Prolactin after baclofen in healthy subjects and prolactinoma patients

Serum prolactin (PRL) levels in basal conditions (two samples) and 30, 60, 90, 120, 150 e 180 minutes after oral administration of baclofen (20 mg) were evaluated in 6 healthy subjects and in 10 patients with prolactinoma. The effect of baclofen (20 mg by mouth) on the PRL secretion cimetidine (400 mg i.v.) or domperidone (20 mg i.v.) induced were evaluated in 9 healthy women by administration of baclofen 60 minutes before cimetidine or domperidone. Baclofen was unable to significantly rise serum PRL levels in healthy subjects and in patients affected by prolactinoma and furthermore did not interfere with PRL rise domperidone induced. On the contrary baclofen decreased PRL rise cimetidine induced. It was concluded that: in basal condition, GABAb receptor don't play an obvious role in modulation of PRL secretion; when H2 istaminergic inhibition on PRL secretion is blocked (at an hypothalamic site), a GABA inhibition, b receptor mediated, on PRL secretion became more clear; the domperidone blockade of hypophysial dopaminergic receptors suggests that GABAb modulation of prolactin secretion don't obtain itself by dopaminergic pathways.     

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.     

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.     

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.     

Differential role of the opioid μ and δ receptors in the activation of prolactin (PRL) and growth hormone (GH) secretion by morphine in the male rat

Administration of naloxazone (50 mg/kg i.v.), an irreversible, selective and long acting antagonist of the μ₁ subclass of the opioid receptors, strongly reduced stimulation of PRL secretion by morphine (5.0 mg/kg i.v.) injected 24 hours later into conscious, unrestrained rats. In contrast, the effect of morphine on PRL release was unimpaired in rats treated 24 hours beforehand with either the reversible opioid antagonist naloxone (50 mg/kg i.v.), or the vehicle for naloxazone. A complete suppression of the PRL response to morphine (3.0 mg/kg i.v.) was observed in animals given intraventricular (IVT) injection of β-funaltrexamine (β-FNA, 2.5 μg), another selective, irreversible and long acting antagonist of the μ receptors, 24 hours beforehand. Neither naloxazone nor β-FNA had any effect on the activation of GH secretion by morphine, which, however, was conspiciously reduced by ICI 154, 129, a preferential δ receptor antagonist, injected IVT (50 μg) 5 minutes before morphine. It is concluded that the PRL stimulating effect of morphine is mediated by the μ receptors, wherease activation of GH probably involves the δ sites.     

Responses of growth hormone to metoclopramide in normal women and amenorrheic women with or without hyperprolactinemia

Response of growth hormone (GH) release to metoclopramide (MCP), a dopamine antagonist, was evaluated in normal women, hyperprolactinemic-amenorrheic patients with pituitary microadenoma and normoprolactinemic-amenorrheic patients. Mean basal concentrations of serum GH and prolactin (PRL) in amenorrheic patients were not significantly different from those in normal women except PRL concentrations in hyperprolactinemic patients. Serum GH concentrations significantly increased after MCP administration in normal women and normoprolactinemic-amenorrheic patients, but not in hyperprolactinemic patients. Dopamine causes modest and transient GH secretion in some subjects. Therefore MCP is not likely to stimulate GH secretion through its effect as a dopamine antagonist, and the mechanism of action of MCP on GH secretion is not known. Although the cause of the absence of GH response to MCP in hyperprolactinemic patients is unclear, it may be related to the increased hypothalamic dopaminergic tone which is operative in such patients or it may reflect a direct action of PRL on hypothalamic-pituitary GH regulation.     

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 taurine on growth hormone and prolactin secretion in rats: possible interaction with opioid peptidergic system

The effect of taurine on growth hormone (GH) and prolactin (PRL) secretion was investigated in the urethane-alpha-chloralose anesthetized rats, considering the interaction with endogenous opioid peptidergic system. Intraventricular injection of taurine (0.25 and 1.0 mumol) stimulated GH and PRL secretion in a dose-dependent manner. However, 4.0 mumol taurine failed to show these effect. The intravenous infusion of naloxone (4 mg/kg b.w.) completely inhibited both the GH and PRL secretion induced by taurine (1.0 mumol). The combined treatment of taurine (1.0 mumol) and FK33-824 (Met-enkephalin derivative, 100 micrograms/kg b.w., i.v.) significantly increased GH and PRL responses induced by taurine or FK33-824 alone. These results indicate that taurine is an effective stimulator of GH and PRL secretion in rats, and that the mechanism of this action involves the opioid peptidergic system in the hypothalamus.     

The effect of bombesin on basal, alpha-methyl-p-tyrosine, haloperidol, morphine, bremazocine and stress-induced prolactin secretion

Intravenously administered bombesin lowered basal PRL levels in conscious male rats and prevented the morphine, bremazocine and stress-induced PRL secretion. The same dose of bombesin had no effect on PRL levels in alpha-methyl-p-tyrosine pretreated rats and did not affect haloperidol-stimulated PRL release. These results show that bombesin given intravenously acts as an inhibitor of PRL secretion and suggests that it does not act on the lactotrope itself but rather by an increase of the inhibitory dopaminergic tone.     

Inhibition of luteinizing hormone secretion by delta9-tetrahydrocannabinol in the ovariectomized rat: effect of pretreatment with neurotransmitter or neuropeptide receptor antagonists.

Acute treatment with delta9-tetrahydrocannabinol [delta9-THC; 0.5 or 1.0 mg/kg b.w. intravenously (i.v.)], the major psychoactive constituent of marijuana, produces a dose-related suppression of pulsatile luteinizing hormone (LH) secretion in ovariectomized rats. To determine whether delta9-THC produces this response by altering neurotransmitter and/or neuropeptide systems involved in the regulation of LH secretion, ovariectomized rats were pretreated with antagonists for dopamine, norepinephrine, serotonin, or opioid receptors, and the effect of delta9-THC on LH release was determined. Pretreatment with the D2 receptor antagonists butaclamol (1.0 mg/kg b.w., intraperitoneally) or pimozide [0.63 mg/kg, subcutaneously (s.c.)], the opioid receptor antagonists naloxone (1-4 mg/kg, i.v.) or naltrexone (2 mg/kg, i.v.), the noradrenergic alpha2-receptor antagonist idazoxan (10 microg/kg, i.v.), or the serotonin 5-HT(1C/2) receptor antagonist ritanserin (1 or 5 mg/kg b.w., i.p.), did not alter delta9-THC-induced inhibition of pulsatile LH secretion. Pretreatment with a relatively high dose of the beta-adrenergic receptor blocker propranolol (6 mg/kg, i.v.) attenuated the ability of the low THC dose to inhibit LH release; however, lower doses of propranolol were without effect. Furthermore, the ability of a relatively nonspecific serotonin 5-HT(1A/1B) receptor antagonist pindolol (4 mg/kg, s.c.) or the specific 5-HT1A receptor antagonist WAY-100635 (1 mg/kg, s.c.) to significantly attenuate THC-induced LH suppression indicates that activation of serotonergic 5-HT1A receptors may be an important mode by which THC causes inhibition of LH release in the ovariectomized rat.     

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.     

Adenohypophyseal hormone response to chronic stress in dexamethasone-treated rats.

The influence of dexamethasone treatment on the basal values of corticosterone, GH, prolactin (PRL), LH and FSH, as well as on the adenohypophyseal hormone response to chronic stress was studied in female rats. Dexamethasone acetate (25 micrograms/100 b.w.), given by gavage twice daily for 10 days, decreased the resting plasma levels of corticosterone, GH, LH and PRL, whereas the FSH titers remained normal. The secretion of ACTH (evaluated indirectly through corticosterone concentrations) and of GH appeared to be most sensitive to the suppressive effect of dexamethasone. The same hormonal response pattern was induced by 8 h of daily immobilization for 10 days, except that ACTH release was enhanced and the plasma LH titers dropped more drastically. Dexamethasone administration in combination with restraint did not alter the characteristic hormonal profile of chronic stress, despite the fact that ACTH secretion was completely blocked. These data suggest that the inhibition of PRL, LH and GH secretion following severe, chronic stress is not causally related to the sustained elevation of plasma ACTH.     

Role of central epinephrine in regulation of anterior pituitary hormone secretion

Hypothalamic regulation of anterior pituitary hormones is thought to be mediated by the release of stimulatory and/or inhibitory peptides that are, in turn, regulated by catecholaminergic neurons. The recent development of selective epinephrine (EPI) synthesis inhibitors has made it possible to disrupt central EPI neurotransmission without affecting norepinephrine or dopamine. These compounds were used in the present investigation to assess the involvement of brain EPI systems in regulation of GH, LH, and prolactin (PRL) in male and ovariectomized female rats. Inhibition of central EPI synthesis (1) inhibited episodic and morphine-, but not clonidine-induced GH release, and (2) blocked the LH surge induced by estrogen and progesterone, but did not affect episodic LH release in hormonally untreated rats. Inhibition of peripheral (adrenal) EPI synthesis had no effect on these hormones. Results of these studies suggest an excitatory role for EPI in regulation of GH and LH secretion, mediated by stimulation of GH-releasing hormone and LHRH, respectively. EPI does not appear to have a major function in regulation of PRL secretion.     

Autocrine-paracrine inhibition of growth hormone and prolactin production by GH3 cell-conditioned medium

Summary In previous work we have shown that perifused GH₃ cells exhibit spontaneously accelerating growth hormone (GH) and prolactin (PRL) secretory rates. This behavior contrasts with GH and PRL secretion rates that are decreasing or stable over the same 3-d period in static cell culture. We now report that GH₃ cells maintained in serum-supplemented medium produce an autocrine-paracrine factor(s) which inhibits GH secretion in plate culture; PRL release is frequently reduced as well. The inhibitory effect of conditioned medium on GH secretion was concentration dependent, whereas PRL release was stimulated at low and inhibited at high concentrations over the same range. Extensive dialysis of conditioned medium using membranes with a molecular weight cut-off of 12 000–14 000 did not remove GH inhibition but produced a retentate that stimulated PRL secretion. Heat-inactivation of conditioned medium did not abolish inhibition of GH release but did remove the PRL-stimulatory effect. IGF-I added to fresh culture medium did not reproduce the GH-inhibitory effects of conditioned medium. We conclude that GH₃ cell secretory behavior in perifusion and plate culture systems may be partially explained by the production of an autocrine-paracrine factor: its accumulation in plate culture inhibits GH and PRL secretion whereas its removal, by perifusing medium, allows GH and PRL secretion to accelerate. Supported by grant DK33388 to M. E. S. from the National Institute of Health, Bethesda, MD, and in part by the Medical Research Service of the Veterans Administration, Washington, DC.     

Inhibition of prolactin and growth hormone secretion by nickel

Nickel (Ni++) is a potent inhibitor of prolactin (PRL) secretion from isolated rat pituitary quarters in vitro, suppressing both basal PRL release and the stimulation of PRL secretion due to theophylline and dibutyryl cyclic AMP. Stimulation of growth hormone (GH) secretion by synthetic GHRH is also blunted by Ni++, although basal GH release and stimulated GH release due to theophylline or dibutyryl cyclic AMP are not suppressed. Ni++ antagonizes the stimulation of both PRL and GH secretion by barium (Ba++) ion, suggesting that the inhibitory effects of Ni++ on hormone release are due to an antagonism of calcium uptake or redistribution.     

The prolactin response to intravenous dextroamphetamine in normal young men and postmenopausal women

D-amphetamine was administered intravenously in doses of 0.1 mg/kg and 0.15 mg/kg to normal young men and postmenopausal women in both morning and evening. No suppression of PRL secretion after amphetamine was found, and, in the postmenopausal women, no significant change in PRL levels in any dose or time condition occured. However, a significant and relatively consistent PRL release was induced in the young men in the evening by the higher dose. This latter response suggests that, in humans, dextroamphetamine can actually stimulate prolactin perhaps by a mechanism other than alteration in dopaminergic tone.     

Prolactin secretion after hypothalamic deafferentation in beef calves: response to haloperidol, alpha-methyl-rho-tyrosine, thyrotropin-releasing hormone and ovariectomy

In ruminant species photoperiod regulates prolactin (PRL) secretion. It is hypothesized that the inhibition of PRL secretion resides in dopaminergic neurons of the medial basal hypothalamus (MBH). To test this hypothesis, anterior (AHD), posterior (PHD) and complete (CHD) hypothalamic deafferentation and sham operation control (SOC) surgeries were carried out during May (long-day photoperiod) in beef heifer calves (6-8 mo old) to measure basal PRL secretion and PRL secretion as affected by intravenous secretagogues. On the day of surgery (day 0), PRL secretion reflected stress of anesthesia and surgery in all groups. Thyrotropin-releasing hormone (TRH), alpha-methyl-rho-tyrosine (alphaMrhoT), and haloperidol (HAL) was iv injected on days 11, 13 and 15, respectively. AHD, PHD, CHD, and SOC calves responded to TRH (100 microg) with an acute increase in PRL that peaked within 20 min. All heifers responded to alphaMrhoT (10 mg/kg BW) with an acute elevation in PRL within 10 min and remaining elevated for 3 h. HAL (0.1 mg/kg BW) induced an acute increase in PRL secretion in all groups, peaking within 15-30 min. Seven months later (December, short-day photoperiod) these heifers were ovariectomized. Basal plasma PRL levels were seasonally low, PRL secretion in AHD, PHD and CHD animals abruptly increased within 15 min to iv injection of 100 microg TRH to a greater amount than seen in SOC heifers. Although a biphasic effect on PRL secretion entrains under long-day and short-day photoperiods, hypothalamic deafferentation in cattle did not affect the pituitary gland's responsiveness to secretagogues.     

Effects of the serotonin agonist, quipazine, on luteinizing hormone and prolactin release: evidence for serotonin-catecholamine interactions

The present study tested whether administration of the serotonin agonist, quipazine maleate, affects the secretion of luteinizing hormone (LH) and prolactin (PRL) and concomitantly, the activity of central noradrenergic and dopaminergic systems. Quipazine (15 mg/kg, ip) significantly reduced LH and increased PRL when administered to ovariectomized rats. Associated with these changes, the depletion of dopamine seen after synthesis inhibition with alpha-methyl tyrosine was reduced by quipazine in the caudate nucleus and median eminence, suggesting a depression of dopaminergic activity. The depletion of norepinephrine in the median eminence was unaffected. In a second experiment, quipazine (1 microM) diminished the potassium-induced release of both norepinephrine and dopamine from fragments of medial basal hypothalamus, in vitro. Release from preoptic area was unaffected. These results suggest that central serotonergic systems may interact with noradrenergic and dopaminergic systems that regulate LH and PRL secretion, respectively.     

Growth hormone response to thyrotropin-releasing hormone in liver cirrhosis: unique alteration in anterior pituitary responsiveness to hypothalamic hormones

Patients with chronic liver diseases were evaluated for: 1) the ability of somatostatin to affect the thyrotropin-releasing hormone (TRH) induced growth hormone (GH) rise; 2) the competence of luteinizing-hormone releasing hormone (LH-RH) to release GH; 3) the non-specific releasing effect of TRH and LH-RH on other anterior pituitary (AP) hormones. In 6 patients, infusion of somatostatin (100 micrograms iv bolus + 375 micrograms i.v. infusion) completely abolished the TRH (400 micrograms i.v.)-induced GH rise; in none of 12 patients, of whom 7 were GH-responders to TRH, did LH-RH (100 micrograms i.v.) cause release of GH; 4) finally, LH-RH (12 patients) did not increase plasma prolactin (PRL) and TRH (7 patients) did not evoke a non-specific release of gonadotropins. It is concluded that: 1) abnormal GH-responsiveness to TRH is the unique alteration in AP responsiveness to hypothalamic hormones present in liver cirrhosis; 2) the mechanism(s) subserving the altered GH response to TRH is different from that underlying the TRH-induced GH rise present in another pathologic state i.e. acromegaly, a condition in which the effect of TRH escapes somatostatin suppression and LH-RH evokes GH and PRL release.     

Prolactin (PRL) release-inhibiting properties of the alpha 2 adrenergic receptor antagonist idazoxan: comparison with yohimbine

The effects of the alpha 2 adrenergic receptor antagonists yohimbine (YOH) and Idazoxan (ID) on secretion of PRL were compared in nonanesthetized male rats bearing permanent intraatrial cannulae for i.v. drug delivery and serial blood sampling. YOH induced a dose-related elevation of basal plasma PRL levels. ID had either no effect or a tendency to lower them and effectively inhibited stimulation of PRL secretion with morphine, 5-hydroxytryptophan (5HTP), quipazine or restraint stress. YOH at low doses did not alter the PRL secretory responses to these stimuli or enhanced them at the highest dose used (1.56 mg/kg). ID inhibited the PRL-stimulating, effect of 5HTP or morphine following inhibition of NE synthesis with FLA63 or pretreatment with clonidine. It also blocked the effect of quipazine in rats pretreated with prazosin. It is concluded that ID, in a complete contrast to YOH effectively inhibits PRL secretion. The inhibitory mechanism appears to be unrelated to its interaction with the alpha adrenergic receptors.