamine-O-sulphate, sodium valproate); (e) histamine H2-receptor agonists; and (f) cholinergic (muscarinic and nicotinic) receptor agonists. Major prolactin-stimulating agents comprise: (a) dopamine receptor antagonists (e.g. classic and atypical antipsychotic drugs); (b) drugs differently capable of impairing central nervous system dopamine function (e.g. blockers of dopamine neurotransmission such as α -methyl-p-tyrosine and 3-iodo-L-tyrosine, false precursors such as α-methyldopa, and inhibitors of L-aromatic amino acid decarboxylase such as carbidopa and benserazide); (c) drugs enhancing serotoninergic neurotransmission (e.g. the serotoninergic precursors tryptophan and 5-hydroxytryptophan, direct-acting serotonin agonists such as quipazine and MK 212, and indirect-acting serotonin agonists such as fenfluramine); (d) blockers of serotonin reuptake (e.g. fluoxetine, fluvoxamine and clovoxamine); (e) H1-receptor agonists; and (f) H2-receptor antagonists (e.g. cimetidine).Some of the above classes of drugs (e.g. the indirect-acting dopamine agonists, dopamine receptor antagonists, GABA-mimetic drugs, dopamine receptor blocking drugs, and H2-antagonists) may be useful for selecting among hyperprolactinaemic patients those with a prolactin-secreting tumour in an early stage of the disease. Direct-acting dopamine receptor agonists, notably the ergot derivatives; are potent antigalactopoietic agents, can revert impaired gonadal function to normal in both female and male patients with hyperprolactinaemia, and may have antiproliferative effects on pituitary prolactin-secreting tumours. All prolactin-stimulating agents, but especially the dopamine receptor antagonists, are liable to induce alterations in gonadal function in subjects of either sex.In addition to their usage for diagnostic or therapeutic purposes, the above drugs appear to be invaluable tools for enabling a better understanding of the neurotransmitter control of prolactin secretion.

CLONIDINE ACCELERATES GROWTH IN CHILDREN WITH IMPAIRED GROWTH HORMONE SECRETION

4 children with isolated growth hormone deficiency (IGHD) and 4 with constitutional growth delay (CGD) were treated with clonidine, 0.1 mg/m2 daily, for 60 days. In 2 children with IGHD and all 4 with CGD, basal growth hormone (GH) and somatomedin-C levels were increased, pituitary GH response to challenges with a synthetic pancreatic GH releasing factor and clonidine was enhanced, and linear growth was stimulated.

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

SummaryA cohort of brain neurotransmitters, especially catecholamines and acetylcholine, play a crucial role in the control of neurosecretory growth hormone-releasing hormone (GH-RH)- and somatostatin (SS)-producing neurons, and hence growth hormone (GH) secretion. Stimulation of α2-adrenoceptors or of muscarinic cholinergic receptors in the hypothalamus stimulates GH release, probably via stimulation of GH-RH and inhibition of somatostatin release, respectively. Additionally, stimulation of dopamine receptors is stimulatory to GH release, while activation of β-receptors inhibits GH release via stimulation of hypothalamic somatostatin function. As a corollary, in GH deficiency states drugs affecting catecholaminergic and cholinergic functions may be exploited for diagnostic and/or therapeutic purposes, and may be useful for a better understanding of the underlying pathophysiology.Levodopa (L-dopa) [125 to 500mg orally], the physiological precursor of the catecholamines, administered either alone or in combination with carbidopa (50mg orally), to prevent its peripheral decarboxylation to dopamine, and/or the β-adrenoceptor antagonist propranolol (0.75 mg/ kg orally), and the α2-adrenoceptor agonist clonidine (0.15 mg/m2 orally), are a fairly reliable stimulus of GH release. In normal subjects, however, false-negative GH responses and wide inter-individual variability may occur with these drugs. Additionally, the GH secretory response to these provocation tests is a poor predictor of endogenous 24-hour GH secretion, since levodopa or clonidine may elicit a response within normal limits in children of short stature with reduced 24-hour GH secretion and good responsiveness to GH therapy.The availability of GH-RH, a direct probe of pituitary somatotrophs, held out promise of unravelling the hypothalamic or pituitary origin of GH secretory disturbance. It soon became apparent, however, that this was not the case, because of the wide inter- and intraindividual variation in the GH response. However, the coadministration of GH-RH and muscarinic cholinergic agonists, for example pyridostigmine (which deprive the pituitary of hypothalamic SS inhibitory influences), is a useful diagnostic probe. In a large group of normal children and adolescents who received an intravenous injection of GH-RH, preceded by oral administration of pyridostigmine (60mg orally), none gave a false-negative response; this was also true for a group of short children with different forms of GH disturbances, in whom 8-hour nocturnal GH secretion was within normal limits. However, some false-negative responses occurred in children following testing with GH-RH, clonidine or pyridostigmine alone. Interestingly, the cut-off point for normality following pyridostigmine + GH-RH was as high as 20 ng/ml, while for the other provocation tests it is only 5 to 10 ng/ml. Responses lower than 20 ng/ml were present in all children with organic and most of the children with idiopathic GH deficiency.The fact that in most subjects with GH deficiency and/or short stature GH-RH evokes variable but unequivocal rises in plasma GH levels points to a dysfunction of hypothalamic regulation; the dysfunction would primarily affect neurotransmitter and not hypophysiotropic neurosecretory neurons. In children with isolated GH deficiency (IGHD), 6 months of oral administration of levodopa (60 mg/kg) or bromocriptine (2.5mg) increased growth velocity, basal GH levels and in some of the children serum somatomedin-C levels. Similarly, clonidine (0.1 mg/m2 orally) given for 3 months to 1 year to children with isolated GH deficiency or constitutional delay of growth (CGD) induced in some of them a clearcut stimulation of linear growth. After 2 months of treatment in a group of children with constitutional delay of growth, clonidine increased the 24-hour GH concentration and the mean GH pulse amplitude. In contrast, pyridostigmine (60 to 180mg orally) does not have growth-promoting therapeutic potential, probably because it fails to potentiate the GH-RH-induced rise in GH at night.A GH hyposecretory dysfunction is also present in obese children and adults. In these patients acute pretreatment with pyridostigmine significantly increased baseline GH levels and the GH response to GH-RH, these indices becoming similar to those of lean control subjects receiving GH-RH alone. However, combined administration of pyridostigmine and GH-RH elicited a higher GH response in lean control subjects than in obese subjects.Decreases in GH pulse amplitude and frequency and marked blunting of the GH response to various secretagogues occurs in both animals and humans during aging. The mechanism of these changes is unclear but studies in aged animals have shown that passive immunisation with antisomatostatin serum or treatment with pilocarpine or clonidine stimulates GH release.A cohort of brain neurotransmitters, especially catecholamines and acetylcholine, play a crucial role in the control of neurosecretory growth hormone-releasing hormone (GH-RH)- and somatostatin (SS)-producing neurons, and hence growth hormone (GH) secretion. Stimulation of α2-adrenoceptors or of muscarinic cholinergic receptors in the hypothalamus stimulates GH release, probably via stimulation of GH-RH and inhibition of somatostatin release, respectively. Additionally, stimulation of dopamine receptors is stimulatory to GH release, while activation of β-receptors inhibits GH release via stimulation of hypothalamic somatostatin function. As a corollary, in GH deficiency states drugs affecting catecholaminergic and cholinergic functions may be exploited for diagnostic and/or therapeutic purposes, and may be useful for a better understanding of the underlying pathophysiology.

Synthetic hpGRF 1–40 stimulates growth hormone and inhibits prolactin secretion in normal children and children with isolated growth hormone deficiency

Intravenously administered synthetic hpGRF 1-40 at doses of 0.1, 0.33 and 1.0 microgram/kg increased plasma GH in a dose-dependent fashion in 4 normal prepubertal children. hpGRF 1-40 at the dose of 1.0 microgram/kg stimulated GH release, though to a lesser extent than in normals, in 7 children with isolated GH-deficiency (IGHD) but failed to do so in a patient with craniopharyngioma. In all normal children and 6/7 patients with IGHD, hpGRF 1-40 at all doses used induced a clear and sustained lowering of plasma prolactin levels; this effect was lacking in the patient with craniopharyngioma. hpGRF 1-40 had no effect on plasma FSH, LH, TSH or glucose levels nor did it influence pulse rate, blood pressure, or body temperature. These results indicate that hpGRF 1-40 is a potent stimulus to GH release in normal prepubertal children and holds promise for treatment of GH-deficient children. In addition, in both normal children and children with IGHD, hpGRF 1-40 is a potent suppressor of prolactin levels.

THE EFFECT OF GALANIN ON BASELINE AND GHRH-INDUCED GROWTH HORMONE SECRETION IN OBESE CHILDREN

We have evaluated the effect of the administration of galanin (Gal), a newly identified hypothalamic peptide, on baseline and GHRH‐induced GH rise in five obese children and in seven controls. The GH response to GHRH (hpGRF(1–29), 1 μg/kg i. v.), and to Gal (15 μg/kg/h for 1 h), evaluated both as the maximum GH peak and as integrated area under the curve (AUC), was significantly lower in the obese children than in the controls. Simultaneous administration of Gal plus GHRH significantly increased the GH response to GHRH in all the obese subjects, so that their mean peak GH levels and AUC after Gal plus GHRH were similar to those of the control children after GHRH. Also, in control children Gal caused a significant augmentation of the GH response to GHRH. Mean peak GH levels and mean AUC after Gal plus GHRH were significantly higher in the controls than in the obese children given the same treatment. Our data indicate that obese children have a blunted GH response to Gal, which, however, is able to enhance the GH response to GHRH. This observation strengthens the view that the mechanism of action of Gal involves modulation of endogenous somatostatin (SRIH) release. In addition, similarity between the effects of Gal and pyridostigmine on baseline and GHRH‐stimulated GH release in obese children may indicate the existence of a cholinergic link in the action of Gal.

THE EFFECT OF OXANDROLONE ON THE GROWTH HORMONE RESPONSE TO GROWTH HORMONE RELEASING HORMONE IN CHILDREN WITH CONSTITUTIONAL GROWTH DELAY

The effect of treatment with oxandrolone, an anabolic steroid, on GH response to GH‐releasing hormone (GHRH) has been evaluated in children with constitutional growth delay. Five subjects, four males and one female, aged 11·0–17·1 years were given oxandrolone 0·1 mg/kg p.o. daily for 2 months, and underwent acute administration of GHRH (GRF 1–40, 1 μg/kg i.v.) before and after withdrawal of oxandrolone therapy. GHRH administration induced a much greater GH response, evaluated either as a peak plasma GH levels or plasma GH integrated area, after than it did before oxandrolone treatment. These findings indicate that in children with constitutional growth delay oxandrolone increases the sensitivity of somatotrophs to exogenous GHRH and, likely, to the endogenously‐released neurohormone.

Gender-, age-, body composition- and training workload-dependent differences of GH response to a discipline-specific training session in elite athletes: a study on the field.

Ninety-nine Italian elite athletes (61 M, 38 F, mean age±SE: 24.1±0.6 yr, age range: 17–47 yr) of different disciplines volunteered to participate in this investigation. Basal GH concentrations were significantly higher (p<0.0001) in females (6.2±1.1 ng/ml) vs males (1.9±0.5 ng/ml). Basal GH values were negatively correlated with age and body mass index (BMI); no significant correlation was found between GH and IGF-I levels. Among female athletes, 8/38 had basal GH values higher than 10 ng/ml [2/8 athletes were taking oral contraceptives (OC)], while among males 6/61 had values higher than 5 ng/ml. In females, training sessions significantly increased (p<0.0001) basal GH concentrations (peak GH: 18.5±1.9 ng/ml), while in males GH responses were lower than in females (11.8±1.4 ng/ml, vs F: p<0.005). Six out of 38 female and 6/61 male athletes were considered GH hypo-responders (i.e. negative difference between peak GH and basal GH values), the large majority of them being subjects with elevated basal GH concentrations. In responsive athletes, peak GH values occurred immediately at the end of the training session both in males and in females; GH concentrations rapidly declined during recovery. No significant correlations were found between peak GH and age, body weight and BMI in either gender. GH responses were directly related (p<0.001) to the intensity of the workload during the sessions. In conclusion, the present study demonstrates that: 1) some elite athletes had increased GH concentrations before training, which were however associated with normal IGF-I levels; 2) GH peaks after a discipline-specific training session were significantly higher in females than in males performing the same discipline, gender-related differences disappearing when post-exercise total GH outputs (area under the curve) were compared; 3) peak GH values were directly correlated with training workload; 4) GH concentrations rapidly declined during recovery, values at the end of the post-training GH sampling being generally lower than those found in basal condition.

Age-Related Modulatory Activity by a Cholinergic Agonist on the Growth Hormone Response to GH-Releasing Hormone in the Rat

Abstract The involvement of the cholinergic system in growth hormone (GH) secretion has acquired increased importance in the last few years. In rats, pretreatment with muscarinic cholinergic agonists potentiates the GH release induced by GH-releasing hormone (GHRH), via inhibition of somatostatin (SRIF) release from the hypothalamus. The aim of this study was to validate the use of cholinergic agonists to probe the functional activity of the hypothalamic SRIF system. It is known that hypothalamic SRIF displays an age-related increase in its functional activity; therefore, rats from 10 days to 29 months of age were used and challenged with GHRH following acute administration of pilocarpine, a cholinergic muscarinic agonist. Following administration of GHRH alone there was an age-related decline in GH responsiveness. Administration of pilocarpine potentiated the GH response to GHRH during the entire life-span of the rats, the only exception being 10-day-old rats in which the drug was without effect. Pilocarpine, though effective in potentiating the GH response to GHRH, did not restore, in senescent rats, GH stimulation to the level of that present in young (3-month old) or adult rats (8-month old). However, the drug was effective in rejuvenating the GH response to GHRH of the older rats (29- and 18-month old) to the level of 15-month-old rats. The present results indicate that modulation of the GH response to GHRH by pilocarpine is consonant with the known changes in the activity of hypothalamic SRIF. Cholinergic drugs may therefore represent a valuable tool to assess SRIF function in physiologic or pathologic conditions of GH secretion, and, in addition, to potentiate GH release during a course of GHRH therapy.

Growth hormone and lactate responses induced by maximal isometric voluntary contractions and whole-body vibrations in healthy subjects

Background: In contrast with maximal voluntary resistance exercise, which is allegedly considered a potent GH stimulus in young subjects, evaluation of GH response to whole-body vibrations (WBV) has yielded conflicting results. Methods: The acute effects of WBV alone (test A), maximal voluntary isometric contractions (MVC) (test B), and combination of WBV and MVC (test C) on serum GH and blood lactate (LA) levels were studied in 9 healthy adult males. Muscle soreness was assessed 24 and 48 h after exercise by a visual analogue scale. Results: GH responses were significantly higher after tests B and C than after test A (GH peaks: 18.8±9.5 ng/ml or 20.8±13.7 ng/ml, respectively, vs 4.3±3.5 ng/ml; p<0.05), with no difference between tests B and C. LA concentrations significantly increased after tests A, B, and C, being significantly higher after tests B and C than after test A (LA peaks: 2.0±0.5 mmol/l or 6.7±2.3 mmol/l, respectively, vs 7.6±0.9 mmol/l; p<0.05). Peak LA values were significantly correlated to GH peaks in the 3 tests (r=0.48; p<0.05). Muscle soreness was significantly higher 24–48 h after tests B and C than after test A, no significant differences being present between tests B and C. Conclusions: WBV stimulates GH secretion and LA production, with no additive effect when combined with repeated isometric voluntary contractions. Optimization of protocols based on WBV seems important to maximize the positive effects of this intervention on the somatotropic function. tis