Acquiring oocyte competence requires optimal mitochondrial function and adequate ATP levels. In this context, CoQ10 supplementation may improve human oocyte quality and subsequent reproductive performance given its role in ATP synthesis and mitochondrial protection from ROS oxidative damage. In infertility treatments, CoQ10 therapy can be orally supplied to promote a more favorable environment for oocyte development in vivo or by its addition to culture media in an attempt to improve its quality in vitro.
CoQ10 has been shown as a safe and well tolerated antioxidant treatment in humans . Some adverse effects, such as nausea, diarrhea and abdominal pain, have been described after CoQ10 intake in the treatment of other diseases . However, they are mild and occasionally-occurring side effects .
It is also a versatile therapy because it can be administered following a wide variety of protocols and at different ART treatment time points. Oral CoQ10 may benefit women with poor ovarian reserve, poor response to ovarian stimulation, advanced age or PCOS. What they all have in common are fewer and, usually less competent, mature oocytes . However, promising results have been found mostly in follicular terms , and an enhancement at the oocyte level has been achieved only in a population of young poor responders . This finding suggests that the lower age-related CoQ10 levels might be too low to be rescued after this antioxidant treatment. These patients may need higher doses or a different administration protocol, which have not yet been defined.
Regarding the beneficial effects of CoQ10 supplementation at the follicular level, higher levels of this molecule may create a more favorable environment for developing competent follicles. It has been proven that oxidative stress leads to higher apoptotic processes in granulosa cells . CoQ10, by means of counteracting oxidative stress, can reduce this programmed granulosa cell death and, thus, reduce follicular atresia. This is evidenced by the higher antral follicle counts and larger number of mature follicles recorded in some reviewed studies . However, this improvement did not suffice to significantly enhance oocyte quality, which has been directly evaluated in only a few studies , but is indirectly evidenced by similar pregnancy outcomes in others . It is important to bear in mind that, although CoQ10 can have an impact at the follicular level, the ultimate objective of every ART treatment is to achieve successful pregnancy, which means that clear upgrades in pregnancy rates are needed to introduce this treatment into our routine clinical practice. A recent systematic review and meta-analysis of five randomized controlled trials (RCTs) concluded that CoQ10 oral supplementation increased clinical pregnancy rates (CPR) compared to a placebo or no treatment [28.8% vs. 14.1%; odds ratio (OR) 2.44, 95% confidence interval (CI) 1.30–4.59, p = 0.006] . However, these results lose relevance given the high heterogeneity in the analyzed RCTs.
Another approach is to supplement CoQ10 directly in vitro during IVF treatment. High levels of this antioxidant come into close contact with the oocyte, although its apparent positive action at the follicular level is absent. In this context, CoQ10 supplementation does not offer any advantage over the standard culture of fertilized oocytes from women of advanced age , which seems logical if we consider that these oocytes had already undergone two consecutive meiotic divisions with age-related damaged cell machinery. For this reason, CoQ10 supplementation during the IVM of immature aged oocytes, which are arrested in the prophase of the first meiosis, seems more plausible. Indeed promising results have been shown in this line , which suggest that CoQ10 might help these aged oocytes to properly resume meiosis, as evidenced by lower aneuploidy rates. CoQ10 might achieve this by improving the mitochondrial function , as evidenced by the increased mitochondrial mass in treated oocytes  and, thus, provides the energy they lacked due to the aging process, which is essential for acquiring final maturation. In any case, the improvement was not fully achieved as more age-related factors contribute to this poor oocyte quality  and CoQ10 treatment itself may not be enough to overcome them. In contrast, CoQ10 addition during IVM of oocytes from young women did not show any advantage , which suggests that these oocytes already had the sufficient energy needed to resume meiosis, and higher CoQ10 levels did not lead to any advantage. Thus other strategies to improve maturation rates in such patients should be investigated.
Nevertheless, MitoQ supplementation during IVM culture showed significant improved oocyte quality regardless of patients’ age . We hypothesize that the advantageous location of this targeted molecule and its ability to concentrate at higher rates in mitochondria may favor its mechanism of action and, thus, exert significant changes on young oocytes. MitoQ, or any other mitochondria-targeted antioxidant, supplementation deserves further research in human clinical trials.
In any case, the majority of the studies herein discussed focused on clinical outcomes, and did not evaluate the effects of CoQ10 on the oxidative stress status or at the mitochondrial level in oocytes. Ma et al. in 2018 and Al-Zubaidi et al. in 2021 were the only ones to analyze such parameters, and proved higher mitochondrial mass and mitochondrial membrane potential, respectively, after CoQ10/MitoQ addition to IVM medium . However, they did not evaluate oxidative stress markers or any other indicator of oocyte energy status as many animal studies have previously done .
Therefore, further research is needed in this field, and should focus mainly on the molecular level to understand the exact mechanism by which CoQ10 enhances mitochondrial function. By solving this research question, we would be able to establish the best protocol, dose, molecular form and approach for its administration. Presently, our recommendation is to continue investigating this antioxidant in the reproductive field, but mostly as oral treatment or during IVM. Its addition to fertilized oocytes during standard culture seems worthless as its main role in improving oocyte competence should be performed prior to completing the second meiosis, and probably even earlier. In addition, more attention should be paid to mitochondria-targeted antioxidants, which have been poorly studied in human clinical trials and seem more efficient than the isolated CoQ10 form.
CoQ10 constitutes a safe well tolerated therapy capable of improving oocyte quality through oxidative stress counteraction and mitochondrial function enhancement. In humans, oral CoQ10 supplementation seems to exert positive effects, especially at the follicular level, by creating a more favorable environment for competent follicle development. However, these benefits are not necessarily translated to substantial oocyte improvements and subsequent gestational results. Indeed, no improvement has been reported regarding finally pregnancy outcome using this therapy. CoQ10 addition to culture media appears effective if performed in immature stages. In this scenario, mitochondria-targeted molecules may confer a certain advantage and offer a better prognosis.
Hence, the available data reviewed in this work do not clearly prove the advantage of CoQ10 supplementation in improving human oocyte quality. It seems promising, thus it deserves further research, specially using these modified CoQ10 forms, as well as molecular studies evaluating the impact of this therapy on oxidative stress status and mitochondrial function in human gametes.