Enhanced response of plasma prolactin to metoclopramide during chronic converting enzyme inhibition

The effect of chronic converting enzyme inhibition with enalapril on the PRA, PRL and plasma aldosterone responses to metoclopramide was studied in 10 patients with mild to moderate essential hypertension. Enalapril reduced supine blood pressure and increased heart rate significantly. PRA and urinary sodium excretion rose significantly. PRA levels did not change after metoclopramide neither during placebo nor during enalapril. The aldosterone response to metoclopramide was not altered by enalapril, indicating that this response is independent of the renin-angiotensin system. The PRL response to metoclopramide was considerably enhanced after 4 weeks of treatment with enalapril. It is proposed that enalapril, by decreasing the formation of angiotensin II, increases the prolactin reserve.     

Clinical use of metoclopramide test in the diagnosis of women with hyperprolactinemia

14 women with elevated prolactin (PRL) serum levels (greater than 25 ng/ml) were given 2.5 mg of metoclopramide, by bolus intravenous injection, to evaluate its diagnosic potential as a stimulus for PRL release. Following metoclopramide injection there was a prompt increase in serum PRL in normal subjects and in patients with moderate PRL elevations associated with galactorrhea-oligomenorrhea. The women with amenorrhea-galactorrhea regardless of the presence of absence of a pituitary tumor, showed a blunted response. Metoclopramide failed to induce TSH secretion in all cases. In conclusion: the use of the metoclopramide test provides no additional clinical information to that furnished by the basal serum PRL concentration for the hyperprolactinemic patient.     

Dopamine control of aldosterone secretion in end-stage renal failure

The role of the tonic inhibitory effect of dopamine on aldosterone secretion has been investigated in 10 patients with chronic renal failure (CRF) on hemodialysis, in 8 normotensive renal transplant recipients (Tx) with normal renal function and in 8 normotensive volunteers (NV). The following tests were performed: the response of plasma aldosterone (PA) to metoclopramide administration; the response of plasma prolactin (PRL) to TRH administration, and the changes induced by Lisuride (a dopaminergic agonist, on the values of PA and PRL). The basal values of PA and PRL were higher in CRF than in NV and Tx. The inverse was true for plasma renin activity (PRA) values. The response of PA and PRL to metoclopramide showed blunted increases in CRF when compared to NV, in the absence of changes of PRA, cortisol and potassium. After TRH administration, PRL increase in CRF was also inferior. Lisuride induced a decrease of both PA and PRL both in CRF and NV. In Tx, basal values of PA and PRL were similar to NV. Nevertheless, the response to metoclopramide and TRH were partially blunted when compared to that of NV. These results point to the existence of a deranged dopaminergic regulation of aldosterone secretion in end-stage renal failure patients. The alterations are partially corrected by a well-functioning kidney graft.     

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.     

Variations of prolactin content in human cerebrospinal fluid after metoclopramide and morphine

Serum and cerebrospinal fluid (CSF) prolactin (PRL) concentrations were determined in fourteen patients of both sexes suffering from hydrocephalus, in basal conditions and after i.m. administration of 10 mg metoclopramide or 10 mg morphine. A significant increase in both serum and CSF hormone values was found after administration of both drugs. Serum and CSF PRL values after metoclopramide administration increased earlier and to a greater extent than after morphine. Furthermore, the metoclopramide induced CSF PRL increase immediately followed the serum peak, whereas after morphine administration an evident delay in the CSF hormone peak with respect to the serum increase was found. These data suggest that PRL entry in the CSF compartment is subject to a controlling mechanism which acts at the blood/brain barrier.     

Antagonism of morphine tolerance and dependence by metoclopramide

Metoclopramide produced significant analgesic activity when tested by acetic acid induced writhing assay. Repeated injections of metoclopramide did not result in the development of tolerance to its analgesic activity. Pretreatment with metoclopramide antagonised acute morphine tolerance and suppressed the withdrawal signs (both in acute dependence type and abrupt withdrawal type). It is suggested that metoclopramide may be a useful tool in the management of morphine dependence.     

Zinc supplementation does not inhibit basal and metoclopramide-stimulated prolactinemia secretion in healthy men.

Dopamine (DA) and zinc (Zn++) share common mechanisms in their inhibition of prolactin (PRL) secretion. Both substances are present in the same brain areas, where Zn++ is released together with DA, suggesting a modulatory effect of Zn++ on dopaminergic receptors. The aim of the present study was to evaluate the effect of Zn++ supplementation on basal and PRL secretion stimulated by metoclopramide (MCP), a dopaminergic antagonist. Seven healthy men were evaluated in controlled study, where MCP (5 mg) was given intravenously, before and after 3 months of oral Zn++ (25 mg) administration. Our results indicate that chronic Zn++ administration does not change basal or MCP-stimulated plasma PRL secretion suggesting that, in humans, Zn++ does not interfere on PRL secretion mediated through dopaminergic receptors.     

Growth hormone and prolactin secretion after metoclopramide administration (DA2 receptor blockade) in fertile women.

In this report, we will describe the results of a cross-sectional study to assess PRL and GH secretion during the early follicular phase in 22 fertile patients after metoclopramide administration in order to achieve a dopaminergic DA2 receptor blockade. Blood samples were collected at - 15, 0, 15, 30, 45 and 60 minutes. PRL, GH, estradiol, IGF-I, TSH, glucose, and insulin were measured in the samples taken at - 15 and 0 minutes. The existence of a correlation between GH and PRL secretion was investigated. All patients presented normal serum levels of estradiol, prolactin, insulin, fasting glucose and IGF-I. Serum GH levels were not changed after metoclopramide infusion (p = 0.302), but there was a significant alteration in serum PRL (p = 0.0001) with the highest levels after 30 (mean: 237.20 ng/ml +/- 95.86) and 45 (mean: 211.80 ng/ml +/- 83.24) minutes. Serum GH levels did not correlate with serum PRL levels after the dopaminergic DA2 blockade. We conclude that GH secretion was not modulated by a direct effect of type 2 dopamine receptor.     

18β-Glycyrrhetinic Acid,a Novel Naturally Derived Agent,Suppresses Prolactin Hyperactivity and Reduces Antipsychotic-Induced Hyperprolactinemia in In Vitro and In Vivo Models

The purpose of this study was to examine the effects of 18β-glycyrrhetinic acid (GA), a novel naturally derived agent, in suppressing prolactin (PRL) hyperactivity and reducing antipsychotic-induced hyperprolactinemia (hyperPRL) and the underlying mechanisms in in vitro and in vivo models. GA treatment for 24 h inhibited PRL synthesis and secretion in MMQ cells and cultured pituitary cells in a dose-dependent fashion; but this effect was not reproduced in GH3 cells that lack the expression of functional dopamine D₂ receptors. GA suppressed elevated PRL level and growth hormone, and normalized several sex hormones in a rat model of hyperPRL, produced by repeated injection of the dopamine blocker metoclopramide. GA also modulated the expression 5-HT_1A and 5-HT_2A receptors in both in vivo and in vitro models. These results indicate that GA is effective in suppressing PRL hyperactivity caused by the blockade of dopamine D2 receptors. This suppressive effect of GA may be related to its modulation of the serotonergic system. This study provides additional evidence in support of GA as an adjunct for the treatment of hyperPRL.     

Differences in cardiac but not in neuroendocrine responses in healthy volunteers after administration of two antimuscarinic agents, atropine and pirenzepine

Neuroendocrine and cardiac responses were studied in healthy volunteers with the classical muscarinic antagonist, atropine and the new antimuscarinic agent, pirenzepine. The secretion of prolactin (PRL) and growth hormone (GH) was increased after metoclopramide. Typically, an antidopaminergic drug such as metoclopramide decreases rather than increases GH concentrations in serum. Pretreatment with both atropine and pirenzepine abolished the increase of GH secretion, which suggests an important role of cholinergic mechanisms in the regulation of GH secretion. The increase of PRL secretion was not inhibited by the two muscarinic antagonists. With the doses used, antimuscarinic activities in serum were comparable after atropine and pirenzepine treatments for the most part of the study. Heart rate was, however, significantly increased during atropine and higher than during saline or pirenzepine treatments throughout the study period. When compared to placebo, pirenzepine lowered heart rate slightly but significantly. The exact mechanism of this effect is unclear. We conclude that in contrast to the identical neuroendocrine effects, the cardiac responses clearly differ during atropine and pirenzepine treatments which confirms the ability of pirenzepine to distinguish muscarinic receptor sites in the central nervous system from those of the heart.     

Macroprolactin in subjects with hyperprolactinaemia: clinical observations and relations between free PRL and PRL complexed with IgG

In some patients with hyperprolactinaemia a large portion of circulating prolactin is bound to authologous gammaglobulin and therefore it is called macroprolactin or Big-Big-Prolactin (BB-PRL). THE AIM: of the study was to select patients with predominance of macroprolactin and to learn more about the natural course of this disorder, in particular about the possible dependence of the presence of clinical features from the amount of circulating "free" PRL level, and also to search whether the quantitative proportions of both forms of PRL are stable or they change parallel to changes of the total serum PRL level. MATERIAL AND METHODS: We identified 58 patients with hyperprolactinaemia, in whom BB-PRL consisted>or=60% of the total PRL concentration. The predominance of macroprolactin was settled using the well accepted method of polyethylene glycol (PEG) precipitation of large m.w. serum proteins, followed by contemporary immunoradiometric measurement of the total and free PRL levels, and calculation of BB-PRL. Repeating such measurements during the long term observation lasting 6-66 months (mean 33 months), which was possible in 18 our patients (13--with idiopathic hyperprolactinaemia and 5--with pituitary adenoma), we could analyze the relations between both forms of PRL during the specific treatment, after it's cessation and, in few cases--during pregnancy. Apart of that, in 18 patients selected from 53 with idiopathic hyperprolactinaemia, we analyzed the shortterm alterations in the ratio between free and complexed PRL during the metoclopramide PRL stimulation test. RESULTS AND CONCLUSIONS: 1. In hyperprolactinaemic patients with predominance of BB-PRL, there was no direct correlation between the presence of clinical features and the concentration of residual "free" PRL. 2. During the long-term observation, in spite of moderate changes in the total PRL concentration induced by the treatment or it's cessation (excluding pregnancy), the ratio of "free" PRL and BB-PRL remained stable. 3. During the short time of metoclopramide stimulation test, there was a marked rise mainly of the total and "free" PRL concentrations, and, in some tested subjects, the predominance of BB-PRL was lost temporally for 1 to 2 hours.     

Effect of L-dopa and bilateral nephrectomy on the aldosterone response to metoclopramide

The dopaminergic antagonist, metoclopramide (MCP) causes an increase in plasma aldosterone (PA) by a processnot well delineated. To investigate the mechanism of action of metoclopramide (MCP), studies were performed in rats after pre-treatment with L-dihydroxy-phenylalanine (L-dopa) and after bilateral nephrectomy. Intra-arterial MCP (200 μg/kg) resulted in a significant elevation in PA and prolactin (PRL) at 5 min and plasma renin activity (PRA) at 10 min without altering serum potassium levels. Pre-administration of L-dopa (30 mg/kg) delayed and markedly blunted PA, PRL and PRA resonses to MCP. In 7 rats, studied 30 hours after bilateral nephrectomy, the PRA was measurable (2.5 ± 0.4 ng/ml h^?1) but displayed no response to MCP. In contrast, the PA and PRL responses to MCP were not significantly affected. L-dopa induced suppression of PRA and PA was prevented by pre-administration of MCP. These results suggest that dopaminergic modulation of PA secretion occurs independently of the renin-angiotensin system.     

Stimulatory effects of quinpirole hydrochloride, D2-dopamine receptor agonist, at low concentrations on prolactin release in female rats in vitro.

Dopamine (DA) has dual actions (inhibitory and stimulatory) in the regulation of prolactin (PRL) release, depending on its concentration. To investigate the stimulatory effects of DA, perifused rat anterior pituitary cells were exposed to the highly-specific DA D2 receptor agonist, quinpirole hydrochloride (LY). Very low concentrations of LY (10(-12)-10(-10) M) stimulated PRL release and potentiated thyrotropin-releasing hormone (TRH)-induced PRL release. Higher concentrations of LY did not stimulate. Pretreatment with pertussis toxin (30 ng/ml, 24 h) completely abolished these effects of LY. The D2 receptor antagonist, metoclopramide, also blocked the potentiation by LY of TRH-induced PRL release. These data indicate that very low concentrations of dopamine stimulate PRL release via an interaction with a D2 receptor connected to a pertussis toxin-sensitive G protein.     

Hyperprolactinaemia--pitfalls in PRL assessment

Prolactin (PRL) is one of the most commonly assessed hormones, and hyperprolactinaemia seems to be often endocrine disorder. Hyperprolactinaemia is not a disease, but only a symptom indicating relevant medical conditions to be diagnosed and properly treated. Laboratory findings should be always cautiously interpreted with reference to clinical context. Possible problems could be evoked by errors during sampling and assessment itself. While interpreting laboratory results, one have to pay attention on pulsate secretion profile of PRL (within hours), and shows marked diurnal cycle (with maximum during sleep period). PRL level depends also on emotional status (stress amplifies PRL secretion), and also on dietary habits and stimulants. Lastly, a growing body of evidence proven that in some cases elevated PRL level could be caused by presence of polymeric form of PRL--so called "macroprolactin". This form has diminished receptor-binding specificity and weak, if any, biological effect while immunoreactivity is preserved. In clinical practice, in cases of macroprolactinaemia high level of circulating hormone does not correlate with slight, if even, clinical symptoms. To avoid errors in prolactin assessment blood should be drawn fasting, preferentially in series or during dynamic test after dopaminergic blockade with metoclopramide. Interpretation must parallel include clinical data. It is essential that PRL level is proportional to pituitary lactotroph tumor size. Extremely high PRL concentration could exceed technical capability of laboratory equipment and remain underestimated, or even undiagnosed. Beneath presented algorithm could be useful in planning diagnostic and therapeutic procedures.     

Effect of metoclopramide-induced prolactin on aldosterone secretion in normal subjects

We investigated the role of prolactin (PRL) on modurating the secretion of aldosterone in normal male subjects. Metoclopramide (5mg) which causes a significant rise of PRL was given by intravenous injection. The peak of PRL level at 30 min. after i.v. injection of metoclopramide (20.0 ± 1.6 ng/ml, mean ± S.E.) was significantly higher than the basal level (6.4 ± 2.1 ng/ml, P < 0.01), but plasma aldosterone, serum sodium, potassium and plasma renin activity did not change significantly throughout the period of the study. Cortisol levels, however, reduced significantly after 30 min. and remained significantly low, probably because of diurnal variation. Present results suggest that PRL might at least not play a physiological role on regulating the secretion of aldosterone in man.     

Serum prolactin is associated with apoptosis in men with human immunodeficiency virus infection

We examined the in vivo and in vitro production of prolactin (PRL) in 20 untreated HIV-infected men compared to 14 uninfected men and its association with the cell cycle and apoptosis. Compared to uninfected men, the HIV-infected men had: (i) higher fasting serum bioactive (BIO) PRL; (ii) lower serum immunoreactive (RIA) and BIO-PRL responses to intravenous metoclopramide; (iii) greater BIO-RIA PRL ratio both fasting and during intravenous metoclopramide; (iv) lower percentage of non-stimulated PBMC in the G0/G1 phase, but a higher percentage in the S phase, of the cell cycle with normal response to Concanavalin-A; and (v) higher in vitro production of BIO-PRL by non-stimulated PBMC, which was blocked after Concanavalin-A. Fasting serum BIO-PRL positively correlated with the percent of non-stimulated PBMC in S + G2/M phases. The percentage of apoptotic PBMC negatively correlated with CD4+ T lymphocytes and with the area under the serum RIA-PRL curve, but positively correlated with the area under the curve for the BIO/RIA ratio. These results suggest that in these HIV-infected men: (i) a diminished dopaminergic tone may exist, as an adaptive mechanism attempting to survive; and (ii) BIO-PRL may participate as a cofactor in the stimulation of T-cell proliferation.     

Responses of growth hormone to metoclopramide in normal women and amenorrheic women with or without hyperprolactinemia

Response of growth hormone (GH) release to metoclopramide (MCP), a dopamine antagonist, was evaluated in normal women, hyperprolactinemic-amenorrheic patients with pituitary microadenoma and normoprolactinemic-amenorrheic patients. Mean basal concentrations of serum GH and prolactin (PRL) in amenorrheic patients were not significantly different from those in normal women except PRL concentrations in hyperprolactinemic patients. Serum GH concentrations significantly increased after MCP administration in normal women and normoprolactinemic-amenorrheic patients, but not in hyperprolactinemic patients. Dopamine causes modest and transient GH secretion in some subjects. Therefore MCP is not likely to stimulate GH secretion through its effect as a dopamine antagonist, and the mechanism of action of MCP on GH secretion is not known. Although the cause of the absence of GH response to MCP in hyperprolactinemic patients is unclear, it may be related to the increased hypothalamic dopaminergic tone which is operative in such patients or it may reflect a direct action of PRL on hypothalamic-pituitary GH regulation.     

Temporal changes in prolactin and corticosterone response during chronic treatment with d-fenfluramine

In order to elucidate the mechanism of development of tolerance to the anorectic effect during chronic treatment with d-fenfluramine (d-F), we examined the temporal changes induced by d-F in food intake and prolactin (PRL) and corticosterone secretion. Male Sprague-Dawley rats were treated for 14 days with d-F (2.5 mg/kg i.p.) or saline twice daily and were given free access to food and water. Groups of 8 rats were sacrificed 30 min after d-F or saline injection at days 1, 4 and 14 for measurements of serum PRL and corticosterone. Food intake and weight gain were reduced significantly by d-F during the first 2-3 days of treatment but not thereafter. Compared with saline, d-F initially increased PRL (57 +/- 9 vs. 7 +/- 0.7 ng/ml) and corticosterone (42 +/- 2 vs. 14 +/- 3 micrograms/dl) serum concentrations. At 4 days, PRL was still significantly increased (43 +/- 5 vs. 10 +/- 4 ng/ml) but corticosterone returned to basal levels. At 14 days, PRL and corticosterone concentrations in the d-F group were not different from corresponding values in the saline group. To verify whether the loss of corticosterone and PRL responses to d-F was not due to a depletion of hormone stores, direct stimulation of corticosterone with corticotrophin and of PRL with metoclopramide were made at days 4 and 14, respectively. Corticotrophin (0.25 mg/kg i.p.) increased corticosterone concentrations similarly in d-F-treated (45 +/- 8 micrograms/dl) and in saline-treated rats (51 +/- 7 micrograms/dl).(ABSTRACT TRUNCATED AT 250 WORDS)     

Prolactin releasing and luteinizing hormone inhibiting activity of dermorphin shorter homologues in the rat

Dermorphin, a heptapeptide isolated from the skin of the frogs Phillomedusa sauvagei and Phillomedusa rhodei, is endowed with potent peripheral and central opioid-like activity. Intracerebroventricular (icv) injection of dermorphin (31.2, 62.5 and 125 pmol/100g) induced in ovariectomized (OVX) rats dose related rises and decreases in prolactin (PRL) and luteinizing hormone (LH) levels, respectively. The aim of this work was to evaluate the same endocrine responses after administration of shorter peptide amide homologues, related to the N-terminal sequence of dermorphin. These compounds retain a substantial analgesic activity although the latter decreases with the decrease in the number of amino acid residues. Icv administration of the hexapeptide homologue (dermorphin 1-6 amide) to OVX rats did not induce any PRL rise or LH inhibition, even at the high dose of 250 pmol/100g. The pentapeptide (dermorphin 1-5 amide), instead, increased PRL and decreased LH secretion, although the effect was significant only at the dose of 250 pmol/100g. Administration of the tetrapeptide (dermorphin 1-4 amide) induced a significant PRL rise and LH inhibition at both the doses of 125 and 250 pmol/100g. The tetrapeptide was the smallest fragment of the dermorphin moiety which caused endocrine responses while the tripeptide (dermorphin 1-3 amide) was completely ineffective in this context. These data indicate that a complete dissociation exists between the behavioral and endocrine effects of the dermorphin homologues examined. In fact, shorter dermorphins whose analgesic potency was directly related to the number of amino acids, exhibited an opposite pattern in evoking endocrine effects.     

Effects of acute hyperprolactinemia on LH pulsatile secretion in hypogonadal and early follicular phase women

To investigate the effects of acute hyperprolactinemia on the 24 h LH pulsatile pattern, 11 women in the early follicular phase (EF, days 3 and 4) and 8 postmenopausal women (PMW) were studied before and during administration of metoclopramide, a dopamine receptor antagonist. Sequential 24 h infusions of either metoclopramide (MCP, 30 micrograms/kg/h) or normal saline were conducted and pulsatile LH activity assessed for 48 hrs. In both EF women and PMW, a prompt (within 90 min, p less than 0.001) and sustained (greater than 45 micrograms/L, p less than 0.001) release of PRL was induced by MCP infusions. MCP-induced hyperprolactinemia failed to modify the LH pulsatile activity in both EF women and PMW. These observations suggest that acute hyperprolactinemia due to dopaminergic blockade has no discernible effect on LH pulsatility and that the reduced LH pulse frequency observed in association with endogenous hyperprolactinemia may result from different neuroendocrine mechanism(s) and/or is time dependent.