Evidence for the existence of gastric cytoprotective effect of atropine and cimetidine in humans

The effects of cimetidine (12.5 mg i.m.) and atropine (0.125 mg i.m.) were studied on the basal (BAO) and pentagastrin (6 micrograms X kg-1 s.c.)-stimulated (MAO) gastric acid secretion; the gastric mucosal microbleeding provoked by one-day treatment with indomethacin (4 X 25 mg orally) in patients with chronic disorders of the joints. The extent of the gastric microbleeding was measured by spectrophotometric determination of haemoglobin in gastric lavage fluid. The aims of this study were to determine the doses of cimetidine and atropine in humans without any significant inhibitory effects either on the basal or on the maximal gastric acid output to evaluate the cytoprotective action of these doses of cimetidine and atropine on the indomethacin-induced gastric microbleeding in the man. It was found that cimetidine (12.5 mg i.m.) and atropine (0.125 mg i.m.) did not cause any significant inhibition either of the BAO or of the MAO; indomethacin (4 X 25 mg orally) significantly increased gastric microbleeding in the patients; cimetidine and atropine, in the above doses, were able to prevent significantly indomethacin-induced gastric microbleeding in the patients. These results provide evidence for the existence of gastric cytoprotective effects of cimetidine and atropine in humans.     

Normalization of thyroid stimulating hormone levels in acromegalic patients after selective adenomectomy

Changes in TSH secretion in six acromegalic patients were studied before and after transsphenoidal adenomectomy (Hardy's method) and compared to normal subjects and six patients with prolactinoma. Basal serum GH levels ranging from 5 to over 250 ng/ml before adenomectomy decreased to below 5 ng/ml after the operation, and the abnormal responses of GH to TRH observed initially in three of the six patients almost disappeared in the post-adenomectomy period. The response of serum TSH to TRH in acromegalic patients improved in each of the six patients after the operation. The TRH-stimulated TSH secretion in patients with prolactinoma of a size and grade similar to those in acromegalic patients was not so extremely low as that in the acromegalic subjects. As indicators of thyroid function, serum triiodothyronine (T3), thyroxine (T4), T3-uptake levels and free T4 indices did not change significantly after adenomectomy as compared with those before the operation in five of the six patients tested. Serum T3, T4 and T3-uptake levels and free T4 indices before adenomectomy were normal or subnormal in each patient except for a high serum T4 level and free T4 index before the operation in only one patient. Thus, it is difficult to conclude that the function of thyrotrophs was decreased by pressure upon the intact pituitary gland by the tumor, or that the thyroid gland also became hypertrophic secondary to the elevated GH, resulting in a large quantity of thyroid hormone being secreted, which caused a suppression of TSH secretion by negative feedback.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pitfalls in the interpretation of thyroid function tests in old age and non-thyroidal illness

In hyperthyroidism, measurement of the serum thyroxine (T4) index or free concentration often suffices to establish the diagnosis. In hyperthyroidism, including 3,3',5-triiodothyronine (T3) toxicosis, thyrotrophin (TSH) response to thyrotrophin-releasing hormone (TRH) is blunted. Sensitive measurement of serum TSH may in the future be the first-line screening test not only for primary hypothyroidism but also for hyperthyroidism. In non-thyroidal illness serum T4, reverse T3 and T3 levels change in relation to severity of disease. In mild disease, T4 is initially increases as the severity of the non-thyroidal illness increases. Reverse T3 increases and serum T3 decreases when the patients become more ill. Serum TSH response to TRH is often blunted. In old age similar changes in serum iodothyronine concentrations may take place, probably related to existing non-thyroidal illness. Also many drugs may have different effects on serum parameters of thyroid function. In acute psychiatric diseases increased serum total and free T4 levels and a blunted TRH test may be encountered.     

The pituitary-thyroid axis in patients with pituitary disorders

The pituitary-thyroid axis of 12 patients, exposed to transsphenoidal pituitary microsurgery because of nonfunctioning adenomas (6), prolactinomas (3) and craniopharyngioma (1), or to major pituitary injury (1 apoplexy, 1 accidental injury), was controlled more than 6 months following the incidents. The patients did not receive thyroid replacement therapy and were evaluated by measurement of the serum concentration of thyroxine (T4), 3,5,3'-triiodothyronine (T3), 3,3',5'-triiodothyronine (rT3), T3-resin uptake test and thyrotropin (TSH, IRMA method) before and after 200 micrograms thyrotropin releasing hormone (TRH) iv. The examination also included measurement of prolactin (PRL) and cortisol (C) in serum. Apart from 1 patient with pituitary apoplexy all had normal basal TSH levels and 9 showed a significant TSH response to TRH. Compared to 40 normal control subjects the 12 patients had significantly decreased levels of T4, T3 and rT3 (expressed in free indices), while the TSH levels showed no change. Five of the patients, studied before and following surgery, had all decreased and subnormal FT4I (free T4 index) after surgery, but unchanged FT3I and TSH. The levels of FT4I were positively correlated to both those of FT3I and FrT3I, but not to TSH. The TSH and thyroid hormone values showed no relationship to the levels of PRL or C of the patients exposed to surgery. It is concluded that the risk of hypothyroidism in patients exposed to pituitary microsurgery is not appearing from the TSH response to TRH, but from the thyroid hormone levels.     

Hypothalamus-hypophysis-thyroid axis function in healthy aging

There is an increased frequency of dysthyroidism in elderly people. We investigated whether there are differences among healthy young middle-aged and elderly people in the 24 hour secretory profiles of TRH, TSH and free thyroxine. The study was carried out on fifteen healthy young, middle-aged subjects (range 36-55 years, mean age±s.e. 44.1±1.7) and fifteen healthy elderly subjects (range 67-79 years, mean age±s.e. 68.5±1.2). TRH, TSH and free thyroxine serum levels were measured in blood samples collected every four hours for 24 hours. The area under the curve (AUC), the mean of 06:00h-10:00h-14:00h and the mean of 18:00h-22:00h-02:00h hormone serum levels and the presence of circadian rhythmicity were evaluated. A normal circadian rhythmicity was recognizable for TRH and TSH in young, middle-aged subjects and for TSH in elderly subjects. Elderly subjects presented lower TSH levels, whereas there was no statistically significant difference in TRH and free thyroxine serum levels between young, middle-aged and elderly subjects. Aging is associated with an altered TSH secretion.     

Acute endocrine effects of a single administration of methylmercury chloride (MMC) in rats

The acute effects of methylmercury chloride (MMC) on the endocrine functions were investigated with doses too small to cause any typical neurological dysfunctions. The hormones included PRL, LH, TSH, ACTH, corticosterone (Bk), testosterone (TLI), total thyroxine (T4) and free thyroxine (free T4). The changes in serum hormone levels from 1 hour through 10 days after a single injection of MMC (12 mg/kg s.c.) (Exp. 1), and dose-response relationships between MMC doses (2 to 16 mg/kg s.c.) and the serum hormone levels at 25 hours after MMC injection (Exp. 2) were examined. The acute effects revealed, which were all reversible, are summarized as follows; MMC might directly inhibit thyroxine synthesis; MMC could affect only stimulatively the pituitary-adrenal axis and PRL synthesis/release, the primary action site for which may be the CNS; and the effects of the pituitary-gonadal axis were inconsistent and, therefore, this axis seems to be relatively resistant to MMC. On the other hand, the responses of PRL and TSH to TRH loading, which were examined for both groups in Exp. 3, suggested that MMC could not affect the metabolizing activity for serum PRL and TSH. The hormone levels of the MMC group enhanced by TRH recovered very rapidly as in the control group. Thus, these acute and reversible endocrine effects seem to indicate relatively earlier development of possible chronic and irreversible effects on the endocrine functions when exposed to methylmercury chronically, and these should be examined further.     

Maturation of the pituitary-thyroid axis during the perinatal period.

To clarify the maturation process of the pituitary-thyroid axis during the perinatal period, thyrotropin (TSH) response to thyrotropin releasing hormone (TRH) and serum thyroid hormone levels were examined in 26 healthy infants of 30 to 40 weeks gestation. A TRH stimulation test was performed on 10 to 20 postnatal days. Basal concentrations of serum thyroxine (T4), free thyroxine (free T4) and triiodothyronine (T3) were positively correlated to gestational age and birth weight (p less than 0.001-0.01). Seven infants of 30 to 35 gestational weeks demonstrated an exaggerated TSH response to TRH (49.7 +/- 6.7 microU/ml versus 22.1 +/- 4.8 microU/ml, p less than 0.001), which was gradually reduced with gestational age and normalized after 37 weeks gestation. A similar decrease in TSH responsiveness to TRH was also observed longitudinally in all of 5 high responders repeatedly examined. There was a negative correlation between basal or peak TSH concentrations and postconceptional age in high responders (r = -0.59 p less than 0.05, r = -0.66 p less than 0.01), whereas in the normal responders TSH response, remained at a constant level during 31 to 43 postconceptional weeks. On the other hand, there was no correlation between basal or peak TSH levels and serum thyroid hormones. These results indicate that (1) maturation of the pituitary-thyroid axis is intrinsically controlled by gestational age rather than by serum thyroid hormone levels, (2) hypersecretion of TSH in preterm infants induces a progressive increase in serum thyroid hormones, and (3) although there is individual variation in the maturation process, the feedback regulation of the pituitary-thyroid axis matures by approximately the 37th gestational week.     

Changes in the hypothalamic-pituitary-thyroid axis during acute starvation in non-obese patients

We investigated changes in the hypothalamic-pituitary-thyroid axis before, during, and after fasting in twenty-one non-obese euthyroid patients with psychosomatic diseases. Blood samples for free T3 (FT3), T3, free T4 (FT4), T4, reverse T3 (rT3), and TSH were obtained from all patients before and on the 5th day of fasting, and in 11 of the same individuals on the 5th day of refeeding. Serum TSH and T3 responses to TRH were also evaluated in 10 patients before and on the 5th day of fasting. During the fast, FT3, T3 and TSH levels decreased significantly and rT3 levels increased significantly whereas FT4 and T4 levels remained within the normal range. Maximal delta TSH, peak TSH levels, max delta T3, peak T3 levels, and net secretory responses to TRH decreased significantly. Peak TSH levels and max delta TSH to TRH correlated well with basal levels of TSH. A statistically significant negative correlation between basal levels of FT4 and TSH was observed. After refeeding, there was a significant increase only in TSH which returned to prefasting values. These results demonstrated that in a state of "low T3" during acute starvation a reduction in serum T3 might depend partly on TSH-mediated thyroidal secretion.     

Abnormalities in pituitary thyroid axis function tests in patients with paroxysmal supraventricular arrhythmias

The study was carried out on 60 consecutive patients (23 males and 37 females) aged between 20 and 83 years (means +/- SD, 40.7 +/- 16) who arrived at our Cardiologic Unit with paroxysmal supraventricular arrhythmias (PSVA) including junctional paroxysmal tachycardia (n = 32), atrial fibrillation (n = 13), atrial flutter (n = 1), premature beats (n = 13) and with no obvious cardiovascular causes. Serum thyroxine and triiodothyronine were normal in all patients and thyroid scintiscan revealed normal shape and size thyroids without autonomously functioning nodule(s). Thyrotropin (TSH) response to thyrotropin releasing hormone (TRH) was normal in 44 subjects in whom normal serum free T4 (FT4) and free T3 (FT3) levels were measured. Six patients with normal FT4 and FT3 levels did not respond to TRH. Abnormalities in thyrotropin response to TRH were observed in 10 patients all exhibiting increased FT4 or also FT3 levels. Among these, 5 patients did not respond to TRH, whereas the remaining 5 exhibited a blunted TSH response to TRH. These results suggest that only in a small proportion (5/60) of consecutive patients with PSVA it is possible to recognize a status of "occult thyrotoxicosis" on the basis of the combined evaluation of free thyroid hormones and TSH response to TRH.     

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.     

Vitamin A-deficiency and thyrotropin secretion in the rat.

Basal serum TSH concentrations and TRH-induced TSH response were studied in control and in vitamin A-deficient rats at different times between the fifth week on diet (when growth of deficient animals was still normal) and the beginning of the weight plateau (as soon as growth of deficient animals had stopped). In deficient rats the TSH values were always lower than in the control rats. TRH injections (50 ng/100 g b.w.) in anaesthetized animals (amobarbital 1 mg/100 g b.w.) resulted in an approximately 12-fold increase in serum TSH levels within 6 minutes. The TSH levels remained elevated for at least 15 minutes and were similar in control and deficient rats. We hypothesize that the lower basal serum TSH concentrations are the result of a feedback mechanism triggered by an increase of serum free thyroxine (FT4) and free triiodothyronine (FT3).     

Thyroid function tests in children with congenital hypothyroidism on L-thyroxine treatment

The plasma levels of thyroxine (T4), triiodothyronine (T3), free T4 (FT4), free T3 (FT3), reverse T3 (rT3) and immunoradiometrically assayed thyrotropin (IRMA TSH) have been measured in 28 L-T4-treated children with congenital hypothyroidism as well as in a control group (group C). The patients were subdivided into 2 groups according to the nonsuppressed (group A) or suppressed (group B) TSH response to TSH-releasing hormone (TRH). Basal IRMA TSH correlated with the TSH increment after TRH and it was significantly lower in group B vs. groups A and C, while no difference was present between groups A and B in regard to T4, FT4 and rT3, all higher than in group C. FT3 levels were similar in the 3 groups. In children, as in adults, basal IRMA TSH seems to be a reliable index in monitoring overtreatment.     

The pituitary-thyroid axis in acromegaly

The pituitary-thyroid axis of 12 acromegalic patients was evaluated by measurement of the serum concentrations (total and free) of thyroxine (T4), triiodothyronine (T3) and reverse T3 (rT3) and thyrotropin (TSH), growth hormone (GH) and prolactin (PRL) before and after iv stimulation with thyrotropin releasing hormone (TRH). Using an ultrasensitive method of TSH measurement (IRMA) basal serum TSH levels of the patients (0.76, 0.07-1.90 mIU/l) were found slightly, but significantly (P less than 0.01), lower than in 40 healthy controls (1.40, 0.41-2.50 mIU/l). The total T4 levels (TT4) were also reduced (84, 69-106 nmol/l vs 100, 72-156 nmol/l, P less than 0.01) and significantly correlated (P less than 0.02, R = 0.69) to the TSH response to TRH, suggesting a slight central hypothyroidism. The acromegalics had, however, normal serum levels of TT3 (1.79, 1.23-2.52 nmol/l vs 1.74, 0.78-2.84 nmol/l, P greater than 0.10), but significantly decreased levels of TrT3 (0.173, 0.077-0.430 nmol/l vs 0.368, 0.154-0.584 nmol/l, P less than 0.01) compared to the controls. The serum concentration of the free iodothyronines (FT4, FT3, FrT3) showed similar differences between acromegalics and normal controls. All the acromegalics showed a rise of serum TSH, GH and PRL after TRH. Positive correlation (P less than 0.05, R = 0.59) was found between the TSH and GH responses, but not between these two parameters and the PRL response to TRH. These findings may be explained by the existence of a central suppression of the TSH and GH secretion in acromegalic subjects, possibly exerted by somatostatin. Euthyroidism might be maintained by an increased extrathyroidal conversion of T4 to T3.     

Ophthalmic Graves's disease: natural history and detailed thyroid function studies.

Of 27 patients with ophthalmic Graves''s disease (OGD) who had been clinically euthyroid three years previously, one became clinically hyperthyroid and seven overtly hypothyroid. Improvement in eye signs was associated with a return to normal of thyroidal suppression by triiodothyronine (T3) and of the response of thyroid-stimulating hormone (TSH) to thyrotrophin-releasing hormone (TRH). Of a further 30 patients with OGD who had not been studied previously, three were overtly hypothyroid. Of the combined series, 46 patients were euthyroid, 18 (40%) of whom had an impaired or absent TSH response to TRH, and 3(6-7%) an exaggerated response. Eleven out of 37 patients (29-7%) had abnormal results in the T3 suppression test. There was a significant correlation between thyroidal suppression by T3 and the TSH response to TRH. Total serum concentrations of both T3 and thyroxine (T4) were closely correlated with T3 suppressibility and TRH responsiveness. Free T4 and T3 (fT3) concentrations were normal in all but three patients, in whom raised fT3 was accompanied by abnormal TSH responses and thyroidal suppression. The presence of normal free thyroid hormone concentrations in patients with impaired or absent TSH responses to TRH is interesting and challenges the concept that free thyroid hormones are the major controlling factors in the feedback control of TSH.     

Serum thyrotropin response to thyrotropin-releasing hormone and free thyroid hormone indices in patients with familial thyroxine-binding globulin deficiency.

The response in serum thyrotropin (TSH) to synthetic thyrotropin-releasing hormone (TRH) as well as serum free thyroxine index (FT4I) and free triiodothyronine index (FT3I) was investigated in six patients with familial thyroxine-binding-globulin (TBG) deficiency. The total serum thyroxine (T4) and triiodothyronine (T3) concentrations were significantly decreased, compared with those of normal subjects (3.4 +/- 0.9 microgram/dl, mean +/- SD. vs. 9.0 +/- 1.5 microgram/dl, p less than 0.01 and 87 +/- 27 ng/dl vs. 153 +/- 37 ng/dl, p less than 0.01, respectively). FT4I was lower than the normal range in all but one (5.3 +/- 1.5 vs. 8.9 +/- 1.6, p less than 0.01), whereas FT3I was all in the normal range and of no significant difference from the normal control (132 +/- 22 vs. 148 +/- 25). Serum TSH concentrations in TBG deficiency were all in the normal range (1.0-4.2 muU/ml) and the maximum TSH increments following TRH 500 microgram iv were 8.9 +/- 2.0 muU/ml and of no significant difference from the normal control (10.2 +/- 4.5 muU/ml). These results indicate that the euthyroid state in familial TBG deficiency is more clearly defined by TRH-test and the normal response to TRH in familial TBG deficiency is presumably under the control of the serum free T3 level rather than the serum free T4 level.     

Influence of D-thyroxine on plasma thyroid hormone levels and TSH secretion.

Triiodothyronine (T3), thyroxine (T4), basal TSH and TSH after stimulation with TRH were determined in healthy subjects and patients treated with D-thyroxine (DT4). After a dosage of 6 mg DT4 the D/L T4 plasma concentration rose about 4-fold 4 hours after application and was only moderately elevated 14 hours later. To achieve constantly elevated T4 levels 3 mg DT4 were applied in the further experiment every 12 hours. The D/L T4 plasma concentration rose 2.5-4-fold and there was a small but significant increase of the D/L T3 plasma concentration. 74 hours after onset of treatment basal TSH was below detectable limits and the increase of TSH 30 min after injection of 200 mug TRH (TRH test) was only about 15% compared to zero time. The time course of TSH suppression was investigated after treatment with DT4 and LT4 (single dosage of 3 mg). TRH-tests were performed before, 10, 26, 50 and 74 hours after the first dosage of D or LT4. There was no difference in the time course of basal TSH and TSH stimulated by TRH. In 10 patients on DT4 long-term therapy, basal and stimulated TSH were found to be below the detectable limits of 0.4 mug/ml. Our results show that (1) plasma half-life of DT4 is less than 1 day, (2) TSH suppression after D and LT4 treatment is very similar, and (3) in patients on long-term DT4 treatment, TSH plasma concentration is below detectable limits even after stimulation with TRH.     

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.     

Comparison between the thyrotropin response to thyrotropin-releasing hormone in summer and that in winter in normal subjects.

A comparison was made between the thyrotropin (TSH) response to 500 microgram thyrotropin-releasing hormone (TRH) in summer and that in winter in ten healthy normal adults living in Supporo. The serum resin triiodothyronine (T3) uptake (RT3U), thyroxine (T4) and T3 levels were also measured. While the TSH response to TRH in summer was similar to that in winter, serum T3 concentration and free T3 index were significantly higher in winter than in summer, associated with the similar values in RT3U and T4 levels in serum. Independently measured 86 specimens (43 in summer and 43 in winter) from normal adults living in the same district also showed a significant increase in serum free T3 index as well as a slight elevation of serum T3 concentration in winter but not in serum T4 level. These results indicate that the primary change in cold winter would be the stimulation of peripheral conversion of T4 to T3 rather than the activation of hypothalamo-pituitary-thyroid axis. The relevance of this interpretation was discussed.     

Relationship of iodide-induced increase in TSH response to TRH to changes in serum thyroid hormones.

Large doses of iodide (500 mg three times a day) administered to normal men for 10--12 days caused a rise in basal serum TSH and a concomitant rise in the peak TSH response to TRH. The basal and peak levels of TSH were highly correlated (p less than 0.001). However, the iodide-induced rise in the peak TSH after TRH was poorly correlated with concomitant changes in serum thyroid hormones. Serum T3 wa not lower after iodide and, while serum T4 was somewhat lower, the fall in serum T4 was unexpectedly inversely rather than directly correlated with the rise in the peak TSH response to TRH. Thus, increased TSH secretion after iodide need not always be directly correlated with decreased concentrations of circulating thyroid hormones even when large doses of iodide are used. Clinically, a patient taking iodide may have an increased TSH response in a TRH stimulation test even though there is little or no change in the serum level of T3 or T4.     

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)