Despite improvements in stimulation protocols in IVF program, the stimulation of poor responders still remains a challenging task for clinicians. There are numerous strategies that have been suggested to improve the outcome in women with the poor ovarian responses (Table 1).

Several trials compared multiple GnRH antagonist protocols with the flpro-up GnRH agonist protocol in poor responders. There trials reported significantly higher mean number of mature oocytes retrieved and higher implantation rate with flare-up GnRH agonist protocol when compared to antagonist protocols (33−35).

Martinez et al., Schmidt et al. and Kahraman et al. noticed no significant differences as regards with any outcome parameters (36−38). These results were confirmed by Devesa et al. in a prospective study and by Berin et al. in a retrospective one. They showed that the flare-up agonist and antagonist protocols were comparable regarding clinical pregnancy rates in poor responders (39, 40).

On the contrary, Lainas et al. concluded that the flexible multiple GnRH antagonist protocol is associated with significantly higher ongoing pregnancy rates compared with the flare-up GnRH agonist protocol in poor responders (41).

Cheung et al. compared the GnRH antagonist fixed multiple protocol with the long GnRH-agonist protocol in poor responders and reported that in the antagonist group, the number of transferred embryos was higher and there was a tendency toward higher clinical pregnancy rates but with no statistically significant differences (42). Two randomized trials comparing the effect of a GnRH flexible multiple antagonist protocol versus a GnRH-agonist long protocol in poor responders showed reduced duration of stimulation and consumption of gonadotrophins in the flexible, multi-dose antagonist group (43−45). While Marci et al. showed increased number of retrieved follicles and oocytes and fewer cancelled cycles in the antagonist group, Sun and Zhu reported lower number of retrieved oocytes in the antagonist group (43, 44). On the other hand, Tehraninejad et al. showed that the duration of stimulation, consumption of gonadotrophins, and number of retrieved follicles and oocytes were similar in both agonist and antagonist groups. However, in the above mentioned trials pregnancy rates were similar in both the agonist and antagonist groups (46).

In a meta-analysis using GnRH-antgonist for ovarian stimulation in poor responders, no differences in clinical outcomes were found, except a significantly higher number of cumulus-oocyte complexes in the GnRH-antagonist multiple dose protocol as compared to GnRH-a long protocol (47). Another meta-analysis did not prove any difference between the two regimens with respect to cycle cancellation rate, number of mature oocytes or clinical pregnancy rate (48). Based on all the above results no firm conclusion could be obtained but better results were demonstrated with the use of GnRH antagonists.

Orvieto et al. used the ultrashort GnRHa regimen combined with a flexible multidose GnRH antagonist protocol in patients with previous failed IVF attempts. The results demonstrated a statistically significant higher number of retrieved oocytes and embryos transferred with a reasonable clinical pregnancy rate (14.3%) (49).

In an attempt to lengthen the follicular phase, GnRH antagonist was given in the luteal phase of the cycle preceding the ovarian stimulation (3 mg cetrorelix) followed by stimulation with rFSH starting on cycle day 2, followed by a flexible GnRH-antgonist protocol (CRASH protocol). The results were compared to the preceding long protocol. There were more follicles, more oocytes and embryos with the prior administration of the antagonist. Moreover, the implantation and pregnancy rates were increased approaching the clinical outcome of normal responder patients (50). Nilsson et al. used GnRH antagonist (ganirelix) daily, from days 3 to 5 before the expected onset of menstruation and continued for 4−7 days. At a leading follicle diameter of 14 mm, ganirelix administration was resumed until the final oocyte maturation was induced by 10,000 IU hCG. GnRH antagonist only marginally affected the intercycle FSH rise; basal levels of FSH remained similar to those seen after 4 days of antagonist administration. The protocol effectively induced low LH levels and luteolysis, but it only led to the collection of 3 oocytes in 49 oocyte retrievals resulting in 5 pregnancies (4 delivered). Despite GnRH antagonist administration in the late luteal phase and menstrual bleeding, FSH was not sufficiently reduced to secure a more synchronic cohort of recruitable follicles (51).

There is no one pituitary downregulation protocol which is best suited for all poor responders. Traditional GnRH agonist flare and long luteal phase protocols do not appear to be advantageous. Reduction of GnRH agonist doses, “stop” protocols, and microdose GnRH agonist flare regimes all appear to improve outcomes, although the proportional benefit of one approach over another has not been convincingly established. GnRH antagonists improve outcome in poor responders, although, in general, pregnancy rates appear to be lower in comparison with microdose GnRH agonist flare regimens. Prediction of decreased response by a thorough assessment of ovarian reserve prior to cycle initiation allows selection of an appropriate COH protocol tailored for each individual patient.