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

OBJECTIVE: 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 17 beta-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. STUDY DESIGN: 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. RESULTS: Conditioned media from progestin-pretreated eutopic endometrial stromal cells but not edometriotic stromal cells significantly stimulated specific protein-1 protein levels, 17 beta-hydroxysteroid dehydrogenase type 2 messenger RNA levels and promoter activity, and binding activity of specific protein-1 to the 17 beta-hydroxysteroid dehydrogenase type 2 promoter region in Ishikawa cells. CONCLUSION: A stromal cell defect in endometriosis blocks formation of progesterone-dependent production of factors leading to 17 beta-hydroxysteroid dehydrogenase type 2 deficiency and defective conversion of estradiol to estrone in epithelium.