triiodothyronine--reverse and triiodothyronine-sulfate

The pattern of circulating iodothyronines in the fetus differs from that in the adult, being characterized by low levels of serum T3. In this study, concentrations of various iodothyronines were measured in sera from neonates of various postconceptional age (PA). Results obtained in cord sera at birth (PA, 24-40 weeks), reflecting the fetal pattern, were compared with those found during extrauterine life in newborns of 5 days or more of postnatal life (PA, 27-46 weeks). The main findings are: Starting at 30 weeks of PA, serum levels increase linearly during extrauterine life; and at 40 weeks, they are more than 200% of those measured in cord sera from newborns of equivalent PA. Serum reverse T3 (rT3) levels during fetal life are higher than those measured during extrauterine life; but they significantly decrease, starting at 30 weeks of PA. Serum T3 sulfate (T3S) does not significantly differ between the two groups, showing the highest values at 28-30 weeks of PA, and significantly decreasing at 30-40 weeks. T3S levels are directly correlated with rT3, both in fetal and extrauterine life, whereas a significant negative correlation between T3S and T3 is found only during extrauterine life.. 1) changes in serum concentrations of iodothyronines in umbilical cord and during postnatal life indicate that maturation of extrathyroidal type I-iodothyronine monodeiodinase (MD) accelerates, starting at 30 weeks of PA; 2) high levels of type III-MD activity in fetal tissues prevent the rise of serum T3, whereas they maintain high levels of rT3 during intrauterine life; 3) an important mechanism leading to the transition from the fetal to the postnatal thyroid hormone balance is a sudden decrease in type III-MD activity; iv) because placenta contains a high amount of type III-MD, it is conceivable that placenta contributes to maintain low T3 and high rT3 serum concentrations during fetal life and that its removal at birth is responsible for most changes in iodothyronine metabolism occurring afterwards.

Topics: Female; Fetal Blood; Gestational Age; Homeostasis; Humans; Infant, Newborn; Iodide Peroxidase; Placenta; Pregnancy; Thyroid Hormones; Triiodothyronine; Triiodothyronine, Reverse

Abnormalities in thyroid function are observed in patients with end stage renal disease. However, there are no data available evaluating sequential changes of thyroid function after renal transplantation. Therefore, we have studied thyroid hormone function in the immediate post-operative period after renal transplantation in order to determine the relationship between improving renal function and changes in thyroid hormone economy.. Thyroid function was evaluated in 22 patients before and on days 1, 3, 7 and 15 after renal transplantation. All patients received prednisone and cyclosporin as immunosuppressive therapy. Twelve patients with normal renal function undergoing comparable surgical procedures served as a control group.. Serum creatinine and thyroid hormone parameters (total T4, total T3, free T4, free T3, thyroxin binding globulin (TBG), reverse T3, T3 sulphate and TSH) were measured.. According to post-operative kidney function after renal transplantation, patients could be subdivided into three groups: five patients had primary graft function (group I); seven patients had delayed graft function because of acute renal failure (group II); 10 patients had delayed graft function requiring high doses of prednisone and some also of OKT3 because of acute rejection (group III). There was a significant fall in T3 and T4 concentrations with a concomitant rise in reverse T3 in all patients up to 3 days after renal transplantation. However, only patients in group I reached pre-operative values on day 15 after renal transplantation (serum creatinine 167 +/- 52 microM), whereas patients in group II (creatinine 609 +/- 118 microM) and group III (creatinine 839 +/- 71 microM) continued to have T3 concentrations well in the hypothyroid range (group I, 1.68 +/- 0.28 nM) vs 0.87 +/- 0.09 nM in group II and 0.76 +/- 0.10 nM in group III; P < 0.01). Serum T4 concentrations were also low in group III (47.7 nM vs 100.2 nM in group I; P < 0.05) 15 days after renal transplantation. These changes were accompanied by a concomitant fall in T3/TBG ratio and in free T3. Elevated reverse T3 returned to normal values in all groups on the 15th day after renal transplantation. TSH fell significantly on the first post-operative day, but did not return to pre-operative values in renal transplantation patients. In the control group, TSH did not change during the study period. T3 sulphate, known to be elevated in chronic renal failure, remained above normal in all patients irrespective of graft function during this study period.. T3 concentrations reflect renal graft function after renal transplantation. T3 is below normal in patients with delayed graft function (acute renal failure or acute rejection). The post-operative period (up to 3 days after renal transplantation) is associated with a low T3 syndrome. TSH does not return to pre-operative values even in patients with primary graft function. This might be due to the administration of prednisone. T3-sulphate is elevated before and after renal transplantation irrespective of graft function.

Topics: Acute Kidney Injury; Adult; Biomarkers; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Postoperative Period; Prednisolone; Thyroid Gland; Thyrotropin; Thyroxine; Thyroxine-Binding Proteins; Triiodothyronine; Triiodothyronine, Reverse

Factors that contribute to the remarkably rapid decrease in serum T3 and increase in reverse T3 (rT3) levels during illness, fasting, or treatment with some drugs (e.g. amiodarone) are not clear. In order to understand better the effect of acute amiodarone administration on T3 metabolism, especially the sulphation pathway, we performed a prospective study in 8 arrhythmic in-patients treated with a loading dose of amiodarone.. Amiodarone was administered by i.v. infusion of 20 mg/kg/day on day 1 and 10 mg/kg/day on day 2, followed by 600 mg/day orally throughout the study. Two serum samples for amiodarone and hormone assays (thyroid hormones, TSH, and the sulphate metabolites of 3'-T1, 3,3'-T2, and T3) were collected before the start of therapy, every 12 h during the first 3 days of amiodarone administration, and then once a day for 2-10 days.. Eight patients (4 men and 4 women, aged 44-82 years), who were treated with amiodarone because of cardiac dysrhythmia, were enrolled in the study.. Serum concentrations of total T4 significantly increased in the last 3 days of the study (ANOVA, P = 0.0002). However, serum total T3 progressively and significantly decreased throughout the study (ANOVA, P < 0.0001). Serum free thyroid hormone concentrations (free T3 and free T4) did not significantly change during the study. Serum rT3 (ANOVA, P < 0.0001) and TSH (ANOVA, P = 0.0009) rapidly and progressively increased throughout the study. Starting from the first 24 h, serum concentrations of T3 sulphate (T3-S) significantly and progressively increased from (mean +/- SD) 0.057 +/- 0.029 nmol/l under basal conditions to 0.089 +/- 0.036 nmol/l after 5 days of amiodarone therapy (ANOVA, P = 0.0011). Since total T3 levels progressively decreased throughout the study, the ratio of the T3-S and total T3 values progressively increased from 4.8 +/- 2.7% under basal conditions to 10.6 +/- 7.3% after 5 days of amiodarone therapy (ANOVA, repeated measures, P < 0.0001). Basal serum concentrations of sulphate metabolites of T2 (T2-S, 2.22 +/- 1.7 nmol/l) and T1 (T1-S, 1.29 +/- 0.74 nmol/l) did not significantly change throughout the study.. Our data indicate that a loading dose of intravenous amiodarone in patients with cardiac dysrhythmias is followed by a very rapid and progressive increase in circulating T3-S levels, possibly due to an inhibition of type 1-iodothyronine de-iodinase. Since T2-S and T1-S, common final metabolites of the thyroid hormone sulphation pathways remained unchanged, our data suggest that the total amount of thyroid hormone degraded by sulphation pathways remains unaltered during amiodarone treatment. Finally our findings are compatible with the view that sulphation represents an important pathway for T3 metabolism in vivo in man.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Amiodarone; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Drug Administration Schedule; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Prospective Studies; Thyrotropin; Thyroxine; Time Factors; Triiodothyronine; Triiodothyronine, Reverse

Sulfation is an important pathway of triiodothyronine (T3) metabolism. Increased serum T3 sulfate (T3S) values have been observed during fetal life and in pathological conditions such as hyperthyroidism and selenium deficiency. Similar variations have also been reported in a small number of patients with systemic non-thyroidal illness, but the underlying mechanisms have not been elucidated. In this study, serum T3S concentrations have been measured by a specific radioimmunoassay in 28 patients with end-stage neoplastic disease (ESND) and in 44 patients with chronic renal failure (CRF); 41 normal subjects served as controls. Both ESND and CRF patients had lower serum total T4 (TT4) and total T3 (TT3) than normal controls, while serum reverse T3 (rT3) was increased significantly in ESND (0.7 +/- 0.5 nmol/l; p < 0.001 vs. controls) but not in CRF (0.3 +/- 0.1 nmol/l). The TT3/rT3 ratio, an index of type I iodothyronine monodeiodinase (type I MD) activity, was reduced significantly in both groups of patients. Serum T4-binding globulin (TBG) was decreased in CRF but not in ESND patients. Serum T3S was significantly higher both in ESND (71 +/- 32 pmol/l) and CRF (100 +/- 24 pmol/l) than in controls (50 +/- 16 pmol/l, p < 0.001). Serum T3S values showed a positive correlation with rT3 values and a negative correlation with both TT3 and FT3 values in ESND, but not in CRF. In the latter group a positive correlation was observed between T3S and TBG values. The T3S/FT3 ratio was higher both in CRF (18 +/- 5) and in ESND (23 +/- 18) as compared to controls (10 +/- 4). Serum inorganic sulfate was increased and correlated positively with T3S values in CRF patients. In conclusion, the results of this study in a large series of patients confirm that patients with systemic non-thyroidal illness have increased serum T3S levels. The mechanisms responsible for these changes appear to be different in ESND and CRF patients. In ESND the increase in serum T3S levels is mainly related to reduced degradation of the hormone by type I MD, whereas in CRF it might be driven by the enhanced sulfate ion concentration, and could be partially dependent on the impaired renal excretion of T3S. Because T3S can be reconverted to T3, it is possible that increased T3S concentrations contribute to maintenance of the euthyroid state in systemic non-thyroidal disease.

Topics: Adult; Aged; Humans; Kidney Failure, Chronic; Middle Aged; Neoplasms; Osmolar Concentration; Triiodothyronine; Triiodothyronine, Reverse

Although the production of thyroxine (T4) in the developing ovine fetus ranges from 20 to 50 micrograms.kg-1.day-1, production rates for 3,5,3'-triiodothyronine (T3) average only 1-2 micrograms.kg-1.day-1, whereas reverse T3 (rT3) production rates approach 5-6 micrograms.kg-1.day-1. Thus the fate of the majority of fetal T4 production is uncertain. Recently we have reported significant concentrations of various thyroid hormone sulfoconjugates in serum and other fetal compartments. In the present study, we used steady-state kinetic techniques in developing sheep to establish the clearance and production rates for T4, T3, and rT3 sulfates. These studies confirm that T4, T3, and rT3 sulfate are predominant metabolites of thyroid hormone in the developing ovine fetus. Plasma clearance rates for T3, T4, and rT3 sulfates are low in the fetus, averaging 0.67 +/- 0.07, 1.46 +/- 0.11, and 4.1 +/- 1 ml.kg-1.min-1, respectively. Clearance rates for these thyrosulfoconjugates increase two to fourfold postnatally, probably reflecting increased activity of 5'-monodeiodinase after birth. Moreover, fetal production rates for these sulfated thyroid hormone metabolites exceed those of 2-wk-old sheep 4- to 10-fold. The data suggest that a significant route of fetal T4 metabolism is sulfation followed by deiodination to rT3 sulfate.

Topics: Aging; Animals; Animals, Newborn; Embryonic and Fetal Development; Fetal Blood; Sheep; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

We recently showed that thyroxine sulfate (T4S) and 3,3',5-triiodothyronine sulfate (T3S) were major thyroid hormone metabolites in ovine fetuses and neonates. To further characterize the sulfation pathway in ovine fetuses, we measured 3,3',5'-triiodothyronine (rT3S) in serum and other body fluids in samples obtained from fetal (n = 23, 94-145 days of gestational age, term = 150 days), newborn (n = 6), and adult (n = 6) sheep. In addition, T3S, T4S, and rT3S levels were measured in tissue fluids and serum samples obtained from ovine fetuses 13 days after total thyroidectomy (Tx) conducted at gestational age of 110-113 days (n = 5). Sham-operated twin fetuses served as controls (n = 5). The relative order of mean rT3S concentration for various tissue fluids in fetuses were meconium > bile > serum > allantoic fluid > urine or amniotic fluid. Peak mean tissue fluid levels generally occurred at 110-130 days gestation. In hypothyroid fetuses, significant decreases in the mean serum concentrations of T4S and rT3S, but not T3S, were noted. The mean rT3S level also was decreased significantly in allantoic fluid, bile, and meconium, whereas T4S and T3S levels were reduced only in bile of the Tx fetuses. These data demonstrate that sulfation is a major pathway in thyroid hormone metabolism in both euthyroid and hypothyroid ovine fetuses.

Topics: Animals; Body Fluids; Fetal Diseases; Fetus; Hypothyroidism; Sheep; Sulfates; Thyroidectomy; Thyronines; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

In humans deiodination and perhaps glucuronidation are important pathways of thyroid hormone metabolism. In animals, sulfation plays an important role in T4 and especially in T3 metabolism, but little is known about sulfate conjugation of thyroid hormone in humans. In this study we used a specific T3 sulfate (T3S) RIA to address this question. Eight normal subjects were given oral T3 (1 microgram/day.kg BW) for 7 weeks. During the fifth week they also received propylthiouracil (PTU; four doses of 250 mg/day) for 2 days and during the seventh week iopanoic acid (IOP; 1 g/day) for 3 days. The mean pre-T3 serum iodothyronine values were: T4, 92 +/- 6 (+/- SE) nmol/L; rT3, 0.24 +/- 0.02 nmol/L; T3, 2.30 +/- 0.10 nmol/L; and T3S, less than 0.1 nmol/L (at or below the detection limit of the RIA). After 4 weeks of T3 administration the mean serum values were: T4, 39 +/- 6; rT3, 0.11 +/- 0.01; T3, 5.31 +/- 0.39; and T3S, 0.10 +/- 0.01 nmol/L. After 2 days of PTU administration, mean serum T4 increased to 48 +/- 7 (P less than 0.005), rT3 to 0.20 +/- 0.03 (P less than 0.025), and T3S to 0.13 +/- 0.01 nmol/L (P = NS), but serum T3 did not change (4.91 +/- 0.35 nmol/L). The effect of IOP was more pronounced; after its administration for 3 days the mean serum T4 was 49 +/- 8 (P less than 0.001), rT3 was 0.48 +/- 0.09 (P less than 0.005), and T3S was 0.29 +/- 0.04 nmol/L (P less than 0.005), and serum T3 decreased to 3.95 +/- 0.25 nmol/L (P less than 0.005). The T3S/T3 ratio was increased by PTU from 0.018 +/- 0.003 to 0.024 +/- 0.004 (P less than = NS) and by IOP to 0.055 +/- 0.007 (P less than 0.005). In conclusion, 1) serum T3S is virtually undetectable (less than 0.1 nmol/L) in normal subjects; 2) low serum T3S concentrations are detected in humans given T3; 3) serum T3S in T3-treated subjects is increased by inhibition of type I deiodinase activity with PTU and especially IOP; and 4) in comparison with previous estimates of the serum T3S/T3 ratio in rats, the low ratio in humans may indicate that sulfation is not an important mechanism of T3 metabolism in humans and/or the kinetics of plasma T3 and T3S differ in humans and rats.

Topics: Adult; Female; Humans; Iopanoic Acid; Male; Propylthiouracil; Radioimmunoassay; Reference Values; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

In contrast to the glucuronide conjugate, T3 sulfate (T3S) undergoes rapid deiodinative degradation in the liver and accumulates in rats and rat hepatocyte cultures if type I iodothyronine deiodinase activity is inhibited. We here report the RIA of plasma T3S in rats treated with the antithyroid drugs propylthiouracil (PTU) or methimazole (MMI), of which only PTU inhibits type I deiodinase. Male Wistar rats were treated acutely by ip injection with 1 mg PTU or MMI/100 g BW and subsequently for 4 days by twice daily injections with these drugs together with 0.5 microgram T4 or 0.25 microgram T3/100 g BW. Blood was obtained 4 h after the last injection, and plasma T4, rT3, T3, and T3S were determined by RIA and compared with pretreatment values. Serum concentrations (mean +/- SEM; nanomoles per liter) in untreated rats were: T4, 51 +/- 1; T3, 1.37 +/- 0.03; T3S, 0.09 +/- 0.01; and rT3, 0.03 +/- 0.002. Serum T3 was decreased, and T3S and rT3 were increased by acute PTU treatment [T3, 1.16 +/- 0.05 (P less than 0.01); T3S, 0.33 +/- 0.04 (P less than 0.001); rT3, 0.27 +/- 0.02 (P less than 0.001)], but unaffected by acute MMI treatment (T3, 1.37 +/- 0.05; T3S, 0.09 +/- 0.01; rT3, 0.02 +/- 0.003). In T4-treated rats, serum T3 was decreased and T4, T3S, and rT3 were increased by PTU vs. MMI [T4, 86 +/- 5 vs. 58 +/- 4 (P less than 0.001); T3, 0.51 +/- 0.07 vs. 0.88 +/- 0.06 (P less than 0.001); T3S, 0.38 +/- 0.03 vs. 0.12 +/- 0.01 (P less than 0.001); rT3, 0.86 +/- 0.19 vs. 0.08 +/- 0.01 (P less than 0.005)]. In T3-substituted rats T3S was increased by PTU vs. MMI (1.09 +/- 0.13 vs. 0.25 +/- 0.03; P less than 0.001). The T3S/T3 ratio in the PTU-treated T3 -replaced rats (0.60 +/- 0.09) was in agreement with that determined by HPLC of serum radioactivity in animals that in addition to this treatment also received about 10 microCi [125I]T3 with the last two injections (0.92 +/- 0.13). In conclusion, this investigation demonstrates the feasibility of the measurement of serum T3S by RIA. Our findings confirm previous observations with radioactive isotopes, suggesting that sulfation is an important pathway for the metabolism of T3 in rats. Analogous to rT3, the accumulation of T3S in PTU-treated rats indicates that this conjugate is metabolized predominantly by type I deiodination.

Topics: Animals; Iodide Peroxidase; Isoenzymes; Male; Methimazole; Propylthiouracil; Radioimmunoassay; Rats; Rats, Inbred Strains; Reference Values; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Previous studies have shown that the inner ring deiodination (IRD) of T3 and the outer ring deiodination (ORD) of 3,3'-diiodothyronine are greatly enhanced by sulfate conjugation. This study was undertaken to evaluate the effect of sulfation on T4 and rT3 deiodination. Iodothyronine sulfate conjugates were chemically synthetized. Deiodination was studied by reaction of rat liver microsomes with unlabeled or outer ring 125I-labeled sulfate conjugate at 37 C and pH 7.2 in the presence of 5 mM dithiothreitol. Products were analyzed by HPLC or after hydrolysis by specific RIAs. T4 sulfate (T4S) was rapidly degraded by IRD to rT3S, with an apparent Km of 0.3 microM and a maximum velocity (Vmax) of 530 pmol/min X mg protein. The Vmax to Km ratio of T4S IRD was increased 200-fold compared with that of T4 IRD. However, formation of T3S by ORD of T4S could not be observed. The rT3S formed was rapidly converted by ORD to 3,3'-T2 sulfate, with an apparent Km of 0.06 microM and a Vmax of 516 pmol/min X mg protein. The enzymic mechanism of the IRD of T4S was the same as that of the deiodination of nonsulfated iodothyronines, as shown by the kinetics of stimulation by dithiothreitol or inhibition by propylthiouracil. The IRD of T4S and the ORD of rT3 were equally affected by a number of competitive inhibitors, suggesting a single enzyme for the deiodination of native and sulfated iodothyronines. In conjunction with previous findings on the deiodination of T3S, these results suggest that sulfation leads to a rapid and irreversible inactivation of thyroid hormone.

Topics: Animals; Diiodothyronines; Dithiothreitol; Iodide Peroxidase; Iodine Radioisotopes; Kinetics; Microsomes, Liver; Peroxidases; Propylthiouracil; Rats; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse