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Endocrinology Vol. 142, No. 5 2123-2128
Copyright © 2001 by The Endocrine Society

ARTICLES

The Type 2 Iodothyronine Deiodinase Is Expressed in the Rat Uterus and Induced During Pregnancy1

Valerie Anne Galton, Elena Martinez, Arturo Hernandez, Emily A. St. Germain, Joanne M. Bates and Donald L. St. Germain

Departments of Physiology and Medicine, Dartmouth Medical School, Lebanon, New Hampshire 03756

Address all correspondence and requests for reprints to: Donald L. St. Germain, Departments of Physiology and Medicine, Dartmouth Medical School, Lebanon, New Hampshire 03756. E-mail: stgermain{at}dartmouth.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Thyroid hormones are of considerable importance for vertebrate reproductive function and during development. To further assess the role of these compounds in this capacity, we examined the expression pattern of the type 2 iodothyronine deiodinase (D2), which converts T4 to the more active hormone T3, in the rat uterus in both the nonpregnant and the pregnant state. D2 activity was identified as the predominant, if not only, 5'-deiodinase in the nonpregnant rat uterus. The expression of D2 messenger RNA was located by in situ hybridization to the endometrial stromal cells, where the signal was particularly enriched in the region adjacent to the epithelial cells of the uterine lumen. During pregnancy, D2 activity increased, peaking on day 17 of gestation (embryonic day 17). At that time, uterine D2 activity exceeded that in the placenta, as well as that in the fetal tissues. In the earlier stages of pregnancy before placental formation (e.g. embryonic days 10–11), D2 messenger RNA in the rat uterus was located outside the decidual tissue, which was observed, as in previous studies, to highly express the inactivating type 3 deiodinase. In summary, the rat uterus, particularly during pregnancy, seems to be a site of active thyroid hormone metabolism, presumably designed to maintain the optimal thyroid hormone environment for both the fetus and the maternal uterine tissue.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
FROM BOTH CLINICAL observations and experimental studies in animal models, it is evident that thyroid hormones play an important role in reproduction and are essential for development in vertebrate species (1). Thus, hypothyroidism in humans is associated with decreased fertility and difficulty in maintaining pregnancy (2, 3, 4), and hypothyroidism in rodents has been reported to induce alterations in the estrous cycle (5, 6), cause alterations in uterine morphology (7), and impair the decidualization response to implantation (8). Although it is not known whether these detrimental effects result from direct or indirect effects of thyroid hormone on the uterus, receptors for T3 have been documented both in the nonpregnant human and rat uterus (9, 10) and in the decidual tissue of the pregnant uterus (11). This indicates that at least some of the detrimental effects of altered thyroid status on uterine function could be a direct effect of thyroid hormone on this organ. This view is substantiated by the findings that thyroid hormones regulate insulin-like growth factor I activity in the uterus (12) and alter the uterine response to estrogens (13, 14, 15).

We have recently shown that the type 3 deiodinase (D3), the enzyme which 5-deiodinates T4 and T3 to the inactive compounds rT3 and 3,3'-diiodothyronine, respectively, is highly expressed in decidual cells of the pregnant rodent uterus (16) and that this expression begins shortly after implantation (Galton and St. Germain, unpublished data). This early uterine D3 response, which is apparent before placental development, may be important in establishing the relatively low levels of T4 and T3 that are characteristic of the early fetal period. However, such high levels of this inactivating deiodinase could render the uterine environment T3-deficient, which, if not countered, might have untoward consequences for uterine function and/or the fetus. Indeed, the detrimental effects of hypothyroidism on the course of pregnancy (vide supra), as well as recent clinical studies suggesting that maternal hypothyroidism during the early stages of pregnancy results in adverse outcomes in the offspring, reinforce the apparent importance of the need for tight control of T3 levels in both the nonpregnant and the early-pregnant uterus.

In the present report, we demonstrate that, in addition to the D3, the uterus also expresses significant levels of the type 2 deiodinase (D2), which activates T4 by converting it to T3 by 5'-deiodination. This uterine D2 activity is increased during pregnancy. We also show that there is a striking spatial separation of the expression of D2 and D3 in the pregnant uterus.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Virgin female rats, timed pregnant rats, and male rats (all 10–12 weeks old) were purchased from Charles River Laboratories, Inc. (North Wilmington, MA). Rats were housed under conditions of controlled lighting and temperature. Timed-pregnant rats were killed for study between embryonic days (E)9 and E21. To obtain uterine tissue at earlier stages of gestation, virgin female rats and male rats were mated in our animal facility. In keeping with the terminology used by Charles River Laboratories, Inc., the morning that sperm were detected in the vaginal smear was designated as E1 of pregnancy. All animal protocols were approved by the Institutional Review Board of Dartmouth Medical School.

Tissue preparation
Rats were killed by decapitation and exsanguination. The uterus was rapidly removed and dissected free of the surrounding adipose tissue. The uteri from nonpregnant rats and rats at E4, which is before implantation, were cross-sectioned into four pieces of approximate equal length. Uteri from rats at E6–E21 were cross-sectioned to separate the individual implantation sites.

At E6–E10, no further dissection was carried out. At E11–E21, some of the implantation sites were opened by making a longitudinal cut along the antimesometrial side of the uterine wall. This part of the uterus lies directly over the dorsal side of the fetus and is on the opposite side of the fetus from the attachment site of the placenta. At E11, the uterine contents, representing primarily decidual tissue surrounding the embryo, were gently scraped away from the uterine wall. At E13–E21, the uterus was folded back over the amniotic sac containing the fetus and the placenta and was then gently peeled free from these tissues. The amniotic sac, fetus, and placenta were then separated from each other. The following tissues or combinations of tissues were obtained: in nonpregnant rats and rats at E4, pieces of uterus plus contents; at E6-E10, whole implantation site; at E11, whole implantation site and separated uterus and uterine contents; at E13–21, fetus, head, body, placenta, and uterus. Tissues were homogenized in 0.25 mM sucrose, 20 mM Tris-HCl, pH 7.6, as previously described (17), to yield approximately a 1:5 homogenate (wt/vol). The homogenates were centrifuged at 1000 x g for 15 min, and the supernatants were stored at -20 C for subsequent assay of 5'-deiodinase (5'D) activity. The tissue samples obtained from rats at E9–E21 were used also for the assessment of D3 activity in pregnant rat uterus, placenta, and fetal tissues, as previously reported (16).

Determination of 5'D activity
5'D activity was assayed according to our published methods (18). Briefly, the reaction mixture (total vol, 50 µl) contained between 25 and 100 µg tissue protein and 1.2 mM EDTA. Protein concentrations were adjusted to ensure that deiodination was less than 20%. The substrate was either 1.0 nM [125I]rT3 or 1.0 nM [125I]T4, and the cofactor was 20 mM dithiothreitol. Incubation was carried out for 1 h at either 37 or 0 C. The percent deiodination of substrate that occurred at 37 C was corrected for any nonenzymic deiodination that took place during the same time period at 0 C. Unless indicated otherwise, 5'D activity is expressed as fmols iodide generated/h.mg protein. In determining 5'D activity, the percent iodide generated was multiplied by 2, because the specific activities of the labeled products were only half that of the substrate. Type 1 (D1) and D2 5'D activities were distinguished by the inclusion of 1 mM 6-n-propyl-2-thiouracil (PTU) and/or 100 nM nonradioactive T4 in the incubation medium. [125I]rT3 and [125I]T4 (specific activities ~1000 µCi/µg) were obtained from Perkin-Elmer Life Sciences (Boston, MA) and were purified by chromatography using Sephadex LH-20 (Sigma, St. Louis, MO) before use. Protein concentrations of all samples were determined according to the method of Comings and Tack (19) using BSA as the standard.

In situ hybridization
Sections (20-µm) of nonpregnant and pregnant uterus implantation sites were subjected to in situ hybridization for the detection of D2 and D3 messenger RNA (mRNA), according to methods described previously (16). The D3 antisense and sense RNA probes corresponded to a portion of the coding region (bp 239–831) of the rat D3 complementary DNA (cDNA) and were synthesized and labeled with [35S]uridine 5'-triphosphate as described (16). The D2 antisense and sense probes were prepared by analogous methods and corresponded to bp 52–315 of the coding region of the rat D2 cDNA. After hybridization and washing, sections were exposed, for 4–5 days, to ß-Max film (Amersham Pharmacia Biotech, Arlington Heights, IL) and then dipped in LM-1 emulsion (Amersham Pharmacia Biotech). After exposure for 1–2 weeks at 4 C, the slides were developed with D19 developer (Eastman Kodak Co., Rochester, NY), fixed, and counterstained with hematoxylin. Slides were examined using both lightfield and darkfield microscopy.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Preliminary studies
Homogenates of rat uteri from E17 dams expressed 5'D activity (Fig. 1Go). To determine which type of deiodinase was present, homogenates were assayed for 5'D activity in the presence or absence of 1 mM PTU (which selectively inhibits D1 activity) or 0.1 µM nonradioactive T4 (which, at this concentration, competitively inhibits the deiodination of 1 nM [125I]rT3 by D2 but not by D1). Homogenates of placenta and liver, which express primarily D2 and D1, respectively, were included as controls to determine the effectiveness of these procedures. The percent deiodination of [125I]rT3 in a homogenate of E17 rat uterus was not affected by the presence of PTU but was completely inhibited in the presence of 0.1 µM T4 (Fig. 1Go). These findings were comparable with those obtained in placenta, a tissue known to express primarily D2 activity (20). In liver, which expresses only D1 (21), the 5'D activity was almost completely inhibited by PTU but not by 0.1 µM T4. In addition, in keeping with the preferred substrate for the D2 being T4, the velocity of deiodination in uterine homogenates, using 1 nM T4 as substrate, was three times that observed with rT3 at the same concentration (data not shown). We therefore conclude that the 5'D activity expressed in uterus is almost exclusively D2.



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  		Figure 1. D1 and D2 activities in homogenates of E17 rat uterus and placenta and in adult rat liver. Homogenates were incubated, in the presence and absence of 1 mM PTU, to inhibit D1 activity; and 0.1 µ M T4 , to inhibit D2 activity. 5'D activity is expressed as the percent deiodination of the substrate [125I]rT3. Bars indicate the means of triplicate assays in which the individual values varied by less than 1.3%.

 
Profiles of D2 activity in uterus, placenta, and fetus during pregnancy
A profile of uterine D2 activity in the nonpregnant state and from E9–E21 is shown in Fig. 2Go. D2 activity was present in the nongravid uterus and in the pregnant uterus at all stages of gestation studied, including the implantation sites on days E9 and E11. In the pregnant uterus, D2 activity gradually increased to a maximum at E17, at which time it was approximately three times that observed in the nonpregnant uterus, and then it declined. It is notable that the D2 activity in the implantation site at E9 was significantly higher that that in the nonpregnant uterus, indicating that this increase in activity may begin relatively early in pregnancy. Placental D2 activity was also measured at the same stages of pregnancy, and levels similar to those in the corresponding preparations of uterus were observed.



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  		Figure 2. D2 activity in the implantation site, uterus, and placenta at different stages of gestation in the rat. All values represent the mean ± SE of four samples obtained from the same pregnant dam at each gestational age. NP, Nonpregnant.

 
No significant D2 activity was observed at E11 in the pregnant uterine contents, which consisted primarily of decidual tissue, or in homogenates of whole fetus or fetal head or body prepared at E13, E15, and E17. At E19, low (but significant) levels of both D1 and D2 activities were detected in the whole fetus and fetal body; and, by E21, increased levels of both types of activity were found in the whole fetus, fetal head, and fetal body (Fig. 3Go).



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  		Figure 3. D1 and D2 activities in whole fetus, head, and body at different stages of gestation. All values represent the mean ± SE of four samples obtained from the same pregnant dam at each gestational age.

 
To determine the gestational stage at which uterine D2 activity is first enhanced, pregnant rats were killed at E4, E6, E7, E8, E10, and E16. Because E4 is before implantation, samples of uterus were assayed. From E6–E10, assays were performed on the implantation site, which was clearly visible in the exposed uterus. At E16, uterus minus contents (i.e. placenta, fetus, and fetal membranes) was assayed. No increase in uterine D2 activity was seen at E4–E8, but an increase was noted at E10 (Fig. 4Go). Thus, from the data presented in Figs. 2Go and 4Go, it seems that uterine D2 activity begins to increase between E8 and E9.



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  		Figure 4. D2 activity in uterus in early pregnancy. Each point represents the mean of values obtained in three tissue samples obtained from the same rat. D2 activity was determined in sections of the uterus at E4, in the implantation site at E6–E10, and in the uterus minus its contents at E16.

 
In situ hybridization studies
The spatial pattern of D2 mRNA expression in the uterus was studied using in situ hybridization in nonpregnant and pregnant rats. Figure 5AGo shows the autoradiograph of a cross-section of an adult nonpregnant rat uterus that has been subjected to in situ hybridization using the D2 antisense probe. Diffuse signal for D2 mRNA is present throughout the section, with marked accentuation seen in the subepithelial stromal cells surrounding the uterine lumen. This is clearly evident in the lightfield and darkfield photomicrographs shown in panels B and C, respectively. Little or no signal was evident when sections were hybridized with the D2 sense probe (D, E, and F). Although D3 activity is present in the nonpregnant uterus (16), in situ hybridization, using the D3 antisense and sense probes, failed to detect any specific signal (data not shown), suggesting that the levels of D3 mRNA expressed under these conditions are below the detection level of this technique.



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  		Figure 5. Pattern of D2 mRNA expression in the rat nonpregnant uterus, as determined by in situ hybridization. A, Autoradiograph of a cross-section of rat uterus after in situ hybridization with the rat D2 antisense probe. Diffuse signal is noted throughout the uterine wall, with accentuation in the perilumenal region. B, Lightfield photomicrograph (40x) after in situ hybridization with the D2 antisense probe, showing a diffuse pattern of deposition of silver grains in the endometrial stromal cells, with a marked accentuation of signal in cells adjacent to the lumenal epithelium. C, Darkfield photomicrograph (10x) after in situ hybridization with the D2 antisense probe. Silver grains are apparent in the endometrial tissue, with accentuation in the perilumenal regions. D, Autoradiograph of a section of rat uterus adjacent to that shown in A after in situ hybridization with the rat D2 sense probe. Only a faint, diffuse pattern of signal is observed. E, Lightfield photomicrograph (40x) after in situ hybridization with the D2 sense probe. Only rare silver grains are apparent. F, Darkfield photomicrograph (10x) after in situ hybridization with the D2 sense probe. As in E, only a nonspecific pattern of silver grains is observed.

 
The expression pattern of D2 mRNA in the early pregnant uterus is shown in longitudinal sections from an E10 specimen in Fig. 6Go. Hematoxylin staining (Fig. 6AGo) demonstrates the mesometrial and antimesometrial decidual reactions, as well as the narrowing of the uterine lumen. At this stage of pregnancy in the rodent, the uterine lumen is discontinuous, having been obliterated by the decidual response at each implantation site. D2 mRNA expression is again clearly evident and seems to be confined primarily to the perilumenal region and a relatively narrow band extending along the mesometrial side of the organ. This is demonstrated in the autoradiograph shown in panel B and the photomicrograph in G. Little or no D2 expression is seen in the decidual cells. This contrasts sharply with the strong pattern of D3 mRNA expression in both the mesometrial and antimesometrial decidua, as previously described and as demonstrated in Fig. 6CGo. A color-enhanced overlay (Fig. 6DGo) of the adjacent tissue sections in Fig. 6Go, B and C, shows the striking segregation of D2 mRNA (magenta) and D3 mRNA (blue) expression in the pregnant uterus. Little or no signal was observed in sections hybridized with the control D2 sense (E and H) or D3 sense (F) probes.



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  		Figure 6. Pattern of D2 and D3 mRNA expression in the rat E10 pregnant uterus, as determined by in situ hybridization. A, Photograph of a hematoxylin-stained longitudinal section of a uterine implantation site. The uterine lumen is indicated. aMD, Antimesometrial decidual; MD, mesometrial decidua. B, Autoradiograph of a section of rat uterus adjacent to that shown in A after in situ hybridization with the rat D2 antisense probe. Prominent signal (arrows) is noted in the perilumenal region and along the mesometrial edge of the decidua. C, Autoradiograph of an adjacent section of rat uterus after in situ hybridization with the rat D3 antisense probe. Intense signal is noted in the mesometrial and in the outer portions of the antimesometrial decidua. D, Composite illustration of the patterns of D2 (magenta) and D3 (blue) mRNA expression, as shown in B and C, respectively. A clear segregation of the expression patterns is apparent. E, Autoradiograph of an adjacent section of pregnant rat uterus after in situ hybridization with the rat D2 sense probe. F, Autoradiograph of an adjacent section of pregnant rat uterus after in situ hybridization with the rat D3 sense probe. G, Lightfield photomicrograph (40x) of the perilumenal region of the pregnant uterus after in situ hybridization with the D2 antisense probe, showing the deposition of silver grains in the stromal cells adjacent to the uterine lumen. H, Lightfield photomicrograph (40x) of the perilumenal region of an adjacent section after in situ hybridization with the D2 sense probe. No silver grains are apparent.

 
At later stages of pregnancy (e.g. E15, Fig. 7AGo), D2 mRNA is most prominent as a thin rim of expression at the interface between the placenta and the maternal uterine tissue (arrows) and surrounding the recanalized uterine lumen (arrowhead).



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  		Figure 7. Pattern of D2 mRNA expression in the rat E15 pregnant uterus, as determined by in situ hybridization. A, Autoradiograph of two adjacent cross-sections through the pregnant rat uterus, showing the products of conception. A localized, intense band of D2 signal is present at the interface of the uterus and the placenta (arrows). Additional signal is noted adjacent to the recanalized uterine lumen (arrowhead). B, Autoradiograph of a near-adjacent section of pregnant rat uterus after in situ hybridization with the rat D2 sense probe.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present studies demonstrate that the rodent uterus expresses substantial levels of D2 in the nonpregnant state, and that these levels increase significantly during pregnancy. The level of activity observed in the nonpregnant uterus, when expressed per milligram of tissue protein, is similar to, or greater than, that observed in the cerebrum, cerebellum, and brown fat of fetal and adult animals (21), tissues where D2 has been implicated as playing an important role in thyroid hormone homeostasis (22). Furthermore, the level of uterine D2 observed on day E17, the time when the highest expression of uterine D2 is observed, is comparable with that observed in the euthyroid pituitary (21).

These observations are consistent with the view that the D2 plays an important role in regulating thyroid hormone action in the uterus. Studies by Kennedy and Doktorcik (8) strongly suggest that thyroid hormone is important for uterine function during pregnancy. Using a combined ovariectomized and hypophysectomized rat model, these investigators examined the role of thyroid and pituitary hormones in the uterine decidualization response. They demonstrated that both T4 and GH were required for the full decidual response of the endometrium to an implantation stimulus, and that pretreatment with these hormones, before stimulus administration, was required. The presence of both hormones was also important for induction of the endometrial vascular permeability that is a prerequisite for the decidual response. Thus, the expression of D2 in the perilumenal stromal cells of the endometrium may be critical for generating the appropriate levels of intracellular T3 required for helping coordinate the uterine decidual response to implantation. Indeed, we have observed that D2 activity in the nonpregnant uterus undergoes cyclic changes that are dependent on the estrus cycle, with the highest levels observed during proestrus (Wasco et al., unpublished data), the time when the uterus is preparing for possible pregnancy.

The uterus is one of relatively few tissues that have been demonstrated to express both D2 and D3. In the central nervous system of the rat, D2 and D3 are expressed concurrently, although it has been demonstrated, by in situ hybridization, that there is a spatial separation in the expression of the two enzymes, in terms of brain regions and individual cell types (23, 24, 25). In the case of developing skin, there is marked temporal separation in the expression of the D2 and D3 (21), with the D2 being expressed primarily during late fetal life, and D3 being expressed almost exclusively in the postnatal period (e.g. postnatal day 12 in the rat). Such observations suggest that thyroid hormones may exert different regulatory effects within a tissue as a result of different complements of deiodinases affecting the local concentration of the active hormone T3.

In this regard, there is dramatic spatial segregation of the D2 and D3 in the pregnant uterus, especially in the early stages of pregnancy (E6-E10) before formation of the placenta. Thus, the decidual tissue, which forms in response to implantation and envelops the embryo, expresses extremely high levels of D3 but little D2. This predominance of D3 activity may create the thyroid hormone-deficient environment that is characteristic of the early fetus, a state where embryonic T3 and T4 levels are much lower than those in the maternal serum. In contrast, D2 activity predominates in the regions of the uterus surrounding the decidual reaction. One may speculate that this D2 activity serves to provide T3 to the nondecidualized uterine tissue, thus preventing it from becoming T3-deficient.

Despite the high levels of D3 activity in the decidua and placenta (26, 27, 28), both T4 and T3 are present in the embryonic trophoblast in the early stages of pregnancy and later in the fetus (29). This indicates that fetal tissue does receive some thyroid hormone from the dam before fetal thyroid function, which begins in the rat on E17. Recent clinical studies have suggested that, in the human, maternal thyroid hormones are important during the initial stages of pregnancy (30, 31). Although the expression of D2 in the pregnant uterus could serve as a source of T3 that is shunted to the embryo, its spatial location, being separated from the fetal tissues by the D3-expressing decidual tissue and later by the placenta and epithelial cells of the recanalized uterine epithelium (which also express high levels of D3), seems to place it at a disadvantage in carrying out this function.

In conclusion, the uterus is an active site of thyroid hormone metabolism, and this is particularly true during pregnancy, when the levels of both D2 and D3 activities are markedly increased. The spatial pattern of expression of these two enzymes suggests that a gradient of T3, and perhaps T4, concentrations exists in the pregnant uterus and that this may be important to both uterine function and fetal development.


   Footnotes
 
1 This work was supported by USPHS Grants HD-09020 (to V.A.G.), T32-DK-07508 (to J.M.B.), and DK-42271 (to D.L.S.) Back

Received November 13, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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