Endocrine control of Na+,K+-ATPase and chloride cell development in brown trout (Salmo trutta): interaction of insulin-like growth factor-I with prolactin and growth hormone.

A 2-factorial (3x3) injection experiment was used to investigate the effect and interaction between different hormones on the initial phase of seawater (SW) acclimation in brown trout (Salmo trutta). Each fish was given 4 injections on alternate days in freshwater (FW). Factor 1 was either saline, 2 micrograms ovine prolactin (oPRL)/g, or 2 micrograms ovine growth hormone (oGH)/g. Factor 2 was either 0, 0. 01, or 0.1 mirograms recombinant human insulin-like growth factor-I (rhIGF-I)/g. In each of the 9 treatment groups, half of the fish were subjected to a 48-h SW-challenge test, and the remaining fish were sham-transferred to FW one day after the last injection. Hypo-osmoregulatory performance was increased by GH and impaired by PRL treatment as judged by changes in plasma osmolality, [Na+], [Cl-], total [Mg] and muscle water content (MWC) after SW transfer. IGF-I reduced plasma osmolality after transfer to SW but had no effect on plasma total [Mg] or MWC. The effects of the two factors on plasma osmolality, [Na+], [Cl-], and MWC were additive. In sham-transferred fish, GH and IGF-I, alone and in combination, stimulated Na+,K+-ATPase alpha-subunit mRNA (alpha-mRNA) content in the gill. This was paralleled by an overall increase in gill Na+, K+-ATPase activity in fish treated with 0.01 micrograms IGF-I/g. Simultaneous administration of PRL completely inhibited the increase in gill alpha-mRNA observed in the IGF-I-injected groups. Combination of GH and IGF-I did not further affect the alpha-mRNA level relative to the single hormone-injected groups. There was an overall decrease in Na+,K+-ATPase activity in pyloric caeca and middle intestine by the low dose and both doses of IGF-I respectively. No effect was observed in the posterior intestine. PRL and GH treatments did not affect enzyme activity in any intestinal segment. Both doses of IGF-I increased Na+,K+-ATPase-immunoreactive (NKIR) cell density in gill primary filaments. PRL and GH had no effect on primary filament NKIR cell density. GH and both doses of IGF-I reduced secondary lamellar NKIR cell density, whereas PRL had no effect. The main conclusion is that IGF-I and GH induce an overall redistribution of NKIR cells away from the secondary lamella onto the primary filament of FWacclimated trout. This is associated with an overall increased alpha-mRNA level in the gill, which may reflect an increased expression within individual NKIR cells in the primary filament. PRL completely abolished the IGF-I stimulation of alpha-mRNA levels, suggesting a desensitisation of the gill tissue to IGF-I, which may explain the overall anti-SW adaptive effect of PRL.     

Consequence of dynorphin-A administration on anterior pituitary hormone concentrations in the adult male rhesus monkey

This study examines the role of dynorphin-A(1-13) and dynorphin-A(1-10)-amide in the neuroendocrine regulation of anterior pituitary hormones in nonrestrained, adult male rhesus monkeys. The effects of these opioids on plasma concentrations of prolactin (PRL), luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyrotropin (TSH) and growth hormone (GH) were assessed. Intravenous administration of dynorphin-A(1-13), 1-120 micrograms/kg, significantly increased plasma PRL levels. Average maximal increases of 90-230% occurred within 5 min and levels remained significantly elevated for up to 120 min. PRL response reached a plateau following the 30 micrograms/kg dose. Dynorphin-A(1-13) had no observable effects on plasma concentrations of LH, FSH, TSH or GH at any dose level studied. Administration of dynorphin-A(1-10)-amide produced significant dose-dependent increases in plasma PRL concentrations. Dose levels of 1-120 micrograms/kg produced mean peak increases from 100 to 230%, 5-10 min postadministration. Dynorphin-A(1-10)-amide had no significant effect on plasma concentrations of LH, FSH, TSH or GH. The increases in plasma PRL concentrations induced by dynorphin-A were naloxone-reversible. These results indicate a selective effect of dynorphin-A on the regulatory mechanisms of PRL secretion over that of other anterior pituitary hormones.     

Discordance between growth hormone (GH) responses after GH-releasing hormone and insulin hypoglycemia in myotonic dystrophy

Plasma GH responses to human GHRH, arginine, L-dopa, and insulin-induced hypoglycemia were determined in seven myotonic dystrophy (MD) patients. An iv bolus injection of GHRH-(1-44)-NH2 (1 microgram/kg BW) only slightly increased plasma GH concentrations in MD patients. The mean peak plasma GH level after GHRH injection [4.2 +/- 0.8 (+/- SE) micrograms/L] was significantly lower than that in 10 age-matched normal subjects (26.7 +/- 4.3 micrograms/L) or that in 6 patients with progressive muscular dystrophy (22.8 +/- 6.6 micrograms/L) whose nutritional status was similar to that of the MD patients. Even with a larger dose of GHRH (3 micrograms/kg BW), the plasma GH rises were minimal in the MD patients (mean peak, 5.9 +/- 1.8 micrograms/L). The plasma GH responses to a 30-min iv infusion of arginine (0.5 g/kg BW) and oral ingestion of L-dopa (0.5 g) were attenuated to a similar extent, whereas insulin-induced hypoglycemia caused a significant increase in plasma GH in all seven MD patients [mean peak, 17.4 +/- 4.1 (+/- SE) microgram/L]. The plasma TSH responses to TRH and plasma insulin-like growth factor I levels were similar in the MD patients and normal subjects. These findings suggest that 1) the impaired GH release after GHRH, arginine, and L-dopa administration in MD patients is not due to somatotroph deficiency, since the GH response to hypoglycemia is well preserved; and 2) insulin-induced hypoglycemia may stimulate GH release at least in part via inhibition of somatostatin release.     

Effects of thyroid hormones on liver binding sites for human growth hormone, as studied in the rat.

Several weeks after thyroidectomy (T), female rats stopped growing, and their pituitary GH content had decreased to less than 2--3% of the values found for age-matched controls (C). The liver membranes of such animals were explored with human GH (hGH). It was found that in the severely hypothyroid T rat, the number, but not the affinity, of the lactogenic binding sites was markedly reduced. Treatment of these rats for 3 weeks with 1.75 micrograms or T4 or 0.5 micrograms T3/100 g body weight/day restored growth, increased pituitary GH content and restored the number of liver lactogenic binding sites were practically to normal. As regards the lactogenic binding sites, similar results were obtained when the severely hypothyroid rats were treated with a much lower T4 dose (0.2 microgram/100 g/day): this dose was clearly growth promoting, and restored to normal both the low circulating GH levels and the pituitary PRL content of the severely hypothyroid rat. The changes in plasma PRL were not clear. The lactogenic binding sites on liver membranes from rats which were both thyroidectomized and hypophysectomized were decreased in number. Treatment with 0.5 microgram T3/100 g/day for 30 days (but not for 12 days) resulted in an increase in the number of lactogenic binding sites, though it did not affect growth or the undetectable plasma GH levels. The effect on the lactogenic binding sites was less marked than in T rats with an intact pituitary. It would appear that minute amounts of thyroid hormones are needed for maintenance of liver lactogenic binding sites; it is possible that this not only occurs through mechanism(s) which involve the pituitary, but also through others which do not. The possible role of these receptors in growth processes is not yet clearly understood.     

Arginine stimulates growth hormone secretion by suppressing endogenous somatostatin secretion

To determine how arginine (Arg) stimulates GH secretion, we investigated its interaction with GHRH in vivo and in vitro. Six normal men were studied on four occasions: 1) Arg-TRH, 30 g arginine were administered in 500 mL saline in 30 min, followed by an injection of 200 micrograms TRH; 2) GHRH-Arg-TRH, 100 micrograms GHRH-(1-44) were given iv as a bolus immediately before the Arg infusion, followed by 200 micrograms TRH, iv; 3) GHRH test, 100 micrograms GHRH were given as an iv bolus; and 4) TRH test, 200 micrograms TRH were given iv as a bolus dose. Blood samples were collected at 15-min intervals for 30 min before and 120 min after the start of each infusion. Anterior pituitary cells from rats were coincubated with Arg (3, 6, 15, 30, and 60 mg/mL) and GHRH (0.05, 1, 5, and 10 nmol/L) for a period of 3 h. Rat GH was measured in the medium. After Arg-TRH the mean serum GH concentration increased significantly from 0.6 to 23.3 +/- 7.3 (+/- SE) micrograms/L at 60 min. TRH increased serum TSH and PRL significantly (maximum TSH, 11.1 +/- 1.8 mU/L; maximum PRL, 74.6 +/- 8.4 micrograms/L). After GHRH-Arg-TRH, the maximal serum GH level was significantly higher (72.7 +/- 13.4 micrograms/L) than that after Arg-TRH alone, whereas serum TSH and PRL increased to comparable levels (TSH, 10.2 +/- 3.0 mU/L; PRL, 64.4 +/- 13.6 micrograms/L). GHRH alone increased serum GH to 44.9 +/- 9.8 micrograms/L, significantly less than when GHRH, Arg, and TRH were given. TRH alone increased serum TSH to 6.6 +/- 0.6 mU/L, significantly less than the TSH response to Arg-TRH. The PRL increase after TRH only also was lower (47.2 +/- 6.8 micrograms/L) than the PRL response after Arg-TRH. In vitro Arg had no effect on basal and GHRH-stimulated GH secretion. Our results indicate that Arg administered with GHRH led to higher serum GH levels than did a maximally stimulatory dose of GHRH or Arg alone. The serum TSH response to Arg-TRH also was greater than that to TRH alone. We conclude that the stimulatory effects of Arg are mediated by suppression of endogenous somatostatin secretion.     

Inhibitory influence of thyrotropin releasing hormone administration on growth hormone response to low doses of growth hormone-releasing hormone in normal man

Literature data show that TRH may have either stimulatory or inhibitory actions on GH release according to pathophysiological conditions of the subject. In view of this dual effect of TRH, we studied the possible interaction of TRH and GRF on GH secretion. Six healthy male volunteers received iv in different occasions and in random order: 1) GRF 0.05 micrograms/Kg; 2) GRF 0.1 micrograms/Kg; 3) GRF 1 microgram/Kg; 4) GRF 0.05 micrograms/Kg + TRH 400 micrograms, simultaneously; 5) GRF 0.05 micrograms/Kg + TRH 20 micrograms, simultaneously; 6) GRF 1 microgram/Kg + TRH 400 micrograms, simultaneously, 7) the vehicle as control treatment. Blood samples were obtained at several time intervals and plasma GH, PRL and TSH were measured by RIA methods. Plasma GH significantly increased in all subjects after all the tested doses of GRF and after the combination of the highest and of the lowest doses of GRF + TRH (treatments 6 and 5). GH responses increased progressively with the dose of GRF administered, even if a clear dose-response relationship could not be demonstrated, owing to the considerable interindividual variability in the responsiveness. The administration of GRF 0.05 micrograms/Kg increased significantly plasma GH levels vs control treatment. The simultaneous administration of a low effective dose of GRF (0.05 micrograms/kg) plus a high dose of TRH (400 micrograms) was able to significantly inhibit the GH secretion elicited by GRF 0.05 micrograms/Kg alone. The other GRF + TRH combinations tested (treatments 5 and 6) did not modify the GH response to the same doses of GRF given alone. Plasma PRL and TSH did not change either after GRF at any dose or after the vehicle.(ABSTRACT TRUNCATED AT 250 WORDS)     

A possible role of prostacyclin to stimulate prolactin and growth hormone release by hypothalamic and pituitary actions, respectively

Prostacyclin (PGI2) (1-5 micrograms in 3 microliters 0.05 M Tris/HCl buffer, pH 7.5) and its stable metabolite, 6-oxo-PGF1 alpha, were microinjected into the third ventricle of ovariectomized rats, and plasma FSH, GH, PRL, and TSH levels were measured by RIA. Control animals received 3 microliters buffer. Injection of 5 micrograms PGI2 dramatically elevated plasma PRL values (4- to 5-fold) at 5 and 15 min, whereas the same dose of 6-oxo-PGF1 alpha produced a significant but smaller (2-fold) stimulatory effect. A delayed increase (1.5-fold) in plasma GH occurred after intraventricular PGI2 at 30 and 60 min. 6-Oxo-PGF1 alpha failed to alter GH levels. There were no alterations in plasma FSH and TSH after intraventricular injection of PGI2. Dispersed, overnight cultured cells from anterior pituitaries of ovariectomized rats were tested with 10(-4)-10(-7) M PGI2 and its metabolite. After 15 min of incubation, 3 X 10(-5) PGI2 produced a highly significant elevation in GH release (P less than 0.001), whereas there was no alteration in PRL levels. Only pharmacological doses of 6-oxo-PGF1 alpha (10(-4) M) stimulated GH release. There was no alteration in PRL release by the cultured cells even in the presence of 10(-4) PGI2. These results suggest that PGI2 stimulates PRL release by a hypothalamic action either to increase the release of PRL-releasing factor, or to decrease release of PRL-inhibiting factor, or by both mechanisms. The delayed stimulatory effect of PGI2 on the release of GH may be exerted via an effect on the anterior lobe itself, since PGI2 was effective in stimulating GH release by the incubated pituitary cells.     

Growth hormone-releasing hormone infusion in patients with active acromegaly

To determine GH-releasing hormone (GHRH)-stimulated GH secretion in patients with active acromegaly, nine patients received a 50-microgram GHRH-(1-44) bolus dose followed by a 2-h infusion with 100 micrograms GHRH/h, after which a second 50-microgram GHRH bolus dose was given. Serum GH, PRL, and immunoreactive GHRH levels were measured from 2 h before to 1 h after the end of the infusion and compared with hormone levels in six normal subjects subjected to the same protocol. In addition, seven of the nine acromegalic patients received 100 micrograms GHRH as an iv bolus dose, followed by a 2-h saline infusion on a different day. After the 100-micrograms GHRH bolus dose, the mean GH level increased from 55.9 +/- 18.0 (+/- SE) to 148.5 +/- 40.0 ng/ml within 15 min. Thereafter, GH levels decreased and were significantly lower at 90 and 120 min compared to the peak level 15 min after GHRH injection. After the 50-micrograms GHRH bolus dose, all acromegalic patients except two also had a clear-cut rise of GH levels, with the mean GH level increasing from 37.5 +/- 13.2 to 108.4 +/- 55.0 ng/ml at 60 min. Thereafter, elevated GH levels were sustained in the acromegalic patients throughout the GHRH infusion. In contrast, normal subjects had a significant decrease in the initially elevated GH levels, despite continuous GHRH infusion. There were no significant differences between PRL secretion and immunoreactive GHRH levels in either group. These findings suggest that patients with active acromegaly not only have elevated basal GH levels, but also have a greater ready releasable GH pool and/or accelerated GH turnover compared to those of normal subjects, which cannot be exhausted by a 2-h GHRH infusion.     

Suppression of the pituitary-gonadal axis in children with central precocious puberty: effects on growth, growth hormone, insulin-like growth factor-I, and prolactin secretion

To assess further the relationship between gonadal sex steroids and PRL, GH, and insulin-like growth factor-I (IGF-I) secretion and to help clarify the mechanism underlying the pubertal growth spurt, we studied 11 children (10 girls) with central precocious puberty before and during gonadal suppression with the GnRH agonist (GnRH-a) leuprolide acetate. Nocturnal sampling for plasma levels of GH and PRL, GH response to GH-releasing factor-(1-44), and plasma IGF-I levels were determined before and 3-6 months after pituitary-gonadal suppression. Treatment caused a significant decrease in the LH and FSH responses to GnRH (P less than 0.01) and the plasma concentration of estradiol (P less than 0.05). The patients' mean height velocity SD score for chronological age, initially 3.8 +/- 1.9, decreased significantly to 0.9 +/- 0.9 with treatment (P less than 0.005). Nocturnal GH secretion (mean GH concentration, sum of GH pulse areas, sum of GH pulse amplitudes, and GH pulse frequency) and mean IGF-I levels (1.38 +/- 0.6 vs. 1.72 +/- 0.34 U/mL) were not significantly altered by treatment. However, the mean peak GH response to GH-releasing factor-(1-44) was 29.2 +/- 6.8 micrograms/L before treatment and declined significantly to 17.7 +/- 3.4 micrograms/L after gonadal suppression (P less than 0.05). PRL secretion was similar before and after GnRH-a-induced suppression. These results indicate that the decrease in height velocity noted during GnRH-a treatment occurred independently of changes in nocturnal GH secretion and IGF-I levels. These data are consistent with the premise that sex steroids can modulate growth by a direct action on skeletal growth.     

The effect of altered thyroid status on pituitary hormone messenger ribonucleic acid concentrations in the rat

To study the effects of altered thyroid status on pretranslational control of pituitary hormones, adult male rats were given propylthiouracil for 6 weeks and underwent the following studies. 1) Rats were injected with T3 at 10 micrograms/100 g BW daily for 10 days. 2) Rats were given T3 injections at 0, 0.01, 0.1, 1.0, or 10 micrograms/100 g BW for 10 days. 3) Rats were killed 0, 1, 6, or 24 h after a single injection of T3 at 10 micrograms/100 g BW or after 5 or 10 days of daily T3 injections. Pituitary mRNA concentrations of TSH beta, alpha-subunit, PRL, GH, POMC, FSH beta, and LH beta were determined for individual animals. Marked increases in TSH beta and alpha-subunit mRNAs occurred after PTU treatment, and these changes were reversed by 1.0 microgram/100 g BW T3 and within 24 h of a single T3 injection of 10 micrograms/100 g BW. Further increases in the dose or time course of T3 administration led to a relatively greater suppression of TSH beta mRNA levels than alpha-subunit mRNA levels. In contrast, GH and PRL mRNA levels were low in hypothyroid animals, and both rose toward control levels with 0.1 microgram/100 g BW T3 and by 24 h after a single T3 dose. Induction of hyperthyroidism did not further increase GH mRNA levels above control, but increased PRL mRNA levels 2-fold over control. No changes were seen in FSH beta, LH beta, or POMC mRNA levels with any treatment. Thus, studies of altered thyroid status in the rat reveal dose-response and time-course variability in the pretranslational control of TSH beta, alpha-subunit, GH, and PRL by thyroid hormone.     

Effects of clonidine on blood pressure, noradrenaline, cortisol, growth hormone, and prolactin plasma levels in high and low intestinal tone subjects

Systolic blood pressure (SBP), diastolic blood pressure (DBP), norepinephrine (NE), cortisol (CRT), growth hormone (GH), and prolactin (PRL) plasma levels were investigated in 46 normal subjects, 28 high intestinal tone (high IT) and 18 low intestinal tone (low IT), before and after the administration of a single intramuscular dose of clonidine (2.5 micrograms/kg). High IT subjects had lower mean values of DBP than low IT subjects, and basal NE was significantly greater in low IT than in high IT subjects. A negative correlation between NE and IT values was found for the high IT, but not for the low IT group, during the preclonidine periods. The drug reduced SBP in high IT, whereas it reduced SBP plus DBP and NE in low IT subjects. Clonidine induced significant reductions of CRT and increases of GH in both groups; furthermore, a slight but significant reduction of PRL was registered in high IT group. The drug also induced increase of distal colon tone in high IT subjects and suppressed phasic activity (waves) in low IT subjects. While a significant positive correlation was found between NE and DBP in low IT subjects during postclonidine periods, no correlation was found between the two parameters in high IT subjects. Other significant positive (+) and negative (-) correlations during postclonidine periods were: CRT/GH (-), CRT/PRL (+), and GH/PRL (-) in high IT subjects; NE/CRT (+), NE/GH (-), CRT/GH (-), CRT/DBP (+), and GH/DBP (-) in low IT subjects. Finally, significant negative correlation was found between NE and distal colon tone during postclonidine periods in high IT subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of mammalian growth hormone on amino nitrogen mobilization in the eel

Hypophysectomy decreased plasma amino nitrogen (PAN) levels of Japanese eels. In contrast, administration of bovine or ovine growth hormone (GH; 2 micrograms/g) produced a delayed increase in PAN levels of both intact and hypophysectomized eels 48 hr after GH injection. The minimum dose of GH required to elevate PAN levels was found to be 0.1-1 micrograms/g body wt. The fact that GH treatment also increased PAN of hepatectomized eels indicates that the increased PAN was at least partly caused by the increased mobilization of amino nitrogen from body protein. GH also increased plasma free fatty acid content of intact and hypophysectomized eels 48 hr after GH injection in one experiment of the present study, but this effect was not reproducible in other experiments. No effect of GH administration was observed either in plasma glucose and lipid of intact and hypophysectomized eels 48 hr after the injection.     

Altered growth hormone response after growth hormone releasing hormone administration in chronic renal failure

Eleven chronic renal failure patients and 11 matched controls, received growth hormone GHRH (1 microgram/kg iv) or TRH (400 microgram iv) on separate occasions, immediately before undergoing hemodialysis. GHRH-induced GH peak in uremics (22.7 +/- 5.2 micrograms/l) was not different from that obtained in control subjects (16.0 +/- 4.3 micrograms/l). However, the uremic patients did not show the habitual post-peak fall, remaining GH levels over 10 micrograms/l till the end of the test. Differences between the two groups were significant (p less than 0.05). Uremic patients showed PRL values higher than in controls, however their TRH-induced PRL peak (20.6 +/- 6.6 micrograms/l) was not different from that of controls (26.5 +/- 3.0 micrograms/l). Again chronic renal failure patients showed PRL plasma values abnormally elevated till the end of the test. Differences between the two groups were significant (p less than 0.05). Administration of placebo to a different group of seven uremic patients did not alter GH and PRL plasma levels. This sustained secretion of both GH and PRL in uremia could be attributed to reduced kidney clearance. However, when subjects were examined individually both the GHRH- and the TRH-induced hormonal peaks and the subsequent fall were not different in both groups. Unlike with controls, in uremic patients GHRH-stimulated GH and TRH-stimulated PRL/GH peaks were dispersed throughout the 120 min period. In controls GH and PRL peaks clustered around 15-30 min. The peak dispersion created a false impression of flattened curves or sustained hypersecretion in uremia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute and chronic estrogen effects upon serum somatomedin activity, growth hormone, and prolactin in man.

Estrogen (E) reduces bioassayable GH-dependent serum somatomedin (SM) activity in acromegalics without affecting plasma growth hormone (GH) levels and inhibits the rise of SM activity normally produced by GH administration in GH-deficient subjects. We have now investigated the effect of E administration on serum SM activity and on plasma GH and prolactin (PRL) in 6 adult male subjects without pituitary pathology. Chronic E administration (ethinyl estradiol 0.5 mg/day for 7 to 70 days) reduced serum SM activity by 40 to 62% in each of 4 subjects (P less than 0.02 to less than 0.001). In 3 of the subjects, basal GH levels increased by 75 to 300% (P less than 0.05 to less than 0.001) and basal PRL levels increased by 90 to 200% (P less than 0.01 to less than 0.001). While iv administration of normal saline did not significantly affect either SM or GH, iv administration of E (bolus injection of 25 mg conjugated estrogens, USP) to 5 subjects resulted in: a) a 46 to 80% decrease in serum SM activity in all subjects, proceeding with an apparent half-life of 2 hours, becoming significant (P less than 0.05) at 2 hours (1 subject) to 3 hours (4 subjects), maximal at 6 hours, and persisting for 12 to 24 hours; b) GH elevation to 3 to 16 times baseline level (P less than 0.01) at 2 to 3 hours in 4 subjects; and c) no significant change of PRL levels in any subject. The mean GH response to iv E was maximal at a time (2 hours) when the mean SM activity had decreased only 20% and subsided well before the nadir of SM activity. The one patient without GH response to chronic or acute E administration may have been affected by absorption of triamcinolone being applied topically during the study. These results demonstrate that in males with normal pituitary function, E reduces serum SM activity, enhances basal GH and PRL secretion, and, upon iv injection, stimulates acute GH release. Although opposite chronic E effects upon GH and SM activity support a putative negative SM-GH feed-back mechanism, iv E administration apparently provokes acute GH release by a different mechanism. The half-life of serum SM activity in the human is probably much shorter than previously estimated.     

EFFECT OF SUBACUTE CABERGOLINE TREATMENT ON PROLACTIN, THYROID STIMULATING HORMONE AND GROWTH HORMONE RESPONSE TO SIMULTANEOUS ADMINISTRATION OF THYROTROPHIN-RELEASING HORMONE AND GROWTH HORMONE-RELEASING HORMONE IN HYPERPROLACTINAEMIC WOMEN

It is known that dopaminergic neurotransmission is involved in the control of PRL, TSH and GH secretion. Cabergoline (CAB) is a new ergolinic derivative with a long-acting dopaminergic activity. We evaluated 11 women with pathological hyperprolactinaemia before and during sub-acute CAB treatment (0.8-1.2 mg/p.o.; 8 weeks). Simultaneous administration of TRH (200 micrograms i.v.) and GHRH 1-44 (50 micrograms i.v.) were carried out before and after 4, 8 and 10 week intervals from the beginning of CAB treatment. Basal PRL levels (2453.5 +/- S.E. 444.5 mU/l) were significantly reduced during CAB administration (week 4: 164.5 +/- 66.5 mU/l; week 8: 168.0 +/- 66.5 mU/l; P less than 0.01) and no variations were observed 2 weeks after drug discontinuation (week 10: 210.0 +/- 98.0 mU/l). PRL percentage change after TRH was increased by CAB (P less than 0.05). No variation in basal and TRH-stimulated TSH levels was found during CAB administration. A slight increase in GH basal levels (3.0 +/- 0.6 mU/l) was found after weeks 4 (6.4 +/- 2.0 mU/l) and 10 (5.8 +/- 1.6 mU/l) (P less than 0.05). GH response to GHRH was significantly enhanced (ANOVA: P less than 0.01) during sub-acute CAB treatment. A positive correlation was found between GH secretory area and weeks of CAB therapy (P less than 0.01). Our data show that CAB is very effective in lowering PRL secretion in hyperprolactinaemia, and is able to modify PRL and GH responses after TRH and GHRH. The increasing trend in GH basal and GHRH-stimulated GH levels seems to indicate that CAB can override the central dopaminergic tone which is operative in hyperprolactinaemia.     

Evidence for a role of alpha-adrenergic mechanisms in regulation of episodic growth hormone secretion in the rat.

The role of catecholamines in regulation of episodic GH secretion was investigated in the male rat. Administration of alpha-methyl-p-tyrosine (alpha-MT; 250 mg/kg ip) caused significant suppression of GH bursts and resulted in marked elevation of plasma PRL. Intravenous administration of apomorphine (.03 and .1 mg/kg) had no effect on decreased GH levels, whereas clonidine (150 micrograms/kg) restored GH secretion. Apomorphine significantly reduced PRL levels in alpha-MT-treated rats whereas, clonidine resulted in a further increase in PRL.     

Hypothalamic hormones that release growth hormone stimulate hepatic 5'-monodeiodination activity in the chick embryo

Plasma GH, tri-iodothyronine (T3), thyroxine (T4) and liver 5'-monodeiodination (5'-D) activity were measured in 18-day-old chick embryos injected with thyrotrophin-releasing hormone (TRH) and human pancreatic growth hormone releasing factor (hpGRF). Injections of 0.1 and 1 microgram TRH and 1.5 micrograms hpGRF increased the concentration of plasma GH while injection of 15 micrograms hpGRF had no effect. Concentrations of plasma T3 were raised after injection of TRH or hpGRF. Injections of TRH but not of hpGRF raised the concentration of plasma T4. The increases in concentration of plasma T3 after injection of TRH or hpGRF were parallelled by increases in liver 5'-D activity. An injection of 0.25 micrograms T4 significantly raised the concentration of T4 in plasma but had no effect on plasma T3 or liver 5'-D activity. It is concluded that the release of chicken GH by TRH or hpGRF is responsible for the observed increase in plasma concentration of T3 and liver 5'-D activity.     

Plasma growth hormone (GH) response to GH-releasing factor in normal children with short stature and patients with pituitary dwarfism

Synthetic human pancreatic GRF (hpGRF-44) was administered as an iv bolus to 28 normal children with short stature and 27 patients with GH deficiency. After a dose of 1 or 2 micrograms hpGRF-44/kg BW, mean plasma GH levels peaked at 15 and 30 min, respectively, with corresponding values of 30.1 +/- 4.7 and 33.2 +/- 3.7 ( +/- SE) ng/ml in normal but short children. The overall plasma GH response was greater than that of other GH stimulation tests such as insulin-induced hypoglycemia, glucagon-propranolol or L-dopa administration. Plasma LH, FSH, TSH, PRL, and cortisol levels were not altered by hpGRF-44 injection. Sixteen of 27 patients with GH deficiency did not respond to a 2 micrograms/kg BW hpGRF-44. However, plasma GH increases to greater than 5 ng/ml occurred in the remaining 11 patients. Their GH levels reached peaks between 15 and 90 min, with values ranging between 5.8 and 17.8 ng/ml. Two of these responding patients were infused iv with hpGRF-44 at 2.5 micrograms/min for 90 min after receiving an iv bolus injection of 2 micrograms/kg BW. Their plasma GH levels increased and remained near peak values throughout the infusion period. However, no increase in plasma GH levels occurred after a second bolus injection of hpGRF-44 given at the end of the infusion. These results suggest that hpGRF-44 is useful for the diagnosis of GH deficiency in individuals with short stature and that some patients with GH deficiency, diagnosed on the basis of established tests, have GH responses to hpGRF-44.     

Stimulation by bombesin of immunoreactive somatostatin release into rat hypophysial portal blood

Bombesin was injected into the cerebral ventricle of male rats anesthetized with urethane to study its effect on plasma levels of immunoreactive somatostatin (IRS) in hypophysial portal and jugular blood. An intraventricular injection of bombesin (0.2 and 2 micrograms/rat) caused a significant and dose-related increase in plasma IRS in hypophysial portal blood but not in jugular blood. Although bombesin placed into the cerebral ventricle is known to stimulate glucagon and epinephrine release, an iv injection of glucagon (100 micrograms/100 g BW) or epinephrine (2.5 micrograms/100 g BW) did not cause any significant changes in plasma IRS levels in hypophysial portal and jugular blood, suggesting that these substances do not mediate bombesin stimulation of portal IRS release. Pretreatment with naloxone (75 micrograms/100 g BW, iv) failed to affect the portal IRS release induced by bombesin (2 micrograms/rat), indicating that the opiate receptor is not likely to be involved in this reaction. To ascertain whether IRS released by bombesin into hypophysial portal blood is biologically active, the effect of bombesin on the plasma GH level was then examined. Bombesin (2 micrograms/rat) injected intraventricularly completely suppressed the rise of plasma GH after the intraventricular injection of beta-endorphin (1 microgram/rat) or the iv injection of prostaglandin E1 (5 micrograms/100 g BW). Bombesin thus appears to stimulate the secretion of IRS, and probably biologically active somatostatin as well, from the hypothalamus into hypophysial portal blood, thereby inhibiting GH release from the anterior pituitary.     

Normal growth hormone (GH) response to GH-releasing hormone in children with thalassemia major before puberty: a possible age-related effect

The plasma GH response to a single iv bolus dose of 2 micrograms/kg BW synthetic GHRH-(1-44)NH2 was evaluated in 13 prepubertal children with thalassemia major (mean age, 7.6 +/- 0.8 yr) with growth retardation and in 15 prepubertal children with nonendocrine short stature. All of the patients showed a significant increase in plasma GH concentration, with a mean peak of 31.4 +/- 4.5 micrograms/L at 15 min (P less than 0.001 vs. basal values; range, 18.4-65 micrograms/L) after GHRH, which was not different from that of the control group of idiopathic short stature children (40.1 +/- 3.4 micrograms/L; range, 21-65.4 micrograms/L). All but 1 of the thalassemic patients had a normal GH response to the arginine-insulin stimulation test. The mean plasma insulin-like growth factor-I level was low (0.12 +/- 0.05 U x 10(3)/L; range, less than 0.02-0.61 U x 10(3)/L). Analysis of these results as well as previously reported data indicating that older thalassemic patients have an impaired GH response indicates that there may be an age-related pituitary and/or hypothalamic dysfunction in thalassemic children. This study also confirms that the insulin-like growth factor-I decrease occurs before any alteration in GH secretion. These changes might play a role in the early growth retardation that occurs in these patients.