THYROTROPHIN, PROLACTIN AND GROWTH HORMONE RESPONSES TO TRH IN BARBITURATE COMA AND IN DEPRESSION

The effects of 200 microgram thyrotrophin-releasing hormone (TRH) i.v. on thyrotrophin (TSH), prolactin (PRL), growth hormone (GH) and triiodothyronine (T3) were studied in eight patients with barbiturate coma due to attempted suicide, in the same patients after recovery, in eight depressive patients and in eight normal controls. The patients with barbiturate coma presented normal basal TSH and PRL, elevated basal GH and normal PRL but blunted TSH responses to TRH; their GH concentrations varied widely without consistent relation to TRH administration. The same patients after recovery from coma presented normal TSH and PRL, slightly elevated basal GH, and normal PRL but blunted TSH responses to TRH; in four of these patients, a clear-cut rise in GH (i.e. more than 10 ng/ml) occurred after TRH administration. The depressive patients presented normal basal TSH and PRL, slightly elevated basal GH, and normal PRL but blunted TSH responses to TRH; in four of these patients, a moderated rise in GH (less than 10 ng/ml) occurred after TRH administration. The increment in T3 concentrations 120 min after TRH was found reduced in the comatose patients only. Basal cortisol was measured in all the subjects and found elevated in the comatose patients only. It is concluded that the abnormal TSH and GH responses to TRH observed in patients with barbiturate coma are more likely related to depressive illness than to an effect of barbiturates at the pituitary level. Barbiturates might affect thyroid secretion.     

Growth hormone response to thyrotropin-releasing hormone in diabetes

The effect of TRH on GH secretion was assessed in 13 insulin-dependent diabetics. PRL and TSH responses to TRH were also determined. Glycosylated hemoglobin levels and serial fasting glucose concentrations indicated that all but 1 of the patients had a period of poor diabetic control for several months before the study. Peak PRL and TSH levels after TRH injection in these diabetic patients did not differ significantly from values observed in nondiabetic individuals. Six of the patients responded to TRH with a significant rise in GH levels; basal GH concentrations were also elevated in these patients. Five of the 6 responders and none of the nonresponders had proliferative diabetic retinopathy. The results suggest that diabetics with elevated basal GH levels hyperrespond to TRH, and that nonspecific secretion of GH in response to TRH occurs in some patients with proliferative diabetic retinopathy. Chronic hyperglycemia does not appear to be the critical factor in determining this response.     

Discordant effects of insulin-hypoglycemia on growth hormone (GH)-releasing hormone-stimulated GH and thyrotropin (TSH)-releasing hormone-stimulated TSH secretion

The hypothesis that insulin hypoglycemia-induced GH release is mediated by a decrease in hypothalamic somatostatin (SRIH) secretion was tested by investigating whether insulin administration enhanced the responses of SRIH-sensitive pituitary hormones to hypothalamic hormone stimulation. Eight normal men were given a combined iv injection of GHRH (1 microgram/kg) and TRH (0.3 microgram/kg) on two occasions, on one of which regular insulin (0.1 U/kg, iv) was given 30 min before GHRH-TRH administration. Insulin hypoglycemia augmented the maximal incremental (P less than 0.01) and integrated (P less than 0.025) plasma GH responses to GHRH. In contrast, plasma TSH responses to TRH were diminished by insulin (maximal increment, P less than 0.025; integrated response, P less than 0.05). TRH-stimulated PRL secretion was not altered by prior insulin administration. The enhancement of GH responsiveness to maximal GHRH stimulation indicates mediation by a non-GHRH pathway. However, the discordant decrease in TSH responsiveness to TRH argues against a reduction in hypothalamic SRIH secretion as a mechanism for the action of insulin.     

Effects of repetitive administration of thyrotropin-releasing hormone at short intervals in acromegaly

We investigated the pattern of GH secretion in response to repetitive TRH administration in patients with active acromegaly and in normal subjects. Nine acromegalic patients and 10 normal subjects received three doses of 200 micrograms of TRH iv at 90-min intervals. There was a marked serum GH rise in acromegalic patients after each TRH dose (net incremental area under the curve [nAUC]: first dose = 4448 +/- 1635 micrograms.min.l-1; second dose = 3647 +/- 1645 micrograms.min.l-1; third dose = 4497 +/- 2416 micrograms.min.l-1; NS), though individual GH responses were very variable. In normal subjects TRH did not elicit GH secretion even after repeated stimulation. Each TRH administration stimulated PRL release in acromegalic patients, though the nAUC of PRL was significantly higher after the first (1260 +/- 249 micrograms.min.l-1) than after the second and the third TRH administration (478 +/- 195 and 615 +/- 117 micrograms.min.l-1, respectively; P less than 0.01). In normal subjects too, PRL secretion was lower after repeated stimulation (first dose = 1712 +/- 438 micrograms.min.l-1; second dose = 797 +/- 177 micrograms.min.l-1; third dose = 903 +/- 229 micrograms.min.l-1 P less than 0.01), though different kinetics of PRL secretion were evident, when compared with acromegalic patients. TSH secretion, assessed in only 4 patients, was stimulated after each TRH dose, though a minimal but significant reduction of nAUC of TSH after repeated TRH challenge occurred. Both T3 and T4 increased steadily in the 4 patients. The same pattern of TSH, T3, and T4 secretion occurred in normal subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Thyrotropin-releasing hormone stimulates growth hormone release from the anterior pituitary of hypothyroid rats in vitro

We have examined the interaction of thyroid hormone and TRH on GH release from rat pituitary monolayer cultures and perifused rat pituitary fragments. TRH (10(-9) and 10(-8)M) consistently stimulated the release of TSH and PRL, but not GH, in pituitary cell cultures of euthyroid male rats. Basal and TRH-stimulated TSH secretion were significantly increased in cells from thyroidectomized rats cultured in medium supplemented with hypothyroid serum, and a dose-related stimulation of GH release by 10(-9)-10(-8) M TRH was observed. The minimum duration of hypothyroidism required to demonstrate the onset of this GH stimulatory effect of TRH was 4 weeks, a period significantly longer than that required to cause intracellular GH depletion, decreased basal secretion of GH, elevated serum TSH, or increased basal secretion of TSH by cultured cells. In vivo T4 replacement of hypothyroid rats (20 micrograms/kg, ip, daily for 4 days) restored serum TSH, intracellular GH, and basal secretion of GH and TSH to normal levels, but suppressed only slightly the stimulatory effect of TRH on GH release. The GH response to TRH was maintained for up to 10 days of T4 replacement. In vitro addition of T3 (10(-6) M) during the 4-day primary culture period significantly stimulated basal GH release, but did not affect the GH response to TRH. A GH stimulatory effect of TRH was also demonstrated in cultured adenohypophyseal cells from rats rendered hypothyroid by oral administration of methimazole for 6 weeks. TRH stimulated GH secretion in perifused [3H]leucine-prelabeled anterior pituitary fragments from euthyroid rats. A 15-min pulse of 10(-8) M TRH stimulated the release of both immunoprecipitable [3H]rat GH and [3H]rat PRL. The GH release response was markedly enhanced in pituitary fragments from hypothyroid rats, and this enhanced response was significantly suppressed by T4 replacement for 4 days. The PRL response to TRH was enhanced to a lesser extent by thyroidectomy and was not affected by T4 replacement. These data suggest the existence of TRH receptors on somatotrophs which are suppressed by normal amounts of thyroid hormones and may provide an explanation for the TRH-stimulated GH secretion observed clinically in primary hypothyroidism.     

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.     

Effects of acute infusion of erythropoietin on paradoxical responses of growth hormone to thyrotropin-releasing hormone in acromegalic patients

OBJECTIVE: Our aim has been to evaluate the effects of i.v. infusion of recombinant human erythropoietin (rhEPO) on the responses of growth hormone (GH), prolactin (PRL) and thyrotropin (TSH) to thyrotropin-releasing hormone (TRH) stimulation in acromegalic patients. METHODS: We studied 16 patients (8 females, aged 29-68 years) with active acromegaly and 12 control subjects (7 females, 24-65 years). All participants were tested with TRH (400 microg i.v. as bolus) and with TRH plus rhEPO (40 U/kg at a constant infusion rate for 30 min, starting 15 min before TRH injection) on different days. Blood samples were obtained between -30 and 120 min for GH and PRL determinations, and between -30 and 90 min for TSH determinations. Hormone responses were studied by a time-averaged (area under the secretory curve (AUC)) and time-independent (peak values) analysis. RESULTS: Twelve patients exhibited a paradoxical GH reaction after TRH administration with great interindividual variability in GH levels. When patients were stimulated with rhEPO plus TRH there were no changes in the variability of GH responses or in the peak and AUC for GH secretion. Infusion with rhEPO did not induce any significant change in GH secretion in normal subjects. Baseline and TRH-stimulated PRL concentrations in patients did not differ from those values found in controls. When TRH was injected during the rhEPO infusion, a significant (P<0.05) increase in PRL concentrations at 15-120 min was found in acromegalic patients. Accordingly, the PRL peak and the AUC for PRL secretion were significantly increased in patients. Infusion with rhEPO had no effect on TRH-induced PRL release in control subjects. Baseline TSH concentrations, as well as the TSH peak and the AUC after TRH, were significantly lower in patients than in controls. Infusion with rhEPO modified neither the peak TSH reached nor the AUC for TSH secretion after TRH injection in acromegalic patients and in healthy volunteers. CONCLUSION: Results in patients with acromegaly suggest that (i) the paradoxical GH response to TRH is not modified by rhEPO infusion, (ii) rhEPO has no effect on TRH-induced TSH release, and (iii) acute rhEPO administration increases the TRH-induced PRL release in acromegalic patients.     

Growth hormone-releasing peptide-2 infusion synchronizes growth hormone, thyrotrophin and prolactin release in prolonged critical illness

OBJECTIVE: During prolonged critical illness, nocturnal pulsatile secretion of GH, TSH and prolactin (PRL) is uniformly reduced but remains responsive to the continuous infusion of GH secretagogues and TRH. Whether such (pertinent) secretagogues would synchronize pituitary secretion of GH, TSH and/or PRL is not known. DESIGN AND METHODS: We explored temporal coupling among GH, TSH and PRL release by calculating cross-correlation among GH, TSH and PRL serum concentration profiles in 86 time series obtained from prolonged critically ill patients by nocturnal blood sampling every 20 min for 9 h during 21-h infusions of either placebo (n=22), GHRH (1 microg/kg/h; n=10), GH-releasing peptide-2 (GHRP-2; 1 microg/kg/h; n=28), TRH (1 microg/kg/h; n=8) or combinations of these agonists (n=8). RESULTS: The normal synchrony among GH, TSH and PRL was absent during placebo delivery. Infusion of GHRP-2, but not GHRH or TRH, markedly synchronized serum profiles of GH, TSH and PRL (all P< or =0.007). After addition of GHRH and TRH to the infusion of GHRP-2, only the synchrony between GH and PRL was maintained (P=0.003 for GHRH + GHRP-2 and P=0.006 for TRH + GHRH + GHRP-2), and was more marked than with GHRP-2 infusion alone (P=0.0006 by ANOVA). CONCLUSIONS: The nocturnal GH, TSH and PRL secretory patterns during prolonged critical illness are herewith further characterized to include loss of synchrony among GH, TSH and PRL release. The synchronizing effect of an exogenous GHRP-2 drive, but not of GHRH or TRH, suggests that the presumed endogenous GHRP-like ligand may participate in the orchestration of coordinated anterior pituitary hormone release.     

A possible direct precursor of thyrotropin-releasing hormone, pGlu-His-Pro-Gly, stimulates prolactin secretion in anorexia nervosa

TRH is produced from its possible direct precursor, pGlu-His-Pro-Gly (TRH-Gly), by alpha-amidating enzyme. The quantitative response of TRH-Gly-stimulated PRL, TSH, and GH was evaluated in nine patients with anorexia nervosa, six age-matched normal women, eight patients with uremia, five patients with acromegaly, and two patients with prolactinoma. Intravenous injection (500 micrograms) of TRH-Gly caused a 2.6-fold increase in PRL secretion in patients with anorexia nervosa (basal level, 10.0 +/- 1.4 vs. 25.9 +/- 2.5 micrograms/L 15 min after injection; P less than 0.01). In contrast, no significant change was observed in TRH-Gly-stimulated PRL secretion in normal women (basal level, 13.5 +/- 2.3 vs. 15.3 +/- 2.5 micrograms/L 15 min after injection; P greater than 0.05). TRH-Gly did not alter PRL levels in patients with uremia, acromegaly, or prolactinoma. Secretion of TSH, but not GH, was slightly increased by TRH-Gly injection in patients with anorexia nervosa (basal level, 1.41 +/- 0.13 vs. 2.86 +/- 0.22 min/L 30 min after injection; P less than 0.01), whereas no significant secretory response was observed in normal women. These data provide evidence that PRL secretion in anorectic patients is quantitatively different from that in normal persons.     

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.     

Different prolactin, thyrotropin, and thyroxine responses after prolonged intermittent or continuous infusions of thyrotropin-releasing hormone in rhesus monkeys

Serum PRL, TSH, and T4 secretion during prolonged continuous or intermittent iv infusions of TRH were studied in 14 adult ovariectomized rhesus monkeys (Macaca mulatta). For 9 days, TRH was administered intermittently at 0.33 or 3.3 micrograms/min for 6 of every 60 min and continuously at 0.33 micrograms/min. With both modes, the PRL levels and responsiveness to TRH simulation peaked on day 1 and then fell to levels that were still higher than the preinfusion values; levels for the intermittently treated group on days 3-9 were 2- to 4-fold above prestimulation levels and significantly (P less than 0.01) higher than levels for the continuously treated group. Elevated basal levels and PRL responses to TRH pulses were similar during the 0.33 and 3.3 micrograms/min pulses of the 9-day treatment period. For both TRH modes, TSH levels were elevated significantly (P less than 0.001) on day 1 [this increase was higher with continuous infusion (P less than 0.001)] and then fell to preinfusion levels by day 3. Serum T4 also increased during both continuous and intermittent TRH stimulations. However, serum T4 levels were significantly lower (P less than 0.01) after intermittent TRH (both 0.33 and 3.3 micrograms/min) than after continuous (0.33 micrograms) TRH (8 +/- 1.1 and 10 +/- 1.8 micrograms T4/dl vs. 18 +/- 3.1 micrograms, respectively). These PRL and T4 responses were replicated when the mode of administering 0.33 micrograms/min TRH was reversed after 9 days. An iv bolus of TRH (20 micrograms) after 9 days of continuous or intermittent TRH infusion caused significant release of PRL and TSH, an indication that neither mode of administration resulted in pituitary depletion of releasable hormone. We have concluded that intermittent TRH is more effective in elevating serum PRL, and continuous TRH is more effective in raising TSH and T4 levels. Thus, the manner of TRH secretion by the hypothalamus may determine its relative physiological importance in the stimulation of lactotropes and thyrotropes.     

Effect of simultaneous administration of GHRH (1-40) and TRH on GH, PRL and TSH secretion in normal man

The GHRH test represents a new tool in the study of secretion in man. Nine normal fasting males received on separate occasions in random order 1) GHRH 1-40 (1 microgram/Kg bw) iv at time 0; 2) TRH (6 micrograms/min) infusion between -30 and +120 min; 3) GHRH 1-40 (1 microgram/Kg bw) iv at time 0 plus TRH (6 micrograms/min) infusion between -30 and +120 min. Blood samples were drawn for GH, PRL and TSH at -90, -60, -30, 0 min and then every 15 min for 2 h. GHRH significantly increased GH in all subjects. The same GH response was found during GHRH plus TRH test. No effect was found either on PRL and TSH secretion after GHRH administration, or on GH pattern after TRH administration. A significant decrease of TSH, but not of PRL response was observed after GHRH plus TRH administration in comparison to TRH alone. These results underline that the inhibitory effect exerted by TRH on GH secretion during some experimental conditions is not linked to a pituitary interference between GHRH and TRH. The difference in TSH secretion, following GHRH plus TRH in comparison with TRH alone, could be due to a GHRH-induced central inhibitory mechanism, probably GHRH-related.     

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.     

Metoclopramide increases prolactin release and milk secretion in puerperium without stimulating the secretion of thyrotropin and thyroid hormones

To explore the effect of metoclopramide (MC) on the secretion of PRL, TSH, and thyroid hormones (T3 and T4) and on defective lactation, 17 mothers with poor lactation were treated with oral MC (10 mg. three times daily) for 3 weeks starting 18-141 days post partum. After a pause of 1 week, the medication was given for a further 2 weeks. The breast milk yield was monitored objectively before and during the trial. Furthermore, iv stimulation tests with MC (10 mg) and TRH (200 microgram) were done before and at the end of oral MC therapies. Oral MC increased the mean (+/-SEM) plasma PRL level from 36.6 +/- 9.2 to 90.6 +/- 7.5 ng/ml (P less than 0.001) after 1 week, and the PRL level remained elevated for as long as MC was administered. During the pause, the PRL level decreased to 19.5 +/- 7.5 ng/ml, but increased once again during the second MC treatment to 85.5 +/- 16.0 ng/ml (P less than 0.01). Plasma TSH, T3, and T4 did not change. The PRL level rose significantly after TRH and MC injections before and during oral treatments with MC, whereas the TSH concentrations were elevated only after TRH stimulation. The PRL response to iv MC or TRH and the TSH response to iv TRH were not affected by oral MC treatment. The mean daily milk volume increased from 433 +/- 55 to 626 +/- 75 ml (P less than 0.001) during the first treatment and from 390 +/- 73 to 606 +/- 56 ml (P less than 0.01) during the second oral MC treatment. Correspondingly, the volume of daily supplemental alimentation decreased from 348 +/- 61 to 280 +/- 59 ml (P less than 0.05) and from 526 +/- 68 to 363 +/- 66 ml (P less than 0.01), respectively. MC caused no significant side effects.     

Pituitary stimulation by combined administration of four hypothalamic releasing hormones in normal men and patients

Ten normal young men (22-28 yr of age), within 10% of their ideal body weight, were given the four releasing hormones (TRH, 200 micrograms; GnRH, 100 micrograms; ovine corticotropin-releasing hormone, 50 micrograms; GH-releasing hormone, 80 micrograms) iv on separate days and then in combination on the same day. Plasma TSH, PRL, FSH, LH, cortisol, ACTH, and GH were measured by RIA in samples collected from 20 min before to 120 min after injection. There were no significant differences in responses to the separate and combined tests for FSH, LH, cortisol, ACTH, and GH. The plasma TSH (0.001 less than P less than 0.01) and PRL (P less than 0.001) responses were significantly higher after the combined test. The tolerance was identical to that of TRH alone. In eight patients studied after pituitary surgery, combined administration provided results comparable to those obtained after separate administration of TRH, GnRH, and insulin.     

Evidence for a thyrotropin inhibitory effect of histamine in man.

Because of certain side effects of cimetidine therapy which may be hormonally mediated (e.g. gynecomastia), there has been recent interest in the possible endocrine effects of this H2 histamine receptor-blocking agent used in the treatment of peptic ulcer disease. Accordingly, the effect of chronic cimetidine therapy on anterior pituitary function was examined in 12 adult men with mild peptic ulcer disease. TRH and insulin-hypolycemic stimulation tests were performed by standard methods. Serum for TSH and PRL RIA was obtained after TRH; serum for GH, cortisol, and PRL RIA was obtained after insulin-induced hypoglycemia. In addition, serum for LH, FSH, testosterone, and PRL was obtained every 4 h for 24 h. After these baseline studies, 300 mg cimetidine were administered orally 4 times a day for 4--8 weeks and the studies were repeated as before. Chronic treatment with cimetidine caused a significant increase in the peak TSH response to TRH at 30 min (mean peak TSH value before cimetidine, 7.0 microU/ml; after cimetidine, 10.2 microU/ml; P less than 0.05) as well as a significant increase in the TSH area under the curve. There was no statistically significant effect of cimetidine on basal TSH or basal or stimulated PRL secretion. Cimetidine had no effect on the GH, PRL, or cortisol response to insulin-induced hypolycemia or the 24-h secretion of LH, FSH, testosterone, or PRL.     

EFFECT OF FENOLDOPAM, A DOPAMINE D-1 RECEPTOR AGONIST, ON PITUITARY, GONADAL AND THYROID HORMONE SECRETION

The influence of fenoldopam, a dopamine (DA) D-1 receptor agonist, on basal and GnRH/TRH stimulated PRL, GH, LH, TSH, testosterone and thyroid hormone secretion was studied in nine normal men. All men received 4-h infusions of either 0.9% saline or fenoldopam at an infusion rate of 0.5 microgram/kg min, 12-16 ml/h, adjusted according to weight. After 3 h of infusion, 50 micrograms GnRH and 100 micrograms TRH was given i.v. Blood samples were collected every 15 min from 1 h before to 1 h after the infusion for a total of 6 h for measurements of PRL, LH, FSH, GH, TSH, testosterone, T4 and T3. The median PRL concentration increased significantly (P less than 0.01) to 128%, range 87-287, of preinfusion levels, compared to the decline during control infusion (85%, 78-114). Basal TSH levels declined significantly to 71% (60-91) during fenoldopam compared with 82% (65-115) during control infusion (P less than 0.05). Basal LH, FSH, GH and thyroid hormones were similar during fenoldopam and control infusions (P greater than 0.05). The LH response to GnRH/TRH was significantly (P less than 0.02) increased by fenoldopam infusion. Basal and stimulated testosterone concentration was lower during fenoldopam (P less than 0.01) infusion compared with control. Other hormones were similar after GnRH/TRH stimulation during fenoldopam and saline infusions. These results suggest that DA D-1 receptors are involved in the modulation of pituitary hormone secretion. We suggest that the effect of fenoldopam on PRL and TSH is mainly at the hypothalamic level. Regarding the effect on LH concentrations, an additional direct effect of fenoldopam on testosterone regulation can not be excluded.     

Comparative maturation of the regulation of prolactin and thyrotropin by serotonin and thyrotropin-releasing hormone in male and female rats

The aim of this study was to compare the effects of TRH, serotonin, and haloperidol on the secretion of PRL and TSH in male and female rats from birth to puberty. Serum PRL in males and females was low from birth to 20 days; it then increased gradually until puberty. TSH did not change significantly throughout the period studied. The PRL-releasing effect of serotonin became evident at 12 days, and at all times when the response occurred, it was greater in males than in females. This was also observed in adult rats in which 2.5 mg/kg ip serotonin caused an increase in serum PRL in males but not in diestrous females. Serotonin did not modify TSH at any age. On the other hand, TRH induced the release of TSH and PRL from the first day of life and no sex difference was observed. Haloperidol caused release of PRL from birth, and the effect increased significantly with age. The PRL increase induced with haloperidol was greater than that obtained with TRH used in supramaximal doses. A clear sexual difference became evident on day 20, the PRL-releasing effect of haloperidol being more pronounced in females than in males. Haloperidol did not modify TSH values. It is concluded that the mechanisms by which TRH and dopamine regulate PRL secretion mature earlier than those influenced by serotonin. Sexual differences in the manifestation of these mechanisms were observed, the male being more sensitive to serotonin and the female to haloperidol. TRH causes release of TSH from birth; the serotoninergic and dopaminergic pathways are not of paramount importance in the regulation of TSH in the prepubertal rat.     

Influence of starvation on hormonal control of hypophyseal secretion in rats

The reduction of hypophyseal hormone secretion during starvation is not completely understood. A previous study showed that the concomitant reduction of plasma TSH and T3 may be related to an increased sensitivity of the thyrotrope cell to T3. This suggests that regulation of hypophyseal secretion by peripheral hormones may be altered in starved rats. As GH and PRL secretion are under the control of thyroid and steroid hormones, the aim of the present study was to investigate the modification of feed-back control by T3 or E2 on hypophyseal secretion during starvation. For this purpose, pituitary GH, PRL and TSH contents and their plasma responses to TRH injection were measured in euthyroid, thyroidectomized (Tx), T3-supplemented Tx and E2-treated male Wistar rats before and after a 3-day starvation. TRH (0.25 micrograms/100 g) was injected iv through a chronically-implanted catheter. Our results show that GH content and GH plasma response to TRH are dramatically increased in T3-treated Tx starved rats, suggesting that starvation also increases the effectiveness of T3 influence on somatotrope cell secretion. By contrast, effects of T3 on PRL secretion remain unchanged during starvation. Furthermore, starvation in E2-treated rats is associated with a marked rise in the PRL and GH responsiveness to TRH without any significant change of hormonal pituitary content. This suggests that, in starved rats, E2 increases the effects of TRH on lactotrope and somatotrope secretion. No significant effect on TSH secretion could be demonstrated. Thus, starvation seems to act differentially on the feed-back mechanisms controlling the hormonal secretion of the three adenohypophyseal target cells to TRH.     

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.