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Instituto de Biofísica Carlos Chagas Filho Universidade Federal do Rio de Janeiro Rio de Janeiro, Brazil 21949-900
Address all correspondence and requests for reprints to: Denise Pires de Carvalho, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil 21949-900. E-mail: dencarv{at}biof.ufrj.br.
The outer ring deiodination of T4 leads to the production of T3, which is considered the active thyroid hormone that interacts with nuclear receptors and regulates gene transcription (1, 2, 3). T3 outer ring deiodination (ORD) also generates another biologically active metabolite, the 3,5-diiodothyronine that exerts important metabolic effects, as described recently (4). Therefore, the ORD is considered an activating thyroid hormone metabolic pathway. Iodothyronine deiodinases are classified into three isoenzymes, based on several biochemical criteria and on different protein sequences: type 1 (D1), type 2 (D2), and type 3 (D3) deiodinases (2, 3, 5, 6, 7, 8, 9, 10, 11). Both D1 and D2 are outer ring deiodinases; D1 also presents the ability to deiodinate the inner ring, although not as efficiently. The type 1 enzyme is responsible for generating most of the circulating T3 and is predominantly found in the adult liver, kidney, and thyroid (2, 3). D2 is present in the cerebral cortex, cerebellum, pituitary, brown adipose tissue, human thyroid, and skeletal muscles and is believed to be the source of intracellular T3 (3, 12). Thus, in tissues that express D2, a greater fraction of nuclear receptors interact with T3 derived from intracellular T4 deiodination and not from the plasma pool (3).
On the other hand, T4 inner ring deiodination leads to the production of rT3, an apparently inactive metabolite (2, 3, 9). Both D1 and D3 are able to deiodinate T4 and generate rT3; however, differently from D1, D3 only deiodinates the inner ring of iodothyronines and therefore is considered a thyroid hormone-inactivating enzyme present in the central nervous system, placenta, and fetal liver (2). The confirmation of D3 as an enzyme responsible for inactivation of thyroid hormones in vivo came from findings of consumptive hypothyroidism caused by the expression of high levels of D3 in hepatic hemangiomas, which clearly demonstrated that the inactivation of T4 by this enzymatic pathway could lead to overt clinical hypothyroidism (13).
Independently of the plasma levels of thyroid hormones, the concentration of T3 in different tissues may vary depending on the presence of deiodinase activities that increase (D2) or decrease (D3) T3 production. As a result, deiodinases are enzymes that can physiologically modulate the cellular or tissue thyroid status. As an example, D2 activity in brown adipose tissue is higher during cold exposure, when the cellular demand of T3 is increased (14, 15). Apart from the role of deiodinases in the regulation of homeostasis, the induction of these enzymes with a precise timing course might also be important during critical periods of development.
T3 is fundamental for normal fetal development; however, high levels of this hormone are deleterious for fetal tissues and may promote malformations and death (16). Thus, serum and intracellular T3 levels during fetal development have to be regulated to be maintained in a narrow range, depending on tissue demands. During embryogenesis, thyroid hormone receptors are expressed and occupied before the onset of fetal thyroid function, showing that an important maternal-fetus thyroid hormone transfer occurs early in gestation (17). Nevertheless, there is a marked gradient of T4 from the mother to the fetus and circulating T4 and T3 are lower in the fetus, probably due to the fact that during development D3 is the predominant enzyme expressed in most rat tissues (18). Furthermore, thyroid hormone transfer from the mother to the fetus seems to be regulated by the increased D3 activity in placenta, which occurs in rats (19) and in humans (20, 21). In rat uterus, D3 activity is also induced during gestation and is even higher than in placenta, probably representing barriers to the passage of maternal thyroid hormones, which could be important for the protection of fetal tissues from elevated T3 levels (19). The definition of the factors involved in the regulation of deiodinase expression in the utero-placenta unit is needed to allow a better understanding of the mechanisms underlying the control of programed deiodinase expression during gestation.
In this issue of Endocrinology, Wasco et al. (22) describe the regulation of D3 expression in rat uterus during early phases of gestation, before and during the implantation period. D3 activity was already significantly increased at embryonic d 6 (E6), around the time of implantation. Further increase in D3 activity in the implantation site was seen until E10, with a progressive decrease later on. To evaluate whether the presence of the blastocyst at the time of implantation could modify, to some extent, deiodinase induction, D2 and D3 activities were measured in decidualized uterus of pseudopregnant rats and of ovariectomized rats treated with estrogen and progesterone. After decidualization, the levels of D3 activity were 30- to 40-fold higher in decidualized uterine horns when compared with the nondecidualized horns from the same rats, and were similar to the activity found in normal pregnancy. The results obtained with decidualization process undertaken in ovariectomized rats pretreated with estrogen and progesterone indicate that D3 activity in nonpregnant uterus might be modulated by steroid hormones or by factors originating from decidual tissues. In contrast, D2 activity was not altered in the decidualized uterus. The present study also evaluated D3 activity in female mice homozygous for an inactivating mutation in the IL-11 receptor 
. These mice are infertile, and only scarce decidual tissue is found, which degenerates before placenta can be formed. Interestingly, D3 activity in homozygous mice is as high as in heterozygous ones, showing that decidualization is the event that triggers D3 induction during gestation. Altogether, these data demonstrate that the formation of placenta and the presence of blastocyst are not essential for the increased D3 activity found during pregnancy in rat uterus.
Maternal to fetal thyroid hormone transfer has been studied in hypothyroid dams (23, 24, 25) and, in these animals, a possible diminished placental D3 induction would be expected because D3 expression is positively modulated by thyroid hormones in several tissues (3). Nevertheless, previous studies showed that placental D3 activity seems not to be altered in hypothyroid dams at E18 and E21 (26); hence, further studies are needed to better evaluate placental D3 modulation in different maternal thyroid status. Maternal to fetal transfer of T4 has been confirmed in studies using normal rats (27), and the findings of a positive correlation between maternal serum hormone levels and those found in fetal compartment suggest that placenta just functions as a limited barrier for thyroid hormone passage (28). As a result, fetal tissues are exposed to significant levels of T4 during early phases of development (29), and, apparently, the availability of this hormone is fundamental for normal fetal development, because maternal hypothyroxinemia is associated to impaired neuropsychological development of the children (30). Recent data corroborating these epidemiological studies demonstrate the presence of morphological changes in several areas of the central nervous system in the progeny of hypothyroxinemic dams (31). The demonstration that T4 is able to cross the placenta has explained the reason why human hypothyroid fetuses can be born with very few signs and symptoms of hypothyroidism, and should also explain the fact that T4 replacement therapy soon after birth leads to an apparently normal postnatal neurological development, despite the known importance of thyroid hormones to intrauterine development. The mechanisms that are involved in the tight control of T4 passage from maternal serum to the fetal compartment remain to be elucidated, but the induction of D3 activity might play a role in this intricate regulation.
D3 mRNA is expressed in the central part of decidual tissue, whereas D2 mRNA expression is located in cells surrounding deciduas (22). D2 expression was not increased by implantation; however, the generation of T3 from T4 after D2 ORD could be important for a subsequent action of D3 to inactivate T3. Regardless of the importance of T4 transfer to the embryo in early gestational phases when fetal thyroid is not functional, D3 activity is high in tissues surrounding the embryo. The physiological significance of this D3 increment in uterus, implantation site, and then in placenta should be the fact that the free passage of T4 from the mother to the fetus could lead to increased fetal serum levels of free T4. Taking into account that, early in fetal development, serum T4 binding proteins are not present or their concentrations are very low, every T4 transferred to the fetus could reach tissues and exert undesirable effects. As a consequence, the early D3 induction should be necessary for the maintenance of normal fetal serum free T4 levels, which are in fact similar to those found in adult rats (29). The findings of high D3 activity in uterus, placenta, and fetal tissues are in agreement with previous descriptions that in hypothyroid dams the fetus’ brain T3 is only normalized by T4 infusion, but not by T3 administration (25). As a consequence, it is reasonable to accept that D3 expression in the utero-placenta tissues corresponds to a regulatory rather than just an inactivating pathway.
Estrogen and progesterone effects on uterine tissue are essential for implantation and normal gestation. Both D2 and D3 activities are expressed in nonpregnant uterus, but not D1 (19, 32); in the present study, Wasco et al. (22) show that uterine D2 and D3 activities are significantly increased during the proestrus, compared with the diestrus phase of the estral cycle. On the other hand, D1 activities found in the ovary were similar in the proestrus and diestrus, whereas ovarian D3 was also increased in the proestrus. The physiological meaning of ovarian D3 regulation by sexual steroids during the estral cycle is a matter of speculation; it might indicate that ovarian T3 levels should be modulated to allow normal folliculogenesis and ovulation, as previously suggested (33).
Because estrogen and progesterone are highest in the proestrus phase of the cycle, the results described above suggested a possible modulation of uterine D2 and D3 by steroid hormones. In fact, uterine D2 activity was significantly increased by estrogen alone or in combination with progesterone. However, D3 in the rat uterus was also stimulated by estrogen, although to a lesser extent, and in the presence of both estrogen and progesterone D3 activity was much higher, indicating that steroid hormones act synergistically to induce D3 in uterus. In conclusion, uterine D2 modulation seems to be mainly dependent on the effect of estrogen; on the other hand, D3 expression depends on the concomitant estrogen and progesterone actions. Although D3 activity is increased by estrogen and progesterone administration to ovariectomized rats, the levels of this enzyme activity are much higher during gestation as a consequence of the implantation process per se. The possibility that D3 induction might be attributable to factors involved in the process of decidualization must be taken into consideration, because epidermal growth factor and transforming growth factors are potent stimulants of D3 activity in vitro.
The importance of D3 induction for the maintenance of normal embryogenesis is surely a matter of future studies, as the induction of this metabolic pathway may play an essential role against the deleterious effects of high T4 levels during embryonic and fetal development.
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Received July 9, 2003.
Accepted for publication July 15, 2003.
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