naloxone and Hyperprolactinemia

To determine the role of opioidergic and dopaminergic activity in the suppression of GnRH0LH in a hyperprolactinemic state.. Case report.. University hospital.. A 68-year-old woman with a macroprolactinoma.. Serial 10-hour IV infusions of naloxone and metoclopramide.. Serum LH concentration.. Naloxone induced a small but significant rise of serum LH levels, which displayed a pulsatile pattern. By contrast, metoclopramide elicited no significant response in LH secretion.. Opioidergic but not dopaminergic neurotransmission plays a direct role in the suppression of LH secondary to hyperprolactinemia.

Topics: Aged; Bromocriptine; Dopamine Agonists; Dopamine Antagonists; Female; Follicle Stimulating Hormone; Humans; Hyperprolactinemia; Hypogonadism; Injections, Intravenous; Luteinizing Hormone; Metoclopramide; Naloxone; Narcotic Antagonists; Pituitary Neoplasms; Postmenopause; Prolactin; Prolactinoma

The underlying mechanisms involved in the pathogenesis of amenorrhoea in hyperprolactinaemic states still remain unclear. Conflicting information exists on the role of endogenous opiates on gonadotrophin disturbances in this pathological condition. In this study we have undertaken a detailed investigation of LH and PRL secretion before and during administration of naloxone, an opioid receptor blocker, in hyperprolactinaemic women with or without ovarian function in order to assess the role of ovarian steroids upon naloxone induced LH and PRL release.. Five anovulatory and six ovulatory subjects with hyperprolactinaemia were studied before and during naloxone infusion. Five normo-prolactinaemic ovulatory subjects were included as controls. All ovulatory subjects were studied during the luteal phase of a menstrual cycle. Blood was sampled every 10-20 minutes over a 16-hour period on two alternate days. On study day 1 (control day), subjects received two sets of saline infusion every 6 hours and one saline bolus at the beginning of the seventh hour; on study day 3 (naloxone day), they received a saline infusion during the first 6 hours, an intravenous bolus of naloxone (20 mg) at the beginning of the seventh hour and then a continuous naloxone infusion (1.6 mg/hour) during the ensuing 6 hours. Pituitary LH responsiveness and reserve were assessed on both study days by the subsequent administration of 5 and 95 micrograms of GnRH 4 hours before the completion of each sampling period.. Serum concentrations of LH, PRL, oestradiol and progesterone were determined by radioimmunoassay. LH and PRL pulse detection and characteristics were analysed by the Cluster program.. Serum PRL levels in hyperprolactinaemic anovulatory and ovulatory subjects were significantly elevated above the normal range. Oestradiol and progesterone serum levels during the luteal phase in women with hyperprolactinaemia and regular menses were similar to those in control ovulatory subjects. Mean LH concentrations increased during naloxone infusion (P < 0.05) in ovulatory hyperprolactinaemia and controls, whereas PRL increased (P < 0.05) only in the group of control subjects. LH pulse amplitude and pulse interval were increased by naloxone (P < 0.05) in all the ovulatory subjects, with no significant changes in anovulatory hyperprolactinaemic women. PRL pulse characteristics were modified significantly by naloxone only in the control group. On day 1, GnRH administration increased LH in all groups, whereas a consistently lower pituitary LH response was observed after naloxone (day 3). Serum PRL levels significantly increased after GnRH administration on day 1 only in normal women, whilst on day 3 this GnRH-dependent PRL releasing effect was significantly attenuated.. The absence of stimulatory effects of naloxone on LH in anovulatory hyperprolactinaemia implies that endogenous opiates do not play a significant role in the mechanisms governing hypothalamic amenorrhoea in this syndrome. The results in subjects with ovulatory hyperprolactinaemia suggest the existence of an active role of ovarian steroids on naloxone induced LH release. These data, along with those previously reported in normal women throughout the menstrual cycle, are consistent with the concept that sex steroid hormones contribute to the underlying mechanisms involved in the opioidergic control of LH and PRL release. Whether PRL by itself or through other non-opioid neuroendocrine pathways alters the hypothalamic-gonadotroph unit still requires further investigation.

Topics: Adolescent; Adult; Case-Control Studies; Chromatography, Gel; Female; Gonadotropin-Releasing Hormone; Humans; Hyperprolactinemia; Luteal Phase; Luteinizing Hormone; Naloxone; Narcotic Antagonists; Ovulation; Pituitary Gland; Prolactin

It is well known that opioids regulate prolactin secretion through unknown mechanisms. The present study describes the effects of morphine and naloxone administration on pulsatile prolactin secretion in adult sham-operated and pituitary-grafted female rats. Animals were rendered hyperprolactinemic by transplanting 2 pituitary glands beneath the kidney capsule. Naloxone (2 mg/kg/h), morphine (50 mg/kg/h)+naloxone or saline (0.5 ml/h) were administered i.v. through a jugular cannula and bled at 7-min intervals for a period of 3 h. Pituitary grafting increased mean serum prolactin levels, the absolute amplitude and the duration of the pulses, but decreased their frequency. Naloxone, in sham-operated rats, reduced mean serum prolactin levels, the absolute amplitude and the frequency of the pulses. However, morphine+naloxone administration increased mean serum prolactin levels and the absolute amplitudes of prolactin pulses in pituitary-grafted rats. Naloxone administration did not decrease previously increased mean serum levels of prolactin in pituitary-grafted rats. These results suggest that opioids synchronize the pulsatile pattern of prolactin and that these effects are blunted in pituitary-grafted animals.

Topics: Animals; Female; Hyperprolactinemia; Infusions, Intravenous; Jugular Veins; Morphine; Naloxone; Organ Transplantation; Pituitary Gland, Anterior; Prolactin; Pulsatile Flow; Radioimmunoassay; Rats; Rats, Sprague-Dawley

It is well known that opioids regulate luteinizing hormone (LH) secretion through not fully understood mechanisms. This study describes the effects of naloxone on the episodic release of LH in adult sham-operated and pituitary-grafted female rats. Animals were rendered hyperprolactinemic by transplanting 2 pituitary glands beneath the kidney capsule. Naloxone (2 mg/kg/h) or saline (0.5 ml/h) were administered iv through jugular cannulae and subjects were bled at 7 min intervals for a period of 3 h. As expected, pituitary-grafting was followed by an increase in mean values of prolactin during the bleeding period. Naloxone administration decreased mean serum prolactin levels in sham-operated rats and did not further change them in pituitary-grafted animals. Hyperprolactinemia was associated with increases in mean serum LH levels during the bleeding period and in the absolute amplitude of LH peaks. Naloxone administration increased mean values of LH and the absolute amplitude of LH peaks, and decreased their frequency in sham-operated rats. Neither pituitary grafting nor naloxone administration modified the frequency, duration or relative amplitude of LH peaks. However, naloxone administration reduced the mean half-life of LH in sham-operated rats to a similar extent than did pituitary grafting. Naloxone failed to further change the mean half-life of LH in pituitary-grafted rats. These results suggest that opioids modulate the pulsatile pattern of LH and that these effects are blunted in pituitary-grafted animals.

Topics: Analysis of Variance; Animals; Disease Models, Animal; Female; Half-Life; Hyperprolactinemia; Luteinizing Hormone; Naloxone; Pituitary Gland; Prolactin; Pulsatile Flow; Radioimmunoassay; Rats; Rats, Sprague-Dawley

Hyperprolactinaemic amenorrhoea is associated with disturbances of pulsatile gonadotrophin secretion. The underlying mechanism remains unclear and the aim of this study was to investigate the 24-hour secretory pattern of gonadotrophins in women with hyperprolactinaemic amenorrhoea. The effect of opioid blockade using naloxone infusion on LH secretory pattern was also studied.. The secretory patterns of LH, FSH, PRL and their responses to naloxone infusion were studied by serial blood samples collected at 10-minute intervals for 24 hours. On the following day, naloxone was infused at a dose of 1.6 mg per hour for 4 hours.. Eight women with hyperprolactinaemic amenorrhoea, two women hyperprolactinaemic but with normal ovarian cycles, and nine control subjects in the early follicular phase of menstrual cycle.. Concentrations of LH, FSH and PRL were measured in plasma samples obtained at 10-minute intervals for 24 hours. In one woman, concentrations of urinary oestrone glucuronide were measured daily during treatment with pulsatile GnRH.. The number of LH pulses per 24 hours was significantly fewer in women with hyperprolactinaemic amenorrhoea than in those with hyperprolactinaemia with normal cycles or control subjects (mean +/- SEM 4.5 +/- 2.4 vs 13.5 +/- 2.5 vs 17.3 +/- 0.8, P < 0.001). The magnitude of each episode of secretion was significantly higher in the hyperprolactinaemic amenorrhoeic women (P < 0.05) so the overall mean concentrations of LH throughout the 24-hour period was similar in the three groups (5.2 +/- 1.1, 4.8 +/- 0.8 and 5.2 +/- 0.4 U/l respectively). In women with hyperprolactinaemic amenorrhoea there was no significant change in the pattern of LH secretion during sleep in contrast to the control women in whom there was a slowing in the LH pulse frequency during the night. There was no significant change in the mean concentrations of LH, FSH and PRL during the naloxone infusion. There were also no significant changes in the LH pulse frequency in response to naloxone infusion when compared with an equivalent period of time in the previous 24 hours. In one hyperprolactinaemic amenorrhoeic woman, follicular development, ovulation and pregnancy were induced when gonadotrophin releasing hormone (GnRH) was infused in a pulsatile manner at a dose of 5 micrograms every 90 minutes.. The suppression of normal ovarian cycles in women with hyperprolactinaemic amenorrhoea is due to a significant reduction in frequency of LH (GnRH) secretion which is not due to an increase in hypothalamic opioid activity. As normal ovarian cycles can occur or be induced by exogenous GnRH in hyperprolactinaemia, it is unlikely that a high level of prolactin by itself inhibits follicular development and ovulation.

Topics: Adult; Amenorrhea; Circadian Rhythm; Estrone; Female; Follicle Stimulating Hormone; Follicular Phase; Humans; Hyperprolactinemia; Luteinizing Hormone; Naloxone; Secretory Rate

The ability to change the frequency and amplitude of pulsatile GnRH secretion may be an important mechanism in maintaining regular ovulatory cycles. Hyperprolactinemia is associated with anovulation and slow frequency LH (GnRH) secretion in women. To assess whether the slow frequency of LH (GnRH) secretion is due to increased opioid activity, we examined the effect of naloxone infusions in eight amenorrheic hyperprolactinemic women (mean +/- SE, serum PRL, 160 +/- 59 micrograms/L). After a baseline period, either saline or naloxone was infused for 8 h on separate days, and LH was measured in blood obtained at 15-min intervals. Additional samples were obtained for plasma FSH, PRL, estradiol, and progesterone. Responses to exogenous GnRH were assessed at the end of the infusions. LH pulse frequency increased in all subjects from a mean of 4.0 +/- 0.5 pulses/10 h (mean +/- SE) during saline infusion to 8.0 +/- 1.0 pulses/10 h during naloxone infusion (P less than 0.01). LH pulse amplitude did not change, and mean plasma LH increased from 7.4 +/- 0.8 IU/L (+/- SE) to 11.2 +/- 1.5 IU/L during naloxone (P less than 0.01). A small but significant increase was seen in mean plasma FSH. Plasma PRL, estradiol, and progesterone were unchanged by naloxone infusion. These data suggest that elevated serum PRL reduces the frequency of LH (GnRH) secretion by increasing hypothalamic opioid activity and suggest that the anovulation in hyperprolactinemia is consequent upon persistent slow frequency LH (GnRH) secretion.

Topics: Adult; Amenorrhea; Circadian Rhythm; Estradiol; Female; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Humans; Hyperprolactinemia; Luteinizing Hormone; Naloxone; Pituitary Neoplasms; Prolactin

To assess whether gonadotropin-releasing hormone (GnRH) release from the hypothalamus might be altered by hyperprolactinemia in the male rat, we measured in chronically hyperprolactinemic rats the pituitary GnRH receptor content and described the pattern of luteinizing hormone (LH) release during the postcastration rise in gonadotropin secretion 24 and 72 h after gonadectomy. In intact rats, the effect of hyperprolactinemia was determined by describing the pattern of LH secretion, pituitary GnRH receptor content and assessment of pituitary responsiveness to small doses of GnRH (1.0 ng). In addition, to determine the role endogenous opioids might play in inhibiting GnRH release in hyperprolactinemic rats, we examined the effect of both a continuous infusion and a bolus injection of the opioid antagonist naloxone on the pattern of LH release. Chronic hyperprolactinemia was achieved by implanting 4 pituitaries under the kidney capsules 3-4 weeks before study. Acute hyperprolactinemia was achieved by injecting rats with 1 mg ovine prolactin every 12 h for 3 days. Control animals were untreated or were chronically hyperprolactinemic rats in which the hyperprolactinemia was transiently reversed by treatment for 3 days with the dopamine agonist 2-alpha-bromoergocryptine. The mean LH concentration was greatly decreased at 24 postcastration in chronically hyperprolactinemic rats relative to controls. This decrease was associated with a decrease in LH pulse height and pulse amplitude and pituitary GnRH receptor content, but not with an increase in the LH interpulse interval. In contrast, the decrease in mean LH concentrations in hyperprolactinemic animals at 72 h postcastration was primarily associated with a significantly longer LH interpulse interval than that observed in control animals. Chronic hyperprolactinemia in intact rats decreased the pituitary GnRH receptor content, in addition to decreasing the mean LH concentrations during pulsatile GnRH administration. Chronic hyperprolactinemia also inhibited LH release relative to controls during the continuous 4-hour infusion of naloxone and in response to a bolus injection of naloxone. However, in acutely hyperprolactinemic intact male rats a bolus injection of naloxone increase LH secretion 20 min later to levels similar to those obtained in control rats. In summary, these results indicate that chronic hyperprolactinemia decreased LH secretion by primarily decreasing GnRH secretion as suggested by a decrease in

Topics: Acute Disease; Animals; Chronic Disease; Hyperprolactinemia; Kinetics; Luteinizing Hormone; Male; Naloxone; Orchiectomy; Pituitary Gland; Rats; Rats, Inbred Strains; Receptors, LHRH

The cause of the amenorrhea that occurs in patients with hyperprolactinemia is unknown. The involvement of endogenous opioid peptides in the inhibition of GnRH release as a central factor leading to the hypogonadotropic state has been recently described. This study analyzed the LH response to opiate receptor blockade by naloxone (4 mg, iv) in groups of subjects with amenorrhea due to hyperprolactinemia of different etiologies. Patients presenting with a PRL-secreting pituitary adenoma (n = 7), idiopathic hyperprolactinemia (n = 9), or hyperprolactinemia during pharmacological treatment for schizophrenia (n = 5) were studied. Furthermore, to evaluate whether high circulating PRL levels influence the activity of the opioid system after the menopause, a group of seven postmenopausal subjects was tested before and 1 week after the administration of metoclopramide (10 mg, three times a day), a dopamine receptor antagonist. Normal premenopausal women (n = 6) served as controls. Naloxone significantly increased plasma LH levels in both prolactinoma and idiopathic hyperprolactinemic patients (P less than 0.01 vs. basal and placebo). In neither of those groups was a significant correlation found between the plasma LH response to naloxone and basal plasma PRL levels. In contrast to pathological hyperprolactinemia, blockade of opiate receptors did not significantly change LH secretion in either amenorrheic women with pharmacologically induced hyperprolactinemia or postmenopausal women. These results suggest that the effect of hyperprolactinemia on opioid modulation of LH secretion is related to the nature of the hyperprolactinemic state, supporting the existence of increased opioid inhibition of LH levels in pathological hyperprolactinemia.

Topics: Adenoma; Adult; Amenorrhea; Antipsychotic Agents; Dopamine Antagonists; Endorphins; Female; Humans; Hyperprolactinemia; Iatrogenic Disease; Luteinizing Hormone; Menopause; Metoclopramide; Naloxone; Pituitary Neoplasms; Schizophrenia

Topics: beta-Endorphin; Endorphins; Female; Humans; Hyperprolactinemia; Naloxone

Although hyperprolactinemia has been reported to decrease reproductive function in male rats, the mechanism of these effects is not fully understood. We examined the effects of chronic hyperprolactinemia and castration on the LHRH content of the medial basal hypothalamus (MBH) and on the basal and evoked in vitro release of LHRH from the MBH-preoptic area (POA). Adult Wistar-Furth male rats were inoculated with MtTW15 tumor fragments; 3 weeks later half of the rats were castrated. Hyperprolactinemic (H) and normoprolactinemic (N) rats were decapitated 2 weeks later to measure MBH LHRH and serum PRL and LH levels. Elevated PRL levels (greater than 2 micrograms/ml) resulted in significantly increased MBH LHRH stores. Castration caused a 57% depletion of MBH LHRH in N rats; in castrated H rats the MBH LHRH content was also reduced by 40%, a significantly lesser extent. Although serum LH levels in intact H rats were only slightly reduced, postcastration LH hypersecretion was significantly attenuated. In a parallel study, the LHRH release rate was assessed by in vitro perfusion of the MBH-POA. The basal LHRH release rates of intact N and H rats were similar. Castrated N rats released LHRH at a reduced rate (50%; P less than 0.01), whereas in castrated H rats the LHRH release rate was reduced by 20%, which corresponded with the partial depletion of the MBH LHRH content in these rats. To examine the possibility of opiate involvement, LHRH release evoked by two consecutive naloxone (NAL) infusions (1 mg/ml for 30 min) was studied. The two NAL infusions resulted in two similar significant increments of LHRH in the MBH-POA of intact N and H rats. However, castration produced different effects on the NAL-induced LHRH release. First, the second NAL pulse was not effective in stimulating LHRH release from the MBH-POA of N and H castrated rats. Further, the first NAL infusion elicited a significant increase in LHRH output from the MBH-POA of N and H castrated rats, but it was significantly lower in comparison with that in their respective intact counterparts. In addition, the NAL-induced LHRH response was higher from the MBH-POA of castrated H than that in castrated N rats. These studies show that neither basal nor evoked LHRH output in vitro is affected by severe and chronic hyperprolactinemia produced by MtTW15 pituitary tumor cells in intact male rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Animals; Gonadotropin-Releasing Hormone; Hyperprolactinemia; Hypothalamus; Hypothalamus, Middle; Luteinizing Hormone; Male; Naloxone; Neoplasm Transplantation; Orchiectomy; Pituitary Neoplasms; Potassium; Preoptic Area; Rats; Rats, Inbred WF

Endogenous opiate peptides are considered to inhibit LH secretion via a dopaminergic mechanism, and increased opioid inhibition of LH secretion has been found in some hyperprolactinemic women with a pituitary microadenoma. To assess the role of endogenous dopaminergic tone in the opioid regulation of LH secretion in such patients, LH responses to an opioid antagonist (naloxone) and a dopamine antagonist (metoclopramide) were determined in 11 women with a prolactinoma. Neither naloxone nor metoclopramide administration induced any change in serum LH levels in normal women during the early follicular phase. In contrast, 7 of the 11 hyperprolactinemic women responded to both antagonists with a significant increase in LH levels. The parallelism in the LH responses to both antagonists in these hyperprolactinemic patients lends further support to a functional link between opioid and dopamine regulation of LH secretion.

Topics: Adenoma; Adult; Dopamine Antagonists; Female; Humans; Hyperprolactinemia; Luteinizing Hormone; Metoclopramide; Naloxone; Pituitary Neoplasms; Prolactin

Plasma methionine-enkephalin (Met-Enk) immunoreactivity has been determined in 24 patients with varying degrees of renal impairment and 14 patients with hepatic failure. Plasma Met-Enk immunoreactivity correlated inversely with creatinine clearance (r = -0.71, P less than 0.001) but was not affected by even severe hepatic failure in the absence of renal impairment. In two patients, with renal failure and elevated plasma prolactin, administration of naloxone (16 mg) had no effect on circulating prolactin concentrations. These studies indicate that the kidney has a major role in Met-Enk metabolism while the liver does not, and further suggest that elevated circulating endogenous opiates are not responsible for the increased production of prolactin found in renal failure.

Topics: Enkephalin, Methionine; Female; Humans; Hyperprolactinemia; Kidney; Kidney Diseases; Kidney Failure, Chronic; Liver; Liver Diseases; Male; Naloxone