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The Analyses of 17ß-Hydroxysteroid Dehydrogenase Isozymes in Human Endometrial Hyperplasia and Carcinoma¹

Departments of Obstetrics and Gynecology (H.U., K.I., R.K., S.S., K.O.) and Pathology (T.S., C.K., J.T., H.S.), Tohoku University School of Medicine, Sendai 980-8574; Research Institute Life Science (J.N., K.K., M.Y.), Snow Brand Company Ltd., Tochigi 329-05; and Department of Biochemistry (N.H.), Fujita Health University School of Medicine, Aichi 470-1192, Japan

Address correspondence and requests for reprints to: Hiroki Utsunomiya M.D., Department of Obstetrics and Gynecology, Tohoku University School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan. E-mail: H-Utsu{at}ob-gy.med.tohoku.ac.jp

Abstract

Intratumoral metabolism and synthesis of estrogens are considered to play very important roles in the pathogenesis and development of human endometrial adenocarcinoma. The 17ß-hydroxysteroid dehydrogenase (17ß-HSD) isozymes catalyze the interconversion of estradiol (E2) and estrone and thereby serve to modulate the tissue levels of bioactive E2. To elucidate the possible involvement of this enzyme in human endometrial carcinoma, we first examined the expression of 17ß-HSD type 1 and type 2 in 20 normal cycling human endometria, 36 endometrial hyperplasia, and 46 endometrial endometrioid adenocarcinoma using immunohistochemistry, and we then studied immunoreactivity of 17ß-HSD type 2 using immunoblotting analyses, the activity of 17ß-HSD type 1 and type 2 using thin-layer chromatography and their expression using RT-PCR in endometrial endometrioid adenocarcinoma. We correlated these findings with various clinicopathological parameters to examine the biological significance of 17ß-HSDs in human endometrial disorders. 17ß-HSD type 2 immunoreactivity in normal endometrium was present in all cases of secretory phase (n = 14), but not in any endometrial mucosa of proliferative phase (n = 6). In addition, 17ß-HSD type 2 immunoreactivity was detected in 27 of 36 (75%) endometrial hyperplasia and 17 of 46 (37%) carcinoma cases. 17ß-HSD type 1 immunoreactivity was not detected in all the cases examined. In both endometrial hyperplasia and carcinoma cases there were significant positive correlations between 17ß-HSD type 2 and progesterone receptor labeling index (LI). In carcinoma cases, a significant inverse correlation was detected between 17ß-HSD type 2 immunoreactivity and age. In addition, 17ß-HSD type 2 immunoreactivity was also correlated with 17ß-HSD type 2 enzymatic activity, and semiquantitative analyses of 17ß-HSD type 2 messenger RNA. No significant correlations were detected between 17ß-HSD type 2 and estrogen receptor LI, Ki67 LI, amount of aromatase messenger RNA or histological grade. These data indicated that the expression of 17ß-HSD type 2 in hyperplastic and/or neoplastic endometrium may represent altered cellular features through hyperplastic and neoplastic transformation. However, 17ß-HSD type 2 may also play some protective and/or suppressive roles toward unopposed estrogenic effects through inactivating E2 in situ, especially in premenopausal patients.

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