Development and Reproduction (한국발생생물학회지:발생과생식)

The Korean Society of Developmental Biology (한국발생생물학회)
권호 표지

The Role of the Endometrium and Embryo in Human Implantation

인간 착상 과정에 자궁내막과 배아의 역할

  • Jee, Byung-Chul (Dept. of Obstetrics and Gynecology, Seoul National University Bundang Hospital)
  • 지병철 (분당서울대학교병원 산부인과)
  • Published : 2009.03.30
Download PDF
⟨ Previous Next ⟩

Abstract

Implantation itself is governed by an array of endocrine, paracrine and autocrine modulators, of embryonic and maternal origin. Window of implantation is the unique temporal and spatial expression of factors allows the embryo to implant via signaling, appositioning, attachment, and invasion in a specific time frame of $2{\sim}4$ days. When the embryo has arrived in the uterine cavity, a preprogrammed sequence of events occurs, which involves the production and secretion of a multitude of biochemical factors such as cytokines, growth factors, and adhesion molecules by the endometrium and the embryo, thus leading to the formation of a receptive endometrium. Cytokines such as LIF, CSF-1, and IL-1 have all been shown to play important roles in the cascade of events that leads to implantation. Integrin, L-selectin ligands, glycodelin, mucin-1, HB-EGF and pinopodes are involved in appositioning and attachment. The embryo also produces cytokines and growth factors (ILs, VEGF) and receptors for endometrial signals such as LIF, CSF-1, IGF and HB-EGF. The immune system and angiogenesis play an important role. The usefulness of these factors to assess endometrial receptivity and to estimate the prognosis for pregnancy in natural and artificial cycles remains to be proven. Integrins, pinopodes, glycodelin and LIF (from biopsies) are promising candidates; from uterine flushings, glycodelin and LIF are also candidates. The ideal serum marker is not available, but VEGF, glycodelin and CSF have some clinical implications. Further evaluation that includes larger groups of infertile women and fertile controls are needed to elucidate whether their presence in plasma, flushing fluid, or endometrial samples can be used as some kind of a screening tool to assess endometrial function and prognosis for pregnancy before and after artificial reproductive therapy. A better understanding of their function in human implantation may lead to therapeutic intervention, thereby improving the success rate in reproduction treatment. New molecular techniques are becoming available for measuring both embryonic and endometrial changes prior to and during implantation. The use of predictive sets of markers may prove to be more reliable than a single marker. Ultimately, the aim is to use these tools to increase implantation in artificial cycles and consequently improve live-birth rates.

착상은 배아측과 모체측의 내분비적, 측분비적 및 자가분비적 인자들의 상호 작용에 의하여 조절된다. 착상의 적기는 $2{\sim}4$일로서 이 특수한 시간대 안에서 signaling, appositioning, attachment 및 invasion을 통하여 순차적으로 배아의 착상이 이루어지는데, 이는 자궁내막과 배아로부터 여러 사이토카인, 성장인자, 부착인자와 같은 다수의 생화학 인자의 생성과 분비를 포함하며 이로 인하여 수용적인 자궁내막이 형성된다. LIF, CSF-1, IL-1과 같은 사이토카인들은 착상을 이끄는 연속적인 사건에서 중요한 역할을 수행하며 integrin, L-selectin ligands, glycodelin, mucin-1, HB-EGF, pinopodes는 appositioning과 attachment에 관여한다. 배아 또한 사이토카인과 성장인자 및 LIF, CSF-1, IGF, HB-EGF에 대한 수용체들을 분비하여 능동적으로 대처한다. 자궁내막의 수용성을 평가하고 자연주기 또는 보조생식술을 이용한 임신의 예후를 예측하는데, 이와 같은 인자들이 유용한지는 앞으로 더 연구되어야 한다. 현재로서는 내막조직으로부터 채취한 integrins, pinopodes, glycodelin, LIF가, 자궁강내 세척액에서는 glycodelin과 LIF가 유망한 인자로 떠오르고 있다. 혈액내 마커로서는 VEGF, glycodelin, CSF가 약간의 연관성을 보여주고 있다. 이러한 인자들이 보조생식술 전후로 자궁내막의 기능과 임신의 예후를 평가하는 선별검사로 이용될 수 있는지를 증명하기 위해서는 향후 불임 여성과 대조군인 가임 여성을 대상으로 한 대규모의 연구가 필요할 것이다. 인간의 착상에서 이들 인자들의 기능을 충분히 이해해야 치료적 기법으로 연결되어 보조생식술에서도 더 높은 성공률을 이루어 낼 것으로 사료된다.

Keywords

References

  1. Achache H, Revel A (2006) Endometrial receptivity markers, the journey to successful embryo implantation. Hum Reprod Update 12:731-746. https://doi.org/10.1093/humupd/dml004
  2. Borthwick 1M, Charnock-Jones DS, Tom BD, Hull ML, Teirney R, Phillips SC, Smith SK (2003) Determination of the transcript profile of human endometrium. Mol Hum Reprod 9:19-33. https://doi.org/10.1093/molehr/gag004
  3. Bourgain C, Devroey P (2003) The endometrium in stimulated cycles for IVF. Hum Reprod Update 9:515-522. https://doi.org/10.1093/humupd/dmg045
  4. Carson DD, Lagow E, Thathiah A, Al-Shami R, FarachCarson MC, Vernon M, Yuan L, Fritz MA, Lessey B (2002) 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 8:871-879. https://doi.org/10.1093/molehr/8.9.871
  5. Devroey P, Bourgain C, Macklon NS, Fuaser BC (2004) Reproductive biology and IVF: ovarian stimulation and endometrial receptivity. Trends Endocrinol Metab 15:84-90. https://doi.org/10.1016/j.tem.2004.01.009
  6. Diedrich K, Fauser BC, Devroey P; Evian Annual Reproduction (EVAR) Workshop Group (2007) The role of the endometrium and embryo in human implantation. Hum Reprod Update 13:365-377. https://doi.org/10.1093/humupd/dmm011
  7. Dimitriadis E, White CA, Jones RL, Salamonsen LA (2005) Cytokines, chemokines and growth factors in endometrium related to implantation. Hum Reprod Update 11:613-630. https://doi.org/10.1093/humupd/dmi023
  8. Dimitriadis E, Stoikos C, Stafford-Bell M, Tan YL, Salamonsen LA (2006) Interleukin-ll receptor alpha and leukemia inhibitory factor are dysregulated in endometrium of infertile women with endometriosis during the implantation window. J Reprod Immunol 69:53-64. https://doi.org/10.1016/j.jri.2005.07.004
  9. Dobson AT, Raja R, Abeyta MJ, Taylor T, Shen S, Haqq C, Pera RA (2004) The unique transcriptome through day 3 of human preimplantation development. Hum Mol Genet 13:1461-1470. https://doi.org/10.1093/hmg/ddh157
  10. Dominguez F, Remohi J, Pellicer A, Simon C (2003) Human endometrial receptivity: a genomic approach. Reprod Biomed Online 6:332-338. https://doi.org/10.1016/S1472-6483(10)61853-6
  11. Dorn C, Reinsberg J, Kupka M, van der Ven H, Schild RL (2003) Leptin, VEGF, IGF-l, and IGFBP-3 concentrations in serum and follicular fluid of women undergoing in vitro fertilization. Arch Gynecol Obstet 268:187-193. https://doi.org/10.1007/s00404-002-0366-8
  12. Emiliani S, Delbaere A, Devreker F, Englert Y (2005) Embryo-maternal interactive factors regulating the implantation process: implications in assisted reproductive. Reprod Biomed Online 10:527-540. https://doi.org/10.1016/S1472-6483(10)60831-0
  13. Fazleabas AT (2007) Physiology and pathology of implantation in the human and nonhuman primate. Semin Reprod Med 25:405-409. https://doi.org/10.1055/s-2007-991037
  14. Guzeloglu-Kayisli O, Basar M, Arici A (2007) Basic aspects of implantation. Reprod Biomed Online 15:728-739. https://doi.org/10.1016/S1472-6483(10)60541-X
  15. Hannan NJ, Salamonsen LA (2007) Role of chemokines in the endometrium and in embryo implantation. Curr Opin Obstet Gynecol 19:266-272. https://doi.org/10.1097/GCO.0b013e328133885f
  16. Hoozemans DA, Schats R, Lambalk CB, Homburg R, Hompes PG (2004) Human embryo implantation: current knowledge and clinical implications in assisted reproductive technology. Reprod Biomed Online 9:692-715. https://doi.org/10.1016/S1472-6483(10)61781-6
  17. Horcajadas JA, Riesewijk A, Dominguez F, Cervero A, Pellicer A, Simon C (2004) Determinants of endometrial receptivity. Ann N Y Acad Sci 1034:166-175. https://doi.org/10.1196/annals.1335.019
  18. Jinno M, Ozaki T, Iwashita M, Nakamura Y, Kudo A, Hirano H (2001) Measurement of endometrial tissue blood flow: a novel way to assess uterine receptivity for implantation. Fertil Steril 76:1168-1174. https://doi.org/10.1016/S0015-0282(01)02897-7
  19. Jones GM, Cram DS, Song B, Kokkali G, Pantos K, Trounson AO (2008) Novel strategy with potential to identifY developmentally competent IVF blastocysts. Hum Reprod 23:1748-1759. https://doi.org/10.1093/humrep/den123
  20. Kao LC, Tulac S, Lobo S, Imani B, Yang JP, Germeyer A, Osteen K, Taylor RN, Lessey BA, Giudice LC (2002) Global gene profiling in human endometrium during the window of implantation. Endocrinology 143:2119-2138. https://doi.org/10.1210/en.143.6.2119
  21. Katz-Jaffe MG, Gardner DK, Schoolcraft WB (2006) Proteomic analysis of individual human embryos to identifY novel biomarkers of development and viability. Fertil Steril 85:101-107. https://doi.org/10.1016/j.fertnstert.2005.09.011
  22. Kennedy TG, Gillio-Meina C, Phang SH (2007) Prostaglandins and the initiation of blastocyst implantation and decidualization. Reproduction 134:635-643. https://doi.org/10.1530/REP-07-0328
  23. Kodaman PH, Taylor HS (2004) Hormonal regulation of implantation. Obstet Gynecol Clin North Am 31:745-766. https://doi.org/10.1016/j.ogc.2004.08.008
  24. Lessey BA, Damjanovich L, Coutifaris C, Castelbaum A, Albelda SM, Buck CA (1992) Integrin adhesion molecules in the human endometrium. Correlation with the normal and abnormal menstrual cycle. J Clin Invest 90:188-195. https://doi.org/10.1172/JCI115835
  25. Lindhard A, Bentin-Ley U, Ravn V, Islin H, Hviid T, Rex S, Bangsboll S, Sofensen S (2002) Biochemical evaluation of endometrial function at the time of implantation. Fertil Steril 78:221-233. https://doi.org/10.1016/S0015-0282(02)03240-5
  26. Margalioth EJ, Ben-Chetrit A, Gal M, Eldar-Geva T (2006) Investigation and treatment of repeated implantation failure following IVF-ET. Hum Reprod 21:3036-3043. https://doi.org/10.1093/humrep/del305
  27. Minas V, Loutradis D, Makrigiannakis A (2005) Factors controlling blastocyst implantation. Reprod Biomed Online 10:205-216. https://doi.org/10.1016/S1472-6483(10)60942-X
  28. Munne S (2003) Preimplantation genetic diagnosis and human implantation-a review. Placenta 24(Suppl B):S70-S76. https://doi.org/10.1016/S0143-4004(03)00177-2
  29. Noyes RW, Hertig AT, Rock J (1950) Dating the endometrial biopsy. Fertil Steril 1:3-25. https://doi.org/10.1016/S0015-0282(16)30062-0
  30. Riesewijk A, Martin J, van Os R, Horcajadas JA, Pohnan J, Pellicer A, Mossehnan S, Simon C (2003) Gene expression profiling of human endometrial receptivity on days LH+2 versus LH+7 by microarray technology. Mol Hum Reprod 9:253-264. https://doi.org/10.1093/molehr/gag037
  31. Robb L, Dimitriadis E, Li R, Salamonsen LA (2002) Leukemia inhibitory factor and interleukin -11: cytokines with key roles in implantation. J Reprod Innnunol 57:129-141. https://doi.org/10.1016/S0165-0378(02)00012-8
  32. Sakkas D, Gardner DK (2005) Noninvasive methods to assess embryo quality. Curr Opin Obstet Gynecol 17:283-288. https://doi.org/10.1097/01.gco.0000169106.69881.3e
  33. Salamonsen LA, Hannan NJ, Dimitriadis E (2007) Cytokines and chemokines during human embryo implantation: roles in implantation and early placentation. Semin Reprod Med 25:437-444. https://doi.org/10.1055/s-2007-991041
  34. Scarpellini F, Sbracia M (2003) Effectiveness of GM-CSF1 in the treatment of habitual abortion in a controlled study. Fertil Steril 80(suppl 3):S288.
  35. Seif M, Edi-Osagie E, Farquhar C, Hooper L, Blake D, McGinlay P (006) Assisted hatching on assisted conception (IVF & ICSI). Cochrane Database Syst Rev CD001894.
  36. Spandorfer SD, Navarro J, Levy D, Black AR, Liu HC, Veeck L, Witkin SS, Rosenwaks Z (2001) Autologous endometrial coculture in patients with in vitro-fertilization (IVF) failure: correlations of outcome with leukemia inhibiting factor (LIF) production. Am J Reprod Innnunol 46:375-380. https://doi.org/10.1034/j.1600-0897.2001.d01-27.x
  37. Srisuparp S, Strakova Z, Brudney A, Mukheljee S, Reierstad S, Hunzicker-Dunn M, Fazleabas AT (2003) Signal transduction pathways activated by chorionic gonadotropin in the primate endometrial epithelial cells. BioI Reprod 68:457-464. https://doi.org/10.1095/biolreprod.102.007625
  38. Stafford-Bell MA, Copeland CM (2001) Surrogacy in Australia: implantation rates have implications for embryo quality and uterine receptivity. Reprod Fertil Dev 13:99-104. https://doi.org/10.1071/RD00044
  39. Sunder S, Lenton EA (2000) Endocrinology of the periimplantation period. Bailliere's Best Pract Res Cli Obstet Gynaecol 14:789-800. https://doi.org/10.1053/beog.2000.0119
  40. Yanaihara A, Otsuka Y, Iwasaki S, Koide K, Aida T, Okai T (2004) Comparison in gene expression of secretory human endometrium using laser microdissection. Reprod BioI Endocrinol 2:66. https://doi.org/10.1186/1477-7827-2-66