Synthesis and central nervous system actions of thyrotropin-releasing hormone analogs containing a 1-substituted 2-oxoimidazolidine moiety

A series of thyrotropin-releasing hormone (TRH) analogs in which the pyroglutamic acid residue was replaced by (S)-2-oxoimidazolidine-4-carboxylic acid (Oic-OH) and the related derivatives was prepared, and the central nervous system (CNS) actions were examined. Of these, 1-benzyl-Oic-His-Pro-NH2 (2c) showed the most potent activities, which were 1.5-8 times greater than those of TRH. Moreover, the thyrotropin (TSH)-releasing activity of 2c was about 1/16 times weaker than that of TRH.     

Prolactin as a marker of dopaminergic activity at different levels of thyroid function in man

To investigate the hypothesis of an altered dopaminergic activity in hypothyroidism, seven patients without thyroid tissue were studied by means of three consecutive tests: an iv bolus of TRH (200 micrograms); a continuous iv infusion (5 mg during 30 min) of metoclopramide (MCP); and a second, post-MCP, iv bolus of TRH (200 micrograms). The study was performed three times: (A) without treatment; (B) on the 15th day while on L-T4 (150 micrograms i.d.); and (C) on the 30th day with the same treatment. Each time was a different situation of thyroid function; on the basis of basal serum TSH (P less than 0.001, A vs B vs C). The response of PRL to the first (non-primed) TRH, expressed as the sum of increments in ng/ml (mean +/- SE), was significantly higher in A (659 +/- 155) than in C (185 +/- 61). Individual PRL responses correlated with circulating T3 (P less than 0.02), but not with T4. A significant increase of PRL occurred after MCP in the three situations, but there were no differences among them. Likewise, the responses to the second (MCP-primed) TRH showed no differences. Although there was an expected high correlation (P less than 0.001) between basal TSH and circulating thyroid hormones, the maximal response of TSH to both non-primed and MCP-primed TRH was in B. After MCP, no measurable increase of TSH could be demonstrated at any of the three levels of thyroid function. These results do not support the hypothesis of an altered dopaminergic activity in hypothyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of non aromatizable androgens on LHRH and TRH responses in primary testicular failure

We have assessed the gonadotropin, TSH and PRL responses to the non aromatizable androgens, mesterolone and fluoxymestrone, in 27 patients with primary testicular failure. All patients were given a bolus of LHRH (100 micrograms) and TRH (200 micrograms) at zero time. Nine subjects received a further bolus of TRH at 30 mins. The latter were then given mesterolone 150 mg daily for 6 weeks. The remaining subjects received fluoxymesterone 5 mg daily for 4 weeks and 10 mg daily for 2 weeks. On the last day of the androgen administration, the subjects were re-challenged with LHRH and TRH according to the identical protocol. When compared to controls, the patients had normal circulating levels of testosterone, estradiol, PRL and thyroid hormones. However, basal LH, FSH and TSH levels, as well as gonadotropin responses to LHRH and TSH and PRL responses to TRH, were increased. Mesterolone administration produced no changes in steroids, thyroid hormones, gonadotropins nor PRL. There was, however, a reduction in the integrated and incremental TSH secretion after TRH. Fluoxymesterone administration was accompanied by a reduction in thyroid binding globulin (with associated decreases in T3 and increases in T3 resin uptake). The free T4 index was unaltered, which implies that thyroid function was unchanged. In addition, during fluoxymesterone administration, there was a reduction in testosterone, gonadotropins and LH response to LHRH. Basal TSH did not vary, but there was a reduction in the peak and integrated TSH response to TRH. PRL levels were unaltered during fluoxymesterone treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of triiodothyronine administration on the plasma TSH and prolactin responses to TRH in patients with hypothalamic-pituitary insufficiency.

A study was carried out in 10 patients with multiple pituitary hormone deficiencies to determine the response of thyroid-stimulating hormone (TSH) and prolactin (PRL) to thyrotropin-releasing hormone (TRH) and their suppressibility by treatment with triiodothyronine (T3) given at a dose of 60 microgram/day for 1 week. In 3 patients the basal tsh values were normal and in 7 patients, 2 of whom had not received regular thyroid replacement therapy, they were elevated. The response of TSH to TRH was normal in 6 patients and exaggerated in 4 (of these, 1 patient had not received previous substitution therapy and 2 had received only irregular treatment). The basal and stimulated levels of TSH were markedly suppressed by the treatment with T3. The basal PRL levels were normal in 7 and slightly elevated in 3 patients. The response of PRL to TRH stimulation was exaggerated in 2, normal in 6 and absent in 2 patients. The basal PRL levels were not suppressible by T3 treatment but in 4 patients this treatment reduced the PRL response to TRH stimulation. From these findings the following conclusions are drawn: (1) T3 suppresses TSH at the pituitary level, and (2) the hyperreactivity of TSH to TRH and the low set point of suppressibility are probably due to a lack of TRH in the type of patients studied.     

Thyroid stimulating hormone and prolactin secretion: reduced sensitivity to TRH-stimulated prolactin release after midpregnancy in rats

Prolactin (PRL) and thyroid stimulating hormone (TSH) plasma concentrations were measured during the latter part of the dark period in early and mid-late pregnancy in the rat. On Days 4-5 and 7-8 of pregnancy, plasma PRL concentrations surged between 22:00 and 06:00 hr and TSH values increased between 22:00 and 02:00 hr. While the TSH pattern was maintained during the second-half of pregnancy, surges in PRL release ceased and PRL levels remained at less than 10 ng/ml. The effects of thyrotropin releasing hormone (TRH) administration on PRL and TSH secretion were then measured to determine whether the second-half of pregnancy is associated with a decrease in sensitivity to an agent that can stimulate PRL release. Injection (iv) of cannulated pregnant rats with a low dosage (20 ng) of TRH stimulated a twofold increase in plasma TSH during both early (Days 5-9) and later (Days 14-18) pregnancy but did not change plasma PRL levels. Treatment with a high dosage (2 micrograms) of TRH induced a sixfold rise in plasma TSH during both phases of gestation. The higher dose of TRH also stimulated elevations in plasma PRL during early and mid-late pregnancy; however, both the absolute increase in the amount of PRL in plasma and the percentage increase over baseline levels were greater from Days 5-9 than from Days 14-16 of gestation. These data indicate that the neuroendocrine sensitivity to factors that stimulate PRL secretion changes as pregnancy progresses, and suggest that nocturnal secretion of PRL and TSH during pregnancy may be regulated, in part, by a common trophic factor.     

Mechanisms underlying intracisternal TRH-induced stimulation of gastric acid secretion in rats

The neurohumoral pathways mediating intracisternal TRH-induced stimulation of gastric acid secretion were investigated. In urethane-anesthetized rats, with gastric and intrajugular cannulas, TRH or the analog [N-Val2]-TRH (1 microgram) injected intracisternally increased gastric acid output for 90 min. Serum gastrin levels were not elevated significantly. Under these conditions the TRH analog, unlike TRH, was devoid of thyrotropin-releasing activity as measured by serum TSH levels. In pylorus-ligated rats, gastrin values were not modified 2 h after peptide injection whereas gastric acid output was enhanced. TRH (0.1-1 micrograms) stimulated vagal efferent discharge, recorded from a multifiber preparation of the cervical vagus in urethane-anesthetized rats and the response was dose-dependent. The time course of vagal activation was well correlated with the time profile of gastric stimulation measured every 2 min. These results demonstrated that gastric acid secretory stimulation elicited by intracisternal TRH is not related to changes in circulating levels of gastrin or TSH but is mediated by the activation of efferent vagal pathways that stimulated parietal cell secretion.     

Exploring relationships between mimic configuration, peptide conformation and biological activity in indolizidin-2-one amino acid analogs of gramicidin S.

Indolizidin-2-one amino acids (I2aas, 6S- and 6R-1) possessing 6S- and 6R-ring-fusion stereochemistry were introduced into the antimicrobial peptide gramicidin S (GS) to explore the relationships between configuration, peptide conformation and biological activity. Solution-phase and solid-phase techniques were used to synthesize three analogs with I2aa residues in place of the d-Phe-Pro residues at the turn regions of GS: [(6S)-I2aa4-5,4'-5']GS (2), [Lys2,2',(6S)-I2aa4-5,4'-5']GS (3) and [(6R)-I2aa4-5,4'-5']GS (4). Although conformational analysis of [I2aa4-5,4'-5']GS analogs 2-4 indicated that both ring-fusion stereoisomers of I2aa gave peptides with CD and NMR spectral data characteristic of GS, the (6S)-I2aa analogs 2 and 3 exhibited more intense CD curve shapes, as well as greater numbers of nonsequential NOE between opposing Val and Leu residues, relative to the (6R)-I2aa analog 4, suggesting a greater propensity for the (6S)-diastereomer to adopt the beta-turn/antiparallel beta-pleated sheet conformation. In measurements of antibacterial and antifungal activity, the (6S)-I2aa analog 2 exhibited significantly better potency than the (6R)-I2aa diastereomer 4. Relative to GS, [(6S)-I2aa4-5,4'-5']GS (2) exhibited usually 1/2 to 1/4 antimicrobial activity as well as 1/4 hemolytic activity. In certain cases, antimicrobial and hemolytic activities of GS were shown to be dissociated through modification at the peptide turn regions with the (6S)-I2aa diastereomer. The synthesis and evaluation of GS analogs 2-4 has furnished new insight into the importance of ring-fusion stereochemistry for turn mimicry by indolizidin-2-one amino acids as well as novel antimicrobial peptides.     

Thyrotropin-releasing hormone stimulates the activity of the rat thyrotropin beta-subunit gene promoter transfected into pituitary cells

In order to investigate the molecular mechanism(s) by which TRH regulates the biosynthesis of TSH, we are studying the effects of TRH on the expression of the TSH subunit genes (alpha and TSH beta). To study the structure-function relation of TRH stimulation of the activity of the single rat TSH beta gene, chimaeric plasmids were constructed. The 5'-flanking region of the rat TSH beta gene including exon 1 (5'-untranslated region) was inserted into a promoterless, modified pBR, chloramphenicol acetyltransferase (CAT) expression vector. After transfection, specific TSH beta promoter activity was evident in both TRH-responsive pituitary-derived GH3 and primary pituitary cell cultures. To determine potential regulation of TSH beta promoter-directed activity in these cells by TRH, cells were incubated with media containing TRH (10(-7) to 10(-11) M) for 1 to 48 h. TRH stimulated a 1.5- to 3-fold increase in TSH beta promoter activity. Concomitant with an increase in CAT activity was an anticipated increase in PRL synthesis in the GH3 cells in response to TRH. The TRH effect on the TSH beta gene was specific; no increase in CAT activity was detected for TKCAT (thymidine kinase of herpes simplex virus promoter), pBRCAT (no promoter), or TSH beta CAT (3'-5'-orientation). Similar results were obtained using primary pituitary cell cultures. Deletion mutation analysis indicated that TRH sensitivity was detected in a 1.1 kilobase, but not in a 0.38 kilobase TSH beta gene fragment suggesting that the TRH responsive element(s) resides at least in part within the 700 base pairs of the 5'-flanking sequence.(ABSTRACT TRUNCATED AT 250 WORDS)     

Dissociated response of thyrotropin and prolactin to dopamine receptor blockade with domperidone in hypothyroid subjects.

To investigate the hypothesis of an altered hypothalamic dopaminergic activity in primary hypothyroidism, eight patients with hypothyroidism and seven normal subjects, all female, were studied. All of them were submitted to two tests: TRH stimulation and after the administration of dopamine receptor-blocking drug, Domperidone. The hypothyroid patients with basal TSH values less than or equal to 60 mU/L (4 cases--group 1) had lower PRL levels than the remaining 4 subjects with TSH greater than 60 mU/L (group 2) (p less than 0.001), despite all patients presenting the PRL levels within the normal range. A significant increase occurred for both TSH and PRL after the administration of TRH and Domperidone in normal as well as in the hypothyroid subjects, except for TSH in group 1 after the administration of Domperidone. The area under the curve for PRL response to THR was not different between the normal subjects and both hypothyroid groups, while that under the curve for TSH was greater in the hypothyroidism as a whole than in the normal subjects (p = 0.006) and between the hypothyroid groups, being greater in group 2 than in 1 (p less than 0.009). In relation to Domperidone, the area under the curve for TSH was significantly higher in group 2 when compared to the normal controls (p less than 0.001), while for PRL it was not different between hypothyroid groups in relation to normal controls and when groups I and II were compared. These results suggest that the hypothalamic dopamine activity is not altered in primary hypothyroidism and favor the small relevance of dopamine on the control of TSH secretion.     

Cyclosporine A inhibits the secretion of certain anterior pituitary hormones in patients with nephrotic syndrome.

To clarify the effects of cyclosporine A (CsA) on the secretion of serum thyrotropin (TSH), prolactin (PRL), luteinizing hormone (LH) and follicular stimulating hormone (FSH), we performed TRH and LH-RH testing in 4 patients with the nephrotic syndrome before and after the administration of CsA, 6 mg/kg/day for 4 to 12 weeks. Prior to CsA all patients responded normally to TRH with respect to TSH and PRL secretion. Two patients showed normal response of LH and FSH to LH-RH stimulation while the response in 2 other patients, who were both menopausal, was exaggerated. By the third or fourth week of CsA administration the basal and peak TSH and PRL values declined significantly in all patients in response to TRH stimulation while those of LH and FSH showed only a modest decrease in response to LH-RH stimulation. Two to 4 weeks after the cessation of CsA the response of TSH, PRL and FSH returned to the pretreatment level. These observations suggest that: 1) CsA exerts an inhibitory effect on the secretion of at least TSH and PRL in humans, and 2) the effect of CsA on the pituitary may be partially reversible after the cessation of the therapy.     

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.     

Galactorrhea in subclinical hypothyroidism

Galactorrhea was found in 5 patients with subclinical hypothyroidism. The galactorrhea consisted of the discharge of a few drops of milk only under pressure. Serum T4 was in the lower level of the normal range, but serum T3 was normal (T4: 6.3 +/- 1.2 micrograms/dl, T3: 113 +/- 7 ng/dl). Basal serum TSH and PRL were slightly increased only in 2 and 1 cases, respectively. The PRL responses to TRH stimulation were exaggerated in all cases, although the basal levels were normal. An enlarged pituitary gland was observed in 1 patient by means of CT scanning. All patients were treated by T4 replacement. In serial TRH tests during the T4 replacement therapy, the PRL response was still increased even when the TSH response was normalized. Galactorrhea disappeared when the patients were treated with an increased dose of T4 (150-200 micrograms/day). Recurrence of galactorrhea was not observed even though replacement dose of T4 was later decreased to 100 micrograms/day in 4 cases. In patients with galactorrhea of unknown origin, subclinical hypothyroidism should not be ruled out even when their serum T4, T3, TSH and PRL are in the normal range. The TRH stimulation test is necessary to detect an exaggerated PRL response, as the cause of the galactorrhea. To differentiate this from pituitary microadenoma, observation of the effects of T4 replacement therapy on galactorrhea is essential.     

Prolactin, cortisol secretion and thyroid function in patients with stroke of mild severity.

Different attempts were made to identify the variables that may be involved in the clinical course of cerebrovascular ischemia. In the case of stroke with mild severity (SMS), the clinical significance of neuroendocrine changes as well as of post-stroke depression (PSD) remains unknown. We therefore evaluated the presence of neuroendocrine changes in the acute and post-acute phase of SMS, and their potential role during convalescence. Serum cortisol, T4, T3, FT4, FT3, TSH and PRL levels were measured in 17 euthyroid patients with stroke on admission (day 1), following morning (day 2), 7 days and 3 months later. TSH and PRL secretion after TRH test were measured. Stroke severity on admission was determined by Scandinavian Stroke Scale (SSS). Montgomery-Asberg Depression Rating Scale (Madrs) was used for assessment of post-stroke depression. On admission, TSH and T3, were within normal limits and were greater compared to values on day 2. Lower basal TSH and decreased TSH response to TRH on day 2, were associated with stroke of greater severity. Delta-PRL after TRH on day 2 was higher in patients who develop PSD. Changes in serum thyroid hormones in SMS, reflects those of non-thyroidal illness. A mild stimulation of hypothalamic-pituitary-adrenal axis was detected. We provide evidence that PRL response to TRH, in the acute phase of stroke may be used as an index for early detection of PSD.     

TSH and prolactin secretions in Hashimoto's thyroiditis following withdrawal of thyroid hormone therapy

Changes in the pituitary-thyroid axis in patients with Hashimoto's thyroiditis following withdrawal of thyroid suppressive therapy were analyzed. The group of patients with thyroid adenoma served as control (group I). Patients with Hashimoto's thyroiditis were divided into 2 groups on the basis of serum TSH levels 8 weeks after discontinuing the exogenous thyroid hormone (group II, less than 10 microunits/ml; group III, more than 10 microunits/ml). During treatment with L-T4(200 micrograms/day) or L-T3(50 micrograms/day), there was no significant difference in serum T4-I and T3 levels among the three groups. Following L-T4 withdrawal, basal serum TSH levels were higher at 2 to 8 weeks in groups II and III than in group I. Serum TSH response to TRH was greater at 4 to 8 weeks in groups II and III than in group I. Following L-T3 withdrawal, basal serum TSH levels were higher at 1 and 2 weeks in group II than in group I, while those of group III were consistently higher during the study. Higher TSH responses to TRH were observed at 1 to 8 weeks in groups II and III. Neither basal nor TRH-induced prolactin (PRL) secretion differed significantly among the three groups. We have demonstrated that pituitary TSH secretion in patients with Hashimoto's thyroiditis is affected more by withdrawal of thyroid hormone therapy than in patients with thyroid adenoma. In addition, the present findings suggest a difference between the sensitivity of thyrotrophs and lactotrophs in Hashimoto's thyroiditis after prolonged thyroid therapy is discontinued.     

Possible interaction of PGF2 alpha with hypothalamus-pituitary-thyroid axis in man

The possible interactions of PGF_{2 alpha} on the hypothalamus-pituitary-thyroid axis are the object of this study.Firstly a significant direct effect of PGF_{2 alpha} infusion (mg2, 5/270 min) on TSH,PRL,LH,FSH and GH pituitary secretion was excluded.Thereafter the possible PGF_{2 alpha} on PRL and TSH pituitary response to TRH was considered: in only two cases PGF_{2 alpha} was able to increase the TSH response.Finally the Authors studied T₃ response to endogenous TSH rise induced by TRH: if they consider the mean peak responses of T₃ the increase is significant only when PGF_{2 alpha} infusion is performed.     

Further evidence that TRH is also a physiological regulator of PRL secretion in man

From results of the effect of synthetic pyroglutamyl-histidylprolineamide, pGlu-His-ProNH₂ or TRH, in normal women and men the most compelling indirect evidence has been obtained which supportes the hypothesis that TRH may be a physiological regulator of both TSH and PRL. The minimum effective dose of TRH which stimulates TSH and PRL release in normal men and women is essentially the same. After the administration of TRH to normal subjects, there was always an increase of PRL as well as TSH. The proposed term prolactin-thyrotropin releasing hormone or PTRH rather than TRH may more precisely indicate the biological activities of pGlu-His-ProNH₂ in man.     

The suppression of TSH in the presence of the normal PRL responses to TRH out of 26 patients with primary hyperparathyroidism

The responses of TSH and PRL to intravenous doses of 500 micrograms of TRH were investigated in 26 patients with primary hyperparathyroidism. Fourteen patients (54%) showed low responses of TSH with peak values of less than 5 microU/ml (Group A). Twelve patients showed normal responses of TSH to TRH (Group B). Among the 26, 12 cases belonging to Group A and eight in Group B were reexamined after the correction of serum calcium level by parathyroidectomy. After successful treatment, the responses of TSH to TRH in six of the 12 patients in Group A returned to normal, whereas those in the remaining six were unchanged. The responses in the eight patients in Group B after surgery were not changed when compared to those before treatment. The basal values of PRL and the responses of PRL to TRH were normal in all patients and did not change after treatment. We showed that patients with primary hyperparathyroidism have a high incidence (54%) of suppressed TSH response to TRH. Hypercalcemia was obviously one of the causative factors in inducing this abnormality in six patients. However, persistently suppressed responses of TSH to TRH were observed in the other six patients in Group A even after the correction of the serum calcium level by surgery. This finding suggests a primary failure of the TSH-regulatory mechanism in some cases of primary hyperparathyroidism.     

Effects of phorbol ester on GH, TSH and PRL release by superfused rat adenohypophysis

The present study was undertaken to examine the effects of 12-0-tetradecanoyl-phorbol-13-acetate (TPA), one of the potent tumor promoting agents, on GH, TSH and PRL release by rat adenohypophyseal dispersed cells and fragments, using a superfusion technique. TPA (10(-6) to 10(-5) M) stimulated GH release from acutely dispersed rat adenohypophyseal cells. Neither TSH nor PRL was affected, but both were increased by TRH in a dose-dependent fashion (10(-9) to 10(-7) M). In fragments, TPA (10(-8) to 10(-6) M) elicited a dose-related release of GH. Exposure of the fragments to 10(-6) M TPA for 5 min promptly caused a 5-fold increase in GH release which continued for at least 40 min after stopping the stimulation. The addition of somatostatin (SRIF) (10(-7) M) decreased basal GH release and abolished GH release induced by 10(-6) M TPA. In contrast to GH, neither TSH nor PRL release was affected by TPA, but both were stimulated by TRH. These results indicate 1) that GH release is more sensitive to stimulation with TPA in normal rat anterior pituitaries in vitro than the release of TSH and PRL, and 2) that SRIF abolishes TPA-induced GH release.     

Synergetic effect of pimozide and thyrotropin releasing hormone on prolactin and thyrotropin release during the drying off of ewes

The effect of pimozide and/or TRH was investigated on plasma prolactin, thyrotropin, T₄ and T₃ and udder distension in 38 ewes during drying off by feed restriction. The effect of daily injections of 2 mg pimozide (s.c.), combined or not with TRH stimulation (200 μg, i.v.) on three different days of the drying off period was examined. Blood samples were taken twice daily in each group for 9 days, while blood sampling on the days of TRH injection was also performed at 0, 15, 30 min, and 1, 2 and 4 h post-injection. Plasma was assayed for PRL, TSH, T₄ and T₃ levels. Udder distension and mastitis incidence were recorded at the end of the drying off period. TRH and pimozide both resulted in elevated plasma PRL levels and acted in a synergetic way. Udder distension and the incidence of mastitis was only influenced by pimozide. The TSH as well as the T₃ response to TRH was increased in ewes under a continuous influence of pimozide and T₃ peaks following TRH injection occurred earlier than T₄ peaks. The higher effect of pimozide upon TRH stimulated PRL and TSH release at day 8 compared to days 0 and 3 indicates a progressive involvement of dopamine on the inhibition of PRL and the sensitivity of the thyrotrophs to TRH during drying off.     

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.