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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 12 4252-4257
Copyright © 1997 by The Endocrine Society

Original Studies

11ß-Hydroxysteroid Dehydrogenase Type II in the Human Endometrium: Localization and Activity during the Menstrual Cycle1

Robin E. Smith, Lois A. Salamonsen, Paul A. Komesaroff, Kevin X. Z. Li, Kathy M. Myles, Mark Lawrence and Zygmunt Krozowski

Laboratories of Molecular Hypertension (R.E.S., K.X.Z.L., Z.K.) and Molecular Physiology (P.A.K., K.M.M.) Baker Medical Research Institute, Prahran; Prince Henry’s Institute of Medical Research, Clayton (L.A.S.); and the Department of Obstetrics and Gynecology, Monash University (M.L.), Melbourne, Australia

Address all correspondence and requests for reprints to: Dr. Z. Krozowski, Molecular Hypertension Laboratory, Baker Medical Research Institute, P.O. Box 348, Prahran 3181, Australia. E-mail: zygmunt.krozowski{at}baker.edu.au


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The 11ß-hydroxysteroid dehydrogenase type II enzyme (11ßHSD2) is a potent inactivator of glucocorticoids and is present in high amounts in the placental syncytiotrophoblast and sodium-transporting epithelia. Placental 11ßHSD2 is thought to protect the fetus from high circulating levels of maternal glucocorticoids, whereas the renal enzyme is important in conferring aldosterone specificity on the mineralocorticoid receptor. An isoform of 11ßHSD (11ßHSD1) is also present in a wide range of tissues, but usually acts as an oxoreductase, converting the biologically inactive cortisone to cortisol. In the present study we have used an immunopurified antibody to the carboxy-terminus of human 11ßHSD2 (HUH23) to demonstrate localization of the enzyme in luminal and glandular epithelia of human endometrium. In some specimens staining was uniformly distributed, but in others there was clear evidence of heterogeneity both between and within epithelia. Although 11ßHSD2 was found mainly in the cytoplasm, some cells showed evidence of nuclear staining only. Western blot analysis showed a band at 41 kDa in endometrium and myometrium, confirming the presence of 11ßHSD2. Measurement of activity throughout the menstrual cycle showed that mean levels (±SEM) of activity were 156 ± 17 and 6.1 ± 1.1 pmol product/min·g homogenate protein for 11ßHSD2 and 11ßHSD1, respectively. Patients taking combined estrogen/progesterone contraceptives had significantly lower activities of both enzymes (76 ± 19 and 1.9 ± 0.4; both P < 0.01) compared with the control group. 11ßHSD2 activity was significantly higher in the secretory than in the proliferative phase of the cycle in controls (193 ± 22 vs. 120 ± 23; P < 0.05). All groups contained outliers with elevated enzyme activities, with some patients displaying 11ßHSD2 levels comparable to those observed in human kidney (>1000 pmol/min·g). Further analysis showed that there was a statistically significant correlation (r = 0.43; P < 0.001) between the levels of 11ßHSD1 and 11ßHSD2. There was no detectable mineralocorticoid receptor binding in endometrial cytosols prepared from patients with a range of 11ßHSD2 activities. It remains to be determined whether elevated or suppressed levels of either isoform are associated with fertility or endometrial pathology.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE ROLE OF adrenocorticoids in reproductive physiology is incompletely understood. Several lines of evidence suggest roles for glucocorticoids in the uterus, including inhibitory effects on implantation (1), endometrial cellular proliferation (2), apoptosis (3), and enzymes involved in endometrial remodeling (4). The action of glucocorticoids has been shown to be modulated by two isoforms of 11ß-hydroxysteroid dehydrogenase (11ßHSD), with 11ßHSD1 acting as an oxoreductase to convert cortisone to cortisol predominantly in the liver, and the dehydrogenase 11ßHSD2 serving as a potent and irreversible inactivator of cortisol.

Accumulating evidence indicates important roles for these enzymes in reproduction. Placental 11ßHSD2 is thought to protect the fetus from the high circulating levels of maternal glucocorticoids, and there is a correlation between term placental enzyme activity and birth weight (5, 6). Furthermore, inhibition of 11ßHSD2 in pregnant rats leads to hypertension in the adult offspring, suggesting glucocorticoid imprinting in the fetus (7). Recently, the activity of both isoforms has been shown to be modulated by estrogen in the pregnant rat myometrium, and 11ßHSD2 is highly expressed in the corpus luteum during the latter stages of pregnancy in the rat (8, 9).

Mutations in the HSD11B2 gene have been shown to account for the syndrome of apparent mineralocorticoid excess, a life-threatening, low renin form of hypertension resulting from overstimulation of the mineralocorticoid receptor by cortisol (10, 11, 12). Although 11ßHSD2 is an irreversible dehydrogenase when acting on natural glucocorticoids, in vivo studies (13) and recent in vitro work (14, 15) have shown oxoreductase activity with 9{alpha}-fluorinated glucocorticoids. This explains their ability to cross the placenta largely intact and the beneficial effects obtained when they are administered to accelerate fetal lung maturation.

Dexamethasone administration has previously been shown to inhibit implantation and to have an antifertility effect in rabbits (16), but the in vivo effects of cortisol are unknown and are sure to be modulated by any 11ßHSD enzymes present. In the present study we show that 11ßHSD2 is localized in the epithelium of the endometrium, that 11ßHSD1 and 11ßHSD2 are present in homogenates of human endometrium, and that the levels of these activities are decreased in patients taking oral contraceptives. There is a linear relationship between the two activities, suggesting that the enzymes may be synchronously regulated.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Steroids

[3H]Corticosterone (88 Ci/mmol) and [3H]aldosterone (60–80 Ci/mmol) were obtained from DuPont-New England Nuclear Products (Boston MA), and unlabeled corticosterone and aldosterone were purchased from Sigma Chemical Co. (St. Louis, MO). RU38486 (17ß-hydroxy-11ß-4-dimethylamino-phenyl-17a-1-propynl-estra-4,9-dien-3-one), a highly specific synthetic glucocorticoid and progesterone antagonist, was a gift from Roussel-UCLAF (Paris, France), and aldosterone was obtained from Sigma Chemical Co..

Immunohistochemical studies

Endometrial tissue for immunohistochemistry was obtained at curettage from women with regular menstrual cycles and no apparent endometrial dysfunction, who gave informed consent for collection of tissue. Approval was given by the human ethics committee at Monash Medical Center (Melbourne, Australia). The women were either of proven fertility and scheduled for tubal ligation or were undergoing testing for patency of the fallopian tubes. Patients with leiomyomas or endometriosis or those who had received any steroid treatment during the past 12 months were specifically excluded from the study. Tissue samples were fixed in phosphate-buffered formalin for 18 h, washed in Tris-buffered saline (pH 7.6), and processed to paraffin wax blocks. Sections were cut at 6 µm, dewaxed, hydrated, and stained with hematoxylin for histological dating of the menstrual cycle by an experienced gynecological pathologist according to the method of Noyes et al. (17).

Immunostaining was performed on additional 6-µm sections with a previously characterized immunopurified antibody, HUH23, using the three-layered immunoperoxidase technique as previously described (18), except that in the present study HUH23 was used at a concentration of 7.5 µg/mL. The control antiserum was a solid phase absorbed rabbit IgG fraction from a healthy nonimmunized animal (Dako Laboratories, Carpenteria, CA). Tissue sections were counterstained with hematoxylin for 1.5 min. Photography was performed using a Weild Leitz microphotography system (Leitz, Rockleigh, NJ).

Western blot analysis

Tissue was homogenized in phosphate-buffered saline (PBS), and homogenates were centrifuged at 100,000 x g for 1 h at 4 C to obtain microsomal pellets. CHOP cells (Chinese hamster ovary cells transformed with papilloma virus) were transfected with the pcDNA1 plasmid expressing the human 11ßHSD2 enzyme, grown, and homogenized as previously described (18). Microsomal proteins (100 µg) were separated on 5–15% gradient SDS-PAGE gels and transferred to nitrocellulose filters (Scheicher and Schuell, Darmstadt, Germany) for 2 h on ice. After blocking nonspecific sites with 5% skim milk powder in PBS, pH 7.4, and 0.1% Tween-20, the blot was incubated overnight at 4 C with 1 µg/mL of the immunopurified HUH23 polyclonal antibody in 0.5% skim milk powder in PBS, pH 7.4, and 0.1% Tween-20. The blot was then washed three times for 15 min each time in PBS containing 0.1% Tween-20. Blots were developed using a chemiluminescense detection kit (DuPont-New England Nuclear, Boston, MA) according to the manufacturer’s instructions.

Estimation of 11ßHSD activity

Samples were obtained from patients undergoing laparoscopy or hysterectomy and represented a different cohort from that used for the immunohistochemical study. Tissue was immediately frozen on dry ice in the operating theater, transported to the laboratory, and stored at -70 C. 11ßHSD2 activity was determined in homogenates using [3H]corticosterone as substrate as previously described (19), with 11ßHSD1 estimated by the inclusion of 500 µmol/L NADP. NAD- or NADP-dependent activity was determined after subtraction of activity obtained in the absence of cofactor. Each sample was assayed over a range of protein concentrations and several time points to ensure that conditions did not limit substrate availability over the course of the reaction. The Km was determined by double reciprocal analysis using a substrate range of 25–800 nmol/L corticosterone for 11ßHSD1 and 2–50 nmol/L for 11ßHSD2.

Determination of mineralocorticoid receptor binding

Specific [3H]aldosterone binding in endometrium and myometrium as well as in rat kidney, as a control, was determined as previously described (20).

Statistical analysis

Groups were compared by t test after the elimination of outliers. Outliers were defined as values greater than 3 SD from the mean. Simple linear regression analysis was performed to determine the relationship between 11ßHSD1 and 11ßHSD2 activities after logarithmic transformation of the raw data.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Figure 1AGo shows HUH23 staining of endometrium on day 13 of the menstrual cycle. Human endometrium exhibited immunohistochemical staining for the 11ßHSD2 enzyme in both the luminal and glandular epithelia. The specificity of staining was determined by a lack of staining when a control antiserum was used (Fig. 1BGo). Similar specific staining of the epithelium was observed in serial sections of day 17 endometrium (Fig. 1Go, C and D). In some sections we observed heterogeneity of epithelial staining. Figure 2AGo shows staining of occasional glands and variable staining of luminal epithelium. Heterogeneous staining was also observed within some glands (Fig. 2BGo), with only occasional cells staining. Most cells staining with the antibody showed a cytoplasmic localization of 11ßHSD2, but occasional cells exhibited clear evidence of nuclear staining. Slight staining of the stromal cells and endothelium of spiral arterioles was also seen in some sections (Fig. 2BGo).



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  		Figure 1. Immunohistochemical staining of endometrium. Staining of day 13 (A) and day 17 (C) endometria was performed with the immunopurified HUH23 antibody. B and D represent serial sections stained with control antiserum. LE, Luminal epithelium; GE, glandular epithelium; ST, stroma. Original magnification, x10.

 


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  		Figure 2. Heterogeneity of endometrial staining. A, Staining of a day 5 endometrium. Moderate staining was seen in some luminal (L1) and glandular (G1) epithelia, with much weaker (L2) or no staining (G2) in others. B, Staining of a day 23 endometrium showing heterogeneous staining within glands. Nuclear staining (arrowheads) and cytoplasmic staining of isolated cells (white arrows) are indicated. A spiral arteriole (SA) appeared to show some staining of the endothelium. Original magnification, x16.

 
Additional evidence for the presence of 11ßHSD2 in the endometrium was obtained by Western blot analysis (Fig. 3Go). When a blot containing endometrium, myometrium, human kidney, and cloned human 11ßHSD2 was probed with HUH23, a band of 41 kDa was observed in all lanes, consistent with the presence of the 11ßHSD2 enzyme. There was a good correlation between the intensity of this band and enzyme activity. The absence of lower mol wt breakdown products suggested that the enzyme was stable during tissue collection and storage.



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  		Figure 3. Western blot analysis. Samples of endometrium (lanes 1–9), myometrium (lanes 10 and 11), human kidney (lane 12), and CHOP cells expressing the human 11ßHSD2 clone (lane 13) were subjected to Western blot analysis and probed with the HUH23 antibody.

 
Further studies were designed to determine the levels of endometrial 11ßHSD2 activity throughout the menstrual cycle (Fig. 4AGo). Most samples (31 of 35) displayed an activity of less than 400 pmol/min·g protein, but there were also 4 outliers ranging in activity from 665-1514 pmol/min·g protein. Given a recent report of low levels of 11ßHSD1 in cultured endometrial stromal cells (21), we took this opportunity to also measure 11ßHSD1 activity. Figure 4BGo shows the activity of 11ßHSD1 over the menstrual cycle. The levels of 11ßHSD1 were more than an order of magnitude lower than those observed for 11ßHSD2. Most samples (33 of 35) displayed 11ßHSD1 activity below 30 pmol/min·g protein, and there were also 2 outliers.



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  		Figure 4. 11ßHSD activity in the endometrium during the menstrual cycle. A, 11ßHSD2; B, 11ßHSD1.

 
When patients were divided according to stage of the menstrual cycle, mean 11ßHSD2 levels were significantly higher in the secretory phase than in the proliferative phase, whereas 11ßHSD1 levels were equivalent in the 2 phases (Table 1Go). During the course of these studies we also collected endometrial specimens from women taking combined estrogen/progesterone contraceptive pills. We observed significantly lower levels of both enzymes in the population taking combined oral contraceptives (Table 1Go). An examination of the outlier population showed that elevated 11ßHSD1 levels were associated with high 11ßHSD2 levels, and that outlier values were observed on days 10–21 of the cycle (Table 2Go). There was no obvious correlation with age or clinical status. When the levels of 11ßHSD1 and 11ßHSD2 were compared (Fig. 5Go), it was found that some patients (11 of 35) had measurable 11ßHSD2 without detectable 11ßHSD1, and that overall, there was a positive linear correlation between the 2 activities (r = 0.43; P < 0.001).


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  		Table 1. 11ßHSD1 and 11ßHSD2 levels in patients divided according to stage of the menstrual cycle and contraceptive status

 

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  		Table 2. 11ßHSD1 activity and clinical status of patients with elevated 11ßHSD2 levels

 


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  		Figure 5. Correlation between 11ßHSD1 and 11ßHSD2 in endometrium. Samples with values less than 1 pmol/min·g protein were all assigned that value to allow logarithmic transformation.

 
Double reciprocal analysis of pooled endometrial homogenates gave Km values of 235 and 5 nmol/L for 11ßHSD1 and 11ßHSD2, respectively. Myometrium displayed low levels of both activities (3 and 22 for 11ßHSD1 and 11ßHSD2, respectively; n = 2), whereas two samples of human kidney gave mean 11ßHSD1 and 11ßHSD2 levels of 22 and 1232 pmol/min·g, respectively (results not shown). Given the association of 11ßHSD2 with the mineralocorticoid receptor, we also measured [3H]aldosterone binding in cytosol preparations of endometrium. No specific binding was observed in five patients displaying moderate levels of 11ßHSD2 activity, whereas a control sample of rat kidney cytosol showed 8.5 fmol receptor/mg cytosol protein (results not shown).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study we have demonstrated the presence of 11ßHSD2 in the glandular and luminal epithelia of the endometrium and in the myometrium. Our inability to demonstrate mineralocorticoid receptor binding suggests that the primary role of 11ßHSD2 is to modulate glucocorticoid action in uterine tissue, given that the metabolism of cortisol occurs at a Km in the low nanomolar range, allowing glucocorticoid concentrations to decrease to levels that will affect glucocorticoid receptor occupancy. The pattern of 11ßHSD2 staining, with some sections showing cytoplasmic or nuclear staining, and others similarly negative, may reflect cell cycle-dependent expression of the enzyme. The demonstration of nuclear 11ßHSD2 immunoreactivity adds to the growing body of evidence from diverse sources such as Western blotting and confocal microscopy (22, 23) and is consistent with receptor binding of glucocorticoids within the nucleus.

The role of 11ßHSD2 in endometrial physiology is unknown, but it has been demonstrated that elevated levels of glucocorticoids disrupt normal uterine development and implantation (2, 16). Mechanisms by which glucocorticoids may influence implantation include their known effects on actin polymerization, lysosomal activity, PG synthase, PGE nitric oxide synthase, and matrix metalloproteinases (4), all of which have known roles in implantation. The effects of glucocorticoids on inhibiting the expression of a number of matrix metalloproteinases suggest that high 11ßHSD2 activity would promote endometrial degradation. Thus, 11ßHSD2 may be part of the complex mechanism facilitating trophoblast invasion of the endometrium. It may also be linked to the ovarian activity reported to mitigate against successful oocyte fertilization and positive outcomes of in vitro fertilization-embryo transfer procedures (24).

Morphological studies have shown that although the average endometrial gland diameter is constant before ovulation, the number of glands shows a slight increase, and glandular size increases 3-fold after ovulation (25). These changes may contribute to the higher levels of 11ßHSD2 activity in the secretory phase. However, the large range in 11ßHSD2 activity observed in the present study would suggest that enzyme activity is not a simple reflection of the amount of glandular epithelium present. The heterogeneous pattern of expression and variations in the site of sampling undoubtably contribute to the variability.

11ßHSD2 activity may be expected to be lowered by progestagen-containing contraceptives, which shift the epithelium/stroma ratio in favor of the stroma (25), a phenomenon that may account for the lower 11ßHSD levels observed in patients taking combined estrogen/progesterone contraceptives in the present study. This suggests that 11ßHSD1 is localized in the epithelium, as 11ßHSD1 activity was also found to be lower in this group. It is important to note that the population of outliers identified in the present study had 11ßHSD2 levels comparable to the high activity found in the kidney. Outliers may reflect pockets of high 11ßHSD2 activity, brief periods of high activity in the normal endometrium, or they may be an early indication of pathology.

11ßHSD1 activity was also detected in homogenates of endometrium, predominantly in those samples expressing elevated levels of 11ßHSD2. Double reciprocal analysis confirmed that the Km was consistent with the presence of the 11ßHSD1 enzyme, and the subtraction of the activity generated in the absence of added cofactor guarantees that this activity is not due to the presence of endogenous NAD. The significant correlation observed between the two enzymes may reflect the induction of 11ßHSD1 by the lowering of local cortisol concentrations or a synchronous induction of both enzymes. Whether 11ßHSD1 is an oxoreductase or a dehydrogenase or metabolizes a different substrate in the human endometrium is an open question. However, the presence of two dehydrogenase activities with significantly different affinities in a single cell would serve to expedite the metabolism of high concentrations of substrate. In vitro studies (21) have shown that decidualizing human endometrial stromal cells in culture have both 11ßHSD1 and 11ßHSD2 activities, although the absolute activities of both enzymes were reported to be several orders of magnitude lower than those observed in the present and previous studies (8, 26).

11ßHSD1 and 11ßHSD2 are also expressed in the myometrium. Glucocorticoids are known to modulate several processes in this tissue, including inhibition of prostacyclin production (27), protection against desensitization to ß-adrenergic agonist (28), and induction of labor in the rabbit (29). As in the endometrium, 11ßHSD2 levels were more than an order of magnitude higher than those of 11ßHSD1, in line with measurements in the rat myometrium (9). These levels may change during the menstrual cycle, as we have previously shown that uterine 11ßHSD1 gene expression changes during the estrous cycle in the rat (30).

Further insights into the role of 11ßHSD2 in reproduction may come from studying patients afflicted with apparent mineralocorticoid excess. Although females of child-bearing age homozygous for the disease have been described in several families, none has produced offspring to date. Infertility may yet prove to be a further complicating feature of this syndrome.


   Acknowledgments
 
The authors thank Dr. Gabor Kovacs for making tissue available, Dr. Andrew Oster for histological dating, and Dr. Geoff Head for help with the statistical analysis.


   Footnotes
 
1 This work was supported by a National Health and Medical Research Council block grant (to the Baker Institute) and National Health and Medical Research Council Grant 971297 (to L.A.S.). Back

Received May 15, 1997.

Revised August 6, 1997.

Accepted August 21, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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  9. Burton PJ, Dharmarajan AM, Hisheh S, Waddell BJ. 1996 Induction of myometrial 11ß-hydroxysteroid dehydrogenase type 1 messenger ribonucleic acid and protein expression late in rat pregnancy. Endocrinology. 137:5700–5706.[Abstract]
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  12. Stewart PM, Krozowski ZS, Gupta A, et al. 1996 Hypertension in the syndrome of apparent mineralocorticoid excess due to mutation of the 11ß-hydroxysteroid dehydrogenase type 2 gene. Lancet. 347:88–91.[CrossRef][Medline]
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  16. Hicks JJ, Duran-Reyes G, Diaz-Flores M. 1994 Effect of dexamethasone as an inhibitor of implantation and embryo development in rat; lysosomal role. Contraception. 50:581–589.[CrossRef][Medline]
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  24. Michael AE, Gregory L, Piercy EC, Walker SM, Shaw RW, Cooke BA. 1995 Ovarian 11ß-hydroxysteroid dehydrogenase activity is inversely related to the outcome of in vitro fertilization- embryo transfer treatment cycles. Fertil Steril. 64:590–598.[Medline]
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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals