Studies (Williams et al. 2002; Fiedler and Ludwig 2003; Lin et al. 2006; Karimzadeh et al. 2010) comparing the CC/gonadotropin/GnRH antagonist protocol to the standard long agonist regimen report similar pregnancy rates in both groups despite a lower number of oocytes in the mild stimulation group. There is a significant reduction in the number of ampoules of gonadotropin used, the number of treatment days, and the costs. Only one non-randomized comparative study (Mansour et al. 2003) reported significantly lower pregnancy rates following ovarian stimulation with a CC/hMG protocol with GnRH antagonist compared with a long GnRH agonist protocol.

Hwang et al. (2003) reported on a combined protocol of CC/gonadotropin/GnRH antagonist with mean number of 8.0 oocytes retrieved and an ongoing pregnancy rate of 35 % per started cycle. The mild stimulation regimen used varies in the different studies. In most studies, a protocol of 100 mg Clomiphene citrate for 5 days soon after the onset of menses is combined with low-dose gonadotropins. The starting dose of gonadotropins, day of initiation, daily or alternate-day injection, and fixed or flexible antagonist dosing vary from study to study.

It has been debated whether hMG or r-FSH should be used in the CC/gonadotropin/GnRH antagonist protocol. Engel et al. (2002) reported that both treatment groups (hMG and rFSH), yielded comparable results concerning gonadotropin dose, stimulation days, and pregnancy rate. Interestingly, one study (Yanaihara et al. 2008) reported that in CC/gonadotropin/GnRH antagonist cycles, when the circulating level of LH is less than one-third at the time of hCG than it was at the beginning of stimulation, both pregnancy and implantation rates are significantly reduced. This observation suggests the relevance of using gonadotropins containing LH or hCG rather than FSH alone in this protocol. Also, mounting evidence indicates that LH or hCG activity during ovarian stimulation treatment is capable of modulating folliculogenesis by reducing the number of small or intermediate-sized follicles (Platteau et al. 2006). The positive effects of exogenous LH or hCG activity derived from hMG on folliculogenesis, embryo quality, and endometrial receptivity have been addressed in large randomized trials (Platteau et al. 2006; Filicori et al. 2002, 2005).

Few studies have evaluated the use of this regimen in poor responders. The first study (Craft et al. 1999) which included only 18 patients compared the CC/gonadotropin/GnRH antagonist protocol to their response in previous long agonist cycles. Smaller cycle cancellation rate, better oocyte yield, and lower gonadotropin requirement were observed in the mild group. Takahashi et al (Takahashi et al. 2004) studied this protocol in 40 poor responders with previous multiple IVF failures using the long agonist protocol. They noted that the ovarian response using the mild protocol was comparable to that obtained in the previous attempts with the long regimen, but the blastocyst development rate and ongoing pregnancy rate (41.2 %) were significantly higher with the mild protocol. D’Amato et al (D’Amato et al. 2004) in a prospective randomized study of poor responders and older women compared a sequential protocol of CC/FSH/GnRH antagonist with the long GnRH agonist protocol and reported a significantly lower cancellation rate, higher peak estradiol level, more retrieved oocytes, and higher pregnancy and implantation rates in the antagonist group. Only in the antagonist group, the results were comparable in younger (<35 years) and older (>35 years) women. In this study, however, high-dose FSH was used and hence, the observations only indicate that this regimen with low-dose gonadotropins may be suitable for poor responders and older women.