Cardiopulmonary bypass: a low T4 and T3 syndrome with blunted thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH)

Thyroid hormone serum concentrations, the thyrotropin (TSH) and prolactin (PRL) response to thyrotropin-releasing hormone (TRH) were evaluated in patients undergoing cardiopulmonary bypass (CPB) conducted in hypothermia. During CPB a marked decrease of thyroxine (T4) and triiodothyronine (T3) concentration with a concomitant increase of reverse T3 (rT3) were observed similarly to other clinical states associated with the 'low T3 syndrome'. Furthermore, in the present study elevated FT4 and FT3 concentrations were observed. In a group of patients, TRH administered during CPB at 26 degrees C elicited a markedly blunted TSH response. In these patients, PRL concentration was elevated but did not significantly increase after TRH. The increased concentrations of FT4 and FT3 were probably due to the large doses of heparin administered to these patients. Thus, the blunted response of TSH to TRH might be the consequence of the elevation of FT4 and FT3 in serum, however, other factors might play a role since also the PRL response to TRH was blocked.     

Effect of repeated stimulation by thyrotropin-releasing hormone (TRH) on thyrotropin and prolactin secretion in perfused euthyroid and hypothyroid rat pituitary fragments

The previously reported refractoriness of pituitary response to thyrotropin-releasing hormone (TRH) stimuli was investigated here in an in vitro perfusion system using pituitary tissue from euthyroid and hypothyroid rats. Thyroid-stimulating hormone (TSH) and prolactin (PRL) responses to TRH (28 pmol) were significantly greater in hypothyroid tissue compared with euthyroid. Hypothyroid tissue showed a reduction in response to two consecutive stimuli in both TSH and PRL, however the TSH decline in response was more marked than PRL. Euthyroid tissue showed no significant decline in response to TRH. An increase in the dose of TRH (112 pmol), administered to euthyroid tissue, resulted in increased TSH and PRL response, but no decline in response to sequential stimuli was observed. Three consecutive stimuli by TRH (28 pmol) of hypothyroid tissue resulted in a consistent decline in TSH response. The decline in PRL response only reached statistical significance by the third stimulation. Euthyroid and hypothyroid pituitary tissue was subjected to sequential depolarising stimulation with KCl (50 mumol). Euthyroid tissue showed no decline in response in either TSH or PRL. In hypothyroid tissue only, the decline in TSH response reached statistical significance. This decline in TSH response was significantly smaller than the decline in response observed in hypothyroid tissue stimulated with TRH. Refractoriness of hypothyroid pituitary tissue to repeated TRH stimuli is reported here. Our data suggest that the decline in hormonal response cannot be explained solely on the basis of tissue depletion.     

Influence of prostaglandins and thyrotropin releasing hormone (TRH) on hormone secretion and growth in wether lambs

A series of experiments were conducted in ewes and wether (castrate male) lambs to evaluate the influence of prostaglandins on secretion of anabolic hormones and to determine if repeated injections of prostaglandin (PG) F₂α would chronically influence the secretion of these hormones and perhaps growth rate as well.A single intravenous injection of PGA₁ and PGB₁ (100 μg/kg) exerted no significant (P > .10) influence on plasma concentrations of prolactin (PRL), growth hormone (GH) or thyrotropin (TSH) in ewes. PGA₁, but not PGB₁, stimulated an increase in the plasma concentration of insulin. Infusion of PGF₂α for 5.5 hr into ewes resulted in increased (P < .05) plasma concentrations of both GH and PRL while TSH and insulin were not significantly influenced. Prostaglandin F₂α, when injected subcutaneously into wether lambs (10 mg twice weekly) stimulated (P < .05) plasma GH concentrations after the first injection, but not after 3 weeks of treatment. Changes in plasma PRL or TSH were not observed consistently in the lambs treated chronically with PGF₂α or TRH.Prostaglandin F₂α, in the present studies, and PGE₁ in previously reported studies (1–3), has been demonstrated to be stimulatory to the secretion of PRL and GH. In contrast, PGA₁ and PGB₁, which lack an 11-hydroxyl group, failed to influence the secretion of either PRL or GH. It would, therefore, appear that the 11-hydroxyl group is a structural requirement for prostaglandins to influence the secretion of these two hormones in sheep.Treatment with thyrotropin releasing hormone (TRH), alone or in combination with PGF₂α, significantly (P < .05) increased growth rate (average daily gains) while PGF₂α did not, despite the fact that both compounds exerted similar effects on plasma GH.     

The effect of L-DOPA administration on thyrotropin (TSH) and thyrotropin releasing hormone (TRH) levels in serum in primary or pituitary hypothyroidism.

The effect of acute administration of L-DOPA on TSH and TRH levels in serum was studied in primary or pituitary hypothyroidism. TRH levels in serum fell and then returned to initial levels after L-DOPA administration in primary or pituitary hypothyroidism. TSH levels in serum fell and then returned to initial levels after L-DOPA administration in primary hypothyroidism. T4 and T3 levels in serum did not change after L-DOPA administration in primary or pituitary hypothyroidism. These data suggested that L-DOPA might act directly to hypothalamus.     

Effects of thyroidectomy, propylthiouracil, and thyroxine on pituitary content and immunocytochemical staining of thyrotropin (TSH) and thyrotropin releasing hormone (TRH)

Previous studies have demonstrated immunocytochemical staining for beta chains of thyroid stimulating hormone (TSH-beta) in rough endoplasmic reticulum of pituitary cells hypertrophied after thyroidectomy ("thyroidectomy cells") (Moriarty CG(1976): J Histochem Cytochem (24:846; Moriarty GC, Tobin RB (1976): J Histochem Cytochem 24:1140). Here we report the localization of thyrotropin releasing hormone (TRH) in serial sections of the same pituitaries to determine if it could be found at similar sites. No staining for TRH was found in hypertrophied TSH cells formed 42 days after the surgery, or after 14, 34, and 70 days of propylthiouracil (PTU) treatment. The loss in immunostaining in the PTU-treated rats was correlated with radioimmunoassay (RIA) measurements that showed a 65% reduction in anterior pituitary TRH content after 34, 70, and 98 days of PTU treatment (from 22.9--7.8 pg/mg wet wt) and a 50% reduction in TSH content after 34 days of treatment. When thyroxine was administered to hypothyroid rats for 3 days before death, our previous studies had demonstrated intense staining for TSH in granules inside the rough endoplasmic reticulum. In this study, the radioimmunoassay showed that TSH content rose dramatically in the hypothyroid animals treated with PTU for 77 days and thyroxine for 2 days before death (from 8.5--64.1 mU/mg wet wt); however, the rise in TRH content was minimal (5.8--9.8 pg/mg wet wt). The immunocytochemical stain for TRH correlated well with the RIA showing a weak reaction mainly on small granules in the cytoplasm. No reaction for TRH was found in rough endoplasmic reticulum. These results suggest that TRH and TSH storage sites are dissimilar in the hypothyroid rat. The presence of stain for TRH in granules in the cytoplasm suggests that it might play a role in the storage or packaging of TSH. Its absence in profiles of rough endoplasmic reticulum staining intensely for TSH suggests that it is not synthesized at this site. No definite conclusions about its origin can be drawn at this time.     

Effect of TRH (thyrotropin-releasing hormone) on the fine structure and replication of TSH and prolactin cells in the rat

Summary In intact male rats after TRH administration for 7 and 14 days, TSH cells showed similar morphological changes to those observed after thyroidectomy. These changes were paralleled by small numerical increases in TSH cell counts. After 34 days of TRH treatment, however, most of the TSH cells had a normal appearance and the number of TSH cells also had returned to normal. TRH treatment for 7, 14 and 34 days caused morphological changes in Prolactin cells similar to those obtained after a suckling stimulus. In the three groups these changes were also paralleled by small numerical increases in Prolactin cell counts. The cell replication after TRH for 7 and 14 days, as measured by incorporation of tritiated thymidine to obtain a labeling index, was slightly but significantly increased.This work was supported by grants MA-552 and MT-2701 from the Medical Research Council of Canada. The authors wish to thank Dr. D.A.J. Ives, Connaught Medical Research Laboratories, Toronto, for providing the TRH, and Mr. G. Penz for technical assistance.Fellow of the Medical Research Council of Canada.     

促甲状腺激素释放激素的分布及生理作用

促甲状腺激素释放激素(TRH)广泛分布于中枢神经系统和某些外周器官中,它除了有促进垂体前叶释放TSH和PRL等内分泌作用外,作为神经递质或神经调质,对中枢神经系统还可产生广泛的生理效应。     

Effects of orexin A on thyrotropin-releasing hormone and thyrotropin secretion in rats.

Effects of orexin A on secretion of thyrotropin-releasing hormone (TRH) and thyrotropin (TSH) in rats were studied. Orexin A (50 microg/kg) was injected iv, and the rats were serially decapitated. The effects of orexin A on TRH release from the rat hypothalamus in vitro and on TSH release from the anterior pituitary in vitro were also investigated. TRH and thyroid hormone were measured by individual radioimmunoassays. TSH was determined by the enzyme-immunoassay method. The hypothalamic TRH contents increased significantly after orexin A injection, whereas its plasma concentrations tended to decrease, but not significantly. The plasma TSH levels decreased significantly in a dose-related manner with a nadir at 15 min after injection. The plasma thyroid hormone levels showed no changes. TRH release from the rat hypothalamus in vitro was inhibited significantly in a dose-related manner with the addition of orexin A. TSH release from the anterior pituitary in vitro was not affected with the addition of orexin A. The findings suggest that orexin A acts on the hypothalamus to inhibit TRH release.     

Thymosin fraction 5 (TF5) stimulates secretion of adrenocorticotropic hormone (ACTH) from cultured rat pituitaries

In vivo administration of a partially purified thymic hormone-containing extract of the thymus gland, TF5, causes an increase in serum glucocorticoids. The lack of a direct effect of TF5 on adrenal corticosterone secretion suggests that it is mediated at the level of the pituitary. Cultured rat pituitary monolayers were used to determine if the effect is mediated by stimulation of ACTH secretion from the pituitary. Two lots of TF5, BPP100 and C114080-01, caused a dose dependent secretion of ACTH from cultured pituitary monolayers. There was a synergistic effect when the cells were treated with both TF5 and corticotropin-releasing factor (CRF). Immunoneutralization studies were done in which the cells were treated with TF5 or CRF and an antibody to CRF. The antibody completely blocked CRF induced ACTH release, but had no effect on TF5 stimulated ACTH release, suggesting that the activity is not due to a CRF-like peptide in TF5. A number of peptides isolated from TF5, and certain other peptides produced by the immune system were evaluated for their ability to stimulate ACTH secretion. These included thymosin (TSN) alpha 1, alpha 11, and beta 4, prothymosin alpha (PT alpha, thymopoeitin 5 (TP5), factuer thymique serique (FTS), interferon alpha (INF alpha), INF gamma, interleukin 1 (IL-1), and interleukin 2 (IL-2). None of these factors had any effect on pituitary ACTH secretion. These results demonstrate that some peptide component of TF5 causes an increase in serum corticosteroids by stimulating pituitary ACTH release.     

Possible involvement of mitogen-activated protein kinase phosphatase-1 (MKP-1) in thyrotropin-releasing hormone (TRH)-induced prolactin gene expression

The role of extracellular signal-regulated kinase (ERK) in mediating the ability of thyrotropin-releasing hormone (TRH) to stimulate the prolactin gene has been well elucidated. ERK is inactivated by a dual specificity phosphatase, mitogen-activated protein kinase phosphatase (MKP). In this study, we examined the induction of MKP-1 protein by thyrotropin-releasing hormone (TRH) in pituitary GH3 cells, and investigated the possible role for MKP-1 in TRH-induced prolactin gene expression. MKP-1 protein was induced significantly from 60 min after TRH stimulation, and remained elevated at 4 h. The effect of TRH on MKP-1 expression was completely prevented in the presence of the MEK inhibitor, U0126. In the experiments using triptolide, a potent blocker for MKP-1, MKP-1 induction by TRH was completely inhibited in a dose-dependent manner. TRH-induced ERK activation was significantly enhanced in this condition. Prolactin promoter activity, activated by TRH, was reduced to the control level in the presence of triptolide in a dose-dependent manner. In GH3 cells, which were transfected with MKP-1 specific siRNA, both the basal and TRH-stimulated activities of the prolactin promoter were significantly reduced compared to the cells transfected with negative control siRNA. Our present results support a critical role of MKP-1 in TRH-induced, ERK-dependent, prolactin gene expression.     

Pituitary thyrotropin-releasing hormone (TRH) receptors: effects of TRH, drugs mimicking TRH action, and chlordiazepoxide

Binding of TRH to specific cell surface receptors on clonal GH4C1 cells is followed within 10 min by receptor sequestration and over 24 h by receptor down-regulation. These experiments were designed to determine if TRH-activated second messenger systems are responsible for changes in receptor localization or number. BAY K8644 and A23187, which increase intracellular calcium, alone or together with 12-O-tetradecanoyl phorbol acetate (TPA), which activates protein kinase C, did not appear to internalize TRH receptors. Drug treatment did not alter the rate of [3H]MeTRH association or internalization, determined by resistance to an acid/salt wash, or the amount of [3H]MeTRH able to bind at 0 C, where only surface receptors are accessible. TPA (0-100 nM) alone or in combination with BAY K8644 or A23187, also failed to change receptor number or affinity after 48 h when TRH caused a 75% decrease in the density of specific binding sites. Chlordiazepoxide has been reported antagonize TRH binding and TRH-induced phospholipid breakdown. Chlordiazepoxide shifted the dose-response curves for TRH stimulation of PRL release and synthesis to the right, and did not change PRL release alone. The affinity of receptors for chlordiazepoxide was not affected by a nonhydrolyzable analog of GTP whereas affinity for TRH was decreased; these properties are consistent with the classification of chlordiazepoxide as a competitive antagonist. Several experiments tested whether chlordiazepoxide would cause receptor internalization and down-regulation. Chlordiazepoxide did not appear to internalize TRH receptors, because TRH-binding sites became available rapidly and at the same rate after they had been saturated with chlordiazepoxide at 0 or 37 C.(ABSTRACT TRUNCATED AT 250 WORDS)     

Correlative studies between the presence of thyrotropin-releasing hormone (TRH) receptors and the in vitro stimulation of growth-hormone (GH) secretion in human GH-secreting adenomas

Specific receptors for TRH were characterized on cellular membranes of 6 out of 13 somatotrophic adenomas obtained from acromegalic patients. These receptors had the same dissociation constant (Kd: 62 +/- 10 nM) as those found in human PRL-secreting adenomas, but their maximal number of binding sites (Bmax: 76 +/- 24 fmol/mg of protein) was six fold smaller. A good correlation was found between the presence of TRH receptors and the in vitro TRH-induced stimulation of GH secretion. The increase in GH release varied from 25 to 200%. It was thus concluded that these receptors are functional. However, why only some of the human somatotrophic adenomas possess TRH receptors and respond to TRH in vitro needs further investigations.     

Characteristics of thyrotropin releasing hormone (TRH) receptors in rat brain

Characteristics of TRH-receptors were studied in the rat central nervous system (CNS). Ion species, pH and temperature importantly influenced TRH-receptor binding. Subcellular distribution of TRH-receptor binding revealed that synaptic membranes had the greatest percentage of total sites. Scatchard analysis suggested that the rat CNS had two distinct TRH binding sites with apparent dissociation constants (Kd) of 5 X 10(09) M and 13 X 10(-8) M. Receptor activity is sensitive to trypsin and phospholipase A digestion, suggesting that protein and phospholipid moieties are essential for the binding of [3H]TRH. Thiol reagents reduced the binding activity of the receptor, suggesting that an intrachain disulfide bond may form an important constituent of the binding site for TRH. The TRH-receptor in the rat brain was successfully solubilized with non-ionic detergent Triton X-100. On gel chromatography with Sepharose 6B column, the solubilized TRH-receptor molecule eluted at the fraction corresponding to an apparent molecular weight of 300,000 daltons, with Stokes' radius of 5.8 nm. The regional distribution of TRH-receptor binding was examined to clarify the site of TRH action. The highest level of binding was in the hypothalamus, cerebral cortex and hippocampus, indicating that TRH affects the CNS function mainly through the limbic system, cerebral cortex and hypothalamus. Moreover, tricyclic anti-depressants and Li+ decreased the binding of [3H]TRH. These findings suggest that endogenous TRH and TRH receptor may play the role of a neurotransmission modulator in the brain to control emotional and mental functions.