Clinical Management of Endometrial Receptivity

Abstract

The endometrial window of implantation (WOI), the cycle days during which normal embryo implantation can occur, has generally been assumed to begin on cycle day 19 or 20 of an idealized 28 days cycle and last for 4 to 5 days. Noyes et al took the first steps in defining the WOI by establishing a set of morphological criteria to evaluate endometrial development and receptivity, but recent studies have invalidated their use in the routine evaluation of infertility. Based on greater than 10 years of extensive research, our group has developed a molecular diagnostic tool (the endometrial receptivity array [ERA] test) based on the specific transcriptomic signature that identifies the receptive endometrium in natural and artificial (hormonal replacement therapy) cycles. The ERA test has shown that some patients have a delayed WOI, others have an advanced WOI, and others can have unusually short windows of receptivity. This identification and characterization of the WOI allows the personalization of the embryo transfer. In this review, we describe the ERA and our experience with its use in assessment of the endometrial receptivity in patients undergoing assisted reproduction.

Keywords

endometrial receptivity - implantation window - personalized medicine - embryo transfer

Notes

David Blesa, PhD and María Ruiz-Alonso, MSc have contributed equally to this work.

• References

• 1 Beier HM, Beier-Hellwig K. Molecular and cellular aspects of endometrial receptivity. Hum Reprod Update 1998; 4 (5) 448-458
• 2 Diedrich K, Fauser BC, Devroey P, Griesinger G ; Evian Annual Reproduction (EVAR) Workshop Group. The role of the endometrium and embryo in human implantation. Hum Reprod Update 2007; 13 (4) 365-377
• 3 Bulun SE, Adashi EY. The physiology and pathology of the female reproductive axis. In: Kronenberg HM, Melmed S, Polonsky KS, Larsen PR, , eds. Williams Textbook of Endocrinology, 11th ed. Philadelphia, PA: Elsevier; 2009: 549-622
• 4 Hawkins SM, Matzuk MM. The menstrual cycle: basic biology. Ann N Y Acad Sci 2008; 1135: 10-18
• 5 Wilcox AJ, Baird DD, Weinberg CR. Time of implantation of the conceptus and loss of pregnancy. N Engl J Med 1999; 340 (23) 1796-1799
• 6 Lessey BA. Assessment of endometrial receptivity. Fertil Steril 2011; 96 (3) 522-529
• 7 Navot D, Scott RT, Droesch K, Veeck LL, Liu HC, Rosenwaks Z. The window of embryo transfer and the efficiency of human conception in vitro. Fertil Steril 1991; 55 (1) 114-118
• 8 Lenton EA, Neal LM, Sulaiman R. Plasma concentrations of human chorionic gonadotropin from the time of implantation until the second week of pregnancy. Fertil Steril 1982; 37 (6) 773-778
• 9 Makker A, Singh MM. Endometrial receptivity: clinical assessment in relation to fertility, infertility, and antifertility. Med Res Rev 2006; 26 (6) 699-746
• 10 Noyes RW, Hertig AT, Rock J. Dating the endometrial biopsy. Fertil Steril 1950; 1: 3-25
• 11 Noyes RW, Haman JO. Accuracy of endometrial dating; correlation of endometrial dating with basal body temperature and menses. Fertil Steril 1953; 4 (6) 504-517
• 12 Murray MJ, Meyer WR, Zaino RJ , et al. A critical analysis of the accuracy, reproducibility, and clinical utility of histologic endometrial dating in fertile women. Fertil Steril 2004; 81 (5) 1333-1343
• 13 Coutifaris C, Myers ER, Guzick DS , et al; NICHD National Cooperative Reproductive Medicine Network. Histological dating of timed endometrial biopsy tissue is not related to fertility status. Fertil Steril 2004; 82 (5) 1264-1272
• 14 Koot YEM, Teklenburg G, Salker MS, Brosens JJ, Macklon NS. Molecular aspects of implantation failure. Biochim Biophys Acta 2012; 1822 (12) 1943-1950
• 15 Lessey BA, Castelbaum AJ, Sawin SW, Sun J. Integrins as markers of uterine receptivity in women with primary unexplained infertility. Fertil Steril 1995; 63 (3) 535-542
• 16 Dubowy RL, Feinberg RF, Keefe DL , et al. Improved endometrial assessment using cyclin E and p27. Fertil Steril 2003; 80 (1) 146-156
• 17 Aghajanova L, Hamilton AE, Giudice LC. Uterine receptivity to human embryonic implantation: histology, biomarkers, and transcriptomics. Semin Cell Dev Biol 2008; 19 (2) 204-211
• 18 Carson DD, Lagow E, Thathiah A , et al. Changes in gene expression during the early to mid-luteal (receptive phase) transition in human endometrium detected by high-density microarray screening. Mol Hum Reprod 2002; 8 (9) 871-879
• 19 Ruiz-Alonso M, Blesa D, Simón C. The genomics of the human endometrium. Biochim Biophys Acta 2012; 1822 (12) 1931-1942
• 20 Riesewijk A, Martín J, van Os R , et al. Gene expression profiling of human endometrial receptivity on days LH+2 versus LH+7 by microarray technology. Mol Hum Reprod 2003; 9 (5) 253-264
• 21 Horcajadas JA, Riesewijk A, Domínguez F, Cervero A, Pellicer A, Simón C. Determinants of endometrial receptivity. Ann N Y Acad Sci 2004; 1034: 166-175
• 22 Horcajadas JA, Riesewijk A, Martín J , et al. Global gene expression profiling of human endometrial receptivity. J Reprod Immunol 2004; 63 (1) 41-49
• 23 Horcajadas JA, Riesewijk A, Polman J , et al. Effect of controlled ovarian hyperstimulation in IVF on endometrial gene expression profiles. Mol Hum Reprod 2005; 11 (3) 195-205
• 24 Horcajadas JA, Sharkey AM, Catalano RD , et al. Effect of an intrauterine device on the gene expression profile of the endometrium. J Clin Endocrinol Metab 2006; 91 (8) 3199-3207
• 25 Horcajadas JA, Mínguez P, Dopazo J , et al. Controlled ovarian stimulation induces a functional genomic delay of the endometrium with potential clinical implications. J Clin Endocrinol Metab 2008; 93 (11) 4500-4510
• 26 Altmäe S, Martínez-Conejero JA, Salumets A, Simón C, Horcajadas JA, Stavreus-Evers A. Endometrial gene expression analysis at the time of embryo implantation in women with unexplained infertility. Mol Hum Reprod 2010; 16 (3) 178-187
• 27 Díaz-Gimeno P, Horcajadas JA, Martínez-Conejero JA , et al. A genomic diagnostic tool for human endometrial receptivity based on the transcriptomic signature. Fertil Steril 2011; 95 (1) 50-60 , e1–e15
• 28 Díaz-Gimeno P, Ruiz-Alonso M, Blesa D , et al. The accuracy and reproducibility of the endometrial receptivity array is superior to histology as a diagnostic method for endometrial receptivity. Fertil Steril 2013; 99 (2) 508-517
• 29 Ruiz-Alonso M, Blesa D, Díaz-Gimeno P , et al. The endometrial receptivity array for diagnosis and personalized embryo transfer as a treatment for patients with repeated implantation failure. Fertil Steril 2013; 100 (3) 818-824
• 30 Hoozemans DA, Schats R, Lambalk CB, Homburg R, Hompes PG. Human embryo implantation: current knowledge and clinical implications in assisted reproductive technology. Reprod Biomed Online 2004; 9 (6) 692-715
• 31 Martínez-Conejero JA, Simón C, Pellicer A, Horcajadas JA. Is ovarian stimulation detrimental to the endometrium?. Reprod Biomed Online 2007; 15 (1) 45-50
• 32 Direito A, Bailly S, Mariani A, Ecochard R. Relationships between the luteinizing hormone surge and other characteristics of the menstrual cycle in normally ovulating women. Fertil Steril 2013; 99 (1) 279-285