The range for plasma CoQ10 concentration in humans is 0.5 – 2 µmol/L. Palan et al. detected serum CoQ10 levels in 50 healthy premenopausal women (38.2 ± 7.9 years) and 33 healthy postmenopausal women (61.6 ± 10.6 years). The serum levels of CoQ10 in the postmenopausal women (0.74 ± 0.4 µmol/L) were signiﬁcantly higher than those in the premenopausal women (0.59 ± 0.4 µmol/L); however, the difference was not statistically significant after normalization to cholesterol. The serum levels of CoQ10 during the follicular phase in 10 healthy premenopausal women (28 – 44 years) were 0.50 ± 0.3 µg/dl in another study by Palan. Chai et al. detected serum CoQ10 levels in 183 premenopausal women (34 – 47 years) (mean = 544 ng/ml, 95% CI: 511 – 578 ng/ml). Serum CoQ10 levels in the POI group were 527.56 ± 112.82 µg/L, and serum CoQ10 levels in the control group were 503.93 ± 145.64 µg/L in our study; therefore, our results are in accordance with the range of serum CoQ10 levels found in the above studies. CoQ10 and cholesterol share parts of a common synthetic pathway, and cholesterol is the main carrier of CoQ10 in serum. Serum cholesterol is the strongest determinant of CoQ10. Therefore, we should take into account the influence of cholesterol when we study CoQ10.
In this study, the adjusted serum CoQ10 levels were found to be significantly lower in POI patients. To the best of our knowledge, this is the first study to evaluate the relationship between CoQ10 and POI in humans. Previous studies on CoQ10 were mainly focused on reproduction and follicular development. Turi et al. demonstrated that CoQ10 exists in the human follicular fluid through using high-performance liquid chromatography on samples from 20 infertile women undergoing IVF-ET. The adjusted CoQ10 levels in the follicular fluids were higher in mature oocytes and high-grade embryos than in immature oocytes and low-grade embryos, respectively. Palan et al. found that serum CoQ10 levels in the follicular phase were significantly lower than those in the luteal phase in healthy premenopausal women. Therefore, CoQ10 may benefit follicular development. Gat et al. reported that the combination of dehydroepiandrosterone (DHEA) and CoQ10 significantly increased antral follicular count (AFC) and improved ovarian responsiveness in patients with decreased ovarian reserve receiving assisted reproductive technology (ART). Bentov et al. reported that women undergoing IVF who received CoQ10 supplementation showed reduced aneuploidy and increased pregnancy rates compared with women in a control group. However, whether CoQ10 is an effective supplemental adjuvant therapy in ART still needs more prospective studies.
In an animal study, Ben-Meir et al. used conditional disruption of Pdss2 to interrupt CoQ10 synthesis in the oocytes of mice. Here, the mice exhibited a decreased number of ovulated oocytes and reduced ovarian reserve compared to control mice shortly after the onset of puberty. In contrast, CoQ10 supplementation was shown to preserve ovarian reserve and improve mitochondrial function in oocytes and ovulation rates. The deficiency of CoQ10 synthesis may induce ovarian insufficiency, which can be improved by CoQ10 supplementation. In a study by Ozcan et al., CoQ10 supplementation was reported to protect the ovarian reserve from OS-induced ovarian damage.
POI is the loss of ovarian function in women younger than 40 years old. Women with POI not only experience the distress of infertility but also undergo complications due to a long-term deficiency of estrogen, such as cardiovascular diseases, osteoporosis, sexual dysfunction and so on. Therefore, exploration of the etiology, mechanism and effective therapies of POI is of great importance. The etiology of POI is diverse, and most of the cases are idiopathic. The major mechanisms of ovarian dysfunction include follicle cell apoptosis, ovarian atrophy, cortical fibrosis, OS and blood-vessel damage[29, 30]. To date, several studies have demonstrated that OS plays an important role in the development of POI[31, 32]. Levels of OS markers in patients with POI had been proven to be significantly higher than those in the control group in previous studies[11, 33]. OS occurs when the accumulation of ROS exceeds the antioxidant defense system. OS can induce mitochondrial DNA mutations and result in mitochondrial dysfunction. Human oocytes contain the largest number of mitochondria. Mitochondrial DNA (mtDNA) copy number in the oocytes of women with ovarian insufficiency is lower than in those of women with normal ovarian cells. Mitochondria, as the energy-transducing organelle of eukaryotic cells, produce adenosine triphosphate (ATP) through oxidative phosphorylation, providing energy for cell activity. Mitochondrial energy production is important in oogenesis and follicle maturation. Mitochondrial dysfunction leads to a higher accumulation of ROS in ovarian tissues, which induces accelerated granulosa cell apoptosis and follicular atresia, finally diminishing ovarian reserve.
CoQ10, as a lipid-soluble antioxidant, is synthesized in the inner mitochondrial membrane and transported from complex I and II to complex III in the respiratory chain. CoQ10 can protect cells from free radicals and play an essential role in adenosine triphosphate (ATP) synthesis. CoQ10 deficiency can increase ROS production, result in OS and reduce respiratory chain activity. CoQ10 deficiency can also reduce ATP synthesis and influence ovarian cell growth. CoQ10 is the only endogenously synthesized lipid-soluble antioxidant, and serum CoQ10 levels may correlate with human antioxidant defense. These results suggest that CoQ10 may be a new biomarker of POI.
In this study, we also found that women with a lower annual household income and education had a higher risk of developing POI. This higher risk may be due to differences in dietary structure and attitudes toward health. Additionally, women with POI had significantly higher total cholesterol levels, which means that they have an increased risk of developing atherosclerosis and coronary heart disease. There were still some limitations of our study. First, although the results of this study are encouraging, our relatively small sample size may have resulted in a shortage of statistical power. Second, CoQ10 exists in its reduced form (ubiquinol) and oxidized form (ubiquinone). Ubiquinol is the primary form of CoQ10 and is responsible for the antioxidant role of CoQ10 in vivo. In this study, we did not distinguish between the two forms of CoQ10. Third, the dietary intake of CoQ10 was not collected. Another limitation of our study was the uncertainty of whether the serum CoQ10 levels detected were a true reflection of the ovarian mitochondrial CoQ10 levels. In future studies, we may directly detect the levels of CoQ10 in ovarian tissues to evaluate the correlation between CoQ10 and ovarian function.
In conclusion, our study revealed a negative correlation between the CoQ10/total cholesterol ratio and risk of POI, which suggests that women with POI may have an increased oxidative burden and is of great value in its clinical application. Therefore, our findings suggest that supplementation with CoQ10 may protect or treat POI by eliminating oxidative stress. Further investigation involving a randomized control trial is needed to verify this hypothesis.