Thyroxine sulfate is a major thyroid hormone metabolite and a potential intermediate in the monodeiodination pathways in fetal sheep.

T3 and rT3 production rates in the fetus account for roughly only a third of the total T4 production rate; thus, the fate of the majority of T4 produced in the fetus is unknown (the "T4 disposal gap"). We developed sensitive and specific T4 sulfate (T4S) and T3 sulfate (T3S) RIAs to investigate the roles of these compounds in fetal T4 metabolism. T3, T4, T3S, and T4S were determined in a variety of tissue fluid and/or serum samples obtained from fetal, newborn (n = 6), and adult (n = 6) sheep. Four groups of fetal animals, with gestational ages of 94 days (n = 5), 110-111 days (n = 6), 130-131 days (n = 6), and 145 days (n = 6; term = 150 days), were studied. In addition, type I 5'-monodeiodinase (5'-MDI) activity was quantified in liver and kidney tissues. 5'-MDI activities were lower in 94- to 131-day-old fetuses than in fetuses near term or in newborn animals. Mean serum T3 concentrations increased progressively from 94 days (19 ng/dl) to term (371 ng/dl), while mean T3S and T4S serum concentrations were highest at 130 days gestation (237 and 989 ng/dl), decreasing to term. Serum T3S and T4S concentrations decreased further in newborns and adult sheep. T4S and T3S levels in allantoic fluid were significantly higher than those in urine and amniotic fluid in all fetal age groups studied. T4S levels in bile were high from 94-130 days gestation (873-1006 ng/dl), decreasing by 50% at term (529 ng/dl). T4S concentrations in meconium were 46- to 83-fold higher than those in bile from 94 days gestation to term. In contrast, bile T3S levels increased progressively from 94-145 days gestation (191-605 ng/dl), while meconium T3S levels decreased during the same period (33-14 micrograms/100 g). These data demonstrate that 1) sulfated iodothyronines, particularly T4S, are major thyroid hormone metabolites in the fetus; 2) both T4S and T3S are excreted into bile and urine and concentrated in meconium and allantoic fluid; and 3) the high levels of T4S and T3S in serum and other fluids may reflect lower tissue type I 5'-MDI activities. We speculate that T4S and T3S may be further metabolized to other sulfated metabolites and may account in part for the T4 disposal gap in fetal sheep.