Alterations in 3,3'5'-triiodothyronine metabolism in response to propylthiouracil, dexamethasone, and thyroxine administration in man.

To elucidate the mechanisms involved in altering serum 3,3',5'-triiodothyronine (rT3) levels with absolute or relative low 3,5,3'-triiodothyronine (T3) states in man, agents capable of lowering circulating T3 levels were sequentially administered to six euthyroid subjects. These agents included propylthiouracil (PTU) (300 mg/6 h X 5 d), dexamethasone (DEX) (2 mg/6 h X 5 d), and thyroxine (T4) (3.0 mg load and 0.3 mg/d X 5 d). [125I] rT3 clearance rates and rT3 production rates were then determined. Increased serum rT3 levels and rT3/T4 values occurred with both PTU and DEX as compared with control, while T4 increased serum rT3 but did so without changing rT3/T4 values. The rT3 clearance rate was significantly decreased by PTU without altering production rate, while DEX increased the rT3 production rate without altering the rT3 clearance rate. T4 administration did not change rT3 clearance but proportionately increased rT3 production. These responses indicate that circulating rT3 predominantly originates from a non-PTU inhibitable deiodinase enzyme system located in extrahepatic tissues. This enzyme system appears to have a high capacity and low affinity for T4 and can be stimulated by DEX administration.

Increased urinary excretion of sulfated 3,3',5-triiodothyronine in patients with nodular goiters receiving suppressive thyroxine therapy.

Increased serum 3,3',5-triiodothyronine sulfate (T3S) levels have been detected in various pathophysiologic states. However, little is known about T3S concentrations in other biological fluids. By employing a highly sensitive, specific, and reproducible radioimmunoassay (RIA), we measured T3S in the serum and urine of 20 premenopausal women with benign nodular goiters before and after administration of thyroxine for 6 months (T4; 3.2 micrograms/kg/day). Serum T3 concentrations did not change significantly after treatment (2.0 vs. 1.7 nmol/L; p > 0.05). However, the mean serum T4 and free T4 concentrations were significantly higher after treatment (138 vs. 88 nmol/L and 28 vs. 17 pmol/L; p < 0.01, respectively). Serum thyroid stimulating hormone (TSH) levels were significantly reduced after T4 treatment (0.13 vs. 0.66 mU/L, p < 0.01) and the serum levels of T3S were significantly increased after treatment (82 vs. 45 pmol/L; p < 0.01). A good correlation was observed between increased serum T3S and T4 concentrations (r = 0.66; p < 0.001). The sulfoconjugate of T3 was significantly increased in creatinine-corrected urine after treatment (606 vs. 253 pmol/umol Cr.; p < 0.01). There was a significant correlation between increased creatinine-corrected urine T3S and increased serum free T4 (r = 0.65; p < 0.001). In summary, significant increases in serum and urine T3S levels were noted in T4-treated patients with subnormal serum TSH and borderline elevated T4. We thus conclude that the sulfation pathway may play a role in the homeostasis of thyroid hormone metabolism in T4-treated subjects with relative hyperthyroxinemia. In addition, the creatinine-corrected urine concentrations of T3S may serve as an index for the evaluation of T4-treated patients with elevated levels of T4.

Thyroxine, 3,5,3' -triiodothyronine and 3,3', 5' -triiodothyronine in human amniotic fluid: relationships between concentrations and turnover.

We have made estimates of the possible contributions of various routes of entry and disposal to the turnover of thyroxine (T4), 3,5,3'-triiodothyronine (T3) and 3,3',5'-triiodothyronine (reverse T3, rT3) in human amniotic fluid (AF). Our calculations suggest that, in normal pregnancy, AF T4 and T3 are derived mainly from the maternal circulation, and that their concentrations depend very largely on binding-protein concentrations. The majority of AF rT3 is unlikely to enter the amniotic sac directly from the maternal circulation, or from the fetal circulation by passive diffusion or fetal urinary excretion; however, our calculations are consistent with the hypothesis it is derived largely from inner-ring deiodination of T4 in the fetal membranes. We propose that the molar ratio of one AF iodothyronine to another may yield more information about fetal thyroid status than the total concentration of any single iodothyronine.

Urinary excretion of 3,3',5'-triiodothyronine (reverse T3).

A simple and sensitive radioimmunoassay for reverse T3 in urine using small Sephadex G25 fine columns is described. The recovery of rT3 added to urine was on average 101.0 +/- 4.2% (mean +/- SEM). Detection limit was 4 pg/column. Urine excretion of rT3 (mean +/- SD) was 72.0 +/- 32.1 ng/24 h in 61 healthy euthyroid subjects with a slight increase with age (P less than 0.05), 28.8 +/- 18.2 ng/24 h in 12 hypothyroid patients and 183.6 +/- 79.7 ng/24 in 25 hyperthyroid patients.

Renal handling of iodothyronines in acromegaly.

Measurement of the free serum concentration, the 24-h urinary excretion and the renal clearance of T4, T3, 3,3',5'-tri-iodothyronine (rT3), 3',5'-diiodothyronine (3',5'-T2) and 3,3'-di-iodothyronine (3,3'-T2) was performed in 13 patients with active acromegaly and in 18 healthy controls. The acromegalic patients had normal serum levels of the free iodothyronines, whereas the urinary excretion of T4 and T3 was increased approximately two-fold in the patients with acromegaly. The creatinine clearance, reflecting the glomerular filtration rate (GFR), was increased in the acromegalic patients, in median 133 ml/min versus 87 ml/min (p less than 0.01) in the controls. Compared to the creatinine clearance the clearance of T3 and 3,3'-T2 was higher (p less than 0.01) in acromegalics as well as in controls. The patients with acromegaly had higher renal clearance of T4 and T3 than controls, in median 81 ml/min versus 33 ml/min, and 269 ml/min versus 137 ml/min, respectively (p less than 0.01). These differences were not due to changes in creatinine clearance. The renal clearance of 3',5'-T2 tended to be enhanced in acromegalic patients (8.2 ml/min versus 3.9 ml/min, p less than 0.10), both before and after correction for creatinine clearance. The data suggest that in acromegaly, as in normal condition, iodothyronines are subject to both glomerular filtration and active tubular transport mechanisms. Further, active acromegaly results not only in increased GFR, but also in changes of the net tubular transport in favour of secretion of at least T4 and T3, and possibly also of 3',5'-T2.

Urinary excretion of thyroxine, triiodothyronine, 3,3',5'-triiodothyronine (reverse T3) and renal function in human newborns.

The urinary excretion and serum levels of thyroxine (T4), triiodothyronine (T3) and 3,3',5'-triiodothyronine (reverse T3) was estimated in a longitudinal study of human newborns. The maternal and cord blood was also studied. Neonatal renal function was evaluated using endogenous creatinine clearance. In cord blood serum T3 was found to be lower than in maternal blood, but reverse T3 highly elevated. During the first 5 days of life serum T4 and T3 increased with maximum at 48 and 24 h in contrast to reverse T3 which remained high and then declined rapidly after 4 days. Creatinine clearance during the first 3 days of life increased from 5.3 to 21.9 ml/min/1.73 m2. In the same period the urinary T4 excretion increased from 79 to 281 ng/24 h, urinary T3 excretion from 16 to 44 ng/24 h and urinary reverse T3 from 4 to 15 ng/24 h. The renal excretion of thyroid hormones, corrected for body surface, was decreased compared to adult controls, corresponding to an immature renal function. The lack of ability to excrete thyroid hormones involved primary T3 and reverse T3 suggesting particular immaturity of tubular secretion of these hormones during the neonatal period.