PRL Response Research Articles

Plasma prolactin concentrations in parental male and female rats: effects of exposure to rat young.

The effects of pup presentation on the PRL responses in parental male rats were measured and compared with those in parental virgin and lactating female rats. Blood samples were collected from rats through indwelling intraatrial cannulas after a suckling challenge, i.e. presentation of rat young. Lactating rats showed full parental behavior and characteristic large surges in plasma PRL levels within the first 5-10 min on each day that rat young were presented (days 4, 8, and 12 of lactation). When pups were not presented, PRL rises did not occur. In contrast to the pattern of PRL responses shown by lactating mothers, parental ovariectomized nulliparous female and parental intact male rats failed to show specific increases in PRL in response to pup presentation. Plasma PRL levels in these groups, as in nonparental female and male rats, occasionally rose in response to blood collection rather than to pup presentation alone. Treatment of nulliparous female as well as male rats with estradiol and progesterone Silastic implants for 21 days before the initiation of behavioral testing significantly reduced the latencies of both nulliparous females and males to respond to foster young from about 5 to 2 days. The PRL responses of these steroid-primed groups were quite different. The steroid-primed females exhibited a pattern of PRL responses to pups identical to that found in lactating rats. The steroid-primed parental males, in contrast, failed to show specific increases in plasma PRL levels in response to young. These data demonstrate a sex difference in the hormonal, but not behavioral, responses of male and female rats to young and are suggestive of possible sex differences in the hypothalamic and/or peripheral regulation of pup-induced PRL secretion.

LACK OF RISE IN SERUM PROLACTIN FOLLOWING YTTRIUM‐90 INTERSTITIAL IRRADIATION FOR ACROMEGALY

We have investigated the possibility that the increase in serum PRL levels observed in patients with acromegaly treated with external irradiation could be due to damage to the hypothalamus or portal vessels, by comparing the effects of yttrium-90 interstitial irradiation, which is highly localised and does not normally extend to the hypothalamus, in a similar series of patients. Sixteen acromegalic patients treated by interstitial irradiation with yttrium-90 are described; GH fell from a mean of 131 mU/l (median 113 mU/l) to 17 mU/l (median 8 mU/l) after one year (P less than 0.001). PRL fell in the five initially hyperprolactinaemic patients (mean fall +/- SD: 39 +/- 17 micrograms/l at one year), but remained unchanged in the normoprolactinaemic group; PRL responsiveness to TRH was retained. Five, out of the seven normoprolactinaemic patients examined, were shown by in vitro studies of their pituitary biopsies, to have tumours that also synthesised or secreted PRL. These results are consistent with the hypothesis that the rise in PRL following external irradiation is the result of damage to the hypothalamus or portal vessels. A less likely explanation is that an overgrowth of radio-resistant PRL-secreting tumour cells is occurring after external irradiation, but not after yttrium-90 implantation.

Effects of short photoperiod on the ability of golden hamster pituitaries to secrete prolactin and gonadotropins in vitro.

Transfer of male golden (Syrian) hamsters from a 14L:10D (light:dark) to a 5L:19D photoperiod induced significant changes in pituitary function tested in vitro. Within 27 days after transfer to a 5L:19D photoperiod, basal prolactin (Prl) release was significantly depressed and response to dopamine (DA) was significantly enhanced as compared to Prl release by pituitaries from 14L: 10D hamsters. Follicle-stimulating hormone (FSH) release tended to be depressed after 9 or 27 days of 5L:19D exposure, but the effect was not significant. After 77 days of 5L:19D exposure, Prl release was further suppressed, while FSH release surpassed that seen in 14L:10D pituitaries. In vitro FSH response to luteinizing hormone releasing hormone (LHRH) was also enhanced at this time. After 15 weeks of exposure to a short photoperiod, FSH secretion was still elevated above control levels, but Prl release and Prl response to DA were no longer different from that of 14L: 10D controls. Secretion of luteinizing hormone (LH) in vitro, either basal or LHRH stimulated, was not affected by photoperiod at any time tested. From these results, we conclude that short photoperiod exposure does not reduce the pituitary's ability to secrete LH or FSH, although secretion of Prl is severely attenuated.

Influence of dopaminergic inhibition on serum levels of thyrotrophin and prolactin in patients with hypothyroidism before and after prolonged oral administration of TRH.

Forty mg TRH/day given orally for 3 weeks to 8 patients with mild primary hypothyroidism decreased serum TSH from a mean of 4.0 ng/ml +/- 1.2 (SE) to 2.0 ng/ml +/- 0.4 (49%), and their mean incremental TSH response to iv TRH was equally reduced from 8.6 ng/ml +/- 2.5 to 4.0 ng/ml +/- 1.9 (46%). In the same patients serum Prl was 8.2 ng/ml +/- 2.2 before oral TRH treatment and 6.6 ng/ml +/- 1.5 (81%) after treatment, and the mean incremental Prl response to iv TRH was reduced from 43.5 ng/ml +/- 5.0 to 35.9 ng/ml +/- 7.5 (83%). The oral administration of 10 mg of the dopamine antagonist metoclopramide increased mean serum TSH from 0.6 ng/ml +/- 0.1 (SE) to 0.7 ng/ml +/- 0.1 (120%) in euthyroid subjects and from 4.0 ng/ml +/- 1.2 to 5.7 ng/ml +/- 1.6 (145%) in patients with primary hypothyroidism, and mean serum Prl from 8.6 ng/ml +/- 0.8 to 109.5 ng/ml +/- 24.3 (1251%) and from 8.2 ng/ml +/- 2.2 to 119.6 ng/ml +/- 45.5 (1460%), respectively. The incremental TSH responses to iv TRH increased 2.3-fold in euthyroid subjects pre-treated with metoclopramide, while no change was observed in the TSH responsiveness in patients with primary hypothyroidism following metoclopramide pre-treatment. In the euthyroid subjects metoclopramide treatment had no effect on the Prl response to iv TRH.(ABSTRACT TRUNCATED AT 250 WORDS)

Nomifensine, TRH and insulin-induced hypoglycemia tests in the diagnosis of prolactinomas.

Nomifensine, TRH and insulin-induced hypoglycemia tests were carried out in 37 cases of hyperprolactinemia: 25 were due to PRL-secreting pituitary tumors, 6 cases to GH and PRL-secreting pituitary tumors and 6 to pituitary and suprasellar non secreting tumors. Nomifensine failed to suppress the serum PRL in all subjects and PRL responses to TRH and insulin-induced hypoglycemia were impaired in all patients, irrespective of the origin of hyperprolactinemia. The uniform pattern of PRL response to the above tests in patients with hyperprolactinemia of variable etiology suggests that none of them is specific for prolactinomas.

The interrelationships between prolactin and thyrotrophin secretion following dopaminergic blockage in patients with mild hyperprolactinaemia without any demonstrable pituitary tumour.

PRL, TSH and gonadotrophin responses to the dopaminergic antagonist, metoclopramide, were studied in mildly hyperprolactinaemic patients with normal sella radiology and CT scan. Eleven female patients with basal PRL levels ranging from 23 to 124 ng/ml were challenged with intravenous metoclopramide (10 mg) and on subsequent occasions with TRH (200 micrograms) and LHRH (100 micrograms). On the basis of the PRL secretory pattern following metoclopramide and TRH stimulation, the patients were divided into two groups. Group I comprised six subjects who were PRL non-responsive to TRH and metoclopramide. Group II (five subjects) demonstrated PRL responses to TRH and metoclopramide indistinguishable from female controls. Mean +/- SD basal PRL levels were 68.5 +/- 29.9 ng/ml in Group I and not different in Group II (40.6 +/- 12.0 ng/ml). Basal LH levels were increased in Group II, whereas FSH was increased in Group I. Basal TSH levels were lower in Group I than the controls. Following metoclopramide, Group I patients had an increase in TSH from a basal of 2.4 +/- 0.7 microU/ml to a peak of 5.9 +/- 2.7 microU/ml (P less than 0.005) which occurred at 30 min. TSH values were increased above basal at all time intervals following metoclopramide. In contrast, TSH levels did not change in Group II patients or the controls after metoclopramide administration. Both patient groups had TSH responses to TRH similar to the controls. Following LHRH, the LH increase was greater in Group II and the FSH in Group I. In neither group nor the controls did gonadotrophin levels change after metoclopramide. In Group II females, PRL responsiveness to metoclopramide was associated with TSH non-responsiveness. In Group I females, PRL levels failed to rise, whereas TSH increased. The PRL and TSH profile in Group I females is typical of a prolactinoma. It is concluded that PRL as well as TSH determinations following metoclopramide are useful indices in the assessment of hyperprolactinaemia and may be of value in differentiating the functional state from that of a pituitary tumour.

Regression of a pituitary adenoma following levothyroxine therapy of primary hypothyroidism

Two patients are described who were suffering from primary hypothyroidism and who developed a pituitary microadenoma and macroadenoma with suprasellar extension, respectively, diagnosed by CT scan of the pituitary. Both patients originally presented with amenorrhea and galactorrhea. In addition to low serum T4 and T3 levels and an elevated TSH level, they also had hyperprolactinemia. The TRH test performed in one of the patients showed an exaggerated response of both TSH and PRL to TRH. Correction of hypothyroidism by prolonged (months) treatment with levothyroxine resulted in normalization of thyroid function tests as well as hyperprolactinemia and in regression of the pituitary tumor. It was concluded that primary hypothyroidism was the cause of the pituitary adenoma and the amenorrhea/galactorrhea syndrome. It is recommended that routine thyroid function tests be obtained for patients with hyperprolactinemia. Demonstrable primary hypothyroidism should be corrected for prolonged periods of time by levothyroxine therapy, and CT scanning of the pituitary should be repeated before any other treatment such as bromocriptine or surgery is attempted.

LRF and TRF test during long-term danazol treatment: increase of the LH and FSH responses but decrease of the prolactin and TSH responses

Seven patients suffering from severe endometriosis were treated with danazol 200 mg X 3 daily for 6 months. Clinical symptoms were alleviated and menses disappeared in response to the treatment. After cessation of the treatment the menstrual bleedings returned in 1-3 months. Blood samples for determination of gonadotrophins, prolactin (Prl), oestradiol (E2), progesterone, thyroid hormones and thyrotrophin in radioimmunoassays were taken and a combined TRF and LRF test carried out in the follicular phase before treatment, at the 6th month of treatment and after reappearance of the first menses. There were no statistically significant changes in the basal levels of serum FSH, LH or TSH during the danazol treatment. Neither was there any change in episodic secretions of FSH, LH or Prl, as determined by the mean coefficients of variation of the hormone levels in seven consecutive samples taken at 20 min intervals. On the other hand, serum E2, Prl and thyroid hormone levels were significantly decreased in the 6th month of treatment. In the TRF-LRF test the responses of serum FSH and LH were significantly higher and those of serum Prl and TSH significantly lower during danazol treatment than before. Prl responses remained lowered after the treatment. It appears that low serum oestrogen levels, induced by the danazol treatment, sensitize the pituitary gonadotrophs to exogenous LRF, but make the sensitivity of thyrotrophs and lactotrophs lower to exogenous TRF. These results thus indicate that danazol does not make the pituitary gonadotrophs insensitive to LRF, but danazol may rather inhibit the secretion of hypothalamic LRF.

Prolactin and thyrotrophin responses to thyroliberin (TRH) in patients with growth hormone deficiency: study in 167 patients.

Both thyrotrophin (TSH) and prolactin (Prl) were studied under thyroliberin (TRH) stimulation tests in 167 hypopituitary dwarfs out of GH or T4 treatment. TSH and/or Prl responses were either low, normal or exaggerated and/or protracted. Various abnormal patterns were observed in most of the patients with low T4 but also in many patients with normal T4. The TSH response should be considered together with the value of T4. A normal response of TSH with a low T4 reflects a relative TSH deficiency from pituitary or hypothalamic origin. There was no clear relationship between the cause or type of hypopituitarism and the pattern of the responses of either TSH or Prl. The abnormalities of TSH and Prl were not related to each other except in patients with a past history of breech delivery. Then both TSH and Prl have to be measured after TRH in order to obtain full information from the test about hypothalamo-pituitary function. The frequency of the exaggerated and/or delayed or protracted responses of TSH and Prl with normal or low T4 is probably mostly related to hypothalamo-pituitary dysfunction. Abnormal responses of TSH or Prl, seldom of both hormones, were observed in otherwise isolated growth hormone (GH) deficiency, leading to a modification of such a diagnosis after the TRH test. Actually, the TRH test may be useful to ascertain the diagnosis of GH deficiency when the GH responses to provocative tests are borderline.

The dissociation of the exaggerated prolactin and thyrotropin responses in seminiferous tubule failure following the administration of a double-pulse of thyrotropin-releaslng hormone

PRL and TSH secretion has been evaluated in 11 patients with seminiferous tubule failure and 9 controls. When compared to the controls, the patients had increased basal FSH, TSH and PRL levels. However, LH, E2, T and thyroid hormone levels were similar to the controls. Both groups were given two pulses of TRH (200 micrograms) at 30 min intervals. Following the initial pulse of TRH, the patients demonstrated exaggerated TSH and PRL responses. The administration of a second pulse of TRH led to a further increment of TSH secretion in the patients. There was, however, no PRL response to the second TRH pulse in either patients or controls although mean PRL levels remained significantly greater in the patients.

Prolactin suppresses luteinizing hormone secretion and pituitary responsiveness to luteinizing hormone-releasing hormone by a direct action at the anterior pituitary.

In pathological or experimental hyperprolactinemia, the elevated circulating levels of PRL are the usual cause of the impairment in gonadotropic function. The present study was undertaken to determine whether PRL could suppress basal LH secretion and LHRH-stimulated LH release by a direct action at the anterior pituitary. Anterior pituitaries from ovariectomized rats were incubated in medium 199 alone or in medium 199 containing ovine PRL, and basal and the LHRH-stimulated LH release were followed for 2 or 3 h in vitro. Ovine PRL at 40 and 80 micrograms/ml suppressed basal LH release by 41% and 72%, respectively, at 2 h of incubation. This suppressive effect of both concentrations of PRL continued to the third hour of incubation. LHRH at 5 ng/ml increased the release of LH from pituitaries incubated in medium alone by 57%, 61%, and 107% at 1, 2, and 3 h of incubation, respectively. However, in the pituitaries treated with 40 micrograms/ml ovine PRL, the stimulatory effects of LHRH were diminished at all time points measured. Pretreatment of anterior pituitaries with ovine PRL for 6 h significantly inhibited by 81% the LHRH (5 ng/ml) stimulation of LH release at 2 h of incubation. On the other hand, inhibition of endogenous PRL release by 10(-6) M bromocriptine enhanced the stimulatory effects of 5 ng/ml LHRH by 2.5-fold at 2 h of incubation. The inhibitory effects of PRL on basal and stimulated LH secretion appeared unique, since neither BSA nor vasopressin could elicit similar suppressive effects on LH. These results suggest that in anterior pituitaries exposed to elevated levels of PRL, LH secretion and pituitary responsiveness to LHRH could be impaired. This phenomenon may contribute in part to the antigonadotropic effects of PRL.

Growth hormone secretion by cultured rat anterior pituitary cells. Effects of culture conditions and dexamethasone.

Optimal conditions were sought for the study of GH secretion by cultured normal pituitary cells. Dispersed rat pituitary cells were cultured for 1 week in four different media supplemented with 10% fetal calf serum. Minimal essential medium resulted in high GH content and secretion during a 4-h incubation period, whereas GH secretion was lower (P less than 0.05) for cells cultured in medium 199, Ham's F-10, and RPMI-1640. GH secretion/24 h declined gradually with time. After 2 weeks in culture hormone secretion amounted to 30% of secretion on day 1, but after 3 weeks GH secretion was still measurable. GH recovery during the 3-weeks culture period was more than 600% of the amount initially plated. GH secretion was positively correlated with the bicarbonate concentration between 0.85 and 2.2 g/liter NaHCO3. When pituitary cells were cultured in concentrations varying from 0.5 X 10(5) to 10 X 10(5) cells per dish, GH secretion and content per cell were constant, suggesting that no direct autofeedback occurred in cultures with high cell densities and thus high medium GH. Dexamethasone stimulated GH secretion and content in a dose-dependent way (0.1 nM-10 microM). The stimulatory effect of 100 nM dexamethasone occurred within 24-48 h. After 7 days of treatment with 100 nM dexamethasone, GH secretion had increased to 190% and GH content to 230% of control. In contrast to the effects on GH, dexamethasone suppressed PRL secretion in a dose-dependent way, but this effect was seen only after 7 days of treatment and not after 4 days of treatment. Cycloheximide and actinomycin D prevented the stimulatory effect of dexamethasone on GH secretion. However, 24 h after cessation of cycloheximide treatment GH secretion was stimulated by dexamethasone. Four days of treatment with 100 nM dexamethasone did not affect the GH response to somatostatin, prostaglandin E1, and theophylline, nor the PRL response to dopamine, TRH, and theophylline. Thus, culture conditions may affect GH production, and dexamethasone can be used to culture somatotrophs for longer periods with steady GH production and normal responsiveness.

No acute effect of pimozide on the plasma GH levels in acromegaly.

In 34 acromegalic patients either untreated or inadequately treated by surgery and/or radiotherapy the plasma GH levels and plasma Prl levels were determined during 8 h after the acute administration of the dopamine agonist bromocriptine and during 150 min after the administration of the dopamine antagonist pimozide. A 50% or more suppression of the basal GH levels was arbitrarily defined as a positive response. Seventeen patients displayed a positive response to bromocriptine, 17 patients displayed a negative response to bromocriptine. Plasma Prl levels were elevated in 6 of 17 bromocriptine responders and in 2 of 17 bromocriptine nonresponders. There was no difference in the plasma GH response to pimozide administration in the patients with a positive or a negative GH response to bromocriptine. With one exception there was in no patient a positive GH response to pimozide. In further experiments the plasma GH response to pimozide was measured during 11 h in 6 bromocriptine sensitive and 6 bromocriptine insensitive patients. Again no difference was found between bromocriptine responders and non-responders. There was also no difference in the Prl response to bromocriptine or pimozide between GH responders and GH non-responders. The Prl response to pimozide was blunted in comparison to a control group. The present study does not not lend support to the idea that there is a fundamental difference in the degree of hypothalamic dopaminergic control of GH or Prl secretion between bromocriptine sensitive and bromocriptine insensitive patients with acromegaly.

Evidence of receptors for thyrotropin-releasing hormone in human prolactin-secreting adenomas.

Specific receptors for TRH were demonstrated on cellular membranes from 8 out of 10 human PRL-secreting adenomas. One binding site was characterized. The mean (+/- SD) value for the dissociation constant (Kd) from 8 adenomas was 68 +/- 7 nM. The maximal number of binding sites varied from 1 adenoma to another (from 50-1200 fmol/mg protein). In 7 of the 8 patients, there was little or no in vivo plasma PRL response to TRH although receptors for TRH were present on their tumors. It is thus suggested that in vivo absence of stimulatory effect of TRH in human PRL-secreting adenomas is not due to the absence of TRH receptors.

The role of thyrotrophin releasing hormone in the diagnosis of isolated gonadotrophin deficiency

We studied the response of PRL and TSH to thyrotrophin-releasing hormone (TRH) in 15 boys with delayed adolescence and 6 male subjects with isolated gonadotrophin deficiency (IGD). TRH tests were repeated in the IGD subjects during and 1 month following hCG treatment. Male IGD subjects showed a significantly decreased basal and TRH induced PRL response compared to male controls and subjects with delayed adolescence. Human chorionic gonadotrophin (HCG) treatment of male IGD subjects restored basal and stimulated PRL levels to the range of normal controls. This was, presumably, an estrogenie effect since non aromatizable androgens did not increase the PRL response; moreover, the antioestrogen, clomiphene, decreased the PRL response when given with HCG. The TSH response to TRH in delayed adolescents was increased as compared to adult male controls and IGD subjects and was similar to adult female controls. HCG treatment of IGD subjects had no effect on basal nor peak TSH levels, although ethinyl oestradiol did increase the TSH response in two IGD subjects. These studies show that the PRL and TSH responses to TRH may differentiate delayed adolescence from IGD. The increased TSH response to TRH in delayed adolescence as compared to adult males, is a manifestation of an enhanced oestrogen effect in these patients. The abnormal PRL dynamics in IGD is a consequence of estrogen deficiency.

Effects of estradiol benzoate and castration on LH in experimental hyperprolactinemia

Female rats of the Wistar strain were rendered hyperprolactinemic by grafting one additional pituitary gland under the right kidney capsule at various ages (5 days group A; 30 days group B and 90 days group C). Age matched animals were sham operated to serve as controls. Plasma levels of PRL and LH were measured by specific double antibody RIA. Basal preoperative PRL levels were increased rapidly after grafting, reaching values over 100 ng/ml, in front of the 20 ng/ml showed by sham operated controls. Plasma LH levels were significantly decreased in all hyperprolactinemic groups as compared to controls. After Estradiol Benzoate (EB) administration all control rats showed an increase in PRL levels in a pulsatile manner with higher values found in the afternoon. PRL response in transplanted rats was less evident and with absence of pulsatility. LH responses to EB in control animals showed a biphasic pattern, with a negative feed-back in the first hours followed by a positive effect at 31 or 55 h after the injection. This pattern of response started in the control rats from group A at 19 days of age. Before that, only the negative feed-back effect was present. In grafted animals from the same group no positive feed-back effect could be detected at any time studied. In group B, a reduction in the positive feed-back effect, more evident after 90 days of hyperprolactinemia was detected. Animals of group C on the contrary showed an increased positive feed-back effect 40 days after grafting. Eight days after castration a reduction in PRL levels was detected in all groups, together with an increase in LH values. PRL values after ovariectomy were less reduced in grafted animals, and these rats also showed a less marked LH increase. This effect is more evident in group B. All these data seem to point out that hyperprolactinemia is capable of modifying the feed-back system between E 2 and LH, and that the age at which hyperprolactinemia starts has a profound effect.

Tubero-infundibular dopaminergic function in cirrhotic patients: evaluation by nomifensine and domperidone.

Cirrhotic patients reportedly show alterations of anterior pituitary hormone secretion, which may reflect an underlying defective central neurotransmitter function. In this study, we have investigated the catecholaminergic control of prolactin (Prl) and growth hormone (GH) secretion in cirrhotic patients by means of an indirectly acting dopamine (DA) and norepinephrine agonist, nomifensine (Nom), and a DA receptor antagonist, domperidone (Dom). Basal GH levels were higher in the 12 female and male cirrhotic patients than in the 12 age- and sex-matched normal controls, while no difference was present in basal Prl values. Administration of Nom (200 mg po) suppressed basal Prl levels (at least 30% inhibition at three consecutive times post-drug administration) in 6/12 controls and in 6/12 cirrhotic patients, the frequency of negative responses not being different between the two groups. Nom induced a slight elevation of GH levels in controls, and evoked a more marked and sustained GH increase in cirrhotic patients. Administration of Dom (4 mg iv) induced similar Prl increments in 6 male controls and 6 male cirrhotic patients. Normal Prl responsiveness to Nom and Dom points to the existence of preserved tubero-infundibular DA function and modulation of pituitary DA receptors in the cirrhotic patients investigated. Higher GH responsiveness to Nom is compatible with a different bioavailability of the drug.

Receptor-mediated mitogenic action of prolactin in a rat lymphoma cell line.

PRL and other lactogenic hormones are potent mitogens in a lymphoma cell line derived from a lymph node of an estrogenized Noble (Nb) rat. The present study demonstrates that these cells (designated Nb2 node) possess receptors that bind only lactogenic hormones. There are approximately 12,000 receptor sites per cell. The kinetics of binding of [125I]iodo-PRL exhibited by Nb2 lymphoma cells is unusual in that PRL binding follows a biphasic pattern. Binding of [125I]iodo-PRL reaches a maximum in 1 h at 37 C, followed by a rapid decline. This pattern was not observed if binding was carried out in the presence of chloroquine, a lysosomotropic agent, or if cell homogenate was used for binding. We also examined the relationship between receptor occupancy and the magnitude of PRL response in these cells. Maximal growth stimulation by PRL occurs when only 35% of the maximal binding of PRL is achieved, suggesting that a majority of the PRL binding sites may be spare receptors. This study also revealed that the dissociation constant (Kd) of the PRL receptors in Nb2 cells is 75 pM, approximately 20-fold higher than that of the receptors in other cell types. PRL at 6 pM produces a half-maximal growth response in the Nb2 cells. Antibodies against the PRL receptors are able to abolish the PRL-induced proliferation of Nb2 cells. In the absence of PRL, these antibodies alone can induce proliferation of Nb2 cells, mimicking the action of PRL. Divalent (Fab)2 fragments, but not monovalent Fab, were also effective. These observations suggest that antibodies to the receptor, or the hormone itself, initiate a biological response possibly by cross-linking PRL receptors on the cell membrane, and that the entry of the PRL molecule, or fragments of it, into the intracellular compartment is not necessary for the biological action of PRL.

Are Fasting-Induced Effects on Thyrotropin and Prolactin Secretion Mediated by Dopamine?

To investigate whether total caloric deprivation influences TSH and/or PRL responsiveness, seven healthy volunteers fasted overnight (8 h) and were injected iv with a small dose (25 micrograms) of TRH and 30 min later with 40 mg cimetidine (CIM). This combined TRH-CIM test was repeated in the same individuals after a fasting period of 56 h. The TRH-stimulated mean maximal TSH increment fell from 5.1 +/- 1.2 to 1.2 +/- 0.6 microU/ml (P less than 0.01) during fasting. In contrast, both the TRH- and CIM-induced PRL responses were unaffected. To exclude methodologic errors on this reduced TSH responsiveness, an additional four normal subjects fasted for 56 h and then were given TRH alone. Two days later the TRH test was repeated after a fasting period of only 8 h. This experimental design also resulted in a significantly lower TSH response after the longer fasting period than after the shorter period, thus demonstrating that prolonged fasting inhibits TSH responsiveness regardless of whether the starvation period precedes or follows the TRH injection, and regardless of whether the pituitary thyrotrophs are stimulated with TRH plus CIM, or with TRH alone. In an additional seven healthy subjects injected with TRH plus CIM before and after a fasting period of 56 h, a dopamine D-2 receptor blocking agent, metoclopramide (MET), was given orally 90 min before the second TRH-CIM load. This priming with MET failed to restore normal TSH responsiveness in the fasting subjects, thus indicating that the suppressed TSH secretion could not have been mediated through dopamine D-2 receptors. However, since oral pretreatment with MET completely abolished the CIM-elicited PRL response in the fasting subjects, it is reasonable to assume that CIM stimulates PRL release via a reduced dopaminergic inhibition of the pituitary lactotrophs.

Evidence for lactotroph dopamine resistance in idiopathic hyperprolactinemia.

Previous studies in patients with idiopathic hyperprolactinemia (IH) that have suggested the presence of decreased central dopaminergic tone have assumed normal responsiveness of lactotrophs to dopamine (DA). We have examined DA sensitivity in 17 women with IH and 19 female controls by evaluating the plasma PRL responses to successive infusions of increasing concentrations of DA (4, 40, and 400 ng/kg . min) as well as to a dopaminergic agonist, bromocriptine (2.5 mg, orally), and to a dopaminergic agonist, bromocriptine (2.5 mg, orally), and to a dopaminergic receptor blocker, domperidone (2 mg, iv). PRL levels in controls were unchanged during a saline infusion, but decreased by 34 +/- 7% (mean +/- SE) at the end of the lowest DA infusion (P less than 0.05 vs. saline). Progressive PRL suppression was produced with each increasing dose. In contrast, in patients with IH, the lowest dose produced no significant suppression from basal PRL levels (P less than 0.001 vs. controls); at 40 ng/kg . min DA, fractional suppression was evident but was less than that in controls (P less than 0.01); at 400 ng/kg . min, fractional PRL suppression in IH patients was indistinguishable from that in controls (70 +/- 6% vs. 73 +/- 4%). Patients with IH also exhibited markedly reduced and delayed PRL response to domperidone (P less than 0.02 vs. controls). Significant impairment of the PRL-lowering effect of bromocriptine was observed in the IH patients between 1 and 2 h (P less than 0.02 vs. controls), and their responses to bromocriptine were again delayed. The results indicate the presence of a relative resistance to DA in patients with IH. This resistance is compatible with a decrease in the number or affinity of lactotroph DA receptors.