To our knowledge, for the first time, we designed a randomized clinical trial that evaluates the effect of myo-inositol on the outcome of the IVF cycle in patients defined as the poor ovarian responder. Our data have shown that myo-inositol therapy significantly decreases the required dose of gonadotropin in poor ovarian responders, and also it significantly increased the ovarian sensitivity index and fertilization rate in poor ovarian responders. Moreover, the number of retrieved oocytes, the number of MII oocytes, the number of embryos transferred, chemical and clinical pregnancy rate showed a positive trend in patients treated by myo-inositol without reaching a statistical significance.
Our data were in line with the result of a controlled observational study of Francesca Caprio, and collogues [14] that reported the myo-inositol therapy was associated with an enhancement in the fertilization rate, implantation rate, grade I embryos rate and pregnancy rate, but they were no statistically significance. Moreover, they have reported that the number of retrieved MII oocyte and ovarian sensitivity index to gonadotropins were significantly higher in poor ovarian responders treated by myo-inositol. As well as, Lisi and colleagues [18] evaluated the effect of myo-inositol combine with folic acid on the quality of oocyte and ovarian response in women without PCOS underwent ART. In consistent to our study, the authors have reported that although the duration of stimulation was similar in myo-inositol and control groups, the total amount of gonadotropin used for follicular maturation was significantly lower in myo-inositol group. Moreover, there was no significant difference between the two groups in the implantation and pregnancy rates. Recently it has been proposed that the ovarian reserve markers including patient’s age, serum day-three FSH, and AMH level showed a good effectiveness for the choice of FSH starting dose and for optimizing the controlled ovarian stimulation during IVF [19]. Therefore, it seems that determination of gonadotropin stating dose in addition to myo-inositol may reduce the required gonadotropin particularly in poor ovarian responder. The possible reduction of the required gonadotropin, as well as the duration of controlled ovarian stimulation may significantly reduce the costs of the IVF due lower number of gonadotropin vials and reduced number of outpatient accesses for the follow-up.
Even the other studies which evaluate the effect of inositol on fertility outcomes in other diseases such as PCOS, their findings were resembled to our finding. Since, accumulating evidence has shown that one of the most important mechanisms of PCOS pathogenesis is the insulin-resistance. For this reason, the use of insulin-sensitizers, such as inositol isoforms, gained increasing attention due to their safety profile and effectiveness. It is noteworthy that there are a specific myo-inositol depletion and D- chiro-inositol overload in the ovary of PCOS patients [20], therefore the restoring of the physiological level of these isomers in the follicular fluid could be correct the ovarian function [21]. For example, Pourghasem et al. [22] compared the effectiveness of myo-inositol and metformin in infertile women with polycystic ovary syndrome treated with letrozole. The authors reported that the addition of inositol and metformin to the treatment of infertile PCOS women with letrozole resistance improves the ovarian function; however, it is not significant. Of note, inositol was more effective than metformin in patients. As well as, Bernd Lesoine and Pedro-Antonio Regidor [15] investigate the effect of myo-inositol with folic acid on oocyte quality, the ratio between follicles and retrieved oocytes, the fertilization rate, and the embryo quality in PCOS patients undergoing ART treatments. Their findings have shown that myo-inositol therapy in women with PCOS results in better fertilization rates and a clear trend to better embryo quality as the number of retrieved oocytes was smaller in the myo-inositol group.
Previous studies have shown that the myo-inositol as an important component of follicular fluid, playing a crucial role in both nuclear and cytoplasmic oocyte development [11, 23]. Moreover, research has shown that the administration of myo-inositol can result in calcium release through the interaction of myo-inositol and its receptors in oocytes [24]. Calcium oscillation has a pivotal role in meiotic resumption and is responsible for the final oocyte development. Previous studies support this claim that myo-inositol, as a second messenger of calcium signaling, plays a critical role in oocyte development [25]. Thus, it can be concluded that myo-inositol can improve the pregnancy rate by supporting oocyte development and modulating hormonal balance.
A high level of D-chiro-inositol has been reported to affect oocyte and blastocyst quality as well as ovarian functionality [26]. A recent study indicated that a high concentration of D-chiro-inositol could inhibit aromatase, an enzyme that converts androgens into estrogens and is involved actively in the biosynthesis of estrogens. Therefore, the altered functioning of the aromatase enzyme accounts for the impairment of androgen conversion into estrogens [27]. This adverse condition may be improved via myo-inositol supplementation, which can enhance the reproductive activities in PCOS patients. Moreover, It has been shown that serum myo-inositol could act as a trophic factor for promotion of in vitro development of preimplantation embryos [28].
Moreover, an interesting and unexpected finding in our study was that six patients excluded from the study due to spontaneous pregnancy in the pretreatment period of intervention group. This finding reflects the positive effects of myo-inositol on the fertility of poor ovarian responders, and suggests that these patients also can achieve optimal results by myo-inositol without the use of expensive IVF cycle. This finding can be explained as follow at ovarian level, myo-inositol has a crucial role in FSH signaling, and therefore, this could lead to reduction in the required dose of gonadotropin [11, 23]. Another mechanism has been proposed for the effect of inositol on IVF outcome is due to inositol potential to reduce the oxidative stress caused by different agents through the induction of natural antioxidant defenses by increasing superoxide dismutaseand catalase levels and intracellular content of glutathione [12].
Several systematic reviews and meta-analyses have shown that myo-inositol outperforms placebo in terms of ovulation and pregnancy rates. In the systematic review and meta-analysis, Pundir et al. revealed that myo-inositol, in comparison with placebo, appeared to improve the ovulation rate, and metabolic and hormonal profiles significantly in women with PCOS [29]. Furthermore, the findings of a comprehensive review by Kamenov et al. and Gateva et al. showed that the use of myo-inositol was an important therapeutic approach to improve the metabolic and reproductive disorders in PCOS patients. In the last two studies mentioned above, remarkable clinical outcomes were obtained through myo-inositol pretreatment, followed by ART protocols [30, 31].
However, this randomized clinical trial study has some limitations: the sample size is too small to offer a great significanceof the result obtained.