Clinical response of patients with galactorrhea to pergolide,a potent,long-acting dopaminergic ergot derivative

Pergolide is an ergot derivative with dopaminergic activity and, like bromocriptine, can suppress prolactin release from the pituitary gland. In a single blind study pergolide was administered for 90 days to three females with idiopathic hyperprolactinemia manifested by galactorrhea and amenorrhea. Response to therapy was followed clinically and by determination of plasma prolactin concentrations. Pergolide lowered plasma prolactin concentrations and suppressed galactorrhea in all patients. Menstruation recurred in both patients with intact GU systems. Side effects were minor and tolerance developed to all but nasal stuffiness. Pergolide appears to be efficacious therapy for patients with amenorrhea/galactorrhea secondary to hyperprolactinemia.     

Effects of CB-154 (2-Br-alpha-ergocryptine) on prolactin and growth hormone release in an acromegalic patient with galactorrhea.

An acromegalic patient with galactorrhea was treated with an ergot alkaloid, 2-Br-alpha-ergocryptine (CB-154). Serum prolactin decreased rapidly to normal level by CB-154 and the complete cessation of galactorrhea was noted. The inhibitory effect of CB-154 On growth hormone (GH) release was also noted, but slight. The mechanism of inhibitory action of CB-154 on both prolactin and GH secretion was discussed in connection with the experimental model of pituitary tumors, in which both hormones were produced by a single type of tumor cells. The discontinuation of CB-154 treatment was associated with the return of both prolactin and GH levels to the initial high values with resumption of galactorrhea.     

Effect of dihydroergocryptine and dihydroergocristine on cyclic AMP accumulation and prolactin release in vitro: evidence for a dopaminomimetic action

Dihydroergocryptine and dihydroergocristine, two C-9, 10-hydrogenated ergot alkaloids, inhibited in a concentration-dependent manner prolactin release and cyclic AMP accumulation in cultured anterior pituitary cells. The inhibitory effect of dihydroergocryptine was more potent and started at lower concentrations than that of dihydroergocristine. Haloperidol and pimozide, two dopamine receptor antagonists, completely abolished the inhibitory activity of the ergot alkaloids. The involvement of the adenylate cyclase-cyclic AMP system in the inhibitory action of the two compounds was demonstrated by the antagonism by pertussis toxin of the reduction of both prolactin release and cyclic AMP accumulation produced by dihydroergocryptine and dihydroergocristine.     

Hyperprolactinemia in nonpregnant women due to pituitary tumors

The human prolactin molecule has been isolated and its structure characterized. This anterior pituitary hormone plays an important function in the induction and maintenance of lactation in the post-partum nursing mother. Prolactin-producing tumors cause inappropriate lactation in the nonpregnant woman. Bromocriptine, an ergot derivative, mimics the action of dopamine in the anterior pituitary gland and does not cure the underlying pathology. Prior to the development of bromocriptine, there was no effective treatment for the symptoms of amenorrhea and galactorrhea. Although the methods of therapy are more sophisticated today, there remain a number of unanswered questions. The unknown long-term risks of bromocriptine therapy must be balanced against the potential risk of osteopenia.     

The effect of mesulergine on prolactin secretion and anterior pituitary cells morphology in diethylstilboestrol-treated female Wistar rats.

Mesulergine (Cu32-085) is an active semisynthetic ergot alkaloid with unusual biphasic antagonistic-agonistic effect on dopamine (DA) turnover in the rat striatum. The present study has been made to elucidate the influence of the long-term treatment of this drug on prolactin secretion and prolactin cells morphology in the female Wistar rats with experimentally-induced hyperprolactinemia. Additionally, the effect of this drug was compared with bromocriptine and pergolide activity, applied in the same experimental conditions. It has been shown that prolonged mesulergine treatment attenuated the stimulatory effect of stilboestrol on prolactin secretion in vivo. It also decreased mean prolactin cells density, above all cells and lactotroph mitotic indexes, estimated in immunohistochemically-stained slides. However, antiproliferative activity of Cu 32-085 was weaker, when compared with bromocriptine and pergolide.     

Disturbed prolactin responses to dopamine-related substances in patients with acromegaly and hyperprolactinemia

We undertook this study, because conflicting data were reported about the dopaminergic regulation of prolactin (PRL) secretion in patients with acromegaly and hyperprolactinemia. In order to clarify the dopaminergic regulation of PRL secretion in patients with acromegaly and hyperprolactinemia, the effects of nomifensine, a central dopamine agonist, FK 33-824, a centrally antidopaminergically acting agent, and domperidone, a peripheral dopamine antagonist, on plasma PRL in these patients were studied. The results were compared with those observed in normal subjects and hyperprolactinemic patients, with or without a pituitary tumor. Nomifensine did not lower the PRL levels and FK 33-824 did not raise the PRL levels in acromegalic patients. In hyperprolactinemic patients, nomifensine did not lower the PRL levels and FK 33-824 failed to raise the PRL levels. Domperidone did not increase PRL in about a third of acromegalic patients, while TRH increased PRL in the all normoprolactinemic acromegalic patients. These results suggest that in acromegalic patients there may be a disturbance in dopamine related neurotransmission and that such disorders also seem to be present in patients with hyperprolactinemia, with or without a pituitary tumor.     

Comparison of efficacy of cysteamine in depleting prolactin immunoreactivity in different hyperprolactinemic animal models

We have examined the effects of cysteamine on its ability to deplete prolactin in various states of hyperprolactinemia. Administration of subtoxic doses of cysteamine (75 and 150 mg/kg,sc) dramatically reduces serum prolactin levels as well as pituitary prolactin content in a dose-dependent manner in estrogen-primed brown Irish ACI female rats. A similar dose-dependent decrease in anterior pituitary prolactin levels was observed in two ectopic prolactin secreting pituitary tumor models (MtTW15 and 7315a). However, a significant reduction in serum prolactin levels was seen in these same tumor bearing animals at only the 150 mg/kg dose of cysteamine. Interestingly, the prolactin content of each of the prolactin secreting tumors, although reduced by cysteamine administration, the effect was neither dose-dependent nor as dramatic as that observed in the anterior pituitary gland proper. These data demonstrate that cysteamine can significantly lower prolactin concentrations in hyperprolactinemia. Further, ectopic prolactin secreting pituitary tissue appears less sensitive to the prolactin-depleting effects of cysteamine. This latter finding may explain, in part, why serum prolactin levels were not as severely reduced in the ectopic tumor bearing female rats as in estrogen-induced hyperprolactinemic animals.     

Chronic hyperprolactinemia depletes hypothalamic dopamine concentrations in male rats

The tuberoinfundibular dopamine (TIDA) system appears to tonically inhibit pituitary prolactin secretion while moderate elevations in serum prolactin levels, in turn, augment the turnover rate of dopamine (DA) without affecting the steady state concentrations of DA in the TIDA neurons (1–5). The present study demonstrates that chronic elevations in serum prolactin, to greater than 2,000 ng/ml, induced by the prolactin secreting MtTW15 tumor, decreased DA concentrations by 47% in the median eminence-arcuate nucleus (ME-ARC) region, by 43% in the medial basal hypothalamus (MBH) and 14% in the preoptic area-anterior hypothalamic region (POA-AH) without influencing the norepinephrine levels in these regions. Thus, chronic stimulation of hypothalamic DA neurons by prolactin may lead to depletion of DA concentrations and this may be an important factor in the reduced DA levels observed in hyperprolactinemia of senescent rats or that produced by chronic estrogen treatment.     

The effect of clozapine on prolactin secretion at the level of the lactotroph

Clozapine is an antipsychotic drug which is unusual in that it has no dopamine receptor-blocking activity. Previous studies gave conflicting results whether administration of clozapine induces hyperprolactinemia. In the present study it was shown that a wide concentration range of clozapine does not interfere with dopamine-mediated inhibition of prolactin (PRL) secretion by normal cultured rat pituitary cells. This in contrast to other neuroleptics, like haloperidol and trifluoperazine. Clozapine does also not antagonize norepinephrine-mediated inhibition of PRL secretion. Clozapine exerts at micromolar concentrations a direct inhibitory action on PRL release by cultured normal rat pituitary cells. In cultured rat pituitary tumor cells, these high concentrations of clozapine directly inhibit PRL release as well as the DNA content of the cells, suggesting a direct antimitotic action. In this model clozapine was about 5-10 times less potent than trifluperazine. Clozapine and trifluoperazine exert an additive inhibitory action both on PRL release and on the DNA content of the pituitary tumor cells. It is concluded that clozapine does not interfere at the pituitary level with dopamine-mediated inhibition of PRL release. At micromolar concentrations clozapine may act on lactotrophs as a calmodulin-inhibitor. These observations suggest that the transient PRL-releasing effects which have been observed in both animal and human studies after clozapine administration are mediated via supra-pituitary actions of the drug.     

Adenylyl cyclase from a prolactin producing tumor cell: The effect of phenothiazines

An adenylyl cyclase stimulated by low concentrations of chlorpromazine was observed in homogenates of a clonal pituitary tumor cell line (GH₃/C14) which releases prolactin and growth hormone. A half-maximal increase in activity of the GH₃/C14 cyclase occurred in the presence of 0.5 × 10^?6M chlorpromazine and a significant increase in activity was observed with a concentration of chlorpromazine as low as 10^?7M. Several derivatives (7-methoxychlorpromazine, 7-hydroxychlorpromazine and 8-hydroxychlorpromazine) were found to mimic the stimulatory action of chlorpromazine on adenylyl cyclase, whereas chlorpromazine-5, N-dioxide was ineffective. Under the assay conditions used, sodium fluoride caused a four-fold increase in activity. However, dopamine at concentrations up to 2 × 10^?4M was ineffective in stimulating or inhibiting the enzyme whether present alone or in combination with chlorpromazine. The ergot alkaloids, ergotamine and ergocryptine, blocked the stimulation of cyclase activity observed in the presence of chlorpromazine (10^?5M). Homogenates of normal pituitaries showed no enhancement of adenylyl cyclase activity by chlorpromazine alone. However, when chlorpromazine was tested in the presence of 5′ guanylimidophosphate [GPP(NH)P], there was a significant increase in cyclase activity in the pituitary similar to that observed in the GH₃/C14 preparation. These results suggest that hyperprolactinemia resulting as a side effect of phenothiazine treatment may be attributable to a direct action of these drugs to increase adenylyl cyclase activity in prolactin-producing cells of the anterior pituitary.     

Effects of physiological and abnormally elevated prolactin levels on the pituitary-testicular axis

Prolactin can influence testicular function both directly, and indirectly via altering release of gonadotropins from the pituitary. Although numerous effects of prolactin on male reproductive functions have been described, only a few were demonstrated in more than one species. These include effects on male accessory reproductive glands, on testicular luteinizing hormone receptors, on the release of gonadotropins and on sexual behavior. In rodents, prolactin appears to play a physiological role in the pituitary regulation of testicular function. This is especially pronounced in the golden hamster. In this seasonally-breeding species, alteration of prolactin release is one of the mechanisms mediating the effects of photoperiod on the testis. In the hamster, prolactin is required for the maintenance of luteinizing hormone and prolactin receptors in the testis and treatment with prolactin can completely reverse testicular atrophy induced by exposure to short photoperiod. In both men and rats, excessive release of prolactin (hyperprolactinemia) leads to suppression of sexual behavior and gonadotropin release. These effects appear to be due to the action of prolactin on the central nervous system. Most, if not all, of the effects of prolactin exhibit striking variability among species. Moreover, prolactin can exert differential effects on the same target tissue in the same species, depending primarily on the dose.     

Effects of hyperprolactinemia on prolactin and LH pulsatile pattern in female rats.

Prolactin (PRL) and luteinizing hormone (LH) secretions are very closely-related. To further understand these mechanisms, the pulsatile secretion pattern of both hormones in experimentally-induced hyperprolactinemia has been studied in adult female rats. Hyperprolactinemia was induced by the transplanting of two pituitary glands. Nine days after the transplant operation, rats were bled (75 or 100 microliters/7 min for 3 h). Serum samples were analyzed for prolactin and LH values by RIA. Hyperprolactinemia modifies pulsatile PRL secretion by increasing the absolute amplitude and duration of the peaks together with a decrease in their frequency. Also, the mean values of the hormone during the whole studied period were increased. Hyperprolactinemia was followed by an increase in the mean values of LH and in the absolute amplitude of the peaks. All these results suggest that hyperprolactinemia induced by pituitary grafting in adult female rats, is followed by a significant change in prolactin and LH pulsatility, which may explain, to some extent, the effects of hyperprolactinemia on reproduction.     

Involvement of the hypothalamus in opiate-stimulated prolactin secretion

Administration of opiate agonists to rats is known to elevate plasma prolactin, an effect which is antagonised by the opiate antagonist naloxone. However, this appears not to be a result of a direct action at the pituitary gland. We report here that opiate agonists stimulate prolactin secretion from isolated adenohypophysial cells when they are coincubated with hypothalamic fragments. Both morphine and Met-enkephalin stimulated prolactin secretion by 1.84 fold and 1.50 fold respectively, and this was antagonised by naloxone. These findings support the hypothesis that one site of action of opioid compounds on pituitary hormone secretion is at the level of hypothalamus.     

Which treatment for hyperprolactinemic females?

This paper has as its first aim the review of the present evidence for risks of chronic hyperprolactinemia as well as benefits and hazards of treatment tools. Among long-term risks, an increased incidence of breast cancer is unlikely while growth of pituitary adenomas occur in a minority. Though control of prolactin secretion can be obtained in most cases, cure of the disease is estimated to be nil with dopaminergic drugs and less than 50% with pituitary surgery. The efficacy of radiotherapy remains questionable. The choice of short- and long-term treatment is discussed according to specific clinical conditions.     

Parasitic fungus Claviceps as a source for biotechnological production of ergot alkaloids

Ergot alkaloids produced by the fungus Claviceps parasitizing on cereals, include three major groups: clavine alkaloids, d-lysergic acid and its derivatives and ergopeptines. These alkaloids are important substances for the pharmatech industry, where they are used for production of anti-migraine drugs, uterotonics, prolactin inhibitors, anti-Parkinson agents, etc. Production of ergot alkaloids is based either on traditional field cultivation of ergot-infected rye or on submerged cultures of the fungus in industrial fermentation plants. In 2010, the total production of these alkaloids in the world was about 20,000 kg, of which field cultivation contributed about 50%. This review covers the recent advances in understanding of the genetics and regulation of biosynthesis of ergot alkaloids, focusing on possible applications of the new knowledge to improve the production yield.     

The dopamine of the rat mammotroph in cell culture as a model for drug action

Dopamine can act directly on pituitary cells to inhibit prolactin release. This action can be blocked by dopamine receptor blocking drugs such as haloperidol, sulpiride and other neuroleptic agents. Comparison of the properties of the mammotroph dopamine receptor with the adenylate cyclase linked dopamine receptor of the limbic forebrain reveals some obvious differences. For example, dopamine receptor stimulants such as S-584 and lergotrile mesylate are inactive in stimulating the adenylate cyclase preparations but are potent in inhibiting pituitary prolactin secretion. Such inhibition of prolactin secretion can be reversed by haloperidol or sulpiride. In contrast to these observations, sulpiride does not block dopamine stimulation of cAMP formation. In addition, dopamine, apomorphine or lergotrile mesylate have no effect on a pituitary adenylate cyclase preparation and dopamine fails to elevate cAMP in the intact cells in culture. Despite the similarity between these two dopamine sensitive systems with respect to a number of agonists and antagonists, the exceptions described suggest that the pituitary system with further study may offer some greater reliability as a predictive test for clinically useful agents. These results also suggest that the receptors for dopamine, like that for norepinephrine, are of two types, only one of which is coupled to adenylate cyclase.     

Studies of anterior pituitary-grafted rats: I. Abnormal prolactin response to thyrotropin releasing hormone,clonidine, insulin,and fasting

Although the rat implanted with extra anterior pituitary glands (AP) under the kidney capsule has been widely used as a model of chronic hyperprolactinemia, its hormonal status has not been fully characterized. Using conscious, unrestrained female pituitary-grafted rats and sham-operated littermates, we investigated prolactin (PRL) secretion in response to the following stimuli: thyrotropin releasing hormone (TRH), clonidine, insulin, and fasting. The AP-implanted rats had a greater and more sustained rise in serum PRL after TRH than control rats, reflecting a direct effect of TRH on the ectopic lactotropes. In contrast after clonidine, which acts via the hypothalamus, the serum PRL rose to much higher levels in sham-operated rats than in rats bearing ectopic pituitary tissue. Both insulin-induced hypoglycemia and fasting decreased serum PRL in control rats, but the AP-implanted animals manifested a rise in serum PRL in response to these stimuli. Thus, the AP-implanted rat is not only a valid model of excess and abnormal PRL secretion, but it may also be useful for distinguishing between stimuli requiring an intact hypothalamic-pituitary unit and agents which act directly on the pituitary gland.     

Studies of anterior pituitary-grafted rats: II. Normal growth hormone secretion

Of the various animal models used to study chronic hyperprolactinemia, the otherwise intact rat implanted with extra anterior pituitary glands (AP) under the kidney capsule is assumed to be normal except for excess circulating prolactin (PRL). Since the ectopic glands contain numerous somatotropes in addition to abundant and active lactotropes, it was important to assess growth hormone (GH) secretion as well in this model of hyperprolactinemia. The structural and functional similarities of PRL and GH are such that it is necessary to demonstrate that metabolic abnormalities noted in AP-implanted rats are due to hyperprolactinemia and not to altered GH secretion. AP-implanted female rats have significantly higher resting serum PRL concentrations when compared to sham-operated control rats, but baseline serum GH levels are similar in normal and pituitary-grafted rats. Suppression of GH by insulin and clonidine is comparable in AP-implanted and control rats. The intrasellar pituitary GH concentration is also similar (ca. 20 μg/mg wet weight) in hyperprolactinemic and normal rats. We conclude that GH secretion is normal in the non-hypophysectomized AP-implanted rat, in contrast to the hypophysectomized AP-implanted rat model which has been reported to have diminished GH secretion. Despite the presence of recognizable somatotropes, the ectopic anterior pituitary does not appear to secrete significant amounts of GH, making the intact rat bearing multiple pituitary grafts an excellent model of chronic hyperprolactinemia.     

Hyperprolactinemia: causes, diagnosis, and treatment

The basic data on hyperprolactinemia (i.e. an excess of PRL above a reference laboratory's upper limits), the most common endocrine disorder of the hypothalamic-pituitary axis are given in this review. The following issues are discussed: regulation of prolactin (Prl) secretion, definition of hyperprolactinemia, its etiology and pathogenesis as well as its symptoms, diagnosis, and treatment (including medical and surgical therapy). It should be stressed that finding of elevated PRL serum concentrations constitute the beginning of diagnostic procedure and, after exclusion of physiologic, pharmacologic, and other organic causes of increased PRL levels, should be followed by detailed diagnosis including MRI. In patients in whom hyperprolactinemia has been confirmed the treatment with dopamine agonists (with prevalence of cabergoline, followed by quinagoline) is currently considered first-choice therapy. Surgery should be performed only in the patients resistant or intolerant to these agents, or in patients who refuse long-term therapy.     

Diabetes insipidus and galactorrhea caused by histiocytosis X.

A 44-year-old woman with diabetes insipidus of 3 years duration was found to have histiocytosis X. This was based on clinical, radiological and pathological findings consistent with the diagnosis. Furthermore, she developed spontaneous galactorrhea during the course. Endocrine studies of hypothalamic-pituitary function revealed completely impaired secretion of gonadotropin, growth hormone and anti-diuretic hormone, and possible partial impairment of adrenocorticotropic hormone secretion, while thyroid stimulating hormone secretion remained intact. Persistently elevated plasma levels of human prolactin were also demonstrated, which were unaffected by administration of either thyrotropin releasing hormone, l-DOPA or water loading, but suppressed significantly by CB-154, an ergot alkaloid. These results suggest that abnormalities of the patient's endocrine function may be mainly accounted for by a single hypothalamic lesion.