Journey of Human Gametes In Vitro: 1978 to 2018

  • Yuval Or
  • Shir Dar
  • Zeev ShohamEmail author


The history of in vitro fertilization (IVF) and embryo transfer (ET) dates back as early as the 1890s when Walter Heape, a professor and physician at the University of Cambridge, England, who had been conducting research on reproduction in a number of animal species, reported the first known case of embryo transplantation in rabbits, long before the applications to human fertility were even suggested.

The field of IVF has developed dramatically during the last 30 years, and what was considered to be a miracle has become a common practice around the world. The field is still being developed in multiple directions to find solutions for couples who are infertile, those wishing to conceive at an older age, and those needing to delay pregnancy for medical reasons.

We can expect further developments in the drug development, reduce the difficulties involved in stimulation of the ovaries moving into natural cycles, and obviously find a way to define the best embryo for replacement which might give the patients the highest chance to become pregnant.


Human gametes In vitro fertilization IVF Embryo transfer History 


  1. 1.
    Chang MC. Fertilization of rabbit ova in vitro. Nature. 1959;184(7):466–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Edwards RG, Donahue RP, Baramki TA, Jones HW Jr. Preliminary attempts to fertilize human oocytes matured in vitro. Am J Obstet Gynecol. 1966;15(96):192–200.CrossRefGoogle Scholar
  3. 3.
    De Kretzer D, Dennis P, Hudson B, Leeton J, Lopata A, Outch K, Talbot J, Wood C. Transfer of a human zygote. Lancet. 1973;29(2):728–9.CrossRefGoogle Scholar
  4. 4.
    Steptoe PC, Edwards RG. Reimplantation of a human embryo with subsequent tubal pregnancy. Lancet. 1976;24(1):880–2.CrossRefGoogle Scholar
  5. 5.
    Steptoe PC, Edwards RG. Birth after the reimplantation of a human embryo. Lancet. 1978;12(2):366.CrossRefGoogle Scholar
  6. 6.
    Lopata A, Johnston IW, Hoult IJ, Speirs AI. Pregnancy following intrauterine implantation of an embryo obtained by in vitro fertilization of a preovulatory egg. Fertil Steril. 1980;33:117–20.PubMedCrossRefGoogle Scholar
  7. 7.
    Szollosi D, Mandelbaum J, Plachot M, Salat-Baroux J, Cohen J. Ultrastructure of the human preovulatory oocyte. J In Vitro Fert Embryo Transf. 1986;3:232–42.PubMedCrossRefGoogle Scholar
  8. 8.
    Trounson AO, Leeton JF, Wood C, Webb J, Wood J. Pregnancies in humans by fertilization in vitro and embryo transfer in the controlled ovulatory cycle. Science. 1981;8(212):681–2.CrossRefGoogle Scholar
  9. 9.
    Fleming R, Adam AH, Barlow DH, Black WP, MacNaughton MC, Coutts JR. A new systematic treatment for infertile women with abnormal hormone profiles. Br J Obstet Gynaecol. 1982;89:80–3.PubMedCrossRefGoogle Scholar
  10. 10.
    Porter RN, Smith W, Craft IL, Abdulwahid NA, Jacobs HS. Induction of ovulation for in-vitro fertilisation using buserelin and gonadotropins. Lancet. 1984;1(2):1284–5.CrossRefGoogle Scholar
  11. 11.
    Gonen Y, Jacobson W, Casper RF. Gonadotropin suppression with oral contraceptives before in vitro fertilization. Fertil Steril. 1990;53:282–7.PubMedCrossRefGoogle Scholar
  12. 12.
    Casper RF, Wilson E, Collins JA, Brown SF, Parker JA. Enhancement of human implantation by exogenous chorionic gonadotropin. Lancet. 1983;19(2):1191.CrossRefGoogle Scholar
  13. 13.
    Frydman R, Cornel C, de Ziegler D, Taieb J, Spitz IM, Bouchard P. Prevention of premature luteinizing hormone and progesterone rise with a gonadotropin-releasing hormone antagonist, Nal-Glu, in controlled ovarian hyperstimulation. Fertil Steril. 1991;56:923–7.PubMedCrossRefGoogle Scholar
  14. 14.
    Itskovitz-Eldor J, Kol S, Mannaerts B, Coelingh Bennink H. First established pregnancy after controlled ovarian hyperstimulation with recombinant follicle stimulating hormone and the gonadotrophin-releasing hormone antagonist ganirelix (Org 37462). Hum Reprod. 1998;13:294–5.PubMedCrossRefGoogle Scholar
  15. 15.
    Germond M, Dessole S, Senn A, Loumaye E, Howles C, Beltrami V. Successful in-vitro fertilisation and embryo transfer after treatment with recombinant human FSH. Lancet. 1170;1992(9):339.Google Scholar
  16. 16.
    Devroey P, van Steirteghem A, Mannaerts B, Bennink HC. Successful in-vitro fertilisation and embryo transfer after treatment with recombinant human FSH. Lancet. 1992;9(339):1170.Google Scholar
  17. 17.
    Agrawal R, West C, Conway GS, Page ML, Jacobs HS. Pregnancy after treatment with three recombinant gonadotropins. Lancet. 1997;4(349):29–30.CrossRefGoogle Scholar
  18. 18.
    Emperaire JC, Ruffié A, Audebert AJ. Ovulation induction by endogenous LH released by the administration of an LHRH agonist after follicular stimulation for in vitro fertilization. J Gynecol Obstet Biol Reprod (Paris). 1992;21:489–94. French.Google Scholar
  19. 19.
    Chian RC, Gülekli B, Buckett WM, Tan SL. Priming with human chorionic gonadotrophin before retrieval of immature oocytes in women with infertility due to the polycystic ovary syndrome. N Engl J Med. 1999;341:1624–6.PubMedCrossRefGoogle Scholar
  20. 20.
    Mohr LR, Trounson AO. The use of fluorescein diacetate to assess embryo viability in the mouse. J Reprod Fertil. 1980;58:189–96.PubMedCrossRefGoogle Scholar
  21. 21.
    Quinn P, Kerin JF, Warnes GM. Improved pregnancy rate in human in vitro fertilization with the use of a medium based on the composition of human tubal fluid. Fertil Steril. 1985;44:493–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Gardner DK, Schoolcraft WB, Wagley L, Schlenker T, Stevens J, Hesla J. A prospective randomized trial of blastocyst culture and transfer in in-vitro fertilization. Hum Reprod. 1998;13:3434–40.PubMedCrossRefGoogle Scholar
  23. 23.
    Jones GM, Trounson AO, Gardner DK, Kausche A, Lolatgis N, Wood C. Evolution of a culture protocol for successful blastocyst development and pregnancy. Hum Reprod. 1998;13:169–77.PubMedCrossRefGoogle Scholar
  24. 24.
    Ali J, Shahata MA, Al-Natsha SD. Formulation of a protein-free medium for human assisted reproduction. Hum Reprod. 2000;15:145–56.PubMedCrossRefGoogle Scholar
  25. 25.
    Roh SI, Dodds WG, Park JM, Awadalla SG, Friedman CI, Kim MH. In vitro fertilization with concurrent pelvic reconstructive surgery. Fertil Steril. 1988;49:96–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Lenz S, Lauritsen JG. Ultrasonically guided percutaneous aspiration of human follicles under local anesthesia: a new method of collecting oocytes for in vitro fertilization. Fertil Steril. 1982;38:673–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Gleicher N, Friberg J, Fullan N, Giglia RV, Mayden K, Kesky T, Siegel I. EGG retrieval for in vitro fertilisation by sonographically controlled vaginal culdocentesis. Lancet. 1983;27(2):508–9.CrossRefGoogle Scholar
  28. 28.
    Wikland M, Enk L, Hamberger L. Transvesical and transvaginal approaches for the aspiration of follicles by use of ultrasound. Ann N Y Acad Sci. 1985;442:182–94.PubMedCrossRefGoogle Scholar
  29. 29.
    Strickler RC, Christianson C, Crane JP, Curato A, Knight AB, Yang V. Ultrasound guidance for human embryo transfer. Fertil Steril. 1985;43:54–61.PubMedCrossRefGoogle Scholar
  30. 30.
    Feichtinger W, Kemeter P. Transvaginal sector scan sonography for needle guided transvaginal follicle aspiration and other applications in gynecologic routine and research. Fertil Steril. 1986;45(5):722–5.PubMedCrossRefGoogle Scholar
  31. 31.
    Trounson AO, Mohr LR, Wood C, Leeton JF. Effect of delayed insemination on in-vitro fertilization, culture and transfer of human embryos. J Reprod Fertil. 1982;64:285–94.PubMedCrossRefGoogle Scholar
  32. 32.
    Asch RH, Ellsworth LR, Balmaceda JP, Wong PC. Pregnancy after translaparoscopic gamete intrafallopian transfer. Lancet. 1984;3(2):1034–5.CrossRefGoogle Scholar
  33. 33.
    Laws-King A, Trounson A, Sathananthan H, Kola I. Fertilization of human oocytes by microinjection of a single spermatozoon under the zona pellucida. Fertil Steril. 1987;48:637–42.PubMedCrossRefGoogle Scholar
  34. 34.
    Ng SC, Bongso A, Ratnam SS, Sathananthan H, Chan CL, Wong PC, Hagglund L, Anandakumar C, Wong YC, Goh VH. Pregnancy after transfer of sperm under zona. Lancet. 1988;1(2):790.CrossRefGoogle Scholar
  35. 35.
    Cohen J, Malter H, Fehilly C, Wright G, Elsner C, Kort H, Massey J. Implantation of embryos after partial opening of oocyte zona pellucida to facilitate sperm penetration. Lancet. 1988;16(2):162.CrossRefGoogle Scholar
  36. 36.
    Palermo G, Joris H, Devroey P, Van Steirteghem AC. Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet. 1992;4(340):17–8.CrossRefGoogle Scholar
  37. 37.
    Cohen J, Scott R, Schimmel T, Levron J, Willadsen S. Birth of infant after transfer of anucleate donor oocyte cytoplasm into recipient eggs. Lancet. 1997;19(350):186–7.CrossRefGoogle Scholar
  38. 38.
    Trounson A, Mohr L. Human pregnancy following cryopreservation, thawing and transfer of an eight-cell embryo. Nature. 1983;20–26(305):707–9.CrossRefGoogle Scholar
  39. 39.
    Gordts S, Roziers P, Campo R, Noto V. Survival and pregnancy outcome after ultrarapid freezing of human embryos. Fertil Steril. 1990;53:469–72.PubMedCrossRefGoogle Scholar
  40. 40.
    Kuleshova L, Gianaroli L, Magli C, Ferraretti A, Trounson A. Birth following vitrification of a small number of human oocytes: case report. Hum Reprod. 1999;14:3077–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Porcu E, Fabbri R, Petracchi S, Ciotti PM, Flamigni C. Ongoing pregnancy after intracytoplasmic injection of testicular spermatozoa into cryopreserved human oocytes. Am J Obstet Gynecol. 1999;180:1044–5.PubMedCrossRefGoogle Scholar
  42. 42.
    Bedaiwy MA, Hussein MR, Biscotti C, Falcone T. Cryopreservation of intact human ovary with its vascular pedicle. Hum Reprod. 2006;21:3258–69.PubMedCrossRefGoogle Scholar
  43. 43.
    Porcu E, Venturoli S, Damiano G, Ciotti PM, Notarangelo L, Paradisi R, Moscarini M, Ambrosini G. Healthy twins delivered after oocyte cryopreservation and bilateral ovariectomy for ovarian cancer. Reprod Biomed Online. 2008;17:265–7.PubMedCrossRefGoogle Scholar
  44. 44.
    Trounson A, Leeton J, Besanko M, Wood C, Conti A. Pregnancy established in an infertile patient after transfer of a donated embryo fertilised in vitro. Br Med J (Clin Res Ed). 1983;286(6368):835–8.CrossRefGoogle Scholar
  45. 45.
    Buster JE, Bustillo M, Thorneycroft IH, Simon JA, Boyers SP, Marshall JR, Louw JA, Seed RW, Seed RG. Non-surgical transfer of in vivo fertilised donated ova to five infertile women: report of two pregnancies. Lancet. 1983;23(2):223–4.CrossRefGoogle Scholar
  46. 46.
    Veeck LL, Wortham JW Jr, Witmyer J, Sandow BA, Acosta AA, Garcia JE, Jones GS, Jones HW Jr. Maturation and fertilization of morphologically immature human oocytes in a program of in vitro fertilization. Fertil Steril. 1983;39:594–602.PubMedCrossRefGoogle Scholar
  47. 47.
    Barnes FL, Crombie A, Gardner DK, Kausche A, Lacham-Kaplan O, Suikkari A-M, Tiglias J, Wood C, Trounson AO. Blastocyst development and birth after in-vitro maturation of human primary oocytes, intracytoplasmic sperm injection and assisted hatching. Hum Reprod. 1995;10:3243–7.PubMedCrossRefGoogle Scholar
  48. 48.
    Cohen J, Simons RF, Fehilly CB, Fishel SB, Edwards RG, Hewitt J, Rowlant GF, Steptoe PC, Webster JM. Birth after replacement of hatching blastocyst cryopreserved at expanded blastocyst stage. Lancet. 1985;16(1):647.CrossRefGoogle Scholar
  49. 49.
    Handyside AH, Pattinson JK, Penketh RJ, Delhanty JD, Winston RM, Tuddenham EG. Biopsy of human preimplantation embryos and sexing by DNA amplification. Lancet. 1989;18(1):347–9.CrossRefGoogle Scholar
  50. 50.
    Handyside AH, Kontogianni EH, Hardy K, Winston RM. Pregnancies from biopsied human preimplantation embryos sexed by Y-specific DNA amplification. Nature. 1990;19(344):768–70.CrossRefGoogle Scholar
  51. 51.
    Verlinsky Y, Ginsberg N, Lifchez A, Valle J, Moise J, Strom CM. Analysis of the first polar body: preconception genetic diagnosis. Hum Reprod. 1990;5:826–9.PubMedCrossRefGoogle Scholar
  52. 52.
    Cohen J, Alikani M, Trowbridge J, Rosenwaks Z. Implantation enhancement by selective assisted hatching using zona drilling of human embryos with poor prognosis. Hum Reprod. 1992;7:685–91.PubMedCrossRefGoogle Scholar
  53. (A).
    Gonen Y, Balakier H, Powell W, Casper RF. Use of GnRH agonist to trigger follicular maturation for in vitro fertilization. J Clin Endocrinol Metab. 1990;71:918–22.PubMedCrossRefGoogle Scholar
  54. (B).
    Utian WH. Successful pregnancy after in vitro fertilization and embryo transfer from an infertile woman to a surrogate. N Engl J Med. 1985;313(21):1351–2.PubMedGoogle Scholar
  55. (C).
    Oktay K, Buyuk E, Libertella N, Akar M, Rosenwaks Z. Fertility preservation in breast cancer patients: a prospective controlled comparison of ovarian stimulation with tamoxifen and letrozole for embryo cryopreservation. J Clin Oncol. 2005;23(19):4347–53.PubMedCrossRefGoogle Scholar
  56. (D).
    Kuang Y, Chen Q, Hong Q, Lyu Q, Ai A, Fu Y, Shoham Z. Double stimulations during the follicular and luteal phases of poor responders in IVF/ICSI programmes (Shanghai protocol). Reprod Biomed Online. 2014;29(6):684–91.PubMedCrossRefGoogle Scholar
  57. (E).
    Wong CC, Loewke KE, Bossert NL, Behr B, De Jonge CJ, Baer TM, Pera RAR. Non-invasive imaging of human embryos before embryonic genome activation predicts development to the blastocyst stage. Nat Biotechnol. 2010;28(10):1115–21.PubMedCrossRefGoogle Scholar
  58. (F).
    McReynolds S, Vanderlinden L, Stevens J, Hansen K, Schoolcraft WB, Katz-Jaffe MG. Lipocalin-1: a potential marker for noninvasive aneuploidy screening. Fertil Steril. 2011;95(8):2631–3.PubMedCrossRefGoogle Scholar
  59. (G).
    Forman EJ, Hong KH, Ferry KM, Tao X, Taylor D, Levy B, Treff NR, Scott RT. In vitro fertilization with single euploid blastocyst transfer: a randomized controlled trial. Fertil Steril. 2013;100(1):100–7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.The IVF, Infertility and Reproductive Medicine Unit, Department of Obstetrics and GynecologyKaplan Medical CenterRehovotIsrael

Personalised recommendations