Determinants of Iodothyronine Deiodinase Activities in Rodent Uterus

Abstract

The deiodinase types 2 and 3 (D2, D3), which convert T4 to active and inactive metabolites, respectively, are expressed in the rodent uterus and highly induced during pregnancy. To examine the factors regulating the expression of these enzymes in this tissue, we studied D2 and D3 activity in pregnant rats, in pseudopregnant rats before and after the induction of artificial decidualization, and in ovariectomized rats treated with 17beta-estradiol (E2) and/or progesterone (P). Our results demonstrate that induction of D3 activity begins immediately after implantation and increases markedly over the next 72 h. A similar time course and magnitude of D3 induction is noted in the artificially decidualized uterus in pseudopregnant rats, whereas only minimal increases in activity are observed in the nondecidualized control uterine horns in the same animal. In contrast, D2 activity is not induced by a decidualization stimulus. In spontaneously cycling female rats, both D2 and D3 were observed to be 3- to 8-fold higher in proestrus, compared with diestrus. Furthermore, levels of D2 and D3 activity were greatly increased in ovariectomized rats given E2 and P in various combinations. D2 activity was stimulated primarily by E2, whereas E2 and P acted synergistically to increase D3 activity. These results demonstrate that E2 and P regulate thyroid hormone metabolism in the uterus, and that the implantation process is a potent stimulus for the induction of D3 activity in this organ. Such precise and profound changes in deiodinase expression are likely to play important physiological roles in fetal development and may influence uterine function.

Iodine deficiency and brain development in the first half of pregnancy

“…There is also an increased degradation of the iodothyronines by the very high activity of D3 in the uterine-placental unit, possibly a consequence of the increased oestrogen concentration 42 . The increase in size of the maternal T 4 pool early in pregnancy has not yet been defined precisely, and may differ in the same woman between pregnancies.…”

“…This impairment is not necessarily detected if the mother's serum TSH concentration is being measured because the concentration usually remains within the normal range in iodine deficient women who are otherwise healthy. On the contrary, both an increase in the serum T 3 /T 4 ratio and the thyroglobulin (Tg) concentration above the normal range for pregnant women reflect an increasing degree of maternal ID 40,42 . This is discussed further below.…”

Deiodinases: implications of the local control of thyroid hormone action

“…While rare, vascular tumors with high D3 activity have been shown to cause severe hypothyroidism in both adults and children (18,19). Increased D3 activity as a general mechanism may have much broader clinical relevance; as fetoplacental and uterine D3 activity increase dramatically during pregnancy (20,21), this activity may be the cause of increased l-thyroxine requirements in pregnant patients with hypothyroidism (22). Individuals with genetic alterations in the deiodinases have not yet been identified, though the clinical implications of several polymorphisms are under investigation (23)(24)(25)(26)(27).…”

Triplets! Unexpected structural similarity among the three enzymes that catalyze initiation and termination of thyroid hormone effects

“…This differential subcellular localization of D1 and D2 may explain why there is such a minimal contribution of the T 3 generated by D1 to the intranuclear T 3 in contrast to large fraction of D2-generated T 3 to this compartment (31)(32)(33)(34). The extracellular location of D3 gives ready access to circulating thyroid hormones, explaining its capacity for rapid inactivation of circulating T 4 and T 3 in patients with hemangiomas and its blockade of the access of maternal thyroid hormones to the human fetus (10,35,36).…”