Impairment in cognitive and exercise performance during prolonged antarctic residence: effect of thyroxine supplementation in the polar triiodothyronine syndrome

Humans who work in Antarctica display deficits in cognition, disturbances in mood, increased energy requirements, a decline of thyroid hormone products, and an increase of serum TSH. We compared measurements in 12 subjects, before deployment (baseline), with 11 monthly studies during Antarctic residence (AR). After 4 months of AR (period 1), half of the subjects (T(4) group) received L-thyroxine [64 nmol.day(-)(1) (0.05 mg.day(-)(1))]; and the other half, a placebo (placebo group) for the next 7 months of AR (period 2). During period 1, there was a 12.3 +/- 5.1% (P < 0.03) decline on the matching-to-sample (M-t-S) cognitive task and an increase in depressive symptoms, compared with baseline. During the intervention in period 2, M-t-S scores for the T(4)-treated group returned to baseline values; whereas the placebo group, in contrast, showed a reduced M-t-S score (11.2 +/- 1.3%; P < 0.0003) and serum free T(4) (5.9 +/- 2.4%; P < 0.02), compared with baseline. The change in M-t-S score was correlated with the change in free T(4) (P < 0.0003) during both periods, and increases in serum TSH preceded worsening scores in depression, tension, anger, lack of vigor, and total mood disturbance (P < 0.001) during period 2. Additionally, the submaximal work rate for a fixed O(2) use decreased 22.5 +/- 4.9% in period 1 and remained below baseline in period 2 (25.2 +/- 2.3%; P < 0.005) for both groups. After 4 months of AR, the L-thyroxine supplement was associated with improved cognition, which seems related to circulating T(4). Submaximal exercise performance decrements, observed during AR, were not changed with this L-thyroxine dose.     

Changes in serum concentrations of 3,3',5'-triiodothyronine and 3,5,3'-triiodothyronine during prolonged moderate exercise.

The effect of moderate bicycle exercise (3.5 h) on peripheral thyroid hormone metabolism was studied under two conditions (with and without glucose infusion) in four normal males. Serum T3, rT3, total protein, plasma glucose, and FFA were determined. Exercise induced an increase in rT3 from 29 to 40 ng/dl (P less than 0.01), a decrease in T3 from 154 to 147 ng/dl (P less than 0.01), and an increase in T4 from 7.1 to 7.5 micrograms/dl (P less than 0.05). When glucose was infused during exercise, the changes in rT3 were blunted (P less than 0.01) and the changes in T3 and T4 were diminished. During exercise, rT3 correlated with FFA (r = 0.95) and plasma glucose (r = -0.87). When glucose was infused during exercise, these correlations decreased (r = 0.81 and -0.56, respectively). Since moderate, prolonged exercise induces a state of early or acute starvation it is concluded that the changes in peripheral thyroid hormone metabolism reported here are similar to those found in starvation. The temporal changes of rT3, FFA, and plasma glucose during exercise suggest a relationship between thyroid hormone metabolism and the uptake and utilization of FFA and glucose or the mixture of these body fuels.     

Nuclear thyroxine and 3,5,3'-triiodothyronine receptors in human mononuclear blood cells during pregnancy

Serum free T4, free T3, TSH and maximal nuclear binding capacity for T4 and T3 in mononuclear blood cells were measured in 12 control women, in 12 normal pregnant women in the first and in 12 women in the third trimester. Serum free T4 and T3 were decreased in late pregnancy compared to control women, serum free T4: 9.1 pmol/l(mean) vs 12.9 pmol/l(mean); serum free T3: 4.0 pmol/l(mean) vs 6.2 pmol/l(mean), without any change in TSH levels: 2.2 mU/l(mean) vs 1.8 mU/l (mean). Concomitantly, the maximal nuclear binding capacity for both T4 and T3 increased, T4: 2.7 fmol T4/100 micrograms DNA vs 1.8 fmol T4/100 micrograms DNA; T3:2.8 fmol T3/100 micrograms DNA vs 2.0 fmol T3/100 micrograms DNA. These data, obtained from healthy women during a normal pregnancy are compatible with mild compensated hypothyroidism. We suggest that euthyroidism are maintained by the increased maximal nuclear binding capacity for these hormones.     

Secretion of thyroxine, 3,5,3'-triiodothyronine and 3,3'5'-triiodothyronine in euthyroid man

The secretion of iodothyronines from the normal human thyroid gland was assessed by radioimmunoassay analyses of the concentrations of thyroxine (T4), 3,5,3'-triiodothyronine (T3) and 3,3',5'-triiodothyronine (reverse T3, rT3) in thyroid venous and peripheral venous blood. The subjects studied were euthyroid patients undergoing parathyroid surgery. Measurements were carried out both under apparently normal conditions, following peroral T3 pre-treatment, and before and after acute administration of TSH into a thyroid artery. In the control subjects, significant gradients between thyroid venous and peripheral venous concentrations were recorded both for T4, T3 and rT3, suggesting that all three iodothyronines are secreted by the normal human thyroid. T3 pre-treatment seemed to reduce this secretion, and acute administration of TSH promoted rapid, marked, and concomitant increments in the thyroid venous concentrations of all three iodothyronines. Hence, it appears that not only T4 but also T3 and rT3 are secreted by the normal human thyroid gland, and that TSH stimulates the secretion of all three iodothyronines. On the other hand, calculations of the relative secretion rates uielded the relation T4:T3:rT3 as 85:9:1. This indicates that, in euthyroid subjects, most of T3, and almost all of rT3, is produced by extrathyroidal conversion of T4 and not by direct thyroidal secretion.     

Conversion of thyroxine to 3,5,3'-triiodothyronine in several rat tissues in vivo: the effect of hypothyroidism

The local conversion of thyroxine (T4) to 3,5,3'-triiodothyronine (T3) has been recognized as a source of T3 at various sites in euthyroid rats. The present study was designed to evaluate the effect of hypothyroidism on the source and quantity of T3 at several of these sites (liver, cerebral cortex (Cx), thymus, testis, brown adipose tissue). For this purpose intact euthyroid rats and radiothyroidectomized (RTx) rats received a continuous iv infusion of [125I]T4 and [131I]T3 until isotopic equilibrium was attained. In addition to the labelled iodothyronines, RTx rats received a continuous iv infusion of 0.75 microgram T4/day, in order to maintain a defined hypothyroid state. At the end of the infusion period the animals were bled and perfused, and homogenates of the various organs were prepared. The mean plasma T4 and T3 levels in T4-maintained RTx rats, as measured by RIA, were 1.5 micrograms/dl and 15 ng/dl (euthyroid values: 5.2 micrograms/dl and 48 ng/dl, respectively). The plasma and tissue homogenates were processed for thin layer chromatography and the [125I]T4, [125I]T3 and [131I]T3 levels determined. From these data the concentrations of T4, total T3 and T3 derived from local T4 to T3 conversion (LcT3(T4)) in tissue could be calculated. The relative mean contribution of LcT3(T4) to the total T3 in Cx (75%), thymus (31%), testis (43%) and brown adipose tissue (65%) from hypothyroid rats was higher than that determined for euthyroid animals (66%, 19%, 29% and 27%, respectively). The reverse was found for the liver (15% vs 39%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanisms governing the relative proportions of thyroxine and 3,5,3'-triiodothyronine in thyroid secretion

In subjects with normal thyroid function only a minor part of firculating 3,5,3'-triiodothyronine (T3) originates directly from the thyroid; the majority is produced in the peripheral tissues by deiodination of thyroxine (T4). However, T3 of thyroidal origin constitutes a relatively high fraction of the total T3 produced in many patients with thyroid hyperfunction or hypofunction. Such a relatively high T3 content in the secretion of the thyroid could be caused by a low T4/T3 ratio in thyroglobulin. Severe iodine deficiency is a well-known inducer of a low T4/T3 ratio, but a low T4/T3 ratio can also be produced independent of the iodine content. This is seen in in vitro studies of thyroglobulin iodination when small amounts of DIT are added to the incubation mixture and in vivo in TSH-treated animals and in patients with Graves' disease. Another mechanism for high thyroidal secretion of T3 could be an enhanced fractional deiodination of T4 to T3 in the thyroid. In vitro thyroid perfusion studies have shown that the T3 content of thyroid secretions is higher than would be expected from the T4/T3 ratio of thyroid hydrolysate and that the major mechanism is deiodination of T4 to T3. Thyroxine deiodinases are also present in the human thyroid, and the amount of T4 deiodinase is enhanced in the thyroids from patients with medically treated Graves' disease and in the hyperstimulated thyroids of rats. Other factors of possible importance for the mixture of T3 and T4 secreted by the thyroid are a relatively faster liberation of T3 than of T4 from thyroglobulin during partial hydrolysis (this faster release of T3 is probably the mechanism behind the more "rapid" secretion of T3 than of T4), or some kind of thyroid heterogeneity leading to pinocytosis and hydrolysis of thyroglobulin with a lower T4/T3 ratio than that of average thyroglobulin.     

Comparison of maternal to fetal transfer of 3,5,3'-triiodothyronine versus thyroxine in rats, as assessed from 3,5,3'-triiodothyronine levels in fetal tissues

Thyroxine (T4) is transferred from the mother to the hypothyroid rat fetus late in gestation, mitigating T4 and T3 deficiency in fetal tissues, the brain included. We have now compared the effects of maternal infusion with T3. Normal and thyroidectomized rats were started on methimazole (MMI) on the 14th day of gestation, given alone, or together with a constant infusion of 0.45 micrograms (0.69 nmol) T3 or of 1.8 microgram (2.3 nmol) T4/100 g per day. Maternal and fetal samples were obtained at the 21st day of gestation. The doses of T3 and T4 were biologically equivalent for the dams, as assessed from maternal plasma and tissue T3, and plasma TSH levels. MMI blocked the fetal thyroid; T4 and T3 levels were low in all fetal tissues, and fetal plasma TSH was high. Maternal infusion with T4 mitigated both T4 and T3 deficiency in all fetal tissues, the brain included, and decreased fetal plasma TSH. In contrast, infusion of T3 normalized fetal plasma T3 and increased the T3 levels in several tissues, but not in the brain. Neither did it decrease the high fetal plasma TSH levels. The results show that when the fetus is hypothyroid, T3 crosses the rat placenta at the end of gestation, but does not affect all tissues to the same degree. In contrast to the effects of maternal T4, maternal T3 does not alleviate the T3 deficiency of the brain or, presumably, of the thyrotrope. Thus, end-points of thyroid hormone action related to TSH release should not be used to measure transfer of maternal T3 to the fetal compartment. Moreover, T4 should be given, and not T3 to protect the hypothyroid fetal brain.     

Effects of prednisone on thyroxine and 3,5,3'-triiodothyronine metabolism in normal dogs.

Pharmacological doses of glucocorticoids may reduce serum T4 and T3 levels in normal dogs and humans due to hypothalamic-pituitary suppression and/or altered peripheral hormone metabolism. To evaluate the chronic effects of antiinflammatory doses of glucocorticoids on peripheral thyroid hormone metabolism, serum T4 and T3 kinetic studies were performed in five thyroidectomized L-T4-replaced (5 micrograms/kg, sc, daily) normocalcemic male dogs at baseline and after 35 days of oral prednisone (0.55 mg/kg every 12 h). Data were analyzed in a three-pool model, with rapidly (liver and kidney) and slowly (muscle and skin) equilibrating pools exchanging with serum and rapid pool losses. Prednisone lowered the percent free fraction of T4 (to 70% of baseline) and total T3 (to 60%) and free T3 (to 51%) levels without significantly changing total or free T4 or percent free fraction of T3. This was associated with reduced T4 fractional transfer rates from serum rapid (to 39%) and slow (42%) pools and from rapid (to 25%) and slow pools (to 7%) to serum, and increased serum free T4 clearance rates (to 144%) as well as binding in the rapid (162%) and slow (710%) pools. Total T4 clearance and degradation rates were not significantly altered. Significant correlations included T4 binding in the rapid pool with percent free fractions of T4 (r = -0.86), T4 fractional transfer rates from rapid pool to serum with rapid pool T4 binding (r = -0.75), and fractional T4 transfer rates from slow pool to serum with slow pool T4 binding (r = -0.88). In contrast, prednisone increased fractional T3 transfer rates from serum to the slow pool (to 289%) and reduced serum (to 42%) and maximum total body degradation and production rates (to 41%) without altering total or free T3 clearance rates. Fractional T3 transfer rates from the slow pool to serum correlated with slow pool T3 binding (r = -0.84). Prednisone redistributed T4 and T3 from the serum and rapid pools to the slowly equilibrating pool. Thus, the peripheral effects of chronic antiinflammatory doses of prednisone on thyroid hormone metabolism include 1) increased T4 binding to serum carrier proteins, which may contribute to lower T4 transfer rates from serum to extravascular sites and increased extravascular T4 binding; 2) reduced fractional transfer rates of T4 from extravascular sites to serum, which may relate to increased tissue binding of T4; 3) redistribution of T4 and T3 from the serum and rapid pools to the slow pool; and 4) decreased T3 production from T4, resulting in reduced serum total and free T3 levels.     

The role of 3,5,3'-triiodothyronine in the physiological action of thyroxine in the premetamorphic tadpole

In premetamorphic tadpoles precocious metamorphosis can be induced by immersion in water containing either T4 or T3. T3 5-deiodinase (5D) activity is present in most tissues, and T4 5'-deiodinase (5'D) activity is present in gut and skin; both systems can be inhibited by iopanoic acid (IOP). If conversion of T4 to T3 is important for the normal physiological action of T4 in these tadpoles, it follows that IOP should decrease the effects of T4 and increase those of T3 on metamorphic events. To test this, tadpoles were immersed in water containing either T4 or T3 (20 nM) with or without 1.75 microM IOP. Two indices of metamorphosis, increased leg length and hepatic carbamyl phosphate synthetase activity, were studied. In vehicle- or IOP-treated animals, change in leg length and carbamyl phosphate synthetase activity were minimal. Both indices were increased after exposure to T3 for 10 days or to T4 for 21 days. Moreover, the effects of T3 were significantly enhanced while those of T4 were inhibited when IOP was also present. Both 5'D and 5D activities determined in vitro were inhibited (95% and 60%, respectively) in IOP-treated tadpoles, and this was associated with an increase in the plasma concentration of hormone. In separate experiments, vehicle- and IOP-treated tadpoles received [125I]T4 or [125I]T3 ip. Plasma, liver, gut, and skin were examined 12-24 h later for 125I-labeled products. After [125I]T4 treatment [125I]T3 was found in skin and gut, but not in plasma or liver. After [125I]T3 treatment [125I]3,3'-diiodothyronine was identified in all extracts studied. In vivo generation of these products was reduced by 50% in IOP-treated tadpoles. These findings indicate that generation of T3 from T4 can take place in vivo in the premetamorphic tadpole and strongly support the hypothesis that this process plays an important role in the physiological action of T4 in this species.     

Studies on the conversion of thyroxine to 3,5,3'-triiodothyronine in normal and thyroidectomized chickens

The possibility of conversion of L-thyroxine (T4) to L-3,5,3'-triiodothyronine (T3) and to 3,3',5'-triiodothyronine (reverse-T3, r-T3) has been investigated in chickens. Reverse-T3 could not be detected in normal animals. Both thyroidectomized and normal animals were able to convert exogenous T4 to T3. The administration of propylthiouracyl blocked this conversion to a greater extent than had been expected from the data on mammals. The conversion ratio is higher than in any other species reported in the literature. Data suggest that, as a result of the adaptation of the peripheral deiodination, thyroidectomized animals were able to convert more T4 to T3 than were normal ones.     

The effect of propylthiouracil and methimazole on the peripheral conversion of thyroxine to 3,5,3'-triiodothyronine in athyreotic thyroxine-maintained rats

The effect of prolonged oral administration of PTU and MMI on the local conversion of T4 to T3 was studied in T4-maintained athyreotic rats. For this purpose the rats were equilibrated with [125I]T4 and [131I]T3 by means of continuous iv infusions. PTU treatment reduced the MCR of both T4 and T3, as well as the T3 levels in plasma, muscle, liver, kidney and cerebellum. In the cerebral cortex the total intracellular T3 concentration was not affected, while in the pituitary it even increased. The amount of T3 derived from local conversion of T4 to T3 (LcT3(T4)) was reduced in the liver. PTU treatment did not influence Lc T3(T4) in the cerebellum, but did cause an increase in the amount of T3 derived from this source in the cerebral cortex and the pituitary gland (both the homogenate and the nuclear fraction). The results indicate that in contrast to that in liver, local T3 production in the brain and pituitary must occur predominantly via a pathway which is not inhibited by PTU. In MMI-treated rats the total T3 concentration in the cerebral cortex and cerebellum was not altered, whereas both the MCR of T3 and the T3 levels in plasma and various other tissues were elevated. The relative contribution of Lc T3(T4) increased in liver and was reduced in the cerebral cortex, cerebellum and pituitary gland. In all experiments in liver the contribution of Lc T3(T4) to nuclear T3 was negligible, whereas this was not the case for the other hepatic subcellular fractions. As in liver, virtually all renal nuclear T3 was derived from plasma. The present findings suggest that the production of T3 in liver and kidney, and its subsequent release into the blood, may provide a mechanism for the regulation of plasma T3 levels but is not a direct source of their nuclear T3. In the pituitary gland and the brain local T4 to T3 conversion functions as a source of T3 for the control of local utilization. In this respect the maintainance of constant T3 levels in the brain might be important. These differences among tissues suggest that different mechanisms are involved in T4 5'-deiodination.     

Hypometabolic effect of 3,3',5'-triiodothyronine in chickens: interaction with hypermetabolic effect of 3,5,3'-triiodothyronine

The effect of 3,3',5'-triiodothyronine (rT3) and 3,5,3'-triiodothyronine (T3) on O2 consumption in 1-day-old chickens was studied. The birds were divided into five groups, each of six chickens: (1) control--without injection; (2) control--injected with 100 microliters of solvent (0.01 N NaOH in saline); (3) injected with 10 micrograms rT3/chicken; (4) injected with 0.5 micrograms T3/chicken; and (5) injected with 10 micrograms rT3 + 0.5 microgram T3/chicken. O2 consumption was measured using a Kipp & Zonen diaferometer at neutral temperature (30 degrees) 0, 1, 2, 3, and 4 hr after injection of hormones. Corresponding groups of other chickens served only for blood collection. rT3 and T3 were measured by radioimmunoassay. Reverse T3 decreased O2 consumption by 10.87%. Contrary to this, T3 increased O2 consumption by 29.41%. Reverse T3, injected together with T3, interacted with the hypermetabolic effect of T3 up to 2 hr after injection; then, O2 consumption started to increase, and was about 16.7% higher compared with the basal level 3 hr after injection. The blood plasma level of rT3 increased about 29-fold at the first hour after injection, without changes in the basal level of T3. Administration of T3 increased its level 6-fold 2 hr after injection, which was accompanied by a gradual decrease in the basal level of rT3 (3.7-fold) 4 hr after injection. Administration of rT3 + T3 increased the rT3 level 30-fold at 2 hr and the T3 level 1.7-fold at the first hour after injection. Thus, rT3 acts hypometabolically and interacts with the hypermetabolic effect of T3; administration of T3 lowered the basal level of rT3; and the plasma level of T3 did not change after administration of rT3.     

Thyroxine and 3,5,3'-triiodothyronine content of thyroglobulin in thyroid needle aspirates in hyperthyroidism and hypothyroidism

Thyroglobulin (Tg) was obtained by fine needle aspiration from patients with untreated hyperthyroidism due to Graves' disease and untreated hypothyroidism to determine whether alterations in its T4 and T3 content could account for the disproportionately high serum T3 compared to serum T4 found in both diseases. For comparison aspiration was performed from normal thyroid tissue in euthyroid patients operated for solitary thyroid lesions. The average amounts of Tg aspirated were: normal 177 +/- 52 (SE) micrograms, n = 7, hyperthyroidism 82 +/- 32 micrograms (n = 8); hypothyroidism 4.6 +/- 1.9 micrograms, n = 9. The iodothyronine content of Tg was, normal, T4 3.7 +/- 0.5 mol/mol, T3 0.28 +/- 0.04 mol/mol, T4/T3 13.7 +/- 1.4; hyperthyroidism, T4 3.8 +/- 1.0, T3 0.59 +/- 0.15, T4/T3 6.8 +/- 1.1; hypothyroidism, T4 3.3 +/- 0.5, T3 0.54 +/- 0.09, T4/T3 6.8 +/- 0.7. The iodine content of Tg was 28 +/- 3.1 atoms/mol in the euthyroid subjects and 31 +/- 7.3 atoms/mol in hyperthyroid patients. Hence, both untreated hyperthyroidism and untreated hypothyroidism were characterized by Tg with a normal T4 but a relatively high T3 content. This is probably related to the prolonged hyperstimulation of functioning follicular cells present in both diseases. The relatively high T3 content of Tg could not alone explain the relatively high T3 production compared to T4 production in these two thyroid diseases.     

A reappraisal of the binding characteristics of human thyroxine-binding globulin for 3,5,3'-triiodothyronine and thyroxine

The binding characteristics of T4 and T3 to dilute plasma were studied separately in five normal euthyroid subjects with normal levels of thyroxine-binding globulin (TBG). Scatchard analyses of these data revealed similar mean affinity constants for T4 [2.0 +/- 0.7 (SD) X 10(9) M-1] and T3 (2.0 +/- 0.7 X 10(9) M-1), but a 5-fold higher capacity for T4 (0.75 +/- 0.18 mol T4/mol TBG) than for T3 (0.14 +/- 0.06 mol T3/mol TBG). Similar results were obtained using various assay buffers, pH concentrations, or separation methods. This characteristic pattern of T4 and T3 binding was retained by thyroid hormone free plasma, with the only difference being a slight parallel shift to the left of the Scatchard plots for both T4 and T3. The calculated affinities (Ka) for T4 and T3 were 5.2 X 10(9) M-1 and 5.2 X 10(9) M-1, respectively. High affinity T4 and T3 binding was abolished in plasma selectively depleted of TBG, but was retained after selective depletion of either prealbumin or albumin. Highly purified TBG, prepared from normal serum, demonstrated binding characteristics for T3 and T4 similar to dilute plasma. Displacement of [125I]T4 from dilute plasma by unlabeled T3 or T4 revealed a binding potency of T3 relative to T4 of 9%. Binding affinities derived from analog displacement studies appear invalid as these calculations assume equal binding capacities of TBG for T4 and T3. It seems clear from these studies, that the binding characteristics of human TBG are inconsistent with a single competitive binding site for thyroid hormones.     

Inhibition by propranolol of 3,5,3'-triiodothyronine formation from thyroxine in isolated rat renal tubules: an effect independent of beta-adrenergic blockade

Recent studies in man have shown a decrease in serum L-T3 (T3) levels in subjects treated with DL-propranolol, but the mechanism of this effect is unknown. Isolated rat renal tubules were used to study the effect of propranolol and related drugs on the formation of T3 from L-T4 (T4). Racemic (DL) propranolol at 100 microM inhibited the net formation of T3 from T4 by 35% (P less than 0.01). The D- and L-isomers of propranolol were also potent in inhibiting T3 formation, but the beta-blockers atenolol and sotalol, which have no significant membrane-stabilizing activity, had no effect at similar concentrations. Quinidine inhibited T3 formation, with a dose-response curve which was similar over the concentrations studied to that of DL-propranolol. L-Epinephrine and L-isoproterenol had no effect on T3 formation, and equimolar amounts of L-isoproterenol did not prevent the inhibition of T3 formation by DL-propranolol. cAMP production was stimulated by 200 micro M L-isoproterenol, and this was blocked by an equimolar concentration of DL-propranolol but not of D-propranolol. It is concluded that DL-propranolol directly inhibits net T3 formation from T4 in this system by a direct membrane-stabilizing or quinidine-like action and not by specific beta-blockade.     

Effects of 5,5'-diphenylhydantoin on thyroxine and 3,5,3'-triiodothyronine concentrations in several tissues of the rat

We studied the effect of 5,5'-diphenylhydantoin (phenytoin, DPH) on the metabolism of thyroid hormones, the intracellular concentration of T4, and the source and concentration of T3. Two groups of six male Wistar rats received a continuous infusion of 10 ml saline/rat. day. One group received DPH in their food (50 mg/kg BW) for 20 days. For both groups [125I]T4 and [131I]T3 were added to the infusion fluid for the last 10 and 7 days, respectively. At isotopic equilibrium the rats were bled and perfused. Compared to the controls, plasma T4 and T3 in the DPH group were reduced (22% and 31%, respectively); TSH did not change. The rate of production of T4 and the plasma appearance rate for T3 were decreased. Thyroidal T3 production was markedly reduced. From the increased [125I]T3/[125I]T4 ratio for plasma, it follows that total body conversion was enhanced. The tissue T4 concentrations decreased in parallel with the plasma T4 level. Total T3 was reduced in all organs. In tissues in which local conversion does not occur, i.e. heart and muscle, the decrease reflected the decrease in plasma T3. In the liver both plasma-derived T3 and locally produced T3 were diminished. In cerebellum and brain the plasma-derived T3 pool was even smaller than was expected from the decrease in plasma T3. This was partly compensated by an increase in local conversion. Only for these two organs was the decrease in the tissue/plasma ratio for [131I]T3 significant. Our results suggest tissue hypothyroidism, caused by a decrease in the production of T4 and T3, which is partly compensated by increased conversion in several organs. The transport of T3 into cerebellum and brain is disturbed, which can be attributed to the mode of action of DPH.     

Regulation of thyroxine 5'-deiodinase activity by 3,5,3'-triiodothyronine in cultured rat anterior pituitary cells

The influence of the medium T3 concentration on iodothyronine 5'-deiodinase activity was studied in cultured anterior pituitary cells derived from chronically hypothyroid rats. Type II (propylthiouracil-insensitive) enzyme activity, measured with T4 as substrate, was reduced by T3 in a dose-dependent manner, with an ED50 of approximately 1.4 X 10(-10) M free T3. Density gradient centrifugation was used to obtain populations of pituitary cells relatively enriched in thyrotrophs, somatotrophs, mammotrophs, or gonadotrophs, and the effect of T3 on type II 5'-deiodinase activity was evaluated in each of these four populations. In the absence of T3, the enzyme activity was 1.5- to 2-fold greater in the somatotroph- and mammotroph-enriched cell pools than in the thyrotroph- and gonadotroph-enriched pools. In contrast, when the cells were cultured in the presence of T3, enzyme activity was reduced to the same low level in all four enriched pools. The results suggest that the increase in whole pituitary type II 5'-deiodinase activity associated with hypothyroidism is due largely or totally to increases occurring within somatotrophs and mammotrophs. The data also suggest that the intrinsic responsiveness of the deiodinase to hypothyroidism is greater in somatotrophs and mammotrophs than in other anterior pituitary cells.     

A prepubertal surge of thyrotropin precedes an increase in thyroxine and 3,5,3'-triiodothyronine in normal children

The variations in plasma levels of TSH, T4, T3, and rT3, during the pubertal period, were studied in 647 school students from the urban area of Santiago in Chile (47% males and 53% females) with ages ranging between 7.5 and 15 yr. The subjects were grouped by age in consecutive intervals of 6 months each, and pubertal development was determined in every subject. TSH showed a significant increase, reaching a peak in the 9- to 9.5-yr interval. The same was found for T3 and T4, which reached a peak by 10 and 11 yr. The T4/T3 ratio did not show any significant variation with age. After 9.5 yr, a decrease in rT3 and increase in the T4/rT3 ratio was found. The TSH peak preceded the onset of clinical pubertal development, while the T3 and T4 peaks coincided with this onset. The variations in rT3 suggest an increase of peripheral conversion of T4 to T3. These transient events, not described until now, could be termed thyroidarche and could have a significant effect on pubertal growth and development.