Catecholamines and pituitary function. VI. Effect of different dopamine doses on TRH-induced prolactin release in women with pathological hyperprolactinemia

The present study was designed to examine the effect of low-dose dopamine (DA) infusion rates (0.02 and 0.1 microgram/kg X min) on both basal and TRH-stimulated prolactin release in normal and hyperprolactinemic individuals. Sixteen normally menstruating women in the early follicular phase of a cycle and 23 hyperprolactinemic patients were studied. 0.1 microgram/kg X min DA was infused in 8 normal women and 15 patients with pathological hyperprolactinemia, while 8 normal controls and 8 patients received 0.02 microgram/kg X min DA TRH (200 micrograms, i.v.) was administered alone and at the 180th min of the 5-hour DA infusion in all controls and patients. A significant reduction in serum PRL levels, which was similar in normal women (-59.5 +/- 4.0%, mean +/- SE) and hyperprolactinemic patients (-48.2 +/- 5.5) was observed in response to 0.1 microgram/kg X min DA. In normal cycling women DA infusion significantly (P less than 0.02) reduced the PRL response to TRH with respect to the basal TRH test (delta PRL 45.0 +/- 7.0 vs. 77.9 +/- 15.4 ng/ml). On the contrary, the PRL response to TRH was significantly higher during 0.1 microgram/kg X min DA than in basal conditions in hyperprolactinemic patients, both in absolute (delta PRL 91.8 +/- 17.6 vs. 38.4 +/- 6.8, P less than 0.03) and per cent (198.5 +/- 67.6 vs. 32.1 +/- 7.5, P less than 0.02) values. A normal PRL response to TRH, arbitrarily defined as an increase greater than 100% of baseline, was restored in 11 out of 15 previously unresponsive hyperprolactinemic patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of luteinizing hormone releasing hormone on the copulatory behavior of hyperprolactinemic male rats

The present study was undertaken to test the hypothesis that the deficits in copulatory behavior observed in hyperprolactinemic male rats may be related to a reduction in hypothalamic release of luteinizing hormone releasing hormone (LHRH). Adult male Fischer 344 rats were made hyperprolactinemic by ectopic pituitary grafts or were sham operated and 30 min prior to being tested for copulatory performance received a single subcutaneous injection of 500 ng LHRH, 100 ng LHRH, or saline. On different occasions, testosterone (T) levels were measured in plasma collected 30 min following identical treatments. Plasma prolactin (PRL) levels were determined in samples collected 30 min after injection of 500 ng LHRH. Pituitary grafting produced the expected, significant increase in plasma PRL levels and significant deficits in copulatory behavior. Treatment of hyperprolactinemic subjects with 500 ng LHRH significantly reduced both the time to first intromission and the time to ejaculation to times comparable with those of sham-operated subjects. The 100-ng dose produced a significant reduction in mount frequency. Plasma T levels were significantly elevated following either dose of LHRH. These results demonstrate that exogenous LHRH can restore normal copulatory performance in hyperprolactinemic male rats and support the hypothesis that a reduction in hypothalamic LHRH release is responsible for the behavioral deficits observed in those animals.     

Catecholamines and pituitary function. III. Restoration of the prolactin response to thyrotropin-releasing hormone by low-dose dopamine infusion in women with pathological hyperprolactinemia

Previous studies in Rhesus monkeys have demonstrated that a dopamine (DA) infusion rate of 0.1 microgram/kg X min induces peripheral DA levels similar to those measured in hypophysial stalk blood and normalizes serum prolactin (PRL) levels in stalk-transected animals. We therefore examined the effect of such DA infusion rate on basal and thyrotropin-releasing hormone (TRH)-stimulated PRL secretion in both normal cycling women and women with pathological hyperprolactinemia. 0.1 microgram/kg X min DA infusion fully normalized PRL serum levels in 8 normal cycling women whose endogenous catecholamine synthesis had been inhibited by alpha-methyl-p-tyrosine (AMPT) pretreatment. Furthermore, DA significantly reduced, but did not abolish, the rise in serum PRL concentrations induced by both acute 500 mg AMPT administration and 200 micrograms intravenous TRH injection in normal women. A significant reduction in serum PRL levels in response to 0.1 microgram/kg X min DA, similar to that observed in normal cycling women when expressed as a percentage of baseline PRL, was documented in 13 amenorrheic patients with TRH-unresponsive pathological hyperprolactinemia. However, a marked rise was observed in the serum PRL of the same patients when TRH was administered during the course of a 0.1-microgram/kg X min DA infusion. The PRL response to TRH was significantly higher during DA than in basal conditions in hyperprolactinemic patients, irrespective of whether this was expressed as an absolute increase (delta PRL 94.4 +/- 14.2 vs. 17.8 +/- 14.1 ng/ml, p less than 0.002) or a percent increase (delta% PRL 155.4 +/- 18.9 vs. 17.9 +/- 7.1, p less than 0.0005), and there was a significant linear correlation between the PRL decrements induced by DA and the subsequent PRL responses to TRH. These data would seem to show that the 0.1-microgram/kg X min DA infusion rate reduces basal PRL secretion and blunts, but does not abolish, the PRL response to both TRH and acute AMPT administration. The strong reduction in PRL secretion and the restoration of the PRL response to TRH by 0.1 microgram/kg X min DA infusion in high majority of hyperprolactinemic patients, seem to indicate that both PRL hypersecretion and abnormal PRL response to TRH in women with pathological hyperprolactinemia are due to a relative DA deficiency at the DA receptor site of the pituitary lactotrophs.     

Comparison between a slow-release oral preparation of bromocriptine and regular bromocriptine in patients with hyperprolactinemia: a double blind, double dummy study.

The efficacy and tolerability of a slow-release preparation of bromocriptine (Parlodel SRO) were compared to those of conventional bromocriptine (Parlodel R) in a double blind, double dummy study of 12 hyperprolactinemic women (plasma PRL 81.3 +/- 4.73, ng/ml mean +/- SEM). For 2 weeks, the patients received 2.5 mg b.i.d. Parlodel R or 5 mg once daily Parlodel SRO; for the following 2 weeks, the dose of the drugs was doubled. The patients were then treated, in an open study, with 2.5-10 mg daily Parlodel SRO for 6 months. Both preparations caused a prompt and sharp PRL fall. Hormone levels remained inhibited over the whole month of observation with both preparations. Daily PRL profiles were very close with either drug although morning PRl levels were slightly higher during Parlodel SRO than during Parlodel R administration. Doubling the doses of the two drugs did not result in further significant lowering of PRL values. During the 6-month study with Parlodel SRO, plasma PRL further decreased and normalized in 11 of 12 patients. Clinical improvement occurred in the majority of cases. Tolerability of Parlodel SRO appeared to be better, though without statistically significant differences, than that of Parlodel R. Side effects were less important with the former compound in their number, severity and duration. In conclusion, thanks to its favourable pharmacological profile, Parlodel SRO appears to be a valuable alternative to regular bromocriptine in the management of hyperprolactinemia.     

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.     

Evidence for a dose-dependent effect in the sex-specific plasma prolactin response to naloxone in humans

In attempt to ascertain if the sex specific plasma PRL response to naloxone, that we suggested in previous studies, was a dose dependent effect, 26 healthy volunteers were studied. They received naloxone 2 mg and 4.8 mg or a volume matched of saline i.v. as a bolus. Blood samples were collected and plasma PRL was measured by double antibody RIA. Naloxone, at dose of 2 mg, was able to decrease significantly plasma PRL levels in normally menstruating women (p less than 0.05 at 60 min.; p less than 0.01 at 120 min.), but not in post-menopausal ones and in men. In addition, the dose of 4.8 mg of the drug did not change plasma PRL in any group. These results suggest a dose-dependent effect in the sex specific PRL response to naloxone in humans.     

Catecholamines and pituitary-function. V. Effect of low-dose dopamine infusion on basal and gonadotropin-releasing hormone stimulated gonadotropin release in normal cycling women and patients with hyperprolactinemic amenorrhea

To verify the role of dopaminergic mechanisms in the control of gonadotropin secretion in normal and hyperprolactinemic women, we examined the gonadotropin response to GnRH (100 micrograms i.v.) administration in both basal conditions and during low-dose dopamine (DA, 0.1 microgram/kg/min) infusion. Hyperprolactinemic women, either with microadenoma or without radiological signs of pituitary tumor, showed significantly enhanced LH and FSH responses to GnRH in comparison with normal cycling women. 0.1 microgram/kg/min DA infusion did not result in any appreciable suppression of serum gonadotropin levels but significantly reduced the LH and FSH responses to GnRH in both normal and amenorrheic hyperprolactinemic women. Although both LH and FSH levels remained higher in hyperprolactinemic patients than in normal women after GnRH, the gonadotroph's sensitivity to DA inhibition was normal in the hyperprolactinemic group, as both control subjects and patients with hyperprolactinemic showed similar per cent suppression of GnRH-stimulated gonadotropin release during DA. These data confirm that hypothalamic DA modulates the gonadotroph's responsiveness to GnRH. The increased LH and FSH responses to GnRH in hyperprolactinemic patients and their reduction during low-dose DA infusion seem to indicate that endogenous DA inhibition of pituitary gonadotropin release is reduced rather than enhanced in women with pathological hyperprolactinemia.     

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.     

Zinc: an inhibitor of prolactin (PRL) secretion in humans

The response of plasma prolactin (PRL) to oral administration of increasing doses of zinc (25.0, 37.5 and 50.0 mg) was studied in 17 normal adult men and women. Blood samples were collected at 10 and 30-min intervals over a period of 120 min after two basal times (-30 and 0 min). PRL concentrations significantly fell below basal levels in all subjects in response to the increase in plasma zinc levels, as compared to the controls. These results suggest that acute hyperzincemia can inhibit basal PRL secretion in normal individuals.     

Intranasal administration of His-D-Trp-Ala-Trp-D-Phe-LysNH2 (growth hormone releasing peptide) increased plasma growth hormone and insulin-like growth factor-I levels in normal men

The effects of intranasal and iv administration of His-D-Trp-Ala-Trp-D-Phe-LysNH2 (GHRP) on plasma GH, PRL, LH, FSH, TSH, cortisol, insulin, IGF-I as well as GHRH-like immunoreactivity (LI) levels were examined in 6 healthy male subjects. An iv bolus injection of GHRP(1 micrograms/kg BW) caused a remarkable increase in plasma GH levels with a mean (+/- SE) peak of 54.9 +/- 4.2-micrograms/L. In addition an intranasal administration of GHRP resulted in a significant, dose-related increase in plasma GH with peaks of 39.6 +/- 15.3 micrograms/L at a dose of 30 micrograms/kg BW, 14.1 +/- 5.0 micrograms/L at 15 micrograms/kg BW and 7.5 +/- 5.7 micrograms/L at 5 microgram/kg BW. Plasma PRL and cortisol levels were slightly but significantly increased after iv administration of GHRP, whereas GHRP totally failed to affect plasma TSH, LH, FSH, insulin, blood sugar and GHRH-LI levels. Seven consecutive, intranasal administrations of 15 micrograms/kg BW GHRP every 8h were well tolerated in all subjects examined. During this treatment, GH responsiveness to GHRP was not attenuated by desensitization and plasma IGF-I was increased from 94.5 +/- 5.8 micrograms/L before GHRP to 125.8 +/- 6.0 micrograms/L after repeated GHRP administration. These findings indicate that intranasal administration of GHRP stimulates GH secretion and consequently enhances IGF-I production in normal subjects. If GHRP is demonstrated to be beneficial in the treatment of some patients with GH deficiency, the intranasal route of administration may be more useful than the painful injection because a prolonged period is required for the treatment.     

Possible thyrotrophs insensitivity to dopamine in hyperprolactinaemic amenorrhoeic patients

The study assessed the sensitivity of the thyrotrophs of hyperprolactinaemic patients to a physiological dose of dopamine (DA). Eight hyperprolactinaemic amenorrhoeic patients received 4-hour infusions of either DA (0.4 micrograms/kg x min) or glucose. Twelve normal women served as controls. In normal women the mean thyrotrophin (TSH) concentration declined significantly (P less than 0.05) from 81 +/- 6.6% of basal levels during glucose infusion to 59 +/- 5.8% of basal levels during DA infusion. In contrast DA infusion to hyperprolactinaemic patients caused no significant reduction in TSH levels compared to glucose infusion (DA infusion 68 +/- 4.7% of basal levels; glucose infusion 73 +/- 4.9% of basal levels). DA infusion caused a significant reduction in serum prolactin (PRL) levels both in hyperprolactinaemic patients (P less than 0.001) and normal women (P less than 0.02), but the PRL suppression was significantly (P less than 0.05) less pronounced in the hyperprolactinaemic patients, compared to normal women. We propose that the abnormal PRL as well as TSH secretion in hyperprolactinaemic amenorrhoeic patients may be due to a common defect. Both the lactotrophs and the thyrotrophs may be relatively insensitive to dopaminergic inhibition.     

Impaired LH-RH release by estrogen in women with sulpiride-induced hyperprolactinemia

The effects of hyperprolactinemia on the release of immunoreactive luteinizing hormone-releasing hormone (LH-RH) and luteinizing hormone (LH) in response to iv injection of 20 mg conjugated estrogens (Premarin) were studied. Five normal cycling women were injected with Premarin on the morning of the 7th day of the first cycle (control cycle), and then the plasma levels of LH-RH, LH, and prolactin (PRL) were determined every 8 to 16 hours for 72 h. Two months later, the same women received 200 mg of oral sulpiride daily for 8 days from the 3rd day of the cycle (sulpiride treated cycle), and then the same protocol as in the control cycle was applied. Mean (+/- SE) plasma levels of PRL on day 7 in the sulpiride treated cycle were significantly higher than those in the control cycle (118 +/- 24 ng/ml vs. 14 +/- 4 ng/ml, p less than 0.001). After estrogen injection, the mean percent increases in immunoreactive LH-RH at 32 h (control: 71 +/- 38% vs. sulpiride: 6 +/- 36%) and 40 h (154 +/- 38% vs. -5 +/- 21%) and in LH at the 48 h (175 +/- 89% vs. 57 +/- 57%) and 56 h (99 +/- 32% vs. 7 +/- 21%) were significantly (p less than 0.01 or p less than 0.05) suppressed in the sulpiride cycle. These data suggest that the impaired positive feedback effect of estrogen on LH-release in hyperprolactinemic anovulatory women may be caused, at least in part, by disturbed LH-RH release.     

Plasma aldosterone response to metoclopramide is unmodified by hyperprolactinemia

It has been previously demonstrated that patients with hyperprolactinemia have impaired PRL response to dopaminergic blockade and increased TSH response. Since inhibitory dopaminergic modulation of aldosterone is well established, we have examined whether prolactinoma patients have an altered aldosterone response to dopaminergic blockade. To investigate this possibility we compared the plasma PRL, TSH and aldosterone responses to the dopamine (DA) antagonist metoclopramide (MCP; 10 mg i.v.) in 10 women with prolactinomas and 7 healthy female controls. Basal PRL levels in prolactinoma patients were elevated and showed a blunted rise following MCP. Although basal TSH levels were similar in the 2 groups of subjects, they significantly increased (p = 0.017) in prolactinoma patients while in contrast they did not significantly change in control subjects. Basal supine plasma aldosterone was similar in patients with prolactinomas (0.23 +/- 0.03 nmol/l) and in healthy subjects (0.25 +/- 0.04 nmol/l) and the increased aldosterone concentrations from 15 to 120 min following MCP were not significantly different in prolactinoma patients and in control subjects. It is concluded that in patients with prolactinomas, the alteration in the dopaminergic regulation is specifically related to the lactotroph.     

Influence of bupropion HCl (Wellbatrin), a novel antidepressant, on plasma levels of prolactin and growth hormone in man and rat.

Bupropion HCl (Wellbatrin®), a non-tricyclic compound with antidepressant effects in man, was evaluated for effects on plasma prolactin (PRL) and growth hormone (GH) levels in normal human subjects, and for effects on plasma PRL levels in a series of pharmacological studies in normal rats. Single oral doses of 50, 100 or 200 mg of bupropion given to male (n=6) and female (n=12) subjects produced a marked suppression (80% decrease) of PRL. Incomplete PRL recovery was observed at the end of 24 hours. One hour after drug administration there was a +0.56 correlation of percent decrease in PRL levels with bupropion plasma levels. GH showed only small and erratic changes in plasma levels at 1–4 hours post-dose. In the rat, single bupropion doses of 25 mg/kg, i.p., failed to lower basal PRL levels. Bupropion, however, significantly decreased PRL in rats in which plasma PRL was elevated by pretreatment with alphamethyltyrosine, 5-hydroxytryptophan or quipazine. Bupropion, on the other hand, did not counteract the PRL-elevating effect of haloperidol. Results in man and rat are consistent with the view that bupropion has significant dopamine mimetic properties. Whether bupropion is a direct dopamine receptor-stimulator or an indirectly acting agonist cannot be determined from the present results.     

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.     

Prolactin after baclofen in healthy subjects and prolactinoma patients

Serum prolactin (PRL) levels in basal conditions (two samples) and 30, 60, 90, 120, 150 e 180 minutes after oral administration of baclofen (20 mg) were evaluated in 6 healthy subjects and in 10 patients with prolactinoma. The effect of baclofen (20 mg by mouth) on the PRL secretion cimetidine (400 mg i.v.) or domperidone (20 mg i.v.) induced were evaluated in 9 healthy women by administration of baclofen 60 minutes before cimetidine or domperidone. Baclofen was unable to significantly rise serum PRL levels in healthy subjects and in patients affected by prolactinoma and furthermore did not interfere with PRL rise domperidone induced. On the contrary baclofen decreased PRL rise cimetidine induced. It was concluded that: in basal condition, GABAb receptor don't play an obvious role in modulation of PRL secretion; when H2 istaminergic inhibition on PRL secretion is blocked (at an hypothalamic site), a GABA inhibition, b receptor mediated, on PRL secretion became more clear; the domperidone blockade of hypophysial dopaminergic receptors suggests that GABAb modulation of prolactin secretion don't obtain itself by dopaminergic pathways.     

Effects of treatment of normal and hyperprolactinemic rats with cyclosporine in vivo on the release of gonadotropins and prolactin from their pituitaries in vitro.

Cyclosporine (CyA) is extremely useful as an immunosuppressant and it is believed that at least some of its actions are due to antagonizing PRL effects. To determine whether the reported ability of CyA to inhibit gonadotropin release can be modified by PRL, we have examined the effects of treatment of normal and hyperprolactinemic rats with CyA in vivo on the release of LH, FSH and PRL from their pituitaries in vitro. Hyperprolactinemia was induced by implantation of capsules containing diethylstilbestrol (DES) and the animals were examined while the capsules were still in place (DES-IN) or after they had been removed (DES-OUT). Treatment with CyA significantly reduced plasma LH levels in control DES-IN rats without reducing basal LH release from the pituitaries of these animals in vitro. In the DES-IN rats, CyA exposure in vivo did not modify plasma PRL levels, but reduced PRL release in vitro, and interfered with the inhibitory action of dopamine (DA) on PRL release. The effect of DA on gonadotropin release in vitro was modified by CyA treatment. Administration of CyA failed to antagonize the suppressive effects of hyperprolactinemia on plasma LH and FSH levels or on the basal rates of gonadotropin release by incubated pituitaries. We conclude that CyA can reduce PRL release but does not interfere with the actions of PRL on anterior pituitary function.     

Biological response modifiers of cancer-related neuroendocrine disorders: efficacy of the long-term dopaminergic agonist cabergoline in the treatment of breast cancer-induced hyperprolactinemia

The evaluation of the biological status of cancer patients should not be limited only to investigation of immune reactivity, but should also include analysis of the endocrine condition, namely concerning those hormones which have appeared to be tumor growth factors, such as prolactin (PRL) for breast and prostate carcinomas. This statement is justified by the fact that the evidence of abnormally high serum concentrations of PRL has been proven to be associated with poor prognosis in breast and prostate cancer patients. Moreover, since hyperprolactinemia negatively influences the efficacy of anticancer therapies in breast cancer, it could be fundamental to achieve a normalization of PRL levels by long-acting dopaminergic agents, such as cabergoline. On this basis, a study was planned to evaluate the effect of cabergoline on PRL levels in hyperprolactinemic metastatic breast cancer subjects. The study included 20 hyperprolactinemic metastatic breast cancer subjects, who were randomized to receive no therapy or cabergoline at 0.5 mg/week orally for 4 consecutive weeks. Cabergoline therapy induced a normalization in all patients, whereas no spontaneous normalization of PRL levels occured in the control group. These results show that a weekly oral administration of the long-acting dopaminergic agent cabergoline is a well tolerated and effective treatment of metastatic breast cancer-related hyperprolactinemia. The possible prognostic impact of PRL normalization needs to be established by successive studies.     

Anterior pituitary and plasma prolactin in rats after 2 to 90 minutes of suckling.

Separation of litter for 6 hr resulted in plasma PRL levels of 48 +/- 5.8 and 45 +/- 5.7 ng per ml and AP PRL concentrations of 6.1 +/- 0.6 and 6.3 +/- 0.5 mug per mg AP in early (4-8 days) and late (20-22 days) lactation, respectively. After a 6-hr separation period, suckling for 2, 30, 60, and 90 min resulted in highly significant increases in the plasma PRL level in early lactaiton. Increases in plasma PRL levels were not seen in late lactation except in the 30-min suckled group. In both stages of lactation the AP PRL concentrations in the suckled groups were significantly lower than in the nonsuckled groups.     

Abnormal dopamine sensitivity in some human prolactinomas

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