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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 1 300-305
Copyright © 1997 by The Endocrine Society

Reproductive Endocrinology

Differential Expression of 11ß-Hydroxysteroid Dehydrogenase Types 1 and 2 in Human Placenta and Fetal Membranes1

Kang Sun, Kaiping Yang and John R. G. Challis

Medical Research Council Group in Fetal and Neonatal Health and Development, Departments of Physiology and Obstetrics and Gynecology, University of Toronto, Toronto; and the Departments of Obstetrics and Gynecology and Physiology, Lawson Research Institute, University of Western Ontario (K.Y.), Ontario, Canada

Address all correspondence and requests for reprints to: Dr. Kang Sun, Department of Physiology, Third Floor, Medical Science Building, Unversity of Toronto, 1 King’s College Circle, Toronto, Ontario, Canada M5S 1A8.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Two isoforms of 11ß-hydroxysteroid dehydrogenase (11ßHSD) are present in mammals. 11ßHSD1 interconverts biologically active cortisol and inactive cortisone, whereas 11ßHSD2 only converts cortisol to cortisone. Placental 11ßHSD has been proposed to protect the fetus from high level of maternal glucocorticoids. Although bidirectional activity of 11ßHSD has been demonstrated in homogenized human placental tissues, the tissue and cellular distribution of 11ßHSD1 has not been resolved. In this study, the cellular localization of 11ßHSD1 protein and levels of its messenger ribonucleic acid (mRNA) in human placenta and fetal membranes were determined by immunohistochemistry and Northern blot analysis, respectively. We found that 11ßHSD1 immunoreactivity was present in the placental extravillous intermediate trophoblasts, chorion trophoblasts, amnion epithelial cells, and stromal cells of the decidua vera. Positive staining was also observed in the endothelium of the blood vessels in both placental villous tissue and umbilical cord. However, in contrast to previous reports of immunoreactive 11ßHSD2 localization, 11ßHSD1 immunoreactivity was undetectable in placental syncytiotrophoblast. Using a human 11ßHSD1 complementary DNA as probe, a 1.5-kilobase mRNA transcript was detected in the chorion, amnion, and placental tissue, with the greatest amount in the chorion. In contrast, the 1.9-kilobase mRNA of 11ßHSD2 was observed only in the placenta, not in the chorion and amnion. The process of labor had no significant effect on levels of 11ßHSD1 or 11ßHSD2 mRNA in the chorion or placenta. We conclude that there is a striking difference in the tissue localization of 11ßHSD1 and 11ßHSD2 expression in the late gestation human placenta and fetal membranes, which may discretely determine the accessibility of bioactive glucocorticoid to specific cell types.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
AN 11ß-hydroxysteroid dehydrogenase (11ßHSD) is the enzyme responsible for the interconversion of biologically active glucocorticoids and their receptor-inactive 11-keto metabolites. Two isoforms of 11ßHSD are present in mammals (1, 2, 3). 11ßHSD1 has oxoreductase activity, is distributed ubiquitously, although it is most abundant in the liver, and interconverts cortisol and cortisone, requiring NADP(H) as its cofactor (4, 5). In contrast, 11ßHSD2 has only dehydrogenase activity and is NAD dependent. It is more regionally distributed, with highest abundance in the kidney, pancreas, and placenta (6, 7, 8, 9, 10). 11ßHSD2 confers specificity of the mineralocorticoid receptor in the kidney and contributes to the placental barrier preventing the passage of maternal glucocorticoids into the fetal circulation by converting active cortisol to inactive cortisone (11, 12, 13). Epidemiological studies have suggested that smaller babies have a higher incidence of cardiovascular diseases in adulthood (14, 15), and this has been attributed by some investigators to excessive exposure to maternal glucocorticoids during fetal life as a result of a deficiency in placental 11ßHSD2 (13).

Although the high affinity of 11ßHSD2 for cortisol is more suited to metabolizing maternal glucocorticoids reaching the placenta, conversion from cortisone to cortisol was clearly demonstrable in homogenized placental and chorionic tissues (16). This activity is regarded as the predominant reaction catalyzed by 11ßHSD1 in intact cells (17). The unique cortisol-regenerating function of 11ßHSD1 might indicate that this enzyme plays some additional roles in pregnancy (18). However, the pattern of tissue and cellular distribution of 11ßHSD1 activity and synthesis in the placenta and fetal membranes of human pregnancy has not been studied, nor is there information on the relative expression of 11ßHSD isoenzymes with labor. We hypothesized that within the placenta and fetal membranes, the distribution of 11ßHSD1 might differ from that reported for 11ßHSD2 (6), thereby conferring discrete cellular availability of bioactive glucocorticoids. We, therefore, examined the localization of 11ßHSD1 and levels of its messenger ribonucleic acid (mRNA) in placenta and fetal membranes using immunohistochemistry and Northern blot analysis and compared these mRNA levels with those of 11ßHSD2 in patients in the presence or absence of labor.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Tissue collection

Human placentae, umbilical cords, and fetal membranes were collected from patients after term elective cesarean section in the absence of labor (CS) or after spontaneous vaginal term delivery (SL). Tissues were either fixed in 4% paraformaldehyde-0.2% glutaraldehyde (n = 3 for CS; n = 4 for SL) or snap-frozen in liquid nitrogen and stored at -70 C (n = 9 for CS; n = 10 for SL). Before freezing, the amnion was peeled away gently from the chorion to study these tissues separately. Frozen samples were used for Northern blot analysis after extraction of total RNA. Fixed tissues were washed and stored in 70% ethanol before embedding them in paraffin wax. The paraffin blocks were sectioned at 5 µm for immunohistochemistry.

Immunohistochemistry analysis

Sections of placenta, umbilical cord, and fetal membranes were stained for immunoreactive 11ßHSD1 (IR-11ßHSD1) using the avidin-biotin peroxidase method (Vector ABC, Vector Laboratories, Burlingame, CA), as described previously (19, 20). The polyclonal primary antibody was raised in rabbits against a synthetic peptide corresponding to amino acids 278–289 from the deduced sequence of ovine 11ßHSD1 protein (21). Western blot analysis using this antibody revealed a 34-kDa immunoreactive protein in homogenates from Chinese hamster ovary cells transfected with 11ßHSD1 complementary DNA (cDNA) (22). The antibody was purified by affinity chromatography (22) and was used at a dilution of 1:450. To test the specificity of the antibody, the sections were also stained with primary antibody preabsorbed with excess 11ßHSD1 synthetic peptide. Sections were counterstained with Carazzi’s hematoxylin and examined by light microscopy.

Total RNA extraction and Northern blot analysis

Total cellular RNA was extracted from placenta, chorion/decidua, and amnion using lithium chloride-urea (23) and quantified spectrophotometrically at 260 nm. The integrity of the RNA was assessed before Northern blot hybridization (24), carried out using a specific human 11ßHSD1 cDNA generated in our laboratory (25) and an 11ßHSD2 cDNA (8) (courtesy of Dr. A. L. Albiston, Baker Medical Research Institute, Melbourne, Australia). A cDNA for mouse 18S ribosomal RNA (rRNA) was used as an internal standard to determine the relative amounts of RNA loaded into each well and the transfer efficiency.

The autoradiographs were scanned using a densitometer (Ultrascan XL LKB 2222–020, LKB Produkter, Bromma, Sweden) to determine the relative optical densities of 11ßHSD1, 11ßHSD2, and 18S rRNA hybridization signals. For each RNA sample, the signal for the transcripts was measured within the linear range of the densitometer, and the ratio of 11ßHSD1 or 11ßHSD2 mRNA signals to 18S rRNA was calculated.

Statistical analysis

All data are shown as the mean ± SEM. Statistical differences between labor and no labor groups were assessed by Student’s t test. Differences in the levels of 11ßHSD1 and 11ßHSD2 mRNA in the placenta, chorion/decidua, and amnion were assessed by one-way ANOVA. Statistical significance was set at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Distribution of IR-11ßHSD1

There were no obvious differences in the distribution and localization of IR-11ßHSD1 between tissues obtained at CS not in labor and those obtained after SL (Table 1Go). IR-11ßHSD1 was undetectable in the syncytiotrophoblast of placental villi. Positive immunoreactivity for 11ßHSD1 was present in the extravillous intermediate trophoblasts and in the endothelial cells lining the fine branches of the umbilical blood vessels in the tertiary villi (Fig. 1Go, A–C, and Table 1Go). Patchy staining for IR-11ßHSD1 was found in some of the amnion epithelial cells of the fetal membranes and in some of the fibroblasts within the subepithelial layer (Fig. 1DGo). Strong cytosolic staining for 11ßHSD1 was present in the chorionic trophoblast layer and in many of the decidual stromal cells that were adherent to the chorion (Fig. 1DGo and Table 1Go). IR-11ßHSD1 was consistently found in the amniotic epithelium surrounding the umbilical cord and in the endothelial cells lining the umbilical blood vessels (Fig. 1Go, E and F). It was not detected in the cells contained in the Wharton’s jelly tissue (Fig. 1FGo).


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  		Table 1. Distribution of immunoreactive 11ßHSD1 staining in human placenta, fetal membranes, and umbilical cord at term after spontaneous labor (SL) or elective cesarean section (CS)

 


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  		Figure 1. Localization of IR-11ßHSD1 in human placenta, fetal membranes, and umbilical cord at term. A, IR-11ßHSD1 in the vascular endothelium (endo) of placental villous tissue, but not in the placental syncytiotrophoblast (st). B, High power view of IR-11ßHSD1 in the vascular endothelium of placental villous tissue. C, IR-11ßHSD1 in the placental extravillous intermediate trophoblasts (int). D, IR-11ßHSD1 in the amnion (a), epithelium (epi), chorion (c), trophoblasts (t), and decidua (d), but not in the atrophic former villi (V). E, IR-11ßHSD1 in the endothelium of umbilical vessels. ua, Umbilical artery. F, IR-11ßHSD1 in the amnion membrane surrounding the umbilical cord. wj, Wharton’s jelly. G, Preabsorption abolished the positive staining in the vascular endothelium and intermediate trophoblasts of the placenta. The scale bar in each picture represents 360 µm (E), 180 µm (F), 90 µm (A and D), and 45 µm (B, C, and G).

 
Preabsorption of the 11ßHSD1 antibody with excess synthetic 11ßHSD1 peptide completely eliminated staining from the placenta (Fig. 1GGo), membranes, and umbilical cord (data not shown), thereby attesting to the specificity of the immunostaining response.

11ßHSD1 and 11ßHSD2 mRNA abundance

By Northern blot analysis, a 1.5-kilobase (kb) 11ßHSD1 mRNA was found in total RNA from term chorion/decidual tissue. A weak signal was detectable in the placenta and in some of the amnion samples. Statistically, the level of 11ßHSD1 mRNA in amnion and placenta was significantly less than that in the chorion/decidua (Fig. 2Go). In contrast, using a human 11ßHSD2 cDNA as probe, 1.9- and 4.0-kb 11ßHSD2 mRNA transcripts were found in the placenta. Under the same conditions, we did not detect 11ßHSD2 transcripts in the chorion/decidua or amnion tissues (Fig. 2Go).



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  		Figure 2. Expression of 11ßHSD1 and 11ßHSD2 mRNA in human placenta (n = 6), amnion (n = 4), and chorion/decidua (n = 6) at term. Top panel, Autoradiographs of Northern blot of 11ßHSD1 and 11ßHSD2 mRNA expression in human placenta and fetal membranes. The same blot was hybridized sequentially in the order 11ßHSD2, 11ßHSD1, and 18S rRNA. Thirty micrograms of total RNA were loaded per lane. Exposure time was 24 h. Lower panel, Ratios of 11ßHSD1 and 11ßHSD2 mRNA to 18S rRNA in human placenta and fetal membranes. **, P < 0.01, by one-way ANOVA.

 
There was no effect of labor on the levels of 11ßHSD1 mRNA in chorion/decidua or on levels of 11ßHSD mRNA in placenta, although there was substantial variability between specimens (Fig. 3Go, a and b).



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  		Figure 3. Effect of labor on the levels of A) 11ßHSD2 mRNA in human placenta (labor group, n = 7; no labor group, n = 5) and B) 11ßHSD1 mRNA in chorion/decidua of patients at term (labor group, n = 10; no labor group, n = 9). Each panel shows autoradiographs of Northern blots and densitometric levels relative to 18S rRNA. In A, 20 µg total RNA were loaded per lane; in B, 30 µg were loaded. The films were exposed for 24 h. There were no statistical differences between the labor and no labor groups (by Student’s t test).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Giannopoulos et al. (16) reported that there was increased conversion of cortisone to cortisol in homogenized human placental tissue toward term, although conversion from cortisol to cortisone predominated at all gestational ages. Further studies indicated that placental 11ßHSD was a reversible enzyme system, and there were at least two species of 11ßHSD in human placenta (26). The present study demonstrated that IR-11ßHSD1 is present in the placenta. The cellular distribution of 11ßHSD1 to extravillous cytotrophoblasts and vascular endothelium is clearly different from that of 11ßHSD2, which is found only in the syncytiotrophoblast (6). Assuming that our measurements of IR-11ßHSD1 are reflective of enzyme bioactivity, we suggest that the increased reductase activity of the placental tissue with gestational age is due to an increase in 11ßHSD1, as demonstrated in this study. 11ßHSD1 was localized to chorion trophoblasts and decidua vera in addition to the placenta. Previously, Stewart et al. (27) suggested that 11ßHSD1 activity in the chorion was probably due to decidual contamination because the enzyme was absent in decidua-free fused chorion obtained from a twin pregnancy. However, the strong positive staining of IR-11ßHSD1 and abundant 11ßHSD1 mRNA in chorion indicate that 11ßHSD1 activity in chorion reflects its local biosynthesis. There are variable amounts of decidua adherent to the chorion in specimens from different patients, and we cannot be certain whether interpatient differences in 11ßHSD1 mRNA reflect this or different levels of the enzyme in chorion. Our results support the suggestion of Stewart et al. (27) that human decidua in late pregnancy expresses 11ßHSD1.

Tanswell et al. (28) reported that human amnion contained increasing 11ßHSD activity during pregnancy, thereby potentially contributing to the rising cortisol concentrations of amniotic fluid. Others have suggested that term amnion has negligible 11ßHSD activity in vitro (29). In the present study we found discrete populations of amniotic epithelial cells that were positive for IR-11ßHSD1, and we found IR-11ßHSD1 localized to cells with the appearance of fibroblasts in the subepithelial mesenchyme. 11ßHSD1 mRNA levels were variable in samples of amnion from different patients. It seems likely that the activity of 11ßHSD1 in the amnion depends in part on which area of the tissue is sampled in addition to patient variability. Of interest, the amniotic epithelial cells surrounding the umbilical cord and the endothelial cells of the umbilical vessels consistently stained for IR-11ßHSD1. This staining was consistent with the intense positive IR-11ßHSD1 in the endothelial cells of the terminal branches of umbilical blood vessels within the placental villae. Bidirectional activity of 11ßHSD in vascular smooth muscle cells of other parts of the body has been reported previously (30). 11ßHSD in blood vessels is thought to influence vascular tone by metabolizing glucocorticoids reaching the vessel wall (31). Effects of glucocorticoids on vascular tone may be direct or indirect through other vasoactive compounds produced in the vascular wall. Glucocorticoids can induce hypertension through either a direct effect on the blood vessel with increasing transmembrane Ca2+ influx (32) or a permissive action to other vascular regulating hormones (33). We speculate that the umbilical vascular 11ßHSD may have a similar role in regulating vascular tone in the umbilical cord and the placental villi, and this possibility seems worthy of further study.

Consistent with our immunohistochemical results, a mRNA for 11ßHSD1 with an expected size of 1.5 kb (25) was detected in chorion, placenta, and amnion using a human 11ßHSD1 cDNA probe. This finding provides conclusive evidence that the enzyme is synthesized in these tissues. However, levels of 11ßHSD1 mRNA were much greater in chorion/decidua than in placenta and amnion, consistent with the more extensive IR-11ßHSD1 staining in chorion trophoblasts. Recently, 11ßHSD1 mRNA was demonstrated in the human placenta using reverse transcriptase-PCR (34), although previously the same researchers were unable to demonstrate 11ßHSD1 mRNA in this tissue (27). The apparent differences in 11ßHSD1 mRNA between different studies and within individual patients may reflect heterogeneity of the tissue, particularly in the content of extravillous cytotrophoblasts, which are major sites of expression.

The highest levels of 11ßHSD2 mRNA were found in the placenta, as shown previously (27). 11ßHSD2 mRNA was not detected in total RNA from the fetal membranes, further indicating the discrete cellular distribution patterns of 11ßHSD1 and 11ßHSD2 in the placenta and fetal membranes. In addition to the 1.9-kb 11ßHSD2 mRNA in placenta, we observed a larger transcript of about 4.0 kb. The presence of this transcript has been reported previously in the mouse kidney (35). It is possible that the larger 4.0-kb transcript is the product of a distinct transcriptional start site within the 11ßHSD2 gene.

In humans, glucocorticoids have been shown to stimulate the synthesis of CRH from the placenta and membranes and to increase levels of placental CRH mRNA (20). Glucocorticoids increase PG synthesis from confluent amnion epithelial cells (36), and CRH and PGs have been implicated in causing uterine contractility, either directly or indirectly (37, 38). Therefore, 11ßHSD in the placenta and fetal membranes could influence the process of labor by metabolizing glucocorticoids reaching the placenta and fetal membranes. However, the lack of change in 11ßHSD1 or 11ßHSD2 mRNA or 11ßHSD1 localization in either the fetal membranes or the placenta in association with labor implies that any influence of 11ßHSD1 on this process is not exerted acutely at the time of parturition, although we cannot preclude a progressive influence through late gestation (26, 39).

Although the affinity of 11ßHSD1 is too low to effectively exclude maternal glucocorticoids from the fetus, the differential distributions of 11ßHSD1 and 11ßHSD2 in the placenta and fetal membranes and the unique cortisol regenerating function of 11ßHSD1 could provide a coordinated mechanism by which the amounts of maternal glucocorticoids reaching the fetus are controlled precisely. Understanding the discrete distribution and functions of 11ßHSD1 and 11ßHSD2 in the placenta and fetal membranes could be important in understanding not only the processes of normal pregnancy, but also the pathophysiology of abnormal pregnancy including preterm delivery, preeclampsia, and fetal growth restriction.


   Footnotes
 
1 This work was supported by operating grants from the Canadian Medical Research Council (Group Grant: Fetal and Neonatal Health and Development to J.R.G.C.; Grant MT12100 to K.Y.). Back

Received May 14, 1996.

Revised August 29, 1996.

Accepted September 8, 1996.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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W. Li, L. Gao, Y. Wang, T. Duan, L. Myatt, and K. Sun
Enhancement of Cortisol-Induced 11{beta}-Hydroxysteroid dehydrogenase Type 1 Expression by Interleukin 1{beta} in Cultured Human Chorionic Trophoblast Cells
Endocrinology, May 1, 2006; 147(5): 2490 - 2495.
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 Endocr. Rev.Home page
V. E. Murphy, R. Smith, W. B. Giles, and V. L. Clifton
Endocrine Regulation of Human Fetal Growth: The Role of the Mother, Placenta, and Fetus
Endocr. Rev., April 1, 2006; 27(2): 141 - 169.
[Abstract] [Full Text] [PDF]

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 J EndocrinolHome page
N. Draper and P. M Stewart
11{beta}-Hydroxysteroid dehydrogenase and the pre-receptor regulation of corticosteroid hormone action
J. Endocrinol., August 1, 2005; 186(2): 251 - 271.
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 Reproductive SciencesHome page
J. F. Johnstone, A. D. Bocking, E. Unlugedik, and J. R.G. Challis
The Effects of Chorioamnionitis and Betamethasone on 11{beta}, Hydroxysteroid Dehydrogenase Types 1 and 2 and the Glucocorticoid Receptor in Preterm Human Placenta
Reproductive Sciences, May 1, 2005; 12(4): 238 - 245.
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 J. Clin. Endocrinol. Metab.Home page
J. P. van Beek, H. Guan, L. Julan, and K. Yang
Glucocorticoids Stimulate the Expression of 11{beta}-Hydroxysteroid Dehydrogenase Type 2 in Cultured Human Placental Trophoblast Cells
J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5614 - 5621.
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J. W. Tomlinson, E. A. Walker, I. J. Bujalska, N. Draper, G. G. Lavery, M. S. Cooper, M. Hewison, and P. M. Stewart
11{beta}-Hydroxysteroid Dehydrogenase Type 1: A Tissue-Specific Regulator of Glucocorticoid Response
Endocr. Rev., October 1, 2004; 25(5): 831 - 866.
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 ReproductionHome page
S McMullen, J C Osgerby, L M Thurston, T S Gadd, P J Wood, D C Wathes, and A E Michael
Alterations in placental 11{beta}-hydroxysteroid dehydrogenase (11{beta}HSD) activities and fetal cortisol:cortisone ratios induced by nutritional restriction prior to conception and at defined stages of gestation in ewes
Reproduction, June 1, 2004; 127(6): 717 - 725.
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 Recent Prog Horm ResHome page
J. R. Seckl, N. M. Morton, K. E. Chapman, and B. R. Walker
Glucocorticoids and 11beta-Hydroxysteroid Dehydrogenase in Adipose Tissue
Recent Prog. Horm. Res., January 1, 2004; 59(1): 359 - 393.
[Abstract] [Full Text]

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 Mol Hum ReprodHome page
P.M. Driver, S. Rauz, E.A. Walker, M. Hewison, M.D. Kilby, and P.M. Stewart
Characterization of human trophoblast as a mineralocorticoid target tissue
Mol. Hum. Reprod., December 1, 2003; 9(12): 793 - 798.
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 EndocrinologyHome page
K. Sun and L. Myatt
Enhancement of Glucocorticoid-Induced 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Expression by Proinflammatory Cytokines in Cultured Human Amnion Fibroblasts
Endocrinology, December 1, 2003; 144(12): 5568 - 5577.
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 Biol. Reprod.Home page
H.G. Klemcke, R. Sampath Kumar, K. Yang, J.L. Vallet, and R.K. Christenson
11{beta}-Hydroxysteroid Dehydrogenase and Glucocorticoid Receptor Messenger RNA Expression in Porcine Placentae: Effects of Stage of Gestation, Breed, and Uterine Environment
Biol Reprod, December 1, 2003; 69(6): 1945 - 1950.
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 J. Clin. Endocrinol. Metab.Home page
N. Alfaidy, W. Li, T. MacIntosh, K. Yang, and J. Challis
Late Gestation Increase in 11{beta}-Hydroxysteroid Dehydrogenase 1 Expression in Human Fetal Membranes: A Novel Intrauterine Source of Cortisol
J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 5033 - 5038.
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M. Girotti and H. H. Zingg
Gene Expression Profiling of Rat Uterus at Different Stages of Parturition
Endocrinology, June 1, 2003; 144(6): 2254 - 2265.
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 Biol. Reprod.Home page
K. Sun, P. He, and K. Yang
Intracrine Induction of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Expression by Glucocorticoid Potentiates Prostaglandin Production in the Human Chorionic Trophoblast
Biol Reprod, November 1, 2002; 67(5): 1450 - 1455.
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 J. Clin. Endocrinol. Metab.Home page
N. Alfaidy, S. Gupta, C. DeMarco, I. Caniggia, and J. R. G. Challis
Oxygen Regulation of Placental 11{beta}-Hydroxysteroid Dehydrogenase 2: Physiological and Pathological Implications
J. Clin. Endocrinol. Metab., October 1, 2002; 87(10): 4797 - 4805.
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 J. Clin. Endocrinol. Metab.Home page
V. E. Murphy, T. Zakar, R. Smith, W. B. Giles, P. G. Gibson, and V. L. Clifton
Reduced 11{beta}-Hydroxysteroid Dehydrogenase Type 2 Activity Is Associated with Decreased Birth Weight Centile in Pregnancies Complicated by Asthma
J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1660 - 1668.
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 J. Clin. Endocrinol. Metab.Home page
F. A. Patel and J. R. G. Challis
Cortisol/Progesterone Antagonism in Regulation of 15-Hydroxysteroid Dehydrogenase Activity and mRNA Levels in Human Chorion and Placental Trophoblast Cells at Term
J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 700 - 708.
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 J. Clin. Endocrinol. Metab.Home page
N. Alfaidy, Z. G. Xiong, L. Myatt, Stephen. J. Lye, J. F. MacDonald, and J. R. G. Challis
Prostaglandin F2{alpha} Potentiates Cortisol Production by Stimulating 11{beta}-Hydroxysteroid Dehydrogenase 1: A Novel Feedback Loop That May Contribute to Human Labor
J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5585 - 5592.
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 J. Clin. Endocrinol. Metab.Home page
C. L. McTernan, N. Draper, H. Nicholson, S. M. Chalder, P. Driver, M. Hewison, M. D. Kilby, and P. M. Stewart
Reduced Placental 11{beta}-Hydroxysteroid Dehydrogenase Type 2 mRNA Levels in Human Pregnancies Complicated by Intrauterine Growth Restriction: An Analysis of Possible Mechanisms
J. Clin. Endocrinol. Metab., October 1, 2001; 86(10): 4979 - 4983.
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 Mol Hum ReprodHome page
P.M. Driver, M.D. Kilby, I. Bujalska, E.A. Walker, M. Hewison, and P.M. Stewart
Expression of 11{beta}-hydroxysteroid dehydrogenase isozymes and corticosteroid hormone receptors in primary cultures of human trophoblast and placental bed biopsies
Mol. Hum. Reprod., April 1, 2001; 7(4): 357 - 363.
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 Biol. Reprod.Home page
W.L. Whittle, F.A. Patel, N. Alfaidy, A.C. Holloway, M. Fraser, S. Gyomorey, S.J. Lye, W. Gibb, and J.R.G. Challis
Glucocorticoid Regulation of Human and Ovine Parturition: The Relationship Between Fetal Hypothalamic-Pituitary-Adrenal Axis Activation and Intrauterine Prostaglandin Production
Biol Reprod, April 1, 2001; 64(4): 1019 - 1032.
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 J. Clin. Endocrinol. Metab.Home page
E. Schoof, M. Girstl, W. Frobenius, M. Kirschbaum, H. G. Dörr, W. Rascher, and J. Dötsch
Decreased Gene Expression of 11{beta}-Hydroxysteroid Dehydrogenase Type 2 and 15-Hydroxyprostaglandin Dehydrogenase in Human Placenta of Patients with Preeclampsia
J. Clin. Endocrinol. Metab., March 1, 2001; 86(3): 1313 - 1317.
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G. Hirasawa, J. Takeyama, H. Sasano, K. Fukushima, T. Suzuki, Y. Muramatu, A. D. Darnel, C. Kaneko, N. Hiwatashi, T. Toyota, et al.
11{beta}-Hydroxysteroid Dehydrogenase Type II and Mineralocorticoid Receptor in Human Placenta
J. Clin. Endocrinol. Metab., March 1, 2000; 85(3): 1306 - 1309.
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 Biol. Reprod.Home page
D.B. Hardy, L.E. Pereria, and K. Yang
Prostaglandins and Leukotriene B4 Are Potent Inhibitors of 11ß-Hydroxysteroid Dehydrogenase Type 2 Activity in Human Choriocarcinoma JEG-3 Cells
Biol Reprod, July 1, 1999; 61(1): 40 - 45.
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G. Hirasawa, H. Sasano, T. Suzuki, J. Takeyama, Y. Muramatu, K. Fukushima, N. Hiwatashi, T. Toyota, H. Nagura, and Z. S. Krozowski
11{beta}-Hydroxysteroid Dehydrogenase Type 2 and Mineralocorticoid Receptor in Human Fetal Development
J. Clin. Endocrinol. Metab., April 1, 1999; 84(4): 1453 - 1458.
[Abstract] [Full Text]

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 Biol. Reprod.Home page
J. Tremblay, D.B. Hardy, L.E. Pereira, and K. Yang
Retinoic Acid Stimulates the Expression of 11ß-Hydroxysteroid Dehydrogenase Type 2 in Human Choriocarcinoma JEG-3 Cells
Biol Reprod, March 1, 1999; 60(3): 541 - 545.
[Abstract]