Can Stimulation Protocols Improve Oocyte Quality?

  • J. Smitz
Part of the Ernst Schering Research Foundation Workshop book series (SCHERING FOUND, volume 41)


Ovarian follicle development in humans is a lengthy process that takes several months. Initial follicle recruitment from the resting pool is regulated by intraovarian factors and independent of circulating gonadotropin concentrations. Once follicles have initiated growth, they progress through a slow preantral growth phase (approximately 4 months) during which the formation of zona pellucida, granulosa cell layers, theca cell layers, and vascularization of the theca externa are accomplished (for review, see Richards 2001). The preantral growth stages are mainly under paracrine/autocrine control but the somatic cells already express the receptors for gonadotropins (Sokka et al. 1996; Oktay et al. 1997). Although the growth of preantral follicles are considered to be gonadotropin-independent, there are arguments that gonadotropin fluctuations may effect these early growing follicles (Parrot and Skinner 1998a,b). Along the lengthy track of follicle growth, granulosa cells are stimulated by a variety of factors such as epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), basic fibroblast growth factor (bFGF), transforming growth factor α (TGF-α) and keratinocyte growth factor (KGF).


Granulosa Cell GnRH Agonist Antral Follicle Keratinocyte Growth Factor Human Oocyte 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Albano C, Platteau P, Nogueira D, Cortvrindt R, Smitz J, Devroey P (2001) Supernumerary pre-ovulatory follicular reduction as measure to avoid mul tiple pregnancy after ovulation induction. Fertil Steril 76: 820–822PubMedCrossRefGoogle Scholar
  2. Armstrong DG, Webb R (1997) Ovarian follicular dominance: the role of intraovarian growth factors and novel proteins. Rev Reprod 2: 139–146PubMedCrossRefGoogle Scholar
  3. Asselin E, Xiao CW, Wang YF, Tsang BK (2000) Mammalian follicular development and atresia: role of apoptosis. Biol Signals Recept 9: 87–95PubMedCrossRefGoogle Scholar
  4. Baird DT (1987) A model for follicular selection and ovulation: lessons from superovulation. J Steroid Biochem 27: 15–23PubMedCrossRefGoogle Scholar
  5. Barnes FL, Kausche A, Tiglias J, et al (1996) Production of embryos from in-vitro matured primary human oocytes. Fertil Steril 65: 1151–1156PubMedGoogle Scholar
  6. Barroso G, Oehninger S, Monzo A, Kolm P, Gibbons WE, Muasher SJ (2001) High FSH: LH ratio and low LH levels in basal cycle day 3: impact on follicular development and IVF outcome. J Assist Reprod Genet 18: 499–505PubMedCrossRefGoogle Scholar
  7. Blondin P, Sirard MA (1995) Oocyte and follicular morphology as determining characteristics for developmental competence in bovine oocytes. Mol Re-prod Dev 41: 54–62CrossRefGoogle Scholar
  8. Brown JB (1978) Pituitary control of ovarian function: concepts derived from gonadotropin therapy. Aust NZ J Obstet Gynaecol 18: 47–54CrossRefGoogle Scholar
  9. Cha KY, Chian RC (1998) Maturation in vitro of immature human oocytes for clinical use. Hum Reprod Update 4: 103–120PubMedCrossRefGoogle Scholar
  10. Cha KY, Koo JJ, Ko JJ, Choi DH, Han SY, Yoon TK (1991) Pregnancy after in vitro fertilization of human follicular oocytes collected from nonstimulated cycles, their culture in vitro and their transfer in a donor oocyte program. Fertil Steril 55: 109–113PubMedGoogle Scholar
  11. Chian RC, Buckett WM, Tulandi T, Tan SL (2000) Prospective randomized study of human chorionic gonadotrophin priming before immature oocyte retrieval from unstimulated women with polycystic ovarian syndrome. Hum Reprod 15: 165–170PubMedCrossRefGoogle Scholar
  12. Child TJ, Gulekli B, Tan SL (2001) Success during in vitro maturation (IVM) of oocyte treatment is dependent on the numbers of oocytes retrieved which are predicted by early follicular phase transvaginal ultrasound measurement of the antral follicle count and peak ovarian stromal blood flow velocity. Hum Reprod 16 (Abstract Book 1): 41CrossRefGoogle Scholar
  13. Cobo AC, Requena A, Neuspiller F, Aragones M, Mercader A, Navarro J, Simon C, Remohi J, Pellicer A (1999) Maturation in vitro of human oocytes from unstimulated cycles: selection of the optimal day for ovum retrieval based on follicular size. Hum Reprod 14: 1864–1868PubMedCrossRefGoogle Scholar
  14. de Ziegler D, Jaaskelainen AS, Brioschi PA, Fanchin R, Bulletti C (1998) Synchronisation of endogenous and exogenous FSH stimuli in controlled ovarian hyperstimulation ( COH ). Hum Reprod 13: 561–564Google Scholar
  15. Driancourt M (1991) Follicular dynamics in sheep and cattle. Theriogenology 35: 55–79CrossRefGoogle Scholar
  16. Dumesic DA, Damario MA, Session DR, Famuyide A, Lesnick TG, Thornhill AR, McNeilly AS (2001) Ovarian morphology and serum hormone markers as predictors of ovarian follicle recruitment by gonadotropins for in vitro fertilisation. J Clin Endocrinol Metab 86: 2538–2543PubMedCrossRefGoogle Scholar
  17. Ethier JF, Findlay JK (2001) Roles of activin and its signal transduction mechanisms in reproductive tissues. Reprod 121: 667–675CrossRefGoogle Scholar
  18. Galli C, Moor RM (1991) Gonadotrophin requirements for the in-vitro maturation of sheep oocytes and their subsequent embryonic development. Theriogenology 35: 1083–1093CrossRefGoogle Scholar
  19. Gougeon A (1986) Dynamics of follicular growth in the human: a model from preliminary results. Hum Reprod 1: 81–87PubMedGoogle Scholar
  20. Gougeon A (1996) Regulation of ovarian follicular development in primates: facts and hypotheses. Endocrine Rev 17: 121–155Google Scholar
  21. Hildebrandt NB, Host E, Mikkelsen AL (2001) Pain experience during trans-vaginal aspiration of immature oocytes. Acta Obstet Gynecol Scand 80: 1043–1045PubMedGoogle Scholar
  22. Hillier SG, Tetsuka M (1997) Role of androgens in follicle maturation and atresia. Baillieres Clin Obstet Gynaecol 11: 249–260PubMedCrossRefGoogle Scholar
  23. Host E, Mikkelsen AL, Lindenberg S, Smidt-Jensen S (2000) Apoptosis in human cumulus cells in relation to maturation stage and cleavage of the corresponding oocyte. Acta Obstet Gynecol Scan 79: 936–940Google Scholar
  24. Johnston LA, O’Brien SJ, Wildt DE (1989) In-vitro maturation and fertilization of domestic cat follicular oocytes. Gamete Res 24: 343–356PubMedCrossRefGoogle Scholar
  25. Lass A, Silye R, Abrams DC, Krausz T, Hovatta O, Margara R, Winston RML (1997) Follicular density in ovarian biopsy of infertile women: a novel method to assess ovarian reserve. Hum Reprod 12: 1028–1031PubMedCrossRefGoogle Scholar
  26. Lu KH, Shi DS, Jiang HS, Goulding D, Boland MP, Roche JF (1991) Comparison of the development capacity of bovine oocytes from superovulated and non-stimulated heifers. Theriogenology 35: 234CrossRefGoogle Scholar
  27. Mattioli M, Bacci ML, Galeati G, Seren E (1991) Effects of LH and FSH on the maturation of pig oocytes in vitro. Theriogenology 36: 95–105PubMedCrossRefGoogle Scholar
  28. McNatty KP, Smith DM, Makris A, Osathanondh R, Ryan KJ (1979) The microenvironment of the human antral follicle: interrelationships among the steroid levels in antral fluid, the population of granulosa cells, and the status of the oocyte in vivo and in vitro. J Clin Endocrinol Metab 49: 851–860PubMedCrossRefGoogle Scholar
  29. Mikkelsen AL, Lindenberg S (2001) Benefit of FSH priming of women with PCOS to the in vitro maturation procedure and the outcome: a randomised prospective study. Reproduction 122: 587–592PubMedCrossRefGoogle Scholar
  30. Mikkelsen AL, Smith SD, Lindenberg S (1998) In vitro maturation of immature human oocytes. Hum Reprod 13 (Abstract Book 1): 23–24Google Scholar
  31. Mikkelsen AL, Smith SD, Lindenberg S (1999) In-vitro maturation of human oocytes from regularly menstruating women may be successful without follicle stimulating hormone priming. Hum Reprod 14: 1847–1851PubMedCrossRefGoogle Scholar
  32. Mikkelsen AL, Host E, Lindenberg S (2001) Incidence of apoptosis in granulosa cells from immature human follicles. Reproduction 122: 481–486PubMedCrossRefGoogle Scholar
  33. Nakahara K, Saito H, Saito T, Ito M, Ohta N, Takahashi T, Hiroi M (1997) The incidence of apoptotic bodies in membrana granulosa can predict prognosis of ova from patients participating in in vitro fertilization programs. Fertil Steril 68: 312–317PubMedCrossRefGoogle Scholar
  34. Oktay K, Briggs D, Gosden RG (1997) Ontogeny of follicle-stimulating hormone receptor gene expression in isolated human ovarian follicles. J Clin Endocrinol Metab 82: 3748–3751PubMedCrossRefGoogle Scholar
  35. Parrott JA, Skinner MK (1998a) Developmental and hormonal regulation of keratinocyte growth factor expression and action in the ovarian follicle. Endocrinol 139: 228–235CrossRefGoogle Scholar
  36. Parrott JA, Skinner MK (1998b) Thecal cell-granulosa cell interactions involve a positive feedback loop among keratinocyte growth factor, hepatocyte growth factor, and Kit Ligand during ovarian follicular development. Endocrinol 139: 2240–2245CrossRefGoogle Scholar
  37. Pavlok A, Lucas-Hahn A, Niemann H (1992) Fertilization and developmental competence of bovine oocytes derived from different categories of antral follicles. Mol Reprod Dev 31: 63–67PubMedCrossRefGoogle Scholar
  38. Richards JS (2001) Perspective: the ovarian follicle — a perspective in 2001. Endocrinology 142: 2184–2193PubMedCrossRefGoogle Scholar
  39. Rizk B, Smitz J (1992) Ovarian hyperstimulation syndrome after superovulation using GnRH agonists for IVF and related procedure. Hum Reprod 7: 320–327PubMedGoogle Scholar
  40. Russell JB, Knezevich KM, Fabian KF, Dickson JA (1997) Unstimulated immature oocyte retrieval: early versus midfollicular endometrial priming. Fertil Steril 67: 616–620PubMedCrossRefGoogle Scholar
  41. Schats R, Schoemaker J (2001) The use of GnRH agonists. In: Gardner, Weissman A, Howles C, Shoham Z (eds) Textbook of assisted reproductive technology. Martin Dunitz, London, pp 483–491Google Scholar
  42. Schipper I, Hop WC, Fauser BC (1998) The follicle-stimulating hormone (FSH) threshold/window concept examined by different interventions with exogenous FSH during the follicular phase of the normal menstrual cycle: duration, rather than magnitude, of FSH increase affects follicle development. J Clin Endocrinol Metab 83: 1292–1298PubMedCrossRefGoogle Scholar
  43. Schramm RD, Bavister BD (1994) Follicle-stimulating hormone priming of rhesus monkeys enhances meiotic and developmental competence of oocytes matured in vitro. Biol Reprod 51: 904–912PubMedCrossRefGoogle Scholar
  44. Scott RT, Toner JP, Muasher SJ, Oehninger S, Robinson S, Rosenwaks Z (1989) Follicle-stimulating hormone levels on cycle day 3 are predictive of in vitro fertilisation outcome. Fertil Steril 51: 651–654PubMedGoogle Scholar
  45. Seifer DB, Scott RT Jr, Bergh PA, Abrogast LK, Friedman CI, Mack CK, Danforth DR (1999) Women with declining ovarian reserve may demonstrate a decrease in day 3 serum inhibin B before a rise in day 3 follicle-stimulating hormone. Fertil Steril 72: 63–65PubMedCrossRefGoogle Scholar
  46. Sirard MA, Picard L, Dery M, Coenen K, Blondin P (1999) The time interval between FSH administration and ovarian aspiration influences the development of cattle oocytes. Theriogenology 51: 699–708PubMedCrossRefGoogle Scholar
  47. Smith SD, Mikkelsen AL, Lindenberg S (2000) Development of human oocytes matured in vitro for 28 or 36 hours. Fertil Steril 73: 541–544PubMedCrossRefGoogle Scholar
  48. Smitz J, Nogueira D, Cortvrindt R, de Matos DG (2001) Oocyte in vitro maturation: state of the ART and basic requirements. In: Gardner, Weissman, Howles, Shoham (eds) Textbook of assisted reproductive technology. Martin Dunitz LTD, London, pp 107–137Google Scholar
  49. Sokka TA, Hamalainen TM, Kaipia A, Warren DW, Huhtaniemi IT (1996) Development of luteinizing hormone action in the perinatal rat ovary. Biol Re-prod 55: 663–670CrossRefGoogle Scholar
  50. Trounson A, Wood C, Kausche A (1994) In vitro maturation and the fertilization and developmental competence of oocytes recovered from untreated polycystic ovarian patients. Fertil Steril 62: 353–362PubMedGoogle Scholar
  51. Trounson A, Anderiesz C, Jones G (2001) Maturation of human oocytes in vitro and their developmental competence. Reproduction 121: 51–75PubMedCrossRefGoogle Scholar
  52. Wynn P, Picton HM, Krapez JA, Rutherford AJ, Balen AH, Gosden RG (1998) Pretreatment with follicle stimulating hormone promotes the numbers of human oocytes reaching metaphase II by in-vitro maturation. Hum Reprod 13: 3132–3138PubMedCrossRefGoogle Scholar
  53. Younis AI, Brackett BG, Fayrer-Hosken RA (1989) Influence of serum and hormone on bovine oocyte maturation and fertilization in vitro. Gamete Res 23: 189–201PubMedCrossRefGoogle Scholar
  54. Yuan W, Giudice LC (1997) Programmed cell death in human ovary is a function of follicle and corpus luteum status. J Clin Endocrinol Metab 82: 3148–3155PubMedCrossRefGoogle Scholar
  55. Zeleznik AJ, Kubik CJ (1986) Ovarian responses in macaques to pulsatile infusion of follicle-stimulating hormone (FSH) and luteinizing hormone: increased sensitivity of the maturing follicle to FSH. Endocrinology 119: 2025–2032PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2002

Authors and Affiliations

  • J. Smitz

There are no affiliations available

Personalised recommendations