PITUITARY FUNCTION IN NORMOPROLACTINAEMIC INFERTILE MEN RECEIVING BROMOCRIPTINE

A double blind trial of bromocriptine 7–5 mg daily versus placebo was carried out in ten infertile men. Pretreatment basal plasma prolactin, thyroid stimulating hormone (TSH) testosterone and luteinizing hormone (LH) concentrations were normal, but plasma follicle-stimulating-hormone (FSH) was raised in four individuals. After 4 months treatment with bromocriptine a significant fall in plasma prolactin was observed ( P< 0.01), both under basal conditions and following thyroid stimulating hormone releasing hormone (TRH). Basal plasma gonadotrophin, testosterone and thyroid stimulating hormone (TSH) concentrations did not alter. No change in sperm density, volume or motility was noted. However an apparent fall in the peak plasma LH (but not FSH) response to gonadotrophin releasing hormone ( LHRH ) was observed in patients receiving bromocriptine. This reduction in plasma LH responsiveness was significant when compared with the baseline response ( P < 0.05) but failed to reach significance when compared with the placebo response. It is concluded that prolonged bromocriptine therapy in normoprolactinaemic men does not suppress FSH secretion, and any reduction in plasma LH responsiveness to LHRH is not accompanied by a significant fall in plasma testosterone.     

CHRONIC DOPAMINE RECEPTOR STIMULATION USING BROMOCRIPTINE: FAILURE TO MODIFY THYROID FUNCTION

Administration of 2.5 mg bromocriptine (Parlodel), a dopamine agonist, on two occasions to six normal volunteers did not alter the plasma TSH response to an i.v. injection of 100 micrograms TRH, but significantly (P less than 0.01) blunted it after 200 micrograms. Chronic bromocriptine treatment (7.5--50 mg/day) of fifteen acromegalic subjects failed to influence basal plasma TSH or the response pattern to 200 micrograms TRH. The thyroxine Binding Index (TBI) and the levels of T3 and T4 were not modified by treatment. These results indicate that chronic dopaminergic therapy with bromocriptine does not alter thyroid function.     

INAPPROPRIATE THYROTROPHIN SECRETION, INCREASED DOPAMINERGIC TONE AND PRESERVATION OF THE DIURNAL RHYTHM IN SERUM TSH

A patient presented with mild hyperthyroidism, elevated serum T4 and T3, and an inappropriately raised serum thyrotrophin (TSH). There was no evidence of pituitary tumour (alpha-subunit secretion and CT scan of the pituitary were normal). The TSH response to TRH was greater than normal. The elevated TSH was suppressed by oral triiodothyronine (100 micrograms daily for 10 d). The normal diurnal variation of TSH was preserved. Intravenous injection of the dopamine receptor blocking agent domperidone led to a greater than normal elevation in TSH (maximum increments 18-20 mU/l). This increased dopaminergic tone was similar in studies carried out in the morning and late evening. The dopamine agonist bromocriptine (2.5 mg twice daily) failed to suppress serum TSH either acutely or over 6 weeks. The circadian rhythm was unaltered by this treatment. Basal serum prolactin levels were normal, and responded appropriately to TRH, domperidone and bromocriptine. These observations indicate that dopamine does not control the diurnal variation of TSH in nontumoral TSH-mediated hyperthyroidism. The increased dopaminergic tone demonstrated may be secondary to the primary failure of pituitary-thyroid feedback in the condition.     

THE ROLE OF DOPAMINERGIC DEPLETION IN THE PATHOGENESIS OF CUSHING''S DISEASE AND THE POSSIBLE CONSEQUENCES FOR MEDICAL THERAPY

In four patients suffering from pituitary dependent Cushing's syndrome plasma ACTH and cortisol were lowered after a single dose of 2.5 mg bromocriptine, but ACTH and cortisol responses to hypoglycaemia remained absent after bromocriptine administration. In contrast, in three of these patients a growth hormone response which had previously been absent appeared to return 3 h after bromocriptine. While untreated, basal prolactin levels were at the upper limit of normal and a subnormal response was seen after hypoglycaemia. With bromocriptine therapy, basal prolactin levels were depressed and no reaction to hypoglycaemia was seen. In three patients 400 μg TRH did not elicit an increase of TSH and growth hormone while a normal increase of prolactin was induced. In one patient a dose of 2.5 mg bromocriptine caused an attack of nausea and hypotension possibly complicated by relative adrenocortical insufficiency. Four patients were studied during treatment with a daily dose of 5–20 mg bromocriptine for 1–20 weeks. In one patient, pituitary-adrenocortical function escaped three times from the effect of bromocriptine treatment. One patient showed an increase of urinary 17-OHCS during treatment lasting 7 days. Two other patients responded well to bromocriptine therapy, In one patient the treatment had to be stopped after 7 days because of complaints of extreme muscle weakness, while urinary 17-OHCS had become low-normal; in another patient Cortisol Secretion Rate was normalized throughout bromocriptine treatment lasting 20 weeks. Our results suggest that a hypothalamic dopaminergic depletion plays a role in the abnormal ACTH and growth hormone secretion in pituitary dependent Cushing's syndrome. The place of bromocriptine in the management of Cushing's disease remains uncertain.     

Cysteamine decreases prolactin responsiveness to thyrotropin-releasing hormone in normal men

Cysteamine depletes pituitary and plasma prolactin in rats. It acts through a nondopaminergic mechanism to alter both immunoactive and bioactive prolactin. The effect of cysteamine on prolactin secretion is reported in normal men. Six normal subjects received a control thyrotropin-releasing hormone (TRH) test at 0900 using 200 micrograms TRH intravenously; serum prolactin and TSH were measured at -10, 0, 10, 20, 30, 60, and 90 min after administration of TRH. Serum calcium and parathyroid hormones levels were measured at -10 min. Seven or more days later, they received cysteamine hydrochloride 15 mg/kg body weight orally every 6 hours for 5 doses. One hour after the last dose, the TRH test was repeated. Peak serum prolactin levels following TRH, prolactin levels at the 10-min time point, and total area from 0 to 30 min under the prolactin secretory curve were significantly decreased by cysteamine administration. TSH levels were unchanged. Serum calcium levels were significantly decreased by cysteamine administration, but parathyroid hormone levels were unchanged. It was concluded that cysteamine reduced TRH-stimulated prolactin secretion. Cysteamine also decreases serum calcium levels and suppresses the anticipated rise in serum parathyroid hormone levels. These effects on serum calcium and parathyroid hormone are similar to those previously shown for WR2721, another sulfhydryl compound. Cysteamine should be further considered as an alternative drug in the treatment of hyperprolactinemia and as a therapeutic agent for hypercalcemia.     

Human foetal prolactin but not thyrotropin secretion is decreased by bromocriptine

In the adult, dopamine inhibits prolactin (Prl) secretion and less so thyrotropin (TSH) release. Little information is available concerning the role of dopaminergic stimuli in the regulation of TSH and Prl secretion in the term human foetus. The dopamine agonist, bromocriptine (5 mg), or placebo were randomly administered orally to 120 pregnant women during labour. Maternal and foetal cord blood was obtained at parturition and analyzed for Prl, TSH, T4, T3 and rT3 concentrations. Since the time of parturition is unpredictable, maternal and cord blood hormone values were grouped at intervals of time from the time of bromocriptine or placebo administration to delivery. Hormone values were compared between the bromocriptine and placebo groups by two-way analysis of variance (ANOVA). Bromocriptine markedly inhibited maternal serum Prl concentrations compared to values in the placebo treated women (P less than 0.001) and this decrease was more marked as the time interval between bromocriptine administration and delivery increased (P less than 0.001, regression analysis). Cord blood Prl was also significantly lower in newborns whose mothers received bromocriptine (P less than 0.001). Bromocriptine significantly inhibited maternal serum TSH concentrations as compared to values in women treated with placebo (P less than 0.006). In contrast, bromocriptine administration did not affect cord blood TSH concentrations. These findings suggest that bromocriptine crosses the term human placenta and suppresses foetal Prl secretion. In contrast to the small inhibition of TSH secretion in pregnant women, bromocriptine does not affect foetal TSH secretion suggesting that regulation of TSH secretion in the term foetus may not be under dopaminergic control.     

EFFECT OF LOW-DOSE DOPAMINE INFUSION ON BASAL AND STIMULATED TSH AND PROLACTIN CONCENTRATIONS IN MAN

Dopamine (DA) infused at pharmacological doses in man inhibits thyrotrophin (TSH) secretion, although the physiological significance of this observation is unclear. The effect of low-dose DA infusion (0.1 microgram/kg/min) on TSH and prolactin (PRL) concentrations during stimulation with thyrotrophin releasing hormone (TRH) in normal male subjects is reported. Six subjects were given intravenous DA or placebo infusions for 165 min on separate days. A bolus of TRH (7.5 micrograms) was given at + 90 min, followed by infusion of the tripeptide (750 ng/min) for 45 min during both DA and placebo studies. In all subjects TRH administration caused a small rise in TSH which was partially inhibited by DA (peak 5.73 +/- 0.85 mU/l vs 4.58 +/- 1.09, P less than 0.05). PRL response to TRH was almost totally inhibited by DA (620 +/- 164 mU/l vs 234 +/- 96, P less than 0.05); integrated TSH and PRL responses to TRH were similarly inhibited by DA. Circulating plasma DA concentration during infusion of the catecholamine was 3.46 +/- 1.00 ng/ml, which is within the range reported in pituitary stalk plasma of other species. These data support the hypothesis that DA is a physiological modulator of TSH secretion in normal man. Major differences in the time course of TSH and PRL responses to TRH, and in the suppressive effect of DA on these responses suggest that there are fundamental differences in stimulus-secretion coupling for TRH and the lactotroph and thyrotroph.     

THE EFFECT OF BROMOCRIPTINE ON INSULIN SECRETION AND GLUCOSE TOLERANCE IN PATIENTS WITH ACROMEGALY

The oral administration of bromocriptine 5 mg 6-hourly to twelve patients with acromegaly for a mean period of 12 (range 3–27) months significantly reduced whole blood glucose, plasma insulin and plasma growth hormone (GH) concentrations during a 50 g oral glucose tolerance test (OGTT). After this period of treatment, bromocriptine was withdrawn for 48 h resulting in a significant rise in whole blood glucose, plasma insulin and plasma GH concentrations during a repeat OGTT. It is concluded that bromocriptine therapy improves glucose tolerance in acromegaly by suppressing GH secretion and consequently GH-mediated antagonism of insulin.     

DIMINUTION OF PROLACTIN AND INCREASE OF THYROTROPHIN RESPONSE TO THYROTROPHIN RELEASING HORMONE OCCURRING INDEPENDENTLY OF CHANGES IN BASAL LEVEL OF THESE HORMONES DURING TREATMENT OF HYPOTHYROIDISM

In order to study the effect of rising thyroid hormone levels in hypothyroidism upon prolactin responses to TRH, in relation to changes in basal prolactin concentration and to changes in TSH responses, we followed 18 patients by performing TRH tests before and after 14, 28, 42 and 56 d on gradually increasing levothyroxine dosages, plus a final test when euthyroidism was achieved. Basal prolactin rose initially, at day 14, followed by a return on days 28, 42 and 56 to a level similar to the pretherapeutic value, while at euthyroidism prolactin had fallen below the original value. The area under the prolactin response curve on TRH stimulation was unchanged at 14 d, notwithstanding the rise of basal prolactin concentration. At 28, 42 and 56 d the responses declined progressively along with basal prolactin concentrations that remained equivalent to the pretreatment level. The TSH response to TRH rose at 14, 28, and 42 d along with a continuous downward course of basal TSH. Thus, substitution with L-thyroxine inhibited the responsivity of prolactin but enhanced that of TSH to TRH. The fact that these changes occurred in opposite directions, appears to rule out a negative feed-back effect of T4 on hypothalamic TRH secretion. The effects on responses were shown to occur independently of those on basal secretion of prolactin and TSH.     

STUDY OF THE EFFECTS OF BROMOCRIPTINE ON SEXUAL IMPOTENCE

Serum testosterone, prolactin, LH, FSH and plasma 17 beta-oestradiol levels were determined in forty-seven male patients with sexual impotence. Low testosterone values and slightly elevated prolactin levels were observed in 19% and in 17% of cases, respectively. Since sexual function in the male seems to be controlled by both dopaminergic stimulatory and serotoninergic inhibitory mechanisms, bromocriptine was given orally to seventeen patients. As the preliminary results appeared encouraging, a double blind study was undertaken in the other thirty patients. No appreciable difference in hormonal pattern was noticed between bromocriptine and placebo treatment. As far as sexual function was concerned, good results were obtained in 52% of cases treated with bromocriptine and in 44% of patients given placebo.     

THE EFFECT OF THYROTROPHIN-RELEASING HORMONE ON PLASMA PROLACTIN AND THYROTROPHIN LEVELS IN PRIMARY HYPOTHYROIDISM

Plasma prolactin and thyrotrophin (TSH) were measured by radioimmunoassay before, at 20 min and 60 min after the intravenous administration of 200 μg thyrotrophin-releasing hormone (TRH) in thirty-two patients with untreated primary hypothyroidism and in sixteen normal volunteers. Whereas basal plasma TSH was markedly elevated in all the patients with hypothyroidism, a slight, but significant increase (P<0.05) in basal plasma prolactin in primary hypothyroidism could only be demonstrated by matching for age, sex and circulating gonadotrophin levels, ten patients with hypothyroidism with ten normal volunteers. There was, however, no significant difference between the two groups, matched or unmatched, in the plasma prolactin levels, in contrast to the plasma TSH levels, following TRH administration. No apparent relationship was found between basal prolactin and follicle-stimulating hormone (FSH), luteinizing hormone (LH) or TSH. Assuming the release of prolactin by TRH to be of physiological significance, the results suggest that TRH secretion by the hypothalamus may be increased in untreated hypothyroidism and that low levels of circulating thyroid hormone increase the sensitivity of the pituitary thyrotrophs, but not the prolactin secreting cells, to TRH. Markedly elevated plasma prolactin levels associated with galactorrhoea were not seen in primary hypothyroidism in the absence of the puerperium or oestrogen therapy.     

Evidence that serotonin is involved in prolactin release by electrical stimulation of the medial basal hypothalamus in the rhesus monkey

The possibility that serotonin plays a role in prolactin secretion after electrical stimulation of the rhesus medial basal hypothalamus (MBH) was investigated. Prolactin responses to electrical stimulation and intravenous injection of 0.5 and 1.0 micrograms of thyrotropin-releasing hormone (TRH) were evaluated before and after administration of methysergide (MES), a serotonin receptor blocker (2 mg orally every 12 h for 48 h), and bromocriptine (CB-154), a dopamine agonist (2.5 mg orally every 12 h for 48 h). Both electrical stimulation and TRH caused prompt increases in serum prolactin. Prestimulation (basal) prolactin levels in both drug-treated groups were not significantly lower than basal levels in control groups. Pretreatment with MES significantly attenuated the electrically induced release of prolactin but had no effect on the TRH-induced release; CB-154 blocked prolactin release induced by both types of stimulation. The study reported here has provided evidence of a possible role for hypothalamic serotinin in releasing pituitary prolactin.     

BROMOCRIPTINE SUPPRESSION OF THE THYROTROPHIN RESPONSE TO THYROTROPHIN RELEASING HORMONE

A single oral dose of 5 mg of bromocriptine significantly lowered the TSH response to 200 microgram TRH intravenously in eight healthy men compared with control experiments in the same subjects. This finding may be relevant in chronic bromocriptine therapy.     

BROMOCRIPTINE SUPPRESSES THE THYROTROPHIN RESPONSE TO THYROTROPHIN RELEASING HORMONE DURING HUMAN PREGNANCY

Thyrotrophin (TSH) responses to 200 microgram of intravenous thyrotrophin releasing hormone (TRH) were measured in fifteen healthy women in normal early pregnancy before and at the end of a bromocriptine treatment of 5.0-7.5 mg daily for 1-2 weeks. Bromocriptine did not change the basal levels of TSH, triiodothyronine (T3) and thyroxine (T4) during pregnancy. Before the start of bromocriptine, TRH caused a significant TSH elevation from 12.8 +/- 0.5 muu/ml (mean +/- SE) to 21.2 +/- 1.9 muu/ml after 20 min. During bromocriptine intake, TRH caused a TSH elevation from 11.9 +/- 0.4 muu/ml to only 15.5 +/- 1.1 muu/ml which is significantly less (P less than 0.001) than before bromocriptine. Similarly, the mean maximal TSH increment of 8.4 +/- 1.5 muu/ml before bromocriptine was greater (P less than 0.001) than that of 3.8 +/- 60 muu/ml during bromocriptine intake. When women were retested with TRH before and during bromocriptine after legal abortion, bromocriptine did not change the basal levels of TSH, T3 and T4 or the TSH response to TRH. Therefore, the TSH inhibition caused by bromocriptine is specifically related to the pregnancy itself, but the mechanism for this inhibition remains unknown.     

EFFECTS OF THE GABAERGIC DRUG, SODIUM VALPROATE, ON THE PROLACTIN RELEASE EVOKED BY PHARMACOLOGICAL STIMULI IN NORMAL WOMEN

Sodium valproate (DPA or Na-dipropylacetate), an anticonvulsant drug activating the endogenous GABAergic system, was administered orally at the dose of 400 mg to seventeen normal women 1 h before intravenous injections with three drugs which stimulate prolactin (PRL) release: TRH (200 ?g bolus; six subjects); domperidone (5 mg bolus; six subjects); and sulpiride (5 mg bolus; five subjects). DPA pretreatment significantly blunted PRL response to both domperidone and sulpiride injections without affecting the PRL response to TRH. In particular, the quantitative PRL secretion (areas under curves) following domperidone and sulpiride tests appeared significantly reduced after DPA treatment in comparison to placebo (P < 0·02 and P <0·01 for domperidone and sulpiride respectively). These results indicate that the pharmacological enhancement of the endogenous GABAergic system by DPA may blunt PRL response to both central and peripheral dopamine receptor blockade. These observations suggest that a GABAergic pathway inhibiting PRL secretion at the hypothalamic level competes, at least in part, with the dopaminergic system. Conversely, the lack of any effect of DPA on PRL response to TRH seems to suggest that pituitary TRH receptors are independent of any GABAergic control.     

BROMOCRIPTINE AND OESTROGEN MODULATION OF GONADOTROPHIN RELEASE IN NORMO-AND HYPERPROLACTINAEMIC PATIENTS WITH AMENORRHOEA

Effects of oestradiol, bromocriptine, and bromocriptine plus oestradiol, on basal and GnRH stimulated gonadotrophin concentrations were studied in normo-(group 1, n= 7) and hyperprolactinaemic (group 2, n= 6) patients with secondary amenorrhoea. Before drug administration, hyper-responsiveness of LH, but normal FSH responses to GnRH were observed in most patients. Oral administration of 2 mg oestradiol for 4 days resulted in increased 17β-oestradiol levels in plasma in normal women (n= 6) in the early follicular phase of the cycle, and in groups 1 and 2. During oestradiol administration plasma LH concentration increased significantly and there was an increase of LH and FSH responses to GnRH in normal subjects, but not in amenorrhoeic women. In groups 1 and 2 basal FSH levels were suppressed but no change in GnRH stimulated gonadotrophin responses was seen. Bromocriptine (5 mg per day for 5 days) significantly decreased prolactin concentrations and increased 17β-oestradiol levels in plasma in group 2 but not in group 1. The mean plasma 17β-oestradiol concentration had increased to levels similar to those obtained during oestradiol administration alone. The mean LH response to GnRH was suppressed in group 2, but not in group 1. Basal and GnRH-stimulated plasma FSH concentrations were not changed by bromocriptine treatment. Compared with the GnRH induced LH response during bromocriptine alone, bromocriptine treatment plus oestradiol administration resulted in a significantly increased LH response in group 2. This was not found in group 1. The present results suggest that there is an increased dopamine activity and inhibition of GnRH at the hypothalamic level and a relative dopamine deficiency at the pituitary level in hyperprolactinaemic patients. Normoprolac-tinaemic patients with hypothalamic amenorrhoea have increased dopaminergic activity at the hypothalamic, as well as the, pituitary level, or alternatively that the LH release is not influenced by dopamine in these patients. Finally bromocriptine sensitizes LH-secreting cells to GnRH in hyperprolactinaemic, but not in normoprolactinaemic, patients.     

BROMOCRIPTINE TREATMENT OF OLIGOSPERMIA: A DOUBLE BLIND STUDY

A double blind controlled study of bromocriptine treatment of oligospermia was carried out. Out of fifty-one men who originally volunteered to the study there were forty who took the drug for 12 weeks as requested. All the partners of these men had failed to conceive, and in each case the pretreatment sperm count had been below 40 million/ml on two or several occasions. The pretreatment serum prolactin concentrations were similar in patients given bromocriptine (N = 20) and placebo (N = 20). There were three men in either group whose pretreatment serum prolactin concentration was in excess of 30 micrograms/l, the highest value being 96 micrograms/l. While bromocriptine effectively decreased the serum prolactin concentration, it had no significant effect over placebo on sperm volume, motility and morphology. In the bromocriptine group, sperm count increased to or above 40 million/ml in five out of twenty men, while in the placebo group this occurred in nine out of twenty patients. The plasma testosterone and dihydrotestosterone levels increased slightly during treatment in both groups, but no significant difference was observed between bromocriptine and placebo treated patients. One wife of a bromocriptine-treated man and two wives of placebo-treated men became pregnant during treatment. In this study bromocriptine was no more effective than placebo in the treatment of oligospermia.     

The relationship between TSH response to TRH and GH response to dopaminergic agents in patients with acromegaly]

The role of dopaminergic agents (DA) in the regulation of growth hormone (GH) secretion was investigated in patients with untreated acromegaly. TRH (0.5 mg iv), bromocriptine (Br) (2.5 mg orally) or L-Dopa (500 mg orally) loading tests were performed, and serum levels of TSH, GH and prolactin (PRL) were measured. Patients were defined as responders to TRH when peak TSH level after TRH test was higher than 5 microU/ml. Br or L-Dopa was considered to be effective when serum GH or PRL levels were suppressed more than 50% of the basal value. The patients were classified into large adenoma group with suprasellar extension or cisternal herniation (L group, n = 7) and intrasellar small adenoma group (S group, n = 11) which was further divided into TRH responder (Sr group, n = 4) and TRH non-responder with suppressed TSH (Ss group, n = 7). Br was effective in 7 or 100% of 7 patients in the Ss group but only in one or 25% of 4 patients in the Sr group. Br was also effective in 5 or 71% of 7 patients in the L group, although most of them were responders to TRH. Percent inhibition of serum GH levels by Br was significantly higher in the Ss group (82.3 +/- 12.3%, p less than 0.001) and in the L group (64.7 +/- 20.5%, p less than 0.05) compared with that in the Sr group (29.3 +/- 21.6%). Suppression of serum GH level by L-Dopa was also observed in the Ss group. In contrast to the difference in the response of GH, serum PRL level was equally suppressed by Br or L-Dopa in each group. Suppression of TSH by administration of exogenous T4 had no effect on the GH suppression effect of Br in the Sr group. Considering the dual effects of DA to enhance growth hormone-releasing hormone (GHRH) secretion in the hypothalamus and to suppress GH secretion in the pituitary gland, these findings suggest that the paradoxical effect of DA to suppress serum GH level is observed when the hypothalamo-pituitary axis is disturbed mechanically by large adenoma in the L group or functionally in the Ss group probably due to enhanced secretion of somatostatin which suppresses TSH secretion and impairs the effect of GHRH.     

EFFECTS OF THE H2 RECEPTOR ANTAGONIST CIMETIDINE ON PITUITARY HORMONES IN MAN

The effects of the histamine (H2) receptor antagonist cimetidine on serum levels of prolactin (PRL), growth hormone (GH), thyroid stimulating hormone (TSH), luteinizing hormone (LH), follicle stimulating hormone (FSH) and cortisol were studied in five normal males. Cimetidine, when given by infusion at the dose of 100 mg/h for 5 h, did not alter adenohypophyseal secretion either basally or after pituitary stimulation with LHRH and TRH. However, 400 mg cimetidine given intravenously as a bolus injection significantly stimulated PRL release in all subjects, without affecting any other measured hormone. A dose-reponse relationship existed, and 200 mg cimetidine seems to be the minimum PRL-releasing dose when given as an intravenous bolus injection. These results suggest that cimetidine releases PRL and that this effect is dose-related, but only when large intravenous injections are given.     

Prolonged secretion of prolactin in response to thyrotrophin-releasing hormone after hypothalamo-pituitary disconnection in the ewe

Surgical disconnection of the ovine hypothalamus from the pituitary gland (hypothalamo-pituitary disconnection; HPD) has provided a useful experimental model for studying the control of gonadotrophin secretion. The objective of the present study was to define the characteristics of prolactin secretion using stimuli acting through the hypothalamus or directly on the pituitary gland in HPD ewes. Prolactin responses to either a stressful stimulus or the dopaminergic antagonists metoclopramide (20 mg i.v.) or chlorpromazine (50 mg i.v.) seen in intact animals (sham-HPD) were completely abolished by HPD. Injection of TRH (100 micrograms i.v.) caused an immediate release of prolactin in both groups of ewes. In the HPD ewes plasma prolactin concentrations remained raised for at least 3 h after TRH injection, whereas in sham-HPD ewes prolactin concentrations began to decline after 20 min. Administration of bromocriptine (1 mg i.v.) 10 min after TRH inhibited the prolonged response to TRH in HPD ewes. The results support the hypothesis that prolactin exerts a short-loop feedback effect on its own secretion at the hypothalamic level.