Differential effects of hypo- and hyperthyroidism on remodeling of contacts between neurons expressing the neuropeptide EI and tyrosine hydroxylase in hypothalamic areas of the male rat.

The Neuropeptide EI (NEI, glutamic acid- isoleucine amide) participates in neuroendocrine function. Previously we demonstrated that NEI concentration is regulated by thyroid hormones in discrete hypothalamic areas in rats. We observed that the thyroid status affects the dopaminergic regulation of the pituitary hormones. In this study we explored possible interactions between NEI and tyrosine hydroxylase (TH) containing elements in selected hypothalamic areas of male rats. Neuronal somas, terminals and boutons were assessed by confocal microscopy, in hypo- and hyperthyroid animals. We observed a remodeling of the contacts between the TH and NEI immunoreactive elements in the incerto-hypothalamic area (IHy, also known as rostromedial zona incerta) according to thyroid function. However, in the dorsolateral zone of the peduncular part of the lateral hypothalamus (DL-PLH) the thyroid hormones affect the dendritic trees of the neurons without perturbing the overall NEI/TH contacts. Also, we demonstrated that TRH Receptor 1 (TRH-R1) is colocalized in NEI immunoreactive neurons in the peduncular part of the lateral hypothalamus (PLH) and NEI precursor mRNA expression increased by hypothyroidism indicating that NEI neurons are responsive to the feedback mechanisms of the Hypothalamic Pituitary-Thyroid Axis (HPT). In conclusion, the hypothyroid status seems to increase the interactions between the NEI neurons and the dopaminergic pathways while hyperthyroidism either decreases or displays no effects. Altogether these observations support the participation of the IHy and PLH NEI as a modulating component of the HPT suggesting that altered neuroendocrine, behavioral and cognitive dysfunctions induced by dysthyroidism could be in part mediated by NEI.

Thyroid hormone inactivation in gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are resistant to traditional chemotherapy but are responsive to the tyrosine kinase inhibitors imatinib and sunitinib. The use of these agents has improved the outcome for patients but is associated with adverse effects, including hypothyroidism. Multiple mechanisms of this effect have been proposed, including decreased iodine organification and glandular capillary regression. Here we report the finding of consumptive hypothyroidism caused by marked overexpression of the thyroid hormone-inactivating enzyme type 3 iodothyronine deiodinase (D3) within the tumor. Affected patients warrant increased monitoring and may require supernormal thyroid hormone supplementation.

N-3 polyunsaturated fatty acids supplementation does not affect changes of lipid metabolism induced in rats by altered thyroid status.

Epidemiological studies have demonstrated that n-3 polyunsaturated fatty acid (PUFA) consumption is associated with a reduced risk of atherosclerosis and hyperlipidemia. It is well known that lipid metabolism is also influenced by thyroid hormones. The aim of our study was to test whether n-3 PUFA supplementation (200 mg/kg of body weight/day for 6 weeks given intragastrically) would affect lipid metabolism in Lewis male rats with altered thyroid status. Euthyroid, hypothyroid, and hyperthyroid status of experimental groups was well defined by plasma levels of triiodothyronine, the activity of liver mitochondrial glycerol-3-phosphate dehydrogenase, and by relative heart weight. Fasting blood glucose levels were significantly higher in the hyperthyroid compared to the euthyroid and hypothyroid rats (5.0±0.2 vs. 3.7±0.4 and 4.4±0.2 mmol/l, respectively). In hyperthyroid animals, the concentration of plasma postprandial triglycerides was also increased compared to euthyroid and hypothyroid rats (0.9±0.1 vs. 0.5±0.1 and 0.4±0.1 mmol/l, respectively). On the other hand, hypothyroidism compared to euthyroid and hyperthyroid status was associated with elevated plasma levels of total cholesterol (2.6±0.2 vs. 1.5±0.1 and 1.6±0.1 mmol/l, respectively), LDL cholesterol (0.9±0.1 vs. 0.4±0.1 and 0.2±0.1 mmol/l, respectively) as well as HDL cholesterol (1.6±0.1 vs. 1.0±0.1 and 1.3±0.1 mmol/l, respectively). Supplementation of n-3 PUFA in the present study did not significantly modify either relative heart weight or glucose and lipid levels in any thyroid status.

Acute effects of leptin on 5'-deiodinases are modulated by thyroid state of fed rats.

Leptin has been shown to modulate deiodinase type 1 (D1) and type 2 (D2) enzymes responsible for thyroxine (T4) to triiodothyronine (T3) conversion. Previously, it was demonstrated that a single injection of leptin in euthyroid fed rats rapidly increased liver, pituitary, and thyroid D1 activity, and simultaneously decreased brown adipose tissue (BAT) and hypothalamic D2 activity. We have now examined D1 and D2 activities, two hours after a single subcutaneous injection of leptin (8 microg/100 g BW) into hypo- and hyperthyroid rats. In hypothyroid rats, leptin did not modify pituitary, liver and thyroid D1, and thyroid D2 activity, while pituitary D2 was decreased by 41% (p<0.05) and hypothalamic D2 showed a 1.5-fold increase. In hyperthyroid rats, thyroid and pituitary D1, and pituitary and hypothalamic D2 were not affected by leptin injection, while liver D1 showed a 42% decrease (p<0.05). BAT D2 was decreased by leptin injection both in hypo- and hyperthyroid states (42 and 48% reduction, p<0.001). Serum TH and TSH showed the expected variations of hypo- and hyperthyroid state, and leptin had no effect. Serum insulin was lower in hypothyroid than in hyperthyroid rats and remained unchanged after leptin. Therefore, acute effects of leptin on D1 and D2 activity, expect for BAT D2, were abolished or modified by altered thyroid state, in a tissue-specific manner, showing an IN VIVO interplay of thyroid hormones and leptin in deiodinase regulation.

High-dose taurine supplementation increases serum paraoxonase and arylesterase activities in experimental hypothyroidism.

1. Hypothyroidism is accompanied by hyperlipidaemia and oxidative stress and is associated with several complications, such as atherosclerosis. Paraoxonase activity has been reported to decrease in several situations associated with atherosclerosis and oxidative stress. In the present study, the effects of different doses of taurine on serum paraoxonase and arylesterase activities, as well as on the serum lipid profile, were investigated in hypothyroid rats. 2. Forty male Sprague-Dawley rats were randomly divided into five groups as follows: Group 1, rats received normal rat chow and tap water; Group 2, rats received standard rat chow + 0.05% propylthiouracil (PTU) in the drinking water; and Groups 3-5, taurine-supplemented PTU groups (standard rat chow + 0.5, 2 or 3% taurine in the drinking water, respectively, in addition to PTU). Paraoxon or phenylacetate were used as substrates to measure paraoxonase and arylesterase activity, respectively. Plasma and tissue malondialdehyde (MDA) levels, indicators of lipid peroxidation, were determined using the thiobarbituric-acid reactive substances method. Serum triglyceride, total cholesterol and high-density lipoprotein-cholesterol (following precipitation with dextran sulphate-magnesium chloride) were determined using enzymatic methods. 3. Serum paraoxonase and arylesterase activities were increased and plasma and tissue MDA levels and serum triglyceride levels were reduced in a dose-dependent manner in taurine-treated hypothyroid rats. Taurine concentrations were positively correlated with enzyme activities and negatively correlated with MDA and triglyceride levels. 4. Further studies are needed to investigate the role of taurine supplementation in hypothyroidism in human subjects.

Genomic-independent action of thyroid hormones on NTPDase activities in Sertoli cell cultures from congenital hypothyroid rats.

The Sertoli cells play an essential role in the maintenance and control of spermatogenesis. The ecto-nucleoside triphosphate diphosphohydrolase (E-NTPDase) and 5'-nucleotidase activities can modulate the extracellular adenine nucleotide levels, controlling nucleotide-mediated signaling events in Sertoli cells. Since thyroid hormones (TH) and adenine nucleotides and nucleosides play important modulatory roles in Sertoli cell proliferation and differentiation, the aim of our study was to investigate the effect of hypothyroidism upon the NTPDase and 5'-nucleotidase activities in Sertoli cell cultures, as well as to verify whether these effects may be reversed by short and long-term supplementation with TH. Congenital hypothyroidism was induced by adding 0.02% methimazole in the drinking water from day 9 of gestation and continually until 18 days of age. Hypothyroidism significantly decreased the extracellular ATP and ADP hydrolysis and this effect was significantly reversed when cell cultures were supplemented with 1 microM T3 or 0.1 microM T4 for 30 min. In contrast, AMP hydrolysis was not altered by hypothyroidism, but was increased by T4 supplementation for 24 h. The presence of the enzymes NTPDase 1, 2 and 3 was detected by RT-PCR in Sertoli cell cultures, however, hypothyroidism was not able to alter the expression of these enzymes. These findings demonstrate that TH modify NTPDase activities in hypothyroid Sertoli cells, probably via nongenomic mechanisms and, consequently, may influence the reproductive function throughout development.

Angiotensinase activity in hypothalamus and pituitary of hypothyroid, euthyroid and hyperthyroid adult male rats.

A local renin-angiotensin system (RAS) that may be involved in their regulatory functions has been identified in hypothalamus and pituitary. Altered thyroid status induces modifications in the secretory function of hypothalamus and pituitary. However, few studies have analyzed the role of the RAS in hypothalamus and, to our knowledge, there is no data on the pituitary RAS during thyroid dysfunction. In the present study, angiotensinase activities (glutamyl, aspartyl and alanyl aminopeptidase: GluAP, AspAP and AlaAP, respectively) were studied in hypothalamus and in the anterior and posterior lobes of pituitary of euthyroid, hypothyroid and hyperthyroid adult male rats. In the anterior pituitary, compared with euthyroid and hyperthyroid rats, hypothyroid animals showed a highly significant increase of GluAP and AspAP activities; the percentage increase in GluAP was markedly higher than the percentage increase in AspAP. This suggests an increased metabolism of angiotensin (Ang) I and Ang II to des-Asp 1-Ang I and Ang III, respectively. We also observed an increase of Ang III-degrading activity (AlaAP) in the hypothalamus of hyperthyroid rats in soluble fraction. Increased Ang I and Ang II metabolism in the anterior pituitary of hypothyroid rats and increased metabolism of Ang III in the hypothalamus of hyperthyroid animals may be related to alterations in the secretory function of hypothalamus and pituitary in these thyroid dysfunctions.

Effects of hypothyroidism induced by 6-n-propylthiouracil and its reversal by T3 on rat heart superoxide dismutase, catalase and lipid peroxidation.

The present study critically evaluates the effects of hypothyroid and hyperthyroid states on lipid peroxidation and two enzymes of active oxygen metabolism, namely superoxide dismutase (SOD) and catalase (CAT) in the rat heart mitochondrial and post-mitochondrial fractions. Lipid peroxidation, an index of oxidative stress, was elevated in the heart tissue in hypothyroid state but reduced upon T3 supplementation. Hyperthyroidism registered increased SOD activity in post-mitochondrial fraction. Mitochondrial SOD activity was reduced in hypothyroid state, which was further reduced by T3 administration. In contrast, different thyroid states had no effect on catalase activity in the mitochondrial fraction. The hypothyroid state however, significantly augmented catalase activity in post-mitochondrial fraction. The results suggest that the antioxidant defence status of cardiac tissue is well modulated by thyroid hormone.

Erythrocyte, plasma, and serum antioxidant activities in untreated toxic multinodular goiter patients.

Erythrocyte, plasma, and serum antioxidant activities were studied in patients with newly diagnosed and untreated toxic multinodular hyperthyroid goiter and compared to healthy control subjects. Erythrocyte antioxidant enzyme activities, glutathione, malondialdehyde, and ceruloplasmin levels were significantly increased, whereas serum vitamin E, plasma vitamin C, and selenium levels were decreased in hyperthyroid patients compared to control subjects. The findings show that untreated toxic multinodular goiter causes profound alterations in components of the antioxidant system in erythrocytes indicative of increased oxidative stress. Taken together, these data suggest that hyperthyroid patients may benefit from dietary supplements of antioxidants.

Effect of hypothyroidism on the subcellular distribution of Ca2+/calmodulin-stimulated protein kinase II in chicken brain during posthatch development.

In developing chicken brain Ca2+/calmodulin-stimulated protein kinase II (CaMPK-II) changes from being primarily cytosolic to being primarily particulate during the protracted maturation period. To investigate whether thyroid hormone levels may be involved in regulating this subcellular redistribution, we raised chickens from 1 day posthatching on food soaked in 0.15% (wt/vol) propylthiouracil (PTU) plus 0.05% (wt/vol) methimazole (MMI). This produced a mild hypothyroidism specifically during the maturation period and resulted in a 67% reduction in the levels of free triiodothyronine (T3) at 42 days. The concentrations of alpha- and beta-CaMPK-II in cytosol (S3) and crude synaptic membrane (P2M) fractions from forebrain were measured by three methods: Ca2+/calmodulin- or ZN2+-stimulated autophosphorylation or binding of biotinylated calmodulin. By all three methods hypothyroid animals showed a marked retardation of the redistribution of both subunits of CaMPK-II: an increase in the concentration of the enzyme in S3 and a corresponding decrease in P2M with no overall change in the total amount of enzyme and little apparent change in the concentration of other proteins. In both fractions, there was a parallel change in the Ca2+/calmodulin-stimulated phosphorylation of endogenous protein substrates but no change in the basal or cyclic AMP-stimulated protein phosphorylation. Supplementing the PTU/MMI-treated diet with thyroxine (0.5 ppm) prevented all of the observed changes.

Specific activities of seminal vesicular phosphomonoesterases and Mg2+-,Ca2+- and Na+/K(+)-adenosine triphosphatases in hypo- and hyperthyroid albino rats.

Hypothyroidism (surgical thyroidectomy) inhibited the activities of acid phosphatase and Mg(2+)-ATPase in seminal vesicular tissue and fluid and that of Ca(2+)- and Na+/K(+)-ATPases in fluid alone, and T4 supplementation restored normalcy in all, except acid phosphatase. Hyperthyroidism (T4 25 micrograms/100g body weight/day for 60 days, im) enhanced the activities of alkaline phosphatase and ATPases in seminal vesicular tissue and fluid, and decreased acid phosphatase activity in tissue alone. Withdrawal of T4 treatment from hyperthyroid rats (after 30 days) augmented the activity of ATPases in tissue and impaired the same in fluid, while phosphomonoesterases remained at hyperthyroid level. The results suggest specific responses of various seminal vesicular phosphatases to altered thyroid hormone status. Modification in the specific threshold of androgen/estrogen action on different phosphatases in seminal vesicles appears to be the plausible mechanism underlying these changes in hypo- and hyperthyroid conditions.

Selenium deficiency and type II 5'-deiodinase regulation in the euthyroid and hypothyroid rat: evidence of a direct effect of thyroxine.

Selenium deficiency in rats is characterized by elevated serum T4 and decreased serum T3 concentrations, and low liver type I (5'D-I) and brain type II (5'D-II) iodothyronine 5'-deiodinase activities. These findings are partially explained by the demonstration that type I 5'D is a selenoprotein; however, 5'D-II does not contain selenium. Since 5'D-II varies inversely with serum T4 concentrations, and serum T4 is elevated in selenium deficiency, the decreased cerebrocortical 5'D-II activity may be secondary to the increased serum T4 levels. To determine the mechanism(s) by which selenium influences 5'D-II activity, we examined the effects of altered selenium intake on brain 5'D-II levels and enzyme turnover in euthyroid and thyroidectomized rats. Rats were fed a selenium-supplemented or selenium-deficient diet for 5 weeks from weaning; half of the animals were also thyroidectomized 3 weeks before death. Selenium deficiency was confirmed by decreased liver and brain glutathione peroxidase activities. In euthyroid rats, selenium deficiency caused a 38% increase in serum T4, and 91% and 39% decreases in 5'D-I and 5'D-II, respectively, compared to those in selenium-supplemented rats. In the thyroidectomized hypothyroid rats, selenium deficiency caused a 60% decrease in 5'D-I, but had no effect on 5'D-II activity, fractional turnover of the enzyme, or the calculated enzyme synthesis rate. The lack of effect of selenium deficiency on 5'D-II levels in hypothyroid rats is consistent with the finding that 5'D-II is not a seleno-enzyme. Thus, the decrease in brain and pituitary 5'D-II activity in selenium-deficient euthyroid rats is due to the T4-dependent increase in the turnover of the enzyme polypeptide.

The changes in hepatic enzyme expression caused by selenium deficiency and hypothyroidism in rats are produced by independent mechanisms.

Selenium (Se) deficiency for 5 weeks in rats produced changes in the activity of a number of hepatic, renal and plasma enzymes. In animals whose food intake was restricted to 75% of normal for 2 weeks, Se deficiency produced significant increases in the activity of hepatic cytosolic 'malic' enzyme and mitochondrial alpha-glycerophosphate dehydrogenase (GPD), two enzymes that are particular sensitive to the thyroid-hormone concentrations in tissue. Propylthiouracil-induced hypothyroidism produced significant decreases in 'malic' enzyme and GPD activities. The effect of hypothyroidism on the activity of 'malic' enzyme, GPD and other enzymes studied in liver and plasma was often opposite to that seen in Se deficiency. Glutathione S-transferase (GST) activity was increased by both Se deficiency and hypothyroidism, but in hypothyroid animals further significant increases in GST were produced by Se deficiency. These data suggest that the changes in enzyme expression observed in Se deficiency are not caused by decreased tissue exposure to thyroid hormones.

The regional hypothalamic distribution of type II 5'-monodeiodinase in euthyroid and hypothyroid rats.

The brain topographical distribution of type II 5'-monodeiodinase (5'D-II), which converts thyroxine (T4) to triiodothyronine (T3), was studied in euthyroid and hypothyroid rats. Low levels of 5'D-II activity were detected in the median eminence, but not in any other brain regions of euthyroid rats. The arcuate nucleus and median eminence were also the sites of highest 5'D-II activity in brains of hypothyroid rats. Under these conditions, the paraventricular nucleus contained almost no detectable 5'D-II, while intermediate enzyme activity was present in other medial basal hypothalamic sites.

Selective persistent reduction in choline acetyltransferase activity in basal forebrain of the rat after thyroid deficiency during early life.

The effect of thyroid deficiency on the activity of choline acetyltransferase (ChAT; the marker for cholinergic neurons) was studied in different parts of the rat brain at ages 5, 10, 15 and 25 days, and at day 130 following 102 days of rehabilitation. During normal development, the activity of ChAT increased in the cerebral cortex, hippocampus and basal forebrain, and decreased in the cerebellum. Neonatal thyroid deficiency resulted in a marked retardation of the developmental patterns of the enzyme activity. In the hippocampus the effect diminished with age even during the period of thyroid hormone deprivation, while in the cerebral cortex and cerebellum the enzyme activity was restored to normal only after rehabilitation. In contrast, ChAT activity in the basal forebrain remained persistently reduced in comparison with controls. The results indicate that neonatal thyroid deficiency causes selective irreversible biological damage to subcortical cholinergic neurons.

Changes in fatty acid profiles of plasma, erythrocytes and polymorphonuclear leukocytes in induced hypothyroidism in man: indirect evidence for altered delta 6 desaturase activity.

Thirteen patients who were athyreotic as a consequence of ablation treatment for well-differentiated thyroid cancer were studied during triiodothyronine supplementation, and subsequently at the end of a two weeks withdrawal of this medication. Serum and plasma lipid concentrations, erythrocyte cholesterol content and plasma and erythrocyte total fatty acid patterns were measured. In addition, total fatty acid profiles of polymorphonuclear leukocytes of eight patients and scanning electron microscopic studies of erythrocytes of nine patients were made. We observed an increase of the serum concentrations of total and unesterified cholesterol and phospholipids in all patients. Except for two, all patients showed an increase in the serum triglyceride concentration. The relative amounts of 18:2c,omega 6 rose and those of 20:3c,omega 6 fell in all studied compartments. In addition, the relative amounts of all other omega 6 fatty acids, 22:6c,omega 3, 20:3c,omega 9, 16:0, 18:0, and total saturated fatty acids decreased in plasma, whereas the levels of all monounsaturated fatty acids increased in the erythrocytes. The level of 20:3c,omega 9 rose in the erythrocytes and the 20:3c,omega 9/20:4c,omega 6 ratio rose in the polymorphonuclear leukocytes. The erythrocyte total fatty acids and cholesterol content and their ratio did not change, nor was any alteration seen in the red cell morphology by scanning electron microscopy. This study reveals that the induction of hypothyroidism in man changes fatty acid patterns of plasma, erythrocytes and polymorphonuclear leukocytes. The nature of these alterations suggests especially a disturbance in the delta 6 desaturase activity. The data point to the possibility of a derangement of eicosanoid synthesis in hypothyroidism.

Thyroxine 5'-deiodinase activity in anterior pituitary glands transplanted under the renal capsule in the rat.

The conversion of T4 to T3 by the anterior pituitary gland appears to be of considerable physiological importance in the control of pituitary function. To determine a possible role of hypothalamic factors in controlling this enzymatic process, iodothyronine 5'-deiodinase (I5'D) activity was studied in rats 6 weeks after homologous transplantation of pituitary (implanted animals) or muscle tissue (sham animals) under the renal capsule. Intrasellar pituitaries remained intact, and serum T3, T4, and TSH levels were similar in both groups. I5'D activity was determined by quantifying T3 production rates in tissue homogenates at T4 concentrations of 0.002-4 microM, and with 20 mM dithiothreitol. Sellar pituitaries from sham and implanted animals displayed similar nonlinear reaction kinetics, suggesting the presence of two enzymatic processes having approximate Michaelis-Menten constant (Km) values of 2 nM and 0.3 microM. Maximum velocity (Vmax) was 51.3 +/- (SE) 4.0 fmol T3/min X mg protein (units) and 40 +/- 6 U for the low and high Km components, respectively. In transplanted pituitary tissue, I5'D activity was markedly altered; the low Km activity was significantly decreased (Km, 6 nM; Vmax, 13.0 +/- 1.1 U; P less than 0.001 compared to sellar pituitaries), whereas the high Km activity was increased 15-fold (Km, 5 microM; Vmax, 620 U). The in vitro addition of 6-n-propyl-2-thiouracil (0.1 mM) inhibited high Km I5'D activity in homogenates of both transplanted pituitary and renal tissue by approximately 50% (P less than 0.001), but had no effect on low Km I5'D activity in either sellar or transplanted pituitaries. In sham and implanted animals rendered hypothyroid by the inclusion of 1 g/dl NaClO4 in their drinking water for 6 weeks, low Km I5'D activity was increased approximately 3-fold in sellar and transplanted pituitary tissue. The levels of activity reached in transplanted tissue, however, were only 20-30% of those noted in sellar pituitary homogenates (P less than 0.001). High Km I5'D activity was estimated to be decreased 55% in transplanted tissue from hypothyroid animals. These studies demonstrate that transplantation of the anterior pituitary gland under the renal capsule in the rat results in marked alterations in two distinct components of pituitary I5'D activity. This suggests that neuroendocrine factors are important in the control of pituitary T4 to T3 conversion. Furthermore, it provides evidence for a unique mechanism whereby the hypothalamus, by modulating local thyroid hormone metabolism, may influence pituitary function.

[Effect of somatotropin on cathepsin D in the liver of hypo- and hyperthyroid rats]. / Vliianie somatotropina na aktivnost' katepsina D, v pecheni gipo- i gipertireoidnykh krys.

In experiments on albino male rats the dependence of the cathepsin D activity on the thyroid hormone- and somatotropin levels in the organism was studied. It was demonstrated that the total cathepsin D activity in the liver of hypothyroid rats is lowered by 37% and that of hyperthyroid animals is augmented by 63%. Somatotropin injected to intact rats within 10 days in doses of 0.5 mg/100 g body weight enhanced the total enzyme activity by 19%. Hormone injection to hypothyroid animals returns to the normal cathepsin D activity, whereas in hyperthyroid rats the enzyme effect is significantly lowered under hormone action. Protein content in the nucleus-free homogenate of the hypothyroid rat liver does not differ from that of intact rats and is increased by 27% in hyperthyroid animals. Exogenous somatotropin returns to normal protein content in hyperthyroid rats.

The role of thyroid hormone deiodination in the regulation of hypothalamo-pituitary function.

There is extensive deiodinative metabolism of thyroxine (T4) in thyroid hormone target organs, including the pituitary and brain. In both rat and man, most of the 3,3',5-triiodothyronine (T3) in the body is produced outside the thyroid gland by deiodination of T4. T3 is the principal active form of thyroid hormone within cells. In the rat, there are at least three enzymatic iodothyronine-deiodinating pathways which can be distinguished by kinetics and substrate and inhibitor specificities. Two of these (types I and II) can convert T4 to T3. The third pathway (type III) converts T4 to the inactive reverse-T3 and T3 to an inactive diiodothyronine. Both the anterior pituitary and the brain produce most of their intracellular T3 locally, by the type-II pathway. Type-III activity is present throughout the brain, but not in the anterior pituitary. Studies in the rat, using the deiodination inhibitor iopanoic acid, show that the capacities of T4 to inhibit thyrotropin release and stimulate growth hormone synthesis require conversion of T4 to T3 in the pituitary. Studies in man strongly suggest that the same is true in the human adenohypophysis, and a syndrome in man of a deficiency in this process possibly exists. The hypothalamus exhibits some responses to thyroid hormone, including changes in somatostatin and substance P content and changes in activities of type-II and III deiodination. The mechanism(s) of action of thyroid hormone in the hypothalamus, and in the brain in general, are not yet well understood.(ABSTRACT TRUNCATED AT 250 WORDS)