To the Editor:
We read with interest the article by Demirol et al. (1) which concluded that microflare leuprolide was superior to GnRH antagonist for poor responders. It is difficult to make such a conclusion because of the very high amount of hMG used. Each 75 IU vial of hMG contains about 10 IU of hCG, which is the predominant source of its LH-like activity. Although the dose of hMG used in this study would raise bio-LH/hCG levels into the normal range as a single dose in women suppressed with a potent GnRH agonist (2), because of the long half-life of hCG, 60 IU daily would result in a high level of LH activity, particularly before the antagonist is begun. In women not pretreated with an oral contraceptive (OC) and stimulated with pure FSH, higher LH levels have been shown to reduce the pregnancy rate in GnRH antagonist cycles, even when the antagonist is begun on day 6 of stimulation (3). Any added LH activity is therefore likely deleterious. For antagonist cycles pretreated with OC, addition of LH activity is most likely helpful, but 75-150 IU of hMG or 10-20 IU of hCG would be the appropriate dose (2,4).
The microflare as originally reported (5-7) was with pure FSH only, because of the release of LH by the microflare. The microflare was begun on the third day off OC and FSH was not begun until the third day of the microflare. The author of that study (W.S.) does now use 150 of hMG because of the known suppression of LH after OC, with results apparently as good as in his original study. However, as with antagonist preceded by OC, larger amounts are assumed to have the potential of lower outcomes.
In this study the use of such a high amount of hMG and the use of OC pretreatment only for the microflare cycles to our mind invalidates any resulting conclusion. Furthermore we would consider it most logical in designing such a study to use each protocol as already reported to be associated with good results.
David R. Meldrum, M.D.
Reproductive Partners Medical Group
Redondo Beach, California
William Schoolcraft, M.D.
Colorado Center for Reproductive Medicine
Lone Tree, Colorado
1. Demirol A, Gurgan T. Comparison of microdose flare-up and antagonist multiple-dose protocols for poor-responder patients: a randomized study
2. Thompson KA, La Polt PS, Rivier J, Henderson G, Dahl K, Meldrum DR: Gonadotropin requirements of the developing follicle. Fertil Steril 1995;63:273-6
3. Kolibianakis EM, Zikopoulos K, Schiettecatte J, Smitz J, Tournaye H, Camus M, et al. Profound LH suppression after GnRH antagonist administration is associated with a significantly higher ongoing pregnancy rate in IVF. Hum Reprod 2004;19:2490-6.
4. Meldrum DR, Scott RT, Levy MJ, Alper M, Noyes N: Oral contraceptive pretreatment in women undergoing controlled ovarian stimulation in ganirelix acetate cycles may, for a subset of patients, be associated with low serum luteinizing hormone levels, reduced ovarian response to gonadotropins and early pregnancy loss. Fert Steril, 2009;91:1963-5.
5. Schoolcraft W, Schlenker T, Gee M, Stevens J, Wagley L. Improved controlled ovarian hyperstimulation in poor responder in vitro fertilization patients with a microdose follicle-stimulating hormone flare, growth hormone protocol. Fertil Steril 1997;67:93.
6. Surrey ES, Schoolcraft WB. Evaluating strategies for improving ovarian response of the poor responder undergoing assisted reproductive techniques. Fertil Steril 2000;73:667–76.
7. Surrey ES, Bower J, Hill DM, Ramsey J, Surrey MW. Clinical and endocrine effects of a microdose GnRH agonist flare regimen administered to poor responders who are undergoing in vitro fertilization. Fertil Steril 1998;69:419–24.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2010.02.001
The Authors Respond:
We thank Dr. Meldrum and Dr. Schoolcraft for their comments on our paper.
The most commonly used ovarian stimulation protocols are initiation of gonadotropins and a GnRH-a together in the follicular phase (the so-called microdose flare protocol) or initiation of the microdose flare after oral contraceptive (OC) pretreatment (the co-flare) and the GnRH antagonist treatment regimens that allow for a more natural recruitment of follicles in the follicular phase in an ovary that has not been suppressed by the absence of FSH and LH caused by a GnRH-a (1). However, the randomized studies comparing the efficacy of these two regimens reported conflicting and non-significant results (2,3). This may be attributed to the small size of the study groups. To our knowledge, our study includes the largest number of poor responders in terms of the comparison of these two controlled ovarian hyperstimulation (COH) regimens. The aim of our prospective randomized study was to compare the efficacy of the microdose flare-up and multiple-dose antagonist protocols in patients with poor ovarian response undergoing intracytoplasmic sperm injection (ICSI) and embryo transfer (ET) cycles.
The patients in one group were stimulated according to the microdose flare-up protocol, while the patients in the other group were stimulated according to antagonist multiple-dose protocol. The mean number of mature oocytes retrieved was the primary outcome measure, and fertilization rate, implantation rate per embryo, and clinical pregnancy rates were secondary outcome measures. The mean age of the women, the mean duration of infertility, basal FSH level, and the number of previous IVF cycles were similar in both groups. The total gonadotropin dose used was significantly higher in antagonist group, while the number of oocytes retrieved was significantly greater in micro-flare group . Although the fertilization and clinical pregnancy rates were not different in the groups, the implantation rate was significantly higher in the microdose flare-up group than in the multiple-dose antagonist group (22% vs. 11%). So, we concluded that the microdose flare-up protocol may have a better outcome in poor-responder patients.
As the authors said, the microflare was originally reported with pure FSH only because of the release of luteinizing hormone (LH) by the microflare. On the other side, in many IVF centers human menopausal gonadotropin (HMG) is being used in microflare and antagonist cycles as well. In a recent study (4) microflare and long luteal agonist protocol was compared for normal responding patients with using the combination of recombinant follicle-stimulating hormone (FSH) and HMG.
We evaluated the comment of the authors and we think that in another study the efficacy of microflare and antagonist should be compared with using recombinant FSH.
Aygul Demirol, M.D
Timur Gürgan M.D
Women’s Health, Infertility and IVF Center
1. Copperman AB. Antagonists in poor-responder patients. Fertil Steril 2003;80(Suppl 1):S16–24. discussion S32–4.
2. Akman MA, Erden HF, Tosun SB, Bayazit N, Aksoy E, Bahceci M. Comparison of agonistic flare-up-protocol and antagonistic multiple dose protocol in ovarian stimulation of poor responders: results of a prospective randomized trial. Hum Reprod 2001;16:868–70.
3. Malmusi S, La Marca A, Giulini S, Xella S, Tagliasacchi D, Marsella T, et al. Comparison of a gonadotropin-releasing hormone (GnRH) antagonist and GnRH agonist flare-up regimen in poor responders undergoing ovarian stimulation. Fertil Steril 2005;84:402–6.
4. Levens ED, Whitcomb BW, Kort JD, Materia-Hoover D, Larsen FW. Microdose follicular flare: a viable alternative for normal-responding patients undergoing in vitro fertilization? Fertil Steril 2009; 91:110-4.
Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2010.02.002