17Beta-hydroxysteroid dehydrogenase-2 deficiency and progesterone resistance in endometriosis.

Estradiol (E2) stimulates the growth and inflammation in the ectopic endometriotic tissue that commonly resides on the pelvic organs. Several clinical and laboratory-based observations are indicative of resistance to progesterone action in endometriosis. The molecular basis of progesterone resistance in endometriosis may be related to an overall reduction in the levels of progesterone receptor (PR). In normal endometrium, progesterone acts via PR on stromal cells to induce secretion of paracrine factor(s) that in turn stimulate neighboring epithelial cells to express the enzyme 17beta-hydroxysteroid dehydrogenase type 2 (HSD17B2). HSD17B2 is an extremely efficient enzyme and rapidly metabolizes the biologically potent estrogen E2 to weakly estrogenic estrone. In endometriotic tissue, progesterone is incapable of inducing epithelial HSD17B2 expression due to a defect in stromal cells. The inability of endometriotic stromal cells to produce progesterone-induced paracrine factors that stimulate HSD17B2 may be due to the very low levels of PR observed in vivo in endometriotic tissue. The end result is deficient metabolism of E2 in endometriosis giving rise to high local concentrations of this mitogen. The molecular details of this physiological paracrine interaction between the stroma and epithelium in normal endometrium and its lack thereof in endometriosis are discussed.

[1]  M. Dawson,et al.  Retinoic acid (RA) regulates 17beta-hydroxysteroid dehydrogenase type 2 expression in endometrium: interaction of RA receptors with specificity protein (SP) 1/SP3 for estradiol metabolism. , 2008, The Journal of clinical endocrinology and metabolism.

[2]  Mette Nyegaard,et al.  Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis. , 2007, Endocrinology.

[3]  S. Bulun,et al.  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. , 2007, American journal of obstetrics and gynecology.

[4]  Takashi Suzuki,et al.  SP1 and SP3 Mediate Progesterone-Dependent Induction of the 17beta Hydroxysteroid Dehydrogenase Type 2 Gene in Human Endometrium1 , 2006, Biology of reproduction.

[5]  P. Yin,et al.  Progesterone resistance in endometriosis: Link to failure to metabolize estradiol , 2006, Molecular and Cellular Endocrinology.

[6]  J. P. Yang,et al.  Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility. , 2003, Endocrinology.

[7]  F. DeMayo,et al.  Subgroup of reproductive functions of progesterone mediated by progesterone receptor-B isoform. , 2000, Science.

[8]  D. Edwards,et al.  Progesterone receptor isoform A but not B is expressed in endometriosis. , 2000, The Journal of clinical endocrinology and metabolism.

[9]  P. Cooke,et al.  Paracrine Regulation of Epithelial Progesterone Receptor and Lactoferrin by Progesterone in the Mouse Uterus1 , 2000, Biology of reproduction.

[10]  C. Clarke,et al.  Colocalization of progesterone receptors A and B by dual immunofluorescent histochemistry in human endometrium during the menstrual cycle. , 1999, The Journal of clinical endocrinology and metabolism.

[11]  P. Giangrande,et al.  The A and B isoforms of the human progesterone receptor: two functionally different transcription factors encoded by a single gene. , 1999, Recent progress in hormone research.

[12]  H. Sasano,et al.  Deficient 17beta-hydroxysteroid dehydrogenase type 2 expression in endometriosis: failure to metabolize 17beta-estradiol. , 1998, The Journal of clinical endocrinology and metabolism.

[13]  N. Weigel,et al.  Differential expression of uterine progesterone receptor forms A and B during the menstrual cycle , 1997, The Journal of Steroid Biochemistry and Molecular Biology.

[14]  P. Vercellini,et al.  Progestins for symptomatic endometriosis: a critical analysis of the evidence. , 1997, Fertility and sterility.

[15]  S. Andersson,et al.  17 beta-Hydroxysteroid dehydrogenase type 2: chromosomal assignment and progestin regulation of gene expression in human endometrium. , 1994, The Journal of clinical investigation.

[16]  M. Fernö,et al.  Oestrogen and progesterone receptors in endometriotic tissue and endometrium: comparison of different cycle phases and ages. , 1993, Human reproduction.

[17]  M. Fernö,et al.  Estrogen and progesterone receptors in endometriotic tissue and endometrium: comparison according to localization and recurrence. , 1993, Fertility and sterility.

[18]  K. O. Elliston,et al.  Expression cloning and characterization of human 17 beta-hydroxysteroid dehydrogenase type 2, a microsomal enzyme possessing 20 alpha-hydroxysteroid dehydrogenase activity. , 1993, The Journal of biological chemistry.

[19]  M. Poutanen,et al.  Steroid biosynthetic enzymes: 17 beta-hydroxysteroid dehydrogenase. , 1993, Annals of medicine.

[20]  A. Prentice,et al.  Ovarian steroid receptor expression in endometriosis and in two potential parent epithelia: endometrium and peritoneal mesothelium. , 1992, Human reproduction.

[21]  P Chambon,et al.  Two distinct estrogen‐regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. , 1990, The EMBO journal.

[22]  J. Simard,et al.  Characterization of two mRNA species encoding human estradiol 17 beta-dehydrogenase and assignment of the gene to chromosome 17. , 1989, Journal of steroid biochemistry.

[23]  J. Shine,et al.  Progestin inhibition of progesterone receptor gene expression in human breast cancer cells. , 1989, Molecular endocrinology.

[24]  B. O’Malley,et al.  Molecular cloning of the chicken progesterone receptor , 1986, Science.

[25]  R. Vihko,et al.  Steroidal regulation of endometriosis tissue: lack of induction of 17 beta-hydroxysteroid dehydrogenase activity by progesterone, medroxyprogesterone acetate, or danazol. , 1985, Fertility and sterility.

[26]  K. Horwitz,et al.  In situ photolinked nuclear progesterone receptors of human breast cancer cells: subunit molecular weights after transformation and translocation. , 1983, Endocrinology.

[27]  K. Horwitz,et al.  The subunit structure of human breast cancer progesterone receptors: characterization by chromatography and photoaffinity labeling. , 1983, Endocrinology.

[28]  P. Satyaswaroop,et al.  Distribution of progesterone receptor, estradiol dehydrogenase, and 20 alpha-dihydroprogesterone dehydrogenase activities in human endometrial glands and stroma: progestin induction of steroid dehydrogenase activities in vitro is restricted to the glandular epithelium. , 1982, Endocrinology.

[29]  E. Gurpide,et al.  Induction of human endometrial estradiol dehydrogenase by progestins. , 1975, Endocrinology.

[30]  E. Gurpide,et al.  Estradiol and 20alpha-dihydroprogesterone dehydrogenase activities in human endometrium during the menstrual cycle. , 1974, Endocrinology.