Acute administration of bromocriptine abolishes the hyperprolactinemic response induced by submaximal exercise in man.

The effective control of hypophysial prolactin (PRL) secretion with a pharmacological agent is a prerequisite for the investigation of the role of hyperprolactinemia observed during exercise. Using bromocriptine, a potent inhibitor of PRL secretion, this study established the proper experimental conditions whereby any significant increase in plasma PRL level can be prevented and basal circulating levels maintained during physical exercise. On three occasions at weekly intervals, 15 male adults, separated into two groups, exercised on an ergocycle (40 min at 65% VO2max) either 1 or 3 h after ingesting either placebo or 1.25 or 2.50 mg of bromocriptine mesylate (Parlodel; Sandoz Canada Inc., Dorval, Qué.). Under all conditions, the plasma PRL elevation observed during exercise after placebo was prevented by the administration of bromocriptine. Resting plasma PRL levels were maintained when exercise was performed 1 h after bromocriptine ingestion, but were significantly reduced when exercise was performed 3 h after administration of either bromocriptine dosages. Considering the primary and secondary effects observed, 1.25 mg of bromocriptine administered 1 h before exercise provides suitable experimental conditions to investigate the role of the increase in plasma PRL during physical exercise.     

Metergoline in the inhibition of puerperal lactation.

Seventy-eight mothers who did not want to breast-feed their newborn infants took part in a trial to assess whether metergoline could effectively suppress puerperal lactation. Metergoline 8 mg/day was given to 69 women within 24 hours after delivery and continued for five days to prevent lactation. The remaining nine women were given a course of metergoline once lactation had started. The drug was effective in both preventing and suppressing lactation. Milk secretion, engorgement, and pain were significantly reduced in women taking metergoline. Metergoline has a similar effect to bromocriptine in suppressing lactation, but its mechanism of action remains unknown.     

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 prolactin on the luteinizing hormone response to gonadotropin- releasing hormone in primary pituitary cell cultures during the ovine annual reproductive cycle

In the sheep pituitary, the localization of prolactin (PRL) receptors in gonadotrophs and the existence of gonadotroph-lactotroph associations have provided morphological evidence for possible direct effects of PRL on gonadotropin secretion. Here, we investigated whether PRL can readily modify the LH response to GnRH throughout the ovine annual reproductive cycle. Cell populations were obtained from sheep pituitaries during the breeding season (BS) and the nonbreeding season (NBS), plated to monolayer cultures for 7 days, and assigned to receive one of the following treatments: 1) nil (control), 2) acute (90- min) bromocriptine (ABr), 3) chronic (7-day) bromocriptine (CBr), 4) ABr and PRL, 5) CBr and PRL, 6) PRL alone, or 7) thyrotropin-releasing hormone. Cells were treated as described above, with the aim of decreasing or increasing the concentrations of PRL in the culture, and simultaneously treated with GnRH for 90 min. The LH concentrations in the medium were then determined by RIA. GnRH stimulated LH in a dose-dependent manner during both stages of the annual reproductive cycle. During the NBS, single treatments did not significantly affect the LH response to GnRH. However, when PRL was combined with bromocriptine, either acutely or chronically, GnRH failed to stimulate LH release at all doses tested (P < 0.01). In contrast, during the BS, the LH response to GnRH was not affected by any of the experimental treatments. These results reveal no apparent effects of PRL alone, but an interaction between PRL and dopamine in the regulation of LH secretion within the pituitary gland, and a seasonal modulation of this mechanism.     

Interactions of steroids with prolactin secretion in vitro

Estrogens prevent or diminish the sensitivity to dopamine of prolactin (PRL) secretion by cultured rat pituitary cells. Cultured tumor cells prepared from a transplantable rat PRL-secreting tumor were insensitive to dopamine and bromocriptine, while the anti-estrogen tamoxifen restored this sensitivity. Cultured normal human pituitary cells were shown to be more sensitive to dopamine, if they were preincubated with estradiol, while cultured human prolactinoma cells became insensitive to bromocriptine after they were exposed to estrogens. This sensitivity was restored, however, by tamoxifen. These results point to an important species difference between primates and rodents with regard to the normal regulation of PRL secretion.     

The effects of prostacyclin (PGI2) on prolactin secretion in vitro

Continuously superfused rat anterior pituitary cells were used to study the effects of exogenous prostaglandins (PGs) and thromboxanes (TXs) on the secretion of prolactin (PRL). No change in hormone release was observed upon superfusion with TXB2 (10(-5)M) or the TX synthesis inhibitor, imidazole (1.5 mM). PGs A2, B2, D2, E1, E2, F1 alpha, F2 alpha, and endoperoxide analogs, U-44069 and U-46619, also had no effect on PRL secretion (all at 10(-5)M). In contrast 10(-5)M PGI2 was repeatedly found to stimulate PRL release to a level at least 125% above control, while producing no apparent change in the amount of hormone secreted in response to TRH. Somatostatin (SRIF), at a dose of 10(-6)M, maximally inhibited TRH-induced PRL output, but failed to alter the PRL response to PGI2. These studies indicate that PGI2 may have a direct effect on the anterior pituitary to modify PRL secretion.     

Prolactin cycles in sheep under constant photoperiod: evidence that photorefractoriness develops within the pituitary gland independently of the prolactin output signal

The present study investigated photorefractoriness in the prolactin (PRL) axis in hypothalamopituitary-disconnected (HPD) sheep exposed to prolonged long days. In experiment 1, HPD Soay rams transferred from short (8L:16D) to long (16L:8D) days for 48 wk to induce a cycle of activation, decline (photorefractoriness), and reactivation in PRL secretion were treated chronically with bromocriptine (dopamine-receptor agonist) or vehicle from the onset of photorefractoriness. Bromocriptine (0.01-0.04 mg kg-1 day-1; 12-24 wk of long days) blocked PRL release and caused a rebound response after the treatment, but it had no effect on the long-term PRL cycle (posttreatment PRL minimum, mean +/- SEM, 35.3 +/- 0.6 and 37.0 +/- 0.4 wk for bromocriptine and control groups, respectively; not significant). In experiment 2, HPD rams were treated with sulpiride (dopamine-receptor antagonist) during photorefractoriness. Sulpiride (0.6 mg/kg twice daily; 22-30 wk of long days) induced a marginal increase in blood PRL concentrations, but again, it had no effect on the long-term PRL cycle (PRL minimum, 37.9 +/- 0.4 and 37.6 +/- 0.9 wk for sulpiride and control groups, respectively; not significant). The 24-h blood melatonin profile consistently reflected the long-day photoperiod throughout, and blood FSH concentrations were minimal, confirming the effectiveness of the HPD surgery. The results support the conclusion that photorefractoriness is regulated at the level of the pituitary gland independently of the PRL output signal.     

Fatty acid profiles in hepatic membranes of rats with different levels of circulating estrogen and prolactin

Plasma and liver microsomal fatty acid patterns of female rats (Rattus norvegicus) with either low or high serum levels of prolactin (PRL) were studied. Hyperprolactinemia was achieved by grafting anterior pituitary glands or by estradiol administration. One group treated with estradiol also received bromocriptine to inhibit PRL secretion. Ovariectomized (OVX) rats showed a decrease in PRL levels as compared with intact animals (controls). Rats possessing high levels of circulating PRL showed a significant decrease of linoleic acid in the fatty acid pattern of total and polar liver microsomal lipids. High PRL levels in the presence of normal estrogen levels significantly increased arachidonic acid in the same group of lipids. The group of rats treated with estrogen evidenced a decrease in arachidonic acid and in the unsaturation index. From these results it is possible to infer a decrease in the activity of the desaturases. The changes observed in the estradiol-treated group were not modified by bromocriptine administration. OVX rats showed no changes when compared with controls. It is concluded that, while PRL decreases the microsomal unsaturation index, estrogen administration causes a decrease in poly-unsaturated fatty acid biosynthesis and that this effect is independent of PRL levels.     

Abnormal dopamine sensitivity in some human prolactinomas

In most of human prolactin (PRL)-secreting adenomas, dopamine and dopamine agonists normally suppress the excessive PRL secretion. Nevertheless, a subpopulation of such patients presents a relative insensitivity to the ergot derivative bromocriptine. Six patients with a macroadenoma (n = 5) or microadenoma (n = 1) were considered resistant to bromocriptine which, at a daily dose of 15-60 mg, did not normalize high plasma PRL levels. Culture studies of these adenoma cells showed that: (1) 10(-8) M bromocriptine produced a 32 +/- 16% inhibition of PRL release versus 65 +/- 12% obtained in the same conditions with normal human pituitary cells; (2) sulpiride (10(-6) M) reversed the inhibitory effects of bromocriptine, and (3) the bacterial endotoxins, cholera toxin (10(-11) M) and pertussis toxin (250 ng/ml), respectively, produced a 45-500% increase and a total abolition of bromocriptine-induced PRL inhibition. These observations and recent data of the literature allow to discuss the possibility of receptor or postreceptor defects in such tumors.     

Management of borderline hyperprolactinemia

Progressively increasing plasma prolactin (PRL) concentrations are currently associated with menstrual disturbances, anovulation and cessation of cyclic activity. Galactorrhea-amenorrhea in the presence of normal plasma PRL is rare, but the favorable response to bromocriptine confirms its lactogen dependency. The concept of "transient hyperprolactinemia' is analyzed and alternative explanations for the positive results of dopamine agonist therapy in this particular condition are proposed. Moderate hyperprolactinemia can be associated with luteal inadequacy and infertility. Inhibition of PRL secretion with bromocriptine can normalize luteal function and restore the ability to conceive.     

Plasma luteinizing hormone and prolactin in normothermic and hyperthermic ovariectomized ewes

The effect of bromocriptine on concentrations of luteinizing hormone (LH) and prolactin (PRL) as well as the rhythmicity of episodic profiles of plasma LH were investigated in twelve ovariectomized ewes exposed to 3-day trials during which ambient temperature/humidity conditions maintained either normothermia or induced an average of 1.4°C increase of rectal temperature (hyperthermia). In 24 of 48 trials, ewes received twice daily subcutaneous injections of 1 mg bromocriptine beginning at 1900 hr on day 1. Plasma PRL and LH were measured at 10-min intervals for 4 hr on days 2 and 3. Bromocriptine significantly decreased plasma PRL (65 ± 6 vs 5 ± 1 ng/ml), mean plasma LH (11.0 ± 0.2 vs 6.5 ± 0.2 ng/ml) and tended (P < 0.1) to decrease LH rhythmicity. In hyperthermic placebo-treated ewes, plasma PRL was increased (65 ± 6 vs 212 ± 20 ng/ml) and mean LH was decreased (11.0 ± 0.2 vs 8.2 ± 0.2 vg/ml) compared to normothermic, placebo-treated ewes, but there was no effect of hyperthermia on LH rhythmicity. Bromocriptine treatment of hyperthermic ewes decreased mean PRL (212 ± 20 vs 32 ± 9 ng/ml) on both days of sampling although mean levels were significantly higher on day 2 than on day 3(54 ± 14 vs 10 ± 6 ng/ml). Perhaps because mean LH was already inhibited in hyperthermic ewes, bromocriptine did not further decrease mean LH (8.2 ± 0.2 vs 6.6 ± 0.2 ng/ml), but LH rhythmicity was decreased (P < 0.01). There was no significant difference in mean LH between normothermic ewes receiving bromocriptine and hyperthermic ewes receiving bromocriptine (6.5 ± 0.2 vs 6.6 ± 0.2 ng/ml). These results indicate that bromocriptine inhibits PRL and LH secretion in normothermic ewes. In hyperthermic ewes, the inhibitory effect of bromoriptine on PRL was even more pronounced, but the effect on LH release was minimal perhaps because LH was already inhibited by hyperthermia.     

The effects of prostacyclin PGI2 on prolactin secretion in vitro

Continuously superfused rat anterior pituitary cells were used to study the effects of exogenous prostaglandins (PGs) and thromboxanes (TXz) on the secretion of prolactin (PRL). No change in hormone release was observed upon superfusion with TXB₂ (10⁻⁵M) or the TX synthesis inhibitor, imidazole (1.5 mM). PGs A2, B2, d2, e1, e2, f1α, F2α, and endoperoxide analogs, U-44069 and U-46619, also had no effect on PRL secretion (all at 10⁻⁵M), In contrast 10⁻⁵M PGI2 was repeteadly found to stimulate PRL release to a level at least 125% above control, while producing no apparent change in the amount of hormone secreted in response to TRH. Somatostatin (SRIF), at a dose of 10⁻M, maximally inhibited TRH-induces PRL output, but failed to alter the PRL response to PGI₂. These studies indicate that PGI₂ may have a direct effect on the anterior pituitary to modify PRL secretion.     

Mixed pituitary tumours--effects of bromocriptine treatment: Parlodel MR and Parlodel LAR.

Majority of pituitary tumours secrete one of the named hormones: PRL, GH, ACTH, proopiomelanocortine, alpha and beta subunit of TSH, LH, and FSH. Some of those tumours secrete two or more hormones. The aim of this study was to determine the effect of bromocriptine (Parlodel MR and LAR) upon secretion of hormones and tumour size in 10 patients with mixed pituitary tumours. In all patients pituitary and peripheral hormones, CT scan and visual fields were examined before and after treatment with bromocriptine: Parlodel MR and LAR. Bromocriptine treatment decreased PRL secretion in all 10 patients; GH--in all 6 in whom it was increased; TSH--in 2, FSH--in 2 and alpha-subunit in all 6 in whom they were increased. In 5 patients treatment resulted in shrinkage of the tumour mass by 20 to 35%. In all examined subjects clinical improvement was achieved. Our results demonstrate that bromocriptine (Parlodel MR and LAR) is very effective and well tolerated in the treatment of patients with mixed pituitary tumours particularly those with hyperprolactinemia.     

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.     

Prepubertal exposure to compounds that increase prolactin secretion in the male rat: effects on the adult prostate

To test the hypothesis that a transient increase in prolactin (PRL) secretion prior to puberty can result in an alteration of the adult prostate, male rats were exposed from postnatal Days (PND) 22 to 32 to compounds that increase PRL secretion. These compounds included pimozide (a dopamine antagonist), estradiol-17beta, and bisphenol A (a monomer of polycarbonate plastics reported to have weak estrogenic activity). During dosing, pimozide (PIM), bisphenol A (BPA), and estradiol-17beta (E(2)) stimulated an increased secretion of PRL. At 120 days of age, the lateral prostate weight was increased in the PIM and BPA groups as compared to the vehicle-injected controls. Examination of the prostates revealed inflammation in the lateral lobes of all treated groups. Results of a myeloperoxidase assay, a quantitative assay to assess acute inflammation, indicated an increase in the percentage of males with neutrophil infiltrate in the lateral prostates of the PIM and E(2) treatment groups compared to their respective controls. The histological evaluations of these tissues confirmed an increase in luminal polymorphonuclear cells and interstitial mononuclear cells of the lateral prostates in all treatment groups. Administration of the dopamine agonist, bromocriptine, to the estradiol-implanted males from PND 22 to 32 reversed the induction of lateral prostate inflammation by estradiol, suggesting that PRL was necessary for the inflammatory effect. This study demonstrates that prepubertal exposures to compounds that increase PRL secretion, albeit through different mechanisms, can increase the incidence of lateral prostate inflammation in the adult.     

Differential effects of bromocriptine treatment on LH release and copulatory behavior in hyperprolactinemic male rats

Hyperprolactinemia (hyperPRL) induced by grafting four pituitary glands under the kidney capsule suppresses copulatory behavior in male rats and sexually naive male mice. In mice sexual experience attenuates the suppressive effects of hyperPRL on mating behavior, thus a comparison of the behavioral consequences of inducing hyperPRL in sexually naive and experienced male rats was undertaken. Hyperprolactinemia had a significant suppressive effect on mating behavior in both groups of animals. Experienced animals showed deficits in all parameters studied except mount frequency and postejaculatory interval, while naive animals differed from respective controls only in mount latency, intromission latency, and intromission frequency. To determine if the inhibition of chronically elevated prolactin (PRL) levels would reverse the suppression of gonadotropin secretion and copulatory behavior in hyperprolactinemic animals, the effects of bromocriptine (CB-154) administration on plasma hormone levels and mating behavior were examined in pituitary-grafted and control rats. Bromocriptine treatment (1 mg/day for 14 days) led to increases in sexual activity in both the sham-operated and grafted animals. In the grafted animals, plasma PRL was reduced and plasma LH significantly increased in the CB-154-treated animals when compared to oil-treated controls. In sham-operated animals, CB-154 produced no significant changes in plasma LH or FSH despite the suppressed PRL levels. These results indicate that (1) hyperPRL induced by pituitary grafts can cause deficits in mating behavior in male rats despite previous sexual experience, and (2) while CB-154 may be acting through other mechanisms to stimulate copulatory behavior, the reduction of chronically elevated PRL levels due to CB-154 treatment is responsible for reversal of the suppressive effects of hyperPRL on LH secretion.     

Prolactin levels in the western spotted skunk: changes during pre- and periimplantation and effects of melatonin and lesions to the anterior hypothalamus

Prolactin (PRL) is the primary pituitary hormone responsible for initiating increased function of the corpus luteum and blastocyst implantation in the western spotted skunk. Therefore, we have designed experiments to validate a PRL RIA, characterize the preimplantation profile in PRL secretion, and determine the effects of exogenous melatonin and lesions to the anterior hypothalamic area (AHA) on PRL secretion in the skunk. These objectives were investigated with a heterologous RIA using canine PRL standards and antiserum. Displacement curves of skunk pituitary extract and serum were parallel to the canine PRL standard curve. Growth hormone-releasing hormone injection did not cause a significant change in plasma PRL levels as detected by the assay (p = 0.74). Injection of pimozide increased and bromocriptine decreased plasma PRL levels (p less than 0.05). A seasonal trend in plasma PRL levels was observed during the preimplantation period, with mean concentrations ranging from 5 ng/ml during the period of short day length in January to 17.1 ng/ml during the long day photoperiod in early May. The average date of blastocyst implantation in this study was 2 May (n = 16). Silastic capsules containing melatonin (n = 5) significantly delayed both the seasonal rise in plasma PRL levels and the time of implantation (p less than 0.05) compared to controls with empty capsules (n = 4). Lesions to the AHA (AHAx, n = 5) eliminated these effects of melatonin on both the rise in PRL and time of implantation. PRL levels were highly correlated with progesterone levels (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term bromocriptine therapy and predictive tests in acromegaly

The value of predictive tests in bromocriptine therapy and the effects of long-term bromocriptine therapy were investigated in acromegalic patients. In 72 acromegalic patients, there was a tendency for patients with a plasma GH response to TRH or with an elevated basal plasma PRL level, but without a plasma GH response to LHRH, to have a plasma GH response to bromocriptine, though statistical analysis did not reveal a significant difference. Acute and chronic effects of bromocriptine were significantly interrelated, while the chronic effect of bromocriptine and abnormal plasma GH response to TRH or elevated plasma PRL levels were not, in 18 acromegalic patients. These results suggest that the acute bromocriptine test is a better predictor than the TRH test and plasma PRL levels for evaluating the effects of chronic bromocriptine therapy. To maintain the low plasma GH levels, increasing doses of bromocriptine were needed in most patients, and failure to control the elevated GH level despite increasing doses was observed in 2 of 18 patients.