Decreased Serum Prolactin Levels Research Articles

Hyperprolactinemia: Long-term effects of bromocriptine

Patients with hyperprolactinemia may be managed by pituitary surgery or irradiation, bromocriptine treatment, or a combination of these methods, and some patients remain untreated. Little is known of the long-term consequences of some of these therapeutic regimens. Forty-six hyperprolactinemic patients (40 female and six male) managed solely with bromocriptine or no treatment over a period of 12 months to six years were therefore evaluated in this study. Nine patients with radiologically normal pituitary fossae were untreated and 10 received bromocriptine, 7.5 to 10 mg daily, while 20 patients with radiologic evidence of a pituitary tumor were treated with bromocriptine, generally 10 to 20 mg daily. Patients were assessed clinically, biochemically, and radiologically before treatment and at least six weeks after discontinuation of therapy. A further seven patients were similarly assessed before and after eight bromocriptine-induced pregnancies. Symptoms persisted in the untreated group of nine patients, although menstruation returned in four of the females with previous amenorrhea; serum prolactin levels remained elevated, other pituitary function did not change, and pituitary fossae remained normal radiologically. In all patients treated with bromocriptine, symptoms improved irrespective of radiologic findings on the pituitary, and were abolished in 67 percent during treatment associated with a decrease in serum prolactin levels in all, and a return of levels to within normal limits in 80 percent of patients. Persistent side effects were usually dose-related, but remained troublesome in 13 percent. Bromocriptine-irtduced tumor regression was evident radiologically in all patients with suprasellar tumor tissue and in some with purely intrasellar adenomas. This effect occurred rapidly and persisted or increased throughout follow-up. On discontinuation of treatment, prolactin levels remained significantly lower than before therapy (mean 2,934 versus 5,052 mU/liter, p < 0.05) but were within the normal range in only two patients. Other pituitary function was unaltered, or improved in some patients with definite tumors. Bromocriptine-induced pregnancy produced no permanent change in clinical, biochemical, or radiologic status. Long-term bromocriptine treatment for hyperprolactinemia is thus highly effective in alleviating symptoms and suppressing prolactin secretion, and induces persistent tumor regression on treatment without deterioration of other pituitary function in patients with macroadenomas. On discontinuation of therapy, however, hyperprolactinemia usually recurs, and treatment may therefore need to be continued for years.

Inhibition of growth of a prolactin-secreting pituitary tumor in rats by analogs of luteinizing hormone-releasing hormone and somatostatin.

We investigated the effects of [D-Trp6]LH-RH [agonistic analog of luteinizing hormone-releasing hormone (LH-RH)], N-Ac-[D-p-Cl-Phe1,2,D-Trp3,D-Phe6,D-Ala10]LH-RH (antagonistic analog), and [D-5-methoxy-Trp8]somatostatin (somatostatin analog) on the growth of the prolactin and corticotropin-secreting pituitary tumor 7315a in female Buffalo rats. Chronic administration of [D-Trp6]LH-RH in a dose of 25 micrograms/day, starting 18 days after inoculation with the tumor, inhibited the growth of the pituitary tumor. Tumor weight and volume also were reduced when this agonist was administered 3 days after inoculation. The antagonistic LH-RH analog, injected in a dose of 50-100 micrograms for 14-24 days, also significantly inhibited the growth of pituitary tumor. Chronic administration of the somatostatin analog in a dose of 25 micrograms twice a day likewise decreased tumor weights in comparison with controls. The inhibition of pituitary tumor growth by LH-RH agonist, LH-RH antagonist, and somatostatin analog was accompanied by a decrease in serum prolactin levels. It was concluded that LH-RH agonist, LH-RH antagonist, and somatostatin analog can inhibit the growth of estrogen-dependent prolactin/corticotropin-secreting pituitary tumor in rats.

GABA-related enzymes in the hypothalamus of rats treated with estradiol

The possibility that the activity of GABA-related enzymes in the hypothalamus, glutamic acid decarboxylase (GAD) and GABA-transaminase (GABA-T), may be modified by circulating prolactin levels was investigated in castrated female and male rats. Estradiol benzoate was chosen to induce an increase, while bromergocriptine was used to obtain a decrease of serum prolactin levels. Acute treatment with estradiol benzoate brought about 3 h later, a significant increase of serum prolactin, and a slight, non-significant increase of GAD activity in the hypothalamus. Chronic treatment with estradiol benzoate for 12 days induced significant increases in serum prolactin and GAD activity in the hypothalamus. Bromergocriptine significantly blocked this increase of GAD activity. Bromergocriptine-treated rats had significant increases of GABA-T activity in the hypothalamus. The results of this investigation support the possibility of the existence of a relationship between GABA-related enzymes in the hypothalamus and circulating prolactin levels.

Effect of Suloctidil on dopaminergic transmission in various rat brain areas: Possible uses as drug for the elderly

Suloctidil is a drug used in the elderly endowed with a mechanism of action at neuronal level which has not been completely explored. The results of the present study indicate that acute treatment with suloctidil induces a decrease of serum prolactin levels and a decrease of 3,4-diidroxyphenylacetic acid concentrations in various rat brain areas. In addition, the repeated injection of small Suloctidil doses produces a down-regulation of dopaminergic receptors. These data suggest that Suloctidil has dopamino-mimetic properties in vivo. This pharmacological activity may be of importance in the clinical action of Suloctidil in the elderly.

Hypoprolactinemic Action of Calcitonin and the Tuberoinfundibular Dopaminergic System

The effects of calcitonin on neurochemical parameters related to the tuberoinfundibular dopaminergic system have been investigated in an attempt to elucidate how calcitonin decreases serum prolactin levels. Intracerebroventricular human or salmon calcitonin injection decreases serum prolactin, medial basal hypothalamic dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) and hypophysial DA and increases hypophysial DOPAC. Results suggest that calcitonin may decrease prolactin secretion via the tuberoinfundibular dopaminergic system.

Possible DA agonist properties of naloxone.

Naloxone is widely if not universally considered to be a pharmacologically 'pure' opiate (mu) receptor antagonist virtually devoid of agonist action when administered in moderate dosages. However, naloxone (NX) appears to possess a striking number of DA agonist properties. Thus, some investigators have found NX capable of inducing stereotyped rearing and locomotor activity in habituated rats (a controversial finding), and decrease serum prolactin levels, improve Parkinsonism, enhance copulatory performance in sexually sluggish animals, and increase striatal HVA levels, in mimicry of centrally acting DA agonists. NX can also significantly potentiate the central effects induced by DA agonists including DA agonist (d-amphetamine) induced 3H-dopamine release, and antagonize a number of the central effects elicited by DA release inhibiting agents. Finally, virtually all of the central effects of morphine reversible by NX have also been found to be antagonized by a variety of dopamine agonists; while DA release inhibiting agents can abolish the ability of NX to antagonize morphine induced effects. Thus, NX may be exerting its central effects through a dopaminergic mechanism. Since NX does not bind DA receptors, it is quite likely that NX may ultimately antagonize the central effects of morphine by enhancing DA release from DA terminals upon which opiate receptors are localized. The same opiate receptors, shown to be localized on DA nerve terminals, have already been implicated in opiate mediated modulation of DA release.

Mechanism of prolactin release by 5-hydroxytryptophan

Male Wistar rats were intraperitoneally administered 300 mg/kg b.w. of α-methyl-p-tyrosine methyl ester(α-MT). These α-MT pretreated rats were anesthetized with urethane and then 5% glucose or dopamine (1 μg/kg b.w./min) was infused for 45 min. At 1 min before or 15 min after dopamine infusion, 10 or 50 mg/kg of 5-hydroxytryptophan (5-HTP) was injected intraperitoneally, and blood samples were taken from the jugular vein for prolactin determination. In rats treated with α-MT, the administration of 5-HTP increases the serum prolactin level in a dose-related manner. Dopamine infusion caused a marked decrease in serum prolactin level. The concomitant administration of dopamine and 5-HTP prevented the dopamine-induced decrease of serum prolactin in α-MT treated rats. These results indicate that the serotonergic stimulus enhanced prolactin release, not by inhibiting the dopaminergic activity, but by stimulating a prolactin-releasing factor or by activating other neurotransmitter systems.

Interactions of cocaine and Δ9-tetrahydrocannabinol with the hypothalamic-hypophysial axis of the female rat

The acute effects of cocaine and/or delta 9-tetrahydrocannabinol (THC) were studied in ovariectomized female rats. Intermediate doses of cocaine (10 or 20 mg/kg) caused an increase in serum luteinizing hormone (LH) and a decrease in serum prolactin levels, whereas a higher dose (40 mg/kg) caused a decrease in serum LH. THC (10 mg/kg) attenuated serum LH and prolactin levels. The THC effect on LH was blocked by cocaine. Neither drug alone or in combination affected serum follicle-stimulating hormone levels. The cocaine-induced changes in LH levels were closely paralleled by changes in hypothalamic norepinephrine content, suggesting a neurochemical basis for cocaine's action on LH release.

Interaction of morphine with the cholinergic system on prolactin release.

AbstractThe effects of morphine, pilocarpine, and two anticholinergic drugs on serum prolactin (PRL) levels were studied in unanesthetized male rats, each previously implanted with an atrial cannula for collection of blood for radioimmunoassay. Morphine induced a threefold increase in serum PRL levels, whereas pilocarpine, a cholinergic agonist, significantly decreased serum PRL levels. When given together, the two drugs partially counteracted each other's effects on PRL release. Atropine, an anticholinergic drug, had no effect on serum PRL levels when injected alone, but when given together with morphine, significantly enhanced morphine induced PRL release. This enhancing effect of muscarinic blockade on morphine induced PRL release was confirmed in a second experiment by using scopolamine, another anticholinergic drug. These results suggest that the stimulating effect of morphine on PRL release may be mediated in part by a decreased activity in the central cholinergic system.

Studies of the neural mechanisms by which hypothyroidism decreases prolactin secretion in the rat

These studies report that chronic hypothyroidism in the rat is accompanied by decreased serum prolactin. An investigation of those mechanisms by which hypothyroidism decreases prolactin secretion revealed the following findings: (1) activation of tyrosine hydroxylase in the median eminence (ME) and increase in the turnover-rate of dopamine (DA) in the ME; (2) a decreased content and in vitro release of prolactin by pituitaries from hypothyroid rats; (3) decreased [ 3H]spiroperidol binding to pituitary homogenates obtained from hypothyroid rats, and (4) normal increase of serum prolactin following administration of haloperidol. Comparison of the effects of hypothyroidism on dopaminergic terminals of the striatum with those of the ME was made and the following tentative conclusions proposed. Hypothyroidism presumably increases the release of DA into the pituitary portal system. A deficiency of thyroid hormone desensitizes the pituitary lactrotrope to inhibition by DA, decreases the total pituitary prolactin content and presumably also reduces the peripheral catabolism of prolactin. The overall net effect of hypothyroidism is therefore, a decrease in serum prolactin levels which can increase normally following haloperidol. The mechanism by which a deficiency of thyroid hormone alters the function of the tuberoinfundibular and striatal dopaminergic systems is unknown.

Endocrine profile and therapeutic employment of a new prolactin-lowering drug, metergoline.

Metergoline is an ergoline derivative with potent peripheral and central antiserotoninergic properties which has recently been shown to possess a marked prolactin (PRL)-lowering activity. This drug significantly decreases serum PRL levels after acute administration in normal subjects, in puerperal women, and in most hyperprolactinemic patients with or without pituitary tumor. Its PRL-lowering effect is unaffected by pimozide pretreatment in healthy subjects, and is frequently dissociated from that of bromocriptine in hyperprolactinemic patients. The drug does not affect the secretion of growth hormone (GH), thyrotropin and gonadotropins, while it blunts the corticotropin response to centrally but not peripherally-acting stimuli in normal subjects. In acromegalics, metergoline reduces serum PRL as well as GH levels, both actions being prevented by pimozide pretreatment. Improvement in oral glucose tolerance with unchanged insulin secretion is observed after a short course of metergoline treatment in patients with chemical diabetes. The PRL-lowering action of the drug is sustained during chronic treatment in hyperprolactinemic subjects. Inhibition of puerperal lactation may be obtained by a few days metergoline treatment in almost all treated women. Normalization of serum PRL levels and restoration of cyclic ovarian function are achieved within 1–4 months of treatment with the drug in most women with hyperprolactinemic amenorrhea. The possible role of metergoline in the treatment of other endocrine disorders such as normoprolactinemic amenorrhea, sexual impotence, Cushing&#8217;s disease, acromegaly and mild diabetes mellitus remains to be determined. Although the PRL-lowering effect and the therapeutic employment of metergoline

Glucocorticoid modulation of casein gene transcription in mouse mammary gland.

The influence of cortisol and prolactin on casein gene expression in the mammary gland of lactating BALB/c mice was measured by using a specific cDNA probe to 15S casein mRNA (cDNAcsn). Casein mRNA (mRNAcsn) level in the mammary gland was decreased by 85% 5 days after adrenal ablation, but then was increased 4.4-fold 12 hr after a single injection of hydrocortisone-21-acetate. An 80% decrease in serum prolactin level, induced by the prolactin inhibitor 2-bromo-alpha-ergocryptin (CB-154), did not alter the level of mRNAcsn in the gland. Specific transcription of the casein gene in nuclei isolated from lactating mammary glands was measured by cDNAcsn hybridization to the in vitro synthesized Hg-CTP-containing RNA (Hg-RNA), which was purified by SH-agarose chromatography. The level of the mRNAcsn in Hg-RNA synthesized in the isolated nuclei was 0.09% and this was decreased 85% by alpha-amanitin, indicating that the mRNAcsn sequences in the Hg-RNA were the products of RNA polymerase II-directed DNA-dependent RNA synthesis. Transcription of the mRNAcsn in isolated nuclei was decreased by 70% 5 days after adrenalectomy and a single injection of the glucocorticoid then increased the transcription level 2-fold at 6 hr. Essentially no alteration of the level of transcription was detectable in mammary nuclei isolated from lactating mice with 80% decreased serum prolactin level, induced by CB-154 treatment. The results thus demonstrate a glucocorticoid involvement on the modulation of casein gene expression at the transcriptional level of control.

Tyrosine administration decreases serum prolactin levels in chronically reserpinized rats

The injection of tyrosine, 200 mg/kg, decreased serum prolactin levels and elevated hypothalamic (and striatal) concentrations of two dopamine metabolites, dihydroxyphenylacetic acid and homovanillic acid, in chronically reserpinized rats. Tyrosine administration had none of these effects in otherwise untreated rats, and did not block the increase in serum prolactin that occurred 4 hours after a single injection of reserpine. As anticipated, the injection of dopa decreased serum prolactin in all rats. Valine, another large neutral amino acid, did not modify serum prolactin in chronically reserpinized animals. Since prolactin secretion is normally inhibited by dopamine released from the hypothalamus, reserpine treatment probably elevates serum prolactin by depleting the hypothalamus of dopamine. Our data suggest that tyrosine injection suppresses serum prolactin levels in chronically reserpinized rats by enhancing the synthesis and release of hypothalamic dopamine. Thus, administration of tyrosine, dopamine's dietary precursor, can alter physiologic functions that depend on dopamine.

Influence of bromoergocryptine on estrogen-modulated prolactin receptors of mouse mammary gland

Modulation of specific binding of prolactin to murine mammary gland as a response to treatment with various doses of estradiol benzoate (EB) was studied. Measurements of serum and pituitary levels of prolactin were also carried out simultaneously. Estradiol benzoate at a dose of 5 μg significantly increased the binding of 125I-labelled rat prolactin (rPRL) to mammary gland concomitant with increased serum prolactin levels in ovariectomized mice. Administration of bromoergocryptine along with EB resulted in decreased serum prolactin levels as well as binding of prolactin to breast tissue. It thus appears that the influence of estradiol on binding of prolactin to mammary gland is mediated primarily via its property of enhancing serum prolactin concentration apart from its possible direct effect at the target tissue level.

Adrenal involvement in the timing of puberty in female rats: interaction with serum prolactin levels.

ABSTRACT Female Sprague-Dawley derived rats were either sham-operated or adrenalectomized at 20 days of age. Treatment of separate groups of rats with progesterone, corticosterone or prolactin was started at 21 days of age, and was continued until the day of vaginal opening. Similarly treated rats were decapitated at 25, 29 and 33 days of age and at the day of vaginal opening and the sera were collected from each animal and assayed for prolactin, LH and FSH. All rats were decapitated between 4–6 p. m. Adrenalectomy, as previously reported, significantly delayed the day of vaginal opening. Prolactin treatment advanced the day of vaginal opening in intact rats and it restored the day of vaginal opening in adrenalectomized rats to that of intact control rats. Progesterone treatment always delayed the day of vaginal opening in intact rats. It caused an even greater delay in vaginal opening than adrenalectomy alone. Corticosterone treatment, on the other hand, was able to reverse the effect of adrenalectomy but had no effect on vaginal opening in intact rats. In intact rats serum prolactin levels rose steadily until the day of vaginal opening. Adrenalectomized and intact rats treated with progesterone had significantly decreased serum prolactin levels. However, in adrenalectomized corticosterone treated rats serum prolactin levels were significantly increased at all ages measured when compared to the untreated rats. The FSH and LH levels showed no significant changes during any of these experimental procedures. Approximately 50 % of the rats showed LH peaks on the day of vaginal opening as well as an increase in FSH. The data indicate a prolactin-adrenal interaction for the timing of the onset of puberty in immature rats, assuming that the day of vaginal opening in association with increased gonadotrophin levels is an indicator for the occurrence of puberty.

Inhibition of prolactin secretion by a direct effect of methysergide on the pituitary lactotrophs in the rat

Methysergide administered i.p. caused a dose dependent decrease of serum prolactin levels in rats of both sexes bearing large bilateral electrolytic lesions in the median eminence. This prolactin release inhibiting action of methysergide was prevented by pretreatment of the animals with dopamine receptor blockers pimozide or spiroperidol, which by themselves had no effect on serum prolactin levels. Similar results were observed when the dopamine receptor agonist piribedil was used instead of methysergide. It is concluded that methysergide is capable of inhibiting prolactin secretion by activation of dopamine receptors of the pituitary lactotrophs.

The psychobiology of premenstrual dysphoria: The role of prolactin

(1) The evidence for a role of prolactin in the premenstrual syndrome is discussed in this review. (2) The timing of the onset and offset of both physical and psychological dysphoric symptoms corresponds with the luteal elevation and menstrual decrease of serum prolactin levels. (3) Women with premenstrual symptoms have been shown to have high prolactin levels throughout the menstrual cycle and especially in the premenstruum. (4) Suppression of prolactin secretion with bromocriptine is reported to be effective in preventing both physical and psychological premenstrual symptoms. (5) The mode of action of bromocriptine requires further study to exclude possible direct central nervous system effects of the drug, independent of its prolactin-suppressing action. (6) Indirect evidence for a role of prolactin in the premenstrual syndrome comes from (a) the actions of prolactin in causing renal retention of water, sodium and potassium; (b) the interactions of prolactin with lithium (which is reported to relieve premenstrual symptoms in some patients); some of the other reported treatments also may suppress prolactin secretion or antagonize its peripheral effects. (7) Prolactin may interact with the ovarian hormones to cause specific types of dysphoric symptoms. High prolactin levels associated with low estrogen levels may cause depressive symptoms. High prolactin levels associated with low progesterone levels may cause symptoms of anxiety or irritable hostility. (8) Interactions of prolactin with the ovarian hormones may also help to account for some related clinical states—mid-cycle mood elevations, elation in late pregnancy, postpartum depression and dysphoric menopausal symptoms.

L-3,4-dihydroxyphenylalanine (L-dopa) as an inhibitor of prolactin release.

A series of experiments was performed on estrogen/progesterone-treated, ovariectomized rats to determine the site of the inhibitory effect of L-3,4- dihydroxyphenylalanine (L-dopa) on prolactin release. After intraarterial injection of L-[3H]dopa (150 μCi), [3H]norepinephrine ([3H]NE), [3H]dopamine ([3H]DA), and L-[3H]dopa were found in the hypothalamus and anterior pituitary. Intra-arterial injection of L-dopa (2, 5, or 10 mg/kg) produced a dose-related inhibition of prolactin release. The magnitude and the duration of inhibition of prolactin release were greater with increasing doses of L-dopa. Hypothalamic concentrations of endogenous DA were significantly increased 30 min after L-dopa (10 mg/kg) and were correlated with decreased serum prolactin levels at this time. Hypothalamic NE content was not affected. L-α-Methyldopa hydrazine, 20 mg/kg (Mk 486), a peripheral aromatic L-amino acid decarboxylase inhibitor, injected 30 min before L-[3H]dopa injection, increased the concentration of L-[3H]dopa in th...

Effect of Bromoergocriptine on TRH-Induced Growth Hormone and Prolactin Release in Acromegalic Patients

In an attempt to evaluate the dynamics of growth hormone (GH) and prolactin secretion in acromegalic patients, the response of serum GH as well as prolactin to 2-bromo-alpha-ergocriptine (CB154) alone or to CB154 combined with thyrotropin-releasing hormone (TRH) was studied in 8 subjects with this disease. Oral administration of CB154 unequivocally decreased serum prolactin levels in all of the 8 patients, while GH-inhibitory action of the drug was observed only in 6 subjects who responded to TRH with secretion of GH. The response of serum GH to TRH was not qualitatively and quantitatively altered by the treatment of patients with CB154 in a daily dose of 5 mg for two weeks. This treatment, on the other hand, remarkably suppressed basal levels of prolactin and completely blocked TRH-induced prolactin release in all of the subjects. The results suggest that there exists a dissociation between GH and prolactin responses to CB154 in acromegalic patients, and that CB154 and TRH may not share a common site of action on GH release in this pathologic state.

Isolation of Gamma-Amino Butyric Acid from Pig Hypothalami and Demonstration of its Prolactin Release-Inhibiting (PIF) Activityin VivoandinVitro*

A non-retarded fraction with prolactin-release inhibiting factor (PIF) activity obtained by chromatography of a concentrate of porcine hypothalami on carboxymethyl-cellulose was chromatographically distinct from catecholamines. This fraction was purified further by six steps involving chromatography on Sephadex G-25, countercurrent distribution, free-flow electrophoresis, and chromatography on triethylaminoethyl cellulose. The PIF-active substance was isolated and identified as gamma-amino-butyric acid (GABA) by: 1) amino acid analyses using sodium as well as lithium-based buffers for resolution of biological fluids, 2) thin-layer chromatography of underivatized material as well as phenylthiocarbamyl derivatives, and 3) mass spectroscopy. Natural and synthetic GABA inhibited prolactin, but not LH release in vitro from isolated rat pituitary halves at doses as low as 0.1 microgram/ml. The inhibition was proportional to the dose; natural and synthetic GABA possessed identical PIF activity. Synthetic GABA also decreased prolactin release in monolayer cultures of rat pituitary cells and inhibited TRH-stimulated prolactin release. The inhibition of prolactin release in vitro by GABA could not be blocked by perphenazine, which inhibits PIF activity of catecholamines. GABA also suppressed prolactin release in vivo, although large doses were needed. Either rapid iv injection or infusion of GABA in doses of 1 to 100 mg in rats significantly decreased serum prolactin levels, which were previously elevated by pretreatment with monoiodotyrosine perphenazine, chlorpromazine, haloperidol, or sulpiride. beta-hydroxy GABA significantly depressed prolactin release, but beta-(p-chlorophenyl)-GABA (Lioresal, CIBA) and 4 other analogs of GABA were not effective in vivo and/or in vitro. The results indicate that GABA can inhibit prolactin release by a direct action on the pituitary gland, but whether this effect is physiologically meaningful still remains to be determined.