Long-term cimetidine does not alter serum prolactin.

The effect of repeated cimetidine ingestion on serum prolactin values was studied prospectively in 17 men with proven duodenal ulcers. These patients received 400 mg of cimetidine twice daily for 12 weeks but showed no alteration in their mean serum prolactin levels. Cimetidine-induced hyperprolactinaemia is not the explanation for the development of gynaecomastia in men exposed to this drug.     

Cimetidine and plasma levels of gonadotropins,prolactin and gonadal steroids in women.

The endocrine effects of cimetidine (Tagamet) during the menstrual cycle were investigated in seven healthy female volunteers. The subjects were studied for six menstrual cycles divided into the pretreatment phase, a phase of therapy with 1.2 g of orally administered cimetidine daily for two cycles, and a post-treatment phase. Cimetidine therapy induced a significant increase in the mean plasma level of follicle-stimulating hormone during the periovulatory period, followed by modest but sustained hyperprolactinemia throughout the luteal phase of each cycle. No significant changes were found in the mean plasma levels of luteinizing hormone and progesterone, and the mean plasma estradiol level was significantly decreased only in the midproliferative phase of each cycle. The mean plasma prolactin levels after a bolus injection of thyrotropin-releasing hormone in the midluteal phase during cimetidine administration did not differ from the mean control levels, which indicates that cimetidine modulates the release of prolactin at the suprapituitary locus. However, the significance of the endocrine changes remains to be established.     

Further studies on the effect of cimetidine and other neurotropic drugs on rat serum prolactin

The hyperprolactinemic effect of H2 histamine receptor antagonists has been described in the rat and in humans. The present study was undertaken to explore more fully the hyperprolactinemic action of cimetidine, and its interrelationship with other neurotropic agents. Adult ovariectomized estrogen-primed rats were injected with mepiramine, diphenhydramine, pilocarpine, atropine, dopamine, cimetidine or saline as control, at different sequences and the effect on serum prolactin was determined. The effect of cimetidine on prolactin release "in vitro" by hemipituitaries of estrogenized male rats during a short time incubation period, was also investigated. Our results indicate that cimetidine is able to release prolactin and that this effect is not prevented by atropine or the classical antihistaminergic agents mepiramine and diphenhydramine. Both pilocarpine and dopamine inhibit the prolactin release due to cimetidine. The hypoprolactinemic action of pilocarpine was completely blocked by atropine, but not by mepiramine or diphenhydramine. Finally, cimetidine was unable to modify significantly the prolactin release by incubated pituitaries. It is postulated that cimetidine acts mainly at the brain and that the hyperprolactinemic effect is not mediated by muscarinic or H1 histaminergic receptors. This action can be prevented by drugs such as dopamine that are able to act on the lactotroph, and also by pilocarpine, probably by stimulating a prolactin inhibiting pathway.     

Catecholamine mechanisms in the feedback effects of estradiol benzoate on the release of LH and prolactin

The role of hypothalamic catecholamines and luteinizing hormone releasing hormone (LHRH) in the negative feedback effect of estradiol benzoate (EB) on luteinizing hormone (LH) release was studied in chronic ovariectomized rats. Administration of 10 micrograms EB decreased plasma LH levels and increased LHRH content in the medial basal hypothalamus (MBH) 1 day after injection. Inhibition of dopamine and norepinephrine synthesis with alpha-methyl-p-tyrosine (alpha-MT) reduced the LHRH content in the MBH in both oil- and EB-treated animals and partially reversed the decrease in plasma LH levels. Inhibition of norepinephrine synthesis with fusaric acid decreased LHRH content in both oil- and EB-treated rats but had no effect on plasma LH levels. The results suggest that at least a portion of the inhibitory effect of EB on LH release is due to the stimulation of an inhibitory dopaminergic mechanism which reduces LHRH release from the MBH. This feedback mechanism is apparently not susceptible to dopaminergic receptor blockade since administration of pimozide had no effect on LH levels. The stimulatory feedback effect of EB on prolactin release was studied in the same animals. alpha-MT and EB produced additive effects on plasma prolactin levels whereas fusaric acid blocked the EB-induced increase in plasma prolactin levels. Pimozide appeared to potentiate the effect of EB on prolactin release. The results reconfirm the possible role of noradrenergic neurons in the release of prolactin induced by EB and also suggest that EB stimulates a dopaminergic mechanism which is inhibitory to prolactin release but is normally masked by increased noradrenergic activity.     

Cimetidine and hyperprolactinemia

Plasma TSH was determined in 12 normal subjects before and after administration of mg 400 of cimetidine i.v., an H2-receptor antagonist. TSH concentration remained unchanged. In 7 normal subjects, pretreated with bromocriptine; variation of plasma prolactin were studied before and after administration of mg 400 and 800 of cimetidine. Bromocriptine inhibited the increase of prolactin secretion, induced by cimetidine. It can be assumed that: a) cimetidine doesn't release hypothalamic TRH in portal vessels; b) that drug has no direct effect on pituitary cells; c) hypothalamic H2-receptor blockade by cimetidine decreases dopamine release from hypothalamus to pituitary gland.     

Effects of cranial cervical ganglionectomy and castration of male lambs. II. 24 hour plasma profiles of luteinizing hormone, testosterone and prolactin

Male lambs were utilized in an experiment designed to evaluate the effects of cranial cervical ganglionectomy (GX), castration and age on hormone secretion profiles. Blood plasma samples were collected at hourly intervals for 24 hours from 24 lambs aged 101 days and 20 lambs aged 277 days, then assayed for concentrations of luteinizing hormone (LH), testosterone and prolactin. At both ages pulsatile secretion of LH and testosterone was confirmed, but no circadian rhythm of LH testosterone or prolactin secretion was detected. Castration elevated LH levels significantly at both ages. GX and its interaction with castration had no effect on LH secretion at 101 days, but at 277 days these factors were significant, largely due to elevated levels being recorded from GX castrates. GX did not affect testosterone levels in entire animals at either age, while plasma from castrates contained no detectable testosterone. GX reduced prolactin concentrations at 101 days of age (summer) but elevated them at 277 days of age (winter). Castration and the interaction of castration with GX had no significant influence on plasma prolactin levels at either age. This study confirmed that the pineal gland of sheep is involved in the regulation of prolactin secretion, and probably influences LH secretion as well.     

The effect of dexamethasone on TSH and prolactin secretion after TRH stimulation

Serum thyrotropin (TSH) and prolactin levels were measured after intravenous administration of 400 μg of synthetic thyrotropin-releasing hormone (TRH) in 13 normal subjects and six hypothyroid patients before and after three days of administration of dexamethasone 2 mg per day. In the normal subjects dexamethasone suppressed baseline serum levels and secretion of TSH after TRH stimulation. On the other hand, it had no effect on the hypothyroid patients. In the control group dexamethasone also suppressed baseline serum levels but not secretion of prolactin after TRH stimulation. Dexamethasone had no effect on prolactin levels in the hypothyroid group. It is concluded that in normal patients short-term administration of dexamethasone has an inhibitory effect on TSH secretion at the pituitary level. As for prolactin, our results could indicate that TRH is a more potent stimulator of prolactin secretion than of TSH secretion, or that TSH and prolactin pituitary thresholds for TRH are different.     

Effects of hypersecretion of growth hormone and prolactin on plasma levels of glucagon and insulin in GH3-cell-tumor-bearing rats, and the influence of bromocriptine treatment

Plasma levels of prolactin, growth hormone, glucagon insulin and glucose were measured in non-treated control rats, bromocriptine-treated control rats and GH3-cell-tumor-bearing rats with and without bromocriptine treatment. Bromocriptine treatment increased plasma levels of glucagon, insulin and glucose in control rats. Tumor-bearing rats had increased body weight and increased plasma levels of prolactin, growth hormone, glucagon, insulin and glucose. Bromocriptine treatment reduced body weight and decreased the plasma levels of prolactin, glucagon and insulin, as compared to non-treated tumor-bearing rats. The drug had no effect on plasma levels of growth hormone and glucose. These results indicate that, in GH3-cell-tumor-bearing rats, prolactin, glucagon and insulin are more sensitive to the action of bromocriptine than growth hormone.     

Effect of histamine and acetylcholine on hypophysial stalk plasma dopamine and peripheral plasma prolactin levels.

To further define the role of dopamine in the regulation of prolactin secretion, we studied the effect on prolactin and hypothalamic dopamine secretion of histamine and acetylcholine (ACh) injected into the lateral ventricle of urethane anesthetized diestrus-1 rats. Histamine (10 μg) caused a 592% increase in plasma prolactin levels and a 26% decrease in stalk plasma dopamine levels. ACh (50 μg) caused a 2090% increase in plasma prolactin levels but no significant change in stalk plasma dopamine concentration.To determine if the 26% fall in stalk plasma dopamine following histamine administration could account for the 6-fold increase in plasma prolactin, we measured the effect on prolactin secretion of a similar decrease in administered dopamine. During an infusion of physiologic levels of dopamine, a 25% decrease in arterial plasma dopamine concentration resulted in only a 2-fold increase in prolactin secretion.The results of these experiments suggest that the effect of histamine on prolactin secretion may be mediated in part by decreased hypothalamic secretion of dopamine but that an additional hypothalamic hormone is probably involved. The stimulatory effect of ACh on prolactin secretion is not mediated by dopamine. These data are consistent with the growing evidence for the participation of multiple hypothalamic factors in the regulation of prolactin secretion.     

Prostacyclin (PGI2) effects on anterior pituitary hormones in the rat in vivo.

Intravenous injection of 600 microgram PGE2 or PGI2 significantly increased serum LH and prolactin levels in estradiol treated ovariectomized rats. There was no effect on serum FSH concentration. PGE2 and PGI2 stimulated LH release in a non-dose dependent manner, while prolactin levels were positively correlated with the dose administered following PGI2 treatment. 6-keto-PGF1 alpha at a comparable dose had no effect on pituitary hormone levels. Subcutaneous administration of 1 mg/kg or 60 mg/kg PGI2 for seven days significantly depressed serum LH level both in male and female rats. These doses had no effect on serum FSH or prolactin levels.     

Effect of long term hormone replacement on plasma prolactin concentrations in women after oophorectomy.

Plasma prolactin concentrations were studied in 88 oophorectomised women who had been receiving mestranol or placebo for three to 11 years. Thirty one of them were also studied under basal conditions and by tests with thyrotrophin releasing hormone. Under basal conditions the mean prolactin concentration was higher in the oestrogen treated group but under non-rested, clinic conditions the difference was lost because of a rise in prolactin value in the placebo group only. Hence the groups showed a different prolactin response to the mild stress of clinic attendance but the same proportionate responsiveness to thyrotrophin releasing hormone. The data suggest that long term hormone replacement has no significant effect on circulating prolactin concentrations under non-rested, everyday conditions and that the prolactin stimulating effects of minor stress and oestrogen may share a similar mechanism.     

The effects of partial opiate agonists on plasma prolactin and growth hormone levels in the rat.

Opiate agonists, partial agonists, and antagonists differed in their effects on release of prolactin and growth hormone. Agonists (morphine, methadone or meperidine) elevated plasma levels of both hormones. An antagonist (naloxone) lowered levels of prolactin but not growth hormone. All partial agonists studied raised growth hormone levels; among these, levallorphan, nalorphine, and ciramadol lowered prolactin levels while pentazocine and meptazinol did not. Naloxone blocked morphine-induced release of prolactin and growth hormone. The partial agonists suppressed morphine-induced prolactin release, and several suppressed the elevated growth hormone levels as well. Data from the opiate radioreceptor assay (displacement of ³H-naloxone) in the presence and absence of sodium agrees with the above placement of agents into three classes. These results suggest that classification of opioid compounds into agonists, partial agonists and antagonists may be made by their effects on prolactin and growth hormone release.     

Analysis of androgen action on pituitary gonadotropin and prolactin secretion in ewes

To study the role of androgens in the control of gonadotropin and prolactin secretion in ther ewe, we have characterized androgen receptors in pituitary cytosol, and investigated the effect of androgens on pituitary hormone release in vivo and in vitro. High affinity, low capacity receptors, with an affinity for methyltrienolone (R1881) greater than 5 alpha-dihydrotestosterone (5 alpha-DHT) greater than testosterone (T) much greater than androstenedione (A4), estradiol-17 beta (E2) and progesterone (P), were identified in pituitary cytosol. Addition of 1 nM 5 alpha-DHT, but not A4, inhibited luteinizing hormone (LH) release from pituitary cells in vitro, induced by 10(10) to 10(-7) M luteinizing hormone releasing hormone (LHRH). The release of follicle-stimulating hormone (FSH) with 10(-9) M LHRH was inhibited when cells were incubated with 1 nM 5 alpha-DHT. 5 alpha-DHT had no effect when higher or lower doses of LHRH were used. In ovariectomized ewes, neither an i.v. injection of 1 mg, nor intracarotid injections of up to 1 mg, 5 alpha-DHT affected plasma LH, FSH or prolactin levels, despite dose-related increases in plasma 5 alpha-DHT levels. Daily or twice daily i.m. injections of 5 mg 5 alpha-DHT in oil did not affect LH or FSH levels, but daily injections of 20 mg significantly reduced plasma LH levels within 4 days and plasma FSH levels within 6 days. Thus, despite the presence of androgen receptors in the ewe pituitary, we conclude that androgens per se are of minimal importance in the regulation of pituitary LH, FSH and prolactin secretion in the ewe. The low binding affinity of A4 and the lack of its effect on hormone secretion in vitro suggests that A4 may act as an estrogen precursor rather than an androgenic hormone. The function of the pituitary androgen receptor remains to be established.     

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.     

Prolactin enhances production of interferon-gamma,interleukin-12, and interleukin-10, but not of tumor necrosis factor-alpha,in a stimulus-specific manner

Prolactin, an anterior pituitary hormone, has been shown to have a role in immunomodulation. Some reports have shown the importance of prolactin in activating lymphocytes and macrophages, while in hyperprolactinemia patients, prolactin was found to decrease lymphocyte activation and natural killer function. In the present work, at physiological (15ng/ml) and stress-induced levels (30ng/ml) of prolactin, interferon-gamma (IFN-gamma) and interleukin (IL)-12 p70 levels, but not of IL-10 and tumor necrosis factor-alpha (TNF-alpha), increased significantly (p<0.05-0.006) in phytohemeagglutinin (PHA)+lipopolysaccharide (LPS)-stimulated whole blood. However, no such effect was observed at high concentrations of prolactin (100-300ng/ml). In addition, 15ng/ml of prolactin reversed hydrocortisone suppressive effect on IFN-gamma, IL-12 p70, and IL-10 production in PHA+LPS-stimulated whole blood. On the other hand, in LPS-stimulated whole blood, prolactin enhanced significantly (p=0.027) the production levels of IL-10, but not of IFN-gamma, IL-12 p70, and TNF-alpha, in non-concentration-dependent manner. These results suggest that prolactin modulates cytokine response during antigenic response, and this modulation is stimulus specific.     

Prostacyclin (PGI2) effets on anterior pituitary hormones in the rat in vivo

Intravenous injection of 600 μg PGE₂ or PGI₂ significantly increased serum LH and prolactin levels in estradiol treated ovariectomized rats. There was no effect on serum FSH concentration. PGE₂ and PGI₂ stimulated LH release in a non-dose dependent manner, while prolactin levels were positively correlated with the dose administered following PGI₂ treatment. 6-keto-PGF_1α at a comparable dose had no effect on pituitary hormone levels. Subcutaneous administration of 1 mg/kg or 60 mg/kg PGI₂ for seven days significantly depressed serum LH level both in male and female rats. These doses had no effect on serum FSH or prolactin levels.     

The effect of d-fenfluramine on anterior pituitary hormone release in the rat: in vivo and in vitro studies

Administration of d-fenfluramine, a serotonin-releasing drug, to male rats induced a dose-dependent increase in both serum prolactin and corticosterone concentrations. Serum growth hormone levels increased, but not significantly, at a dose of 1.25 mg/kg i.p. and decreased significantly at higher doses. When rats were pretreated with the serotonin uptake inhibitor fluoxetine (10 mg/kg i.p.) 30 min prior to injection of d-fenfluramine (5 mg/kg i.p.), the serum prolactin response to d-fenfluramine was partially inhibited, whereas the growth hormone response was not significantly modified. Fluoxetine pretreatment increased the serum corticosterone to the same level as did d-fenfluramine. d-Fenfluramine's effect on prolactin and growth hormone release was further tested in a hypothalamic-pituitary in vitro system. The addition of d-fenfluramine (5-500 ng/mL) for 30 min to rat hypothalami resulted in an enhancement of prolactin and growth hormone-releasing activities. These were expressed as the ability of the media in which the hypothalami had been incubated to stimulate prolactin and growth hormone release by cultured pituitary cells. The data suggest that the effect of d-fenfluramine on prolactin secretion is exerted through the hypothalamus and is probably mediated, at least partially, by a serotoninergic mechanism. The mechanism of d-fenfluramine's effect on corticosterone and growth hormone release needs further evaluation.     

Stress response patterns of plasma corticosterone, prolactin, and growth hormone in the rat, following handling or exposure to novel environment.

Corticosterone, prolactin, and growth hormone responses to 5 s of handling or 3 min of novel environment were compared in rats at crest and trough of the diurnal adrenal rhythm 0, 5, 15, 30, and 60 min after stimulation. All hormones responded to stimulation, corticosterone and prolactin with a dramatic rise, and growth hormone with a precipitous fall. Resting corticosterone levels evidenced the expected diurnal variation, and prolactin but not growth hormone also showed a baseline diurnal variation of small magnitude at the times studied. Growth hormone response characteristics were unaffected by time of day or type of stimulation. Both corticosterone and prolactin response profiles differed at both times of day and following both types of stimulation. Corticosterone and prolactin levels were highly correlated and each was negatively correlated with growth hormone levels. This study confirms that hormone responses to stress are complex and depend not only on the stimulus but the context of stimulation.     

The glycopeptide moiety of vasopressin-neurophysin precursor is neurohypophysial prolactin releasing factor

All of the classically-described hypothalamic, hypophysiotropic factors that regulate anterior pituitary hormone secretion have now been isolated and identified except for prolactin releasing factor. We report here that the 39-amino acid glycopeptide comprising the carboxyterminus of the neurohypophysial vasopressin-neurophysin precursor stimulates prolactin release from cultured pituitary cells as potently as does thyrotropin releasing hormone but has no effect on the secretion of other pituitary hormones. Furthermore, antisera to the glycopeptide administered to lactating rats attenuated suckling-induced prolactin secretion. Thus, this glycopeptide appears to be the neurohypophysial prolactin releasing factor.