Retinoids have recently been proposed to modulate estrogenic actions in various sex
steroid-dependent
neoplasms, but little has been studied in human endometrial disorders. Therefore, in this study, we first examined the immunolocalization of
retinoic acid receptor alpha, beta, and gamma, and
retinoid X receptor (RXR) alpha, beta, and gamma in 20 normal cycling human endometria, 34
endometrial hyperplasia, and 46 endometrioid endometrial
adenocarcinomas. We then correlated these findings with other clinicopathological parameters, especially in the correlation between
retinoid receptor subtypes and the status of
steroid hormone receptors, 17 beta-
hydroxysteroid dehydrogenase (17 beta-HSD) and
aromatase. We also then examined the effects of
retinoic acid on the expression of 17 beta-HSD type 2 in cell lines derived from
endometrial carcinoma using Northern blotting analysis to examine the possible roles of
retinoids in in situ endometrial
estrogen metabolism. Among these six
retinoid receptors examined, RXR gamma immunoreactivity was exclusively detected in the epithelial cells of the secretory phase endometrium but not of the proliferative phase, which was well correlated with 17 beta-HSD type 2 immunolocalization. However, in
endometrial hyperplasia, RXR gamma was not correlated with 17 beta-HSD type 2. In endometrioid endometrial
adenocarcinoma, there was a statistically significant correlation between 17 beta-HSD type 2 immunoreactivity and RXR gamma labeling index (LI) (P < 0.001) and between RXR gamma LI and
progesterone receptor LI (r = 0.501, P = 0.003). A significant inverse correlation was also detected between RXR gamma LI and patient age (r = 0.449, P = 0.015). No statistically significant correlation was obtained between LIs of receptors and other clinicopathological parameters including the status of intratumoral
aromatase examined by immunohistochemistry. In the
endometrial carcinoma cell line, RL95-2,
retinoic acid markedly increased the level of 17 beta-HSD type 2
messenger RNA in a time- and dose-dependent manner. These results all suggest that retinoic
acids may be involved in modulation of in situ
estrogen metabolism in both normal and neoplastic human endometrium possibly through RXR gamma by stimulating the expression of 17 beta-HSD type 2.