Growth hormone after baclofen in normal and acromegalic subjects

Serum growth hormone (GH) levels in basal conditions (two samples) and 30, 60, 90, 120, 150 and 180 minutes after oral administration of baclofen (20 mg) were evaluated in 6 healthy subjects and in 6 acromegalic patients. The effect of cimetidine (400 mg i.v.) administrated 45 minutes after baclofen (20 mg by mouth) were evaluated in 9 healthy women. Baclofen was able to significantly rise serum GH levels in normal subjects but no in acromegalic patients. Cimetidine suppress GH increase induced by baclofen. It was concluded that: 1) baclofen, GABAb receptor agonist, stimulate GH secretion by inhibition of GIF secretion or by stimulation of GRF secretion; 2) istamine, through H2 receptors in the hypothalamus, is important to mediate GH release induced by stimulation of GABAb receptors.     

Plasma aldosterone response to metoclopramide is unmodified by hyperprolactinemia

It has been previously demonstrated that patients with hyperprolactinemia have impaired PRL response to dopaminergic blockade and increased TSH response. Since inhibitory dopaminergic modulation of aldosterone is well established, we have examined whether prolactinoma patients have an altered aldosterone response to dopaminergic blockade. To investigate this possibility we compared the plasma PRL, TSH and aldosterone responses to the dopamine (DA) antagonist metoclopramide (MCP; 10 mg i.v.) in 10 women with prolactinomas and 7 healthy female controls. Basal PRL levels in prolactinoma patients were elevated and showed a blunted rise following MCP. Although basal TSH levels were similar in the 2 groups of subjects, they significantly increased (p = 0.017) in prolactinoma patients while in contrast they did not significantly change in control subjects. Basal supine plasma aldosterone was similar in patients with prolactinomas (0.23 +/- 0.03 nmol/l) and in healthy subjects (0.25 +/- 0.04 nmol/l) and the increased aldosterone concentrations from 15 to 120 min following MCP were not significantly different in prolactinoma patients and in control subjects. It is concluded that in patients with prolactinomas, the alteration in the dopaminergic regulation is specifically related to the lactotroph.     

Role of aging on growth hormone and prolactin release after growth hormone-releasing hormone and domperidone in man

Growth hormone (GH) and prolactin (PRL) secretion after GH-releasing hormone (GHRH) and domperidone (DOM), an antidopaminergic drug which does not cross the blood-brain barrier (BBB), was evaluated in 8 healthy elderly men (65-91 years) and in 7 young adults (23-40 years). All received in random order at 2-day intervals: GHRH(1-40) (50 micrograms i.v.) bolus, DOM (5 mg/h) infusion, GHRH(1-40) (50 micrograms i.v.) plus DOM (5 mg/h i.v.), saline solution. In elderly men GH increase after GHRH was significantly lower than in young men. DOM alone did not change GH secretion in either of these groups, whereas it increased the GH response to GHRH only in young adults. PRL levels increased in both young and elderly men during both DOM and GHRH plus DOM, but the PRL release was more marked in young than in elderly men. Both integrated secretion of GH after GHRH and of PRL after DOM were inversely correlated to chronological age. Our data show an impairment of GH rise after GHRH and of PRL after DOM in elderly adults. It is also stressed that peripheral blockade of dopamine receptors by DOM is unable to amplify the GH response to GHRH only in elderly men. A reduction in GH release after GHRH might be related to aging, perhaps through a reduction of dopaminergic tonus.     

Zinc supplementation does not inhibit basal and metoclopramide-stimulated prolactinemia secretion in healthy men.

Dopamine (DA) and zinc (Zn++) share common mechanisms in their inhibition of prolactin (PRL) secretion. Both substances are present in the same brain areas, where Zn++ is released together with DA, suggesting a modulatory effect of Zn++ on dopaminergic receptors. The aim of the present study was to evaluate the effect of Zn++ supplementation on basal and PRL secretion stimulated by metoclopramide (MCP), a dopaminergic antagonist. Seven healthy men were evaluated in controlled study, where MCP (5 mg) was given intravenously, before and after 3 months of oral Zn++ (25 mg) administration. Our results indicate that chronic Zn++ administration does not change basal or MCP-stimulated plasma PRL secretion suggesting that, in humans, Zn++ does not interfere on PRL secretion mediated through dopaminergic receptors.     

Prolactin release in liver cirrhosis with impaired glucose tolerance (IGT)

The effects of acute TRH and cimetidine administration on the plasma prolactin (PRL) response have been studied in cirrhotic patients with impaired glucose tolerance (IGT). I v. TRH administration stimulates PRL release both in cirrhotics and controls; i.v. cimetidine did not induced a significant rise of PRL in liver cirrhosis. Present findings demonstrate that PRL is not responsible for the deterioration of glucose handling in alcoholic cirrhotic patients examined.     

The anti-oestrogen tamoxifen does not interfere with the dopaminergic control of prolactin and TSH release in normogonadotrophic oligozoospermic man

This study was designed to investigate the role of endogenous oestrogens in the dopaminergic regulation of prolactin and TSH release in 16 normogonadotrophic oligozoospermic men. Three months' administration of the oestrogen-receptor antagonist tamoxifen (10 mg twice daily), blocking oestrogen-receptors both in the CNS and peripherally, did not affect basal prolactin and TSH levels. Neither was the prolactin or TSH response to stimulation with the anti-dopaminergic agents metoclopramide (10 mg i.v.) (acting both in the CNS and peripherally) and domperidone (10 mg i.v.) (acting peripherally) affected by tamoxifen administration. The response of prolactin and TSH to metoclopramide proved to be no greater than to domperidone. It is concluded that: Endogenous oestrogens, in as far as receptor-mediated, do not affect basal or anti-dopaminergic stimulated release of both prolactin and TSH in normogonadotrophic oligozoospermic men. The anti-dopaminergic activity of metoclopramide in the release of prolactin and TSH is likely for the greater part peripheral.     

Possible direct effect of serotonin on pituitary prolactin secretion: in vivo and in vitro studies

In this work we analyze the possibility of serotonin (5-HT)-releasing prolactin (PRL) through a direct action at the pituitary level. 5-HT (2 mg/kg i.v.) stimulates PRL secretion in hypophysectomized autotransplanted animals (HAG) significantly and this effect was not influenced by pretreatment with the dopaminergic antagonist domperidone. In perifused pituitaries, 5-HT administration (0.01, 0.1 and 1 microM for 90 min, or 1, 10, 100 microM for 15 min) was ineffective in stimulating PRL release. In pituitaries obtained from animals previously treated with the neurotoxic 5,7-dihydroxytryptamine (5,7-DHT) or vehicle and incubated in the presence of 5-HT (2.5, 5 and 10 microM), no response in PRL secretion was observed. These results suggested that 5-HT does not release PRL through a direct pituitary action, and that the effect observed in HAG animals could be mediated through the release of a PRL-releasing factor after 5-HT administration.     

Adrenergic and dopaminergic control of growth hormone secretion in urethan anesthetized adult male rats

The effects of drugs which interfere with alpha-adrenergic and dopaminergic mechanisms, involved in GH and PRL secretion, have been analyzed in urethane anesthetized rats. Clonidine induced a dose-dependent release of GH (0.0032--0.1 mg/kg i.v.) as well as of PRL (0.032--1.0 mg/kg i.v.). The lowest dose of clonidine, when given into the third ventricle, provoked a very pronounced release of GH. Phentolamine, given intravenously, inhibited the clonidine-induced GH release in a dose-dependnet manner. L-Dopa administered intravenously and apomorphine administered intravenously or intraventricularly did not affect basal secretion of GH bu- produced a dose-dependnet inhibition of clonidine-induced GH release. Pimozide did not change basal GH secretion. Furthermore pimozide did not attenuate the inhibition of clonidine-induced GH secretion seen after apomorphine administration, however, it completely reversed apomorphine-induced PRL inhibition. These findings demonstrate that an alpha-adrenoceptor-mediated stimulatory mechanism is involved in GH and PRL secretion. An inhibitory dopaminergic mechanism is confirmed for PRL secretion and suggested for GH secretion.     

A patient with a prolactinoma associated with an aldosterone producing adrenal adenoma: differences in dopaminergic regulation of PRL and aldosterone secretion.

A patient with a rare combination of prolactinoma and aldosterone producing adrenal adenoma (APA) was reported in relation to studies concerning dopaminergic regulation of PRL and aldosterone secretion. The patient is a 38-year-old female with plasma PRL and aldosterone concentrations (PAC) of 563 ng/ml and 54 ng/dl, respectively. A bolus of 10 mg of metoclopramide significantly increased plasma PRL in 6 normal subjects and in 4 patients with APA, whereas the responses were blunted in 7 patients with prolactinoma and in our patient. The response of aldosterone to metoclopramide was less than that of PRL, but similar in all studied subjects, indicating that the dopaminergic inhibition of aldosterone secretion is less than that of PRL in normal subjects and did not change in patients with APA or prolactinoma. Oral administration of 2.5 mg of bromocriptine suppressed plasma PRL significantly in all the subjects studied, but did not produce any consistent changes in PAC. Discrepancies in the response of PRL and aldosterone to metoclopramide and to bromocriptine suggest a difference in the dopaminergic regulation of PRL and aldosterone secretion in both normal subjects and patients with prolactinoma and APA. It is unlikely that reduced dopaminergic inhibition is the basis for hypersecretion of PRL and aldosterone in our patient.     

Effects of serotonin depletion byp-chlorophenylalanine,p-chloroamphetamine or 5,7-dihydroxytryptamine on central dopaminergic neurons: Focus on tuberoinfundibular dopaminergic neurons and serum prolactin

Three serotonin (5-HT) neurotoxins,p-chlorophenylalanine (PCPA, 125 and 250 mg/kg, i.p.),p-chloroamphetamine (PCA, 10 mg/kg, i.p.) and 5,7-dihydroxytryptamine (5,7-DHT, 200 µg/rat, i.c.v.) were used to examine whether depletion of central 5-HT has an effect on central dopaminergic (DA) neuronal activities or on prolactin (PRL) secretion. Adult ovariectomized Sprague-Dawley rats primed with estrogen (polyestradiol phosphate, 0.1 mg/rat, s.c.) were treated with one of three neurotoxins and then decapitated in the morning after 3–7 days. Blood sample and brain tissues were collected. The acute effect of PCA (from 30 to 180 min) was also determined. The concentrations of 5-HT, DA and their metabolites, 5-hydroxyindoleacetic acid and 3,4-dihydroxyphenylacetic acid, in the median eminence, striatum and nucleus accumbens were determined by HPLC-electrochemical detection. All three toxins significantly depleted central 5-HT stores by 11–20%. Except for PCPA, neither PCA nor 5,7-DHT had any significant effect on basal DA neuronal activities or PRL secretion. PCA also exhibited an acute effect on the release and reuptake of 5-HT and DA. In summary, depletion of central 5-HT stores to a significant extent for 3–7 days did not seem to affect basal DA neuronal activity and PRL secretion.     

Effect of zinc administration on thyrotropin releasing hormone-stimulated prolactinemia in healthy men

Previous in vitro studies have demonstrated zinc (Zn⁺⁺) inhibition of basal and of potassium (K⁺) or thyrotropin-releasing hormone (TRH)-stimulated prolactin (PRL) secretion, in a selective, reversible, and dose-dependent manner. Thus, Zn⁺⁺ may regulate physiologically pituitary PRL secretion. Furthermore, studies with patients with uremia, cirrhosis or prolactinoma, have shown the coexistence of hypozincemia and hyperprolactinemia and zinc supplementation did not correct hyperprolactinemia in these patients. In normal individuals Zn⁺⁺ administration produced controversial results on PRL secretion. Here, we investigated whether zinc administration affects TRH-stimulated PRL in healthy men. We found that Zn⁺⁺ administration does not change the TRH-stimulated PRL. Therefore, in normal conditions, Zn⁺⁺ does not inhibit TRH-stimulated prolactinemia. In addition, we found that acute increases of blood PRL and TRH do not alter blood Zn⁺⁺ levels.     

The effect of transient dopamine antagonism on thyrotropin-releasing hormone-induced prolactin release in female rats during the estrous cycle

Prolactin (PRL) release induced by TRH was examined on each day of the estrous cycle in female rats in which pituitary dopamine (DA) receptors were blocked pharmacologically. The objective was to determine if an interaction exists between hypothalamic inhibitory and releasing hormones with regard to prolactin (PRL) secretion. Domperidone (0.01 mg/rat i.v.) followed 5 minutes later by the administration of the DA agonist 2-Br-alpha-ergocryptine maleate (CB-154, 0.5 mg/rat i.v.) were used to produce a transient (less than 1 hr) dopamine blockade. One hour later, thyrotropin-releasing hormone (TRH, 1.0 microgram/rat i.v.) was given to stimulate PRL release. On the morning of proestrus, TRH released a significantly greater quantity of PRL into the plasma after DA antagonism compared to control animals which did not receive the dopamine antagonist. Dopamine antagonism also enhanced the effectiveness of TRH on the mornings of estrus and metestrus. The response on estrus was significantly greater than the response on proestrus. However by the morning of diestrus, TRH-"releasable" PRL was greatly diminished. Our results suggest that DA antagonism is able to shift differing quantities of PRL into a TRH "releasable" pool on several days of the estrous cycle and that the control of this mechanism is acute.     

Inhibition of prolactin secretion by gastrin releasing peptide (GRP) in the rat

Synthetic gastrin releasing peptide (GRP) injected intraventricularly (1 microgram/rat), but not intravenously, suppressed rat prolactin (PRL) release induced by a Met-enkephalin analog, FK33-824 (10 micrograms/100 g body wt., iv). GRP also blunted PRL release induced by a dopamine antagonist, domperidone (1 microgram/100 g body wt., iv). In contrast, GRP did not suppress elevated plasma PRL levels sustained by a large dose of domperidone (10 micrograms/100 g body wt., iv). GRP (10(-5) M) had no effect on PRL release from superfused pituitary cells in vitro. These results suggest that GRP inhibits PRL secretion in the rat by acting through the brain to stimulate the dopaminergic mechanism.     

Effect of metoclopramide-induced prolactin on aldosterone secretion in normal subjects

We investigated the role of prolactin (PRL) on modurating the secretion of aldosterone in normal male subjects. Metoclopramide (5mg) which causes a significant rise of PRL was given by intravenous injection. The peak of PRL level at 30 min. after i.v. injection of metoclopramide (20.0 ± 1.6 ng/ml, mean ± S.E.) was significantly higher than the basal level (6.4 ± 2.1 ng/ml, P < 0.01), but plasma aldosterone, serum sodium, potassium and plasma renin activity did not change significantly throughout the period of the study. Cortisol levels, however, reduced significantly after 30 min. and remained significantly low, probably because of diurnal variation. Present results suggest that PRL might at least not play a physiological role on regulating the secretion of aldosterone in man.     

Pharmacological activation of the GABAergic system does not affect GH and PRL release in acromegaly

An extensive hypothalamic neurotransmitter impairment has been proposed in acromegaly. However, at the moment, the hypothalamic GABAergic system has been little investigated in this disorder. Since GABA has been shown to modulate growth hormone (GH) and prolactin (PRL) secretion in human subjects, it seemed reasonable to investigate hypothalamic GABAergic functioning through the assessment of basal GH and PRL responses to pharmacological activation of this system. 800 mg of sodium valproate (SV), a drug with GABA facilitating properties, were administered orally to 7 acromegalic patients and 9 healthy volunteers. Blood samples were collected before and after the drug administration for the measurement of plasma GH and PRL levels. SV induced a clear-cut rise in basal GH and a decrease in basal PRL in healthy subjects, but it did not induce any change in the basal levels of these hormones in acromegalics. These results suggest that the response of GH and PRL to SV in acromegaly is qualitatively different from normal controls.     

Evidence for increased endogenous dopaminergic inhibition of aldosterone secretion in prolactinoma

Aldosterone responsiveness to consecutive i.v. injections of metoclopramide 1 mg, 2.5 mg and 10 mg was studied in 8 patients with prolactinoma and normally preserved adrenal function and in 14 healthy volunteers. In the patients, aldosterone response to metoclopramide 1 mg was blunted. After metoclopramide 10 mg, aldosterone rose to the same levels in patients and volunteers. In the patients, however, percentage rise of aldosterone was enhanced, since the appropriate base line concentration of aldosterone was decreased. Thus, there is evidence for increased endogenous dopaminergic inhibition of aldosterone secretion in prolactinoma.     

Further evidence for the inhibitory action of baclofen on a prolactin-releasing factor

The mechanism of action of a specific gamma-aminobutyric acid B receptor agonist, beta-p-chlorophenyl-gamma-aminobutyric acid or baclofen, in its inhibitory action on prolactin release, was studied. Dose-response studies of the effect of baclofen on prolactin (PRL) secretion were performed in stressed male rats. Furthermore, the action of the drug was evaluated in (i) rats treated with haloperidol or alpha-methyl-p-tyrosine, (ii) stressed or suckled rats pretreated with sulpiride, and (iii) animals treated with serotonin, alone, or with alpha-methyl-p-tyrosine. Baclofen showed a clear dose-dependent inhibition of prolactin secretion in males under stress. The drug was unable to inhibit the prolactin release induced by haloperidol or alpha-methyl-p-tyrosine, although it reduced the PRL secretion induced by serotonin. It also inhibited PRL release in sulpiride-pretreated stressed or suckled rats. These results suggest that the dose-dependent effect of baclofen on PRL secretion is the consequence of an inhibition exerted on the prolactin-releasing factor component of the neuroendocrine responses evoked by stress or suckling, possibly acting at the serotonergic system.     

Dopamine control of aldosterone secretion in end-stage renal failure

The role of the tonic inhibitory effect of dopamine on aldosterone secretion has been investigated in 10 patients with chronic renal failure (CRF) on hemodialysis, in 8 normotensive renal transplant recipients (Tx) with normal renal function and in 8 normotensive volunteers (NV). The following tests were performed: the response of plasma aldosterone (PA) to metoclopramide administration; the response of plasma prolactin (PRL) to TRH administration, and the changes induced by Lisuride (a dopaminergic agonist, on the values of PA and PRL). The basal values of PA and PRL were higher in CRF than in NV and Tx. The inverse was true for plasma renin activity (PRA) values. The response of PA and PRL to metoclopramide showed blunted increases in CRF when compared to NV, in the absence of changes of PRA, cortisol and potassium. After TRH administration, PRL increase in CRF was also inferior. Lisuride induced a decrease of both PA and PRL both in CRF and NV. In Tx, basal values of PA and PRL were similar to NV. Nevertheless, the response to metoclopramide and TRH were partially blunted when compared to that of NV. These results point to the existence of a deranged dopaminergic regulation of aldosterone secretion in end-stage renal failure patients. The alterations are partially corrected by a well-functioning kidney graft.     

Calcitonin inhibition of physiological and stimulated prolactin secretion in rats

The administration of salmon Calcitonin (sCT) intravenously (2.5 or 10 μg/kg) or into the lateral cerebral ventricles (2.5 or 25 ng/rat, i.c.v.) of unanaestized male rats induced clearcut decreases in plasma prolactin(PRL) levels. The i.c.v. injection of one of these doses of sCT (25 ng/rat) into rats with median eminence lesions was completely ineffective, while it induced a dramatic decrease in plasma PRL levels of sham-operated rats. Morphine- and heat stress-stimulated PRL levels were also abolished by sCT injection (250 ng/rat i.c.v.). The sCT-induced decrease in PRL levels was completely overcome by haloperidol, a dopamine-receptor blocker. We conclude that sCT may affect PRL secretion via an hypothalamic system, probably involving dopaminergic neurons. The present results indicate that CT, like many others peptides, may affect PRL secretion, directly or indirectly, even though further research is necessary to determine whether this effect has pharmacological or physiological importance.     

Stimulation of prolactin secretion by morphine: role of the central serotonergic system.

Unanesthetized male rats with indwellinh right atrial cannulae were injected with morphine (MOR) i.v. which produced a dose-related increase in plasma prolactin levels (PRL). This effect was blocked partially by naloxone (NAL) at a dose of 0.06 mg/kg and totally by 0.6 mg/kg NAL. Interruption of central serotonergic neurotransmission by receptor blockade, with metergoline (MET) or cyproheptadine (Cypro), inhibition of tryptophan hydroxylase by para-chlorophenylalanine or destruction of serotonin neurons by 5, 7-dihydroxytryptamine antagonized the morphine (3 mg/kg) induced elevation in PRL release. Depression of dopaminergic activity with α-methyl-para-tyrosine elevated the basal PRL levels, but it did not prevent a further increase of prolactin levels by morphine (3 mg/kg). These data are compatible with the hypothesis that morphine stimulates PRL release by activation of the central serotonergic system.