Retinoid receptors in the human endometrium and its disorders: A possible modulator of 17β-hydroxysteroid dehydrogenase

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 α, β, and γ, and retinoid X receptor (RXR) α, β, and γ 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, 17β-hydroxysteroid dehydrogenase (17β-HSD) and aromatase. We also then examined the effects of retinoic acid on the expression of 17β-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, RXRγ immunoreactivity was exclusively detected in the epithelial cells of the secretory phase endometrium but not of the proliferative phase, which was well correlated with 17β-HSD type 2 immunolocalization. However, in endometrial hyperplasia, RXRγ was not correlated with 17β-HSD type 2. In endometrioid endometrial adenocarcinoma, there was a statistically significant correlation between 17β-HSD type 2 immunoreactivity and RXRγ labeling index (LI) (P < 0.001) and between RXRγ LI and progesterone receptor LI (r = 0.501, P = 0.003). A significant inverse correlation was also detected between RXRγ 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 17β-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 RXRγ by stimulating the expression of 17β-HSD type 2.