Authors’ Response: A Randomized Comparison of Two Ovarian Stimulation Protocols with Gonadotropin-Releasing Hormone (GnRH) Antagonist Cotreatment for in Vitro Fertilization Commencing Recombinant Follicle-Stimulating Hormone on Cycle Day 2 or 5 with the Standard Long GnRH Agonist Protocol

B. C. J. M. Fauser and N. S. Macklon

Center of Reproductive Medicine, Erasmus Medical Center, Rotterdam 3015 GD, The Netherlands

Address correspondence to: Bart C. J. M. Fauser, M.D., Ph.D., Erasmus University Medical Center Rotterdam, Division of Reproductive Medicine, Department of Obstetrics and Gynecology, Dr. Molewaterplein 40, Rotterdam 3015 GD, The Netherlands. E-mail: b.fauser{at}erasmusmc.nl.

To the editor:

We thank Dr. Broekmans and colleagues (1) from Utrecht for their interest in our recent in vitro fertilization (IVF) study, published in the January issue of JCEM (2), and welcome the opportunity to have an overseas public discussion concerning the interpretation of the study results.

We agree with their point that the good embryo quality and improved IVF outcome in patients undergoing minimal ovarian stimulation who were not canceled could be explained by patient selection. Women of more advanced reproductive age are indeed more likely to be canceled before oocyte pick up. This suggestion is not new to us, and we address it in the article (2). As reported, chronological age was increased and early follicular-phase FSH levels augmented in these "low response" patients. We would stress that it was not our intention to develop minimal stimulation protocols to counteract ovarian aging. In fact, a recent systematic review demonstrated that no regimen whatsoever was effective in the clinical management of such patients (3). Therefore, the study was conducted in women less than 38 yr of age.

The current study was developed to test the clinical usefulness in IVF of the hypothesis that interference with decremental FSH during the mid to late follicular phase of the menstrual cycle is capable of inducing multiple, dominant follicle development. This concept was initially put forward by Zeleznik et al. (4) almost two decades ago, based on studies in the monkey model, and was tested more recently by us both in anovulatory women (5) and in regularly cycling volunteers (6). The current study suggests that this patient-friendly approach may be useful in clinical IVF, confirming a recent pilot study (7). In our view, the most important conclusion from this study is that a "normal response to low stimulation" is demonstrated to be distinctly different from a "low response to maximal stimulation," despite the fact that similar numbers of oocytes are retrieved. Following minimal stimulation, significantly more pregnancies occurred in cases 1–4, in which four oocytes were retrieved, compared with maximal stimulation—which points to a difference in oocyte quality. Both stimulation regimens were randomly applied in similar patients. Hence, the conclusion seems justified that the importance of the availability of large numbers of embryos for successful IVF (8)—as has been the dogma for many years—only holds true for conventional maximal stimulation. In this respect, the applied cancellation criteria may need to be revised for minimal stimulation, as stated in our article (2). Obviously, this will reduce the cancellation rate, coinciding with minimal stimulation. Further data regarding oocyte– embryo quality in low-response patients with this modified approach is now awaited.

We suggest that the current study be viewed as a step toward improving the overall health economics of IVF treatment. The presented data indicate that a similar IVF outcome can be achieved with minimal ovarian stimulation in women of normal reproductive age, coinciding with less patient discomfort, lower costs, and presumably fewer complications. We would reassure Dr. Broekmans and colleagues that a multicenter study is underway to further substantiate this concept. Moreover, a separate study is ongoing to provide additional information regarding the intriguing question whether a relationship exists between the quantity and quality (i.e. chromosomal constitution) of stimulated oocytes.

Received May 21, 2003.

References

  1. Broekmans FJ, Weima SM, te Velde ER 2003 A randomized comparison of two ovarian stimulation protocols with gonadotropin-releasing hormone (GnRH) antagonist cotreatment for in vitro fertilization commencing recombinant follicle-stimulating hormone on cycle day 2 or 5 with the standard long GnRH agonist protocol. J Clin Endocrinol Metab 88:4510 (Letter)[Free Full Text]
  2. Hohmann FP, Macklon NS, Fauser BC 2003 A randomized comparison of two ovarian stimulation protocols with gonadotropin-releasing hormone (GnRH) antagonist cotreatment for in vitro fertilization commencing recombinant follicle-stimulating hormone on cycle day 2 or 5 with the standard long GnRH agonist protocol. J Clin Endocrinol Metab 88:166–173[Abstract/Free Full Text]
  3. Tarlatzis B, Zepiridis L, Grimbizis G, Bontis J 2003 Clinical management of low ovarian response to stimulation for IVF: a systematic review. Hum Reprod Update 9:61–76[Abstract/Free Full Text]
  4. Zeleznik AJ, Hutchison JS, Schuler HM 1985 Interference with the gonadotropin-suppressing actions of estradiol in macaques overrides the selection of a single preovulatory follicle. Endocrinology 117:991–999[Abstract]
  5. van Santbrink EJ, Fauser BC 1997 Urinary follicle-stimulating hormone for normogonadotropic clomiphene-resistant anovulatory infertility: prospective, randomized comparison between low dose step-up and step-down dose regimens. J Clin Endocrinol Metab 82:3597–3602[Abstract/Free Full Text]
  6. 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 83:1292–1298[Abstract/Free Full Text]
  7. de Jong D, Macklon NS, Fauser BC 2000 A pilot study involving minimal ovarian stimulation for in vitro fertilization: extending the "follicle-stimulating hormone window" combined with the gonadotropin-releasing hormone antagonist cetrorelix. Fertil Steril 73:1051–1054[CrossRef][Medline]
  8. Templeton A, Morris JK, Parslow W 1996 Factors that affect outcome of in-vitro fertilisation treatment. Lancet 348:1402–1406[CrossRef][Medline]




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