Progesterone resistance in a baboon model of endometriosis

The development of a baboon model of induced endometriosis, which recapitulates the retrograde menstruation hypothesis, has greatly facilitated our understanding of the early events associated with the disease process. Sequential analysis of the eutopic endometrium following the establishment of disease suggests that the development of progesterone resistance is a gradual process and becomes evident after 6 months of disease induction. This resistance is manifested by a decreased responsiveness of the progesterone receptor and its chaperone immunophilins as well as epigenetic modifications of progesterone-regulated genes. In comparative studies, the time-dependent changes observed in the baboon eutopic endometrium are similar to those that have been reported to be altered in women with endometriosis. The baboon model therefore provides insight into the potential mechanisms by which genes in the eutopic endometrium are dysregulated and how this alteration results in infertility that is associated with endometriosis.

Baboon - endometriosis - infertility - progesterone resistance

- 1 Eskenazi B, Warner M L. Epidemiology of endometriosis. Obstet Gynecol Clin North Am. 1997; 24(2) 235-258 - 2 Italiano G. Prevalence and anatomical distribution of endometriosis in women with selected gynaecological conditions: results from a multicentric Italian study. Gruppo italiano per lo studio dell'endometriosi. Hum Reprod. 1994; 9(6) 1158-1162 - 3 Sampson J. Peritoneal endometriosis due to menstrual dissemination of endometrial tissue into the pelvic cavity. Am J Obstet Gynecol. 1927; 14 422-469 - 4 Blumenkrantz M J, Gallagher N, Bashore R A, Tenckhoff H. Retrograde menstruation in women undergoing chronic peritoneal dialysis. Obstet Gynecol. 1981; 57(5) 667-670 - 5 Giudice L C, Kao L C. Endometriosis. Lancet. 2004; 364(9447) 1789-1799 - 6 Awwad J T, Sayegh R A, Tao X J, Hassan T, Awwad S T, Isaacson K. The SCID mouse: an experimental model for endometriosis. Hum Reprod. 1999; 14(12) 3107-3111 - 7 Bruner K L, Matrisian L M, Rodgers W H, Gorstein F, Osteen K G. Suppression of matrix metalloproteinases inhibits establishment of ectopic lesions by human endometrium in nude mice. J Clin Invest. 1997; 99(12) 2851-2857 - 8 Zamah N M, Dodson M G, Stephens L C, Buttram Jr V C, Besch P K, Kaufman R H. Transplantation of normal and ectopic human endometrial tissue into athymic nude mice. Am J Obstet Gynecol. 1984; 149(6) 591-597 - 9 Rossi G, Somigliana E, Moschetta M et al.. Dynamic aspects of endometriosis in a mouse model through analysis of implantation and progression. Arch Gynecol Obstet. 2000; 263(3) 102-107 - 10 D'Hooghe T M. Clinical relevance of the baboon as a model for the study of endometriosis. Fertil Steril. 1997; 68(4) 613-625 - 11 D'Hooghe T M, Bambra C S, Raeymaekers B M, De Jonge I, Lauweryns J M, Koninckx P R. Intrapelvic injection of menstrual endometrium causes endometriosis in baboons (Papio cynocephalus and Papio anubis). Am J Obstet Gynecol. 1995; 173(1) 125-134 - 12 Dick Jr E J, Hubbard G B, Martin L J, Leland M M. Record review of baboons with histologically confirmed endometriosis in a large established colony. J Med Primatol. 2003; 32(1) 39-47 - 13 Fazleabas A T, Brudney A, Gurates B, Chai D, Bulun S. A modified baboon model for endometriosis. Ann N Y Acad Sci. 2002; 955 308-317 discussion 40-342 396-406 - 14 MacKenzie W F, Casey H W. Animal model of human disease. Endometriosis. Animal model: endometriosis in rhesus monkeys. Am J Pathol. 1975; 80(2) 341-344 - 15 Story L, Kennedy S. Animal studies in endometriosis: a review. ILAR J. 2004; 45(2) 132-138 - 16 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 - 17 D'Hooghe T M, Bambra C S, Raeymaekers B M, De Jonge I, Lauweryns J M, Koninckx P R. Intrapelvic injection of menstrual endometrium causes endometriosis in baboons (Papio cynocephalus and Papio anubis). Am J Obstet Gynecol. 1995; 173(1) 125-134 - 18 Hastings J M, Fazleabas A T. A baboon model for endometriosis: implications for fertility. Reprod Biol Endocrinol. 2006; 4(Suppl 1) S7 - 19 Donnez J, Smoes P, Gillerot S, Casanas-Roux F, Nisolle M. Vascular endothelial growth factor (VEGF) in endometriosis. Hum Reprod. 1998; 13(6) 1686-1690 - 20 Fedele L, Bianchi S, Marchini M, Franchi D, Tozzi L, Dorta M. Ultrastructural aspects of endometrium in infertile women with septate uterus. Fertil Steril. 1996; 65(4) 750-752 - 21 Fujishita A, Hasuo A, Khan K N, Masuzaki H, Nakashima H, Ishimaru T. Immunohistochemical study of angiogenic factors in endometrium and endometriosis. Gynecol Obstet Invest. 1999; 48(Suppl 1) 36-44 - 22 Goteri G, Lucarini G, Filosa A et al.. Immunohistochemical analysis of vascular endothelial growth factor cellular expression in ovarian endometriomata. Fertil Steril. 2004; 81(6) 1528-1533 - 23 Takehara M, Ueda M, Yamashita Y, Terai Y, Hung Y C, Ueki M. Vascular endothelial growth factor A and C gene expression in endometriosis. Hum Pathol. 2004; 35(11) 1369-1375 - 24 Tan X J, Lang J H, Liu D Y, Shen K, Leng J H, Zhu L. Expression of vascular endothelial growth factor and thrombospondin-1 mRNA in patients with endometriosis. Fertil Steril. 2002; 78(1) 148-153 - 25 Absenger Y, Hess-Stumpp H, Kreft B et al.. Cyr61, a deregulated gene in endometriosis. Mol Hum Reprod. 2004; 10(6) 399-407 - 26 Jones C L, Inuwa I M, Nardo L G, Litta P, Fazleabas A T. Eutopic endometrium for women with endometriosis shows altered ultrastructure and glycosylatin compared to that from healthy controls—a pilot observational study. Reprod Sci. 2009; 16(6) 559-572 - 27 Donaghay M, Lessey B A. Uterine receptivity: alterations associated with benign gynecological disease. Semin Reprod Med. 2007; 25(6) 461-475 - 28 Lessey B A, Palomino W A, Apparao K B, Young S L, Lininger R A. Estrogen receptor-alpha (ER-alpha) and defects in uterine receptivity in women. Reprod Biol Endocrinol. 2006; 4(Suppl 1) S9 - 29 Vitiello D, Kodaman P H, Taylor H S. HOX genes in implantation. Semin Reprod Med. 2007; 25(6) 431-436 - 30 D'Hooghe T M, Bambra C S, Raeymaekers B M, Riday A M, Suleman M A, Koninckx P R. The cycle pregnancy rate is normal in baboons with stage I endometriosis but decreased in primates with stage II and stage III–IV disease. Fertil Steril. 1996; 66(5) 809-813 - 31 Schenken R S, Asch R H, Williams R F, Hodgen G D. Etiology of infertility in monkeys with endometriosis: measurement of peritoneal fluid prostaglandins. Am J Obstet Gynecol. 1984; 150(4) 349-353 - 32 Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of endometriosis on in vitro fertilization. Fertil Steril. 2002; 77(6) 1148-1155 - 33 Pellicer A, Oliveira N, Ruiz A, Remohí J, Simón C. Exploring the mechanism(s) of endometriosis-related infertility: an analysis of embryo development and implantation in assisted reproduction. Hum Reprod. 1995; 10(Suppl 2) 91-97 - 34 Arici A, Oral E, Bukulmez O, Duleba A, Olive D L, Jones E E. The effect of endometriosis on implantation: results from the Yale University in vitro fertilization and embryo transfer program. Fertil Steril. 1996; 65(3) 603-607 - 35 Hastings J M, Jackson K S, Mavrogianis P A, Fazleabas A T. The estrogen early response gene FOS is altered in a baboon model of endometriosis. Biol Reprod. 2006; 75(2) 176-182 - 36 Gashaw I, Hastings J M, Jackson K S, Winterhager E, Fazleabas A T. Induced endometriosis in the baboon (Papio anubis) increases the expression of the proangiogenic factor CYR61 (CCN1) in eutopic and ectopic endometria. Biol Reprod. 2006; 74(6) 1060-1066 - 37 Braundmeier A G, Fazleabas A T, Lessey B A, Guo H, Toole B P, Nowak R A. Extracellular matrix metalloproteinase inducer regulates metalloproteinases in human uterine endometrium. J Clin Endocrinol Metab. 2006; 91(6) 2358-2365 - 38 Kim J J, Lu Z, Ladham O, Wu Y, Guo S W, Fazleabas A T. Alterations in HOXA10 expression in endometriosis: potential role in decidualization. Biol Reprod. 2007; 13(5) 323-332 - 39 Jackson K S, Hastings J M, Mavrogianis P A, Bagchi I, Fazleabas A T. Alterations in the Calcitonin and Calcitonin modulated proteins, E-cadherin and the enzyme tissue Transglutaminase II during the window of implantation in a baboon model of endometriosis. J Endometriosis. 2009; 1 57-67 - 40 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 - 41 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 - 42 Lessey B A, Castelbaum A J. Integrins in the endometrium of women with endometriosis. Br J Obstet Gynaecol. 1995; 102 347-348 - 43 Jackson K S, Brudney A, Hastings J M, Mavrogianis P A, Kim J J, Fazleabas A T. The altered distribution of the steroid hormone receptors and the chaperone immunophilin FKBP52 in a baboon model of endometriosis is associated with progesterone resistance during the window of uterine receptivity. Reprod Sci. 2007; 14(2) 137-150 - 44 Buchanan D L, Setiawan T, Lubahn D B et al.. Tissue compartment-specific estrogen alpha participation in the mouse uterine epithelial secretory response. Endocrinology. 1999; 140 484-491 - 45 Kurita T, Young P, Brody J R, Lydon J P, O'Malley B W, Cunha G R. Stromal progesterone receptors mediate the inhibitory effects of progesterone on estrogen-induced uterine epithelial cell deoxyribonucleic acid synthesis. Endocrinology. 1998; 139 4708-4713 - 46 Kurita T, Lee K, Saunders P T et al.. Regulation of progesterone receptors and decidualization in uterine stroma of the estrogen receptor-alpha knockout mouse. Biol Reprod. 2001; 64(1) 272-283 - 47 Kurita T, 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; 62 831-838 - 48 Kurita T, Lee K J, Cooke P S, Lydon J P, Cunha G R. Paracrine regulation of epithelial progesterone receptor by estradiol in the mouse female reproductive tract. Biol Reprod. 2000; 62 821-830 - 49 Cooke P S, Buchanan D L, Young P et al.. Stromal estrogen receptors mediate mitogenic effects of estradiol on uterine epithelium. Proc Natl Acad Sci U S A. 1997; 94(12) 6535-6540 - 50 Tranguch S, Cheung-Flynn J, Daikoku T et al.. Cochaperone immunophilin FKBP52 is critical to uterine receptivity for embryo implantation. Proc Natl Acad Sci U S A. 2005; 102(40) 14326-14331 - 51 Kumar S, Zhu L J, Polihronis M et al.. Progesterone induces calcitonin gene expression in human endometrium within the putative window of implantation. J Clin Endocrinol Metab. 1998; 83(12) 4443-4450 - 52 Kumar S, Brudney A, Cheon Y P, Fazleabas A T, Bagchi I C. Progesterone induces calcitonin expression in the baboon endometrium within the window of uterine receptivity. Biol Reprod. 2003; 68 1318-1323 - 53 Yang Z, Wolf I M, Chen H et al.. Fk506 binding protein 52 is essential to uterine reproductive physiology controlled by the progesterone receptor A isoform. Mol Endocrinol. 2006; 20 2682-2694 - 54 Hirota Y, Tranguch S, Daikoku T et al.. Deficiency of immunophilin FKBP52 promotes endometriosis. Am J Pathol.. 2008; 173 1747-1757 - 55 Li Q, Wang J, Armant D R, Bagchi M K, Bagchi I C. Calcitonin down-regulates E-cadherin expression in rodent uterine epithelium during implantation. J Biol Chem. 2002; 277(48) 46447-46455 - 56 Li Q, Bagchi M K, Bagchi I C. Identification of a signaling pathway involving progesterone receptor, calcitonin, and tissue tranglutaminase in Ishikawa endometrial cells. Endocrinology. 2006; 147(5) 2147-2154 - 57 Overduin M, Harvey T S, Bagby S et al.. Solution structure of the epithelial cadherin domain responsible for selective cell adhesion. Science. 1995; 267(5196) 386-389 - 58 Nagar B, Overduin M, Ikura M, Rini J M. Structural basis of calcium-induced E-cadherin rigidification and dimerization. Nature. 1996; 380(6572) 360-364 - 59 Fujimoto M, Kanzaki H, Nakayama H et al.. Requirement for transglutaminase in progesterone-induced decidualization of human endometrial stromal cells. Endocrinology. 1996; 137(3) 1096-1101 - 60 Nose A, Takeichi M. A novel cadherin cell adhesion molecule: its expression patterns associated with implantation and organogenesis of mouse embryos. J Cell Biol. 1986; 103(6 Pt 2) 2649-2658 - 61 Campbell S, Swann H R, Seif M W, Kimber S J, Aplin J D. Cell adhesion molecules on the oocyte and preimplantation human embryo. Hum Reprod. 1995; 10(6) 1571-1578 - 62 Martinez J, Chalupowicz D G, Roush R K, Sheth A, Barsigian C. Transglutaminase-mediated processing of fibronectin by endothelial cell monolayers. Biochemistry. 1994; 33(9) 2538-2545 - 63 Kojima S, Nara K, Rifkin D B. Requirement for transglutaminase in the activation of latent transforming growth factor-beta in bovine endothelial cells. J Cell Biol. 1993; 121(2) 439-448 - 64 Nunes I, Gleizes P E, Metz C N, Rifkin D B. Latent transforming growth factor-beta binding protein domains involved in activation and transglutaminase-dependent cross-linking of latent transforming growth factor-beta. J Cell Biol. 1997; 136(5) 1151-1163 - 65 Gentile V, Thomazy V, Piacentini M, Fesus L, Davies P J. Expression of tissue transglutaminase in Balb-C 3T3 fibroblasts: effects on cellular morphology and adhesion. J Cell Biol. 1992; 119(2) 463-474 - 66 Fesus L, Thomazy V, Falus A. Induction and activation of tissue transglutaminase during programmed cell death. FEBS Lett. 1987; 224(1) 104-108 - 67 Nakaoka H, Perez D M, Baek K J et al.. Gh: a GTP-binding protein with transglutaminase activity and receptor signaling function. Science. 1994; 264(5165) 1593-1596 - 68 Fesus L, Szondy Z. Transglutaminase 2 in the balance of cell death and survival. FEBS Lett. 2005; 579 3297-3302 - 69 Robinson N J, Glazier J D, Greenwood S L, Baker P N, Aplin J D. Tissue transglutaminase expression and activity in placenta. Placenta. 2006; 27(2-3) 148-157 - 70 Robinson N J, Baker P N, Jones C J, Aplin J D. A role for tissue transglutaminase in stabilization of membrane-cytoskeletal particles shed from the human placenta. Biol Reprod. 2007; 77(4) 648-657 - 71 Klemmt P A, Carver J G, Koninckx P, McVeigh E J, Mardon H J. Endometrial cells from women with endometriosis have increased adhesion and proliferative capacity in response to extracellular matrix components: towards a mechanistic model for endometriosis progression. Hum Reprod. 2007; 22(12) 3139-3147 - 72 Minici F, Tiberi F, Tropea A et al.. Endometriosis and human infertility: a new investigation into the role of eutopic endometrium. Hum Reprod. 2008; 23(3) 530-537 - 73 Aghajanova L, Hamilton A, Kwintkiewicz J, Vo K C, Giudice L C. Steroidogenic enzyme and key decidualization marker dysregulation in endometrial stromal cells from women with versus without endometriosis. Biol Reprod. 2009; 80(1) 105-114 - 74 Bulun S E. Endometriosis. N Engl J Med. 2009; 360(3) 268-279 Asgerally T FazleabasPh.D. Professor and Associate Chair, Dept. of OB/GYN and Reprod Bio, College of Human Medicine, Michigan State University 234 Division Ave N, Suite 410, Grand Rapids, MI 49503 Email: [email protected]