Reduced Expression of αvβ3 Integrin in the Endometrium of Unexplained Infertility Patients with Recurrent IVF-ET Failures: Improvement by Danazol Treatment

Purpose : To determine whether there is any association between the expression of endometrial integrin α v β3 and repeated IVF-ET failure and to examine the effect of danazol treatment on α v β3 expression.

This prospective study was performed using a semiquantitative immunohistochemical analysis on the staining intensity of α v β3 in the mid-secretory endometria derived from 10 fertile women and 57 infertile patients with a history of repeated IVF-ET failures. Nine patients randomly selected from these 22 patients with unexplained infertility were then treated with oral danazol administration for 12 weeks and reexamined at the first mid-secretory phase after the danazol treatment. Result(s) : The levels of endometrial α v β3 expression were lower in 22 patients with unexplained infertility than in the fertile control and 35 patients with explained infertility. The 9 patients treated with danazol showed a significant increase in the α v β3 staining. Conclusion(s) : The significantly decreased expression of endometrial integrin α v β3 suggested that functional, but not morphological, endometrial defect may be one of the causes for the patients with unexplained infertility. Danazol may have a therapeutic potential in improving endometrial function together with up-regulation of α v β3. Similar content being viewed by others

Centers for Disease Control and Prevention (CDC): 1999 assisted reproductive technology success rates, National Summary and Fertility Clinic Reports, 2001. Available online at http://www.cdc.gov/nccdphp/drh/ART99/index99.ht Noyes RW, Hertig AT, Rock J: Dating the endometrial biopsy. Fertil Steril 1950;1:3–25 Peters AJ, Wentz AC: Endometrial receptivity and the luteal phase. Curr Opin Obstet Gynecol 1992;4:736–742 Lessey BA, Castelbaum AJ, Sawin SW, Sun J: Integrins as markers of uterine receptivity in women with primary unexplained infertility. Fertil Steril 1995;63:535–542 Carson DD, Bagchi I, Dey SK, Enders AC, Fazleabas AT, Lessey BA, Yoshinaga K: Embryo implantation. Dev Biol 2000;223:217–237 Daftary GF, Taylor HS: Molecular markers of implantation: Clinical implications. Curr Opin Obstet Gynecol 2001;13:269–274 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;67:799–811 Lessey BA, Damjanovich L, Coutifaris C, Castelbaum AJ, Albelda SM, Buck CA: Integrin adhesion molecules in the human endometrium. Correlation with the normal and abnormal menstrual cycle. J Clin Invest 1992;90:188–195 Lessey BA, Castelbaum AJ, Buck CA, Lei Y, Yowell CW, Sun J: Further characterization of endometrial integrins during the menstrual cycle and in pregnancy. Fertil Steril 1994;62:497–506 Lessey BA: The use of integrins for the assessment of uterine receptivity [editorial; comment]. Fertil Steril 1994;61:812–814 Lessey BA, Castelbaum AJ, Sawin SW, Buck CA, Schinnar R, Bilker W, Strom BL: Aberrant integrin expression in the endometrium of women with endometriosis. J Clin Endocrinol Metab 1994;79:643–649 Meyer WR, Castelbaum AJ, Somkuti S, Sagoskin AW, Doyle M, Harris JE, Lessey BA: Hydrosalpinges adversely affect markers of endometrial receptivity. Hum Reprod 1997;12:1393–1398 Illera MJ, Cullinan E, Gui Y, Yuan L, Beyler SA, Lessey BA: Blockade of the αvβ3 integrin adversely affects implantation in the mouse. Biol Reprod 2000;62:1285–1290 Creus M, Balasch J, Ordi J, FÁbregues F, Casamitjana R, Quinto L, Coutifaris C, Vanrell JA: Integrin expression in normal and out-of-phase endometria. Hum Reprod 1998;13:3460–3468 Hii LLP, Roger PAW: Endometrial vascular and glandular expression of integrin αvβ3 in women with and without endometriosis. Hum Reprod 1998;13:1030–103 Acosta AA, Elberger L, Borghi M, Calamera JC, Chemes H, Doncel GF, Kliman H, Lema B, Lustig L, Papier S: Endometrial dating and determinaton of the window of implantation in healthy fertile women. Fertil Steril 2000;73:788–798 Gonzalez RR, Palomino A, Boric A, Vega M, Devoto L: A quantitative evaluation of α1, α4, αV and β3 endometrial integrins of fertile and unexplained infertile women during the menstrual cycle. A flow cytometric appraisal. Hum Reprod 1999;14:2485–2492 Hodivala-Dilke KM, McHugh KP, Tsakiris DA, Rayburn H, Crowley D, Ullman-Culleré M, Ross FP, Coller BS, Teitelbaum S, Hynes RO: β3-integrin-deficienct mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival. J Clin Invest 1999;103:229–238 Tei C, Miyazaki T, Kuji N, Tanaka M, Sueoka K, Yoshimura Y: Effect of danazol on the pregnancy rate in patients with unsuccessful in vitro fertilization-embryo transfer. J Reprod Med 1998;43:541–546 Dmowski WP: Danazol—a steroid derivative with multiple and diverse biological effects. Br J Clin Pract 1988;42:343–347 Hill JA, Barbieri RL, Anderson DJ: Immunosuppressive effects of danazol in vitro. Fertil Steril 1987;48:414–418 Ahn YS, Harrington WJ, Simon SR, Mylvaganam R, Paul LM, So AG: Danazol for the treatment of idiopathic thrombocytopenic purpura. N Engl J Med 1983;308:1396–1399 Klentzeris LD, Bulmer JN, Trejdosiewicz LK, Morrison L, Cooke ID: Beta-1 integrin cell adhesion molecules in the endometrium of fertile and infertile women. Hum Reprod 1993;8:1223–1230 Cheresh DA, Spiro RC: Biosynthetic and functional properties of an Arg-Gly-Asp-directed receptor involved in human melanoma cell attachment to vitronectin, fibrinogen, and von Willebrand factor. J Biol Chem 1987;262:17703–17711 Budwit-Novotny DA, McCarty KS, Cox EB, Soper JT, Mutch DG, Creasman WT, Flowers JL, McCarty KS Jr.: Immunohistochemical analyses of estrogen receptor in endometrial adenocarcinoma using a monoclonal antibody. Cancer Res 1986;46:5419–5425 Tabibzadeh S: Patterns of expression of integrin molecules in human endometrium throughout the menstrual cycle. Hum Reprod 1992;7:876–882 Yoshimura Y, Shiokawa S, Nagamatsu S, Hanashi H, Sawa H, Koyama N, Katsumata Y, Nakamura Y: Effects of beta-1 integrins in the process of implantation. Horm Res 1995;44(Suppl 2):36–41 Crosignani PG, Collins J, Cooke ID, Diczfalusy E, Rubin B: Unexplained infertility. Hum Reprod 1993;8:977–980 Lessey BA, Ilesanmi AO, Yeh I, Korzeniowski P, Castelbaum AJ, Sun J, Fritz MA, Chwalisz K: Endometrial progesterone receptors and markers of uterine receptivity in the window of implantation. Fertil Steril 1996;65:477–483 Simón C, Gimeno MJ, Mercader A, O'Connor JE, Remohí J, Polan ML, Pellicer A: Embryonic regulation of integrins β3, α4, and α1 in human endometrial epithelial cells in vitro. J Clin Endocrinol Metab 1997;82:2607–2616 Somkuti SG, Yuan L, Fritz MA, Lessey BA: Epidermal growth factor and sex steroids dynamically regulate a marker of endometrial receptivity in Ishikawa cells. J Clin Endocrinol Metab 1997;82:2192–2197 Giudice LC: Growth factors and growth modulators in human uterine endometrium: Their potential relevance to reproductive medicine. Fertil Steril 1994;61:1–17 Kelly RW, King AE, Critchley HOD: Cytokine control in human endometrium. Reproduction 2001;121:3–19 Kokko E, Jänne O, Kauppila A, Rönnberg L, Vihko R: Danazol has progestin-like actions on the human endometrium. Acta Endocrinol 1982;99:588–593 Braun DP, Gebel H, Dmowski WP: Effect of danazol in vitro and in vivo on monocyte-mediated enhancement of endometrial cell proliferation in women with endometriosis. Fertil Steril 1994;62:89–9 Greenblatt RB: Danazol in the treatment of infertility. Drugs 1980;19:362–36 Iffland CA, Shaw RW, Beynon JL: Is danazol a useful treatment in unexplained primary infertility? Eur J Obstet Reprod Biol 1989;32:115–121 Van Dijk JG, Frolich M, Brand EC, van Hall EV: The “treatment” of unexplained infertility with danazol. Fertil Steril 1979;31:481–485 Author information Authors and Affiliations Rights and permissions About this article Cite this article Tei, C., Maruyama, T., Kuji, N. et al. Reduced Expression of αvβ3 Integrin in the Endometrium of Unexplained Infertility Patients with Recurrent IVF-ET Failures: Improvement by Danazol Treatment. J Assist Reprod Genet 20, 13–20 (2003). https://doi.org/10.1023/A:1021254620888 Issue date: DOI: https://doi.org/10.1023/A:1021254620888