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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 9 3292-3296
Copyright © 2000 by The Endocrine Society

Original Studies

Progesterone Induction of 17ß-Hydroxysteroid Dehydrogenase Type 2 during the Secretory Phase Occurs in the Endometrium of Estrogen-Dependent Benign Diseases But Not in Normal Endometrium

Jo Kitawaki, Hisato Koshiba, Hiroaki Ishihara, Izumi Kusuki, Katsumi Tsukamoto and Hideo Honjo

Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan

Address correspondence and requests for reprints to: Jo Kitawaki, M.D., Ph.D., Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan. E-mail: kitawaki{at}koto.kpu-m.ac.jp


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
In the human endometrium, inactivation of 17ß-estradiol to estrone is catalyzed by 17ß-hydroxysteroid dehydrogenase type 2 (17ßHSD2). Previous studies have shown that the 17ßHSD2 activity in the endometrium is elevated during the secretory phase, as compared with the level during the proliferative phase, and that the elevation is in response to progesterone via the progesterone receptors. Recently, it has been demonstrated that aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis, is not present in the endometrium obtained from normal menstruating women with cervical cancer in situ showing no other gynecological disease (defined as "disease free"), but present in the endometrium obtained from patients with endometriosis, adenomyosis, and/or leiomyomas (defined as "diseased"). However, the previous 17ßHSD studies have been performed without distinguishing between disease-free and diseased endometria. We, therefore, analyzed 17ßHSD2 distinguishing between disease-free and diseased endometria. During the proliferative phase, the abundance of messenger RNA (mRNA) and activity of 17ßHSD2 were comparable in both disease-free and diseased endometrium. However, during the secretory phase, while the abundance of mRNA and activity of 17ßHSD2 increased 4- to 6-fold in diseased endometrium, the 17ßHSD2 remained unchanged in the disease-free endometrium. Kinetic studies showed that the Km was identical among the four groups of endometria, suggesting that the elevation of 17ßHSD2 simply resulted from increased mRNA transcription. Organ culture of proliferative endometria in the presence of progestins resulted in the stimulation of 17ßHSD2 in diseased endometria via the progesterone receptors, whereas disease-free endometrium was not stimulated by progestins. These results suggest that the previous paradigm that 17ßHSD2 activity in the endometrium is elevated during the secretory phase is confined to diseased endometrium but not to disease-free endometrium and that the estrogen metabolism is altered in the endometria of the patients with estrogen-dependent benign diseases.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
INTERCONVERSION OF 17ß-estradiol (E2) and estrone (E1) occurs in the human endometrium, where an oxidative reaction that forms E1 from E2 is predominant. E2 is the most potent, whereas E1 is less potent in binding to estrogen receptors. This reaction is catalyzed by 17ß-hydroxysteroid dehydrogenases (17ßHSDs). To date, six isozymes encoded by distinct genes have been identified in humans (1), and 17ßHSD type 1 and type 2 (17ßHSD2) are expressed in the human endometrium (2, 3). 17ßHSD type 1 is responsible for production of E2, whereas 17ßHSD2 is responsible for production of E1 (4). 17ßHSD2 is abundantly expressed in the human endometrium (5) and, therefore, plays a substantial role in the inactivation of E2. The regulation of the enzymatic activity to oxidize E2 to E1 in the endometrium was studied extensively in the 1970s by Tseng et al. (6, 7, 8) and Pollow et al. (9, 10). The activity was approximately 10 times greater in the secretory endometrium than in the proliferative endometrium, and elevation of the enzyme activity was induced by progesterone that was secreted from the corpus luteum during the secretory phase via the progesterone receptor-mediated action. Similar findings have been reported by several other investigators (11, 12, 13). 17ßHSD2 is localized exclusively in the glandular epithelial cells as demonstrated by immunohistochemistry (14) and in situ hybridization (15).

A recent finding that led us to reevaluate the endometrial 17ßHSD2 is that the mRNA and protein of aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis, are not present in the endometrium of disease-free uterus (16, 17, 18, 19), but present in the eutopic endometrium of patients with endometriosis, adenomyosis, and/or leiomyomas (18, 19). Although histologically the eutopic endometria of patients with benign uterine diseases resemble the endometria of disease-free uterus, the estrogen metabolism may be remarkably different (18, 19). However, the "normal" endometrial specimens used in the previous 17ßHSD studies had been obtained mostly by hysterectomy conducted for various benign diseases including endometriosis, adenomyosis, and leiomyomas, but not necessarily for disease-free uteri.

The present study was, therefore, conducted to analyze the mRNA expression and activity of 17ßHSD2 in the endometrium during the menstrual cycle. The groups were divided as disease-free endometria that were defined as only those obtained from normal menstruating women with cervical cancer in situ but showing no other gynecological disease and diseased endometria that were defined as those obtained from patients with endometriosis, adenomyosis, and/or leiomyomas.


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

Endometrial biopsy specimens were obtained for diagnostic purposes from patients scheduled for laparotomy or laparoscopy at the Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine. This study protocol was approved by the Kyoto Prefectural University of Medicine institutional review board, and informed consent was obtained from each patient. All patients were of reproductive age with normal menstrual cycles. The patients were not receiving any endocrine therapy, such as GnRH analog, danazol, or pseudopregnancy therapy. Endometrial specimens were classified into disease groups as described previously (19). Endometriosis, adenomyosis, and/or leiomyomas were diagnosed by histological examination using excised uteri or laparoscopy. Endometria obtained from patients with cervical cancer in situ but showing no other gynecological disease (n = 23), or those obtained from patients with tubal occlusion or adhesion but without endometriosis, adenomyosis, or leiomyomas (n = 9) were defined as "disease free." The following cases were excluded from the study: malignant neoplasms other than cervical carcinoma in situ, ovarian neoplasms, pelvic inflammation, and pregnancy. A total of 65 patients met the criteria; nineteen patients in the proliferative phase and 13 patients in the secretory phase with endometriosis, adenomyosis, and/or leiomyomas, and 20 patients in the proliferative phase and 13 patients in the secretory phase without disease. The mean age was 38.9 ± 8.3 yr (mean ± SD, 26–48 yr), and the mean body mass index (BMI) was 21.5 ± 2.2 (16.9–24.8), respectively. There was no significant difference in the mean ages or BMI among the groups with endometriosis, adenomyosis, leiomyomas, and disease free. Endometrial specimens were obtained according to chronological dating, basal body temperature, and transvaginal ultrasound sonography and were histologically diagnosed according to the criteria of Noyes et al. (20). Fresh tissue samples were divided into two portions: one was frozen immediately at -80 C and stored for total RNA extraction and 17ßHSD2 assay, and the other was fixed with 4% paraformaldehyde for histological diagnosis.

RNA isolation and RT-PCR

Total RNA was extracted using Trizol (Life Technologies, Inc., Gaithersburg, MD), and the first-strand cDNA synthesis from total RNA was catalyzed by Superscript II RT (Life Technologies, Inc.) using oligo(deoxythimidine)12–18, as described previously (18). The resulting first-strand cDNA was used for PCR amplification with the following primers: 5'-CTGAGGAATTGCGAAGAACC-3' (forward, nucleotides 445–464) and 5'-GAAGTCCTTGCTGGCTAACG-3' (reverse, nucleotides 1037–1018) (21) for human 17ßHSD2; and human G3PDH amplimer set for glyceraldehyde-3-phosphate dehydrogenase (G3PDH) (CLONTECH Laboratories, Inc., Palo Alto, CA). Because the 17ßHSD2 gene encodes two alternatively spliced mRNAs (22), the primer set for 17ßHSD2 is designed to detect the mRNA encoding the previously identified 17ßHSD type 2A protein that has enzymatic activity, but not the mRNA encoding 17ßHSD type 2B protein that lacks enzymatic activity. The PCR mixture comprised 1 µL first-strand cDNA, 0.2 µmol/L of each of the primers mentioned above, 0.2 mmol/L dNTP, and 1 µL AdvanTaq DNA polymerase (CLONTECH Laboratories, Inc.), in a total volume of 50 µL PCR buffer provided by the manufacturer. After an initial denaturation at 95 C for 1 min, PCR was carried out for 35 cycles at 95 C for 30 sec, at 60 C (for 17ßHSD2) or 55 C (for G3PDH) for 30 sec, and at 68 C for 30 sec.

Northern blot analysis

Northern blotting was performed as described previously (23). Briefly, 20 µg total RNA was electrophoresed in a 1% agarose/formaldehyde gel and transferred to a nylon membrane (Hybond N+; Amersham Pharmacia Biotech, Piscataway, NJ) by capillary blotting and UV cross-linked. Membranes were prehybridized for 1 h at 65 C in 0.5 mol/L Na2HPO4/H3PO4 buffer (pH 7.2) containing 1 mmol/L EDTA and 7% SDS. The radiolabeled probes for 17ßHSD2 and G3PDH were derived from the amplified cDNA fragments produced in the RT-PCR of term placental tissues. DNA bands were excised from the agarose gel and extracted using a NucleoTrap DNA purification kit (CLONTECH Laboratories, Inc.). Aliquots of the DNA products were sequenced by the dye terminator method using a model 100 DNA analyzer (PE Applied Biosystems, Inc., Foster City, CA) and the sequence for 17ßHSD2 was confirmed to be equal to the sequence reported in the Genbank databank. The probes were radiolabeled with [{alpha}-32P]dCTP using a Random primer plus extension labeling system (NEN Life Science Products, Boston, MA). After hybridization for 24 h at 60 C, membranes were washed three times for 5 min each at 65 C, followed by a wash for 15 min at 65 C in 0.04 mol/L Na2HPO4/H3PO4 buffer (pH 7.2) containing 1% SDS. The hybridized signal was analyzed using a bioimazing analyzer (BAS 2000; Fujix, Tokyo, Japan).

Assay of 17ßHSD2 activity

17ßHSD2 activity was measured according to the methods of Tseng and Gurpide (6), with modification (12). The endometrial specimens were homogenized in 0.05 mol/L Tris-HCl buffer (pH 8.0) and centrifuged at 800 x g. The resulting supernatant (~0.8 mg protein/mL) was incubated for 60 min at 37 C in air with [6, 7-3H]E2 (NEN Life Science Products; 1.5 x 106 dpm, 37 µmol/L) and nicotinamide adenine dinucleotide (NAD+; Sigma, St. Louis, MO) (1.4 mmol/L) in a total incubation volume of 0.4 mL. The reaction was stopped by the addition of 2 mL diethyl ether containing [4-14C]E1 (NEN Life Science Products; 2x103 dpm) as well as nonradioactive standards E1 and E2 (0.2 mg each). The organic phase was extracted three times with diethyl ether, and the tritiated E1 formed was isolated by thin-layer chromatography using Silicagel 60 F254 (0.25 mm; E. Merck, Darmstadt, Germany) in the systems of chloroform-ethyl acetate (4:1, v/v) and benzene-ethyl acetate (1:1, v/v). The radioactivity of the control incubation without NAD+ was subtracted; however, it was usually negligible. The specific activity was calculated from the 3H/14C ratio of E1 formed.

For kinetic studies, the 800 x g supernatant of the endometrial homogenate was incubated for 10 min with varying concentration of [3H]E2 and NAD+ (1.4 mmol/L) in a total incubation volume of 0.4 mL. The protein concentration of the reaction mixture was determined by Bio-Rad Laboratories, Inc. Protein Assay Kit (Bio-Rad Laboratories, Inc., Hercules, CA), with BSA as the standard.

Organ culture

Organ culture of endometrial tissues were performed as described previously (12, 24). Briefly, the endometrial tissue was washed immediately after sampling and cut into ~1-mm cubes in ice-cold HBSS (Life Technologies, Inc.). The tissue fragments were placed on several pieces of l-cm cubes of Spongel (Yamanouchi Pharmaceuticals, Tokyo, Japan), which were immersed in 10 mL DMEM/Ham’s F12 medium (1:1) with 15 nmol/L HEPES buffer without Phenol red (Life Technologies, Inc.) supplemented with 10% FBS (Life Technologies, Inc.), penicillin (100 IU/mL), streptomycin (100 µg/mL), and fungizone (0.25 µg/mL). The FBS had been treated twice with charcoal (6.25 mg/mL) and Dextran T-70 (0.625 mg/mL) and then incubated at 56 C for 30 min to remove endogenous cytokines and steroids. The tissue fragments were cultured with or without steroid for 48 h in a humidified atmosphere of 5% CO2-95% air. The fragments were washed with saline and were subjected to the enzyme assay.

Statistics

Differences in ages, BMI, 17ßHSD2 activity, and mRNA levels among groups were analyzed with the one-factor ANOVA, and multiple comparisons were performed using Scheffé’s procedure. The relation between 17ßHSD2 activity and age and between 17ßHSD2 activity and BMI was analyzed by Spearman’s correlation coefficient by rank test.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
In Northern blot analysis 17ßHSD2 mRNA was detected in all of the endometrial specimens examined (Fig. 1AGo). In the proliferative phase, the amount of 17ßHSD2 mRNA expression relative to G3PDH mRNA was comparable in the endometria obtained from the patients free of disease and those with endometriosis, adenomyosis, and/or leiomyomas (Fig. 1Go, A and B). In the secretory phase, however, the level of 17ßHSD2/G3PDH mRNA expression in the endometria obtained from the patients with estrogen-dependent benign uterine diseases showed an approximately 4- to 5-fold increase (P < 0.01), whereas the level of 17ßHSD2/G3PDH mRNA expression in the patients free of disease remained comparable with that in the proliferative phase (Fig. 1Go, A and B).



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  		Figure 1. Northern analysis for 17ßHSD2 mRNA in the endometrium. A, Representative Northern blots of total RNA (20 µg) from endometrial specimens of the proliferative or secretory phases. The specimens were obtained from the patients free of disease (DF) or those with endometriosis (E), adenomyosis (Ad), and/or leiomyomas (L). 17ßHSD2 and G3PDH mRNA were hybridized using the corresponding radiolabeled probes. Placental tissue (Pl) was used as control. B, The abundance of 17ßHSD2 mRNA expression relative to G3PDH mRNA in the endometrial specimens of the proliferative (Prol.) or secretory (Secr.) phase. The level of 17ßHSD2/G3PDH mRNA was calculated based on the Northern blots in panel A. Each bar represents the mean ± SEM of 10 cases (a vs. b, P < 0.01).

 
Similarly, in the proliferative phase, the 17ßHSD2 activity was comparable in the endometria obtained from the patients free of disease and diseased patients. In the secretory phase, the activity remained comparable in the patients free of disease, whereas the activity increased approximately 5- to 6-fold in diseased patients (P < 0.001) (Fig. 2Go). There was no difference in the activity of secretory endometria among the groups of endometriosis, adenomyosis, and leiomyomas. In the proliferative phase, there was no relation between the 17ßHSD2 activity and patient’s age (rs = 0.29, P = 0.21) or between the 17ßHSD2 activity and BMI (rs = 0.37, P = 0.10).



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  		Figure 2. 17ßHSD2 activity in the endometrial specimens of the proliferative (Prol.) and secretory (Secr.) phases. The specimens were obtained from the patients free of disease (DF) or those with endometriosis, adenomyosis, and/or leiomyomas (D). 17ßHSD2 activity was determined by [3H]estrone formation following incubation of the 800 x g supernatant of endometrial homogenates with [3H]estradiol (37 µmol/L) and NAD+ (1.4 mmol/L). Each bar represents the mean ± SEM of 10 cases (c vs. d, P < 0.001).

 
We examined the enzymatic kinetic characteristics for 17ßHSD2 activity using the classical Lineweaver-Burk plot analysis. The Km was 3.3 µmol/L for each of the four endometrial groups of diseased and disease-free patients in the proliferative and secretory phases (Fig. 3Go).



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  		Figure 3. Lineweaver-Burk plot of 17ßHSD2 activity in the endometrial specimens of the proliferative ({triangleup} and {blacktriangleup}) and secretory ({circ} and •) phases. The specimens were obtained from the patients free of disease ({triangleup} and {circ}) or those with endometriosis, adenomyosis, and/or leiomyomas ({blacktriangleup} and •). The initial velocity (V) of 17ßHSD2 activity was determined by [3H]estrone formation following incubation of the 800 x g supernatant of endometrial homogenates with varying concentrations (S) of [3H]estradiol in the presence of NAD+ (1.4 mmol/L). Each plot is the mean of four determinations of two specimens.

 
In an attempt to reproduce the stimulation of 17ßHSD2 by progestins, the endometrial tissue obtained in the proliferative phase was organ cultured in the presence or absence of progestins, including progesterone, the natural progestin, and medroxyprogesterone acetate, a potent synthetic progestin. As expected, both 17ßHSD2 mRNA expression and 17ßHSD2 activity remained unchanged following exposure to progestins of the proliferative phase endometria of disease-free patients, whereas both the mRNA and activity were stimulated 4- to 5-fold when the proliferative phase endometria of diseased patients were exposed to progestins (Fig. 4Go, A and B). The progestin stimulation was blocked by a concomitant addition of mifepristone, an inhibitor of progesterone receptors (Fig. 4Go, A and B), indicating that the progestin stimulation was mediated via the progesterone receptors.



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  		Figure 4. Lack of progestin induction of 17ßHSD2 activity in the proliferative phase endometria obtained from the patients free of disease ({square}). The specimens obtained from the patients with endometriosis, adenomyosis, and/or leiomyomas were used as diseased ({blacksquare}). The 1-mm cubes of endometrial specimens were organ cultured for 72 h in the absense (Cont) or presence of progesterone (P; 10-6 mol/L), medroxyprogesterone acetate (MPA; 10-8 mol/L), and/or mifepristone (Mife; 10-6 mol/L). A, The level of 17ßHSD2/G3PDH mRNA was calculated based on the Northern blots of total RNA (20 µg) from cultured endometria. B, 17ßHSD2 activity was then determined as [3H]estrone formation following incubation of the 800 x g supernatant of endometrial homogenates with [3H]estradiol (37 µmol/L) and NAD+ (1.4 mmol/L). Each bar represents the mean ± SEM of 5–10 cases (a vs. b, P < 0.01; and c vs. d, P < 0.001).

 

   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present study demonstrates that during the proliferative phase the abundance of mRNA and activity of 17ßHSD2 are comparable in both disease-free and diseased endometrium. However, during the secretory phase, while the abundance of mRNA and activity of 17ßHSD2 increase 4- to 6-fold in diseased endometrium, as shown by previous studies (6, 7, 8, 9, 10, 11, 12, 13), those of 17ßHSD2 remain unchanged in disease-free endometrium. The Km was comparable with that reported by Pollow et al. (10) and Tseng et al. (8) and was identical among the four groups of endometria, suggesting that the elevation of 17ßHSD2 is simply a result of increased mRNA transcription. Using an organ culture of proliferative endometria in the presence of progestins, the stimulation of 17ßHSD2 in diseased endometria was reproduced by the progesterone receptor-mediated fashion, whereas disease-free endometrium is not stimulated by progestins. The previous paradigm that 17ßHSD2 activity in the endometrium is elevated during the secretory phase by progesterone receptor-mediated action (6, 7, 8, 9, 10, 11, 12, 13) seems to hold for diseased endometrium, but not for disease-free endometrium.

The discrepancy demonstrated in the present study could be attributed to two possibilities. First, the expression status of the progesterone receptors may be different in disease-free and diseased endometria. It is well established that the progesterone receptor concentration in the endometrium increases during the proliferative phase. The concentration remains high during the early secretory phase and declines in the mid- to late secretory phase (25, 26). Recently, the cyclic variation for the two splice variant isoforms, progesterone receptors A and B, has been demonstrated immunohistochemically (27, 28). However, these studies were performed without distinguishing disease-free from diseased endometrium. Whereas the eutopic endometrium of patients with endometriosis shows a cyclic change in the 17ßHSD2 activity, the endometriotic implants obtained from the same patients lack 17ßHSD2 expression (29). Because the estrogen and progesterone receptors are also expressed in the endometriotic tissues, this difference may not be explained only by the steroid receptor status. Second, another unknown factor that may be present in diseased endometrium but not in disease-free endometrium could be needed for action with progestin to stimulate 17ßHSD2 mRNA transcription. The 5'-flanking region of the 17ßHSD2 gene contains several known transcription factor-binding sites, including an inverse progesterone receptor-binding site, PEA3 binding sites, AP1 sites, and an ISGF2 recognition site (22). However, the postprogesterone receptor mechanism by which progestins induce 17ßHSD2 has not been elucidated. Additional studies on the molecular mechanism of induction are required.

Taken together with the finding that aromatase cytochrome P450 is absent in disease-free endometrium (16, 17, 18, 19) and present in diseased endometrium (18, 19), the estrogen metabolism in the human endometrium should be reevaluated. In disease-free endometrium during the secretory phase, the local E2 concentration may be higher than that in diseased endometrium, despite the fact that local E1 synthesized by aromatase is negligible. E1 is further inactivated to E1-sulfate by sulfotransferase. Although the converse reaction of E1-sulfate to E1 catalyzed by sulfatase occurs simultaneously and that the activities of sulfotransferase (30) and sulfatase (31) have been shown to elevate in the secretory phase, conjugation occurs predominantly in the secretory endometrium. In addition to the inactivation of E2, 17ßHSD2 simultaneously possesses 20{alpha}-hydroxysteroid dehydrogenase activity, which oxidates 20{alpha}-dihydroprogesterone to the more active progestin progesterone (4, 6). In disease-free endometrium during the secretory phase, the local progesterone concentration may be lower than that in diseased endometrium. Conversely, empiric evidence supports administration of progestins during the secretory phase, so-called luteal support, may improve the pregnancy rate. This discrepancy should also be elucidated. The accumulation of information on the distinction of pathologic endometria contributes to the better understanding of estrogen-dependent diseases.

Received March 3, 2000.

Revised May 11, 2000.

Accepted June 7, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals