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Semin Reprod Med 2021; 39(05/06): 227-232
DOI: 10.1055/s-0041-1735199
Review Article

Endometrial Factor in Unexplained Infertility and Recurrent Implantation Failure

Xavier Santamaria
1   Igenomix Foundation, INCLIVA Health Research Institute, Valencia, Spain
2   Vall Hebron Institut de Recerca (VHIR), Barcelona, Spain
,
Carlos Simón
1   Igenomix Foundation, INCLIVA Health Research Institute, Valencia, Spain
3   Department of Obstetrics and Gynecology, University of Valencia, Valencia, Spain
4   Department of Obstetrics and Gynecology, BIDMC, Harvard University, Boston
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Abstract

Unexplained infertility (UI) and recurrent implantation failure (RIF) are diagnoses based on failed pregnancy attempts within current infertility treatment models. Both diagnoses are made when fertility is unexplained based on current diagnostic methods and has no clear cause; UI is diagnosed when testing is inconclusive, and RIF is diagnosed after three failed in vitro fertilization cycles. In both cases, interventions are often introduced without an understanding of the cause of the infertility, frequently leading to frustration for patients and caregivers. Here, we review evidence to support an influence of endometrial factor in patients given these poorly defined diagnoses and possible treatments targeting the endometrium to improve outcomes in these patients.

Keywords

unexplained infertility - recurrent implantation failure - infertility - in vitro fertilization - endometrial factor


Publication History

Article published online:
23 August 2021

© 2021. Thieme. All rights reserved.

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  • References

  • 1 Gunn DD, Bates GW. Evidence-based approach to unexplained infertility: a systematic review. Fertil Steril 2016; 105 (06) 1566-1574.e1
    CrossrefPubMedGoogle Scholar
  • 2 Bellver J, Simón C. Implantation failure of endometrial origin: what is new?. Curr Opin Obstet Gynecol 2018; 30 (04) 229-236
    CrossrefPubMedGoogle Scholar
  • 3 Olivius C, Friden B, Borg G, Bergh C. Why do couples discontinue in vitro fertilization treatment? A cohort study. Fertil Steril 2004; 81 (02) 258-261
    CrossrefPubMedGoogle Scholar
  • 4 Mol BW, Tjon-Kon-Fat R, Kamphuis E, van Wely M. Unexplained infertility: Is it over-diagnosed and over-treated?. Best Pract Res Clin Obstet Gynaecol 2018; 53: 20-29
    CrossrefPubMedGoogle Scholar
  • 5 Edi-Osagie ECO, Seif MW, Aplin JD, Jones CJP, Wilson G, Lieberman BA. Characterizing the endometrium in unexplained and tubal factor infertility: a multiparametric investigation. Fertil Steril 2004; 82 (05) 1379-1389
    CrossrefPubMedGoogle Scholar
  • 6 Graham RA, Seif MW, Aplin JD. et al. An endometrial factor in unexplained infertility. BMJ 1990; 300 (6737): 1428-1431
    CrossrefPubMedGoogle Scholar
  • 7 Lessey BA, Castelbaum AJ, Sawin SW, Sun J. Integrins as markers of uterine receptivity in women with primary unexplained infertility. Fertil Steril 1995; 63 (03) 535-542
    CrossrefPubMedGoogle Scholar
  • 8 Manohar M, Khan H, Sirohi VK. et al. Alteration in endometrial proteins during early- and mid-secretory phases of the cycle in women with unexplained infertility. PLoS One 2014; 9 (11) e111687
    CrossrefPubMedGoogle Scholar
  • 9 Dorostghoal M, Ghaffari HO, Marmazi F, Keikhah N. Overexpression of endometrial estrogen receptor-alpha in the window of implantation in women with unexplained infertility. Int J Fertil Steril 2018; 12 (01) 37-42
    PubMedGoogle Scholar
  • 10 Cicinelli E, Matteo M, Trojano G. et al. Chronic endometritis in patients with unexplained infertility: Prevalence and effects of antibiotic treatment on spontaneous conception. Am J Reprod Immunol 2018; 79 (01) 79
    CrossrefPubMedGoogle Scholar
  • 11 Demirol A, Gurgan T. Effect of treatment of intrauterine pathologies with office hysteroscopy in patients with recurrent IVF failure. Reprod Biomed Online 2004; 8 (05) 590-594
    CrossrefPubMedGoogle Scholar
  • 12 Valdes CT, Schutt A, Simon C. Implantation failure of endometrial origin: it is not pathology, but our failure to synchronize the developing embryo with a receptive endometrium. Fertil Steril 2017; 108 (01) 15-18
    CrossrefPubMedGoogle Scholar
  • 13 Stewart JD, Pasternak MC, Pereira N, Rosenwaks Z. Contemporary management of unexplained infertility. Clin Obstet Gynecol 2019; 62 (02) 282-292
    CrossrefPubMedGoogle Scholar
  • 14 Gleicher N, Barad D. Unexplained infertility: does it really exist?. Hum Reprod 2006; 21 (08) 1951-1955
    CrossrefPubMedGoogle Scholar
  • 15 Steures P, van der Steeg JW, Hompes PGA. et al; Collaborative Effort on the Clinical Evaluation in Reproductive Medicine. Intrauterine insemination with controlled ovarian hyperstimulation versus expectant management for couples with unexplained subfertility and an intermediate prognosis: a randomised clinical trial. Lancet 2006; 368 (9531): 216-221
    CrossrefPubMedGoogle Scholar
  • 16 Buckett W, Sierra S. The management of unexplained infertility: an evidence-based guideline from the Canadian Fertility and Andrology Society. Reprod Biomed Online 2019; 39 (04) 633-640
    CrossrefPubMedGoogle Scholar
  • 17 Ray A, Shah A, Gudi A, Homburg R. Unexplained infertility: an update and review of practice. Reprod Biomed Online 2012; 24 (06) 591-602
    CrossrefPubMedGoogle Scholar
  • 18 Kliman HJ, Frankfurter D. Clinical approach to recurrent implantation failure: evidence-based evaluation of the endometrium. Fertil Steril 2019; 111 (04) 618-628
    CrossrefPubMedGoogle Scholar
  • 19 Coughlan C, Ledger W, Wang Q. et al. Recurrent implantation failure: definition and management. Reprod Biomed Online 2014; 28 (01) 14-38
    CrossrefPubMedGoogle Scholar
  • 20 Teh WT, McBain J, Rogers P. What is the contribution of embryo-endometrial asynchrony to implantation failure?. J Assist Reprod Genet 2016; 33 (11) 1419-1430
    CrossrefPubMedGoogle Scholar
  • 21 Ahirwar N, Shukla P, Natung P. Full term extrauterine abdominal pregnancy. J Evol Med Dent Sci 2014; 3: 1895-1899
    CrossrefPubMedGoogle Scholar
  • 22 Dahab AA, Aburass R, Shawkat W, Babgi R, Essa O, Mujallid RH. Full-term extrauterine abdominal pregnancy: a case report. J Med Case Reports 2011; 5: 531
    CrossrefPubMedGoogle Scholar
  • 23 Mpogoro F, Gumodoka B, Kihunrwa A, Massinde A. Managing a live advanced abdominal twin pregnancy. Ann Med Health Sci Res 2013; 3 (01) 113-115
    CrossrefPubMedGoogle Scholar
  • 24 Guo Y, Manatunga AK, Chen S, Marcus M. Modeling menstrual cycle length using a mixture distribution. Biostatistics 2006; 7 (01) 100-114
    CrossrefPubMedGoogle Scholar
  • 25 Simón C, Giudice LC. 2017. The Endometrial Factor: A Reproductive Precision Medicine Approach.
    Google Scholar
  • 26 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 (01) 114-118
    CrossrefPubMedGoogle Scholar
  • 27 Shapiro BS, Daneshmand ST, Garner FC, Aguirre M, Ross R. Contrasting patterns in in vitro fertilization pregnancy rates among fresh autologous, fresh oocyte donor, and cryopreserved cycles with the use of day 5 or day 6 blastocysts may reflect differences in embryo-endometrium synchrony. Fertil Steril 2008; 89 (01) 20-26
    CrossrefPubMedGoogle Scholar
  • 28 Li TC, Dockery P, Rogers AW, Cooke ID. A quantitative study of endometrial development in the luteal phase: comparison between women with unexplained infertility and normal fertility. Br J Obstet Gynaecol 1990; 97 (07) 576-582
    CrossrefPubMedGoogle Scholar
  • 29 Kliman HJ, Feinberg RF, VanDeerlin P, Barmat LI, Moomjy M, Grifo JA. 1997. Glandular developmental arrest (GDA): a unifying model of reproductive endometrial pathology. [abstract no. P-009]. , p.S96.
    Google Scholar
  • 30 Ordi J, Creus M, Quintó L, Casamitjana R, Cardesa A, Balasch J. Within-subject between-cycle variability of histological dating, alpha v beta 3 integrin expression, and pinopod formation in the human endometrium. J Clin Endocrinol Metab 2003; 88 (05) 2119-2125
    CrossrefPubMedGoogle Scholar
  • 31 Dimitriadis E, Nie G, Hannan NJ, Paiva P, Salamonsen LA. Local regulation of implantation at the human fetal-maternal interface. Int J Dev Biol 2010; 54 (2-3): 313-322
    CrossrefPubMedGoogle Scholar
  • 32 Koot YEM, Teklenburg G, Salker MS, Brosens JJ, Macklon NS. Molecular aspects of implantation failure, Biochimica et Biophysica Acta (BBA)- . Mol Basis Dis 2012; 1822: 1943-1950
    CrossrefPubMedGoogle Scholar
  • 33 Cicinelli E, Matteo M, Tinelli R. et al. Prevalence of chronic endometritis in repeated unexplained implantation failure and the IVF success rate after antibiotic therapy. Hum Reprod 2015; 30 (02) 323-330
    CrossrefPubMedGoogle Scholar
  • 34 Moreno I, Codoñer FM, Vilella F. et al. Evidence that the endometrial microbiota has an effect on implantation success or failure. Am J Obstet Gynecol 2016; 215 (06) 684-703
    CrossrefPubMedGoogle Scholar
  • 35 Ponnampalam AP, Weston GC, Trajstman AC, Susil B, Rogers PAW. Molecular classification of human endometrial cycle stages by transcriptional profiling. Mol Hum Reprod 2004; 10 (12) 879-893
    CrossrefPubMedGoogle Scholar
  • 36 Talbi S, Hamilton AE, Vo KC. et al. Molecular phenotyping of human endometrium distinguishes menstrual cycle phases and underlying biological processes in normo-ovulatory women. Endocrinology 2006; 147 (03) 1097-1121
    CrossrefPubMedGoogle Scholar
  • 37 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 (05) 253-264
    CrossrefPubMedGoogle Scholar
  • 38 Díaz-Gimeno P, Horcajadas JA, Martinez-Conejero JA. et al. A genomic diagnostic tool for human endometrial receptivity based on the transcriptomic signature. Rev Iberoamericana Fertil Reprod Human 2010; 27: 337-351
    PubMedGoogle Scholar
  • 39 Ruiz-Alonso M, Blesa D, Simón C. The genomics of the human endometrium. Biochim Biophys Acta 2012; 1822 (12) 1931-1942
    CrossrefPubMedGoogle Scholar
  • 40 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 (02) 508-517
    CrossrefPubMedGoogle Scholar
  • 41 Simón C, Gómez C, Cabanillas S. et al; ERA-RCT Study Consortium Group. A 5-year multicentre randomized controlled trial comparing personalized, frozen and fresh blastocyst transfer in IVF. Reprod Biomed Online 2020; 41 (03) 402-415
    CrossrefPubMedGoogle Scholar
  • 42 Wang W, Vilella F, Alama P. et al. Single-cell transcriptomic atlas of the human endometrium during the menstrual cycle. Nat Med 2020; 26 (10) 1644-1653
    CrossrefPubMedGoogle Scholar
  • 43 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 (03) 818-824
    CrossrefPubMedGoogle Scholar
  • 44 Ruiz-Alonso M, Galindo N, Pellicer A, Simón C. What a difference two days make: “personalized” embryo transfer (pET) paradigm: a case report and pilot study. Hum Reprod 2014; 29 (06) 1244-1247
    CrossrefPubMedGoogle Scholar
  • 45 Koot YE, van Hooff SR, Boomsma CM. et al. An endometrial gene expression signature accurately predicts recurrent implantation failure after IVF. Sci Rep 2016; 6: 19411
    CrossrefPubMedGoogle Scholar
  • 46 Koler M, Achache H, Tsafrir A, Smith Y, Revel A, Reich R. Disrupted gene pattern in patients with repeated in vitro fertilization (IVF) failure. Hum Reprod 2009; 24 (10) 2541-2548
    CrossrefPubMedGoogle Scholar
  • 47 Tapia A, Gangi LM, Zegers-Hochschild F. et al. Differences in the endometrial transcript profile during the receptive period between women who were refractory to implantation and those who achieved pregnancy. Hum Reprod 2008; 23 (02) 340-351
    CrossrefPubMedGoogle Scholar