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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 10 3710-3715
Copyright © 1998 by The Endocrine Society

Original Studies

17ß-Hydroxysteroid Dehydrogenase Types 1 and 2 in Human Placenta: An Immunohistochemical Study with Correlation to Placental Development1

Junji Takeyama, Hironobu Sasano, Takashi Suzuki, Kazuie Iinuma, Hiroshi Nagura and Stefan Andersson

Department of Pathology (J.T., H.S., T.S., H.N.) and Pediatrics (J.T., K.I.), Tohoku University School of Medicine, Sendai, Japan; Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center (S.A.), Dallas, Texas 75235

Address all correspondence and requests for reprints to: Junji Takeyama, M.D., Department of Pathology, Tohoku University School of Medicine, 2–1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan. E-mail: j-takeyama{at}patholo2.med.tohoku.ac.jp


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
In estrogen metabolism, the enzymatic properties of the 17ß-hydroxysteroid dehydrogenase (17ßHSD) isozymes play very important roles in steroid hormone metabolism in various tissues, including the placenta. 17ßHSD type 1 catalyzes primarily the reduction of estrone (E1) to estradiol (E2), whereas 17ßHSD type 2 catalyzes primarily the oxidation of E2 to E1. In this study, we examined immunohistochemical localization of 17ßHSD types 1 and 2 in human placenta (31 cases) ranging from 4–40 weeks gestation. The immunoreactivity of 17ßHSD type 1 was exclusively detected in syncytiotrophoblast from 4 weeks gestation to term placenta. Immunoreactivity of 17ßHSD type 2 first appeared in endothelial cells of intravillous vessels at 12 weeks gestation, and the number of 17ßHSD type 2-positive endothelial cells markedly increased up to 19 weeks, then reached a plateau. We quantitatively evaluated the 17ßHSD type 2-positive endothelial cells in chorionic villi and determined the ratio of 17ßHSD type 2-positive endothelial cells using immunohistochemistry of CD34, an endothelial antigen, in serial mirror tissue sections and subsequent image analysis using CAS 200. CD34 was detected from 4 weeks gestation, and its positive areas continued to increase toward term. The 17ßHSD type 2-positive area per CD34-positive area markedly increased from 13 weeks gestation and reached a plateau at 19 weeks gestation, in which almost all endothelial cells were positive for 17ßHSD type 2. 17ßHSD type 2, therefore, is considered to prevent the passage of excessive estrogens into the fetal circulation at endothelial cells of the intravillous fetal capillaries by catalyzing the inactivation of E2 to E1.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
DURING pregnancy, approximately 95% of total estriol circulates in a conjugated form, compared to 75% of estrone (E1) and only 5% of estradiol (E2), which suggests that the marked estrogenic effects during pregnancy are dependent on E2 (1, 2). Maternal blood levels of estrogen rise continuously from the beginning to the end of pregnancy (3), and the increase in the plasma concentrations of all estrogens was demonstrated to correlate better with fetal weight than with placental weight (2). However, it is also well known that the level of E2 in the umbilical vein does not necessarily increase in parallel with that in the maternal vein, whereas the level of E1 in the umbilical vein continues to increase during pregnancy (4). It has been considered that E2 produced in trophoblasts enter the maternal circulation through secretion into the intervillous space, whereas E1 is secreted at similar rates into both fetal and maternal circulations (5, 6, 7), which may account for such a gradient of E1 and E2 between fetal and maternal circulations. However, the detailed mechanism of these different secretory patterns of E1 and E2 in human placenta has remained unknown.

E2 production in placenta initially involves the production of E1 from C19 precursors of both maternal and fetal adrenal origins in combination with aromatase cytochrome P-450 (1). Immunohistochemical study demonstrated that aromatase is exclusively localized in syncytiotrophoblast in placenta (8). 17ß-Hydroxysteroid dehydrogenase (17ßHSD) catalyzes the interconversion between E1 and E2. Recently, several isoforms of this enzyme were identified in humans (9, 10, 11). 17ßHSD type 1 is a cytosolic enzyme highly specific for estrogens, whereas 17ßHSD type 2 is a microsomal enzyme reactive with estrogens, androgens such as androstenedione and testosterone, and C21 steroids, including 20{alpha}-dihydroprogesterone and progesterone, with nearly comparable activities (11, 12). In estrogen metabolism, 17ßHSD type 1 catalyzes primarily the reduction of E1 to E2, whereas 17ßHSD type 2 catalyzes primarily the oxidation of E2 to E1 (11, 13). Both 17ßHSD type 1 and type 2 are abundantly expressed in human placenta (11, 12, 13, 14), and the patterns of expression of these different isozymes have been postulated to be involved in the different secretory patterns of E1 and E2 in human placenta. 17ßHSD type 1 expression is confined to the syncytiotrophoblast, as in aromatase (8). Very recently, Moghrabi et al. reported that 17ßHSD type 2 is immunolocalized in the endothelial cells of fetal capillaries and cotyledonary vessels in full-term placenta (15). However, spatial and temporal expressions of 17ßHSD type 1 and type 2 in human placenta throughout pregnancy have not been examined. Therefore, in this study, we studied the distribution of 17ßHSD types 1 and 2 in various stages of human placenta using immunohistochemistry, including double immunostain, to elucidate the possible physiological roles of these isozymes in human placental and fetal development. In addition, 17ßHSD type 2 immunoreactivity was quantitatively analyzed using the computer-assisted image analysis system and correlated to the development of endothelial cells of intravillous fetal vessels.


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

Placental tissues (n = 31) with no significant histopathological abnormalities were retrieved from surgical pathology files of Tohoku University Hospital (Sendai, Japan). This study protocol was approved by the ethics committee of Tohoku University School of Medicine (Sendai, Japan). The gestational age of the placenta examined ranged from 4–40 weeks (Table 2Go). Tissue samples had been routinely fixed in 10% neutral formalin for 24–48 hours at room temperature and embedded in paraffin wax.


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  		Table 2. Summary of CD34 or 17ßHSD type 2-positive areas

 
Primary antibodies

The source, optimal dilution, and pretreatment methods of immunostain are summarized in Table 1Go. The monoclonal antibody, mAb-C2–12 (subclass IgG1 {kappa}), was produced by immunizing mice with a synthetic carboxyl-terminal peptide corresponding to amino acids 375–387 of 17ßHSD type 2. Detailed characterization of the monoclonal antibody was previously reported (15). 17ßHSD type 1 antibody was a rabbit polyclonal antibody against the enzyme purified from human placenta (16), provided by Dr. Vihko (Department of Clinical Chemistry, University of Oulu, Oulu, Finland). Antibody against hCG, which was employed as a marker of syncytiotrophoblast; CD34; factor VIII-related antigen (FVIIIAg); and Ulex europaeus agglutinin type 1 lectin (UEA-1) were employed as immunohistochemical markers for endothelial cells were commercially obtained.


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  		Table 1. Characteristics of primary antibodies employed in this study

 
Immunohistochemistry

Immunohistochemical procedures employed in this study were previously described in detail (17, 18). Immunohistochemical staining was performed by a streptavidin-biotin method with alkaline-phosphatase or peroxidase conjugated streptavidin using a Histofine kit (Nichirei Co., Tokyo, Japan), and the antigen-antibody complex was visualized by Vector red (Vector Laboratories, Inc., Burlingame, CA) or 3,3'-diaminobenzidine. For negative controls of immunostain, the sections were incubated with 0.01 mol/L phosphate-buffered saline or normal mouse or rabbit IgG instead of primary antibodies. No specific immunoreactivity was detected in these sections. Detail of histochemical staining of UEA-1 were previously reported (19).

Double immunostain

Double immunohistochemical staining of 17ßHSD types 1 and 2 was performed as previously reported (20, 21) with some modifications. Immunoreactivity of 17ßHSD type 1 was first visualized as brown by 3,3'-diaminobenzidine using Envision (Dako Corp., Copenhagen, Denmark). Immunostaining of 17ßHSD type 2 was subsequently performed on the same reacted tissue sections using the streptavidin-biotin method, and the immunoreactivity was visualized as blue by Vector blue (Vector Laboratories). For negative controls, the sections were incubated with 0.01 mol/L phosphate-buffered saline or normal mouse or rabbit IgG instead of the primary antibodies. No specific immunoreactivity was detected in these sections.

Quantitative evaluation

The CAS 200 computed analysis system (Becton Dickinson Co., Lincoln Park, NJ) was used for quantitative evaluation of the immunoreactive area for CD34 and 17ßHSD type 2. We used a set of serial mirror tissue sections to evaluate the immunoreactivity of CD34 and 17ßHSD type 2 in the same endothelial cells of chorionic villi. The CD34- and 17ßHSD type 2-positive areas in the same villous tissues were measured by a newly developed imaging program of quantitative angiogenesis (version 1.0.03, Becton Dickinson Co.). The percentage of total CD34-positive area per villous tissues represents the percentage of vascular endothelial area per villous tissues. We evaluated 10 representative fields of the villous tissues and merged the data from these fields. The results were cumulated from all measured fields.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Immunohistochemistry

The results are summarized in Figs. 1Go and 2Go. Immunoreactivity of 17ßHSD type 1 was exclusively present in syncytiotrophoblast, which was also positive for hCG, but not in cytotrophoblast or other cell types (Fig. 1Go, A and B). Immunoreactivity of 17ßHSD type 1 was detected in all placental tissues examined from 4–40 weeks gestation. Immunoreactivity of 17ßHSD type 2 was not detected in placental tissue until 11 weeks gestation (Fig. 1CGo). At 12 weeks gestation, immunoreactivity of 17ßHSD type 2 was sporadically detected in endothelial cells of fetal capillaries in chorionic villi that were positive for CD34, FVIIIAg, and UEA-1 (Fig. 1EGo). 17ßHSD type 2-positive areas tended to increase as pregnancy progressed, and scattered weak immunoreactivity was also detected in interstitial cells of the villous core from 12 weeks gestation. These interstitial cells were not positive for CD34, FVIIIAg, or UEA-1 (Figs. 1Go and 2Go). Almost all endothelial cells in chorionic villi were positive for 17ßHSD type 2 after 19 weeks gestation (Fig. 1Go, G and I, and Fig. 2Go, A and C). Immunoreactivity of 17ßHSD type 2 was also detected in endothelial cells of chorionic veins, but not in endothelial cells of chorionic arteries of the chorionic plate (Fig. 2EGo) or umbilical veins (Fig. 2FGo) and arteries. Immunoreactivity or reactivity of vascular endothelial cell markers CD34 (Fig. 1Go, D, F, H, and J), FVIIIAg (Fig. 2BGo), and UEA-1 (Fig. 2DGo) was detected from 4 weeks gestation and increased as pregnancy progressed. The great majority of vascular endothelial cells were positive for these three markers, but FVIIIAg immunoreactivity and UEA-1 reactivity were not detected in the endothelial cells.



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  		Figure 1. A and B, Immunohistochemical staining of 17ßHSD type 1 (A) and hCG (B) at 8 weeks gestation in serial mirror tissue sections. 17ßHSD type 1 is exclusively immunolocalized in syncytiotrophoblast positive for hCG. C–J, Immunohistochemical staining of 17ßHSD type 2 at 8 (C), 12 (E), 19 (G), and 40 (I) weeks gestation and of CD34 at 8 (D), 12 (F), 19 (H), and 40 (J) weeks gestation in serial mirror tissue sections. Immunoreactivities of 17ßHSD type 2 and CD34 are present in vascular endothelial cells. Scattered and weak immunoreactivity of 17ßHSD type 2 is also detected in interstitial cells of the villous core. Magnification, x200. Hematoxylin is used as the nuclear stain.

 


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  		Figure 2. A and B, Immunohistochemical staining of 17ßHSD type 2 (A) and FVIIIAg (B) at 19 weeks gestation in serial mirror sections. C and D, Immunohistochemical staining of 17ßHSD type 2 (C) and UEA-1 (D) at 19 weeks gestation in serial mirror sections. E, 17ßHSD type 2 immunoreactivity is detected in the endothelial cells lining the chorionic vein (v), whereas no immunoreactivity is present in the endothelial cells lining the chorionic artery (a). F, No 17ßHSD type 2 immunoreactivity is detected in the endothelial cells lining the umbilical vein (v). G, Double immunostaining of 17ßHSD types 1 and 2 at 20 weeks gestation. 17ßHSD type 1-positive cells appear brown as a result of diaminobenzidine colorimetric reaction, and 17ßHSD type 2-positive cells appear blue as a result of Vector blue colorimetric reaction.

 
Double immunostain of 17ßHSD types 1 and 2 also revealed the immunolocalization of type 1 enzyme in syncytiotrophoblast and that of type 2 enzyme in endothelial cells of fetal capillaries in the same chorionic villi (Fig. 2GGo).

Quantitative evaluation

The results of quantitative evaluation of CD34- and 17ßHSD type 2-positive area per villous tissue are summarized in Table 2Go. Immunopositive areas of both 17ßHSD type 2 and CD34 in chorionic villi increased as pregnancy progressed (Fig. 1Go, C–J). We determined 17ßHSD type 2-positive area vs. CD34-positive area of villous tissues in all stages of placental tissue to study the ratio of endothelial cells of intravillous fetal capillaries that express 17ßHSD type 2 enzyme. The 17ßHSD type 2-positive area per CD34-positive area markedly increased from 13 weeks gestation and reached a plateau at 19 weeks gestation (Fig. 3Go).



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  		Figure 3. 17ßHSD type 2-positive area vs. CD34-positive area of villous tissues throughout the course of pregnancy.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
It is well known that estrogens play very important roles in pregnancy and confer various benefits to both mother and fetus. On the other hand, it is also true that excessive exposure to estrogens in utero occasionally has deleterious effects on fetal development, as demonstrated in the offspring of women given diethylstilbestrol during pregnancy to prevent miscarriage (22, 23, 24). Therefore, it is important for feto-placental units to produce and secrete large quantities of biologically active estrogens to maintain pregnancy as well as to protect the fetus from excessive estrogens.

17ßHSD type 2, which preferentially converts E2 and testosterone to less biologically potent E1 and androstenedione, respectively, has been recently isolated and cloned (11). High levels of 17ßHSD type 2 messenger ribonucleic acid were detected in human placenta, liver, and small intestine (13), and the immunoreactivity was very recently localized to the endothelial cells of the fetal capillaries and the hepatocytes of fetal liver (15). Our present study revealed that 17ßHSD type 1 was immunolocalized in syncytiotrophoblast, whereas 17ßHSD type 2 immunoreactivity was predominantly present in endothelial cells of fetal capillaries, with sporadic immunoreactivity in interstitial cells of the villous core. This is consistent with previously reported immunohistochemical studies of 17ßHSD types 1 and 2 (8, 15). However, immunoreactivity of 17ßHSD type 1 was detected in syncytiotrophoblast of chorionic villi in as early as 4 weeks gestation, but immunoreactivity of 17ßHSD type 2 was not detected until 12 weeks gestation. This finding indicates that E2 produced in syncytiotrophoblast may directly enter the fetal circulation until 12 weeks gestation, but portions of E2 start to be converted into E1 after 12 weeks gestation in endothelial cells of fetal capillaries in chorionic villi. In addition, a progressive increase in 17ßHSD type 2 immunoreactivity from mid- to late pregnancy suggests that the active conversion of E2 to E1 occurs during this period. This is also consistent with the sizable maternal fetal gradient for E2 observed in mid- to late pregnancy (4, 5, 6, 7). Therefore, one of the biological significances of 17ßHSD type 2 in human placenta of mid- to late gestational ages is as a placental barrier, preventing the passage of excessive estrogens into the fetal circulation to protect the fetus from placental and maternally derived estrogens and possibly androgens. However, further investigations, including the analysis of the possible biological significance of 17ßHSD type 2 immunoreactivity in interstitial cells of the villous core, are required for clarification of this point.

The presence of the enzyme in endothelial cells of the vessels adjacent to syncytiotrophoblast can contribute greatly to the effective conversion of E2 to E1 or the prevention of diffusion of excessive amounts of E2 into the fetal circulation. Therefore, it becomes important to examine the correlation between vascular development and expression of 17ßHSD type 2 in chorionic villi. Immunohistochemical or histochemical staining of CD34, FVIIIAg, and UEA-1 has been used as a marker(s) for vascular endothelial cells (25, 26, 27, 28). However, in this study, FVIIIAg immunoreactivity and UEA-1 reactivity were not present in all endothelial cells, as reported previously by others (25, 26). On the other hand, an antibody against CD34 can immunohistochemically detect almost all endothelial cells with less background staining, which makes it more suitable for image analysis (27). In addition, Qiao et al. reported that CD34 was the most suitable immunohistochemical marker for labeling the vessels in chorionic villi (28). Therefore, in this study, we determined the ratio of 17ßHSD type 2-positive endothelial cells in chorionic villi employing immunohistochemistry of CD34 and 17ßHSD type 2 in serial mirror tissue sections and the CAS 200 image analysis system. Relatively small portions of endothelial cells started to demonstrate 17ßHSD type 2 immunoreactivity from 12 weeks gestation. The ratio of 17ßHSD type 2-positive endothelial cells increased markedly from 12 to 19 weeks gestation, then reached a plateau. After 19 weeks, almost all endothelial cells in chorionic villi demonstrated 17ßHSD type 2 immunoreactivity. This changing pattern of 17ßHSD type 2 immunolocalization in human placental development is consistent with an alteration of E2 levels in umbilical vein reported by Tulchinsky (4). Therefore, these results indicate that the spatial and temporal distribution patterns of 17ßHSD type 1 and type 2 immunoreactivity in placental tissue play very important roles in estrogen production and metabolism throughout the course of development of the human feto-placental unit.


   Footnotes
 
1 This work was supported by Grant RO1-DK-52167 (to S.A.), from the National Institutes of Health. Back

Received February 19, 1998.

Revised May 5, 1998.

Accepted June 9, 1998.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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  18. Sasano H, Frost AR, Saitoh R, et al. 1996 Aromatase and 17ß-hydroxysteroid dehydrogenase type 1 in human breast carcinoma. J Clin Endocrinol Metab. 81:4042–4046.[Abstract/Free Full Text]
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