Download PDF
Semin Reprod Med 2010; 28(1): 044-050
DOI: 10.1055/s-0029-1242992
© Thieme Medical Publishers

17β-Hydroxysteroid Dehydrogenase-2 Deficiency and Progesterone Resistance in Endometriosis

Serdar E. Bulun1 , You-Hong Cheng1 , Mary Ellen Pavone1 , Ping Yin1 , Gonca Imir2 , Hiroki Utsunomiya3 , Stephen Thung4 , Qing Xue5 , Erica E. Marsh1 , Hideki Tokunaga3 , Hiroshi Ishikawa6 , Takeshi Kurita1 , Emily J. Su1
  • 1Division of Reproductive Biology Research, Department Obstetrics and Gynecology Northwestern University Feinberg School of Medicine, Chicago, Illinois
  • 2Department of Obstetrics and Gynecology, Cunhuriyet University School of Medicine, Sivas, Turkey
  • 3Department of Obstetrics and Gynecology, Tohoku University School of Medicine, Sendai, Japan
  • 4Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, Connecticut
  • 5Department of Obstetrics and Gynecology, First Hospital of Peking University, Beijing, P.R. China
  • 6Department of Reproductive Medicine, Chiba University, Inohana Chuo-ku, Chiba, Japan
Further Information

Publication History

Publication Date:
27 January 2010 (online)

    Permissions and Reprints

ABSTRACT

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 17β-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.

KEYWORDS

17β-HSD-2 - HSD17B2 - endometriosis - endometrium - estradiol - progesterone - receptor - resistance - retinoic acid - paracrine - epithelial-stromal

REFERENCES

  • 1 Kastner P, Krust A, Turcotte B et al.. Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B.  EMBO J. 1990;  9(5) 1603-1614
    PubMedGoogle Scholar
  • 2 Horwitz K B, Alexander P S. In situ photolinked nuclear progesterone receptors of human breast cancer cells: subunit molecular weights after transformation and translocation.  Endocrinology. 1983;  113(6) 2195-2201
    CrossrefPubMedGoogle Scholar
  • 3 Alexander I E, Clarke C L, Shine J, Sutherland R L. Progestin inhibition of progesterone receptor gene expression in human breast cancer cells.  Mol Endocrinol. 1989;  3(9) 1377-1386
    CrossrefPubMedGoogle Scholar
  • 4 Lessey B AAP, Alexander P S, Horwitz K B. The subunit structure of human breast cancer progesterone receptors: characterization by chromatography and photoaffinity labeling.  Endocrinology. 1983;  112(4) 1267-1274
    CrossrefPubMedGoogle Scholar
  • 5 Conneely O M, Sullivan W P, Toft D O et al.. Molecular cloning of the chicken progesterone receptor.  Science. 1986;  233(4765) 767-770
    CrossrefPubMedGoogle Scholar
  • 6 Giangrande P H, McDonnell D P. The A and B isoforms of the human progesterone receptor: two functionally different transcription factors encoded by a single gene.  Recent Prog Horm Res. 1999;  54 291-313, discussion 313–314
    PubMedGoogle Scholar
  • 7 Mulac-Jericevic B, Mullinax R A, DeMayo F J, Lydon J P, Conneely O M. Subgroup of reproductive functions of progesterone mediated by progesterone receptor-B isoform.  Science. 2000;  289(5485) 1751-1754
    CrossrefPubMedGoogle Scholar
  • 8 Mangal R K, Wiehle III R D, Poindexter III A N, Weigel N L. Differential expression of uterine progesterone receptor forms A and B during the menstrual cycle.  J Steroid Biochem Mol Biol. 1997;  63(4-6) 195-202
    CrossrefPubMedGoogle Scholar
  • 9 Attia G R, Zeitoun K, Edwards D, Johns A, Carr B R, Bulun S E. Progesterone receptor isoform A but not B is expressed in endometriosis.  J Clin Endocrinol Metab. 2000;  85(8) 2897-2902
    CrossrefPubMedGoogle Scholar
  • 10 Mote P A, Balleine R L, McGowan E M, Clarke C L. Colocalization of progesterone receptors A and B by dual immunofluorescent histochemistry in human endometrium during the menstrual cycle.  J Clin Endocrinol Metab. 1999;  84(8) 2963-2971
    CrossrefPubMedGoogle Scholar
  • 11 Kurita T LK, Lee K J, Cooke P S, Lydon J P, Cunha G R. Paracrine regulation of epithelial progesterone receptor and lactoferrin by progesterone in the mouse uterus.  Biol Reprod. 2000;  62(4) 831-838
    CrossrefPubMedGoogle Scholar
  • 12 Tseng L, Gurpide E. Estradiol and 20alpha-dihydroprogesterone dehydrogenase activities in human endometrium during the menstrual cycle.  Endocrinology. 1974;  94(2) 419-423
    CrossrefPubMedGoogle Scholar
  • 13 Tseng L, Gurpide E. Induction of human endometrial estradiol dehydrogenase by progestins.  Endocrinology. 1975;  97(4) 825-833
    CrossrefPubMedGoogle Scholar
  • 14 Satyaswaroop P G, Wartell D J, Mortel R. 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.  Endocrinology. 1982;  111(3) 743-749
    CrossrefPubMedGoogle Scholar
  • 15 Wu L EM, Einstein M, Geissler W M, Chan H K, Elliston K O, Andersson S. Expression cloning and characterization of human 17 beta-hydroxysteroid dehydrogenase type 2, a microsomal enzyme possessing 20 alpha-hydroxysteroid dehydrogenase activity.  J Biol Chem. 1993;  268(17) 12964-12969
    PubMedGoogle Scholar
  • 16 Casey M L, MacDonald P C, Andersson S. 17b-Hydroxysteroid dehydrogenase type 2: chromosomal assignment and progestin regulation of gene expression in human endometrium.  J Clin Invest. 1994;  94 2135-2141
    CrossrefPubMedGoogle Scholar
  • 17 Mustonen M V, Isomaa V V, Vaskivuo T et al.. Human 17b-hydroxysteroid dehydrogenase type 2 messenger ribonucleic acid expression and localization in term placenta and in endometrium during the menstrual cycle.  J Clin Endocrinol Metab. 1998;  83 1319-1324
    CrossrefPubMedGoogle Scholar
  • 18 Yang S, Fang Z, Gurates B et al.. Stromal progesterone receptors mediate induction of 17beta-hydroxysteroid dehydrogenase type 2 expression in human endometrial epithelium: a paracrine mechanism for inactivation of estradiol.  Mol Endocrinol. 2001;  15 2093-2105
    CrossrefPubMedGoogle Scholar
  • 19 Cheng Y H, Imir A, Suzuki T et al.. SP1 and SP3 mediate progesterone-dependent induction of the 17beta hydroxysteroid dehydrogenase type 2 gene in human endometrium.  Biol Reprod. 2006;  75(4) 605-614
    CrossrefPubMedGoogle Scholar
  • 20 Cheng Y H, Yin P, Xue Q, Yilmaz B, Dawson M I, Bulun S E. 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.  J Clin Endocrinol Metab. 2008;  93(5) 1915-1923
    CrossrefPubMedGoogle Scholar
  • 21 Bulun S E, Cheng Y H, Yin P et al.. Progesterone resistance in endometriosis: link to failure to metabolize estradiol.  Mol Cell Endocrinol. 2006;  248(1-2) 94-103
    CrossrefPubMedGoogle Scholar
  • 22 Prentice A, Randall B J, Weddell A et al.. Ovarian steroid receptor expression in endometriosis and in two potential parent epithelia: endometrium and peritoneal mesothelium.  Hum Reprod. 1992;  7 1318-1325
    PubMedGoogle Scholar
  • 23 Bergqvist A, Ferno M. Oestrogen and progesterone receptors in endometriotic tissue and endometrium: comparison of different cycle phases and ages.  Hum Reprod. 1993;  8(12) 2211-2217
    PubMedGoogle Scholar
  • 24 Bergqvist A, Fernö M. Estrogen and progesterone receptors in endometriotic tissue and endometrium: comparison according to localization and recurrence.  Fertil Steril. 1993;  60(1) 63-68
    PubMedGoogle Scholar
  • 25 Zeitoun K M, Takayama K, Sasano H et al.. Deficient 17beta-hydroxysteroid dehydrogenase type 2 expression in endometriosis: failure to metabolize 17beta-estradiol.  J Clin Endocrinol Metab. 1998;  83(12) 4474-4480
    CrossrefPubMedGoogle Scholar
  • 26 Vierikko P KA, Kauppila A, Rönnberg L, Vihko R. Steroidal regulation of endometriosis tissue: lack of induction of 17 beta-hydroxysteroid dehydrogenase activity by progesterone, medroxyprogesterone acetate, or danazol.  Fertil Steril. 1985;  43(2) 218-224
    PubMedGoogle Scholar
  • 27 Isomaa V V, Ghersevich S A, Mäentausta O K, Peltoketo E H, Poutanen M H, Vihko R K. Steroid biosynthetic enzymes: 17 beta-hydroxysteroid dehydrogenase.  Ann Med. 1993;  25(1) 91-97
    CrossrefPubMedGoogle Scholar
  • 28 Labrie F, Luu-The V, Labrie C et al.. Characterization of two mRNA species encoding human estradiol 17beta-dehydrogenase and assignment of the gene to chromosome 17.  J Steroid Biochem. 1989;  34 189-197
    CrossrefPubMedGoogle Scholar
  • 29 Vercellini P, Cortesi I, Crosignani P G. Progestins for symptomatic endometriosis: a critical analysis of the evidence.  Fertil Steril. 1997;  68(3) 393-401
    CrossrefPubMedGoogle Scholar
  • 30 Cheng Y H, Imir A, Fenkci V, Yilmaz M B, Bulun S E. 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.  Am J Obstet Gynecol. 2007;  196 391-398
    PubMedGoogle Scholar
  • 31 Kao L C, Germeyer A, Tulac S et al.. Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility.  Endocrinology. 2003;  144(7) 2870-2881
    CrossrefPubMedGoogle Scholar
  • 32 Burney R O, Talbi S, Hamilton A E et al.. Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis.  Endocrinology. 2007;  148(8) 3814-3826
    CrossrefPubMedGoogle Scholar

Serdar E BulunM.D. 

George H. Gardner Professor of Clinical Gynecology, Division of Reproductive Biology Research, Department Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine

303 E. Superior St., 4-123, Chicago, IL 60611

Email: s-bulun@northwestern.edu

      >