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We have studied the effects of intra-amniotic administration of an anti-GH-releasing hormone serum (GHRH-Ab) on day 16 of fetal life in the rat, when the ontogenetic development of the GHRH neuronal system occurs. Control animals received normal rabbit serum. Following delivery, body weight was monitored for the next 30 days as an index of somatic growth, and the following indices of somatotrophic function were determined: plasma and pituitary GH, pituitary GH mRNA, hypothalamic GHRH and somatostatin mRNA, and the in vivo GH responsiveness to GHRH. At birth, GHRH-Ab-treated rats had a body weight that was equivalent to that of control rats but, starting from postnatal day 6 up to day 30, they had a significantly reduced body weight. Pituitary weight, the absolute pituitary GH content and GH mRNA levels were lower in experimental compared with control rats, while pituitary GH concentrations were similar in the two groups, thus implying that there was a defect, not only in GH synthesis, but also in GH release. In agreement with this theory, basal GH levels and GHRH-stimulated GH secretion were reduced in GHRH-Ab-treated rats but, in contrast, hypothalamic regulation of GH secretion appeared to be working in these rats as they were still able to respond to the low plasma GH by increasing GHRH and decreasing somatostatin mRNA levels. These findings indicate that deprivation of GHRH during fetal life induces long-lasting changes of growth rate and somatotrophic function. In addition, when comparing these changes with those in rats given GHRH-Ab postnatally, it would appear that deprivation of GHRH affects different regulatory levels of the hypothalamo-pituitary-somatotroph axis depending on when the deprivation occurs. Journal of Endocrinology (1994) 140, 111–117

The effect of caloric restriction (CR) on the growth hormone (GH) response to compounds reportedly capable of acting via somatostatinergic influences, i.e. cholinergic agonist or antagonist drug, glucose or thyrotropin-releasing hormone (TRH), administered alone or combined with GH-releasing hormone (GHRH), was evaluated in dogs. Eight beagle dogs, aged 4–5 years, underwent a 26-day period of increasing CR; they were evaluated either under basal conditions or starting from day 13 of CR, according to a schedule which allowed the mean length of CR to be similar among individual tests. CR resulted in a significant increase in basal GH levels, and starting from day 13 in a significant decrease in plasma somatomedin C levels; plasma glucose levels were significantly diminished on day 13 of CR and then remained unaltered. Administration of GHRH (GHRH1–44, 2 µg/kg, i.v.) induced a rise in plasma GH levels strikingly higher during CR than under basal conditions. Pyridostigmine (2 mg/kg orally), a muscarinic cholinergic agonist reportedly capable of restraining hypothalamic release of somatostatin (SS), enhanced the GH response to GHRH under basal conditions, but failed to do so during CR. Conversely, pirenzepine (0.6 mg/kg, i.v.), a muscarinic cholinergic antagonist, abolished the GHRH-induced GH rise under basal conditions, but only reduced it during CR. Only by doubling the dose of pirenzepine was complete inhibition of the GHRH-induced GH rise effected. Glucose alone (2 g/kg, p.o.) failed to modify basal GH secretion either before or during CR, but significantly inhibited the GHRH-induced GH rise either before or during CR. TRH (5 µg/kg, i.v.) did not modify plasma GH levels under basal conditions, but partially counteracted the rise in plasma GH occurring during CR. Like glucose, TRH significantly inhibited the GHRH-induced GH rise either before or during CR. Neither glucose nor TRH alone induced a ‘paradoxical’ rise in plasma GH during CR. In summary, (1) the data obtained with drugs affecting cholinergic transmission suggest that the latter is increased in dogs during CR and this likely results in a reduced hypothalamic SS tone, and (2) the data obtained with glucose and TRH suggest that these compounds may be effective to trigger not only hypothalamic SS release but also synthesis or, alternatively, they may act via inhibitory influences other than SS.

The effect of acute administration of growth hormone-releasing hormone (GHRH), clonidine (CLO), an alleged GHRH releaser, or GHRH and clonidine given simultaneously was studied in young and old dogs. Simultaneous administration of CLO induced in young dogs an additive effect on GH release and potentiated in old dogs the GHRH-induced GH release, with the GH response being clearly higher than the sum of the GH responses to GHRH or CLO alone. These data suggest that CLO promotes GH release in the dog also by inhibition of somatostatin release.

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 microgram/kg i.v.), and to Gal (15 micrograms/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 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.

It is known that in adult rats, GH by itself and by promoting secretion of the somatomedins acts at the level of the hypothalamus to trigger release of somatostatin and decrease output of GH-releasing hormone (GHRH), thereby inhibiting further secretion of GH. To assess whether these mechanisms are already operative in the early postnatal period, we have evaluated the effect of short-term administration of GH in 10-day-old rats. Twice-daily s.c. administration of 25 μg human GH/rat, from days 5 to 9 of life, significantly reduced pituitary content of GH, decreased hypothalamic levels of GHRH mRNA and abolished the in-vivo GH response to a challenge dose of GHRH (20 ng/100 g body weight, s.c.). GHRH (20 ng/100 g body weight, twice daily, s.c.) given concomitantly with the GH treatment, completely counteracted the inhibitory effect of the latter on pituitary content of GH and restored to normal the in-vivo GH response to the GHRH challenge. These data indicate that impaired secretion of GHRH is involved in the inhibitory effect elicited by GH treatment in infant rats. However, concomitant involvement of hypothalamic somatostatin as a result of GH treatment cannot be ruled out. In fact, pituitaries from rats pretreated with GH responded in the same manner as pituitaries from control rats to the GHRH challenge in vitro. Journal of Endocrinology (1990) 124, 199–205

The effect of galanin (Gal), a 29-amino acid peptide widely distributed in mammalian CNS, was investigated in cultured pituitary cells of rats of different ages. Gal (0.1-10/microM) stimulated GH release in a concentration-dependent manner in 5-and 10-day-old rat pituitaries (EC50: 0.87 and 1.73/microM, respectively) but was ineffective (0.01-1/microM) or even inhibitory (10/microM) in 40-day-old male rat pituitaries. Gal (0.1-10/microM) was ineffective to alter stimulation of GH release induced by GHRH (10 nM) in 5-day-and 40-day-old rat pituitary cells, but Gal (1/microM) slightly inhibited (24%) it in 10-day-old rat pituitaries. Gal (1 and 10/microM) also inhibited GH secretion (45 and 58%, respectively) from 40-day-old pituitary cells when a lower GHRH dose (0.1 nM) was used for stimulation. The results of this study indicate that Gal has the ability to either stimulate or inhibit GH release from dispersed pituitary cells and that its effects are closely related to the age of the rats.

4 children with isolated growth hormone deficiency (IGHD) and 4 with constitutional growth delay (CGD) were treated with clonidine, 0·1 mg/m 2 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.

In unanaesthetized dogs iv administration of the cholinesterase inhibitor eserine (0.5 mg) or the cholinergic muscarinic receptor agonist oxotremorine (0.25 mg) induced a clear-cut rise in plasma canine growth hormone (cGH) levels. Complete suppression of the GH-releasing effect of eserine and oxotremorine was induced by blockade of cholinergic muscarinic receptors by atropine (80 or 20 μg/kg, 30 min before) but not by scopolamine-N-butyl bromide (0.8 mg/dog, 30 min before), an anticholinergic drug which does not cross the blood brain barrier (BBB). In contrast, activation of cholinergic nicotinic receptors by nicotine (6 mg) failed to alter resting cGH concentrations, and pre-treatment with the nicotinic receptor blocker mecamylamine (5 mg, 30 min before) did not counteract the GH-releasing effect of eserine. Other cholinomimetic drugs, e.g. pilocarpine, 4-aminopyridine, carbachol and bethanechol failed to induce a rise in plasma cGH concentrations. These data indicate that: 1) cholinergic muscarinic but not nicotinic receptors located in the central nervous system (CNS) inside the BBB play a facilitatory role in tonic cGH release; 2) pharmacologically distinct muscarinic receptors may exist in the CNS.

SUMMARY 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.

The existence of independent control mechanisms of beta-endorphin (beta-EP) secretion from the anterior (AP) and intermediate (NIL) pituitary lobes is now ascertained. The aim of this study was to evaluate the effect of surgical separation from the hypothalamus of the two pituitary lobes on beta-EP secretion. Two experimental models of surgical hypothalamo-pituitary disconnection were used: 1) rats with ablation of the medial basal hypothalamus (MBH); 2) rats bearing two entire ectopic pituitaries or two anterior pituitaries (APs) only, transplanted under the kidney capsule. In rats with MBH-ablation plasma beta-EP levels were significantly higher than in sham-operated controls. Plasma beta-EP levels increased in rats transplanted with entire pituitaries 3 days after surgery and were still elevated after 1 week. In rats transplanted with APs only, no significant beta-EP changes in plasma were evident. In both experimental conditions no significant difference was present in beta-LPH plasma levels. Concentrations of beta-EP in the ectopic NILs decreased gradually after transplantation. In all these results indicate that that NIL but not the AP is capable, when is disconnected from the hypothalamus, or secreting autonomously beta-EP.

The response of GH to acute administration of GH-releasing hormone (GHRH) was evaluated in 19 patients with thalassemia major and 8 normal children. In 13 of the 19 patients, GHRH induced a definite increase (greater than 5 ng/ml) in plasma GH levels, with peaks occurring 5-45 min postinjection. In 6 patients there was little or no GH rise after GHRH treatment. Overall, the mean GH response to GHRH of patients with thalassemia was lower than that of normal children. These data indicate that in thalassemia major, in addition to the described defect at the hepatic GH receptor or postreceptor level which impedes generation of somatomedins, there may be a marked impairment in somatotroph function. In one patient in whom the GH response to GHRH was superimposable on that of normal subjects, there was a blunted GH response to insulin hypoglycemia. This finding indicates that functional damage in hypothalamic structures for GH control can also occur in thalassemic patients.

We have evaluated the effect of galanin (Gal), a newly identified hypothalamic peptide, on growth hormone (GH) secretion in 10 children with normal stature (NS), nine with constitutional growth delay (CGD), and five with isolated GH deficiency (IGHD). Gal was infused intravenously at a rate of 8 or 15 pg/kg/h. All children also underwent an acute oral clonidine test (0.15 mg/m2). In CGD children the mean plasma GH peak after 8 pg/kg/h of Gal infusion (13.3 f 1.7 ng/mL; mean f SEM) was higher (p < 0.02) than in NS children (8.5 f 0.8 ng/mL). When the dose of Gal was increased to 15 pglkglh the mean plasma GH peak in CGD children (18.5 f 3.5 ng/ mL) was still higher than in the NS group (13.2 f 2.9 ng/ mL), although not significantly so. In IGHD children the mean plasma GH peak elicited by 8 or 15 pg/kg/h of Gal (3.8 f 0.7 and 3.9 f 0.5 ng/mL, respectively) was lower than that obtained in either CGD (p < 0.0002) or NS children (p < 0.001). In NS children the mean plasma GH peak after acute clonidine administration (22.3 f 3.0 ng/ mL) was higher than that observed after either dose of Gal used (p < 0.001 and p < 0.05 with 8 and 15 pg/kg/h, respectively). In CGD or IGHD children mean plasma GH peak after acute clonidine (14.8 f 2.6 and 4.1 f 1.2 ng/ mL, respectively) was not significantly different from that observed after either dose of Gal. No correlation was found between peak plasma GH responses to clonidine and to Gal infusion at either dose used. Gal infusion did not cause any significant change in LH, FSH, prolactin, and TSH plasma levels. We conclude that Gal stimulates GH secre- tion in CGD as well in NS children but not in children with isolated GH deficiency. Gal, at least under our experimen- tal conditions, does not seem to be of help in the differential diagnosis of children with short stature. (Pediatr Res 26:316-319, 1989) Abbreviations CGD, constitutional growth delay Gal, galanin GH, growth hormone GHRH, GH-releasing hormone IGHD, isolated GH deficiency NS, normal stature

The effect of one of the new human pancreatic growth hormone releasing factors (hpGRFs) was assessed in children or young adults with different forms of growth retardation or endocrine-metabolic diseases. Intravenously administered synthetic hpGRF-40 (1 microgram/kg) induced a clear-cut and prompt rise in plasma growth hormone (GH) levels in 8 normal prepubertal children and a definite GH rise in 11 out of 14 children with isolated GH deficiency (IGHD) and one child with the Silver-Russel syndrome. In two out of three subjects with craniopharyngioma hpGRF-40 did not induce any plasma GH increase. In seven out of ten children with constitutional growth delay (CGD), hpGRF-40 induced a biphasic GH response, with a prompt small GH increment followed by a second, more consistent rise. Both in children with IGHD and with CGD the rise in plasma GH following hpGRF-40 was markedly lower than in controls. In children with CGD the GH response to hpGRF-40 was defective, despite the fact that in most of them the GH response to standard pharmacological stimuli was normal according to generally accepted criteria. hpGRF induced a small but sustained plasma GH rise in four hypothyroid subjects, while in three out of four children with idiopathic obesity the GH response to hpGRF was strikingly reduced. These data demonstrate that hpGRF is a potent stimulus of GH release in normal prepubertal children and a physiological means of investigating GH function in diseases associated with growth impairment.

Using immunohistochemical techniques, we have studied the ontogenetic development of growth hormone-releasing factor (GRF) immunoreactive structures in the rat hypothalamus. Frozen sections of rat hypothalami were stained by the avidin-biotin complex (ABC) method using a specific antiserum against rat GRF. Immunoreactive GRF nerve terminals but not perikarya were first detected in rat fetuses on the 20th day of gestation in the external layer of the median eminence (ME). An increased number of immunoreactive nerve terminals in the ME were observed at 1 and 2 days of age. In addition, perikarya containing immunoreactive GRF-like material were observed in the arcuate nucleus (ARC). Rats at 5 days of age showed a further increase in GRF immunoreactive terminals, which now were also present in the internal layer of the ME. In 10- and 20-day-old rats immunoreactive nerve terminals were only moderately increased in the ME. GRF immunoreactive perikarya were observed in the ARC and also in proximity to the ventromedial nucleus. Moreover, GRF containing fibers were seen projecting from the ARC to the ME. Colchicine treatment of postnatal rats reduced immunostaining of the nerve animals in the ME, but did not affect that of the perikarya. These results are consistent with the view that the neural control of growth hormone secretion develops in the rat during late gestation and continues to mature during the early postnatal period.

Age-related changes in GH secretion were studied in the dog. In preliminary experiments, administration of GH-relasing hormone (GHRH-40, 2 μg/kg, iv) or the α2-adrenoceptor agonist clonidine (4 μg/kg, iv) elicited significantly higher plasma GH rises in 3 to 4 years old than in 10 to 14 years old beagle dogs. The pulsatile patterns of GH secretion in both young and old dogs under baseline conditions and after prolonged fasting or clonidine administration were studied. Samples were taken every 10 min from 09.00 to 15.00 h from five young and five old dogs of both sexes. Under baseline conditions, GH peak frequency, total peak area, and integrated GH secretion were significantly lower in old than in young dogs. In old dogs, 5-day complete fasting or 14-day clonidine administration (75 μg/dog, po, twice daily) increased the frequency and amplitude of spontaneous GH bursts, the total peak area, and the integrated GH secretion. After either stimulus, the GH secretory pattern was quantitatively and qualitatively indistinguishable from that of young dogs under baseline conditions. Similarly, the foregoing indices were significantly increased in young dogs by either stimulus, except for the inability of clonidine to affect peak frequency. These data demonstrate that the defective GH secretion in old dogs is not irreversible, since it is normalized when old dogs are exposed to central nervous system-directed stimuli.

THE regulation of somatic growth is complex and requires a number of hormones, including growth hormone, somatomedin C (insulin-like growth factor I), thyroid hormones, insulin, and sex steroids. A...

Six male prepubertal children with constitutional growth delay (CGD), and a subnormal growth hormone (GH) response to insulin hypoglycemia, and four normal prepubertal children were given in different occasions 1 microgram/Kg iv synthetic hpGRF-40 or a single oral dose of 0.15 mg/m2 clonidine (Clon), an effective growth hormone (GH) secretagogue. In the normal children brisk and clear-cut GH rises were detected in plasma after hpGRF-40 (peak GH levels at 15-30 min) or clonidine (peak GH levels 60-90 min). In CGD children hpGRF-40 induced a biphasic response, e.g. a slight increase in plasma GH at 15 min followed by a delayed and erratic GH rise occurring 45-120 min post-injection. Also the GH response to Clon was sluggish and delayed and peak plasma GH levels were attained only 90-180 min post-drug administration. These data indicate that the CGD children of our study have a defect in the pituitary GH reserve.

We evaluated the effect of chronic clonidine administration on 24-h integrated GH secretion (IC-GH) in eight children (six boys and two girls; age, 6.0-13.0 yr) with constitutional growth delay (CGD). Clonidine was given orally in a daily dose of 0.1 mg/m2 at bedtime for 6 months; 24-h secretion studies were performed before and after 2 months of treatment. Clonidine caused a significant augmentation (P less than 0.02) of mean IC-GH from 2.6 +/- 0.4 (+/- SE) to 4.6 +/- 0.6 micrograms/L. The increase in IC-GH was mainly the result of increased GH pulse amplitude, which rose from 12.3 +/- 1.3 to 18.2 +/- 2.1 micrograms/L (P less than 0.01). The mean GH pulse amplitude was significantly higher (P less than 0.02) during sleep (15.9 +/- 2.4 micrograms/L) than during the awake hours (8.4 +/- 1.5 micrograms/L) before treatment. During clonidine treatment the mean GH pulse amplitude during the awake hours (15.0 +/- 3.8 micrograms/L) was similar to that during sleep (20.3 +/- 3.1 micrograms/L). GH pulse frequency was not altered by treatment during either the awake or sleep hours. The mean insulin-like growth factor I levels after 2 (1400 +/- 300 U/L) and 6 (1760 +/- 430 U/L) months of treatment were significantly higher (P less than 0.02 and P less than 0.05, respectively) than the pretreatment value (920 +/- 240 U/L). After 2 months of clonidine treatment, growth velocity increased from 3.1 +/- 0.5 to 10.2 +/- 1.0 cm/yr (P less than 0.001), and after 6 months of treatment is was still significantly higher (7.0 +/- 0.7 cm/yr; P less than 0.02) than that before treatment. These results confirm the ability of clonidine to accelerate growth in children with CGD and indicate that clonidine is capable of increasing IC-GH levels. They also reinforce the view that many children with CGD have decreased endogenous GH secretion.

Summary Comparative studies were performed to verify the effect of growth hormone releasing hormone (GHRH) or clonidine (CLON), a compound thought to act via release of endogenous GHRH, in stimulating GH biosynthesis in the pituitary from neonatal and adult rats. In vitro preincubation for 1 h with GHRH (hpGRF-40, 10 −8 M) increased the incorporation of L-[ 3 H]leucine in the electrophoretic band of GH in the pituitary from 10-day-old rats, but not in the gland from adult rats. Ex-vivo treatment with GHRH or CLON for 5 days was effective in stimulating GH biosynthesis only in the pituitary from neonatal rats. These data demonstrate that neonatal somatotropes are particularly sensitive to the GH-synthesizing activity of GHRH or a GHRH-releasing stimulus.

Summary Administration of diclofensine (5, 10 and 20 mg/kg ip) and CDCI (25 and 50 mg/kg ip), two potent inhibitors of dopamine (DA) reuptake, with virtually no DA releasing activity at the doses used, failed to alter either baseline plasma prolactin (PRL) or anterior pituitary DA concentrations in unanesthetized male rats. In contrast, nomifensine (5 and 10 mg/kg ip), a drug which induces both DA release and blockade of DA reuptake, lowered plasma PRL levels and increased anterior pituitary DA concentrations. The same effects were shared by diclofensine when administered at doses (45 and 100 mg/kg ip), reportedly capable of also affecting DA release. These data indicate that DA recapture into tuberoinflundibular DA nerve terminals does not play a major role in the removal of DA released into the hypophyseal portal system and that this mechanism is not operative in the inhibitory control of DA over PRL secretion.

Intravenously administered synthetic hpGRF 1–40 at doses of 0.1, 0.33 and 1.0 μg/kg increased plasma GH in a dose-dependent fashion in 4 normal prepubertal children. hpGRF 1–40 at the dose of 1.0 μg/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.

In unanaesthetized dogs iv administration of the cholinesterase inhibitor eserine (0.5 mg) induced a clear-cut rise in plasma canine growth hormone (cGH) levels. Diphenhydramine and meclastine, two antagonists of histamine (H) H1 receptors completely suppressed the GH-releasing effect of eserine, while cimetidine, an H2 receptor antagonist, only blunted and delayed it. Two long-lasting serotonin (5-HT) receptor antagonists, metergoline and pizotifen, partially or completely suppressed, respectively, GH release evoked by eserine, whereas fenfluramine, a releaser of neuronal stores of 5-HT and hence a functional activator of 5-HT neurotransmission, was ineffective in this context. Pimozide, a long-acting dopamine receptor antagonist, abolished the effect of eserine, whereas domperidone, which has the same pharmacological properties but does not cross the blood brain barrier, failed to do so. Finally, phentolamine, an antagonist of α-adrenoceptors, and propranolol, a β-adrenergic antagonist, were completely ineffective in preventing the rise in plasma cGH levels induced by eserine, as was naloxone, an antagonist of opiate receptors. All these data demonstrate that, although cholinergic mechanisms are involved in the mechanism(s) underlying cGH release, the final common pathway for GH secretion is not cholinergic. Preservation of dopaminergic and H1 neurotransmission, probably within the blood barrier, is needed to allow the neuroendocrine transduction of cholinergic inputs, whereas the role of 5-HT neurotransmission remains uncertain.

Drugs 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) gamma-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 alpha-methyl-p-tyrosine and 3-iodo-L-tyrosine, false precursors such as alpha-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.

Intravenous administration of methoxamine ( METHOX , 5 mg, iv), a specific alpha 1-adrenergic agonist, reduced baseline GH levels of four unanesthetized beagle dogs 45 and 60 min post-injection and completely abolished the GH-releasing effect of the alpha 2-adrenergic agonist clonidine ( CLON , 4/ micrograms/kg, iv). Prazosin (PRA, 0.1 mg/kg, iv), an alpha 1-adrenergic antagonist, administered before METHOX re-instituted the GH-releasing effect of CLON . METHOX administered at the starting of an arginine infusion (ARG, 10% solution, 3.3 ml/min X 30 min) reduced consistently the GH releasing effect of the latter while, conversely, pretreatment with PRA, strikingly potentiated the GH-releasing effect of the amino acid (2 dogs). METHOX did not alter the GH-releasing effect of human pancreatic GH-releasing factor (hpGRF-40, 1/microgram/kg, iv), though it consistently delayed the occurrence of the GH secretory peak following hpGRF-40. These data indicate that alpha 1-adrenergic receptors located in the central nervous system, inhibit in the dog tonic and stimulated GH secretion.

In all mammalian species studied so far, growth hormone (GH) is released in a pulsatile manner which would be crucial for proper somatomedin secretion and normal growth rhythm (Martin 1978; Muller 1987). This is true also in humans beings, in whom a deficiency in spontaneous GH pulsatility isassociated with short stature (Howse et al. 1977; Albertsson-Wikland et al. 1983; Thorner et al. 1986). However, an shown by Spiliotis et al. (1984), a reduced spontaneous GH secretion during the day is not always due to a pituitary secretory inability. In fact, there are many children in whom, in spite of low 24-h GH secretion, a marked somatotroph responsiveness to provocative tests is present. These children have been defined as having GH neurosecretory dysfunction, i.e., an altered GH neuroregulation that leads to a GH deficiency. Therefore, from a clinical viewpoint, the importance of studying the neural control of GH secretion is evident.

In previous studies we have shown that the alpha 2 -adrenergic receptor agonist clonidine (CLON) releases growth hormone (GH) in conscious dogs, an effect abolished by the selective alpha 2-receptor antagonist yohimbine (YOH) and by reserpine, but not by the alpha 1-receptor antagonist prazosin (1). In the present work intravenous (iv) administration of CLON in conscious dogs evoked a dose-related rise in plasma GH at doses of 2-8 /micrograms/Kg, but not at 16 and 32 /micrograms/Kg. Acute pretreatment with the selective inhibitor of norepinephrine (NE) synthesis, DU-18288, or with a potent antagonist of presynaptic alpha 2-receptors, mianserin abolished the GH rise induced by CLON (4 /micrograms/Kg iv). In contrast, a 10-day-pretreatment with YOH greatly enhanced the GH-releasing effect of CLON (2 /micrograms/Kg iv). In all these data indicate that in the dog: 1) CLON induces GH release via activation of alpha 2-adrenergic receptors; 2) these receptors are likely located on presynaptic sites [experiments with reserpine (1), DU-18288, mianserin, dose-response curve with CLON 2-32/micrograms/kg iv]; 3) the adrenergic receptors involved in GH release exhibit supersensitivity upon (YOH-induced) chronic pharmacologic denervation. In view of the inhibitory action of presynaptic alpha 2-adrenergic receptors (autoreceptors) on NE function, it may be envisioned that in the dog noradrenergic activation is inhibitory and not stimulatory to GH release.

1 Administration of the potent 5-hydroxytryptamine (5-HT) re-uptake inhibitor fluvoxamine (25 mg/kg i.p. for 14 days) to adult cycling female rats did not alter either the number of oestrous episodes or the plasma concentrations of luteinizing hormone determined on days 2, 9 and 14 of treatment. 2 Fluvoxamine (25 mg/kg i.p.) induced in male rats a clear-cut lowering of beta-endorphin-like immunoreactivity from the anterior pituitary, but not the neurointermediate lobe, and increased concomitantly plasma levels of beta-endorphin and beta-lipotropin. 3 Fluvoxamine (12.5 and 25 mg/kg i.p.) stimulated, although not strikingly, prolactin (PRL) secretion in adult male rats, and at 25 mg/kg i.p. potentiated the PRL-releasing effect of 5-hydroxytryptophan (30 mg/kg i.p.). 4 In male rats treated daily with fluvoxamine (25 mg/kg i.p.) the PRL-releasing effect of an additional acute fluvoxamine administration (same dose) was abolished after 4 days maintenance treatment. One week after withdrawal of maintenance, which had been given for 14 days, the challenge dose of fluvoxamine was still unable to raise plasma PRL levels. 5 The endocrine effects of acute fluvoxamine administration are compatible with activation of 5-HT neurotransmission in the central nervous system. The mechanism(s) underlying tolerance to the PRL-releasing action of the drug is presently obscure. Its elucidation should provide insight into the mechanism of action of antidepressant drugs affecting 5-HT function.

The mechanism underlying the GH-releasing effect of galanin (GAL), a novel 29-amino acid peptide, was investigated in the neonatal rat. The effect of galanin was compared to that of clonidine (CLO), a drug known to release GH via endogenous GHRF. GAL administration (5-25 micrograms/kg BW, sc) induced in 10-day-old pups a clear-cut and dose-related rise in plasma GH 15 min postinjection. CLO (50-450 micrograms/kg BW, sc) induced a marked rise in plasma GH, but no dose-related effect was evident. Inhibition of hypothalamic norepinephrine and epinephrine biosynthesis by DU-18288 (6 mg/kg BW, ip) or selective inhibition of epinephrine biosynthesis by SKF-64139 (50 mg/kg BW, ip) completely abolished the GH-releasing effect of GAL (25 micrograms/kg, sc), but left unaltered the GH rise induced by CLO (150 micrograms/kg, sc). Passive immunization with an anti-GHRF serum decreased basal GH levels and prevented the GH-releasing effect of either GAL or CLO, whereas in pups pretreated with an antisomatostatin serum, CLO, but not GAL, increased the already elevated plasma GH titers. In all these data indicate that in the infant rat 1) GAL is a potent GH secretagogue; 2) the action of GAL is not exerted directly on GHRF- or somatostatin-secreting structures, but requires the intervention of catecholaminergic neurons; 3) the GH-releasing effect of GAL is ultimately exerted via GHRF release, although a mechanism operating to inhibit hypothalamic somatostatin release cannot be ruled out; and 4) differently from GAL, CLO releases GH via postsynaptic stimulation of GHRF-secreting neurons.

Intravenous administration of clonidine (CLO), (2,4 and 8/micrograms/Kg), a predominantly alpha 2-adrenergic receptor agonist, induced in unanesthetized dogs clear-cut and dose-related rises in plasma GH (cGH) levels. Pretreatment with the selective antagonist of alpha 1-adrenergic receptors prazosin (0.1 mg/Kg iv) left unaltered the cGH rise induced by 4/micrograms/Kg of CLO whilst blockade of alpha 2-adrenergic receptors by yohimbine (2.5 mg/Kg iv) completely prevented it. In dogs treated 24 h previously, with reserpine (0.5 mg/Kg iv), a depletor of brain catecholamine stores, CLO was ineffective to stimulate cGH release. These data indicate that in the dog the GH-releasing effect of CLO occurs via stimulation of alpha 2-adrenergic receptors and suggest that the latter are located presynaptically in relation to norepinephrine neurons.

It is now a tenet of neuroendocrinology that the secretion of anterior pituitary (AP) hormones is regulated by the central nervous system (CNS) through a family of hypophysiotropic neuropeptides, the releasing and inhibiting hormones. In addition, the neuroregulation of a given AP hormone is influenced by a host of neurotransmitters and neuropeptides, which at hypothalamic and suprahypothalamic levels provide intermediate and obligatory links between hypophysiotropic and both exogenous and endogenous influences on hormone secretion (1,2), Figure 1 depicts schematically how neurotransmitter-neurohormonal interactions may occur at the hypothalamic level. The complexity of the system stems from the abundance of different neurotransmitter and neuropeptide neurons present in the mediobasal hypothalamus (MBH) and the various ways they may reciprocally interact. Another reason for complexity is the phenomenon of coexistence, which ultimately results from cotransmission, i.e., occurrence and then release of two transmitter substances present in the same nerve endings (3). Though cotransmission undoubtedly provides greater versatility and sophistication to the vocabulary of synaptic transmission (3), it compounds the understanding of the physiology and pathophysiology of neuroendocrine control.

In 10-day-old rats made hypothyroid by giving dams propylthiouracil (PTU) in the drinking water since the day of parturition, simultaneous radioimmunoassay (RIA) determinations of basal and stimulated growth hormone (GH) secretion, hypothalamic GH-releasing hormone (GHRH)-like immunoreactivity (LI) content, immunocytochemical localization of somatotrophs, and hypothalamic GHRH-LI-positive structures were performed. The frequency of somatotrophs was also determined. One-day-old hypothyroid rats, whose mothers had been given PTU since the 14th day of pregnancy, were also used for comparison. In 10-day-old hypothyroid rats, pituitary and plasma GH levels and the number of somatotrophs were considerably lower and plasma TSH levels were significantly higher than those in age-matched control rats; however, GHRH-LI titers in the mediobasal hypothalamus and the morphology of GHRH-LI-positive structures were unaltered. In 1-day-old rats the only alteration present, in addition to elevated plasma TSH levels, was a clear-cut decrease in plasma GH levels. An acute challenge with GHRH (20 ng/100 g body wt, sc) or clonidine (15 micrograms/100 g body wt, sc) induced a clear-cut rise in plasma GH levels 15 min postinjection in 10-day-old control rats but failed to do so in age-matched hypothyroid rats. Both compounds failed to rise plasma GH in both hypothyroid and control 1-day-old rats. Taken together these data indicate that in neonatal and infant rats deprivation of thyroid hormones acts primarily to depress pituitary somatotroph function and that possible changes in GHRH-secreting structures represent a later postnatal event.

The aim of this study was to evaluate whether in infant rats, as in adult rats, the brain adrenergic mechanisms regulate plasma GH levels and, if so, to determine the contribution of GH-releasing hormone (GHRH) and/or somatostatin (SS) pathways. In 10-day-old rats, activation of alpha 2-adrenoceptors by clonidine (CLO) was effective to stimulate GH release starting from 50 micrograms/kg ip and up to 450 micrograms/kg ip, though no dose-related effect was evident. Conversely, alpha 2-adrenoceptor blockade by yohimbine (YOH, 10 mg/kg, ip) decreased baseline GH levels. Administration of methoxamine (METHOX, 10 micrograms/rat, ip), a alpha 1-adrenoceptor agonist, significantly reduced plasma GH concentrations, while prazosin (5 mg/kg BW, ip), a specific alpha 1-adrenoceptor antagonist, stimulated plasma GH secretion. Administration of an anti-SS serum (SS-ab, 300 microliters, ip) induced a significant rise in plasma GH levels, while administration of an anti-GHRH serum (GHRH-ab, 100 microliters, ip) was associated with a striking fall in GH levels. In rats pretreated with SS-ab, administration of CLO induced a further rise in plasma GH levels. GHRH-ab significantly reduced plasma GH levels, and this effect was not altered by subsequent CLO administration. Administration of SS-ab and YOH resulted in plasma GH levels intermediate between those of rats treated with SS-ab alone or YOH alone, while pretreatment with GHRH-ab induced a lowering of plasma GH greater than when YOH was given alone. in rats pretreated with SS-ab, the GH-lowering effect of METHOX was completely lacking, while GHRH-ab and METHOX induced a lowering of plasma GH similar to that ensuing after METHOX alone or GHRH-ab alone. Administration of prazosin in rats pretreated with SS-ab did not elicit any further rise in plasma GH, while combined administration with GHRH-ab elicited a GH-lowering effect comparable to that elicited by GHRH-ab alone. These data demonstrate that in the infant rat: brain adrenergic mechanisms involved in the neural regulation of GH secretion are operative; different neuropeptide mechanisms mediate the effect of activation or inhibition of alpha 1- and alpha 2-adrenoceptors. In particular, activation of alpha 2-adrenoceptors stimulates GH secretion via endogenous GHRH release, although a mechanism operating to inhibit hypothalamic SS release cannot be excluded; stimulation of alpha 1-adrenoceptors is inhibitory to GH secretion exclusively via an increased release of hypothalamic SS.

34 pubertal children with constitutional growth delay (CGD) were treated with clonidine orally twice a day. In 25 of the children the height velocity rose on clonidine treatment, and in 21 of them by more than 2 cm/yr during the first 6 months of treatment (mean [SD] growth increment 4.4 [0.5] cm/yr). Of the 22 who were treated for 12 months the increment in height velocity was maintained in 13 (3.4[0.4] cm/yr). Withdrawal of clonidine for 6 months did not stop the stimulatory effect of the drug on linear growth in 6 children, but in the other 8 children height velocities fell to pretreatment levels or below. In a few children reinstitution of clonidine for 2-4 months resulted in a new increment in height velocity. A high height standard deviation score and low growth velocity before treatment were predictive of a good growth response to clonidine. Clonidine did not induce noticeable side-effects. It may be a useful form of therapy for children with CGD.

Administration of human pancreatic GH-releasing factor 1-40 (hpGRF-40) at doses of 1, 10, 20, 100, and 500 ng/100 g BW sc induced in 10-day-old rats a clear-cut rise in plasma GH 15-min post-injection, although the effect was not dose-related and peak GH levels were already present after the lowest GRF dose. In 25-day-old rats, hpGRF induced only a slight rise in plasma GH at the dose of 500 ng/100 g BW sc, whereas it was completely ineffective at the lower doses. In 5-day-old rats, hpGRF (20 ng/100 g BW sc twice daily), administered for 5 days, induced a marked rise in pituitary GH content and plasma GH levels determined 14 h after the last hpGRF injection. In these rats, at the end of treatment, a challenge hpGRF dose (20 ng/100 g BW) induced a rise in plasma GH significantly higher than in infant rats receiving only the challenge hpGRF dose. These data show that: 1) pituitary responsiveness to hpGRF is strikingly higher in infant than in post-weaning rats; 2) in infant rats, subacute administration of hpGRF stimulates GH synthesis and release.

We have investigated the effect of hypothalamo-pituitary disconnection in the rat on the growth hormone (GH) responsiveness to human pancreatic GH-releasing factor (hpGRF). Adult female rats, sham-operated (sham-op) or bearing a complete mechanical ablation of the mediobasal hypothalamus (MBH-A) were challenged, while under urethane anesthesia, with hpGRF-40 (20,100,500 ng/rat i.v.) at different time intervals after surgery. In sham-op rats only 500 ng/rat of hpGRF-40 stimulated GH release, while in 1-and 7-day MBH-A rats the stimulation also occurred with the lower hpGRF doses and the rise in plasma GH was greater than in sham-op controls. Twenty-one and 42 days after the placing of the lesions the GH response to hpGRF-40 was still present at the 500 ng/rat dose, though it was smaller than in sham-op controls. Evaluation of pituitary GH content demonstrated a progressive and rapid decline starting the first day after the placing of the lesions. These data indicate that GH responsiveness to hpGRF is: 1) enhanced in the anterior pituitary shortly after hypothalamo-pituitary disconnection and, 2) despite a striking reduction of the pituitary GH stores, it is maintained after these lesions. The physiologic growth hormone (GH) releaser in the rat is GH-releasing factor and, recently, a group of peptides has been characterized from human pancreatic tumors (hpGRFs) (1,2) which are potent and specific GH-releasers in both animals (3) and man (4). The availability of these peptides, which show a high degree of homology with the physiologic rat hypothalamic GRF (5), offers the unique opportunity to assess somatotrope responsiveness to GRF molecules in rats with hypothalamo-pituitary disconnection. In this study we have first evaluated the GH pituitary responsiveness to increasing doses of hpGRF-40 in rats following mechanical ablation of the mediobasal hypothalamus (6). These rats, by definition, lack the effect of both central nervous system (CNS) inhibitory (e.g. somatostatin) and stimulatory (e.g. GRF) influences to GH release. With the aim to ascertain how the lack of these two opposing inputs reflects on the secretory capacity of the somatotropes, we also investigated the GH response to hpGRF-40 at different time intervals after the lesioning. In a study in rats with electrolytic lesions of the ventromedial-arcuate region of the hypothalamus Tannenbaum et al (7) had shown persistence of the GH response to huge doses of a hpGRF analog.

Over the past few years, a number of new findings have led to a better understanding of the pathophysiology of growth hormone (GH) secretion. The isolation of GH-releasing hormone (GHRH) (Guillemin et al. 1982; Rivier et al. 1982) has led to the conclusion that most GH-deficient patients can produce normal amounts of GH when stimulated with GHRH (Grossman et al. 1983; Pintor et al. 1983; Thorner et al. 1983; Schriock et al. 1984). GH hyposecretory states may therefore result from a primitive abnormality of the somatotrophs or, more frequently, from reduced GHRH synthesis and/or release. The latter may be caused by hypofunction of stimulatory neurotransmitter pathways. More recently, it has been observed that a number of short children, with normal GH responses to Standard pharmacological stimuli, have low 24-h GH secretion (IC-GH) and show a positive response to treatment with exogenous GH. This has strengthened the argument for the existence of a central abnormality of GH neuroregulation (Spiliotis et ai 1984; Zadik et al. 1985).

The effect on plasma prolactin (PRL) of d-amphetamine (Amph) was studied in normo- and hyperprolactinemic subjects. In normoprolactinemic women Amph failed to lower plasma PRL levels when infused intravenously over 1 h at the dose of 7.5 mg, but induced at the dose of 15.0 mg a modest inhibition of plasma PRL (maximum PRL inhibition 20 +/- 4.5% at 45 min). Likewise, in puerperal women Amph at the dose of 7.5 mg did not decrease significantly plasma PRL levels but it was active in this respect (maximum inhibition 37 +/- 10% at 120 min) at the dose of 15.0 mg. In subjects with presumptive evidence of a PRL-secreting adenoma, Amph at either the 7.5 mg or the 15.0 mg dose failed to alter baseline PRL levels. These results indicate that Amph is a poor PRL suppressor in either normo- or hyperprolactinemic subjects. It is proposed that this may be due to the drug's ability to effect release of dopamine mainly from a non-granular pool of the amine.

The demonstration that GH-releasing factor (GRF) stimulates GH synthesis and release in rat pups prompted studies to evaluate the effects on the same indices of clonidine (CLO), an alpha 2-adrenoceptor and potent GH secretagogue, purported to act in adult rats via GRF release. Our first aim was to ascertain whether CLO elicits GH release in rat pups via GRF, and if this is the case, to evaluate the ontogenetic development in 1- to 10-day-old pups of the GH response to acute CLO or GRF administration and, finally, the effects of short term CLO or GRF treatment on plasma and pituitary GH concentrations and on the GH response to an acute challenge with the homologous secretagogue. CLO (15 micrograms/100 g BW, sc) induced a clearcut GH rise in 10-day-old rats but not in pups pretreated with a specific anti-GRF serum. Moreover, unlike GRF (10(-8) M), CLO (10(-6) to 10(-5) M) did not stimulate GH release in vitro from anterior pituitaries of 10-day-old rats. In 1-day-old rats, neither CLO (15 micrograms/100 g BW, sc) nor GRF (20 ng/100 g BW, sc) stimulated GH release, whereas significant GH stimulation was elicited by GRF, but not CLO, in 5-day-old rats and by both secretagogues in 10-day-old rats. Short term treatment with CLO (15 micrograms/100 g BW, sc, twice daily) or GRF (20 ng/100 g BW, sc, twice daily) on postnatal days 1 through 5 did not modify either plasma or pituitary GH concentrations 14 h after the last drug administration, but did so when either secretagogue was administered on postnatal days 5 through 9. Finally, an acute challenge with GRF, but not with CLO, induced a further rise in the already elevated plasma GH levels of pups pretreated from postnatal day 5 through 9, but neither secretagogue did so in pups pretreated from postnatal days 1 to 5. Viewed together, these data indicate that in infant rats CLO releases GH via GRF release and that the somatotropes respond earlier to GRF (5 days) than the GRF-secreting structures do to alpha 2-adrenergic stimulation (10 days). Both GRF and CLO stimulate GH synthesis when administered repeatedly. However, whereas repeated GRF treatment has a priming effect on the somatotropes, CLO does not, probably because of down-regulation of hypothalamic alpha 2-adrenoceptors.

In an attempt to examine the effect of prolonged physical activity on the function of the GH/IGF-1 axis during the aging process in man, we have evaluated basal and GHRH (GHRH-29: 1 microgram/kg i.v. as a bolus) stimulated GH secretion as well as basal plasma IGF-1 levels in a group of 25 healthy runners (50-60 years, mean age 55.5 +/- 0.6) and 24 age-matched relatively sedentary normal controls (mean age 55.8 +/- 0.7). The runners had a minimum distance in kilometers of 26 km/week for at least 15 years, and competed in distances ranging from 16 km to the marathon. In runners, GHRH induced an increase of GH which was significantly higher (p0.001) than that observed in the age-matched controls. Baseline IGF-1 levels were significantly higher (p0.001) in trained runners (171 +/- 8.4 micrograms/1) compared to the controls (91.1 +/- 5.5 micrograms/1). These data show that in middle-age prolonged physical activity increases the function of the GH/IGF-1 axis. To clarify the possible mechanisms underlying the GH/IGF-1 secretory pattern in the runners, the GH responses to both single and combined administration of GHRH and arginine (ARG: 30 g infused over 30 min), a GH secretagogue likely acting via inhibition of hypothalamic somatostatin release, were investigated in 6 runners (mean age 55 +/- 1.9 years) and 6 controls (mean age 55 +/- 0.9 years). ARG clearly increased the GH response to GHRH in the controls, whereas it was unable to further potentiate the GH-releasing effect of GHRH in runners, thus suggesting that the increased GH responsiveness to GHRH might be due to an exercise-related decrease in endogenous hypothalamic somatostatinergic activity.

We have evaluated the plasma GH response to a single injection of 1 microgram/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 less than 0.01) and the IC-GH (r = -0.554, P less than 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.

Withdrawal of a somatostatin infusion (SSIW) is followed by a rebound rise of GH in both animals and normal adult men, a phenomenon likely mediated by endogenous GHRH function. In the present study, we have evaluated the GH response to SSIW in a group of 28 prepubertal children (18 boys and 10 girls; aged 3.7‐11.1 yr). Six children had GH deficiency [GHD; GH responses to pyridostigmine (PD)1GHRH and to clonidine ,20 and ,7 mg/L, respectively], 4 children had GH neurosecretory dysfunction (GHND; GH responses to PD1GHRH and to clonidine $20 and .7 mg/L, respectively; mean integrated nighttime GH concentrations ,3 mg/L), and 18 children were short normal children [normal controls (NC)]. All children received a constant infusion of SS at the dose of 3 mg/Kgzh for 90 min. SSIW elicited a clear-cut GH rise in NC children (13.7 6 1.0 mg/L), but not in GH-deficient children, regardless of the underlying etiology (GHD, 1.6 6 0.4 mg/L; GHND, 2.4 6 0.3 mg/L). The GH response to SSIW was similar between GHD and GHND children. There was no overlapping of the maximum SSIW-stimulated GH peaks between NC and GHD or GHND children. In conclusion, we have demonstrated that SSIW elicits a significant GH rise in NC children, but not in GH-deficient children, regardless of the underlying etiology (GHD or GHND). This resulted in complete discrimination of NC from GHD or GHND children. Were these present findings confirmed on a larger number of children, SSIW, because of its testing efficaciousness and safety, procedural simplicity, and economy holds promise of being a useful diagnostic tool for GH-dependent growth disorders. (J Clin Endocrinol Metab 84: 4426 ‐ 4430, 1999)

A significant increase of cell multiplication in inoculated ascitic and solid tumors was demonstrated in both DBA/2 and C57BL/6 mice as well as in Wistar rats after radiofrequency lesions in the median hypothalamus (ventromedial and dorsomedial nuclei; part of arcuate nucleus). The following tests were performed: mitotic and metaphasic index, doubling time of tumor, incorporation of tritiated thymidine into DNA, cell cycle parameters and growth fraction. The increased rate of cell proliferation measured was predominantly due to the higher speed of DNA biosynthesis with a minor contribution by an increase of the growth fraction. In the animals with hypothalamic lesions we demonstrated a slight decrease in the secretory activity of the adenohypophysis. Because it is generally stated that failure of hypophysis function hinders cell multiplication in normal and neoplastic tissues, we think that heightened cell proliferation after hypothalamic lesions is due to suppression of an inhibitory mechanism located in the hypothalamus and which is independent of the hypophysis.

Hypothalamic neurochemical alterations in mammals underlie disturbances of food intake. There is scarce information on these topics in elderly persons; therefore, the aims of the present study were: (i) to evaluate the orexigenic effects of a growth hormone secretagogue, administered to young and old rats and dogs, alone or in combination with molsidomine, a donor of nitric oxide and (ii) to evaluate by reverse transcription-polymerase chain reaction in the whole hypothalamus of young and old rats messenger RNA levels of a wide number of anabolic and catabolic peptides, receptors, and enzymes involved in the control of feeding behavior, relating the detected titers, whenever possible, to the feeding responses to growth hormone secretagogue. In all, the results obtained strengthen the proposition that, in the hypothalamus of old rats, anti-anorexigenic compensatory mechanisms are operative, aimed at maintaining a "normal" feeding pattern. Thus, the occurrence of a primary, age-related alteration in the feeding mechanisms is unlikely.