The management for poor responders with diminished ovarian reserve is still a challenge, although many studies have been performed to seek for a method of efficient ovarian stimulation for infertile women with reduced ovarian reserve. There have been many studies assessing various controlled ovarian stimulation (COS) regimens to improve the outcome of poor responders undergoing IVF, no particular protocol was demonstrated to be best suited for all such patients [1]. GnRH agonist long protocol (LP) has been a standard COS method since it was introduced in assisted reproduction in the late 1980's to prevent premature LH surge and luteinization [2], and GnRH agonist low-dose regimens was advocated as one of important protocols for poor responders in terms of improvement in COS response and reduced duration and dose of gonadotropin stimulation [3,4]. More recently, GnRH antagonists have been administered to poor responders during COS with inconsistent results [5-9]. Although a limited number of randomized controlled trials compare the efficacy of GnRH antagonist protocol and the agonist long protocol for COS in poor responders undergoing IVF, a meta-analysis by Griesinger et al. [10] demonstrated that GnRH antagonist protocol results in significantly more cumulus oocyte complexes (COCs) and similar clinical outcome. COS using GnRH antagonists is also likely to become one of the treatment options for poor responders.

After the introduction of GnRH antagonists in COS, oral contraceptive pill (OCP) has been used for cycle scheduling purpose. OCP is effective in allowing prediction of timing events in an IVF cycle regarding scheduling and is frequently used before IVF and may influence IVF outcome [11,12]. In a randomized controlled trial by Kolibianakis et al. [13] and a meta-analysis by Griesinger et al. [14], a significant difference in ongoing pregnancy rates between patients who received OCP pretreatment and those who did not was not found. However, subjects for these studies were not poor responders and the available randomized studies on OCP pretreatment in poor responders undergoing IVF have not been reported. It is thought that OCP pretreatment in GnRH antagonist cycles can result in different ovarian response to COS and IVF results in poor responders, compared with normal responders.

The present study was performed to investigate the effectiveness of GnRH antagonist multiple-dose protocol (MDP) with OCP pretreatment in poor responders undergoing IVF/ICSI, compared with GnRH antagonist MDP without OCP pretreatment and GnRH agonist low-dose LP.

There were no differences in the age of patients, duration of infertility, body mass index, the proportion of nullipara, AFC and basal endocrine profile among three groups (Table 1).

In group 1 and 3, no patient was lost to follow-up or withdrawn from the study and there were no cancellation of cycle by premature LH surge or any other reasons. In group 2, 1 out of 40 cycles initiated (2.5%) was cancelled before ET, because no oocytes were obtained despite a follicular aspiration for oocyte retrieval. However, there was no significant difference in cycle cancellation rate among three groups (Table 2).

Total doses (2,925.0±423.9 IU vs. 2,905.0±421.8 IU vs. 3,273.6±438.3 IU) and days (9.9±1.3 days vs. 9.8±1.3 days vs. 11.3±1.5 days) of rhFSH required for COS were significantly higher in group 3 than in group 1 or 2 (p<0.001, p<0.001) (Table 2). The number of follicles ≥14 mm and endometrial thickness on hCG day, number of oocytes retrieved were similar among three groups, but the number of mature oocytes (4.0±1.6 vs. 2.8±1.2 vs. 3.8±1.6), fertilized oocytes (3.9±1.6 vs. 2.8±1.1 vs. 3.8±1.6) and grade I, II embryos (2.2±1.1 vs. 1.3±0.9 vs. 2.1±1.0) were significantly lower in group 2 than in group 1 or 3 (p=0.001, p=0.002, p<0.001, respectively) (Table 2). However, significant differences were not found among three groups regarding clinical pregnancy rate per cycle initiated, implantation rate and live birth rate per cycle initiated (Table 2).

The present study evaluated the effectiveness of GnRH antagonist MDP with or without OCP pretreatment, compared with GnRH agonist low-dose LP that have been popularly used since the 1990's in poor responders undergoing IVF/ICSI. Total dose and duration of rhFSH used for COS were significantly higher in GnRH agonist low-dose LP group than in GnRH antagonist MDP groups, which suggests the advantage of GnRH antagonist protocol. It is well known advantage of GnRH antagonist protocols compared with GnRH agonist LP, and Howles et al. [18] reported that the GnRH antagonists offer comparable therapeutic efficacy to agonists and have a number of potential advantages over agonists for use in COS protocols, such as avoiding the initial "flare-up" of LH, shortening the overall treatment period and reducing the risk of OHSS and menopausal side effects in women of advanced maternal age. In group 1, the numbers of mature oocytes, fertilized oocytes and grade I, II embryos were comparable to those in group 3, whereas these were significantly lower in group 2. This implicates OCP pretreatment in GnRH antagonist MDP is effective in improving the ovarian response to COS and IVF outcome with similar level to GnRH agonist low-dose LP. In patients with elevated basal serum FSH levels by diminished ovarian reserve, antral follicle sizes during the early follicular phase are often markedly heterogeneous because FSH-sensitive follicles are early exposed to gradient FSH concentrations during the preceding luteal phase. Therefore, in poor responders, ovarian stimulation without pituitary suppression is likely to induce asynchronous follicular development and a limited number of dominant follicles. The COS results of present study may result from pituitary suppression prior to ovarian stimulation. Actually, a study by Fanchin et al. [19] showed that luteal FSH suppression by either estradiol or GnRH antagonists administration improves the homogeneity of early antral follicles during the early follicular phase, thereby improving ovarian response to short GnRH agonist and antagonist protocols.

In terms of clinical pregnancy rate in our study, GnRH antagonist MDP with OCP pretreatment seemed to work better than GnRH antagonist MDP without OCP pretreatment, but the difference was not statistically significant. GnRH antagonist MDP with OCP pretreatment yielded comparable IVF results and pregnancy outcome to GnRH agonist low-dose LP with fewer dose and days of rhFSH required.

Assessment of various COS regimens for poor responders is difficult because there is no universal definition for poor responder and lack of a large number of prospective randomized trials demonstrating the advantage of a specific single protocol [20]. However, low-dose GnRH agonist protocols, microdose GnRH agonist flare regimens and GnRH antagonist protocols are considered as beneficial regimens in poor responders [1,20]. Olivennes et al. [4] prospectively analyzed 98 patients with low-dose GnRH agonist protocol, which leuprolide acetate of 0.5 mg daily was initiated in the mid-luteal phase and then decreased to 0.25 mg daily after menses when gonadotropin stimulation was commenced. They reported improvement of COS results with reduced duration and doses of gonadotropin stimulation. Several studies have recently evaluated GnRH antagonist protocols comparing to alternative regimens designed for poor responders. Copperman suggested GnRH antagonist protocol in poor responders could reduce the cancellation rate of the cycle and increase the ongoing pregnancy rate, when compared with GnRH agonist microdose flare protocol [21]. Cheung et al. [22] also reported a fixed, multiple-dose GnRH antagonist protocol could be utilized for poor responders although they failed to demonstrate an overall improvement in ovarian responsiveness. These recent studies implicate the effectiveness of GnRH antagonist use in COS for poor responders.

The OCP pretreatment in IVF cycles is the simplest method for cycle scheduling, and it can be beneficial in improving ovarian responses by inhibition of intrinsic gonadotropins before ovarian stimulation. A recent meta-analysis demonstrated no significant differences between patients with and those without OCP pretreatment regarding the number of cumulus-oocyte complexes, fertilization rates and ongoing pregnancy rates [14]. However, we showed OCP pretreatment in GnRH antagonist cycles can offer advantages in IVF results in poor responders. Copperman also reported a higher proportion of patients obtained more than eight oocytes, a significantly higher pregnancy rate when OCP pretreatment was performed in poor responders [21]. It is thought that OCP pretreatment in GnRH antagonist cycles can result in different ovarian response to COS and IVF results in poor responders, compared with normal responders, and OCP pretreatment might be more advantageous in poor responders than in normal responders.

The present study demonstrated that GnRH antagonist MDP with OCP pretreatment is at least as effective as GnRH agonist low-dose LP in poor responders and can be advantageous to poor responders because of the shortened time required for follicular maturation and the diminished amount of rhFSH required to provide adequate ovarian stimulation. Therefore, GnRH antagonist protocol with OCP pretreatment might be a useful choice of COS for poor responders. Larger studies with standardized methods will be needed for confirmation of our conclusions.