Discussion
a reduced number, OHSS, r-FSH, PCOS, preeclampsia
ANDERSEN, INTRAUTERINE GROWTH RESTRICTION, GESTATIONAL HYPERTENSION, MISCARRIAGE, PREECLAMPSIA
The present RCT was done to reach the optimal OS protocol for IVF in patients with PCOS, and based on the findings of the present study, the minimal-OS with u-HMG is one of optimal methods of control OS in this patients.The effectiveness of OS in the ART cycles has been investigated in several studies by considering the pivotal role of OS protocol (GnRH-antagonist vs. agonist), medication protocol (mild-OS vs. minimal-OS), and the type of gonadotropin administered (r-FSH vs. HMG) [One of the objectives of minimal-OS is to achieve an adjusted serum level of estradiol. Recently, studies shown high estradiol level, more than 3000 pg/ml in day of triggering final OOCYTE maturation of fresh ET cycles, could be predisposed to preeclampsia, intrauterine growth restriction, gestational hypertension, and small for gestational age infants [In this study, the highest serum levels of estradiol in the day of triggering final OOCYTE maturation pertained to one of the two minimal-OS protocols. On the other hand, the lowest serum levels of estradiol were seen in the Mild-HMG and Minimal-HMG groups. Therefore, the administered gonadotropin type is an effective factor in the adjusting the serum estradiol level on the day of triggering final OOCYTE maturation, regardless of the COS protocol (mild-OS vs. Minimal-OS). In other words, both OS protocols with HMG could adjust the serum estradiol level on the day of triggering final OOCYTE maturation. Karimzadeh et al. also achieved a lower level of serum estradiol in minimal-OS cycles; however, the minimal-OS protocol was compared to the common protocol of OS with GnRH-agonist in the patients with a good fertility prognosis. Moreover, the administered gonadotropin was a combination of r-FSH and u-HMG [The present study showed that Minimal-FSH resulted the highest serum progesterone level on the day of triggering final OOCYTE maturation; whereas, the other three protocols were not significantly different in this regard. Given the effects of serum progesterone level on the fertility outcome on the day of triggering final OOCYTE maturation, Minimal-FSH is not an appropriate protocol. Andersen et al. showed that the progesterone level in OS GnRH-agonist cycles with r-FSH is higher than with the u-HMG [This study showed that Mild-HMG requires the highest gonadotropin dose; whereas, Minimal-FSH requires a lower gonadotropin dose. It is interesting that despite the least dose of gonadotropin in the Minimal-FSH protocol in comparison with the other three protocols, it has the highest serum estradiol level. Therefore, gonadotropin dose < 150 IU may be more prudent. It is worth noting that the OS protocol does not affect the number of prescribed antagonists, that no difference was observed between the four study groups in this regard. The lower gonadotropin dose in mild-OS or minimal-OS has been reported as the advantage of these two protocols [In a meta-analysis CC combined with gonadotropins and GnRH-antagonist versus conventional OS without CC, CC combined with GnRH-antagonist is likely to reduce the gonadotropin dosage [This study illustrated that Mild-FSH group possessed the shortest OS duration. Regardless of the type of prescribed gonadotropin, minimal-OS protocols were associated with a lower prescribed dose of gonadotropin without increasing the OS duration, which is an advantage in using these protocols. The meta-analysis of OS protocols, with and without CC, demonstrated a reduction in the OS duration in the presence of CC [This study showed no significant difference in the endometrial thickness on the day of triggering final OOCYTE maturation among groups. Finding presents rejects the negative effects of CC on the endometrial thickness in the minimal-OS cycles. Karimzadeh et al. did not observe any difference in endometrial thickness between minimal-OS with CC and common OS with GnRH-agonist [The present study showed that the Minimal-FSH is associated with the highest number of obtaining OOCYTE, OOCYTEs at the MII stage, number of 2PN, number of obtained embryos, and number of frozen embryos. The Mild-FSH was second to Minimal-FSH in these factors. It can be concluded that the type of prescribed gonadotropin (r-FSH) is the main factor in the obtaining a higher amount of OOCYTE and embryos in an OS cycle in the PCOS patients. It is worth noting that although the Mild-HMG and Minimal-HMG protocols were associated with a lower number of OOCYTE and embryo in comparison with the two other protocols, the number of obtaining OOCYTEs and embryos was in the acceptable range. Considering the dose of prescribed gonadotropin, the patients in Minimal-HMG protocol received less gonadotropin. Although, the Mild-HMG and Minimal-HMG were associated with a lower number of frozen embryos in comparison with the two other protocols, the patients can freeze their embryos. The difference in the obtaining embryos in our groups also applies to the embryos quality and has been associated with a significant difference in the number of high-quality embryos. In addition, Mild-HMG has been associated with the least number of high-quality embryos. However, this difference in good and poor quality is less tangible. Rinaldi et al. showed no significant difference between the mild-OS protocol with GnRH-antagonist and OS with GnRH-agonist in the number of embryos and their quality among patients with a history of OHSS [Despite of qualitative and quantitative differences among our groups in terms of administering gonadotropin dose, OS duration, and the number of OOCYTE and embryos, there is no significant difference in the rates of fertilization, implantation, and miscarriage. Finding presents is confirmed by meta-analyses that compared mild and minimal protocols with common protocols of OS with GnRH-agonist or antagonist. Also these meta-analyses on the role of administering gonadotropin confirmed our findings [It is worth noting that the cancellation of the OS cycle due to inadequate ovarian response was observed only in the OS protocol with u-HMG. Although, this difference is not statistically significant, this finding present the form of prescribed gonadotropin as an effective factor in the cancellation of the OS cycle, regardless of the type of protocol. Recent meta-analysis showed that although the mild-os protocol reduced the gonadotropin administration dose and OHSS incidence, it is associated with a reduced number of obtained OOCYTE and also a considerable increase in the cancellation of OS cycles due to POR [The present study showed that Minimal-FSH exposes more than 90% of the patients at the risk of OHSS, so they subjected to GnRH-agonist triggering with triptorelin 0.2 mg s.c and freeze all embryos. Given that the risk of OHSS is a serious concern in the patients with PCOS, the Minimal-FSH protocol is not recommended for OS in these patients. The risk of OHSS is higher among the patients in Mild-FSH group and Minimal-FSH group. Therefore, the incidence of OHSS is affected by the prescribed gonadotropin type, regardless of the administered protocol. However, previous meta-analyses reported that the administration of CC in the OS cycles with GnRH-antagonist reduced the incidence rate of OHSS [The present study showed that the Minimal-HMG protocol, followed by the Mild-HMG protocol, present a greater chance of having fresh ET; however, the Mild-FSH is the preferred protocol based on the clinical pregnancy rate. In addition, Minimal-HMG is comparable to it. It is worth noting that the available meta-analyses do not show a significant difference between protocols or the type of gonadotropin in the pregnancy rate, which can be attributed to the difference in their target population with the present study [The present study showed that the PCOS phenotypes have not a significant role in the IVF cycle outcome of patients with PCOS, regardless of the OS protocol.As was mentioned earlier, the lack of a similar study on the PCOS patients, as the target population, was a research limitation to the comparison of the present study with other similar studies to determine the best OS protocol. The major research limitation was because of economic constrain that inhibited blinding. Given that there are scant RCTs on IVF in patients with PCOS, further studies are recommended.