Exaggerated circadian variation in basal thyrotropin (TSH) and in the dopaminergic inhibition of TSH release in pathological hyperprolactinemia: evidence against a hypothalamic dopaminergic defect

In order to delineate more accurately the dopaminergic control of anterior pituitary function in normal subjects and in patients with pathological hyperprolactinemia, we investigated the nature of the circadian variation in the dopaminergic inhibition of TSH release in such subjects. Ten euthyroid women with hyperprolactinemia due to presumed PRL-secreting microadenomas (aged 18-60 yr) were compared with 11 normal, euthyroid women (aged 18-32 yr). Each received the dopamine receptor blocking drug domperidone (10 mg, iv) at 1100 and 2300 h (tests randomized and separated by at least 1 week). Blood was sampled 10, 20, 30, 45, and 60 min after drug administration. Normal women had a greater TSH response to domperidone and, hence, greater dopaminergic inhibition of TSH release at 2300 than at 1100 h (sum of TSH increments; mU/liter mean +/- SE, 8.5 +/- 1.3 vs. 4.8 +/- 0.5, P less than 0.01), whereas there was no difference in the dopaminergic inhibition of PRL release at each time of day. Hyperprolactinemic women also had a significantly greater TSH response to domperidone at 2300 than at 1100 h (42.0 +/- 10.2 vs. 19.1 +/- 2.8, P less than 0.001). The hyperprolactinemic women had a greater TSH response to domperidone than normal women at each time of day studied (1100 h, 19.1 +/- 2.8 vs. 4.8 +/- 0.5, P less than 0.001; 2300 h, 42.0 +/- 10.2 vs. 8.5 +/- 1.3, P less than 0.001). The incremental PRL responses to domperidone were significantly less in hyperprolactinemic than in normal women and did not differ at each time of day. In conclusion, the circadian change in the dopaminergic inhibition of TSH secretion is specific for TSH and not PRL. This indicates that the dopaminergic control of TSH and PRL secretion can be dissociated in normal subjects. Second, hyperprolactinemic women with presumed PRL-secreting microadenomas had qualitatively normal but quantitatively exaggerated circadian pattern of dopaminergic inhibition of TSH release. These data argue against a hypothalamic dopaminergic defect in hyperprolactinemia and support the view that the established dopaminergic defect in the inhibition of PRL release is related specifically to PRL control and may well be at the anterior pituitary level.     

RECIPROCAL PATTERN OF THE TSH AND PRL RESPONSES TO DOPAMINE RECEPTOR BLOCKADE IN WOMEN WITH PHYSIOLOGICAL OR PATHOLOGICAL HYPERPROLACTINAEMIA

The TSH and PRL responses to administration of the two dopamine (DA) receptor antagonists sulpiride and domperidone, were studied in fifteen normoprolactinaemic subjects, twenty-two post-partum women and sixteen subjects with presumptive evidence of (six subjects) or surgically confirmed (ten subjects) prolactinomas. Sulpiride (100 mg i.m.) or domperidone (10 mg i.v.) elicited a slight increase in basal TSH levels in both normoprolactinaemic and post-partum women, but induced a clear-cut TSH rise in subjects with a tumour. Conversely, sulpiride and domperidone strikingly stimulated PRL secretion in normoprolactinaemic and post-partum women, but only slightly enhanced base-line PRL levels in women with prolactinomas. The reason for the reciprocal pattern of TSH and PRL responsiveness to DA receptor blockade of post-partum women and subjects with prolactinomas is presently obscure. Since baseline PRL levels in the two hyperprolactinaemic states overlapped widely, it would appear that hyperprolactinaemia per se is not responsible for such behaviour.     

THE INFLUENCE OF OESTROGENS ON THE SENSITIVITY OF PRL, TSH AND LH TO THE INHIBITORY ACTIONS OF DOPAMINE IN HYPERPROLACTINAEMIC PATIENTS

The effects of oestrogen priming on the response of serum PRL, LH and TSH to dopamine (DA) infusion have been studied in hyperprolactinaemia. Seven hyperprolactinaemic females (aged 22-57 years; basal PRL 911-5130 mU/l, normal less than 420 mU/l), had submaximal DA infusions (0.06 micrograms/kg/min) over 3 h. The DA was repeated at the same dose after pretreatment with ethinyl oestradiol (E2) 100 micrograms daily by mouth for 3 d, and after a further 2 week interval, following pretreatment with tamoxifen (TAM) 20 mg twice a day by mouth for 3 d. Ethinyl oestradiol pretreatment stimulated a rise in basal PRL levels in all subjects (mean +/- SE, mU/l; 2903 +/- 761 vs 2293 +/- 684, P less than 0.05) while TAM produced a higher but more variable increase in basal PRL levels (mean +/- SE, mU/l; 3402 +/- 757, P = n.s.). The individual increments in basal PRL levels after both E2 and TAM pretreatment showed a significant positive correlation with the greater decrement in PRL levels during E2 and TAM primed DA infusions (E2, r = 0.93, P less than 0.01, TAM, r = 0.83, P less than 0.05). E2 pretreatment produced a rise in basal LH levels in 5/7 patients, and there was a significant positive correlation between the rise in basal LH levels after E2 and the decremental change in LH levels in E2 primed DA infusions (r = 0.94, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Prolactin and thyrotropin response to blockade of dopamine synthesis by monoiodotyrosine in subjects with postpartum and pathological hyperprolactinemia

To better understand the state of dopamine (DA) neurotransmission in the tuberoinfundibular DA system (TIDA), monoiodotyrosine (3-iodo-L-tyrosine, MIT), a potent inhibitor of DA synthesis, was acutely administered to 8 normal women, 7 postpartum women, 8 women with pathological hyperprolactinemia and 5 women after successful removal of a prolactinoma. The effects on plasma prolactin (PRL) and thyrotropin (TSH) were compared to those induced in the same subjects by the DA receptor antagonist domperidone (DOM). MIT (1 gpo) and DOM (10 mg iv) induced qualitatively similar hormonal responses, although the PRL- and TSH-releasing effects of DOM were always greater than those of MIT. In control subjects, MIT treatment induced a consistent rise in plasma PRL (peak increment 45.2 +/- 13 ng/ml at 120 min); in the same subjects DOM induced a prompter and higher PRL response, (peak increment 147.8 +/- 26 ng/ml at 30 min). MIT failed to alter plasma TSH levels, while DOM induced a significant rise in plasma TSH. In postpartum women MIT induced a prompter and higher PRL rise than that occurring in controls (peak increment 180.3 +/- 20 ng/ml at 90 min), though also in this instance DOM proved to be a more potent PRL releaser (peak increment 345.7 +/- 88 ng/ml at 30 min) than MIT. MIT was unable to stimulate TSH secretion, while DOM induced a significant rise in plasma TSH. In women with pathological hyperprolactinemia MIT failed to alter baseline PRL levels while DOM slightly increased them (peak increment 14.7 +/- 3 ng/ml at 30 min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Thyrotropin alpha- and beta-subunit responses to thyrotropin-releasing hormone and domperidone in normal subjects and in patients with microprolactinomas.

Microprolactinoma is a particular pathological situation characterized by the presence of increased hypothalamic dopaminergic tone reactive to tumoral hyperprolactinemia. Since dopamine (DA) is a physiological regulating factor of the secretion of thyroid-stimulating hormone (TSH), we investigated the responses of serum TSH (holo-TSH) and its subunits (alpha-subunit: alpha-sub, and TSH-beta) to thyrotropin-releasing hormone (TRH) and domperidone (DOM; an antidopaminergic drug acting outside the blood-brain barrier) in 36 euthyroid subjects (20 controls and 16 patients with microprolactinoma) in order to evaluate the possible in vivo effects of DA excess on TSH subunit secretion. No significant difference in serum TSH increase after TRH (200 micrograms i.v.) was observed between patients with microprolactinoma and controls (TSH net incremental area under the curve, nAUC: 146 +/- 9, mean +/- SE, and 143 +/- 7.7 micrograms/l/60 min, respectively), while serum alpha-sub and TSH-beta responses were markedly reduced in patients with microprolactinoma as compared to those found in normals (alpha-sub nAUC: 3.0 +/- 0.5 vs. 19.8 +/- 2.2 micrograms/l/60 min, p less than 0.001; TSH-beta nAUC: 5.0 +/- 0.8 vs. 9.5 +/- 0.9 micrograms/l/60 min, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

The properties of prolactin secretion in patients with prolactin secreting pituitary adenomas

Plasma prolactin (PRL) responses to several exogenous agents are variable in patients with prolactinomas. In this study the factors determining the responsiveness to exogenous stimuli were investigated in 35 patients with prolactinomas. Among these patients, 14 patients were responder (greater than 150% increase of basal value) to TRH, sulpiride (DA D2-receptor blocker) and arginine, and remaining 21 were non-responder to these three agents. Plasma TSH responses to sulpiride, an indirect indicator of hypothalamic dopaminergic tone on pituitary gland, were similar between responder (delta TSH: M +/- SEM; 5.3 +/- 0.2 microU/ml) and non-responder (delta TSH: 5.6 +/- 0.2 microU/ml), and were greater than those in normal subjects (delta TSH: 0.7 +/- 0.2 microU/ml, n = 18) (P less than 0.001). The plasma PRL responses to dopaminergic agents (L-dopa, CB-154, dopamine) were greater in responders than in non-responders (% of basal: L-dopa, 33.7 +/- 3.7% vs 51.6 +/- 5.6% at 150 min, P less than 0.05; CB-154, 16.5 +/- 2.6% vs 30.9 +/- 2.8% at 6 hr, P less than 0.05; dopamine, 31.7 +/- 5.6% vs 44.9 +/- 4.3% at 90 min, P less than 0.05). When all patients were divided into microadenoma (n = 12) and macroadenoma patients (n = 23), there were no differences in plasma PRL responses to these agents between the two groups. Again, there were no differences in the duration of illness between the responder and non-responder patients (61.9 +/- 13.7 vs 54.1 +/- 12.0 months). During the short term CB-154 treatment (7.5mg/day for 3 approximately 5 weeks) in 8 responders and 15 non-responders, all responder patients showed normalization of plasma PRL levels, while such normalization was observed in only 6 non-responder patients. These results suggest that in prolactinoma patients variable responsiveness to several exogenous agents are depending on the sensitivity to several exogenous agents are depending on the sensitivity of prolactinoma itself, regardless of the endogenous hypothalamic dopaminergic tone, tumor size or duration of the illness.     

Effects of dopamine and metoclopramide in polycystic ovary syndrome

A relative deficiency in dopamine has been suggested to explain the inappropriate gonadotropin secretion and postulated increased GnRH secretion characteristic of polycystic ovary syndrome (PCO). Previous studies demonstrated an exaggerated decrement in serum LH after large iv doses of dopamine (DA, 4-5 micrograms/kg X min). Normoprolactinemic patients with PCO and weight- and estrogen-matched normal women received iv infusions of DA in two doses (0.5 and 4 micrograms/kg X min). After DA, each subject also received iv metoclopramide (MCP; 10 mg). Serum LH decreased (P less than 0.05) during DA infusion to a similar degree in PCO [23 +/- 3% (+/- SE)] and normal women (20 +/- 2%). In PCO patients, the decrease in LH was similar with both DA doses. Serum PRL and TSH responses to DA were also similar in PCO and normal women. After MCP treatment, serum LH did not change, but serum PRL increased more in PCO (801 +/- 100%) than in normal women (467 +/- 73%; P less than 0.05), as did serum TSH. These data suggest that the sensitivity of LH to DA in patients with PCO is not increased. Further, increased responses of PRL and TSH to MCP may reflect increased dopaminergic activity or, in the case of PRL, the influence of chronic hyperestrogenism.     

Dopamine affects basal and augmented pituitary hormone secretion.

Although the role of the neurotransmitter, dopamine (DA), in the regulation of PRL has been well documented, controversy exists regarding its participation in the regulation of the other pituitary hormones. Consequently, we infused DA into six healthy male subjects (ages 19-32) and studied its effects on both basal pituitary hormone levels and augmented hormonal release induced by insulin hypoglycemia (ITT), TRH, and gonadotropin-releasing hormone (GnRH). DA alone produced a modest though significant increase in GH concentration from 2.2 +/- 0.5 to 11.9 +/- 3.7 ng/ml (P less than 0.05) by 60 min, but the peak incremental GH response to ITT was significantly inhibited by DA (43.5 +/- 5.0 vs. 16.3 +/- 3.3 ng/ml; P less than 0.01). PRL concentrations fell during the DA infusion (20.4 +/- 3.0 to 10.6 +/- 1.5 ng/ml; P less than 0.02) at 235 min, and the PRL responses to both ITT and TRH were completely abolished. Although the basal LH and FSH concentrations were unaffected by DA, the incremental LH response to GnRH was inhibited (45.5 +/- 10.6 to 24.4 +/- 5.4 mIU/ml; P less than 0.05), while the FSH response was unchanged. DA significantly reduced the basal TSH concentration from 3.9 +/- 0.2 to 2.5 +/- 0.2 micro U/ml (P less than 0.01) at 230 min and blunted the peak incremental TSH response to TRH (6.0 +/- 1.5 vs. 2.9 +/- 0.9 microU/ml; P less than 0.01). DA had no effect on basal cortisol levels, the cortisol response to ITT, basal plasma glucose, or the degree of hypoglycemia after ITT. Our data provide new evidence that DA has an inhibitory as well as a stimulatory role in the regulation of GH secretion in normal humans. It inhibits centrally as well as peripherally mediated PRL secretion and blunts the LH response to GnRH. In addition, DA lowers both basal and TRH-mediated TSH release, confirming the reports of other investigators.     

Increased dopaminergic activity inhibits basal and metoclopramide-stimulated prolactin and thyrotropin secretion

The influence of physiological to pharmacological doses of dopamine (DA) on basal and metoclopramide (MTC)-stimulated PRL and TSH secretion was studied in 11 regularly menstruating women between days 3 and 8 of the cycle. In groups of 6, the women received 5-h infusions of either 5% glucose or DA in a solution of 5% glucose at a rate of 12-16 ml/h, adjusted according to weight. Infusion rates of DA were 0.04 microgram/kg . min (low), 0.4 microgram/kg . min (medium), and 4.0 micrograms/kg . min (high). After 3 h of infusion, 10 mg MTC were given iv. Blood samples were collected every 15 min from 1 h before to 2 h after the infusion, for a total of 8 h, for measurements of PRL and TSH. The mean serum PRL concentrations declined significantly (P less than 0.05) during DA infusions to nadir values of 62 +/- 5% (+/- SEM; low), 43 +/- 3% (medium), and 43 +/- 6% (high) of the basal levels, whereas basal TSH levels declined significantly, to 64 +/- 5% of basal levels (P less than 0.05), during both the medium and high dose DA infusions. On paired comparisons, the hormone responses to MTC were lower (P less than 0.05) during the infusion of high dose DA (PRL, 2286 +/- 495% vs. 891 +/- 328%; TSH, 100 +/- 43% vs. 60 +/- 15%), but were not changed when MTC was given during the low and medium doses of DA. A rebound phenomenon was found for PRL (P less than 0.05) after the medium and high doses of DA and for TSH (P less than 0.05) after the high dose. These results indicate that doses of DA considered physiological inhibit PRL and TSH secretion and larger doses inhibit their responses to the DA antagonist MTC.     

The TSH response to domperidone reflects the biological activity of prolactin in macroprolactinaemia and hyperprolactinaemia

OBJECTIVE: To test the hypothesis that patients with hyperprolactinaemia due to biologically inactive macroprolactin will not show the characteristically increased dopaminergic inhibition of TSH release seen in patients with microprolactinomas secreting biologically active monomeric PRL. DESIGN: Comparison of the TSH and PRL responses to dopamine antagonism with domperidone (10 mg i.v.) in patients with hyperprolactinaemia due to macroprolactinaemia or microprolactinomas. PATIENTS: Twenty-two patients referred for the investigation of their hyperprolactinaemia were studied: 11 patients with macroprolactinaemia and 11 patients with hyperprolactinaemia due to microprolactinoma. MEASUREMENTS: TSH and PRL levels were measured at baseline and 30 min following domperidone in both groups. RESULTS: Patients with macroprolactinaemia showed normal TSH and PRL responses to dopamine antagonism whereas patients with microprolactinomas showed exaggerated TSH responses and reduced PRL responses. Although there was considerable overlap between the PRL responses in the two groups, there was very clear separation between the PRL/TSH response ratios (normal > 1.0) of 4.0 +/- 1.8 for the macroprolactinaemia group and 0.4 +/- 0.2 for the microprolactinoma group (P < 0.0001). CONCLUSIONS: These data support the hypothesis that elevated circulating levels of macroprolactin, as opposed to biologically active monomeric PRL, do not exert increased positive feedback on the hypothalamic dopaminergic inhibition of TSH release.     

Gonadotropin-releasing hormone pulsatile administration restores luteinizing hormone pulsatility and normal testosterone levels in males with hyperprolactinemia

Hyperprolactinemia in men is frequently associated with hypogonadism. Normalization of serum PRL levels is generally associated with an increase in serum testosterone (T) to normal. To determine the mechanism of the inhibitory effect of hyperprolactinemia on the hypothalamic-pituitary-gonadal axis, we studied the effect of intermittent pulsatile GnRH administration on LH pulsatility and T levels in four men with prolactinomas. All patients had high PRL values (100-3000 ng/ml), low LH (mean +/- SEM, 2.2 +/- 0.1 mIU/ml), and low T values (2.3 +/- 0.3 ng/ml), with no other apparent abnormality of pituitary function. GnRH was administered iv using a pump delivering a bolus dose of 10 micrograms every 90 min for 12 days. No LH pulses were detected before treatment. Pulsatile GnRH administration resulted in a significant increase in basal LH levels (6.7 +/- 0.6 mIU/ml; P less than 0.001) and restored LH pulsatility. In addition, T levels increased significantly to normal values in all patients (7.8 +/- 0.4 ng/ml; P less than 0.001) and were normal or supranormal as long as the pump was in use, although PRL levels remained elevated. These data, therefore, suggest that hyperprolactinemia produces hypogonadism primarily by interfering with pulsatile GnRH release.     

Growth hormone inhibitory and stimulatory actions of L-dopa in patients with acromegaly

It is not clear whether dopamine (DA) has a central stimulating activity on GH secretion in patients with acromegaly, as it does in normal subjects. To clarify this, we compared the GH inhibitory potencies of DA, which does not cross the blood-brain barrier (BBB), and L-dopa or bromocriptine, which do cross the BBB, in 23 patients with acromegaly. Further, we examined the central effects of L-dopa after selectively blocking peripheral (median eminence and pituitary) DA receptors with domperidone (a DA D2 receptor blocker which does not cross the BBB). After the administration of DA (5 micrograms/kg X min, iv, for 90 min), L-dopa (500 mg, orally), or bromocriptine (2.5 mg, orally), the mean plasma GH decrease was greatest after DA [maximum decrement, 71.9 +/- 3.8% (+/- SEM); n = 21] compared to L-dopa (44.1 +/- 5.6%; n = 23; p less than 0.001) or bromocriptine (58.9 +/- 5.0%; n = 20; p less than 0.02). Eleven of these patients received a single infusion of domperidone (0.22 mg/min, iv, for 180 min) or a combination of domperidone and L-dopa. Mean plasma GH levels did not change during domperidone alone. However, plasma GH levels in these patients increased significantly when L-dopa was administered 30 min after the start of domperidone infusion (vs. control study: at 90 min, 137.3 +/- 10.8% vs. 100.2 +/- 3.9%, p less than 0.01; at 120 min, 138.8 +/- 19.7% vs. 106.5 +/- 3.1%, p less than 0.05). In contrast, one patient who had a distinct plasma GH increase in response to the domperidone-L-dopa test had no increase in plasma GH when given L-dopa 30 min after the start of a sulpiride infusion (DA D2 receptor blocker which crosses the BBB; 1.1 mg/min, iv, for 180 min). Unlike GH, plasma PRL responses to domperidone infusion were not modified by the additional administration of L-dopa. These results suggest that in acromegaly, DA has not only direct suppressive effects on the pituitary tumor somatotrophs, but also indirect stimulatory effects via the hypothalamus; therefore, the hypothalamic GH-releasing system is not entirely suppressed by excessive tumor GH secretion.     

Endocrine, renal, and hemodynamic responses to graded dopamine infusions in normal men

The present study was performed to determine the hemodynamic, hormonal, and natriuretic responses to infusions of dopamine (DA) that reflect physiological as well as pharmacological levels in blood or tissue. In six normal men, DA was infused for 2 h at three fixed dosages (0.03 or 0.1, 0.3, and 3.0 micrograms/kg X min) on three separate occasions, which resulted in increases in mean plasma DA concentrations from basal levels of less than 0.03 ng/ml to 0.69 +/- 0.12, 3.73 +/- 0.40, and 38.4 +/- 3.80 (+/- SE) ng/ml. Mean plasma PRL decreased and DA excretion increased significantly from basal levels during all three DA infusions. Plasma LH decreased and norepinephrine (NE) excretion increased during both the middle and high dose infusions, while sodium excretion, plasma NE, and heart rate increased only during the high dose DA infusion. Basal plasma aldosterone values were low and did not change with DA treatment. PRA, TSH, and FSH also did not change. GH responses were difficult to assess because of the frequency of episodic secretions. Since DA concentrations in hypophysial-portal blood may equal or exceed 1 ng/ml, these results support a role for DA in the acute regulation of PRL, and possibly LH, in normal men. As a natriuretic response occurred only at supraphysiological concentrations of circulating DA, if DA has a physiological role in modulating sodium excretion during normal sodium intake, it must be released from dopaminergic neurons or otherwise locally produced in very high concentrations in the kidney.     

Megavoltage pituitary irradiation in the management of prolactinomas: long-term follow-up

OBJECTIVE To determine the long-term effects of external beam megavoltage radiotherapy (RT: 4500 cGy via three portals at 180 cGy or less total daily dose) on endocrine function in prolactinomas. DESIGN Longitudinal study following radiotherapy with periodic re-assessment at regular intervals, at least 2 months off dopamine agonist therapy. PATIENTS Thirty-six female patients, age range 19-50 years, with either macroprolactinomas (12 patients) or microprolactinomas (24 patients), but without significant suprasellar extensions. MEASUREMENTS Clinical appraisal, and anterior and posterior pituitary assessment: basal levels at yearly intervals or less, with dynamic screening with TRH, LHRH and hypoglycaemic stimulation every 2-3 years. RESULTS Before RT, serum prolactin (PRL) levels ranged from 1150 to 34,000 mU/l; after RT (mean 8.5 years, range 3-14), serum PRL fell to normal (i.e. less than 360 mU/l) in 18 of the 36 patients (50%), and to just above the normal range (378-780 mU/l) in a further 10 (28%). Two patients had PRL levels at their last follow-up higher than those at presentation, with one patient showing evidence of tumour recurrence on CT scan. A total of eight of the 36 patients (23%) developed post-RT gonadal deficiency by the end of follow-up at 8 +/- 3.1 years (+/- SD, range 3-11), but six were aged over 40 years at that time. GH deficiency was frequent, occurring in 94% of patients, usually from 2 to 3 years post-RT, while TSH deficiency and reduced ACTH reserve was uncommon (each 14%), and occurred later. In the subgroup of 12 patients with macroprolactinomas, results were broadly comparable. CONCLUSIONS Megavoltage RT produces a progressive fall in serum prolactin in the great majority of patients with prolactinomas, with a relatively low incidence of TSH or ACTH deficiency. As it is now clear that dopamine agonist therapy alone provides sufficient management for microprolactinomas, RT may be used for the long-term control of macroprolactinomas, together with interim dopamine agonist therapy. It allows pregnancy to be safely undertaken but, in view of the delayed onset of gonadal deficiency, its administration should be timed with respect to the desired onset of conception in women.     

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.     

ALTERED DOPAMINERGIC REGULATION OF THYROTROPHIN RELEASE IN PATIENTS WITH PROLACTINOMAS: COMPARISON WITH OTHER TESTS OF HYPOTHALAMIC-PITUITARY FUNCTION

This study was carried out to test the hypothesis that sustained hyperprolactinaemia in patients with prolactinomas stimulates hypothalamic dopaminergic activity via a short loop positive feedback effect of prolactin (PRL). The intensity of dopamine (DA) effects on the pituitary around the adenoma was evaluated by measuring thyroid stimulating hormone (TSH) responses to intravenous injection of domperidone (10 mg) a new DA receptor blocking drug that does not penetrate the blood-brain barrier. TSH responses have been compared with those of PRL to the same agent. Eight females with prolactinomas showed greater TSH release after domperidone than nine normal females (sum of TSH increments over 120 min 17·5 ± 1·7 v. 8·9±1·5 mu/l, P < 0·001) whilst PRL release was reduced (sum of PRL increments over 120 min 5·9 ± 2·4 v. 21·8 ± 3·8 mu/l ± 10^?3, P < 0·01). Amongst nineteen hyperprolactinaemic females with apparently normal pituitary fossae (plain skull X-ray), ten showed an exaggerated TSH response (ΔTSH, 4·2 ± 0·6 mu/l, range 2·5–9·40 mu/l) and reduced PRL response to domperidone, comparable with established tumour cases. In the remaining nine normal fossa hyperprolactinaemic females, the TSH and PRL responses to domperidone were similar to normal females. These results support the initial hypothesis and indicate the coexistence of a defect in the dopaminergic inhibition of PRL release and increased dopaminergic inhibition of TSH release in patients with prolactinomas. The presence of an exaggerated TSH response to DA antagonism in a euthyroid, radiologically normal (plain skull X-ray), hyperprolactinaemic patient is compatible with the presence of an autonomously-functioning, PRL secreting, pituitary microadenoma and the TSH changes seen in these patients after DA antagonist administration can be readily detected by sensitive TSH radioimmunoassay.     

Metoclopramide effect on serum prolactin LH and FSH in patients with polycystic ovary syndrome

In order to investigate the DA activity in polycystic ovary syndrome (PCOS) we studied the response of LH, FSH and PRL to a dopamine receptor antagonist metoclopramide (MCP-10 mg iv) in 12 PCO subjects (7 with normal and 5 with elevated levels of prolactin). The prolactin and LH responses to metoclopramide were compared to those obtained in 6 normal cycling women. Although a significant increase in PRL levels was documented after MCP administration in all PCO patients and normal cycling women (p less than 0.01), the highest increment in PRL levels was observed in normoprolactinemic PCO subjects. In contrast a blunted PRL response was observed in hyperprolactinemic PCO patients. There was a negative correlation between basal PRL levels and the maximum net increase in PRL after MCP. In both groups of PCO subjects MCP administration caused initial decrease in LH levels followed by an increase after 4 h. In hyperprolactinemic PCO patients this observed MCP effect on LH was more pronounced and significantly different in comparison with normoprolactinemic PCO patients (p less than 0.01). MCP administration did not cause significant acute alterations in LH levels in normal cycling women and no significant FSH changes in either PCO or control subjects. A relative dopamine deficiency might cause hypersecretion of PRL and LH in patients with PCOS and hyperprolactinemia.     

Nocturnal melatonin plasma levels in patients with OSAS: the effect of CPAP.

Melatonin is a pineal hormone that regulates the human cycle of sleep and wakefulness. Plasma melatonin levels were investigated in patients with obstructive sleep apnoea syndrome (OSAS). In total, 20 patients with OSAS and 11 healthy controls were studied. OSAS patients were tested twice: on the night of diagnostic polysomnography and the night of continuous positive airway pressure (CPAP) titration. Controls were tested on one occasion. Plasma melatonin levels were determined at 23:00 h (light period), at 02:00 h (dark period) and at 06:00 h (light period) in patients and control subjects using the radioimmunoassay method. The control subjects showed a nocturnal melatonin peak value at 02:00 h (70.6+/-14 pg.mL(-1)). However, this nocturnal melatonin peak was absent in the OSAS patients. The highest melatonin value was found in OSAS patients on the night of diagnosis, at 06:00 h (49.3+/-36.8 pg.mL(-1)). It was found that the melatonin level in OSAS patients at 06:00 h was significantly lower in the night of titration (35.6+/-37.9 pg.mL(-1)) than in the diagnosis night. However, the melatonin levels at either 23:00 h or 02:00 h in OSAS patients did not differ significantly when comparing levels in the night of diagnostic polysomnography (23:00 h: 31.6+/-29.8 pg.mL(-1); 02:00 h: 47.4+/-33.8 pg.mL(-1)) with levels in the night of CPAP titration (23:00 h: 20.2+/-10.3 pg.mL(-1); 02:00 h: 37.7+/-27.5 pg.mL(-1)). Patients with obstructive sleep apnoea syndrome have an abnormal melatonin secretion pattern. The absence of a nocturnal serum melatonin peak could be partially related to the difficulty that these patients have in achieving a normal sleep-wakefulness pattern.     

Differential regulation of the nocturnal and diurnal prolactin surges in pregnant rats revealed by dopamine receptor antagonism.

We have explored temporal changes in the magnitude of dopamine (DA) interaction (DA tone) at the anterior pituitary lactotrophs related to both the nocturnal and diurnal prolactin (PRL) surges on day 8 of pregnancy, by utilizing a competitive DA D2 antagonist, domperidone (DOM). After withdrawal of blood from pregnant rats on day 7 in order to demonstrate the presence of a PRL surge, experimental rats received DOM (100 micrograms/kg i.v. or i.a.) at various times on day 8. Blood samples were taken immediately before and following injection of DOM at 5, 15, 30 and 60 min. The peak PRL response to DOM occurred 15 min after injection. Comparisons were made between circulating PRL levels immediately prior to and at several times following DOM administration for the various times of the day, and represented as incremental increases in PRL following DOM. During times on day 8 when PRL levels were normally low (24:00, 06:00, 12:00 and 16:00 h), pregnant rats exhibited a substantial PRL response to DOM. However, during the nocturnal PRL surge (02:00, 04:00 h) the peak PRL response to DOM was significantly lower. In sharp contrast, the PRL response to DOM administered during the diurnal PRL surge (18:00 h) was significantly higher than all other times of the day tested. In a dose-response study in which 10, 100 and 1,000 micrograms/kg DOM was administered at the two critical times when the response to DOM differed greatly, 02:00 and 18:00 h, there was a significantly reduced PRL response to DOM at 02:00 h compared to 18:00 h.(ABSTRACT TRUNCATED AT 250 WORDS)     

THE PREOPERATIVE AND POSTOPERATIVE INVESTIGATION OF TSH AND PROLACTIN RELEASE IN THE MANAGEMENT OF PATIENTS WITH HYPERPROLACTINAEMIA DUE TO PROLACTINOMAS AND NONFUNCTIONAL PITUITARY TUMOURS: RELATIONSHIP TO ADENOMA SIZE AT SURGERY

We report here our results of the pre- and post-operative assessment of prolactin and TSH status in 41 hyperprolactinaemic patients who underwent pituitary surgery over a 5 year period. Preoperatively in patients with prolactinomas (n = 33) the TSH response to domperidone decreased with increasing adenoma size. When the data are expressed on a group mean basis the exaggerated TSH response to domperidone in preoperative prolactinoma patients was reduced significantly in patients rendered normoprolactinaemic by surgery but persisted in those who remained hyperprolactinaemic. Similarly the reduced preoperative PRL responses to domperidone and TRH were significantly increased by successful surgery. In contrast patients with stalk-compression hyperprolactinaemia (n = 6) due to larger lesions which were not prolactinomas all showed reduced or absent TSH responses to domperidone. The PRL responses to domperidone and TRH were reduced or absent both in patients with prolactinomas and in those with stalk-compression hyperprolactinaemia. All patients with stalk-compression hyperprolactinaemia showed a delayed pattern of TSH response to TRH with 60 min values being greater than 20 min ones. In contrast a normal pattern of TSH response to TRH was observed in all patients with hyperprolactinaemia due to prolactinomas. Postoperatively TSH and PRL responses were largely unchanged in patients with stalk-compression hyperprolactinaemia regardless of whether normoprolactinaemia was restored by surgery. In conclusion a reduced or absent PRL response to TRH or domperidone is not diagnostic of the presence of a prolactinoma since it occurs in hyperprolactinaemic patients with prolactinomas or stalk-compression. In contrast, the TSH response to acute dopamine antagonism is exaggerated in most patients with small prolactinomas but not in those with stalk-compression hyperprolactinaemia and we have found this to be helpful diagnostically since the presence of an exaggerated TSH response to dopamine antagonism is evidence against the presence of stalk-compression hyperprolactinaemia. The observation of a delayed TSH response to TRH in a hyperprolactinaemic patient should alert the clinician to the possibility of stalk-compression hyperprolactinaemia due to a large lesion which may not be a prolactinoma.