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.     

The favorable prognostic significance of surgery-induced hyperprolactinemia in node-positive breast cancer patients: ten-year disease-free survival results

It has been shown that each manipulation of the mammary region, including breast surgery, may stimulate prolactin secretion. However, it has also been observed that in more than 50% of breast cancer patients surgical removal of the tumor is not followed by enhanced prolactin secretion. This might be indicative of an altered psychoneuroendocrine control of the mammary gland, which could lead to the onset of more biologically aggressive breast cancer. In fact, surgery-induced hyperprolactinemia has been proven to be associated with a better prognosis in terms of survival in node-negative breast cancer patients. The present study was performed to investigate the impact of postoperative hyperprolactinemia on the disease-free survival (DFS) of breast cancer patients with axillary node involvement. The study included 100 consecutive node-positive breast cancer patients who were followed for at least 10 years. Surgery-induced hyperprolactinemia occurred in 45/100 (45%) patients without any significant correlation with the main prognostic variables including number of involved nodes and ER status. The two groups of patients received the same adjuvant therapies. After a median follow-up of 151 months, the recurrence rate in patients with surgery-induced hyperprolactinemia was significantly lower than in patients with no postoperative hyperprolactinemia (23/45 vs 43/55, p<0.01). Moreover, DFS was significantly longer in hyperprolactinemic patients than in patients who had no enhanced secretion of prolactin postoperatively. In agreement with the results described previously in node-negative breast cancer, our study demonstrates the favorable prognostic significance of surgery-induced hyperprolactinemia in terms of DFS duration also in breast cancer patients with axillary node involvement, independent of the other well-known prognostic variables, thereby confirming that the psychoneuroendocrine status of cancer patients may influence the prognosis of their disease.     

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.     

The pathophysiology of hyperprolactinemic states and the role of newer ergot compounds in their treatment.

Studies of prolactin secretion in humans have confirmed the concept, derived originally from animal investigations, that prolactin is predominantly controlled by tonic inhibition from the hypothalamus. The locus of action of dopamine and dopaminergic agents such as the ergot alkaloids inhibiting prolactin secretion appears to be primarily at the pituitary level, though a hypothalamic action to increase secretion of prolactin inhibitory factor may also contribute. Prolactin hypersecretion, through any of several possible mechanisms, is frequently but not always found in patients with galactorrhea. Recent studies have shown that hyperprolactinemia is considerably more common than was previously appreciated among patients without galactorrhea. It is present in at least two-thirds of all patients with pituitary tumors and in a significant minority of patients with secondary amenorrhea. Its clinical measurement in these conditions is therefore of considerable diagnostic importance. Whatever the pathophysiology of its production, hyperprolactinemia of all forms is responsive to treatment with the newer ergot alkaloids. The potential use of these agents for therapeutic purposes, particularly in the treatment of infertility, appears to be wider than was originally anticipated.     

Effect of Pituitary Graft-Induced Hyperprolactinemia on Adrenal Orcadian Rhythmicity

Prolactin is involved in the regulation of several endocrine functions. In this study, the possible influence of hyperprolactinemia on circadian corticosterone secretion has been investigated. Pituitary grafted male and female rats exhibited increased plasma PRL levels at 1000 when compared to sham-operated controls. This increase was only maintained over the 24 h period in grafted female rats but not in males, thus suggesting a different sex dependent modification of the regulatory mechanisms of prolactin. The corticosterone secretion pattern in sham operated male and female rats was similar to those described earlier but was altered by hyperprolactinemia according to the sex of the animal. There was a significant decrease in the total amount of corticosterone secreted in a 24 h period in grafted males as compared to control animals, whereas no significant differences were observed in grafted female rats as compared to controls. Grafted females showed a 4 h delay in the 24 h secretion rhythm as compared to control animals. These data suggest that pituitary transplant induced hyperprolactinemia, directly or through modifications in catecholamine turnover, is able to modify adrenal rhythmicity.     

Effect of Pituitary Graft-Induced Hyperprolactinemia on Adrenal Orcadian Rhythmicity

Prolactin is involved in the regulation of several endocrine functions. In this study, the possible influence of hyperprolactinemia on circadian corticosterone secretion has been investigated. Pituitary grafted male and female rats exhibited increased plasma PRL levels at 1000 when compared to sham-operated controls. This increase was only maintained over the 24 h period in grafted female rats but not in males, thus suggesting a different sex dependent modification of the regulatory mechanisms of prolactin. The corticosterone secretion pattern in sham operated male and female rats was similar to those described earlier but was altered by hyperprolactinemia according to the sex of the animal. There was a significant decrease in the total amount of corticosterone secreted in a 24 h period in grafted males as compared to control animals, whereas no significant differences were observed in grafted female rats as compared to controls. Grafted females showed a 4 h delay in the 24 h secretion rhythm as compared to control animals. These data suggest that pituitary transplant induced hyperprolactinemia, directly or through modifications in catecholamine turnover, is able to modify adrenal rhythmicity.     

Cooperative synthesis of dopamine in rat mediobasal hypothalamus as a compensatory mechanism in hyperprolactinemia

Dopamine (DA), synthesized in the mediobasal hypothalamus by dopaminergic neurons containing two enzymes of DA synthesis–tyrosine hydroxylase and decarboxylase of aromatic L-amino acids, or by monoenzymatic non-dopaminergic neurons containing one DA synthesis enzyme in cooperation, is known to have an inhibitory effect on prolactin secretion. Deterioration of this inhibitory control leads to an increase in prolactin concentration in the blood and to the development of hyperprolactinemia syndrome. In a rat model of hyperprolactinemia induced by administration of a neurotoxin causing degeneration of dopaminergic and noradrenergic neurons, the level of DA first decreases, leading to an increase in prolactin level (decompensation stage), while later both levels are restored to normal (compensation stage). However, the mechanism of such compensation is still not clear. The aim of the present study was to analyze whether the increase in cooperative synthesis of DA by monoenzymatic neurons during hyperprolactinemia is a manifestation of a compensatory mechanism representing a particular case of neuroplasticity. The level of cooperative synthesis in the hyperprolactinemia model and in the control was estimated as the level of synthesis of DA and L-dihydroxyphenylalanine (L-DOPA)–an intermediate product of DA synthesis, when L-DOPA transfer from neurons containing tyrosine hydroxylase into neurons containing aromatic L-amino acid decarboxylase is inhibited. The level of DA synthesis during the decompensation stage was not changed, while during the compensation stage it was lower than the control. Along with a reduction in DA level, during the compensation stage an increase in the extracellular L-DOPA level in the medium was detected. Thus, the compensation of DA deficiency after degeneration of dopaminergic neurons in the mediobasal hypothalamus is due to the increase in cooperative synthesis of DA by monoenzymatic neurons containing one of the complementary enzymes of the DA synthesis pathway.     

Prolactin suppresses GnRH but not TSH secretion

BACKGROUND/AIMS: In animal models, prolactin increases tuberoinfundibular dopamine turnover, which has been demonstrated to suppress both hypothalamic GnRH and pituitary TSH secretion. To test the hypothesis that prolactin suppresses GnRH and TSH secretion in women, as preliminary evidence that a short-feedback dopamine loop also operates in the human, the effect of hyperprolactinemia on GnRH and TSH secretion was examined. METHODS: Subjects (n=6) underwent blood sampling every 10 min in the follicular phase of a control cycle and during a 12-hour recombinant human prolactin (r-hPRL) infusion preceded by 7 days of twice-daily subcutaneous r-hPRL injections. LH and TSH pulse patterns and menstrual cycle parameters were measured. RESULTS: During the 7 days of r-hPRL administration, baseline prolactin increased from 16.0+/-3.0 to 101.6+/-11.6 microg/l, with a further increase to 253.7+/-27.7 microg/l during the 12-hour infusion. LH pulse frequency decreased (8.7+/-1.0 to 6.0+/-1.0 pulses/12 h; p<0.05) with r-hPRL administration, but there were no changes in LH pulse amplitude or mean LH levels. There were also no changes in TSH pulse frequency, mean or peak TSH. The decreased LH pulse frequency did not affect estradiol, inhibin A or B concentrations, or menstrual cycle length. CONCLUSION: These studies demonstrate that hyperprolactinemia suppresses pulsatile LH secretion but not TSH secretion and suggest that GnRH secretion is sensitive to hyperprolactinemia, but that TSH secretion is not. These data further suggest that the degree of GnRH disruption after 7 days of hyperprolactinemia is insufficient to disrupt menstrual cyclicity.     

Effects of pimozide and domperidone administration on prolactin levels in neonatally estrogenized female rats

The effects of two dopaminergic blockers, pimozide and domperidone, on the prolactin secretion were investigated in adult female rats treated neonatally with estrogens (100 micrograms of estradiol benzoate s.c. on day 1). These rats showed hyperprolactinemia (556 micrograms/l vs 57.7 in oil-injected) and treatment with pimozide or domperidone failed to increase prolactin levels in the adult age. These results suggest that the hyperprolactinemia in neonatally estrogenized female rats is produced by loss of the dopaminergic inhibition on prolactin secretion, so that the pharmacological blockade of dopaminergic receptors is uneffective. The dopamine levels in hypothalamus were similar in control and estrogenized females suggesting that failure in dopaminergic inhibition is due to a decrease in dopamine secretion to portal vessels.     

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.     

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.     

Hypogonadism Due to Hyperprolactinemia and Subsequent First Episode of Psychosis

BackgroundHyperprolactinemia causes hypogonadotrophic hypogonadism. Hyperprolactinemia can be pre-existing in some patients with schizophrenia. Dopamine is the most important prolactin-inhibiting factor, and dopaminergic hyperactivity has been implicated in the pathophysiology of psychosis.ObjectiveSince dopamine is a prolactin-inhibiting factor and dopamine imbalanced has been implicated in the pathophysiology of psychotic disorders, we investigated the probable relationship between hyperprolactinemia and the development of psychotic symptoms, in a patient with hypogonadism due to hyperprolactnemia and subsequent first episode of psychosis. Since dopamine is a prolactin-inhibiting factor and dopamine imbalance has been implicated in the pathophysiology of psychotic disorders, we investigated the probable relationship between hyperprolactinemia and the development of psychotic symptoms.MethodsWe present the case of a patient with hypogonadism secondary to chronic, untreated hyperprolactinemia who developed acute psychotic symptoms.ResultsPsychotic symptoms resolved soon after treatment with aripiprazole in conjunction with cabergoline, with a concomitant decrease in serum prolactin level.ConclusionThis is an interesting case illustrating a complicated relationship among hypogonadism secondary to a prolactinoma and dopamine and psychosis.     

Serum Prolactin and Macroprolactin Levels among Outpatients with Major Depressive Disorder Following the Administration of Selective Serotonin-Reuptake Inhibitors: A Cross-Sectional Pilot Study

Clinical trials evaluating the rate of short-term selective serotonin-reuptake inhibitor (SSRI)-induced hyperprolactinemia have produced conflicting results. Thus, the aim of this study was to clarify whether SSRI therapy can induce hyperprolactinemia and macroprolactinemia. Fifty-five patients with major depressive disorder (MDD) were enrolled in this study. Serum prolactin and macroprolactin levels were measured at a single time point (i.e., in a cross-sectional design). All patients had received SSRI monotherapy (escitalopram, paroxetine, or sertraline) for a mean of 14.75 months. Their mean prolactin level was 15.26 ng/ml. The prevalence of patients with hyperprolactinemia was 10.9% for 6/55, while that of patients with macroprolactinemia was 3.6% for 2/55. The mean prolactin levels were 51.36 and 10.84 ng/ml among those with hyperprolactinemia and a normal prolactin level, respectively. The prolactin level and prevalence of hyperprolactinemia did not differ significantly within each SSRI group. Correlation analysis revealed that there was no correlation between the dosage of each SSRI and prolactin level. These findings suggest that SSRI therapy can induce hyperprolactinemia in patients with MDD. Clinicians should measure and monitor serum prolactin levels, even when both SSRIs and antipsychotics are administered.     

Involvement of hypothalamic dopamine in the regulation of prolactin secretion

The neuroendocrine control of prolactin (PRL) secretion is known to be a multifactorial process, but dopamine (DA) secreted by the tuberoinfundibular dopaminergic (TIDA) neurons of the hypothalamus is believed to exert a predominant inhibitory control on the secretion of PRL. The secretory activity of the TIDA neurons, including the rate of biosynthesis of DA and the rate of release of the neurohormone into hypophysial portal blood, can be readily evaluated in the rat. In most conditions in which an altered secretion of PRL has been documented, an altered secretory activity of the TIDA neurons has been found. When an acute reduction in the secretion of DA is observed, an increased secretion of PRL is associated, with an inverse relationship between DA and PRL concentrations in hypophysial portal and systemic blood, respectively. However, the secretion of PRL can be regulated by PRL itself through stimulation of the secretory activity of the TIDA neurons, and consequently hyperprolactinemia can be observed concomitantly with a sustained high secretion of DA, as seen after treatment with estrogen. The short loop feedback of PRL secretion seems to be impaired in the aging rat, since a sustained reduced hypothalamic secretion of DA is observed in spite of long-term 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.     

Tachykinins and the control of prolactin secretion

Tachykinins are present in the pituitary gland and in brain areas involved in the control of the secretion of pituitary hormones. Tachykinins have been demonstrated to stimulate prolactin release acting directly on the anterior pituitary gland. These peptides have also been revealed to be able to act at the hypothalamic level, interacting with neurotransmitters and neuropeptides that have the potential to affect prolactin secretion. Tachykinins seem to act by stimulating or inhibiting the release of the factors that affect prolactin secretion. Among them, tachykinins have been demonstrated to stimulate oxytocin and vasopressin release, which in turn results in prolactin release. Tachykinins also potentiated the response to vasoactive intestinal peptide (VIP) and reinforced the action of glutamate, which in turn result in prolactin release. They have also been shown to interact with serotonin, a neurotransmitter involved in the control of prolactin secretion. In addition, tachykinins have been shown to inhibit GABA release, a neurotransmitter with prolactin-release inhibiting effect. This inhibition may result in an increased prolactin secretion by removal of the GABA inhibition. On the other hand, tachykinins have also been shown to stimulate dopamine release by the hypothalamus, an action that results in an inhibition of prolactin release. Dopamine is a well known inhibitor of prolactin secretion. In conclusion, although tachykinins have been shown to have a predominantly stimulatory effect on prolactin secretion, especially at the pituitary level, under some circumstances they may also exert an inhibitory influence on prolactin release, by stimulating dopamine release at the hypothalamic level.     

Relation between surgery-induced prolactin increase and the menstrual cycle phase at time of surgery in premenopausal breast cancer

It has been suggested that both the menstrual cycle phase and postoperative changes in prolactin (PRL) secretion at the time of surgery may influence the prognosis of breast cancer. The present study was carried out to evaluate the relation between menstrual cycle period and surgery-induced PRL variations. We evaluated 32 premenopausal women with operable breast carcinoma; 17 were in perimenstrual phase (days 1-6 and 21-28) and 15 were in the mid-cycle (days 7-20) period at the time of surgery. To investigate serum levels of PRL, venous blood samples were collected before and 7 days after surgery. Postoperative hyperprolactinemia occurred in 17/32 patients and it was statistically more frequent in patients surgically treated during the perimenstrual phase than in the mid-cycle phase (12/17 vs 5/15; p less than 0.05), while no other parameter (including axillary node and estrogen receptor status) showed a significant influence on hyperprolactinemia rate. The results suggest that in premenopausal breast cancer patients surgery-induced hyperprolactinemia may be influenced by the menstrual cycle phase at the time of surgery.     

Absence of suppressive effect of somatostatin on prolactin levels in patients with hyperprolactinemia

The effect of somatostatin (SRIF: 10 micrograms/min during 120 min) on serum prolactin (PRL) levels was studied in eleven patients with hyperprolactinemia of varying causes: 2 patients with acromegaly; 2 with primary hypothyroidism; 4 with prolactinoma and 3 with drug (sulpiride) induced hyperprolactinemia. During SRIF infusion, no significant change in PRL levels was observed in any of the 4 groups studied except in one female patient with a prolactinoma. The biological activity of SRIF was demonstrated by the significant inhibition (P less than 0.05) of insulin levels seen in all 11 patients (52% fall in relation to basal) without simultaneous modification of glycemia. These data suggest that SRIF does not decrease PRL secretion in most patients with hyperprolactinemia.     

Effects of hyperprolactinemia on rat prostate growth: evidence of androgeno-dependence

The effects of the polypeptide hormone prolactin (PRL) in the development and regulation of benign prostate hyperplasia (BPH) and also in prostate cancer are not very well characterized. This study examines the action of PRL, either alone or in association with androgens [testosterone (T) or dihydrotestosterone (DHT)], in the rat prostate gland. The effects of PRL and androgens were investigated after 30 and 60 days in control, castrated, castrated with a substitutive implant of T or DHT, and sham-operated Wistar rats. To enhance PRL release, we induced hyperprolactinemia by administering chronic injections of sulpiride (40 mg. kg(-1). day(-1)). Chronic hyperprolactinemia induces enlargement and inflammation of the lateral rat prostate without any histological changes on ventral and dorsal lobes. We also demonstrate that hyperprolactinemia induces Bcl-2 overexpression in the lateral rat prostate and that this could inhibit the level of apoptosis. The in vivo model established here is a useful in vivo approach for studying the hormonal regulation of normal and pathological prostate development.     

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.