Increased gonadotrophin stimulation does not improve IVF outcomes in patients with predicted poor ovarian reserve

  • Dharmawijaya N Lekamge
  • Michelle Lane
  • Robert B Gilchrist
  • Kelton P Tremellen



This retrospective study was carried out to evaluate whether increasing the starting dose of FSH stimulation above the standard dose of 150 IU/day in patients with low predicted ovarian reserve can improve IVF outcomes.


A total of 122 women aged less than 36 years in their first cycle of IVF were identified as having likely low ovarian reserve based on a serum AMH measurement below 14 pmol/l. Thirty five women were administered the standard dose of 150 IU/day FSH, while the remaining 87 received a higher starting dose (200–300 IU/day FSH). There were no significant differences in age, BMI, antral follicle count, serum AMH, FSH or aetiology of infertility between the two dose groups.


No significant improvement in oocyte and embryo yield or pregnancy rates was observed following an upward adjustment of FSH starting dose. While increasing the dose of FSH above 150 IU/day did not produce any adverse events such as OHSS, it did consume an extra 1,100 IU of FSH per IVF cycle.


The upward FSH dose adjustment in anticipation of low ovarian reserve can not be advocated as it is both expensive and of no proven clinical value.


Anti-Müllerian hormone Predicted poor ovarian reserve controlled ovarian hyper-stimulation FSH dose adjustment IVF 



Dharmawijaya Lekamge was supported by an International Post-Graduate Research Scholarship (IPRS) and Adelaide University Scholarship. We wish to thank staff at Repromed for friendly assistance.


  1. 1.
    De Vries MJ, De Sutter P, Dhont M. Prognostic factors in patients continuing in vitro fertilization or intracytoplasmic sperm injection treatment and dropouts. Fertil Steril. 1999;72:674–8. doi: 10.1016/S0015-0282(99)00334-9.PubMedCrossRefGoogle Scholar
  2. 2.
    Sharma V, Allgar V, Rajkhowa M. Factors influencing the cumulative conception rate and discontinuation of in vitro fertilization treatment for infertility. Fertil Steril. 2002;78:40–6. doi: 10.1016/S0015-0282(02)03160-6.PubMedCrossRefGoogle Scholar
  3. 3.
    Popovic-Todorovic B, Loft A, Bredkjaeer HE, Bangsboll S, Nielsen IK, Andersen AN. A prospective randomized clinical trial comparing an individual dose of recombinant FSH based on predictive factors versus a ‘standard’ dose of 150 IU/day in ‘standard’ patients undergoing IVF/ICSI treatment. Hum Reprod. 2003;18:2275–82. doi: 10.1093/humrep/deg472.PubMedCrossRefGoogle Scholar
  4. 4.
    Pantos C, Thornton SJ, Speirs AL, Johnston I. Increasing the human menopausal gonadotropin dose—does the response really improve? Fertil Steril 1990;53:436–9.PubMedGoogle Scholar
  5. 5.
    Popovic-Todorovic B, Loft A, Lindhard A, Bangsboll S, Andersson AM, Andersen AN. A prospective study of predictive factors of ovarian response in ‘standard’ IVF/ICSI patients treated with recombinant FSH. A suggestion for a recombinant FSH dosage normogram. Hum Reprod 2003;18:781–7. doi: 10.1093/humrep/deg181.PubMedCrossRefGoogle Scholar
  6. 6.
    Seifer DB, Maclaughlin DT. Mullerian Inhibiting Substance is an ovarian growth factor of emerging clinical significance. Fertil Steril. 2007;88:539–46. doi: 10.1016/j.fertnstert.2007.02.014.PubMedCrossRefGoogle Scholar
  7. 7.
    de Vet A, Laven JS, de Jong FH, Themmen AP, Fauser BC. Antimullerian hormone serum levels: a putative marker for ovarian aging. Fertil Steril. 2002;77:357–62. doi: 10.1016/S0015-0282(01)02993-4.PubMedCrossRefGoogle Scholar
  8. 8.
    Muttukrishna S, McGarrigle H, Wakim R, Khadum I, Ranieri DM, Serhal P. Antral follicle count, anti-mullerian hormone and inhibin B: predictors of ovarian response in assisted reproductive technology? BJOG. 2005;112:1384–90. doi: 10.1111/j.1471-0528.2005.00670.x.PubMedCrossRefGoogle Scholar
  9. 9.
    McIlveen M, Skull JD, Ledger WL. Evaluation of the utility of multiple endocrine and ultrasound measures of ovarian reserve in the prediction of cycle cancellation in a high-risk IVF population. Hum Reprod. 2007;22:778–85. doi: 10.1093/humrep/del435.PubMedCrossRefGoogle Scholar
  10. 10.
    van Rooij IA, Broekmans FJ, te Velde ER, Fauser BC, Bancsi LF, de Jong FH, et al. Serum anti-Mullerian hormone levels: a novel measure of ovarian reserve. Hum Reprod. 2002;17:3065–71. doi: 10.1093/humrep/17.12.3065.PubMedCrossRefGoogle Scholar
  11. 11.
    Seifer DB, MacLaughlin DT, Christian BP, Feng B, Shelden RM. Early follicular serum mullerian-inhibiting substance levels are associated with ovarian response during assisted reproductive technology cycles. Fertil Steril. 2002;77:468–71. doi: 10.1016/S0015-0282(01)03201-0.PubMedCrossRefGoogle Scholar
  12. 12.
    Hazout A, Bouchard P, Seifer DB, Aussage P, Junca AM, Cohen-Bacrie P. Serum antimullerian hormone/mullerian-inhibiting substance appears to be a more discriminatory marker of assisted reproductive technology outcome than follicle-stimulating hormone, inhibin B, or estradiol. Fertil Steril. 2004;82:1323–9. doi: 10.1016/j.fertnstert.2004.03.061.PubMedCrossRefGoogle Scholar
  13. 13.
    Muttukrishna S, Suharjono H, McGarrigle H, Sathanandan M. Inhibin B and anti-Mullerian hormone: markers of ovarian response in IVF/ICSI patients? BJOG. 2004;111:1248–53. doi: 10.1111/j.1471-0528.2004.00452.x.PubMedCrossRefGoogle Scholar
  14. 14.
    Eldar-Geva T, Ben-Chetrit A, Spitz IM, Rabinowitz R, Markowitz E, Mimoni T, et al. Dynamic assays of inhibin B, anti-Mullerian hormone and estradiol following FSH stimulation and ovarian ultrasonography as predictors of IVF outcome. Hum Reprod. 2005;20:3178–83. doi: 10.1093/humrep/dei203.PubMedCrossRefGoogle Scholar
  15. 15.
    Tremellen KP, Kolo M, Gilmore A, Lekamge DN. Anti-mullerian hormone as a marker of ovarian reserve. Aust N Z J Obstet Gynaecol. 2005;45:20–4. doi: 10.1111/j.1479-828X.2005.00332.x.PubMedCrossRefGoogle Scholar
  16. 16.
    Penarrubia J, Fabregues F, Manau D, Creus M, Casals G, Casamitjana R, et al. Basal and stimulation day 5 anti-Mullerian hormone serum concentrations as predictors of ovarian response and pregnancy in assisted reproductive technology cycles stimulated with gonadotropin—releasing hormone agonist—gonadotropin treatment. Hum Reprod. 2005;20:915–22. doi: 10.1093/humrep/deh718.PubMedCrossRefGoogle Scholar
  17. 17.
    Ficicioglu C, Kutlu T, Baglam E, Bakacak Z. Early follicular antimullerian hormone as an indicator of ovarian reserve. Fertil Steril. 2006;85:592–6. doi: 10.1016/j.fertnstert.2005.09.019.PubMedCrossRefGoogle Scholar
  18. 18.
    Nelson SM, Yates RW, Fleming R. Serum anti-Mullerian hormone and FSH: prediction of live birth and extremes of response in stimulated cycles—implications for individualization of therapy. Hum Reprod. 2007;22:2414–21. doi: 10.1093/humrep/dem204.PubMedCrossRefGoogle Scholar
  19. 19.
    Lekamge DN, Barry M, Kolo M, Lane M, Gilchrist RB, Tremellen KP. Anti-Mullerian hormone as a predictor of IVF outcome. Reprod Biomed Online. 2007;14:602–10.PubMedCrossRefGoogle Scholar
  20. 20.
    La Marca A, Giulini S, Tirelli A, Bertucci E, Marsella T, Xella S, et al. Anti-Mullerian hormone measurement on any day of the menstrual cycle strongly predicts ovarian response in assisted reproductive technology. Hum Reprod. 2007;22:766–71. doi: 10.1093/humrep/del421.PubMedCrossRefGoogle Scholar
  21. 21.
    Smeenk JM, Sweep FC, Zielhuis GA, Kremer JA, Thomas CM, Braat DD. Antimullerian hormone predicts ovarian responsiveness, but not embryo quality or pregnancy, after in vitro fertilization or intracyoplasmic sperm injection. Fertil Steril. 2007;87:223–6. doi: 10.1016/j.fertnstert.2006.06.019.PubMedCrossRefGoogle Scholar
  22. 22.
    Lashen H, Ledger W, Lopez Bernal A, Evans B, Barlow D. Superovulation with a high gonadotropin dose for in vitro fertilization: is it effective? J Assist Reprod Genet. 1998;15:438–43. doi: 10.1007/BF02744938.PubMedCrossRefGoogle Scholar
  23. 23.
    Harrison RF, Jacob S, Spillane H, Mallon E, Hennelly B. A prospective randomized clinical trial of differing starter doses of recombinant follicle-stimulating hormone (follitropin-beta) for first time in vitro fertilization and intracytoplasmic sperm injection treatment cycles. Fertil Steril. 2001;75:23–31. doi: 10.1016/S0015-0282(00)01643-5.PubMedCrossRefGoogle Scholar
  24. 24.
    Out HJ, Lindenberg S, Mikkelsen AL, Eldar-Geva T, Healy DL, Leader A, et al. A prospective, randomized, double-blind clinical trial to study the efficacy and efficiency of a fixed dose of recombinant follicle stimulating hormone (Puregon) in women undergoing ovarian stimulation. Hum Reprod. 1999;14:622–7. doi: 10.1093/humrep/14.3.622.PubMedCrossRefGoogle Scholar
  25. 25.
    Hoomans EH, Mulder BB. A group-comparative, randomized, double-blind comparison of the efficacy and efficiency of two fixed daily dose regimens (100- and 200-IU) of recombinant follicle stimulating hormone (rFSH, Puregon) in Asian women undergoing ovarian stimulation for IVF/ICSI. J Assist Reprod Genet. 2002;19:470–6. doi: 10.1023/A:1020358419073.PubMedCrossRefGoogle Scholar
  26. 26.
    Yong PY, Brett S, Baird DT, Thong KJ. A prospective randomized clinical trial comparing 150 IU and 225 IU of recombinant follicle-stimulating hormone (Gonal-F*) in a fixed-dose regimen for controlled ovarian stimulation in in vitro fertilization treatment. Fertil Steril. 2003;79:308–15. doi: 10.1016/S0015-0282(02)04583-1.PubMedCrossRefGoogle Scholar
  27. 27.
    Pruksananonda K, Suwajanakorn S, Sereepapong W, Virutamasen P. Comparison of two different fixed doses of follitropin-beta in controlled ovarian hyperstimulation: A prospective randomized, double blind clinical trial. J Med Assoc Thai. 2004;87:1151–5.PubMedGoogle Scholar
  28. 28.
    Popovic-Todorovic B, Loft A, Ziebe S, Andersen AN. Impact of recombinant FSH dose adjustments on ovarian response in the second treatment cycle with IVF or ICSI in “standard” patients treated with 150 IU/day during the first cycle. Acta Obstet Gynecol Scand. 2004;83:842–9. doi: 10.1111/j.0001-6349.2004.00573.x.PubMedCrossRefGoogle Scholar
  29. 29.
    Cook CL, Siow Y, Taylor S, Fallat ME. Serum mullerian-inhibiting substance levels during normal menstrual cycles. Fertil Steril. 2000;73:859–61. doi: 10.1016/S0015-0282(99)00639-1.PubMedCrossRefGoogle Scholar
  30. 30.
    La Marca A, Malmusi S, Giulini S, Tamaro LF, Orvieto R, Levratti P, et al. Anti-Mullerian hormone plasma levels in spontaneous menstrual cycle and during treatment with FSH to induce ovulation. Hum Reprod. 2004;19:2738–41. doi: 10.1093/humrep/deh508.PubMedCrossRefGoogle Scholar
  31. 31.
    Hehenkamp WJ, Looman CW, Themmen AP, de Jong FH, Te Velde ER, Broekmans FJ. Anti-Mullerian hormone levels in the spontaneous menstrual cycle do not show substantial fluctuation. J Clin Endocrinol Metab. 2006;91:4057–63. doi: 10.1210/jc.2006-0331.PubMedCrossRefGoogle Scholar
  32. 32.
    Fanchin R, Taieb J, Lozano DH, Ducot B, Frydman R, Bouyer J. High reproducibility of serum anti-Mullerian hormone measurements suggests a multi-staged follicular secretion and strengthens its role in the assessment of ovarian follicular status. Hum Reprod. 2005;20:923–7. doi: 10.1093/humrep/deh688.PubMedCrossRefGoogle Scholar
  33. 33.
    Land JA, Yarmolinskaya MI, Dumoulin JC, Evers JL. High-dose human menopausal gonadotropin stimulation in poor responders does not improve in vitro fertilization outcome. Fertil Steril. 1996;65:961–5.PubMedGoogle Scholar
  34. 34.
    Klinkert ER, Broekmans FJ, Looman CW, Habbema JD, te Velde ER. Expected poor responders on the basis of an antral follicle count do not benefit from a higher starting dose of gonadotrophins in IVF treatment: a randomized controlled trial. Hum Reprod. 2005;20:611–5. doi: 10.1093/humrep/deh663.PubMedCrossRefGoogle Scholar
  35. 35.
    Pal L, Jindal S, Witt BR, Santoro N. Less or more; increased gonadotropin use for ovarian stimulation adversely influences clinical pregnancy and live birth after in vitro fertilisation. Fertil Steril. 2008;89(6):1694–701. doi: 10.1016/j.fertnstert.2007.05.055.PubMedCrossRefGoogle Scholar
  36. 36.
    Loutradis D, Drakakis P, Vomvolaki E, Antsaklis A. Different ovarian stimulation protocols for women with diminished ovarian reserve. J Assist Reprod Genet. 2007;24:597–611. doi: 10.1007/s10815-007-9181-2.PubMedCrossRefGoogle Scholar
  37. 37.
    Gougeon A. Regulation of ovarian follicular development in primates: facts and hypotheses. Endocr Rev. 1996;17:121–55. doi: 10.1210/er.17.2.121.PubMedCrossRefGoogle Scholar
  38. 38.
    La Marca A, Volpe A. Anti-Mullerian hormone (AMH) in female reproduction: is measurement of circulating AMH a useful tool? Clin Endocrinol (Oxf). 2006;64:603–10. doi: 10.1111/j.1365-2265.2006.02533.x.CrossRefGoogle Scholar
  39. 39.
    Lee TH, Liu CH, Huang CC, Wu YL, Shih YT, Ho HN, et al. Serum anti-mullerian hormone and estradiol levels as predictors of ovarian hyperstimulation syndrome in assisted reproduction technology cycles. Hum Reprod. 2008;23:160–7. doi: 10.1093/humrep/dem254.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Dharmawijaya N Lekamge
    • 1
  • Michelle Lane
    • 1
  • Robert B Gilchrist
    • 2
  • Kelton P Tremellen
    • 1
  1. 1.Research Centre for Reproductive Health, Discipline of Obstetrics & Gynaecology, School of Paediatrics and Reproductive HealthUniversity of AdelaideAdelaideAustralia
  2. 2.Research Centre for Reproductive Health, Discipline of Obstetrics & Gynaecology, School of Paediatrics and Reproductive HealthAdelaideAustralia

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