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.     

PROLACTIN AND TSH RESPONSES TO BOTH DOMPERIDONE AND TRH IN NORMAL AND HYPERPROLACTINAEMIC WOMEN AFTER DOPAMINE SYNTHESIS BLOCKADE

A study of the effect of alpha-methyl-1-tryosine (metyrosine) blockade (2 g/d for 2 d) of dopamine (DA) synthesis on the PRL and TSH response to domperidone (DOM) and TRH in normal women and subjects with pathological hyperprolactinaemia is reported. In the normal subjects, there was a marked increase in basal PRL (51.7 +/- 11.1 vs 5.7 +/- 1.0 ng/ml) and the PRL and TSH responses to DOM were abolished. The PRL response to TRH was also reduced. In the hyperprolactinaemic subjects, metyrosine had no effect on basal PRL nor on the virtually non-existent PRL response to DOM, whereas it abolished the exaggerated TSH response. The conclusion is drawn that the response of both PRL and TSH to DA receptor blockers is really dependent upon DA inhibitory tone. A fall in this tone can also be postulated as responsible for the hyporesponsiveness of PRL to DOM frequently observed in pathological hyperprolactinaemia. In addition, the fact that metyrosine also abolished the exaggerated TSH response to DOM shows that the latter is totally dependent on enhanced DA inhibition of the thyrotrophs. Lastly, the reduced PRL response to TRH after metyrosine indicates that DA partly determines the ability of the lactotrophs to respond to TRH.     

Low recurrence rate after partial hypophysectomyfor prolactinoma: the predictive value ofdynamic prolactin function tests

OBJECTIVE: To determine the factors influencing the outcome of transethmoidal partial hypophysectomy for suspected prolactinoma and the predictive value of pre and post-operative dynamic PRL function tests. DESIGN: A retrospective study of patients undergoing surgery for a suspected prolactinoma in Cardiff between 1979 and 1989. PATIENTS: Eighty-two hyperprolactinaemic patients (75 women, seven men) diagnosed as having a prolactinoma on the basis of dynamic PRL function tests, radiological investigation and exclusion of other causes. MEASUREMENTS: TSH and PRL responses to domperidone (10 mg i.v.) and TRH (200 micrograms i.v.) measured preoperatively, 2 months post-operatively, and annually thereafter. CT scan performed preoperatively in 58 patients. Operative findings, including adenoma size, documented in each case. RESULTS: Forty-two patients (51%) had microadenomas (less than 10 mm), 37 (46%) had macroadenomas and in three no tumour was found at operation. Preoperatively, normal responses of both TSH (incremental rise less than 2.0 mU/l) and PRL (greater than 100% rise) to domperidone were observed in two patients only: both had an abnormal vascular supply to the pituitary rather than an adenoma. Serum PRL was normalized in the early post-operative period (less than 72 h; 'early cure') in 65 patients (79%). The highest early cure rate (96%, n = 26) was in patients with adenomas of 5-9 mm, lower rates being achieved for lesions of 10-19 mm (80%, n = 30), less than 5 mm (63%, n = 19) or greater than or equal to 20 mm (57%, n = 7). The early cure rate was strongly correlated with preoperative PRL, ranging from 100% in patients with PRL less than 1000 mU/l (n = 13) to zero in those with PRL greater than 10,000 mU/l. Dopamine agonist therapy of between 5 weeks and 4 years duration prior to surgery was associated with a significantly reduced early cure rate (60 vs 94%, P less than 0.02) in macroadenoma but not microadenoma patients. Recurrent hyperprolactinaemia during mean follow-up of 51.7 months occurred in eight patients (12%), in five cases within 2 months of surgery and in the others at 26, 48 and 50 months. Recurrence could not be predicted from any preoperative parameter, but a serum PRL greater than 150 mU/l 1-3 days following microadenomectomy was associated with early recurrence and probably indicates failed surgery. An abnormal response of TSH to domperidone was documented 2 months post-operatively in 11/60 patients with normal basal PRL, and preceded all three late recurrences. Of four patients with abnormal responses of both PRL and TSH at this time, two have relapsed to date. CONCLUSIONS: In carefully selected patients, partial hypophysectomy is an acceptable alternative to medical treatment for prolactinoma. Preoperatively, dynamic tests accurately identified those patients whose hyperprolactinaemia was non-adenomatous in origin and, post-operatively, identified a subgroup of patients at increased risk of late recurrence.     

EFFECT OF SUBACUTE CABERGOLINE TREATMENT ON PROLACTIN, THYROID STIMULATING HORMONE AND GROWTH HORMONE RESPONSE TO SIMULTANEOUS ADMINISTRATION OF THYROTROPHIN-RELEASING HORMONE AND GROWTH HORMONE-RELEASING HORMONE IN HYPERPROLACTINAEMIC WOMEN

It is known that dopaminergic neurotransmission is involved in the control of PRL, TSH and GH secretion. Cabergoline (CAB) is a new ergolinic derivative with a long-acting dopaminergic activity. We evaluated 11 women with pathological hyperprolactinaemia before and during sub-acute CAB treatment (0.8-1.2 mg/p.o.; 8 weeks). Simultaneous administration of TRH (200 micrograms i.v.) and GHRH 1-44 (50 micrograms i.v.) were carried out before and after 4, 8 and 10 week intervals from the beginning of CAB treatment. Basal PRL levels (2453.5 +/- S.E. 444.5 mU/l) were significantly reduced during CAB administration (week 4: 164.5 +/- 66.5 mU/l; week 8: 168.0 +/- 66.5 mU/l; P less than 0.01) and no variations were observed 2 weeks after drug discontinuation (week 10: 210.0 +/- 98.0 mU/l). PRL percentage change after TRH was increased by CAB (P less than 0.05). No variation in basal and TRH-stimulated TSH levels was found during CAB administration. A slight increase in GH basal levels (3.0 +/- 0.6 mU/l) was found after weeks 4 (6.4 +/- 2.0 mU/l) and 10 (5.8 +/- 1.6 mU/l) (P less than 0.05). GH response to GHRH was significantly enhanced (ANOVA: P less than 0.01) during sub-acute CAB treatment. A positive correlation was found between GH secretory area and weeks of CAB therapy (P less than 0.01). Our data show that CAB is very effective in lowering PRL secretion in hyperprolactinaemia, and is able to modify PRL and GH responses after TRH and GHRH. The increasing trend in GH basal and GHRH-stimulated GH levels seems to indicate that CAB can override the central dopaminergic tone which is operative in hyperprolactinaemia.     

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.     

Hyperprolactinaemia in hypothyroidism: clinical significance and impact of TSH normalization

OBJECTIVES: Menstrual irregularities in hypothyroidism have been reported to occur less frequently than previously described. We therefore studied the influence of serum PRL in patients with newly diagnosed subclinical and overt hypothyroidism and in hyperprolactinaemic patients treated with T4 to distinguish the impact of hypothyroidism from that of confounding drugs on hyperprolactinaemia and menstrual irregularities. PATIENTS AND METHODS: PRL was determined in 1003 consecutive hypothyroid patients (TSH > 4.0 mU/l) at referral, and after TSH normalization in 84 (8%) initially hyperprolactinaemic (female, > 480 mU/l; male, > 432 mU/l) subjects. Medical history (psychotropic drugs and oestrogens) and menstrual patterns were assessed at referral and after 8 +/- 5 (mean +/- SD) months of T4 therapy. Pituitary magnetic resonance imaging (MRI) was offered to patients with persistently elevated PRL. RESULTS: Menstrual disturbancies (oligomenorrhoea/secondary amenorrhoea, O/A) were not more common (P = NS) in hyper- than in normoprolactinaemic women (26% and 16%, respectively). We observed no galactorrhoea and no correlation between PRL and TSH or O/A except in pregnant or lactating women (N = 11). Oestrogens or antidepressants (including selective serotonin reuptake inhibitors) did not cause hyperprolactinaemia but antipsychotic drugs did. PRL decreased with T4 therapy (P < 0.01) in patients not using confounding drugs (from 720 +/- 288 to 360 +/- 192 mU/l) but menstrual irregularities persisted. PRL remained unchanged in patients receiving antipsychotic treatment. PRL was also unchanged in patients with pituitary abnormalities (seven micro-, one macroadenoma). CONCLUSIONS: Hyperprolactinaemia was not an important feature in patients with newly diagnosed hypothyroidism. Neuroleptic drugs may cause persisting hyperprolactinaemia after TSH normalization. In addition, menstrual disturbancies do not relate to hyperprolactinaemia in hypothyroidism.     

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.     

An audit of the diagnostic usefulness of PRL and TSH responses to domperidone and high resolution magnetic resonance imaging of the pituitary in the evaluation of hyperprolactinaemia

BACKGROUND AND OBJECTIVE The usefulness of dynamic tests of PRL release in determining underlying pathology in hyperprolactinaemic patients is not well recognized by endocrinologists, only 15% of whom routinely perform such tests. High resolution pituitary magnetic resonance imaging (MRI) has become more widely available during the past 5 years and is now generally regarded as the pituitary imaging method of choice. Since few prolactinoma patients are now submitted to surgery, it is important to ascertain the usefulness of these techniques in suggesting a pathological diagnosis. DESIGN A 3 year retrospective audit of the information derived from measurement of PRL and TSH responses to the dopamine antagonist domperidone and from high resolution pituitary MRI in patients being investigated for hyperprolactinaemia in regional endocrine unit. PATIENTS Eighty-four patients (10 male, 74 female) whose investigation of hyperprolactinaemia included a domperidone test and high resolution pituitary MRI. Patients who had domperidone tests performed after pituitary surgery or who did not have pituitary MRI were excluded from the analysis. MEASUREMENTS PRL and TSH were measured basally and at 30 and 60 minutes following domperidone (10 mg i.v.) and gadolinium-enhanced pituitary MRI was performed in all patients. RESULTS 20 patients had a normal PRL response to domperidone (defined as PRL_30′/PRL_0′ >3) and this group included five patients in whom hyperprolactinaemia was not sustained. Pituitary MRI showed evidence of a microadenoma in only two patients, imaging being unequivocally normal in the majority. Sixty-four patients had an abnormal PRL response to domperidone and 18 of these had a macrolesion (nine prolactinomas, nine other tumours). Pituitary MRI was performed in the remaining 46 patients with abnormal PRL response to domperidone and suggested microadenoma in 29 (63%), identified other structural abnormalities in six cases but was entirely normal in 11 cases. Neither the basal PRL level nor the TSH response could refine the diagnosis further because of overlap between the various subgroups. CONCLUSIONS The majority of patients with a normal dynamic response of PRL to domperidone had a normal or near normal pituitary MRI scan. In the two cases where an abnormality was detected it could have been an incidental microadenoma or cyst, thus suggesting that pituitary scanning could normally be omitted in patients whose PRL response to domperidone is normal (24% of our total). The group of patients with an abnormal dynamic response of PRL to domperidone was not generally amenable to further diagnostic refinement by considering the degree of hyperprolactinaemia or the TSH response to domperidone because of overlap of these parameters between the diagnostic subgroups. Therefore any degree of hyperprolactinaemia associated with a blunted PRL response to domperidone warrants pituitary imaging.     

Arginine stimulates growth hormone secretion by suppressing endogenous somatostatin secretion

To determine how arginine (Arg) stimulates GH secretion, we investigated its interaction with GHRH in vivo and in vitro. Six normal men were studied on four occasions: 1) Arg-TRH, 30 g arginine were administered in 500 mL saline in 30 min, followed by an injection of 200 micrograms TRH; 2) GHRH-Arg-TRH, 100 micrograms GHRH-(1-44) were given iv as a bolus immediately before the Arg infusion, followed by 200 micrograms TRH, iv; 3) GHRH test, 100 micrograms GHRH were given as an iv bolus; and 4) TRH test, 200 micrograms TRH were given iv as a bolus dose. Blood samples were collected at 15-min intervals for 30 min before and 120 min after the start of each infusion. Anterior pituitary cells from rats were coincubated with Arg (3, 6, 15, 30, and 60 mg/mL) and GHRH (0.05, 1, 5, and 10 nmol/L) for a period of 3 h. Rat GH was measured in the medium. After Arg-TRH the mean serum GH concentration increased significantly from 0.6 to 23.3 +/- 7.3 (+/- SE) micrograms/L at 60 min. TRH increased serum TSH and PRL significantly (maximum TSH, 11.1 +/- 1.8 mU/L; maximum PRL, 74.6 +/- 8.4 micrograms/L). After GHRH-Arg-TRH, the maximal serum GH level was significantly higher (72.7 +/- 13.4 micrograms/L) than that after Arg-TRH alone, whereas serum TSH and PRL increased to comparable levels (TSH, 10.2 +/- 3.0 mU/L; PRL, 64.4 +/- 13.6 micrograms/L). GHRH alone increased serum GH to 44.9 +/- 9.8 micrograms/L, significantly less than when GHRH, Arg, and TRH were given. TRH alone increased serum TSH to 6.6 +/- 0.6 mU/L, significantly less than the TSH response to Arg-TRH. The PRL increase after TRH only also was lower (47.2 +/- 6.8 micrograms/L) than the PRL response after Arg-TRH. In vitro Arg had no effect on basal and GHRH-stimulated GH secretion. Our results indicate that Arg administered with GHRH led to higher serum GH levels than did a maximally stimulatory dose of GHRH or Arg alone. The serum TSH response to Arg-TRH also was greater than that to TRH alone. We conclude that the stimulatory effects of Arg are mediated by suppression of endogenous somatostatin secretion.     

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.     

The inability of dynamic tests of prolactin and TSH secretion to differentiate between tumorous and non-tumorous hyperprolactinemia

Certain hyperprolactinemic patients have an obvious pituitary tumor while others with normal pituitary radiology may or may not harbor a pituitary microadenoma. A variety of biochemical tests have been proposed to distinguish between those with and those without pituitary tumors. The aims of this study were: firstly to examine these tests to assess their efficacy in differentiating between patients with radiologically-demonstrated pituitary tumors and normal controls; and secondly to establish if those hyperprolactinemic patients with normal radiology formed two distinct groups biochemically as might be expected if some did and some did not have tumors. The prolactin (PRL) and thyroid stimulating hormone (TSH) response to domperidone and the PRL response to TRH and insulin-induced hypoglycemia have thus been examined in hyperprolactinemic subjects with and without radiological evidence of an adenoma and in normal controls. The basal serum PRL was similar in patients with and without radiological evidence of a pituitary adenoma. The serum PRL response to all stimuli studied, expressed as a percentage of initial values, was blunted in patients with known pituitary tumors with total separation from values in control subjects. Results for patients with normal pituitary radiology were similar to those for patients with tumors with minimal overlap with controls. The peak TSH increment after domperidone was exaggerated in patients with known tumors, but overlap with control values was observed in 25%. In patients with normal radiology the peak TSH increment after domperidone was similarly increased but again overlap with control values occurred in 28%. Cluster analysis showed no evidence of two subgroups of response with in the hyperprolactinemic patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Serum thyrotropin and prolactin in the syndrome of generalized resistance to thyroid hormone: responses to thyrotropin-releasing hormone stimulation and short term triiodothyronine suppression

Serum TSH and PRL levels and their response to TRH were measured in 11 patients with generalized resistance to thyroid hormone (GRTH), 6 euthyroid subjects, and 6 patients with primary hypothyroidism. TSH and PRL levels and their response to TRH were also measured after the consecutive administration of 50, 100, and 200 micrograms T3 daily, each for a period of 3 days. Using a sensitive TSH assay, all GRTH patients had TSH values that were elevated or within the normal range. On the basis of a normal or elevated TSH level, GRTH patients were classified as GRTH-N1 TSH (5 patients) or GRTH-Hi TSH (6 patients), respectively. Only GRTH patients with previous thyroid ablative therapy had basal TSH values greater than 20 mU/L. TSH responses, in terms of percent increment above baseline, were appropriate for the basal TSH level in all subjects. No GRTH patient had an elevated basal PRL level. PRL responses to TRH were significantly increased only in the hypothyroid controls compared to values in all other groups. On 50 micrograms T3, 7 of 12 (58%) nonresistant (euthyroid and hypothyroid) and 1 of 11 (9%) resistant subjects had a greater than 75% suppression of the TSH response to TRH. On the same T3 dose, 2 of 12 (17%) nonresistant and 4 of 11 (36%) resistant subjects had a greater than 50% suppression of the PRL response to TRH. On 200 micrograms T3, all subjects, except for 1 with GRTH, had a greater than 75% suppression of the TSH response to TRH. On the same T3 dose, while 11 of 12 (92%) nonresistant subjects had a greater than 50% reduction of the PRL response to TRH, only 3 of 10 (30%) resistant patients showed this degree of suppression (P less than 0.005). Without previous ablative therapy, serum TSH in patients with GRTH is usually normal or mildly elevated. The TSH response to TRH is proportional to the basal TSH level and is suppressed by exogenous T3. However, on 200 micrograms T3 basal TSH was not detectable (less than 0.1 mU/L) in all euthyroid subjects, but it was measurable in three of four GRTH patients with normal TSH levels before T3 treatment. PRL levels in GRTH are normal even when TSH is elevated. The PRL response to TRH is not increased in GRTH. In all subjects, exogenous T3 suppresses the PRL response to TRH to a lesser degree than the TSH response, but this difference is much greater in patients with GRTH.     

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.     

Evaluation of endocrine tests. A: the TRH test in patients with hyperprolactinaemia

BACKGROUND: In a previous study, we determined reference values for basal and thyrotropin-releasing hormone (TRH)-stimulated plasma concentrations of prolactin (PRL). The aim of the present study was to determine the clinical usefulness of the PRL response to TRH in the work-up of patients with hyperprolactinaemia. METHODS: We studied 92 consecutive patients referred for evaluation of hyperprolactinaemia. Patients with confirmed hyperprolactinaemia were divided into three groups: group A (pharmacological hyperprolactinaemia; n=2), group B (pathological hyperprolactinaemia; n=6) and group C (all other patients). Patients in group C underwent MRI of the pituitary and were subdivided into C1 (normal pituitary on MRI; n=6), C2 (slightly abnormal MRI; n=21), and C3 (evident microadenoma or macroadenoma on MRI; n=25 and 12, respectively). The MRI was technically insufficient in four patients. Basal PRL as determined by fluoroimmunometric assay and the PRL response to 400 microg TRH were determined in all patients. RESULTS: Hyperprolactinaemia was confirmed in 83% of the referred patients. Non-response, defined as a <2.5-fold PRL increase after TRH, occurred in one patient (50%) in group A, in 66% of patients in group B and in 99% of patients in group C. Within group C, basal PRL was not different between group C1 and C2, but higher (p=0.06) in group C3. The absolute PRL increase after TRH did not differ between the three subgroups. The relative PRL increase was smaller (p=0.03) in group C3 but overlapped considerably with groups C1 and C2. All patients except one in group C were so-called non-responders. Basal PRL and absolute PRL increases after TRH correlated with the adenoma diameter on MRI (r=0.66, p=0.0002 and r=0.49, p=0.008, respectively). CONCLUSION: In patients referred for elevated serum PRL, hyperprolactinaemia should be confirmed under standardised conditions. The absolute or relative PRL increase after 400 microg TRH does not help to differentiate between patients with prolactinoma or idiopathic hyperprolactinaemia. Therefore, the TRH stimulation test is not useful in the work-up of hyperprolactinaemia.     

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)     

Thyrotropin suppression by 3,5-dimethyl-3'-isopropyl-L-thyronine in man.

The thyromimetic activity of 3,5-dimethyl-3'-isopropyl-L-thyronine (DIMIT), a nonhalogenated thyroid analog, was studied in adult men using suppression of TRH-induced TSH release to assess this activity. In nine men, aged 30-58 yr, the TSH increment after 500 microgram TRH iv was compared to the TSH response to TRH 24 h after oral administration of 1 mg DIMIT. Eight euthyroid subjects had normal baseline TSH levels of 1.5 +/- 0.2 (SE) microunit/ml that fell significantly to 0.7 +/- 0.2 microunit/ml 24 h after DIMIT (P less than 0.005). Their TSH increments after TRH fell from 15.3 +/- 2.8 to 6.7 +/- 1.6 microunit/ml 24 h after DIMIT (P less than 0.001). One subject with probable Hashimoto's thyroditis had an elevated TSH of 18 microunit/ml, with an exaggerated TSH response to TRH of 72 microunit/ml. His basal TSH fell to 7.6 and his TSH increment fell to 14.3 microunit/ml 24 h after DIMIT. The suppression of TSH was relatively prolonged. In four subjects, the TSH response to TRH was still blunted from 5-12 days after DIMIT. In one subject, the TSH increment returned to normal 15 days after DIMIT. DIMIT had no significant effect on PRL secretion. There was no evidence of toxicity in patients receiving DIMIT. DIMIT has effective thyromimetic activity in man, as shown by its significant and prolonged suppression of TSH secretion.     

Bromocriptine treatment of microprolactinomas: evidence of stable prolactin decrease after drug withdrawal

Thirty-six women with PRL-secreting pituitary microadenomas [mean PRL, 114 +/- 12.5 (+/- SE) ng/ml] were treated with bromocriptine (BRC; 2.5-10 mg/day) for 12 months. During BRC treatment, serum PRL decreased in all patients. After termination of treatment, mean serum PRL levels, evaluated at 15, 30, and 45 days, were significantly decreased (-41.6%, -43.0%, and -40.2%, respectively) compared to pretreatment values. The patients were arbitrarily divided into 3 groups: 12 responders, in whom the PRL persistent posttreatment decrease was greater than 50%, 8 hyporesponders, in whom the PRL decrease was between 30% and 50%, and 16 nonresponders with absent or negligible PRL decrease. Four patients had normal PRL levels and clinical remission for 14-30 months after BRC withdrawal. In 18 women, BRC treatment was repeated for another 12 months. After termination of treatment, 11 patients were responders, 1 was a hyporesponder, and 6 were nonresponders. Four of these 18 patients still had normal PRL levels 8-28 months after drug discontinuation. The responses of PRL to TRH and domperidone were compared before and after termination of treatment at 30 and 45 days, respectively. Both mean peak values of PRL and absolute increases after TRH treatment were similar before and after BRC administration; however, a PRL response to TRH was present in 15% of 26 patients before treatment and in 42% after treatment. The mean peak values after domperidone were similar before and after BRC treatment, but the absolute increase over the basal value was much higher after BRC; PRL response to domperidone was present in 16% of 19 patients before BRC treatment and in 74% after BRC. These data suggest that BRC is effective in the treatment of some microprolactinomas; BRC effectiveness improves after prolonged periods of administration. The variations in PRL responses to TRH and domperidone suggest profound modification of PRL secretion after BRC treatment.     

STUDIES OF TWO THYROTROPHIN-SECRETING PITUITARY ADENOMAS: EVIDENCE FOR DOPAMINE RECEPTOR DEFICIENCY

Of 22 previously reported patients with TSH-secreting pituitary adenomas challenged with dopamine agonists, 18 showed no decrease in serum TSH. There have been few in-vitro studies of these rare tumours so the mechanism of the dopaminergic resistance has remained obscure. We describe two further patients with thyrotrophinomas; the first was thyrotoxic (T3 6.1 nmol/l, TSH 7 mU/l) and the second was diagnosed after radioiodine for presumed Graves' disease. The second patient had an alpha-subunit: TSH molar ratio less than unity (0.27). In-vivo TSH responses to TRH, bromocriptine and domperidone were compared with those of the resected tumour cells in vitro, the latter studied using a continuous perifusion system. Dopamine receptors were sought in membranes from each tumour using a radioreceptor assay employing 3H-spiperone. Patient 1 showed significant increases in serum TSH (7 to 13 mU/l) and alpha-subunit (18.7 to 385 ng/ml) after 200 micrograms TRH (i.v.) but patient 2 showed no such increases (TSH: 69 to 72 mU/l, alpha-subunit: 4.9 to 5.2 ng/ml). Neither patient showed a change in serum TSH following bromocriptine 2.5 mg (orally) or domperidone 10 mg (i.v.), though serum PRL responded normally. Serum TSH from patient 1 was of apparently normal molecular size but increased bioactivity (B/I ratio 3.8) and that from patient 2 was of increased molecular size but reduced bioactivity (B/I ratio 0.1). Tumour cells from each patient immunostained for TSH beta and alpha-subunit, and secreted TSH in vitro. The first showed dose-dependent TSH release after TRH (1-100 ng/ml) which could not be inhibited by dopamine (5 mumol/l) but the second was unresponsive to TRH in vitro. Neither tumour showed inhibition of TSH release by dopamine (5 mumol/l) or bromocriptine (0.01-10 nmol/l) and neither contained membrane-bound dopamine receptors. The results suggest that the dopaminergic resistance typical of most TSH-secreting pituitary adenomas may be due to altered or absent membrane-bound dopamine receptors.     

Effects of disodium EDTA and calcium infusion on prolactin and thyrotropin responses to thyrotropin-releasing hormone in healthy man

To determine the impact of induced hypo- and hypercalcemia on TRH (400 micrograms)-stimulated TSH and PRL release, healthy subjects (n = 11) were infused with 5% glucose in water (n = 11), disodium EDTA (n = 11), or calcium gluconate (n = 7). TRH was given as an iv bolus 60 min (5% glucose and EDTA) and 120 min (calcium) after initiation of the respective infusion. Basal plasma concentrations of TSH remained unchanged during induced hypo- and hypercalcemia, whereas those of PRL fell during the latter (P less than 0.05). The mean sum of increments (0-90 min) in PRL and TSH was considerably greater during hypocalcemia than during hypercalcemia (PRL, P less than 0.002; TSH, P less than 0.005). The increments in the plasma hormone concentration above basal after iv TRH were increased compared to those in normocalcemia (PRL, 98.4 +/- 37.9 ng/ml; TSH, 38.9 +/- 11.8 microU/ml) during hypocalcemia [PRL, 128 +/- 47.8 ng/ml (P less than 0.002); TSH, 46.7 +/- 12.8 microU/ml; (P less than 0.005)], but were impaired during hypercalcemia [PRL, 70.1 +/- 27 ng/ml (P less than 0.002); TSH, 28.9 +/- 8.5 microU/ml (P less than 0.025)]. The mean sum of increments in PRL was related to concentrations of both serum calcium (r = -0.59; P less than 0.01) and PTH (r = 0.51; P less than 0.05). A relation was also seen between the incremental responses of TSH and serum calcium (r = -0.52; P less than 0.05), PTH (r = 0.55; P less than 0.01), and phosphorus (r = -0.55; P less than 0.01). We conclude that in healthy man, TRH-mediated release of both PRL and TSH are inversely related to serum calcium concentrations in such a manner that hormone secretion is enhanced by acute hypocalcemia, but blunted by hypercalcemia.