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Local Modulation by 11ß-Hydroxysteroid Dehydrogenase of Glucocorticoid Effects on the Activity of 15-Hydroxyprostaglandin Dehydrogenase in Human Chorion and Placental Trophoblast Cells¹

University of Toronto, Departments of Physiology (F.A.P., K.S., J.R.G.C.) and Obstetrics and Gynaecology (J.R.G.C.), Medical Research Council Group in Fetal and Neonatal Health and Development (J.R.G.C.), Samuel Lunenfeld Research Institute, Mount Sinai Hospital (J.R.G.C.), Toronto, Canada

Address all correspondence and requests for reprints to: Ms. Fal Patel, Department of Physiology, 3rd Floor, Medical Sciences Building, University of Toronto, 1 King’s College Circle, Toronto, Ontario M5S 1A8, Canada. E-mail: fal.patel{at}utoronto.ca

	Abstract

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NAD⁺-dependent 15-hydroxy-PG dehydrogenase (PGDH) is the major enzyme involved in the initial inactivation of PGs, and its activity is reduced by glucocorticoids, cortisol (F), and dexamethasone (DEX). In turn, glucocorticoid regulation of PGDH activity in placenta and chorion could be regulated indirectly by 11ß-hydroxysteroid dehydrogenase (11ß-HSD) activity. In the placenta, 11ß-HSD2 is the dominant isoform, acting as a dehydrogenase [F to cortisone (E)]; and in chorion, 11ß-HSD1 predominates as a reductase (E to F). The present study was designed to determine whether glucocorticoid regulation of PGDH activity in placenta and chorion could be regulated indirectly by 11ß-HSD activity. We obtained Percoll-purified human placental and chorion trophoblast cells from uncomplicated term pregnancies, cultured them for 72 h, then treated the cells with cortisol (100 nmol/L), cortisone (1 µmol/L), or DEX (100 nmol/L), in the presence or absence of carbenoxolone (CBX, 800 nmol/L), an 11ß-HSD inhibitor, for 24 h. Activity of PGDH was assessed by incubation (4 h) with PGF₂ (282 nmol/L) and measurement of conversion to 13,14-dihydro-15-keto PGF₂. CBX alone had no effect on PGDH activity in either placenta or chorion trophoblast cells. In chorion, E significantly inhibited PGDH activity, and this effect was reversed by addition of CBX. F and DEX significantly inhibited PGDH, and this effect was unaltered by coadministration of CBX. In contrast, in placenta, there was no effect of E, or of E with CBX, on PGDH activity. However, F and DEX inhibited PGDH, and the effect of F (but not DEX) was greater in the presence of CBX. In conclusion, we suggest that effects of E and F on PGDH are modified by the tissue-specific expression of 11ß-HSD isoforms.

	Introduction

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PGs HAVE been implicated strongly as uterotonins at the time of labor, affecting myometrial contractility and cervical dilatation (1, 2). The amnion and chorion are major sites of PG synthesis in the human uterus (3, 4). At labor, these tissues have increased output of stimulatory PGs and increased expression of the inducible PG H2 synthase enzyme (5, 6, 7, 8). NAD⁺-dependent 15-hydroxy-PG dehydrogenase (PGDH) is the major enzyme involved in the initial inactivation of PGs (9, 10). PGDH messenger RNA (mRNA) and protein have been localized to placental syncytiotrophoblast and to the trophoblast layer of chorion (11, 12, 13), where the enzyme may act as a metabolic barrier to prevent passage of primary PGs, generated in amnion or chorion, to the underlying decidua and/or myometrium (14, 15). Recent in vitro studies have suggested that PGDH activity in chorionic and placental trophoblasts from term pregnancies is increased by progesterone and inhibited by cortisol (16). The effect of progesterone may be exerted in an autocrine/paracrine fashion, because the enzyme 3ß-hydroxysteroid dehydrogenase (3ß-HSD) that converts pregnenolone to progesterone also localizes to trophoblast cell types (17, 18, 19). PGDH activity was reduced by addition of a 3ß-HSD inhibitor to the cells in culture but was restored with addition of progesterone (16).

Glucocorticoids could also affect PGDH by local mechanisms. Cortisol (F) and cortisone (E) are interconverted by the enzyme 11ß-HSD (20, 21). This enzyme exists as, at least, two isoforms; 11ß-HSD1 (which is bidirectional but favors reduction of inactive cortisone to active cortisol) and 11ß-HSD2 (which operates essentially as a unidirectional dehydrogenase, converting F to E) (22, 23, 24, 25, 26). 11ß-HSD1 localizes predominantly to chorion trophoblasts, and 11ß-HSD2 is present predominantly in placental syncytiotrophoblast (27, 28, 29). Thus, these enzymes colocalize with PGDH in chorion and in placenta. Moreover, we found that trophoblast cells, prepared from chorion and placenta, retained their distinct patterns of 11ß-HSD activity during primary cell culture (30).

We reasoned that the presence of 11ß-HSD isozymes in human chorion and placenta could determine local metabolism of corticosteroids and, thereby, the effect of cortisol or cortisone on PGDH activity. We hypothesized that, in chorion, 11ß-HSD1 activity would reduce cortisone to cortisol, allowing it to act through glucocorticoid receptors (GR), present in chorion and placenta (31, 32, 33), as an active glucocorticoid. In placenta, 11ß-HSD2 normally attenuates the effects of cortisol (21, 24). We have therefore examined effects of cortisone or cortisol on PGDH activity in placental and chorion trophoblast cells in the absence or presence of carbenoxolone (CBX), an inhibitor of 11ß-HSD. We also examined effects of dexamethasone (DEX) on PGDH activity by placental and chorion trophoblast cells in vitro. DEX is a synthetic glucocorticoid that traverses the placental barrier in vivo (34) and is a relatively poor substrate for the 11ß-HSD isozymes (35, 36).

	Materials and Methods

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Tissue collection

Placenta and choriodecidual tissue was obtained from uncomplicated, normal term pregnancies after elective cesarean section (n = 11 patients) or spontaneous vaginal delivery (n = 1 patient). Tissue was obtained from Mt. Sinai Hospital, under the guidelines of a protocol approved by the local ethics committee. The tissue was digested with trypsin (0.125%, Sigma Chemical Co., St. Louis, MO) in the presence of 0.02% deoxyribonuclease 1 (Sigma Chemical Co.) or 0.2% collagenase (Sigma Chemical Co.), as described previously (16, 30). Dispersed cells were purified using continuous Percoll density gradient separation (37) to obtain cytotrophoblasts. The cells were then diluted with DMEM culture medium containing 10% FCS (GIBCO BRL, Grand Island, New York, NY) and were plated at a density of 1 million cells per well in 5% CO₂-95% air at 37 C, as described (16, 30).

Tissue culture and analyses

Trophoblast cells were grown for 3 days, then incubated for 24 h in serum-free fresh medium containing cortisol, cortisone, or DEX (0–1000 nmol/L), in the absence or presence of CBX (800 nmol/L). Control cultures were maintained without additives, or in the presence of CBX alone. The amount of CBX was established in preliminary experiments. Each treatment was performed in duplicate or triplicate for each preparation of cells. After 24 h, the medium was replaced with fresh medium containing PGF₂ (100 ng/mL; 282 nmol/L) without steroids for 4 h. The medium was then collected and stored at -80 C for later assessment of PGDH activity by RIA of the concentration of 13,14-dihydro-15-keto PGF₂ (PGFM), the stable metabolite of PGF₂, in the culture medium, as described previously (16).

At the end of each experiment, representative wells of cells were fixed and immunostained for cytokeratin and vimentin using primary antibodies (Dako Corp., Santa Barbara, CA) at 1:1000 and 1:100 dilutions, respectively (11, 16). Other cultures were stained for PGDH, with a polyclonal primary antibody raised against purified human placental type 1 PGDH (Cayman Laboratories, Ann Arbor, MI).

Cortisol:cortisone interconversions

We conducted preliminary studies to determine the dose-dependent effect of CBX on the activity of 11ß-HSD1 in chorion and 11ß-HSD2 in placental cells. ³H-cortisol (SA, 64.0 Ci/mmol; Amersham Life Science, Buckinghamshire, UK) was purified by thin-layer chromatography (TLC) in the solvent system chloroform:ethanol (95:5, vol/vol). ³H-cortisone was prepared from ³H-cortisol, by oxidation with chromium trioxide (38), and purified by TLC before use.

After 3 days culture, cells were washed in culture medium free of calf serum, then incubated with 100 nmol/L cortisol containing 0.5 x 10⁶ dpm ³H-cortisol to assess 11ß-HSD2, or 1 µmol/L cortisone containing 0.5 x 10⁶ dpm ³H-cortisone to assess 11ß-HSD1 in the presence of increasing concentrations of CBX. At the end of 24 h incubation, medium was collected and radioactivity corresponding in mobility on TLC (chloroform:ethanol; 95:5, vol/vol), to authentic cortisol and cortisone, was separated, eluted, and counted as described previously (30). Enzyme activities were expressed as the percentage formation of product (E or F) from precursor (F or E).

Statistical analysis

Results are expressed as mean ± SEM for the number of different tissues (patients) studied. We have shown previously that effects of cortisol on PGDH activity from chorion obtained after elective cesarean section or after spontaneous vaginal delivery were similar (16), and results from chorion tissue collected at these times have been pooled. Effects of treatment on concentrations of PGFM in the culture medium were examined by one-way ANOVA, corrected for repeated measures, when appropriate. Differences between treatments were examined using Student-Newman-Keuls multiple-range tests, when the data were not distributed normally. Statistical significance was set at P < 0.05. Calculations were performed using SigmaStat (Jandel Scientific Software, San Rafael, CA).

	Results

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Cell morphology

At the end of the culture period, placental trophoblast cells tended to form aggregates, thought to correspond to syncytium formation in vivo, that were more than 95% cytokeratin positive and vimentin negative. Chorion trophoblast cells were present as clumps of cells or as single cells. These were predominantly cytokeratin positive (>75–90%). Both placental and chorion trophoblast cell cultures stained positively for immunoreactive (ir)-PGDH, as described previously (16).

Effects of CBX on 11ß-HSD activity

CBX caused a dose-dependent inhibition of 11ß-HSD enzyme activities (Fig. 1), although 11ß-HSD2 was affected more than 11ß-HSD1 (n = 4, for both chorion and placenta). IC₅₀ values were 0.4 µmol/L for 11ß-HSD1 and 0.1 µmol/L for 11ß-HSD2. For both isoforms, 11ß-HSD activity was reduced to less than 20% conversion at 800 nmol/L CBX (Fig. 1), the concentration used in subsequent experiments.

View larger version (21K): [in this window] [in a new window]   Figure 1. Dose-dependent inhibition by CBX on cortisol-to-cortisone conversion by 11ß-HSD2 in cultured human placental syncytiotrophoblast and on cortisone-to-cortisol conversion by 11ß-HSD1 in cultured human chorion trophoblast cells.

CBX alone (800 nmol/L) had no significant effect on PGDH activity in placental cells (Fig. 2). In placenta, there was no effect of cortisone, in the presence or absence of CBX on PGDH activity (Fig. 2). Cortisol, however, inhibited PGDH activity in a dose-dependent fashion, and the inhibitory effect of cortisol was enhanced in the presence of CBX (P < 0.05, Fig. 3A). DEX also produced a dose-dependent inhibition of PGDH activity. However, there was no effect of CBX on DEX-induced PGDH inhibition (Fig. 3B), in marked contrast to the effect of CBX on the effectiveness of cortisol action.

View larger version (15K): [in this window] [in a new window]   Figure 2. Effects of CBX (800 nmol/L), cortisone (1 µmol/L), and cortisone in the presence of CBX (800 nmol/L) on PGF2-to-PGFM conversion in cultured human placental syncytiotrophoblast cells. Cells were preincubated for 24 h with the steroids and ir-PGFM (13, 14-dihydro-15-keto PGF2) measured after a 4-h incubation with added PGF2 (282 nmol/L). All values are means ± SEM (n = 4).

View larger version (15K): [in this window] [in a new window]   Figure 3. A, Effects of CBX (), cortisol (circf), and cortisol in the presence of fixed 800 nmol/L CBX (circo) on PGFM (13, 14-dihydro-15-keto PGF2) formation in cultured term human placental syncytiotrophoblast. All values are means ± SEM (n = 4); *, P < 0.05. B, Effects of CBX (), DEX (), and DEX in the presence of fixed 800 nmol/L CBX () on PGFM (13, 14-dihydro-15-keto PGF2) formation in cultured term human placental syncytiotrophoblast as in 3A. All values are means ± SEM (n = 4); *, P < 0.05.

CBX alone (800 nmol/L) had no significant effect on PGDH activity in chorion trophoblast cells (Fig. 4). Cortisol and DEX (both 100 nmol/L) inhibited PGDH activity in chorion trophoblast cells, as in placenta. There was no further effect in the presence of CBX. Addition of cortisone (1 µmol/L) produced a profound inhibition of PGDH (P < 0.01), in total contrast to its lack of effect on placental cells (Fig. 4). However, the inhibitory effect of cortisone on PGDH activity in chorion cells was reversed completely in the presence of CBX, an inhibitor of chorionic 11ß-HSD1 (P < 0.01).

View larger version (13K): [in this window] [in a new window]   Figure 4. Effects of CBX (800 nmol/L; P = 0.7), cortisone (1 µmol/L), cortisone + CBX (P = 0.5), cortisol (100 nmol/L) ± CBX, and DEX (100 nmol/L) ± CBX, on PGF2-to-PGFM conversion in cultured human chorion trophoblast cells. Cells were preincubated for 24 h with the steroids and ir-PGFM (13, 14-dihydro-15-keto PGF2), measured after a 4-h incubation period with added PGF2 (282 nmol/L). All values are means ± SEM (n = 4); *, P < 0.05.

	Discussion

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We have shown previously that human placental and chorion trophoblast cells, grown in primary culture, maintain the same pattern of expression of 11ß-HSD isozymes as in vivo (30). Thus, chorion trophoblasts interconvert cortisol (F) and cortisone (E), but cortisone reduction to cortisol predominates. This is consistent with the presence of 11ß-HSD1 mRNA and ir-11ß-HSD1 in chorion tissue collected from women at term (28). There is little, if any, 11ß-HSD2 in chorion (28). Placental trophoblasts form aggregates in vitro (40) that are thought to correspond to syncytium formation. These cells express high 11ß-HSD2 (F to E) activity, corresponding to measurement of mRNA encoding 11ß-HSD2 (28) and positive staining for 11ß-HSD2 in syncytiotrophoblast from term placental tissue (29). Both 11ß-HSD1 and 11ß-HSD2 activities were inhibited in a dose-dependent fashion by CBX, although the inhibition of 11ß-HSD2 was greater than that of 11ß-HSD1. At 800 nmol/L CBX, we obtained substantial, although not complete, inhibition of both 11ß-HSD1 and 11ß-HSD2. Importantly, this concentration of CBX had no effect by itself on PGDH activity.

Our results in placenta can be explained by CBX inhibition of 11ß-HSD2. DEX is a poor substrate for 11ß-HSD2, and its levels are unaltered by CBX. Cortisol, the major 11ß-HSD2 substrate in human placenta, inhibited PGDH activity, and this effect was much greater in the presence of CBX, presumably because the steroid was protected from metabolism by 11ß-HSD2 to inactive cortisone. Thus, the activity of 11ß-HSD2 in placenta affects the ability of cortisol to inhibit PGDH, and the two enzymes seem to localize to the same cell types. Based on our previous studies, it is likely that the inhibitory effect of glucocorticoid was on levels of PGDH mRNA, as well as on enzymatic activity (conversion of PGF₂ to PGFM) (16). Human placenta also expresses 11ß-HSD1 in endothelial cells and in intermediate trophoblast (27, 28). The activity of 11ß-HSD1 by placental cells in vitro is approximately 15% that of 11ß-HSD2 (29). Hence, there is minimal conversion of cortisone to cortisol, and cortisone is not active on PGDH, either in the presence or absence of CBX.

DEX also inhibited PGDH activity in placental syncytiotrophoblast cells, but the effect of DEX alone was not as potent as that of cortisol + CBX, raising the interesting possibility that cortisol may be binding to another receptor species, such as the mineralocorticoid receptor, and that the effects of cortisol on PGDH activity were therefore exerted through interaction of cortisol with the mineralocorticoid receptor.

In chorion, the pattern was quite different. This tissue expresses 11ß-HSD1 and little or no 11ß-HSD2 (27, 28). Cortisol was effective in inhibiting chorionic PGDH (16), and this activity was not altered by CBX because chorionic 11ß-HSD1 acts predominantly as a reductase. DEX is a poor substrate for 11ß-HSD1, and its inhibitory effect on PGDH activity was unaffected by the presence of CBX. The most striking result was obtained with addition of cortisone. Generally regarded as a biologically inactive corticosteroid (39, 41), cortisone inhibited PGDH activity almost as effectively as cortisol. However, this action was inhibited by CBX, indicating strongly that it depended on conversion of cortisone to cortisol by the cells. Thus, 11ß-HSD1 locally activates cortisone to cortisol in chorion trophoblasts, allowing autocrine/paracrine regulation of PGDH activity.

The present results may be combined with those reported previously for progesterone effects on PGDH (16, 42, 43, 44, 45), to develop a scheme by which PGDH expression and activity in chorion and placental trophoblasts may reflect a balance between opposing influences of cortisol and progesterone (Fig. 5, A and B). We found previously that progestin analogs stimulated PGDH activity (16). Progestin antagonists reduced basal PGDH activity, an effect similar to that seen in the presence of trilostane, a 3ß-HSD inhibitor. The effect of trilostane was overcome with exogenous progesterone, and it suggested that endogenous, locally-produced progesterone by the trophoblast cells themselves, was responsible for maintaining PGDH activity. These results suggest that, in human chorion at term, PGDH activity in trophoblasts might be regulated, in opposing directions, by cortisol and progesterone, which may be produced from cortisone and pregnenolone, respectively, in the trophoblast cells (17, 18, 19, 29, 30). Given the rather limited vascular supply to chorion (46, 47), steroid substrates could be gained from the maternal (decidual) circulation or from amniotic fluid (47). This possibility does not preclude effects of systemically-derived progesterone or cortisol on chorionic PGDH activity. In placenta, steroid modulation of PGDH activity in syncytiotrophoblast likely depends on generation of progesterone by trophoblast cells (19), and on systemic, circulating cortisol that escapes inactivation by 11ß-HSD2. DEX escapes extensive metabolism in chorion and placenta, and it inhibits PGDH in both tissues. In addition, it is possible that other factors, including cytokines, are involved in the regulation of PGDH in intrauterine tissues, particularly in the setting of infection (48).

View larger version (15K): [in this window] [in a new window]   Figure 5. A, Schematic representation of regulation by progesterone and glucocorticoids (cortisol and DEX) of PGDH activity in placenta in vitro; B, schematic representation of regulation by progesterone and glucocorticoids (cortisol, cortisone, and DEX) of PGDH activity in chorion in vitro. Note that cortisone is active in chorion but not in placenta, because it can undergo reduction to cortisol by 11ß-HSD1 in chorionic trophoblast cells.

	Acknowledgments

 
We thank Lindsay McWhirter and Dr. S. J. Lye (Mt. Sinai Hospital) for their assistance in collecting tissues, and Dr. W. Gibb (University of Ottawa) for his thoughtful discussion.

	Footnotes

 
¹ This work was supported by the Medical Research Council of Canada (Group Grant in Fetal and Neonatal Health and Development).

Received September 1, 1998.

Revised October 22, 1998.

Accepted October 27, 1998.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 

1. Novy MJ, Liggins GC. 1980 Role of prostaglandins, prostacyclin, and thromboxanes in the physiologic control of the uterus and parturition. Semin Perinatol. 4:45–66.[Medline]
2. Mitchell MD. 1984 The mechanism(s) of human parturition. J Dev Physiol. 6:107–118.[Medline]
3. Mitchell MD, Bibby J, Hicks BR, Turnbull AC. 1978 Specific production of prostaglandin E₂ by human amnion in vitro. Prostaglandins. 15:377–382.[CrossRef][Medline]
4. Okazaki T, Casey ML, Okita J, MacDonald PC, Johnston JM. 1981 Initiation of parturition XII. Biosynthesis and metabolism of prostaglandins in human fetal membranes and uterine decidua. Am J Obstet Gynecol. 139:373–381.[Medline]
5. Mijovic JE, Zakar T, Nairn TK, Olson DM. 1997 Prostaglandin-endoperoxide H synthase-2 expression and activity increases with term labor in human chorion. Am J Physiol 272:E832–840.
6. Olson DM, Skinner K, Challis JRG. 1983 Prostaglandin output in relation to parturition by cells dispersed from human intrauterine tissues. J Clin Endocrinol Metab. 57:694–699.[Abstract]
7. Skinner KA, Challis JRG. 1985 Changes in the synthesis and metabolism of prostaglandins by human fetal membranes and decidua at labor. Am J Obstet Gynecol. 151:519–523.[Medline]
8. Teixeira FJ, Zakar T, Hirst JJ, et al. 1994 Prostaglandin endoperoxide-H synthase (PGHS) activity and immunoreactive PGHS-1 and PGHS-2 levels in human amnion throughout gestation, at term and during labor. J Clin Endocrinol Metab. 78:1396–1402.[Abstract]
9. Keirse MJNC. 1979 Endogenous prostaglandins in human parturition. In: Keirse MJNC, Anderson ABM, Bennebrock-Gravenhorst J, eds. Human parturition. Leiden: University Press; 15:101–142.
10. Tai H-H. 1976 Enzymatic synthesis of (15S)-[15-³H] prostaglandins and their use in the development of a simple and sensitive assay for 15-hydroxyprostaglandin dehydrogenase. Biochemistry. 15:4586–4592.[CrossRef][Medline]
11. Cheung PYC, Walton JC, Tai H-H, Riley SC, Challis JRG. 1990 Immunocytochemical distribution and localization of 15-hydroxyprostaglandin dehydrogenase in human fetal membranes, decidua, and placenta. Am J Obstet Gynecol. 163:1445–1449.[Medline]
12. Cheung PYC, Walton JC, Tai H-H, Riley SC, Challis JRG. 1992 Localization of 15-hydroxyprostaglandin dehydrogenase in human fetal membranes, decidua, and placenta during pregnancy. Gynecol Obstet Invest. 33:142–146.[Medline]
13. Sangha RK, Walton JC, Ensor CM, Tai H-H, Challis JRG. 1994 Immunohistochemical localization, mRNA abundance and activity of 15-hydroxyprostaglandin dehydrogenase in placenta and fetal membranes during term and pre-term labor. J Clin Endocrinol Metab. 78:982–989.[Abstract]
14. Nakla S, Skinner K, Mitchell BF, Challis JRG. 1986 Changes in prostaglandin transfer across human fetal membranes obtained after spontaneous labor. Am J Obstet Gynecol. 155:1337–1341.[Medline]
15. Sullivan MH, Roseblade CK, Elder MG. 1991 Metabolism of prostaglandin E₂ on the fetal and maternal sides of intact fetal membranes. Acta Obstet Gynecol Scand. 70:425–427.[Medline]
16. Patel FA, Clifton VL, Chwalisz K, Challis JRG. 1999 Steroidal regulation of prostaglandin dehydrogenase activity and expression in human term placenta and chorio-decidua in relation to labor. J Clin Endocrinol Metab. 84:291–299.[Abstract/Free Full Text]
17. Gibb W, Lavoie J-C, Roux JF. 1978 3ß-hydroxysteroid dehydrogenase activity in human fetal membranes. Steroids. 32:365–372.[CrossRef][Medline]
18. Mitchell BF, Challis JRG. 1988 Estrogen and progesterone metabolism in human fetal membranes. In: Mitchell BF, ed. The human fetal membranes structure and function. New York: Perinatology Press; 5–28.
19. Riley SC, Dupont E, Walton JC, et al. 1992 Immunohistochemical localization of 3ß-hydroxy-5-ene-steroid dehydrogenase/⁵⁴ isomerase in human placenta and fetal membranes throughout gestation. J Clin Endocrinol Metab. 75:956–961.[Abstract]
20. Pasqualini JR, Nguyen BL, Uhrich F, Wiqvist N, Diczfalusy E. 1970 Cortisol and cortisone metabolism in the human feto-placental unit at midgestation. J Steroid Biochem Mol Biol. 1:209–219.
21. Murphy BEP, Clark SJ, Donald IR, Pinsky M, Vedady D. 1974 Conversion of maternal cortisol to cortisone during placental transfer to the human fetus. Am J Obstet Gynecol. 118:538–541.[Medline]
22. Tannin GM, Agarwal AK, Monder C, New MI, White PC. 1991 The human gene for 11ß-hydroxysteroid dehydrogenase. Structure, tissue distribution, and chromosomal localization. J Biol Chem. 266:16653–16658.[Abstract/Free Full Text]
23. Kenouch S, Coutry N, Farman N, Bonvalet JP. 1992 Multiple patterns of 11ß-hydroxysteroid dehydrogenase catalytic activity along the mammalian nephron. Kidney Int. 42:56–60.[Medline]
24. Brown RW, Chapman KE, Edwards CR, Seckl JR. 1993 Human placental 11ß-hydroxysteroid dehydrogenase: evidence for and partial purification of a distinct NAD-dependent isoform. Endocrinology. 132:2614–2621.[Abstract]
25. Stewart PM, Murray BA, Mason JI. 1994 Human kidney 11ß-hydroxysteroid dehydrogenase is a high affinity NAD⁺-dependent enzyme and differs from the cloned "type I" isoform. J Clin Endocrinol Metab. 79:480–484.[Abstract]
26. Albiston AL, Obeyesekere VR, Smith RE, Krozowski ZS. 1994 Cloning and tissue distribution of the human 11ß-hydroxysteroid dehydrogenase type 2 enzyme. Mol Cell Endocrinol. 105:R11–R17.
27. Stewart PM, Rogerson FM, Mason JI. 1995 Type 2 11ß-hydroxysteroid dehydrogenase messenger ribonucleic acid and activity in human placenta and fetal membranes: its relationship to birth weight and putative role in fetal adrenal steroidogenesis. J Clin Endocrinol Metab. 80:885–890.[Abstract]
28. Sun K, Yang K, Challis JRG. 1997 Differential expression of 11ß-hydroxysteroid dehydrogenase type 1 and 2 in human placenta and fetal membranes. J Clin Endocrinol Metab. 82:300–305.[Abstract/Free Full Text]
29. Krozowski Z, Maguire JA, Stein-Oakley AN, Dowling J, Smith RE, Andrews RK. 1995 Immunohistochemical localization of the 11ß-hydroxysteroid dehydrogenase type II enzyme in human kidney and placenta. J Clin Endocrinol Metab. 80:2203–2209.[Abstract]
30. Sun K, Yang K, Challis JRG. 1997 Differential regulation of 11ß-hydroxysteroid dehydrogenase type 1 and 2 by nitric oxide in cultured human placental trophoblast and chorionic cell preparation. Endocrinology. 138:4912–4920.[Abstract/Free Full Text]
31. Giannopoulos G, Jackson K, Tulchinsky D. 1983 Specific glucocorticoid binding in human uterine tissues, placenta and fetal membranes. J Steroid Biochem Mol Biol. 19:1375–1378.
32. Sun M, Ramirez M, Challis JRG, Gibb W. 1996 Immunohistochemical localization of the glucocorticoid receptor in human fetal membranes and decidua throughout gestation. J Endocrinol. 149:243–248.[Abstract/Free Full Text]
33. Karalis K, Goodwin G, Majzoub JA. 1996 Cortisol blockade of progesterone: a possible mechanism involved in the initiation of human labor. Nat Med. 2:556–560.[CrossRef][Medline]
34. Ballard P, Ballard R. 1995 Scientific basis and therapeutic regimens for use of antenatal glucocorticoids. Am J Obstet Gynecol. 173:254–262.[CrossRef][Medline]
35. Brown RW, Chapman KE, Kotelevtsev Y, et al. 1996 Cloning and production of antisera to human placental 11ß-hydroxysteroid dehydrogenase type 2. Biochem J. 313:1007–1017.
36. Langley-Evans SC. 1997 Intrauterine programming of hypertension by glucocorticoids. Life Sci. 60:1213–1221.[CrossRef][Medline]
37. Kliman HJ, Nestler JE, Sermasi E, Sanger JM, Strauss III JF. 1986 Purification, characterization and in vitro differentiation of cytotrophoblasts from human term placentae. Endocrinology. 118:1567–1582.[Abstract]
38. Shaw DA, Quincey RV. 1963 The preparation of tritium-labelled cortisol metabolites of high specific activity. J Endocrinol. 26:577–578.
39. Bamberger CM, Schulte HM, Chrousos GP. 1996 Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids. Endocr Rev. 17:245–261.[CrossRef][Medline]
40. Kliman HJ, Feinman MA, Strauss III JF. 1987 Differentiation of human cytotrophoblast into syncytiotrophoblast in culture. Trophoblast Res. 2:407–421.
41. Rousseau GG, Baxter JD, Tomkins GM. 1972 Glucocorticoid receptors: relations between steroid binding and biological effects. J Mol Biol. 67:99–115.[CrossRef][Medline]
42. Alam NA, Russell PT, Tabor MW, Moulton BC. 1976 Progesterone and estrogen control of uterine prostaglandin dehydrogenase activity during deciduomal growth. Endocrinology. 98:859–863.[Abstract]
43. Bedwani JR, Marley PB. 1975 Enhanced inactivation of prostaglandin E₂ by the rabbit lung during pregnancy or progesterone treatment. Br J Pharmacol. 53:547–554.[Medline]
44. Myatt L, Jogee M, Elder MG. 1983 Regulation of prostacyclin metabolism in human placental cells in culture by steroid hormones. In: Lewis PJ, Moncada S, O’Grady J, eds. Prostacyclin in pregnancy. New York: Raven Press; 119–129.
45. Xun CQ, Ensor CM, Tai H-H. 1991 Regulation of synthesis and activity of NAD⁺-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) by dexamethasone and phorbol ester in human erythroleukemia (HEL) cells. Biochem Biophy Res Commun. 177:1258–1265.[CrossRef][Medline]
46. Kaufmann P, Stark J, Stegner HE. 1977 The villous stroma of the human placenta. I. The ultrastructure of fixed connective tissue cells. Cell Tissue Res. 177:105–121.[Medline]
47. Thomsen K, Hiersche HD. 1969 The functional morphology of the placenta, the foetus, the membranes and the umbilical cord. In: Klopper A, Diczfalusy E, eds. Foetus and placenta. Oxford and Edinburgh: Blackwell Scientific Publications; 61–137.
48. Keelan JA, Mesnage S, Goodwin V, Mitchell MD. Inhibition of 15-hydroxy prostaglandin dehydrogenase expression and activity by cytokines in human placental trophoblasts. Proc of the 45th Annual Meeting of The Society for Gynecol Investigation, , 1998 (Abstract 39).
49. Sun K, Yang K, Challis JRG. 1998 Regulation of 11ß-hydroxysteroid dehydrogenase Type 2 by progesterone, estrogen, and the cyclic adenosine 5'-monophosphate pathway in cultured human placental and chorionic trophoblasts. Biol Reprod. 58:1379–1384.[Abstract/Free Full Text]

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