No abstract

Using a previously reported in vivo isotopic displacement technique, we have demonstrated limited nuclear binding sites for L-triiodothyronine (T 3 ) in the following rat tissues: liver, kidney, heart, anterior pituitary, brain, spleen and testis. The concentration of these sites expressed both per mg DNA and per g tissue (wet wt) varied widely. If liver is normalized to 1, the relative binding capacity per mg DNA is: pituitary, 1.3; liver, 1.0; kidney, 0.87; heart, 0.65; brain, 0.44; spleen, 0.03; testis, 0.004. The relative binding capacity per g tissue is: pituitary, 3.7; kidney, 1.5; liver, 1.0; heart, 0.45; brain, 0.24; spleen, 0.18; and testis, 0.01. Approximately 40-50% of available sites are saturated at endogenous levels of circulating T 3 and the calculated association constants of nuclear binding appear similar in the various tissues studied. The relatively low concentration of binding sites in brain, spleen, and testis is of interest since these tissues do not respond to thyroid hormone with the expected increase in oxygen consumption and in the level of mitochondrial alphaglycerophosphate dehydrogenase. A high proportion (53%) of cellular T 3 in the anterior pituitary is associated with specific nuclear sites and accounts for our previous demonstration of limited capacity sites in unfractionated pituitary. (Endocrinology 95: 897, 1974) W E have previously reported the existence of limited capacity high affinity triiodothyronine (T 3 ) binding sites in the nuclei of rat liver and kidney (1). Hormone bound to these sites exchanges readily with T 3 in cytoplasm (2). The nuclear binding site has been identified as a nonhistone nuclear protein of molecular weight 60-65,000 (3). The structural requirements of iodothyronines for nuclear binding have been detailed in the intact animal (4) and in vitro (5). When account is taken of differences in the metabolism and distribution of the analogues tested, a strong correlation was observed between the published hormonal potencies of the analogues and their ability to bind liver and heart nuclei. In light of the earlier studies by Tata and associates (6,7) indicating that the effect of T 3 is mediated by the formation of new RNA, our findings sug-

Metabolic balance studies were carried out to determine the interrelationships of thyroid hormone-induced lipogenesis, Hipolysis, and energy balance in the free-living rat. Intraperitoneal doses of 15 ;&g triiodothyronine (T3)/100 g body wt per d caused an increase in caloric intake from 26.5±1.7 (mean±SEM) kcal/100 g per d to 38.1±1.5 kcal/100 g per d. Food intake, however, rose only after 4-6 d of treatment and was maximal by the 8th day. In contrast, total body basal oxygen consumption rose by 24 h and reached a maximum by 4 d. Since total urinary nitrogen excretion and hepatic phosphoenolpyruvate carboxykinase mRNA did not rise, gluconeogenesis from protein sources did not supply the needed substrate for the early increase in calorigenesis. Total body fat stores fell -50% by the 6th day of treatment and could account for the entire increase in caloric expenditure during the initial period of T3 treatment. Total body lipogenesis increased within 1 d and reached a plateau 4-5 d after the start of T3 treatment. 15-19% of the increased caloric intake was channeled through lipogenesis, assuming glucose to be the sole substrate for lipogenesis. The metabolic cost of the increased lipogenesis, however, accounted for only 3-4% of the T3-induced increase in calorigenesis. These results suggest that fatty acids derived from adipose tissue are the primary source of substrate for thyroid hormoneinduced calorigenesis and that the early increase in lipogenesis serves simply to maintain fat stores. Since the mRNAs coding for lipogenic enzymes rise many hours before oxygen consumption and lipolysis, these results suggest that T3 acts at least in part by an early coordinate induction of the genes responsible for these processes. (J. Clin. Invest. 1991. 87:125-132.)

A change in the formulation of the levothyroxine preparation Synthroid (Flint) in 1982 prompted us to reevaluate the replacement dose of this drug in 19 patients with hypothyroidism. The dose was titrated monthly until thyrotropin levels became normal. The mean replacement dose (+/- SD) was 112 +/- 19 micrograms per day, significantly less (P less than 0.001) than the dose of an earlier formulation--169 +/- 66 micrograms per day--used in a similar study (Stock JM, et al. N Engl J Med 1974; 290:529-33). The fractional gastrointestinal absorption of a tablet of the current formulation is 81 percent, considerably higher than the earlier estimate of 48 percent. Using high-performance liquid chromatographic analysis, we found that the current tablet contains the amount of thyroxine stated by the manufacturer. By measuring the bioavailability of the earlier type of tablet in five patients, we inferred that the strength of the previous tablet had been overestimated. In the present study, the thyrotropin levels of patients on replacement therapy returned to normal when serum triiodothyronine concentrations were not significantly different from those of controls (122 vs. 115 ng per deciliter [1.87 vs. 1.77 nmol per liter]), but when serum thyroxine levels were significantly above those of controls (11.3 vs. 8.7 micrograms per deciliter [145 vs. 112 nmol per liter], P less than 0.001). These findings suggest the possibility that in humans, serum triiodothyronine may play a more important part than serum thyroxine in regulating the serum thyrotropin concentration.

Serum thyroxine (T4) and triiodothyronine (T3) concentration and binding were measured in 34 clinically euthyroid patients hospitalized for a wide variety of nonthyroidal diseases. Despite clinical euthyroidism, serum T3 was in the hypothyroid range (less than 90 ng/100 ml) in 24 of the 34 patients, and the mean serum T3 of this group, 78.4 +/- 38.3 (SD), was significantly decreased from that of control, 134.0 +/- 29.3 ng/200 ml. Mean serum T4 levels were essentially the same in both groups, 7.3 +/- 2.0 for sick patients and 7.2 +/- 1.0 mug/100 ml for the controls. Plasma binding of both T4 and T3 was decreased in the patient group to 69.9 and 78% of control values, respectively. In accord with previous studies, the mean free T4 index, proportional to free T4 concentration, was significantly increased to 10.0 +/- 4.1 in the patient group (control, 7.6 +/- 1.3). However, the mean free T3 index of the patient group, 92.9 +/- 38.4 remained decreased from that of control, 138.9 +/- 34.4. Of the 24 patients with decreased serum T3 (less than 90 ng/100 ml), low T3 levels could be attributed to decreased plasma binding in 8; in 5, serum T3 was within the normal range for their advanced age. Mean TSH was greater in the patient group 2.6 +/- 1.9, than in the controls, 1.9 +/- 1.1 muU/ml. Moreover, the TSH response to administered TRH was moderately exaggerated in 7 patients with low free T3 index compared to 7 patients with normal free T3 index. Although significant statistically, neither the basal nor TRH induced TSH levels were in the range generally found in primary hypothyroidism. The data suggest that the high incidence of low serum T3 (70%) and free T3 index (32%) in nonthyroidal disease may be related to the catabolic state that accompanies illness rather than to specific disease entities. At the present time, the use of serum T3 or free T3 measurements for the diagnosis of hypothyroidism does not appear justified in patients with nonthyroidal disease.