Unchanged thyrotropin and prolactin responses to thyrotropin releasing hormone after indomethacin treatment.

Experimental effects of prostaglandin synthetase inhibitors have been considered in the literature as a clue to the possible interactions of prostaglandins with the hypothalamic releasing hormones at the pituitary level. Some results of the administration to man of these drugs are apparently in contrast with the in vivo and in vitro animal data. The present investigation deals with the comparison between the thyrotropin releasing hormone (TRH) effect on prolactin and thyrotropin when the hormone was administered intravenously at doses of 50, 100 and 200 microgram respectively to three groups of six men (aged 22 to 30 years), before and on the sixth day of indomethacin administration (50 mg orally at 6-hour intervals). No significant change in the releasing hormone effect was observed either in the case of prolactin, where TRH caused a consistently similar release of the hormone at every dose employed, or in the case of thyrotropin, where a dose-dependent releasing effect was obtained before and after indomethacin treatment.     

Ontogeny of the subcellular compartmentalization of thyrotropin releasing hormone and luteinizing hormone releasing hormone in the rat hypothalamus.

The 900 x g supernatant fluid prepared from hypothalamic homogenates from male and female rats (ranging in age from -1 to 120 days) was fractionated by means of continuous sucrose density gradient centrifugation. Thyrotropin releasing hormone (TRH) and LH releasing hormone (LHRH) in the gradient fractions were quantified by radioimmunoassay. In adult hypothalamic homogenates, TRH and LHRH were associated with two populations of particles distinguishable by their sedimentation properties. Each peptide was in turn distributed in two subpopulations of parties differing in size but similar in density. The distribution of each peptide within its subpopulations of particles was found to be a function of age. In hypothalami of 22-day-old fetuses, TRH was associated almost entirely with the subpopulation of small particles. However, in the neonates, an age-dependent increase in the fractional amount of the TRH confined to the subpopulation of large particles was observed. By the 7th day of age, the peptide was equally distributed in the two subpopulations. The buoyant density of the 1-day-old neonatal particles and that of the adult small and large particles containing TRH was similar. The ontogeny of the subcellular compartmentalization of LHRH differed appreciably from that of TRH. LHRH was barely detectable in hypothalami of 22-day-old neonates. Nevertheless, at this age, the peptide was confined primarily to the subpopulation of large particles, and a similar compartmentalization was noted in hypothalami of 5- and 7-day-old neonates. However, in hypothalami of 14-day-old males and 21-day-old females, association of LHRH with the subpopulation of small particles was evident. It is concluded that 1) the nature of the hypothalamic subcellular compartmentalization of TRH and LHRH is age dependent, 2) the compartmentalization of each peptide in neonatal hypothalami differs from that in the adults, and 3) the development of the mature profile of subcellular compartmentalization of TRH and LHRH proceeds asynchronously.     

Distribution of thyrotropin releasing hormone receptor in rats: an immunohistochemical study

Thyrotropin releasing hormone (TRH) receptor was identified immunohistochemically in the rat tissues using anti-peptide antiserum. Anti-TRH receptor antiserum was raised in New Zealand white rabbits immunized with a conjugate of synthetic TRH-receptor peptide (15-28) to bovine serum albumin. Immunohistochemical analysis was performed by the avidin-biotin complex method. TRH-receptor immunoreactivity was visualized in the central nervous system and anterior pituitary thus supporting previous investigations of TRH receptor distribution using in vitro autoradiographic ligand binding. Significant stain was detected in neural perikarya, axons and dendrites as well as in many cells of the retina, adrenal medulla, stomach mucosa, Auerbach's nervous branch and Mysner's nervous branch of the stomach, small intestine and colon. When using antiserum preincubated with synthetic TRH-receptor peptide (15-28) or rat anterior pituitary homogenate which contains TRH-receptor peptide, no significant stain of the anterior pituitary cells or neurons in the hypothalamus was detected. These findings suggest that TRH-receptor is widely distributed and that this method is valuable in studying the distribution of TRH-receptor in rats.     

Release of luteinizing hormone releasing hormone and thyrotropin releasing hormone from a synaptosome-enriched fraction of hypothalamic homogenates.

A mitochondrial fraction prepared from homogenates of rat hypothalamic tissue was found by means of electron microscopy to be enriched with synaptosomes. The release of luteinizing hormone releasing hormone (LHRH) and thyrotropin releasing hormone (TRH) from this preparation was investigated. After incubation, the synaptosomes were re-isolated by ultrafiltration; and the concentration of LHRH and TRH in the ultrafiltrate was determined by radioimmunoassay. When the synaptosome-enriched preparation was incubated in 0.32M sucrose at 1 or 30 C, less than 10% of the total LHRH and TRH was recovered in the ultrafiltrate. The two hormones were released by depolarizing concentrations (60 mM) of K+ in a Ca++-dependent manner, and the stimulatory effect of K+ was essentially complete within 2 min. In the presence of 2 mM Ca++, the release of LHRH and TRH increased with increasing K+ concentrations in the range 30-120 mM. Prostaglandin E2 (PGE2), PGF2 alpha, and PGF2 beta had little if any effect on LHRH or TRH release. When the synaptosome-enriched fraction was incubated in Hanks' balanced salt solution, the release of LHRH and TRH was about 10 times greater than that seen in 0.32M sucrose. It is concluded that a synaptosome-enriched fraction from the hypothalamus contains readily releasable pools of LHRH and TRH which are mobilized rapidly by depolarizing concentrations of K+ in a Ca++-dependent manner.     

Apomorpine inhibits the prolactin but not the TSH response to thyrotropin releasing hormone.

Pretreatment of normal subjects with apomorphine, a dopamine receptor agonist, resulted in significant impairment of the subsequent prolactin (PRL) response to thyrotropin releasing hormone (TRH). The mean maximal increment of PRL was 27.9+/-2.4 ng/ml after TRH alone, and 11.9+/-3.0 ng/ml (P less than 0.001) after apomorphine plus TRH. In contrast, the.thyrotropin (TSH) response to TRH was unaffected by apomorphine (10.5+/-2.9 vs. 9.5+/-1.8 muU/ml, P greater than 0.5). These results demonstrate that dopaminergic effects are capable of inhibiting PRL responses to TRH, probably via a direct effect on the lactotrope cell. They also suggest that dopaminergic influences are not important in the regulation of TSH secretion.     

Participation of serotonin in thyrotropin release. I. Evidence for the action of serotonin on thyrotropin releasing hormone release.

Injection of serotonin (5-HT) into the third ventricle of the rat resulted in a rapid increase of serum TSH; a significant effect was observed 5 min after injection, whereas the maximal effect appeared 10 min after the injection of 1 microgram 5-HT. This stimulating effect of 5-HT was completely prevented by pretreatment with cyproheptadine, a blocker of 5-HT receptors, whereas fluphenazine, a dopamine receptor blocker, was unable to block it. Third venticle injection of 5-HT in rats bearing anterior hypothalamic lesions (which did not affect the suprachiasmatic nucleus or the medio-basal hypothalamus) also induced an increase of serum TSH similar to that observed in normal rats despite the fact that these animals show a lower basal TSH. In vitro, the addition of 5-HT to an incubation medium containing one hemi-anterior pituitary did not modify medium TSH, whereas 5-HT addition induced an increase of medium TSH in the system containing one hemi-anterior pituitary and two hypothalami. We conclude that 5-HT acts on TSH function probably through a stimulation of TRH release.     

Plasma triiodothyronine response to thyrotropin releasing hormone,thyrotropin and propranolol in old age

The blood T₃ levels were lower and the rT₃ levels higher in 70–90-year-old healthy subjects than in 20–40-year-old people. Similar T₄ and T₃ elevations could be seen after exogenous and endogenous (TRH induced) TSH stimulus in both groups. The pituitary TSH content in old age was sooner exhausted by repeated oral TRH administration. A persistent T₃ elevation after endogenous TSH stimulus could be detected only in the control group, probably as a sign of peripheral T₃ generation. Even small quantities of T₃ significantly suppressed the TRH-induced TSH response in the old age group investigated. Propranolol, at the dosage used, inhibited T₄-T₃ conversion only in the old subjects, while the rT₃ increased in both groups. These findings suggest that a more pronounced inhibitory effect of T₃ on the pituitary TSH release is responsible for the decrease of TSH secretion and consecutive diminution of T₃ secretion from the thyroid in old age. The peripheral generation of T₃ seems to be inhibited too, probably by the elevated rT₃ levels.     

Serum levels of thyrotropin, thyroid hormones and their response to thyrotropin releasing hormone in infective febrile illnesses.

In 25 patients suffering from fever of infection, serum levels of thyrotropin (TSH), thyroxine (T4), triiodothyronine (T3), and thyroxine binding globulin (TBG) were estimated on two consecutive days during the febrile period and again 3 to 10 days after the fever had subsided. The serum TSH and T3 responses to 100 mug iv TRH were also studied during fever. Hormones were estimated by specific radioimmunoassays and TBG by radioligand binding assay. As compared with age and sex matched normal controls, patients with fever of infection had significantly lowered levels of total serum T3 and TBG. The serum TSH and total T4 concentrations were not significantly altered. During fever both % FT4 and absolute FT4 were significantly elevated, whereas only % FT3 was significantly increased and due to lowered serum total T3 levels the absolute FT3 were not significantly altered as compared to that in normal subjects. After the fever had subsided, the serum T3 levels returned to normal and the serum TBG levels increased. There was no correlation between basal serum levels of T3 and TSH during fever. Although in response to iv TRH the mean rise in serum TSH during fever was comparable to that in normal subjects, the overall TSH response showed an inverse correlation with serum TT3 levels. Following iv TRH there was a significant increase in serum T3 levels and the T3 response in fever was comparable to that in normal subjects. These data suggest that hormone secretion by the thyroid and its responsiveness to endogenous TSH are maintained during fever. The lowered T3 levels are not suggestive of a hypothyroid state, but perhaps could be due to decreased peripheral conversion of T4 to T3 and to decreased binding of T3 to serum proteins. The exact mechanism or significance of these alterations in thyroid function during febrile illness remains to be elucidated.     

Pituitary-thyroid hormone economy in healthy aging men: basal indices of thyroid function and thyrotropin responses to constant infusions of thyrotropin releasing hormone

In order to assess the effects of aging, as distinct from those of thyroid disease or extrathyroidal illness, on certain indices of thyroid function, we studied 74 healthy, ambulatory men recruited from the Baltimore Longitudinal Study on Aging. We determined basal serum values of T4, T3, rT3, thyroxine-binding globulin (TBG), and T3 resin uptake (T3RU) and calculated the free T4 index (FT4I = T4 X T3RU/100), free T3 index (FT3I = T3 X T3RU/100), and T4/TBG ratio for each subject. We used an ultrasensitive RIA to measure variations in basal concentrations of TSH within the normal range. We then infused TRH at a constant rate (0.4 microgram/min iv) for 240 min into 63 of the same men; serum samples, collected at 15-min intervals during the infusion, were analyzed for TSH by routine RIA. Subjects were divided into 3 groups according to age; A (n = 26, mean age = 39.4), B (n = 23, mean age = 60.0), and C (n = 25, mean age = 79.6). Analysis of variance with Duncan's multiple range test and regression analysis were used to evaluate data. There was no significant (P greater than 0.05) variation with age of basal serum values of T4, TBG, or T3RU. Comparison of groups A and C showed significant decreases of mean values of serum T3 (-11%, P less than 0.05), FT3I (-13%, P = 0.02), FT4I (-11%, P less than 0.01), and T4/TBG ratio (-12%, P less than 0.01) and an increase in serum TSH (+38%, P less than 0.05). For these variables, the mean values for group B were intermediate between, but not significantly different from, those of A and C. Regression analysis showed significant correlations of age with T3, FT3I, FT4I, T4/TBG, and TSH at P levels similar to those obtained by Duncan's test. No elderly individual exhibited a baseline elevation of TSH (greater than 7 microU/ml) or depression of T4 (less than 5 micrograms/dl), suggesting that primary hypothyroidism was not present in our old group. The basal TSH concentration did not correlate significantly with any index of thyroid function except with FT3I in group C (r = -0.43, P less than 0.05). In all age groups the TSH responses to TRH exhibited a biphasic pattern with early and late peaks.(ABSTRACT TRUNCATED AT 400 WORDS)     

Luteinizing hormone pulsatile secretion and pituitary response to gonadotropin releasing hormone and to thyrotropin releasing hormone in male epileptic subjects on chronic phenobarbital treatment

Endocrine changes have been reported in treated epileptic subjects, who often exhibit sexual dysfunctions, but the endocrine effects of single antiepileptic drugs have not been completely elucidated. In this study we have investigated the influence of phenobarbital (PB) on adenopituitary function and on peripheral sexual steroid pattern in 8 epileptic males. Chronic PB treatment does not modify luteinizing hormone (LH) pulsatile secretion. In the same subjects, LH and follicle stimulating hormone (FSH) response to Gonadotropin Releasing Hormone was blunted with respect to healthy controls both in terms of absolute values and of secretion areas. No difference was found in prolactin (PRL) response to Thyrotropin Releasing Hormone. In the epileptic group a significant increase in the levels of sex hormone binding globulin and a consequent decrease of the percent free testosterone have been observed. PB treatment also significantly lowers 17-beta-estradiol mean levels. These data suggest that PB independently affects both gonadotropin secretion and peripheral steroid pattern.