Effects of the dopamine agonist cabergoline on the pulsatile and TRH-induced secretion of prolactin, LH, and testosterone in male beagle dogs

In the present study, the pulsatile serum profiles of prolactin, LH and testosterone were investigated in eight clinically healthy fertile male beagles of one to six years of age. Serum hormone concentrations were determined in blood samples collected at 15 min intervals over a period of 6 h before (control) and six days before the end of a four weeks treatment with the dopamine agonist cabergoline (5 microg kg(-1) bodyweight/day). In addition, the effect of cabergoline administration was investigated on thyrotropin-releasing hormone (TRH)-induced changes in the serum concentrations of these hormones. In all eight dogs, the serum prolactin concentrations (mean 3.0 +/- 0.3 ng ml(-1)) were on a relatively constant level not showing any pulsatility, while the secretion patterns of LH and testosterone were characterised by several hormone pulses. Cabergoline administration caused a minor but significant reduction of the mean prolactin concentration (2.9 +/- 0.2 ng ml(-1), p < 0.05) and did not affect the secretion of LH (mean 4.6 +/- 1.3 ng ml(-1) versus 4.4 +/- 1.7 ng ml(-1)) or testosterone (2.5 +/- 0.9 ng ml(-1) versus 2.4 +/- 1.2 ng ml(-1)). Under control conditions, a significant prolactin release was induced by intravenous TRH administration (before TRH: 3.8 +/- 0.9 ng ml(-1), 20 min after TRH: 9.1 +/- 5.9 ng ml(-1)) demonstrating the role of TRH as potent prolactin releasing factor. This prolactin increase was almost completely suppressed under cabergoline medication (before TRH: 3.0 +/- 0.2 ng ml(-1), 20 min after TRH: 3.3 +/- 0.5 ng ml(-1)). The concentrations of LH and testosterone were not affected by TRH administration. The results of these studies suggest that dopamine agonists mainly affect suprabasal secretion of prolactin in the dog.     

The effect of dexamethasone on TSH and prolactin secretion after TRH stimulation

Serum thyrotropin (TSH) and prolactin levels were measured after intravenous administration of 400 μg of synthetic thyrotropin-releasing hormone (TRH) in 13 normal subjects and six hypothyroid patients before and after three days of administration of dexamethasone 2 mg per day. In the normal subjects dexamethasone suppressed baseline serum levels and secretion of TSH after TRH stimulation. On the other hand, it had no effect on the hypothyroid patients. In the control group dexamethasone also suppressed baseline serum levels but not secretion of prolactin after TRH stimulation. Dexamethasone had no effect on prolactin levels in the hypothyroid group. It is concluded that in normal patients short-term administration of dexamethasone has an inhibitory effect on TSH secretion at the pituitary level. As for prolactin, our results could indicate that TRH is a more potent stimulator of prolactin secretion than of TSH secretion, or that TSH and prolactin pituitary thresholds for TRH are different.     

Growth hormone response to thyrotropin-releasing hormone in acromegalic patients: reproducibility and dose-response study.

The aim of the study was to analyze 14 consecutive patients with active acromegaly who had not undergone any therapy, the dose response of growth hormone (GH) to thyrotropin-releasing hormone (TRH), the existence of reproducibility of such response as well as to rule out the possibility of spontaneous fluctuations of GH which would mimic this response. On several nonconsecutive days, we investigated the GH response to saline serum, 100, 200 (twice) and 400 micrograms of TRH administration. We also studied both basal serum prolactin, serum prolactin after TRH administration and thyrotropin values. Our results show an absence of GH response after saline serum infusion, whereas after TRH doses, 36.3 42.8 and 45.4% positive responses were obtained, respectively. All GH responders were concordant to the different doses administered. The mean of GH concentrations of the different doses at different times did not reach significant differences. The response to the administration of the same dose brought about a significative increase, although it was not identical. It demonstrated a progressive increase of the area under the response curve, as did the means of increments after each TRH administration, albeit without reaching statistical significance. Between the GH-responding and GH-nonresponding groups there were no differences in either basal serum prolactin or serum prolactin and thyroid-stimulating hormone levels after TRH stimulation. The present study clearly shows that TRH elicits serum GH release from GH-secreting pituitary tumors. The response was reproducible in qualitative terms rather than quantitative, and no dose-response relationship was found between the TRH concentrations and the amounts of GH secreted.     

Optical microscopic study of the effect of the hypothalamic hormone T.R.H. on certain cell types of rat anterior hypophysis]

A cytological and optical microscopic study of the anterior lobe of hypohysis in the Wistar adult rat 10, 30 or 60 minutes after intravenous injection of 50 mug of synthetic TRH discloses modifications of thyrotropic cells and prolactin cells. It's possible to recognize a quick degranulation of the prolactin cells (with a maximum at the 10th minute) and a slower degranulation of the thyrotropic cells (perceptible at the 10th minute and very pronounced at the 60th minute). The somatrotopic cells did not show any modification.     

Growth hormone response to thyrotropin releasing hormone in a pellagrin

An abnormal hyperresponse of GH to intravenous injection of TRH in a 66-year-old female pellagra patient with typical 3'D's was reported. Diagnosis of pellagra was mainly based on her clinical course and manifestations, although serum levels of nicotinic acid and serotonin were within the normal range. Serum vitamin A and B2 levels were low. However, these findings did not exclude the diagnosis. The abnormal GH response to TRH observed in this patient was decreased at 2 months and thoroughly disappeared at 10 months after admission. GH response to arginine showed an exaggerated and sustained response on admission, decreased at 2 months and showed an almost normal pattern at 10 months after admission. TSH and prolactin response to TRH were normal throughout the clinical course. LH and FSH response to LH-RH were exaggerated, suggesting post-menopausal hypogonadism. Cortisol response to ACTH showed slightly sustained reactions at both times of the provocation. Oral glucose tolerance test revealed a slight impairment in this patient. These results suggest that pellagra is one of the disorders which exhibit an abnormal hyperresponse of GH to intravenous administration of TRH.     

Thyroidal and prolactin secretion in agalactic mares

A study was designed to examine serum concentrations of prolactin (PRL) and iodothyronines before and after thyrotropin releasing hormone (TRH) administration to agalactic (n = 26) and normally (n = 8) lactating mares. Two mg TRH was given intramuscularly (i.m.) twice daily on Day 1 (day of delivery) through Day 5. Jugular venous blood was collected on Days 1 and 5 before TRH (time 0) and at 1 and 3 h post-TRH. Basal serum concentrations of thyroxin (T(4)) were different (P < 0.05) on Day 1 (1.87 vs 1.37 mug/dl) and Day 5 (1.72 vs 1.13 mug/dl) in the normal mares and agalactic mares, respectively. There was no difference in the T(4) response to TRH. While basal serum concentrations of triiodothyronine (T(3)) were not different, agalactic mares responded with greater (P < 0.05) serum concentrations T(3) to TRH on Day 1. Following linear regression of the PRL response to TRH, slope of the lines between groups did not differ; however, elevations were significantly (P < 0.05) greater (1.79 vs 1.28 ng/ml) in control mares compared with agalactic mares, respectively, on Day 1.at 1 h post-TRH. A similar difference existed at time 0 and 1 h on Day 5. Consequently, agalactic mares had reduced basal serum T(4) values; the PRL data leads us to suggest that secretion of this hormone may be insufficient in agalactic mares.     

In vivo and in vitro effect of naloxone on prolactin response to TRH in rat

In adult male Wistar rats submitted to a standardized noise stress, intravenous TRH induced a prolactin (PRL) secretory response. Prior IV naloxone administration not only lowered plasma PRL levels in those stressed rats but abolished also the stimulatory action of TRH. This effect was further studied by superfusion experiments on enriched PRL cell suspensions (70% lactotrophs) from female adult Wistar rats. Naloxone kept unaffected the basal PRL secretion but lowered significantly that induced by TRH. These experiments suggest a dual effect of naloxone on rat PRL secretion, one exerted on central opioid receptors lowering stress-related increased basal PRL levels, the other inhibiting the TRH-dependent PRL secretion exerted at the lactotroph level itself.     

Age-related differences in the pituitary prolactin response to thyrotropin-releasing hormone

We have previously reported that human subjects undergoing surgery for inguinal hernias exhibit an age-related attenuation in the plasma prolactin response, with no differences during resting conditions. We suggested that these differences were due to age-related neuroendocrine changes, but that peripheral factors may play a role as well. In the present study, we have assessed the pituitary response to 500 micrograms of thyrotropin-releasing hormone (TRH) in the very same subjects previously studied during surgery. Blood samples were drawn immediately prior to, as well as 10, 20, 40 and 60 minutes following the intravenous administration of TRH. There was a clear-cut age-related attenuation in the pituitary prolactin response with no difference in the thyrotropin (TSH) response. Maximum prolactin response in the young subjects was 31.7 micrograms/l and 19.2 micrograms/l in old subjects (F(4) = 3.5, p less than .01, two-way ANOVA). These results indicate that the age-related differences in the prolactin response to stress are mainly due to pituitary changes. However, prolactin-secreting cells are under the control of the hypothalamus. Therefore, the possibility must be considered that aging or other concurrent factors could be exerting their influence via the hypothalamus and not necessarily directly at the pituitary level.     

Bioactivity of plasma prolactin in ovariectomized, diethylstilbestrol-treated Long-Evans and Holtzman rats after thyrotropin-releasing hormone or bromocriptine administration

The objective of this study was to determine the effects of thyrotropin-releasing hormone (TRH) and bromocriptine on plasma levels of biologically active prolactin in ovariectomized, diethylstilbestrol (DES)-treated rats. Female Long-Evans and Holtzman rats were ovariectomized and each was given a subcutaneous implant of diethylstilbestrol (DES). One week later, groups of DES-treated rats were fitted with indwelling intra-atrial catheters, and 2 days later blood samples were withdrawn before and at 1, 2, 5, 10, and 20 min after intravenous administration of TRH (250, 500, or 1000 ng/rat). Blood samples were obtained from other groups at 4 weeks of DES treatment by orbital sinus puncture under ether anesthesia before and at 30, 60, and 120 min after bromocriptine administration (2.5 mg/rat sc). Plasma was assayed for prolactin by conventional radioimmunoassay (RIA) and by Nb2 lymphoma bioassay (BA). Holtzman rats released significantly more prolactin following TRH than did Long-Evans rats when the RIA was used to measure prolactin. However, when the BA was used to assay prolactin in the same samples, the Long-Evans rats released more prolactin than did the Holtzman rats. In addition, the ratio of the BA to RIA values was significantly increased in both strains following TRH, but the greatest increase was observed in the Long-Evans rats, in which the ratio was 4.5 at the peak of the TRH-induced rise in plasma prolactin. Gel filtration chromatography of plasma obtained at 5 min after TRH treatment in Long-Evans rats revealed large molecular forms of prolactin with BA to RIA ratios of 4-5. In addition, monomeric prolactin had a BA to RIA ratio of 2. Bromocriptine treatment reduced prolactin levels in both strains, but the effect was more rapid in Holtzman than in Long-Evans rats. In addition, bromocriptine treatment of Holtzman, but not Long-Evans, rats significantly reduced the BA to RIA ratio of plasma prolactin. The results indicate that TRH and bromocriptine affect the release of biologically active prolactin to a greater extent than prolactin detected by antibody in the RIA, and that Long-Evans and Holtzman rats respond to these secretagogues differently with regard to BA to RIA comparisons.     

Cadmium does not inhibit pulsatile prolactin secretion through TRH

This work was undertaken to analyse the effects of acutecadmium administration on the pulsatile patternof prolactin release, in adult male rats.For this purpose, animals were cannulated 40 h before the experi-mentto allow a continuousblood withdrawal. Two hours after the administration of one dose of cadmiumchloride (4.5 mg kg1 ), the pulsatile pattern of prolactin, during three hours, was studied. The effects oftwopulses of thyrotropin-releasing hormone (TRH) (1 mg per rat), given 60 and 120 min afterstarting the periodof blood sampling, were studied. The mean values of prolactin during thebleeding period and the absolutepulse amplitude were decreased by acute cadmium chlorideadministration. However, no changes in anyother parameters of prolactin pulsatility were observed.TRH administration to control rats increased meanprolactin levels, and absolute andrelative pulse amplitudes, but decreased the mean half-life of the hormone.In animals pretreated withcadmium, TRH increased the mean levels of prolatin, and absolute and relativeamplitudes ofthe hormone pulses. No other parameter studied was changed by TRH in cadmiumpretreatedrats. These data suggest that acute administration of cadmium did not inhibit thepulsatile prolactin releasethrough TRH.     

Impact of euglycaemia and hyperglycaemia on the release of growth hormone and prolactin in type II-diabetics

The influence of different blood glucose concentrations on the arginine (30 g/30 min i.v.) and TRH (400 micrograms i.v.) induced release of growth hormone and prolactin was studied in six male type II-diabetic patients. Blood glucose concentrations were clamped at euglycaemic (4-5 mmol/l) or hyperglycaemic (12-18 mmol/l) levels by means of an automated glucose-controlled insulin infusion system. The response of growth hormone to arginine, and irregular spikes in growth hormone concentrations following TRH seen in the euglycaemic state were suppressed during hyperglycaemia. The suppression of the arginine-induced release of growth hormone by hyperglycaemia was observed both with and without concomitant administration of exogenous insulin. The rise in serum prolactin concentrations in response to arginine was unaffected by hyperglycaemia, whereas the TRH-induced release of prolactin was suppressed. Since arginine induces the release of growth hormone and prolactin via the hypothalamus, while TRH acts at the pituitary level, the glycaemic state appears to exert a modulatory effect on the secretion of growth hormone and prolactin in type II-diabetics at both locations.     

Evaluation of GnRH administration on the prolactin response to thyrotrophin-releasing hormone in normal women

To determine whether GnRH modifies prolactin (PRL) secretion in response to thyrotrophin-releasing hormone (TRH) in normal women, a group of eleven normal women, 23 to 40 years of age, was studied in the mid-follicular phase of the menstrual cycle. The PRL response to TRH was evaluated in serum under control conditions and after GnRH infusion. GnRH administration augmented basal PRL release and amplified TRH-induced PRL release. These results suggest that GnRH may be involved in PRL release, partly by increasing the sensitivity of the lactotrophs to TRH.     

Inhibition of ovarian function in subordinate female marmoset monkeys (Callithrix jacchus jacchus)

Plasma concentrations of progesterone, cortisol, LH and prolactin were measured in dominant and subordinate female marmosets in 10 well-established peer groups. Subordinate females never ovulated, had a reduced LH response to LH-RH and showed no positive feedback LH surge after oestrogen administration. There was no evidence of elevated plasma cortisol levels or hyperprolactinaemia in subordinates and all showed a similar prolactin response to TRH in comparison with dominants. However, subordinates showed a reduced prolactin response to metoclopramide. These results clearly indicate that high circulating levels of cortisol or prolactin are not responsible for the inhibition of ovulation in female marmosets.     

Bromocriptine is unable to suppress TRH-stimulated beta-endorphin/beta-lipotropin and cortisol secretion in normal pregnant women after delivery

The course of plasma beta-endorphin/beta-lipotropin, cortisol and prolactin (PRL) levels was followed from 0.5 till 5 h after normal delivery in 13 healthy women. Six subjects who did not want to breast-feed their child received 2.5 mg bromocriptine orally 1 h after delivery. After 3 h the effect of the intravenous administration of 200 micrograms thyrotropin-releasing hormone (TRH) was also measured. Elevated plasma beta-endorphin and cortisol levels decreased after delivery in a (log) linear fashion which was not influenced by bromocriptine. TRH elicited a significant short-lived identical increase in plasma beta-endorphin/beta-lipotropin concentrations in the control and the bromocriptine-treated subjects. TRH similarly delayed the rapid decline in plasma cortisol levels in both groups of women. Basal and TRH-induced PRL levels were rapidly suppressed by bromocriptine. These studies show the presence of a paradoxical increase of beta-endorphin/beta-lipotropin and cortisol levels in response to TRH occurring shortly after delivery in normal women. This response cannot be mediated by the placenta. The absence of an inhibiting effect of bromocriptine on basal and TRH-induced beta-endorphin and cortisol release does not lend support to the hypothesis of the presence of a functionally active intermediate pituitary lobe in man early in puerperium.     

Oral thyrotropin-releasing hormone (TRH) test in acromegaly

The effects of 40 mg oral and 200 microgram intravenous TRH were studied in patients with active acromegaly. Administration of oral TRH to each of 14 acromegalics resulted in more pronounced TSH response in all patients and more pronounced response of triiodothyronine in most of them (delta max TSh after oral TRh 36.4 +/- 10.0 (SEM) mU/l vs. delta max TSH after i.v. TRH 7.7 +/- 1.5 mU/l, P less than 0.05; delta max T3 after oral TRH 0.88 +/- 0.24 nmol/vs. delta max T3 after i.v. TRH 0.23 +/- 0.06 nmol/l, P less than 0.05). Oral TRH elicited unimpaired TSH response even in those acromegalics where the TSH response to i.v. TRH was absent or blunted. In contrast to TSH stimulation, oral TRH did not elicit positive paradoxical growth hormone response in any of 8 patients with absent stimulation after i.v. TRH. In 7 growth hormone responders to TRH stimulation the oral TRH-induced growth hormone response was insignificantly lower than that after i.v. TRH (delta max GH after oral TRH 65.4 +/- 28.1 microgram/l vs. delta max GH after i.v. TRH 87.7 +/- 25.6 microgram/l, P greater than 0.05). In 7 acromegalics 200 microgram i.v. TRH represented a stronger stimulus for prolactin release than 40 mg oral TRH (delta max PRL after i.v. TRH 19.6 +/- 3.22 microgram/, delta max PRL after oral TRH 11.1 +/- 2.02 microgram/, P less than 0.05). Conclusion: In acromegalics 40 mg oral TRH stimulation is useful in the evaluation of the function of pituitary thyrotrophs because it shows more pronounced effect than 200 microgram TRH intravenously. No advantage of oral TRH stimulation was seen in the assessment of prolactin stimulation and paradoxical growth hormone responses.     

Further Observations on the Effect of Synthetic Thyrotrophin-releasing Hormone in Man

Synthetic thyrotrophin-releasing hormone (TRH) given intravenously in doses of 50 μg or more causes a significant rise in serum thyroid-stimulating hormone (TSH) levels but has no effect on serum growth hormone, plasma luteinizing hormone, or plasma 11-hydroxycorticosteroids under carefully controlled basal conditions.The peak TSH response to intravenous TRH occurs at 20 minutes. The mild and transient side effects, which occur only after intravenous TRH, include nausea, a flushing sensation, a desire to micturate, a peculiar taste, and tightness in the chest. There is considerable variability in response to a given dose of TRH in the same subject on different occasions and in different subjects. Oral administration of TRH in doses of 1 mg and above causes a rise in serum TSH, maximal at two hours, a consistent response being obtained at doses of 20 mg and above. A rise in serum protein-bound iodine (P.B.I.) follows that of TSH, a consistent response being observed at 40-mg doses of TRH orally. Measurements of serum TSH after intravenous administration of TRH or of serum TSH or serum P.B.I. after oral TRH should prove useful tests of pituitary TSH reserve.     

PMA-sensitive protein kinase C is not necessary in TRH-stimulated prolactin release from female rat primary pituitary cells.

In GH3 cells and other clonal rat pituitary tumor cells, TRH has been shown to mediate its effects on prolactin release via a rise of cytosolic Ca2+ and activation of protein kinase C. In this study, we examined the role of protein kinase C in TRH-stimulated prolactin release from female rat primary pituitary cell culture. Both TRH and PMA stimulated prolactin release in a dose-dependent manner. When present together at maximal concentrations, TRH and PMA produced an effect which was slightly less than additive. Pretreatment of rat pituitary cells with 10(-6) M PMA for 24 hrs completely down-regulated protein kinase C, since such PMA-pretreated cells did not release prolactin in response to a second dose of PMA. Interestingly, protein kinase C down-regulation had no effect on TRH-induced prolactin release from rat pituitary cells. In contrast, PMA-pretreated GH3 cells did not respond to a subsequent stimulation by either PMA or TRH. Pretreatment of rat pituitary cells with TRH (10(-7) M, 24 hrs) inhibited the subsequent response to TRH, but not PMA. Forskolin, an adenylate cyclase activator, stimulated prolactin release by itself and in a synergistic manner when incubated together with TRH or PMA. The synergistic effects of forskolin on prolactin release was greater in the presence of PMA than TRH. Down-regulation of protein kinase C by PMA pretreatment abolished the synergistic effect produced by PMA and forskolin but had no effect on those generated by TRH and forskolin. sn-1,2-Dioctanylglycerol (DOG) pretreatment attenuated the subsequent response to DOG and PMA but not TRH. The effect of TRH, but not PMA, on prolactin release required the presence of extracellular Ca2+. In conclusion, the mechanism by which TRH causes prolactin release from rat primary pituitary cells is different from that of GH3 cells; the former is a protein kinase C-independent process whereas the latter is at least partially dependent upon the activation of protein kinase C.     

Hormonal responses of lactating dairy cattle to TRH and ACTH in a shade management system within a subtropical environment

Lactating cows (64) were balanced by breed (54 Holstein and 10 Jersey) and assigned randomly to shade (S) or no shade (NS) management treatments for a continuous 20 wk trial beginning 5-5-76. A sub-sample of Holstein cows, five S and five NS, were fitted with jugular catheters 84 days after initiation of experiment. Thyrotropin Releasing Hormone (TRH; 100 mug) was administered intravenously at 1200 h to evaluate prolactin responses. Two days later each cow received intravenously 200 IU of ACTH at 1100 h to compare acute corticoid responses to ACTH. Mean prolactin response to TRH was greater for NS cows (291 vs 169 ng/ml; P < .01) as was peak plasma concentrations at 20 min (467 vs 267 ng/ml; P < .01). Mean corticoid response to ACTH injection was less for NS cows (52 vs 70 ng/ml; P < .10). Corticoid concentrations of plasma in both treatments had declined 65% by 7 h postinjection. These endocrine differences may be associated with thermoregulation and/or metabolic adjustments of cows exposed to different environmental systems of management during a seasonal period of thermal stress.     

Prolactin release in liver cirrhosis with impaired glucose tolerance (IGT)

The effects of acute TRH and cimetidine administration on the plasma prolactin (PRL) response have been studied in cirrhotic patients with impaired glucose tolerance (IGT). I v. TRH administration stimulates PRL release both in cirrhotics and controls; i.v. cimetidine did not induced a significant rise of PRL in liver cirrhosis. Present findings demonstrate that PRL is not responsible for the deterioration of glucose handling in alcoholic cirrhotic patients examined.     

Effect of sulpiride on serum growth hormone and prolactin concentrations following L-DOPA administration in man.

The effect of chronic administration of sulpiride on serum human growth hormone (hGH), prolactin and thyroid stimulating hormone (TSH) was examined in 6 normal subjects. Sulpiride was given orally at a dose of 300 mg (t.i.d.) for 30 days. Sulpiride raised serum prolactin levels in all subjects examined. In addition, sulpiride suppressed hGH release induced by L-dopa, although the basal hGH level was not changed. Sulpiride treatment appeared to antagonize partially the inhibitory effect of L-dopa on prolactin release. Following thyrotropin-releasing hormone (TRH) injection, the percent increment in prolactin levels from the baseline in sulpiride-treated subjects was less than in controls without sulpiride. In contrast, both the basal and TRH-stimulated TSH levels were not influenced by sulpiride. These observations suggest that sulpiride suppresses L-dopa-induced hGH release and stimulates prolactin release, presumably by acting against the dopaminergic mechanism either on the hypothalamus or on the pituitary. The decreased prolactin response to TRH after sulpiride treatment may indicate a diminished reserve capacity in pituitary prolactin release.