Semin Reprod Med 2010; 28(1): 069-074
DOI: 10.1055/s-0029-1242996
© Thieme Medical Publishers

Molecular Mechanisms of Treatment Resistance in Endometriosis: The Role of Progesterone–Hox Gene Interactions

Hakan Cakmak1 , Hugh S. Taylor1
  • 1Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut
Further Information

Publication History

Publication Date:
26 January 2010 (online)

ABSTRACT

HOX genes, encoding homeodomain transcription factors, are dynamically expressed in endometrium, where they are necessary for endometrial growth, differentiation, and implantation. In human endometrium, the expression of HOXA10 and HOXA11 is driven by sex steroids, with peak expression occurring at time of implantation in response to rising progesterone levels. However, the maximal HOXA10 and HOXA11 expression fails to occur in women with endometriosis. In endometriosis, altered progesterone receptor expression or diminished activity may lead to attenuated or dysregulated progesterone response and decreased expression of progesterone-responsive genes including HOX genes in the eutopic endometrium. In turn, other mediators of endometrial receptivity that are regulated by HOX genes, such as pinopodes, αvβ3 integrin, and IGFBP-1, are downregulated in endometriosis. HOXA10 hypermethylation has recently been demonstrated to silence HOXA10 gene expression and account for decreased HOXA10 in the endometrium of women with endometriosis. Silencing of progesterone target genes by methylation is an epigenetic mechanism that mediates progesterone resistance. The relatively permanent nature of methylation may explain the widespread failure of treatments for endometriosis-related infertility.

REFERENCES

  • 1 Gehring W J, Hiromi Y. Homeotic genes and the homeobox.  Annu Rev Genet. 1986;  20 147-173
  • 2 Apiou F, Flagiello D, Cillo C, Malfoy B, Poupon M F, Dutrillaux B. Fine mapping of human HOX gene clusters.  Cytogenet Cell Genet. 1996;  73(1-2) 114-115
  • 3 Scott M P. Vertebrate homeobox gene nomenclature.  Cell. 1992;  71(4) 551-553
  • 4 Dekker E E, Kitson R P. 2-Keto-4-hydroxyglutarate aldolase: purification and characterization of the homogeneous enzyme from bovine kidney.  J Biol Chem. 1992;  267(15) 10507-10514
  • 5 Taylor H S, Vanden Heuvel G B, Igarashi P. A conserved Hox axis in the mouse and human female reproductive system: late establishment and persistent adult expression of the Hoxa cluster genes.  Biol Reprod. 1997;  57(6) 1338-1345
  • 6 Block K, Kardana A, Igarashi P, Taylor H S. In utero diethylstilbestrol (DES) exposure alters Hox gene expression in the developing müllerian system.  FASEB J. 2000;  14(9) 1101-1108
  • 7 Benson G V, Lim H, Paria B C, Satokata I, Dey S K, Maas R L. Mechanisms of reduced fertility in Hoxa-10 mutant mice: uterine homeosis and loss of maternal Hoxa-10 expression.  Development. 1996;  122(9) 2687-2696
  • 8 Taylor H S, Arici A, Olive D, Igarashi P. HOXA10 is expressed in response to sex steroids at the time of implantation in the human endometrium.  J Clin Invest. 1998;  101(7) 1379-1384
  • 9 Taylor H S, Igarashi P, Olive D L, Arici A. Sex steroids mediate HOXA11 expression in the human peri-implantation endometrium.  J Clin Endocrinol Metab. 1999;  84(3) 1129-1135
  • 10 Gendron R L, Paradis H, Hsieh-Li H M, Lee D W, Potter S S, Markoff E. Abnormal uterine stromal and glandular function associated with maternal reproductive defects in Hoxa-11 null mice.  Biol Reprod. 1997;  56(5) 1097-1105
  • 11 Ma L, Benson G V, Lim H, Dey S K, Maas R L, Abdominal B. Abdominal B (AbdB) Hoxa genes: regulation in adult uterus by estrogen and progesterone and repression in müllerian duct by the synthetic estrogen diethylstilbestrol (DES).  Dev Biol. 1998;  197(2) 141-154
  • 12 Akbas G E, Song J, Taylor H SA. A HOXA10 estrogen response element (ERE) is differentially regulated by 17 beta-estradiol and diethylstilbestrol (DES).  J Mol Biol. 2004;  340(5) 1013-1023
  • 13 Martin R, Taylor M B, Krikun G, Lockwood C, Akbas G E, Taylor H S. Differential cell-specific modulation of HOXA10 by estrogen and specificity protein 1 response elements.  J Clin Endocrinol Metab. 2007;  92(5) 1920-1926
  • 14 Hsieh-Li H M, Witte D P, Weinstein M et al.. Hoxa 11 structure, extensive antisense transcription, and function in male and female fertility.  Development. 1995;  121(5) 1373-1385
  • 15 Satokata I, Benson G, Maas R. Sexually dimorphic sterility phenotypes in Hoxa10-deficient mice.  Nature. 1995;  374(6521) 460-463
  • 16 Bagot C N, Troy P J, Taylor H S. Alteration of maternal Hoxa10 expression by in vivo gene transfection affects implantation.  Gene Ther. 2000;  7(16) 1378-1384
  • 17 Daftary G S, Taylor H S. Endocrine regulation of HOX genes.  Endocr Rev. 2006;  27(4) 331-355
  • 18 Salehnia M. Different pattern of pinopodes expression in stimulated mouse endometrium.  Exp Anim. 2005;  54(4) 349-352
  • 19 Nikas G, Drakakis P, Loutradis D et al.. Uterine pinopodes as markers of the ‘nidation window’ in cycling women receiving exogenous oestradiol and progesterone.  Hum Reprod. 1995;  10(5) 1208-1213
  • 20 Singh M M, Chauhan S C, Trivedi R N, Maitra S C, Kamboj V P. Correlation of pinopod development on uterine luminal epithelial surface with hormonal events and endometrial sensitivity in rat.  Eur J Endocrinol. 1996;  135(1) 107-117
  • 21 Bagot C N, Kliman H J, Taylor H S. Maternal Hoxa10 is required for pinopod formation in the development of mouse uterine receptivity to embryo implantation.  Dev Dyn. 2001;  222(3) 538-544
  • 22 Lessey B A, Damjanovich L, Coutifaris C, Castelbaum A, Albelda S M, Buck C A. Integrin adhesion molecules in the human endometrium. Correlation with the normal and abnormal menstrual cycle.  J Clin Invest. 1992;  90(1) 188-195
  • 23 Sueoka K, Shiokawa S, Miyazaki T, Kuji N, Tanaka M, Yoshimura Y. Integrins and reproductive physiology: expression and modulation in fertilization, embryogenesis, and implantation.  Fertil Steril. 1997;  67(5) 799-811
  • 24 Daftary G S, Troy P J, Bagot C N, Young S L, Taylor H S. Direct regulation of beta3-integrin subunit gene expression by HOXA10 in endometrial cells.  Mol Endocrinol. 2002;  16(3) 571-579
  • 25 Hustin J, Philippe E, Teisner B, Grudzinskas J G. Immunohistochemical localization of two endometrial proteins in the early days of human pregnancy.  Placenta. 1994;  15(7) 701-708
  • 26 Irwin J C, Suen L F, Faessen G H, Popovici R M, Giudice L C. Insulin-like growth factor (IGF)-II inhibition of endometrial stromal cell tissue inhibitor of metalloproteinase-3 and IGF-binding protein-1 suggests paracrine interactions at the decidua:trophoblast interface during human implantation.  J Clin Endocrinol Metab. 2001;  86(5) 2060-2064
  • 27 Foucher I, Volovitch M, Frain M et al.. Hoxa5 overexpression correlates with IGFBP1 upregulation and postnatal dwarfism: evidence for an interaction between Hoxa5 and Forkhead box transcription factors.  Development. 2002;  129(17) 4065-4074
  • 28 Kim J J, Jaffe R C, Fazleabas A T. Insulin-like growth factor binding protein-1 expression in baboon endometrial stromal cells: regulation by filamentous actin and requirement for de novo protein synthesis.  Endocrinology. 1999;  140(2) 997-1004
  • 29 Kim J J, Taylor H S, Lu Z et al.. Altered expression of HOXA10 in endometriosis: potential role in decidualization.  Mol Hum Reprod. 2007;  13(5) 323-332
  • 30 Lim H, Paria B C, Das S K et al.. Multiple female reproductive failures in cyclooxygenase 2-deficient mice.  Cell. 1997;  91(2) 197-208
  • 31 Lim H, Ma L, Ma W G, Maas R L, Dey S K. Hoxa-10 regulates uterine stromal cell responsiveness to progesterone during implantation and decidualization in the mouse.  Mol Endocrinol. 1999;  13(6) 1005-1017
  • 32 Cermik D, Selam B, Taylor H S. Regulation of HOXA-10 expression by testosterone in vitro and in the endometrium of patients with polycystic ovary syndrome.  J Clin Endocrinol Metab. 2003;  88(1) 238-243
  • 33 Daftary G S, Taylor H S. Hydrosalpinx fluid diminishes endometrial cell HOXA10 expression.  Fertil Steril. 2002;  78(3) 577-580
  • 34 Rackow B W, Taylor H S. Submucosal uterine leiomyomas have a global effect on molecular determinants of endometrial receptivity.  Fertil Steril. 2008 June 12; 
  • 35 Taylor H S, Bagot C, Kardana A, Olive D, Arici A. HOX gene expression is altered in the endometrium of women with endometriosis.  Hum Reprod. 1999;  14(5) 1328-1331
  • 36 Houston D E. Evidence for the risk of pelvic endometriosis by age, race and socioeconomic status.  Epidemiol Rev. 1984;  6 167-191
  • 37 Strathy J H, Molgaard C A, Coulam C B, Melton III L J. Endometriosis and infertility: a laparoscopic study of endometriosis among fertile and infertile women.  Fertil Steril. 1982;  38(6) 667-672
  • 38 Simón C, Gutiérrez A, Vidal A et al.. Outcome of patients with endometriosis in assisted reproduction: results from in-vitro fertilization and oocyte donation.  Hum Reprod. 1994;  9(4) 725-729
  • 39 Tummon I S, Maclin V M, Radwanska E, Binor Z, Dmowski W P. Occult ovulatory dysfunction in women with minimal endometriosis or unexplained infertility.  Fertil Steril. 1988;  50(5) 716-720
  • 40 Ulukus M, Cakmak H, Arici A. The role of endometrium in endometriosis.  J Soc Gynecol Investig. 2006;  13(7) 467-476
  • 41 Kao L C, Tulac S, Lobo S et al.. Global gene profiling in human endometrium during the window of implantation.  Endocrinology. 2002;  143(6) 2119-2138
  • 42 Metzger D A, Olive D L, Haney A F. Limited hormonal responsiveness of ectopic endometrium: histologic correlation with intrauterine endometrium.  Hum Pathol. 1988;  19(12) 1417-1424
  • 43 Winkel C A, Scialli A R. Medical and surgical therapies for pain associated with endometriosis.  J Womens Health Gend Based Med. 2001;  10(2) 137-162
  • 44 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
  • 45 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
  • 46 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
  • 47 Okulicz W C, Savasta A M, Hoberg L M, Longcope C. Immunofluorescent analysis of estrogen induction of progesterone receptor in the rhesus uterus.  Endocrinology. 1989;  125(2) 930-934
  • 48 Mulac-Jericevic B, Lydon J P, DeMayo F J, Conneely O M. Defective mammary gland morphogenesis in mice lacking the progesterone receptor B isoform.  Proc Natl Acad Sci U S A. 2003;  100(17) 9744-9749
  • 49 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
  • 50 Lee B, Du H, Taylor H S. Experimental murine endometriosis induces DNA methylation and altered gene expression in eutopic endometrium.  Biol Reprod. 2009;  80(1) 79-85
  • 51 Fazleabas A T, Brudney A, Chai D, Langoi D, Bulun S E. Steroid receptor and aromatase expression in baboon endometriotic lesions.  Fertil Steril. 2003;  80(Suppl 2) 820-827
  • 52 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
  • 53 Kamat A A, Younes P S, Sayeeduddin M, Wheeler T M, Simpson J L, Agoulnik A I. Protein expression profiling of endometriosis: validation of 2-mm tissue microarrays.  Fertil Steril. 2004;  82(6) 1681-1683
  • 54 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
  • 55 Klemmt P A, Carver J G, Kennedy S H, Koninckx P R, Mardon H J. Stromal cells from endometriotic lesions and endometrium from women with endometriosis have reduced decidualization capacity.  Fertil Steril. 2006;  85(3) 564-572
  • 56 Lessey B A, Castelbaum A J, Sawin S W et al.. Aberrant integrin expression in the endometrium of women with endometriosis.  J Clin Endocrinol Metab. 1994;  79(2) 643-649
  • 57 Vitiello D, Kodaman P H, Taylor H S. HOX genes in implantation.  Semin Reprod Med. 2007;  25(6) 431-436
  • 58 Troy P J, Daftary G S, Bagot C N, Taylor H S. Transcriptional repression of peri-implantation EMX2 expression in mammalian reproduction by HOXA10.  Mol Cell Biol. 2003;  23(1) 1-13
  • 59 Daftary G S, Taylor H S. EMX2 gene expression in the female reproductive tract and aberrant expression in the endometrium of patients with endometriosis.  J Clin Endocrinol Metab. 2004;  89(5) 2390-2396
  • 60 Taylor H S, Fei X. Emx2 regulates mammalian reproduction by altering endometrial cell proliferation.  Mol Endocrinol. 2005;  19(11) 2839-2846
  • 61 Reik W, Dean W, Walter J. Epigenetic reprogramming in mammalian development.  Science. 2001;  293(5532) 1089-1093
  • 62 Ehrlich M. Expression of various genes is controlled by DNA methylation during mammalian development.  J Cell Biochem. 2003;  88(5) 899-910
  • 63 Jones P A, Baylin S B. The fundamental role of epigenetic events in cancer.  Nat Rev Genet. 2002;  3(6) 415-428
  • 64 Robertson K D. DNA methylation and human disease.  Nat Rev Genet. 2005;  6(8) 597-610
  • 65 Wu Y, Halverson G, Basir Z, Strawn E, Yan P, Guo S W. Aberrant methylation at HOXA10 may be responsible for its aberrant expression in the endometrium of patients with endometriosis.  Am J Obstet Gynecol. 2005;  193(2) 371-380
  • 66 Wu Y, Strawn E, Basir Z, Halverson G, Guo S W. Aberrant expression of deoxyribonucleic acid methyltransferases DNMT1, DNMT3A, and DNMT3B in women with endometriosis.  Fertil Steril. 2007;  87(1) 24-32

Hugh TaylorM.D. 

Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine

333 Cedar Street, New Haven, CT 06520-8063

Email: hugh.taylor@yale.edu

    >