Stromal cells of endometriosis fail to produce paracrine factors that induce epithelial 17beta-hydroxysteroid dehydrogenase type 2 gene and its transcriptional regulator Sp1: a mechanism for defective estradiol metabolism.

Abstract

In endometrium, stromal progesterone receptors mediate production of paracrine factors, which enhance binding of the transcription factor specific protein-1 to the promoter of the gene encoding the 17beta-hydroxysteroid dehydrogenase type 2 enzyme responsible for converting biologically active estradiol to estrone in epithelium. The objective of this study is to define the cellular defect responsible for the disruption of this stromal-epithelial interaction in endometriosis. We determined the effects of conditioned media generated from primary human eutopic endometrial stromal cells vs endometriotic stromal cells on Ishikawa malignant endometrial epithelial cells. Conditioned media from progestin-pretreated eutopic endometrial stromal cells but not endometriotic stromal cells significantly stimulated specific protein-1 protein levels, 17beta-hydroxysteroid dehydrogenase type 2 messenger RNA levels and promoter activity, and binding activity of specific protein-1 to the 17beta-hydroxysteroid dehydrogenase type 2 promoter region in Ishikawa cells. A stromal cell defect in endometriosis blocks formation of progesterone-dependent production of factors leading to 17beta-hydroxysteroid dehydrogenase type 2 deficiency and defective conversion of estradiol to estrone in epithelium.