V. Locatelli

GABAergic control of anterior pituitary hormone secretion

Anatomical and biochemical studies have identified a hypothalamic tubero-infundibular GABAergic system, which plays a functional role on anterior pituitary hormone secretion. Experimental and clinical evidence support the presence of a dual component in the action of GABA; one mediated via the central nervous system and the other exerted directly at the anterior pituitary level. The two sites of action may be responsible for the excitatory and inhibitory effects of GABA on pituitary hormone and especially prolactin secretion. The future characterization of this system will provide a better understanding of the involvement of GABA in the physiology of anterior pituitary hormone secretion and will contribute to the development of new pharmacological agents for the therapy of neuroendocrine disorders.

Prolactin-Releasing Effect of a Novel Anti-Dopaminergic Drug, Domperidone, in the Rat

The prolactin (PRL)-releasing effect of domperidone (DOM), a blocker of dopamine receptors which does not cross the blood-brain barrier, was studied in unanesthetized male rats and compared to that of

CLONIDINE TREATMENT FOR SHORT STATURE

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.

INTERACTION BETWEEN THE THYROTROPHIN-RELEASING HORMONE-INDUCED GROWTH HORMONE RISE AND DOPAMINERGIC DRUGS: STUDIES IN PATHOLOGIC CONDITIONS OF THE ANIMAL AND MAN

A rise in plasma growth hormone (GH) after thyrotrophin‐releasing hormone (TRH) and a striking reduction after dopaminergic drugs is present in acromegalic (‘responder’) patients. We have investigated the GH response to dopaminergic stimuli in two conditions of animals and man, which, like acromegaly, are characterized by a TRH‐induced GH rise, i.e. rats with electrolytic lesions of the median eminence (ME) and patients with hepatic cirrhosis. In addition, we have studied the TRH‐induced GH rise in rats with ME lesions, in the cirrhotic patients and in a group of‘responder’acromegalics before and after administration of dopaminergic drugs. In rats with ME lesions an infusion of dopamine (DA) neither modified baseline GH levels nor the TRH‐induced GH rise. In five out of six cirrhotic patients oral administration of l‐Dopa was followed by the usual rise in plasma GH. Infusion of DA increased plasma GH levels in three out of seven cirrhotic patients and in four out of five subjects an earlier GH rise after TRH was seen. However, in the‘responder’acromegalics, the infusion of DA, besides lowering baseline plasma GH, was capable of reducing the TRH‐induced GH rise. Collectively these data indicate that the TRH‐induced GH rise emphasizes defects in the neurohormonal links between the central nervous system and the anterior pituitary. Instead, the paradoxical fall of GH after dopaminergic drugs appears to be a prerequisite of acromegaly and may be attributable to receptors for DA located on the tumorous tissue.

Ultrastructure of Somatotrophs of Rats with Median Eminence Lesions: Studies in Basal Conditions and after Thyrotropin-Releasing Hormone Stimulation

Anterior pituitaries from female Sprague-Dawley rats (160-200 g b.w) bearing electrolytic lesions of the median eminence were qualitatively and quantitatively investigated by electron microscopy and the findings compared with those from intact animals or sham-operated controls. This study was performed in basal conditions and after stimulation with thyrotropin-releasing hormone. Animals with lesions showed a reduction of both the number of somatotrophic cells and growth hormone granules. After injection of thyrotropin-releasing hormone exocytosis of growth hormone granules from somatotrophs was frequent in rats with lesions of the median eminence but rare in sham-operated animals. The differences were statistically significant.

Effect of 5-Hydroxytryptophan on Prolactin and Growth Hormone Release in the Infant Rat: Evidence for Different Neurotransmitter Mediation

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.

Mechanisms underlying the prolactin-lowering effect of metergoline in the rat

Abstract Metergoline (MCE), an ergoline derivative with anti-serotoninergic activity was used in rats to determine its effect on the release of prolactin (PRL) and, possibly, the mechanism(s) of this neuroendocrine effect. MCE given by oral, intraperitoneal or subcutaneous route to reserpinized male and female rats proved to be an effective and long-lasting anti-prolactin agent. MCE lowered PRL in hypophysectomized (hypox) rats bearing an ectopic anterior pituitary (AP) when administered parenterally but was completely ineffective when administered orally. In rats with CNS-AP disconnection, blockade of pituitary dopamine (DA) receptors by pimozide completely prevented the PRL-lowering effect of parenterally administered MCE, whereas treatment with 5-hydroxytryptophan (5- HTP) did not impair the effect of MCE on PRL release. In intact male rats, oral administration of MCE completely antagonized the PRL-releasing effect of quipazine and 5-HTP, stimuli which activate the serotoninergic system. MCE slightly inhibited PRL release from AP fragments in vitro .

Drug-induced changes of brain serotoninergic tone and insulin-induced growth hormone release in the dog.

Drugs capable of modifying central serotoninergic neurotransmission were studied for their ability to affect the release of growth hormone (GH) which follows insulin-induced hypoglycemia in the unanesthetized dog. Chlorimipramine, a blocker of serotonin (5-HT) reuptake, induced a striking suppression of the GH response during the first 90 min post-insulin administration, but was unable to suppress GH levels at later time intervals (90–180 min). Two long-lasting 5-HT re-uptake blockers, FG4963 and Fluoxetine (Lilly 110140), induced, instead, a sustained inhibition of the hypoglycemia-induced GH rise. Similarly, fenfluramine, a rapid releaser of 5-HT neuronal stores and hence functional activator of 5-HT neurotransmission, was capable of blunting the GH response to the metabolic stimulus. The bulk of these data suggested an inhibitory role for 5-HT in the GH response to insulin hypoglycemia in the dog. In contrast with such conclusion, was the observation that administration of both Cyproheptadine (Cy) and Methysergide (Meth), two alleged 5-HT receptor blockers inhibited insulin-induced GH rise. The discrepancy between previous and the latter findings may indicate that the inhibitory effect of Cy and Meth was due to reason(s) alien to 5-HT receptor blockage. Support to this view was given in our study by the finding that methergoline, another drug endowed with 5-HT antagonistic activity, enhanced the GH response to insulin. An explanation for the inhibitory effect of Cy, whose

Pituitary Hormones and Ergot Alkaloids

From the data presented it appears that ergot drugs are both a useful tool for use in the study of neuroendocrine control of pituitary hormone secretion and a valid pharmacologic weapon for treatment of hyperprolactinemic states, GH and, probably, ACTH and MSH hypersecretion. In fact, they are capable of a long-lasting disruption of PRL secretion from a normal or tumoral pituitary gland, are unable to affect directly the somatotrophs of an intact AP, but inhibit GH and, possibly, ACTH secretion from a hyperplastic or tumoral gland. Ergolines also exert clear-cut PRL-lowering effects and are capable of suppressing GH secretion in acromegaly. The intimate mechanism(s) and hence site(s) of action of some of these compounds await clarification.