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To investigate the respective role in PRL secretion of gamma-aminobutyric acid (GABA), either derived from the central nervous system or circulating in plasma, experiments were performed using ethanolamine-O-sulfate (EOS), a specific inhibitor of GABA catabolism. Intracerebroventricular injection of EOS (2 mg/kg) induced in unanesthetized male rats 2-8 h post injection a clear-cut rise in hypothalamic, anterior pituitary (AP), and plasma GABA concentrations. Rises in GABA titers occurred earlier in the hypothalamus and AP (2 h) than in the plasma (4 h). Concomitant to alterations of GABA, there was a striking lowering of plasma PRL evident at 2 h and still present 24 h after EOS administration. In contrast, systemic administration of graded doses of EOS (200-400 mg/kg, iv) did not induce significant changes in plasma GABA concentrations 4 h post injection; only the 600 mg/kg dose of EOS increased GABA concentrations 4 h post injection in the hypothalamo-AP system and decreased plasma PRL concentrations. Finally, in hypophysectomized rats bearing ecotopic pituitaries, despite the occurrence of rises in the hypothalamic GABA after intracerebroventricular or systemic (600 mg/kg) administration of EOS, AP, plasma GABA, and plasma PRL concentrations were not altered. In all these findings indicate that: 1) changes in plasma PRL are best correlated to variations in the amino acid titers occurring in the hypothalamo-AP systems; and 2) circulating GABA does not play a functional role in the control of PRL secretion. Finally, since alterations in blood GABA levels after central or systemic administration of EOS appear to reflect primary changes occurring in the brain concentration of the amino acid, circulating GABA may be a reliable indicator of central nervous system GABAergic function.

The growth hormone (GH)-releasing effect of thyrotropin-releasing hormone (TRH) was investigated in rats in which central nervous system (CNS)-anterior pituitary (AP) connections had been experimentally interrupted. Sprague-Dawley (SD) female and male rats, underwent bilateral electrolytic lesions in the median eminence (ME) or the ventromedial nuclei (VMN) or were sham-operated (sham-op). Fifteen days after surgery, 0.9% NAACl or TRH was injected iv into sham-op rats or those with lesions in the CNS, anesthetized with urethane, and blood was drawn at 5 and 10 min posttreatment. In the rats with ME lesions, TRH at all the doses used (0.1, 0.4 and 0.8 microng/100 g BW) induced a marked, although not dose-related GH rise, which was not present in sham-op rats after TRH, or after NaCl administration to either rats with ME lesions or sham-op rats. In SD male rats lesioned in the VMN, TRH at doses of 0.4 and 0.8 microng/100 g BW induced significant GH rises, while the lowest TRH dose (0.1 microng/100 g BW) was ineffective; again, TRH was ineffective at all doses used in sham-op rats. Concomitant evaluation of the prolactin (PRL)-releasing effect of TRH (0.1-0.8 microng/100 g BW), showed a striking elevation of plasma PRL in both female and male sham-op controls, but no PRL rise in the rats with ME lesions. The results reveal that in the rat with surgical separation of the anterior pituitary from the CNS, a direct GH-releasing effect of TRH can be obtained, whereas its PRL-releasing effect is no longer observed, and suggest that, by analogy, the GH-releasing effect of TRH present in some disease states of the human may be due to an impairment of CNS-AP connections.

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 thyrotrophin (TSH) and prolactin (Prl)-releasing effects of TSH-releasing hormone (TRH) were investigated in 20 subjects with Parkinson's disease (PD), unmedicated, on chronic treatment with a combination levodopa-benserazide (Madopar) or levodopa-carbidopa (Sinemet) or withdrawn from therapy. Administration of TRH (200 micrograms iv) induced in unmedicated patients TSH and Prl responses significantly lower than those of sex-and age-matched controls. In patients on Madopar therapy the TSH and Prl responses to TRH were greater than in unmedicated patients and comparable to those of controls, while in patients on Sinemet therapy the pituitary responses were undistinguishable from those of unmedicated subjects. Withdrawal of Madopar therapy resulted in a marked diminution of the TSH response but did not affect the Prl response to TRH. Withdrawal of Sinemet therapy did not alter the TSH and Prl responses to TRH. Concomitant evaluation of growth hormone (GH) levels, in none of the subjects evidenced non-specific changes in plasma GH following TRH. Since TSH and Prl responses to TRH are inhibited by an enhancement of the dopaminergic tone, it would appear that the latter is preserved in the tuberoinfundibular system of unmedicated subjects and subjects on chronic Sinemet therapy, but is defective in subjects on chronic Madopar therapy.

The effect of acute administration of the opioid receptor antagonist naloxone hydrochloride (5 mg/kg, s.c.) on plasma LH levels was evaluated in female and male rats 24, 36 and 48 h and 1, 3 and 5 weeks after gonadectomy and in 5-week gonadectomized rats after acute or chronic (2 weeks) administration of oestradiol benzoate (OB, 10 micrograms/rat per day, s.c.), testosterone propionate (TP, 150 micrograms/rat, s.c.) or dihydrotestosterone propionate (DHT, 150 micrograms/rat, s.c.) respectively. Concurrent evaluation of plasma LH after administration of LH releasing hormone (LHRH, 1 microgram/kg, i.p.) was performed in the same experimental groups. In rats of both sexes, a significant rise in plasma LH after naloxone was observed in sham-operated and recently gonadectomized rats (24-48 h); in female rats 36 and 48 h after gonadectomy the rise was higher than in controls. One, 3 and 5 weeks after gonadectomy, naloxone failed to stimulate LH release in both female and male rats. In gonadectomized rats undergoing steroid replacement therapy, OB administered 72 h before testing, TP (16 and 72 h) and DHT (16 h) were the most effective in reinstituting the LH response to naloxone. Chronic administration of gonadal steroids did not restore normal LH responsiveness to naloxone. In most experimental groups, LH responses after naloxone were clearly unrelated to pituitary LH responsiveness to LHRH, which indicates that the opioid antagonist was acting via the central nervous system.(ABSTRACT TRUNCATED AT 250 WORDS)

The thyrotrophin (TSH) and prolactin (Prl) releasing effects of domperidone, a recently developed antidopaminergic drug which does not cross the blood-brain barrier, were investigated in 8 women affected by primary hypothyroidism, and were compared to those elicited by another antidopaminergic drug, sulpiride. Domperidone (4 mg iv) induced a clear-cut and sustained rise in both plasma TSH and Prl, with peak levels occurring 15 and 30 min post-injection, respectively. The increments in plasma Prl after domperidone were significantly higher than those in plasma TSH. The TSH and Prl responses induced by domperidone were almost superimposable to those provoked in the same subjects by sulpiride (100 mg im). In view of the inability of domperidone to penetrate into the central nervous system (CNS), these findings imply a 'peripheral' site(s) of action (i.e. anterior pituitary and/or median eminence) for the effect of antidopaminergic drugs on TSH secretion, and, re-iterate the notion that the same 'peripheral' sites are involved in the Prl-releasing effect of these compounds.

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.

It is known that in normal subjects repeated administration of the growth hormone-releasing factor (GRF) induces a state of partial refractoriness of the somatotropes to GRF. Studies were conducted to verify whether the cholinergic system plays a role in the mechanism(s) underlying the reduced GH responsiveness to the neuropeptide. In five healthy men, the GH response to three consecutive injections of GRF (50 micrograms iv), administered at 2 h intervals, was considerably blunted after the second and third GRF bolus. Administration of the inhibitor of cholinesterase, pyridostigmine bromide (120 mg orally) 30 min before the second GRF bolus, not only restored but greatly potentiated the GH responsiveness to the second GRF bolus. The GH response to the third GRF bolus was not apparently influenced by pre-treatment with pyridostigmine. These data reinforce the view that cholinergic neurotransmission plays an important role in the control of GH secretion in human.

Nomifensine, an antidepressant agent which activates dopamine (D) neurotransmission mainly by inhibiting DA reuptake in the central nervous system, was administered either to puerperal lactating women or to subjects with nonpuerperal hyperprolactinemia. In 10 postpartum women and in 7 women with no evidence of PRL-secreting tumor, oral administration of nomifensine (100 or 200 mg, respectively) induced in the following 5 h a clear-cut inhibition of plasma PRL levels; in 10 patients with PRL-secreting tumors, the drug did not lower plasma PRL levels. In 2 of these patients nonsupressibility of plasma PRL levels to nomifensine was the only indication of the existence of a pituitary microadenoma. It is proposed that acute nomifensine testing may be a valid neuropharmacological tool for discriminating between individuals with and without pituitary adenoma.

In 10 day-old female and male rats, administration of 5-hydroxytryptophan (5-HTP) induced a prompt elevation in plasma prolactin (Prl) and growth hormone (GH) levels. Pretreatment with 2 serotonin (5-HT) receptor blockers, methysergide (Meth) and metergoline (MCE), markedly reduced the 5-HTP-induced Prl rise but failed to alter the GH response to 5-HTP. Administration of 2 selective inhibitors of presynaptic 5-HT reuptake, 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenyl-propylamine and chlorimipramine (CIM), potentiated the 5-HTP-stimulated Prl rise but significantly reduced the 5-HTP-induced GH release. Blockade of dopaminergic or alpha-adrenergic receptors by pretreatment with pimozide (Pim) or phentolamine (Phent), respectively, or central sympathectomy by intraventricularly (i.vt.) injected 6-hydroxydopamine (6-OHDA) were capable of reducing the 5-HTP-induced GH release without affecting the 5-HTP-induced Prl rise. These data indicate that in the infant rat the 5-HTP-induced Prl release is mediated via the brain 5-HT system and that a nonspecific activation of the catecholaminergic system is responsible for the GH response to the drug.

We administered growth-hormone releasing hormone (GHRH), clonidine or thyrotropin-releasing hormone (TRH) as intravenous boli each in three different randomized mornings to nine well-controlled Type 1 diabetic men and to six age-matched healthy men who served as controls. GHRH and clonidine evoked a prompt and brisk GH release both in diabetic and in control subjects with no significant difference being evident between the two groups. Only one diabetic subject showed a paradoxical GH release after TRH when he was under long-term poor metabolic control. These results indicate that in insulin-dependent patients with good control of the metabolic disease the response of somatotropes to pituitary- or central nervous system-directed stimuli is normal. These data are supportive of the idea that altered GH secretion in Type 1 diabetes rather than reflecting a primary hypothalamic and/or pituitary alteration may be a state-dependent phenomenon related to the metabolic state of the disease.

Withdrawal from chronic haloperidol exposure was associated to unaltered circulating levels of prolactin (PRL), decreased 3H-spiperone binding sites in the anterior pituitary and increased 3H-spiperone binding sites in the striatum of male rats. Haloperidol (0.1 mg/kg ip) induced similar rises in plasma PRL in haloperidol-or saline-treated rats and the dose of 0.01 mg/kg was ineffective in both groups. These findings illustrate the poor relatedness existing at the pituitary D2 receptor between biochemical and functional indices.

In women with physiological puerperal hyperprolactinaemia, acute administration of Piribedil (100 mg po), a drug which stimulates dopamine receptor sites, was as effective as that of 2-Br-alpha-ergocryptine (CB 154, 5 mg po) in suppressing the elevated baseline plasma prolactin (PRL) levels. In two hyperprolactinaemic women with radiological evidence of an intrasellar pituitary tumour, Piribedil (100 mg po), in contrast to CB 154 (5 mg po), failed to modify plasma PRL levels, whereas in 3 other hyperprolactinaemic women with no radiological evidence of pituitary tumour, its effect was not clear-cut, even though it could not be differentiated from that of CB 154. These results indicate that Piribedil is an effective suppressor of plasma PRL levels in the human and suggest that its action is more evident in puerperal than in pathological hyperprolactinaemia.

It is now indisputably established that a cohort of neurotransmitters and neuropeptides affect the secretion of anterior pituitary hormones by modulating the functional activity of specific hypophysiotropic regulatory hormones. Some salient aspects of the role of gamma-aminobutyric acid in the control of prolactin secretion and of catecholamines and acetylcholine in the control of growth hormone secretion are reviewed, also underlying some diagnostic and therapeutic applications of the new findings in neuroendocrine disorders.

The prolactin lowering activity of dihydroergocristine, a dihydrogenated ergopeptine derivative, was evaluated in male rats. The drug caused a significant decrease of prolactin levels both in the normoprolactinemic animals and in reserpine-induced hyperprolactinaemia at 5 mg/kg p.o. while 0.2 and 1 mg/kg p.o. were ineffective. In a second experiment the prolactin lowering activity of dihydroergocristine (0.2; 1.5 mg/kg), in reserpine-induced hyperprolactinaemia was compared with bromocryptine (0.1; 0.5; 2.5 mg/kg) administered intraperitoneally. Both dihydroergocristine and bromocryptine caused a significant decrease of prolactin plasma concentrations at all dose levels. Moreover the prolactin lowering effect was independent of the dose administered. Our data suggest prolactin lowering activity of oral or i.p. dihydroergocristine both on normal plasma concentrations and on the experimentally-induced hypersecretion of the hormone.

Age-related changes in GH secretion were studied in dog. In preliminary experiments, administration of GH-releasing hormone (GHRH-40, 2 micrograms/kg, iv) or the alpha 2-adrenoceptor agonist clonidine (4 micrograms/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 micrograms/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.

To determine how the sensitivity of the ectopic anterior pituitary gland to the GH-releasing effect of thyrotrophin releasing hormone (TRH) might be affected by the time lapse from transplantation, TRH (0-15 and 0-6 microng) was injected i.v. into hypophysectomized (hypox)-transplanted rats under urethane anaesthesia 1,3,8,15,30 and 60 days after transplantation, and plasma samples were taken 5 and 10 min later. Baseline GH values gradually decreased with time from about 16-0 ng/ml (1 day) to about 3-0 ng/ml (30 and 60 days). The TRH-induced GH release was absent 1 day after transplantation, present only with the higher TRH dose 3 and 8 days after transplantation, and clearly elicitable, also with the lower TRH dose (0-15 microng), from 15 up to 60 days. Determination of plasma prolactin concentrations showed a decline from about 85-0 ng/ml (1 day) to about 32-0 ng/ml (8 days); subsequently (15-60 days) prolactin values stabilized. Plasma prolactin levels increased 15 and 60 days after transplantation only when a dose of 0-6 microng TRH was given. In intact weight-matched rats, TRH induced a GH response only at the dose of 1-2 microng while a short-lived but clear-cut prolactin response could be obtained even with the 0-3 microng dose. The present results indicate that: (1) disconnexion between the central nervous system and the anterior pituitary gland greatly enhances GH responsiveness while blunting prolactin responsiveness to TRH; (2) the sensitivity of the anterior pituitary gland to the GH-releasing effect of TRH increases with time from transplantation; (3) TRH is a more effective prolactin- than GH-releaser on the pituitary gland in situ.

To throw light onto the mechanism(s) by which the cholinergic system influences growth hormone (GH) release, the effects of two muscarinic receptor blockers, pirenzepine and atropine, and of an acetylcholinesterase inhibitor, pyridostigmine bromide, on the GH response to GHRH-44 were studied in 19 normal volunteers. Moreover, the effects of pirenzepine administration on plasma GH levels both in basal conditions and after stimulation by GHRH-44 and TRH were studied in 9 acromegalics. Both pirenzepine (0.6 mg/kg i.v., 5 min before GHRH) and atropine (1 mg i.m., 15 min before GHRH) blunted the GH response to GHRH (1 microgram/kg i.v. bolus) (area under the response curve, AUC: 81.3 +/- 17.3 vs. 481.2 +/- 211.3 ng/ml/h for pirenzepine and 100.2 +/- 27.0 vs. 364.7 +/- 81.0 ng/ml/h for atropine; p less than 0.01). Pyridostigmine (120 mg orally, 30 min before GHRH) induced a variable but significant (p less than 0.02) rise in basal plasma GH levels and, furthermore, an unequivocal potentiation of the GH response to GHRH (AUC: 1044.6 +/- 245.3 vs. 481.2 +/- 211.3 ng/ml/h; p less than 0.01). In all but one acromegalics 0.6 mg/kg i.v. pirenzepine was unable to modify the basal GH levels whilst it showed a variable inhibitory effect on the GH response to GHRH. The GH response to TRH (200 micrograms i.v. bolus) was instead unmodified by pirenzepine. In conclusion, muscarinic receptor blockade inhibits while cholinergic potentiation seems to positively modulate the GH response to GHRH. Therefore, the cholinergic system seems to positively modulate the GHRH effect on somatotrophs.(ABSTRACT TRUNCATED AT 250 WORDS)

It is known that animals or patients bearing a prolactin (PRL)-secreting tumor (PST) do not suppress PRL levels after administration of indirectly acting dopamine agonists, namely nomifensine (Nom), and are not responsive to the PRL releasing effect of antidopaminergic drugs and opioid peptides. Since the action of these drugs is mediated through the tuberoinfundibular dopaminergic (TIDA) system, these findings have been taken to indicate that animals and humans bearing prolactinomas have a defective TIDA function. Alternatively, PRL unresponsiveness to these drugs could be due to hyperfunction of TIDA system for the feedback action of high PRL levels. To clarify whether hypo- or hyperfunction of the TIDA system was responsible for such behaviour, we tested the effect of a synthetic opioid peptide (FK 33-824), a DA receptor antagonist, domperidone (Dom), and of Nom on PRL secretion in two experimental models of non-tumoral hyperprolactinemia, i.e. rats bearing ectopic pituitaries since 3 days (TP rats), or treated with ovine PRL (oPRL 250 micrograms, twice daily for 3 days), in which existence of an increased TIDA function has been demonstrated. FK 33-824 (0.5 mg/kg i.p.) increased significantly plasma PRL levels in control rats but failed to do so in TP rats and it elicited a significantly lower PRL response than in controls in rats treated with oPRL. In both experimental models, a PRL secretagogue, e.g. 5-hydroxytryptophan (50 mg/kg i.p.), elicited the same response as in controls, indicating that the pituitary PRL pool was preserved.(ABSTRACT TRUNCATED AT 250 WORDS)

LHRH (median eminence) and LH (pituitary and plasma) from male and female Sprague-Dawley rats were assayed 1 month after streptozotocin injection and compared with values in controls either fed ad libitum or offered a restricted diet. Plasma LH was also assayed after stimulation with exogenous LHRH or naloxone. In diabetic males, the median eminence LHRH content and the plasma LH response to exogenous LHRH were unaltered, pituitary LH was increased, and plasma LH was decreased under basal conditions and after naloxone treatment. In diabetic females, while the median eminence LHRH content and the plasma LH response to exogenous LHRH or naloxone were reduced, pituitary and plasma LH levels were not different. Measurements made in undernourished rats excluded the possibility that the alterations found in diabetic animals were nutrition dependent. In parallel experiments, hypothalami and pituitaries were examined morphologically. In diabetic animals, degenerate axons, mainly of the LHRH type, were found in the arcuate nucleus and median eminence, and LH gonadotrophs were altered and more numerous. Strong differences between control males and females were revealed by morphometry; moreover, diabetic females had higher brain weights and fewer LH gonadotroph changes than diabetic males. These studies indicate that 1) the hypothalamo-pituitary changes that occur early in our streptozotocin-treated rats are unrelated to undernourishment and are possibly caused by insulin deficiency; 2) the LHRH axonal lesions might play a primary pathogenic role in the hypothalamo-pituitary disorder; 3) some anatomical data indicate that the brain and pituitary are less severely affected by diabetes in female than in male animals; and 4) differences between control males and females may account for some of the dissimilarities between the sexes observed under diabetic conditions.

To better understand the state of dopamine (DA) neurotransmission in the tuberoinfundibular DA system (TIDA), monoiodotyrosine (3-iodo-L-tyrosine, MIT), a potent inhibitor of DA synthesis, was acutely administered to 8 normal women, 7 postpartum women, 8 women with pathological hyperprolactinemia and 5 women after successful removal of a prolactinoma. The effects on plasma prolactin (PRL) and thyrotropin (TSH) were compared to those induced in the same subjects by the DA receptor antagonist domperidone (DOM). MIT (1 gpo) and DOM (10 mg iv) induced qualitatively similar hormonal responses, although the PRL- and TSH-releasing effects of DOM were always greater than those of MIT. In control subjects, MIT treatment induced a consistent rise in plasma PRL (peak increment 45.2 +/- 13 ng/ml at 120 min); in the same subjects DOM induced a prompter and higher PRL response, (peak increment 147.8 +/- 26 ng/ml at 30 min). MIT failed to alter plasma TSH levels, while DOM induced a significant rise in plasma TSH. In postpartum women MIT induced a prompter and higher PRL rise than that occurring in controls (peak increment 180.3 +/- 20 ng/ml at 90 min), though also in this instance DOM proved to be a more potent PRL releaser (peak increment 345.7 +/- 88 ng/ml at 30 min) than MIT. MIT was unable to stimulate TSH secretion, while DOM induced a significant rise in plasma TSH. In women with pathological hyperprolactinemia MIT failed to alter baseline PRL levels while DOM slightly increased them (peak increment 14.7 +/- 3 ng/ml at 30 min).(ABSTRACT TRUNCATED AT 250 WORDS)

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-[3H]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.

It has been shown recently that SKF 38393-A (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine-7-ol), a D-1 receptor agonist, possesses a prolactin-releasing effect in the rat, though the pituitary or central nervous system location of the receptors involved has not been clarified. The aim of our study was to elucidate this point. SKF 38393-A administered to freely moving adult female and male rats induced a striking, short-lived increase of basal prolactin levels. The prolactin stimulatory effect of SKF 38393-A was counteracted by pretreatment with SCH 23390, A D-1 receptor blocker. SKF 38393-A (10(-11)-10(-6)M) added to monolayer primary cultures of anterior pituitary cells from rats of both sexes failed to modify prolactin release. At higher concentrations (10(-5)-10(-4) M) the drug induced a slight inhibition of prolactin release. Similarly, SKF 38393-A failed to stimulate adenylate cyclase activity in anterior pituitary membranes from rats of both sexes at low concentrations, while it inhibited enzyme activity at higher concentrations (10(-5)-10(-3) M). The latter effect was counteracted by concomitant addition of the antagonist of D-2 receptors, 1-sulpiride. These data demonstrate that: (1) the anterior pituitary does not contain D-1-dopamine receptors (positively coupled to adenylate cyclase) stimulatory to prolactin release; (2) the striking prolactin-releasing effect of SKF 38393-A in the rat is due to activation of extra-pituitary D-1 dopamine receptors; (3) SKF 38393-A, at high concentrations, is capable of activating pituitary D-2 receptors.

The mechanism(s) underlying the prolactin (PRL)-releasing effect of benserazide (Bz), a peripheral inhibitor of L-aromatic amino-acid decarboxylase, was investigated in the rat. In intact male and female rats, Bz was ineffective to increase significantly plasma PRL at 0.8 mg/kg i.p. but elicited an already maximal effect at 1.6 mg/kg. Bz added to in vitro incubated anterior pituitaries (APs) did not alter PRL secretion at the dose of 3.8 X 10(-6)M but increased PRL release at 10(-4)M. Bz, even at very high doses (up to 10(-3) M), did not displace [3H]spiroperidol binding from AP membrane preparations. In rats having had mechanical ablation of the medio basal hypothalamus (MBH), Bz (15 mg/kg i.p.) induced no rise in plasma PRL and did not counteract the striking inhibitory effect of a dopamine (DA) infusion (5 micrograms/kg per min per 120 min). Administration of Bz (15 mg/kg i.p.) into intact male rats decreased significantly the DA concentrations in the median eminence (ME) but not in the residual hypothalamus and the AP. In the same rats 1-dopa (50 mg/kg i.p.) increased significantly the DA concentrations not only in the ME but also in the hypothalamus and the AP. Bz given concurrently with 1-dopa markedly reduced the rise in DA concentrations induced by 1-dopa in the ME, and greatly potentiated the increase in DA concentrations in the hypothalamus. These data indicate that the mechanism whereby a single administration of Bz increases PRL secretion in the rat is not consistent with the postulated DA receptor antagonist action of the drug, but instead implies inhibition of the decarboxylation of 1-dopa at dopaminergic nerve terminals of the ME.

The prolactin (PRL)-releasing effect of domperidone (DOM), a novel antidopaminergic drug which does not cross the blood-brain barrier, was investigated in normoprolactinemic subjects, in subjects with physiologic puerperal hyperprolactinemia or pathological hyperprolactinemia. DOM (4 mg i.v.), administered to 8 normoprolactinemic women, induced a clear-cut and sustained rise in plasma PRL, with peak levels occurring 15-30 min postinjection; the effect of the drug was also evident in 3 normoprolactinemic women at the dose of 0.25 mg i.v. Also in 8 puerperal women (postpartum day 2) intravenous administration of 4 mg DOM was followed by an increase in plasma PRL (51-517% of baseline levels, 15-45 min postinjection). Administration of DOM (4 mg i.v.) to 16 subjects with pathological hyperprolactinemia, evidenced the presence of 14 DOM-nonresponder (maximum percent increase of baseline PRL 48%) and 2 DOM-responder subjects. In 8 of the DOM-nonresponder subjects the existence of a pituitary tumor was established at surgery by selective removal of an adenoma (7 subjects) or a teratoma (1 subject): of the 6 subjects who did not undergo surgery, 3 had biochemical and/or radiologic evidence suggestive of a PRL-secreting tumor and 1 was acromegalic. These results indicate that DOM is capable of releasing PRL both in normoprolactinemic subjects and subjects with puerperal hyperprolactinemia. In contrast, DOM is unable to modify PRL levels in most subjects with pathological hyperprolactinemia, with proven or suspected pituitary tumors.

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.

To verify the diagnostic capacity of some dynamic tests of the prolactin (Prl) secretion, the findings obtained by high-resolution computed tomography (CT) were compared with results obtained from tests using nomifensine (NOM) domperidone (DOM) and thyrotrophin-releasing hormone (TRH) in 72 patients with pathological hyperprolactinaemia. None of the patients with tumours had a positive Prl response to NOM or to DOM administration; however, a positive response to these tests was present in only 24 and 41%, respectively, of the patients with normal CT picture. The results of TRH testing were similar to those obtained with DOM. Different neuroendocrine patterns were disclosed by comparing pituitary Prl and thyrotrophin (TSH) responses to DOM: 1) some subjects had a reduced Prl response together with an exaggerated or normal TSH response to DOM; they comprised patients with tumour, empty sella, and normal CT picture; 2) other patients with normal CT picture had a positive Prl and a normal TSH response to DOM. These results demonstrate that a negative Prl response to NOM and DOM characterizes all patients with adenoma; however, the tumour-like responses in patients with no visible tumours seem to reduce the diagnostic value of these tests, unless the latter may predate the radiological appearance of an adenoma. On the other hand, a positive Prl and a normal TSH response to DOM exclude the presence of a pituitary tumour. This diagnostic finding is strengthened by the positive response also to NOM. Whatever may be the diagnostic validity of dynamic tests, they provide sound information on the functional state of dopamine neurotransmission.

Thirty acromegalic subjects underwent chronic CB154 therapy (10-20 mg daily) for periods ranging from 3 months up to 2 years. In 18 out of 21 patients, who exhibited consistent HGH reduction following acute administration of the drug, there was also during chronic treatment, a suppression of the plasma HGH levels exceeding 50% of base line values, e.g. from mean daily values between 14-197 ng/ml (mean +/- SEM = 57.8 +/- 12.4 ng/ml pre-treatment) to 2-19 ng/ml (mean 8.3 +/- 1.2 ng/ml post-treatment). In 12 of the subjects who responsed to chronic CB154 treatment, the mean daily values of HGH were below 10 ng/ml. The suppression of plasma HGH was maintained unaltered throughout the whole course of therapy. In the 9 subjects, in whom no consistent HGH decrease was evidenced with acute CB154 administration, there was accordingly a minor or no suppression of HGH values during the chronic treatment. In 13 subjects, irrespective of the degree of their GH responses, the plasma prolactin levels were constantly inhibited by CB154; instead the drug failed to modify significantly the TRH or insulin-induced GH release. These changes in the hormonal parameters were paralleled by marked clinical amelioration and improvement of some of the metabolic alterations frequently encountered in acromegaly, e.g. reduced carbohydrate tolerance, increased insulin resistance, diminished fall of plasma phosphorus after insulin, decreased urinary excretion of phosphate, hyper-hydroxyprolinuria and hyper-calciuria. Collectively, these data demonstrate that CB154 thrapy is effective in reducing HGH hyper-secretion in many acromegalic patients during long-term treatment.

Seventy-three staphylococcal strains isolated from pyrodermatitis in dogs were classified as Staphylococcus intermedius (52 strains) or Staphylococcus aureus (21 strains) on the basis of acetoin formation, anaerobic mannitol fermentation, aerobic maltose fermentation, pigmentation, coagulation of human plasma, and reaction on crystal violet agar. Enterotoxin was produced by 13 of the 52 S. intermedius strains and 6 of the S. aureus strains. The highest percentage of enterotoxigenic strains produced enterotoxins C (6 strains), D (7 strains), and E (6 strains). Four strains produced the toxic shock syndrome toxin-1. There was little difference in the antibiotic susceptibility between the enterotoxigenic and non-enterotoxigenic strains.

The present study reports data on brain serotonin (5-HT) metabolism in two experimental conditions which have in common a lack of pituitary growth hormone (GH) and refers also the effect of a GH replacement therapy. In hypophysectomized female rats or genetically dwarf mice, which have a more selective deficiency of GH, brain tryptophan (TP) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were significantly higher than in age-matched controls. Brain levels of 5-HT were practically unchanged. A GH replacement therapy resulted in both hypophysectomized rats and dwarf mice in a significant reduction of brain TP and 5-HIAA concentrations. These results suggest that GH may exert an inhibitory action on 5-HT metabolism. Consonant with this view are the preliminary findings that in 7 individuals with elevated plasma GH levels for acromegaly, plasma TP levels were lower than in control subjects.

Prolactin (Prl) and growth hormone (GH) responses to different pharmacologic probes acting at the central nervous system (CNS) or the anterior pituitary (AP) level were evaluated in patients with distinct neuro-endocrine disorders. Thirteen patients with Prl-secreting tumours (PST), 10 acromegalics (A) and 8 patients with hypothalamic lesions (HL), as assessed on clinical, radiological and surgical grounds, underwent on separate occasions acute testing with the opioid peptide FK 33-824 (0.5 mg iv), the indirect dopamine (DA) agonist nomifensine (NOM, 200 mg po), the DA receptor antagonist domperidone (DOM, 10 mg iv), TRH (200 microgram iv) and insulin (ITT, 0.10-0.15 IU/kg iv). All patients were evaluated pre-surgery and 4 of them also post-surgery. Prl and GH were evaluated by RIA at different time intervals following treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

Cabergoline 1-[(6-allylergolin-8 beta-yl)carbonyl]-1-[3-(dimethylamino) propyl]-3-ethylurea is a recently developed ergot derivative with a long-lasting dopamine agonist action. We now studied the ability of cabergoline to counteract the development of a prolactin-secreting tumor (prolactinoma) induced in female rats by long-term administration of high doses of estrogens. The effect of cabergoline was compared to that of bromocriptine. Cabergoline (0.6 mg/kg p.o.) had a marked and sustained prolactin-lowering effect in freely moving female rats, its effect still being present 3 days after a single dose. Bromocriptine, at a dose 5-fold higher (3 mg/kg s.c.), induced a strong and short-lasting prolactin inhibitory effect which, however, had completely disappeared 24 h post-injection. Intermittent administration of cabergoline (0.6 mg/kg p.o. every 3 days), starting from the first day of estrogen treatment, completely counteracted the development of the prolactinoma, as judged by the weight of the pituitary and the stimulating effect of estrogens on plasma prolactin and mitotic rate and DNA synthesis of pituitary cells. These effects of cabergoline were shared by a 5-fold higher dose of bromocriptine (3 mg/kg s.c.) given daily. The potent anti-tumorigenic effect of cabergoline, coupled to a sustained prolactin-lowering effect, the most prolonged ever seen with an ergot derivative, makes cabergoline a most suitable drug for the treatment of human macroprolactinomas.