Deiodination Of T4 Research Articles

Metabolic clearance and production rates of 3.3'-diiodothyronine, 3',5'-diiodothyronine and 3'-monoiodothyronine in hyper- and hypothyroidism.

SUMMARYComplete turnover studies of thyroxine (T4), 3,5,3′‐triiodothyronine (T3), 3,3′,5′‐triiodothyronine (rT3), 3,3′‐diiodothyronine (3,3′‐T2), 3′,5′‐diiodothyronine (3′,5′‐T2) and 3′‐monoiodothyronine (3′‐T1) were performed in each of eight healthy subjects, eight hyperthyroid and eight hypothyroid patients, using the single injection, non‐compartmental approach. The median metabolic clearance rate (litre per day per 70 kg) in controls was, T4 1·19; T3 19·7. rT3 147; 3,3′‐T2 1073; 3′,5′‐T2 256 and 3′‐T1 518. Hyperthyroid patients had increased and hypothyroid patients reduced values. The median production rate (PR) (nmol per day per 70 kg) in controls was, T4 117, T3 39, rT3 52, 3,3′‐T2 35, 3′,5′‐T2 14 and 3′‐T1 27. The PR of all iodothyronines studied was increased in hyperthyroidism, the increase in PR of T3 being the most pronounced. Hypothyroid patients had reduced PRs, a reduction which was relatively less pronounced for T3. Assuming thyroidal secretion contributes little rT3 and 3′,5′‐T2, the conversion rates (CRs) of T4 to rT3 and further to 3′,5′‐T2 were calculated. CR of T4 to rT3 in controls was in median 34%. By comparison the CR in hyperthyroid patients was increased to 56% (P < 0·05). In contrast the CR of rT3 to 3′,5′‐T2 was similar in controls and hyperthyroid patients, 26% v. 31%.Our data demonstrate, that quantitatively important amounts of 3,3′‐T2, 3′,5′‐T2 and 3′‐T1 are produced in man, and that deiodination of T4, the T3s and the T2s is a major metabolic pathway both in eu‐, hyper‐ and hypothyroidism. The daily production of all six iodothyronines studied is influenced by hyper‐ and by hypothyroidism. The activity of the 5‐deiodination of T4 seems to be enhanced during hyperthyroidism, possibly tending to counteract the hypermetabolic state. In contrast the 5‐deiodination of rT3 is unaltered in hyperthyroidism, thus suggesting the existence of more than one 5‐deiodinase in man.

Rat placenta is an active site of inner ring deiodination of thyroxine and 3,3',5-triiodothyronine.

Inner ring deiodination of L-T4 and L-T3 by rat placental homogenates resulted in the generation of rT3 from T4 and 3,3'-diiodothyronine and 3'-monoiodothyronine from T3. Dithiothreitol is required in the incubation medium. There was little or no detectable outer ring deiodination of T4 and T3. These findings suggest that placenta enzymatic inner ring monodeiodination of T4 and T3 could prevent the transplacental passage of T4 and T3 from dam to fetus. They also provide an explanation for our previous observations that fetal serum rT3 is partially dependent on maternal thyroid function.

Proposed mechanism for increased thyroxine deiodination in cold-acclimated rats.

Groups of male rats were administered isoproterenol (ISO), thyroxine (T4), or both (ISO + T4) daily for 20 days in an attempt to mimic the effect of cold acclimation on the rate of outer-ring deiodination of T4 to triiodothyronine (T3) by 2,000-g supernatants of homogenates of liver and kidney. The rates of hepatic and renal deiodination of T4 to T3 in an additional group of rats exposed to 4 +/- 1 degree C for 20 days were 53 and 71% higher, respectively, than control. Administration of ISO (100 micrograms . kg-1 . day-1) did not affect the rate of deiodination of T4 to T3 by either hepatic or renal tissue. Administration of T4 (50 micrograms . kg-1 . day-1) resulted in rates of hepatic and renal deiodination of T4 that were 297 and 222% higher, respectively, than control. Administration of ISO + T4 resulted in a rate of conversion of T4 to T3 not significantly different from that observed when T4 was administered alone. Serum concentration of T4 was elevated after administration of both T4 and ISO + T4, whereas serum concentration of T3 was elevated significantly above that of control only in the cold-acclimated group. These results suggest that the increased rate of 5'-monodeiodination of T4 by hepatic and renal homogenates from cold-acclimated rats is not a result of increased beta-adrenergic activity but can be accounted for by the increase in thyroid activity observed in these animals.

Suppression of the night increase in serum TSH during development of ketosis in diabetic patients.

The alterations in metabolic parameters, circulating iodothyronines and serum TSH were studied during a 21 h period of insulin withdrawal in 6 young patients with juvenile type diabetes mellitus. Concomitant with the derangement of metabolic state a significant fall in serum T3 (in average 27%), serum free T3 (28%), and T4 (12%) was observed. SErum free T4 remained unchanged. Before and after the period of ketosis the normal diurnal pattern of high serum TSH at night and low levels during the daytime period was observed. During the period of ketosis the night level of serum TSH was significantly depressed (46 +/- 9% lower at 23.00 h, p less than 0.01) while no significant alterations occurred in daytime TSH. Both the variations in T3, reverse T3 (rT3) and night TSH were correlated to the increase in blood-3-hydroxybutyrate. The depression of the night surge in serum TSH may be of importance for the fall in circulating levels of active iodothyronines during the initial phase of illness, together with the well known inhibition of T4 deiodination to T3 in peripheral tissues occurring in acute illness.

Extrathyroidal Effects of Low Concentrations of Thiourea on Rainbow Trout, Salmo gairdneri

Chronic exposure of fed immature rainbow trout (Salmo gairdneri) to a low ambient thiourea (TU) concentration did not depress circulating levels of T4 (thyroxine) or triiodothyronine, T4 degradation rate, or T4 deiodination rate indicating no significant T4 influence on thyroidal hormone output. However, TU increased the hematocrit and decreased distribution spaces for iodide and T4, indicating direct sensitivity of extrathyroidal processes to TU.Key words: thiourea, thyroxine, hematocrit, iodide metabolism, rainbow trout

Human Placenta Is an Active Site of Thyroxine and 3,3',5-Triiodothyronine Tyrosyl Ring Deiodination*

Human placental homogenate deiodinates the tyrosyl ring of T4 and T3, converting these active thyroid hormones to the inactive iodothyronines, rT3 from T4, and 3,3'-diiodothyronine and 3'-monoiodothyronine from T3. The conversion of T4 or rT3 is time, temperature, pH, and protein content dependent and does not occur in the absence of the thiol-regenerating agent dithiothreitol. Phenolic ring deiodination of T4, T3, and rT3 was not detected. Failure of the transplacental passage of T4 and T3 from mother to fetus may be secondary to the placental tyrosyl ring deiodination of these iodothyronines.

Dynamics of inhibition of iodothyronine deiodination during propylthiouracil treatment of thyrotoxicosis.

Serum 3,3',5'-triiodothyronine (rT3), 3,5,3'-triiodothyronine (T3), thyroxine (T4) and propylthiouracil (PTU) were measured before and at short intervals for 8 hours after oral administration of 200 mg PTU to six patients with untreated thyrotoxicosis. The study was repeated on the 4th day of treatment with 200 mg PTU every 8 hours. Six other patients with untreated thyrotoxicosis were studied after a single administration of 800 mg PTU. The results indicated that PTU inhibition of T4 deiodination to T3, evaluated by the fall in serum T3, was of the same duration as the PTU inhibition of rT3 deiodination, evaluated by the increase in serum rT3. After 200 mg PTU inhibition was maximal for only a few hours, and there was no cumulative effect of PTU during the first four days of treatment, when 200 mg PTU was given every 8 hours. After 800 mg PTU the full effect was maintained for the 9 hour period studied, after which serum T3 had fallen to 65 +/- 2% of the pretreatment level (mean +/- SE). Thus, to obtain a permanent full effect of PTU on iodothyronine deiodination during the treatment of thyrotoxicosis it is necessary to use large doses or frequent administration.

Thyroid hormones in acute myocardial infarction.

Thyroid hormones were serially measured over a 2-week period in thirty-four consecutive patients with acute myocardial infarction (AMI). A transient increase in plasma rT3 and a decrease in plasma T3 was found, with the maximum changes occurring on the third day after the onset of AMI. The changes in plasma rT3 and T3 were greater in the seventeen patients with a complicated AMI (mean peak SGOT 145 mu/l) than in the seventeen patients with an uncomplicated AMI (mean peak SGOT 79 mu/l). A correlation was found between infarct size (as estimated by the peak SGOT value) and the following indices: delta r T3, delta T3, highest rT3/t3 and highest rT3/T4 ratios. A transient increase in plasma TSH (peak on days 4 and 5) and in plasma T4 and FT4 index (peak on days 6 and 7) was also observed, whereas T3 resin uptake (T3U) decreased. These findings suggest that the following sequence of events occurs in thyroid hormone metabolism during AMI: (1) inhibition of the 5'-deiodination of T4, resulting in increased plasma rT3 and decreased plasma T3 values, and in a lower metabolic clearance of T4. (2) Increased secretion of TSH (provoked by the lower T3 levels) resulting in increased thyroidal secretion of T4 and T3, which is then switched off by the negative feedback of thyroid hormones on the pituitary.

Phenolic and nonphenolic ring iodothyronine deiodinases from rat thyroid gland.

A particulate fraction of rat thyroid gland sedimenting between 1,500–100,000 ×g contains enzymatic activities that catalyze the sequential deiodination of T4 to 3,3′-diiodothyronine (T2) via both T3 and rT3. The T4-5′-deiodinase of this particulate fraction has been studied in some detail using a specific T3 RIA. The presence of a sulfhydryl compound such as dithiothreitol was required for activity which was optimal at pH 6.5 and was twice as high for fractions prepared at 7.4 and assayed at 6.5 than for material both prepared and assayed at 6.5. The apparent Km for T4 was 3.1 μM, and the Vmax was 53 pmol/mg protein·min. Activity was destroyed by heating for 30 min at 60 C, was completely inhibited by 50 μM 6-propyl-2- thiouracil, but was unaffected by methimazole. T3 production values agreed closely when measured by RIA and by paper chromatography using [125I]T4 as substrate. Propanol in reaction mixtures, contributed by labeled T4 stock solutions (50% propanol-50% H2O) or added to mixtures containing u...

Effects of an inhibitor of hepatic drug metabolism, 2-diethylaminoethyl-2,2-diphenylvalerate HCl (SKF 525-A), on thyroxine metabolism in the rat.

We have examined some effects of 2ndash;diethylaminoethyl- 2,2-diphenylvalerate HC1 (SKF 525-A), an inhibitor of hepatic drug metabolism and of cytochrome P-450-mediated reactions, on T4 metabolism by rat liver slices and by rats in vivo. Incubation of liver slices with labeled T4 in medium containing 0.1 mM SKF 525-A reduced deiodination to 27% of control and did not affect T3 formation; at 1.0 mM SKF 525-A, deiodination and T3 formation both declined (to 7% and 60% of control levels, respectively), while degradation of rT3 was not affected. Hypoxia had effects similar to SKF 525-A, i.e. inhibition of T4 deiodination, while formation of T3 from T4 and degradation of rT3 were not inhibited. During a constant infusion of [125I]T4, SKF 525-A (3.5 mg/100 g BW, ip) caused an acute increase in the MCR of T4. It was then found that SKF 525-A added to serum in vitro increased the free T4 fraction; injected in vivo, it caused a prompt rise in the free T4 fraction accompanied by a fall in serum TSH. In rats receiv...

Iodothyronine 5′-Deiodinase from Rat Kidney: Substrate Specificity and the 5′-Deiodination of Reverse Triiodothyr onine *

Renal membranes (crude microsomal fraction) which catalyze the thiol-dependent outer ring deiodination of LT4 with the formation of L-T3 are also capable of the 5′-deiodination of rT3 with the production of equivalent amounts of I and 3,3′-T2. rT3 deiodination was followed by measuring the amount of 125I released from 125I-labeled (3′ or 5′-) L-rT3; iodide and iodothyronines were separated by a rapid method using Dowex 50W cation exchange columns. Iodide release was proportional to tissue concentration, was heat labile, and was unaffected by methylmercaptoimidazole. The reaction had a rapid phase (∼ 10–15 sec) which was unaffected by thiols and a slower thiol-dependent phase which was linear with time. Double reciprocal plots of product formation vs. rT3 concentration at fixed thiol concentrations yielded a family of parallel lines. Parallel lines were also obtained when the thiol concentration was variable and the rT3 concentration was fixed. These patterns of initial velocity kinetics resemble those obtained with L-T4 as a substrate. Limiting Michaelis constants Ka for rT3 and Kb, for dithiothreitol were 0.46 μM and 8.1 mM, respectively, and the V1 was 0.99 nmol I released protein-min; the Kb and V1 were at least 15 times greater than comparable values for T4 5′ deiodination whereas the Ka values for the iodothyronine substrates were nearly equivalent. Pretreatment of the renal microsomal fraction with 10 μ 6-propy1-2-thiouracil and increasing concentrations of rT3 resulted in increasing degrees of persistent 6-propyl-2-thiouracil inhibition of both T4 and rT3 5′-deiodination reactions. The substrates, T4 and rT3, were found to protect iodothyronine 5′-deiodinase from inactivation by iodoacetate. These findings are consistent with the idea that the same enzymecatalyzes the 5′-deiodination of both T4 and rT3, that measuring I release from rT3 is an effective method for assay of the enzymatic activity, and that thiol availability may determine the relative rates of T4 and rT3 metabolism via this enzyme.

Blood spot thyroxine-binding globulin: A means to reduce recall rate in a screening strategy for neonatal hypothyroidism

inat ion? However, epinephrine does not appear to have any effect on T4 deiodination in human beings? Thyroid hormones are thermogenic, increase oxygen consumption, and have anabolic and catabolic effects. The reduction in extra-thyroidal T3 production that occurs in many illnesses would be expected to reduce the rate of many of these processes. In this context, it is not surprising that hypoxia should have a similar effect on extrathyroidal thyroid hormone metabolism. In this setting, reduced oxygen consumption in tissues sensitive to thyroid hormone, e.g., liver, would spare oxygen for those tissues in which oxygen consumption is not regulated by thyroid hormones, e.g., brain. Almost 30 years ago, it was demonstrated that experimentally induced hypothyroidism in the rat increased the animal 's resistance to anoxia. ' ~

Secretion of 3,3'-diiodothyronine by the perfused canine thyroid isolated in situ.

Previous studies employing perfused dog thyroid lobes have shown that thyroidal secretion is modulated by intrathyroidal deiodination of T4 to T3 and rT3. To characterize further the intrathyroidal iodothyronine-deiodinating processes 3,3'-diiodothyronine (3,3'-T2) and T4 were measured in hydrolysate and effluent from isolated dog thyroid lobes during single passage perfusion with a synthetic hormone-free-medium. In five experiments the concentrations in effluent from unstimulated thyroid lobes were: 3,3'-T2, 208 +/- 62 pmol/liter; and T4, 12.8 +/- 2.8 nmol/liter (mean +/- SE). During the infusion of 100 microU/ml TSH, there was a parallel increase in the secreton of 3,3'-T2 and T4. After approximately 90 min of TSH infusion, effluent concentrations were: 3,3'-T2, 2490 +/- 420 pmol/liter; and T4, 204 +/- 24 nmol/liter. In a pronase hydrolysate of the thyroid lobes, the amounts were: 3,3'-T2, 2.44 +/- 0.56 pmol/mg; and T4, 1070 +/- 125 pmol/mg. Expressed as a percent of T4, the amount of 3,3'-T2 in thyroid effluent was approximately 10 times higher than that in thyroid hydrolysate. This relative hypersecrection of 3,3'-T2 was abolished by the infusion of 10(-3) or 10(-5) M propylthiouracil, an inhibitor of peripheral and intrathyroidal iodothyronine deiodination. Thus, thyroid secretion contains small amounts of 3,3'-T2, most of which seems to originate from intrathyroidal deiodination of T3 and/or rT3.

The effect of iodothyronines on the conversion of thyroxine into 3,3'-5-tri-iodothyronine in isolated rat renal tubules.

Isolated rat renal tubules prepared by collagenase digestion were used to study the effects of 3,3',5'-tri-iodothyronine ('reverse T3', rT3) and other iodothyronines on the formation of 3,3',5-tri-iodothyronine (T3) from thyroxine (T4). rT3 inhibited the conversion with a dose response over the concentration range 1.5nM-1.5microM. The inhibition was competitive in nature. Both 3,3'-di-iodothyronine and 3',5'-di-iodothyronine also inhibited the production of T3 and T4 in isolated rat renal tubules, but tetraiodothyroacetic acid and 3,5-di-iodothyronine were found to have no effect. These experiments demonstrate in an intact cell system that some naturally occurring iodothyronines have significant effects on T4 deiodination.

In vivo and in vitro effects of adrenaline on conversion of thyroxine to triiodothyronine and to reverse‐triiodothyronine in dog liver and heart

Infusion of adrenaline in healthy dogs in a dose simulating spontaneous release of the catecholamine during experimental myocardial infarction produced a significant decrease in the conversion of thyroxine (T4) to triiodothyronine (T3) and a moderate increase in the conversion of T4 to reverse-triiodothyronine (rT3). Similar changes in deiodination of T4 to T3 and to rT3 were also observed when adrenaline was added in vitro to liver and heart homogenates. These results are consistent with a direct effect of adrenaline on T4 deiodination as degradation of exogenous T4, T3 and rT3 was only slightly increased under the experimental condition employed. The present study suggests that increased tissue exposure to adrenaline might contribute to the hormonal changes seen in at least some case of the 'low T3 syndrome'.

Endocrine abnormalities in patients undergoing long-term hemodialysis: The role of prolactin

The possible role of hyperprolactinemia in the sexual and thyroid abnormalities of patients with end-stage renal failure was studied in 56 patients undergoing long-term hemodialysis. Seventy-three per cent of the women and 25 per cent of the men receiving no prolactin (PRL)-enhancing drugs had elevated PRL levels (25 to 200 ng/ml, normal <20 ng/ml), and all those patients who were receiving α-methyldopa treatment (13 patients) had even higher PRL levels (30 to 1,107 ng/ml). The response of PRL to the administration of thyrotropin-releasing hormone (TRH) was blunted and prolonged, suggesting that hyperprolactinemia was in part due to prolonged plasma half-life of the hormones; this was confirmed by the insufficient PRL lowering effect of a single dose of bromocriptine in a short-term test, whereas a longer trial of six weeks demonstrated the PRL-suppressive effect of the drug. Amenorrhea or oligomenorrhea was a constant feature in women, four of whom also showed galactorrhea; during bromocriptine treatment, recurrence of menses was observed in some of the hyperprolactinemic amenorrheic women. Men with impotence had higher PRL levels than men with normal potency. Lack of appropriate elevation of luteinizing hormone (LH) levels despite low estradiol or testosterone levels was observed in approximately one third of the hyperprolactinemic subjects of both sexes, but also in a similar proportion of normoprolactinemic ones. However, treatment with bromocriptine resulted in an increase in basal LH in 13 of 16 patients with hyperprolactinemia. These data demonstrate that PRL measured in patients with advanced renal failure is biologically active and that hyperprolactinemia is one of the major factors in the hypogonadism of these patients. In addition, integrated circulating LH after the injection of exogenous luteinizing hormone-releasing hormone (LHRH) was normal, despite prolonged plasma half-life, suggesting that pituitary response was in fact impaired. Unrelated to PRL levels, 47 per cent of the patients had slightly elevated thyroid-stimulating hormone (TSH) levels, with normal total and free thyroxine (T4). Although triiodothyronine (T3) tended to cluster in the low-normal area, reverse-T3 levels were not consistent with preferential deiodination of T4 to reverse-T3. Elevation of the basal TSH levels was, at least in part, due to prolonged plasma half-life of the hormone. These biochemical changes were not related to clinically detectable dysfunction of the thyroid.

Sequential deiodination of thyroxine to 3,3'-diiodothyronine via 3,5,3'-triiodothyronine and 3,3',5'-triiodothyronine in rat liver homogenate. The effects of fasting versus glucose feeding.

The characteristics of thyroxine (T4) deiodination to 3,5,3'-triiodothyronine (T3) and 3,3',5'-triiodothyronine (rT3) and of each of the latter to 3,3'-diiodothyronine (3,3'T2) were examined in rat liver homogenate. Each of the four reactions was enzymatic in nature, demonstrating pH and temperature optima, and tissue and time dependence. All reactions were considerably augmented (greater than 10-fold) by the presence of a thiol agent. At pH 7.2 with 2 muM T4 as substrate, rT3 generation was 3.3 +/- 0.44 (S.E.) and T3 formation was 4.8 +/- 0.57 pmol/min/100 mg of homogenate protein. Fasting for 72 h resulted in a significant inhibition of T4 deiodination, compared to that in the glucose-fed animals, in a 2% homogenate preparation. Enzyme activity for T4 to T3 was reduced by 54% (p less than 0.05) in the homogenate from the fasted rats. Fasting lowered the enzyme activity of T4 to rT3 by 56% (p less than 0.05). Although the monodeiodination of T3 to 3,3'-T2 was also significantly depressed (p less than 0.01) by fasting, rT3 deiodination to 3,3'-T2 was not. The in vitro additon of 5 mM dithioerythritol did not reverse the effect of fasting on any reaction. These results demonstrate that a 72-h fast significantly impairs the sequential deiodination of T4 in liver homogenate. The effect of fasting appears to be mediated mainly through a reduction in enzyme concentration rather than co-factor availability.

Significance of thyrotropin excess in untreated primary adrenal insufficiency.

Thyroid hormones and TSH were assessed before and after steroid replacement in 10 consecutive patients with nontuberculous primary adrenal insufficiency in order to study the numerous interactions between corticosteroids and thyroid function. Although none had clinical features of thyroid disease, 6 showed increased levels of plasma TSH before treatment in association with a wide range of circulating thyroid hormone levels. In 1 patient with positive thyroid autoantibodies, biochemical features of primary hypothyroidism resolved after steroid replacement, although TSH excess has persisted. In 5 patients, 2 of whom had adrenal insufficiency due to metastatic carcinoma, TSH decreased to normal after steroid replacement, and in 3 of these, the TSH decrease occurred without a change in normal circulating thyroid hormone levels, consistent with a direct influence of glucocorticoids on TSH release. Steroid treatment did not cause inverse changes in T3 and rT3, suggesting that physiological levels of adrenal steroids are not major determinants of T4 deiodination. The capacity of T4-binding globulin showed no significant change. These findings suggest two reasons why a high plasma TSH level in untreated adrenal insufficiency can be an unreliable index of thyroid failure. Firstly, thyroid function can return towards normal after corticosteroid replacement. Alternatively, TSH may be increased as a direct result of steroid deficiency without thyroid malfunction. Hence, when TSH is assessed in adrenal insufficiency, a distinction must be made between values obtained before and after adrenal replacement.

Tyrosine hydroxylase and the conversion of L-thyroxine into 3',3,5-triiodo-L-thyronone in the rat.

We have studied the effects of alpha-methyl-p-tyrosine (alpha-MPT), an inhibitor of tyrosine hydroxylase, on the in vivo conversion of L-T4 (T4) to 3',3,5-triiodo-L-thyronine (T3), and on the biological effectiveness of T4. Thyroidectomized rats were used and were injected daily with T4 maintenance doses. Three different types of experiments were carred out. The first involved isotopic equilibration with 125I-labeled T4 and measurement of urinary 125I excretion. The second series involved the injection of a single dose of [125I]T4, with the amounts of [125I]T3 in different tissues being studied 7 or 20 h later. The third series involved daily treatment for 13 days with T4 and alpha-MPT, at the end of ehich the liver alpha-glycerophosphate dehydrogenase activity was measured as a parameter of the biological effects of the hormone. Though the experimental approaches used clearly disclosed the well known effects of 6-propyl-2-thiouracil, no clear-cut effects of alpha-MPT were observed. It is concluded that alpha-MPT neither inhibits the conversion of T4 to T3 in vivo in rats nor affects the biological potency of a given dose of T4, at least to an extent compararble to that observed when 6-propyl-2-thiouracil is used. Thus, present results do not support the hypothesis that tyrosine hydroxylase is involved in the extrathyroidal deiodination of T4 to T3.

Sex-Related Differences in Outer Ring Monodeiodination of Thyroxine and 3,3′,5′-Triiodothyronine by Rat Liver Homogenates*

The present studies were undertaken to evaluate possible sex-related differences in the peripheral outer ring deiodination of T4 to T3 in vitro by fresh liver homogenates. Hepatic T3 generation from T4 in female rats was similar to that observed in age-matched male rats from days 1-24. However, at 30 days of age, a significant decrease in T3 generation was observed in the female rat, becoming more pronounced with increasing age until puberty and then remaining approximately 50% of that observed in age-matched male rats through 90 days of age. In vitro addition of dithiothreitol, a thiol-protecting agent, did not affect these sex-related differences, suggesting a decrease in the 5′-deiodinating enzyme per se in the female rat rather than decreased concentrations of reducing cofactor(s). The sex-related differences in hepatic T4 to T3 conversion are related, at least in part, to sex steroids, since prepubertal castration at 20 days of age prevented these sex-related changes, and peripubertal castration at 4...