Association of Micronutrient Intakes with Female Infertility: Review of Recent Evidence

In the human body, reactive oxygen species (ROS) are formed under physiologic and pathologic condition ( 5, 19). They can be produced from endogenous sources, for instance during aerobic metabolism and due to different metabolic pathways, or as part of defense mechanism of the body ( 5). In addition, ROS can be formed exogenously as a result of numerous environmental pollutants and by cigarette and alcohol use ( 5). Data have been implicated that regulated levels of ROS in ovaries, endometrium, fallopian tube, embryos, and peritoneal fluid play a role in tissue remodeling, hormone signaling, ovarian steroidogenesis, folliculogenesis, maturation of oocyte, tubal function, and cyclical and endometrial changes ( 5, 20). However, pathologic levels of ROS have resulted in considerable damage to cell structure (11). Moreover, some evidence reported that ROS are involved in developing female infertility ( 19- 21). Substantial increase in OS levels has been linked with damage to the DNA of the oocytes and spermatozoa, resulting in defective fertilization ( 20). Even if fertilization is achieved, ROS induce apoptosis leading to implantation failure, abortion, and embryo fragmentation ( 21). Under normal condition, antioxidants are capable to inhibit ROS production, scavenge presenting free radicals, and trigger the repair of cell structure damage, which are induced by ROS ( 21). There are two nonenzymatic and enzymatic antioxidants ( 5). The first group includes vitamin C, vitamin E, selenium, zinc, beta-carotene, carotene, taurine, hypotaurine, systeamine, and glutathione ( 5). The second group consists of super oxide dismutase (SOD), catalase, glutathione peroxidase, glutaredoxin, and glutathione reductase ( 5). Total antioxidant capacity (TAC) is often considered as the degree of antioxidant defense ( 11). A study by Paszkowski et al. showed that selenium and glutathione peroxidase levels of peritoneal fluid in cases with idiopathic infertility were considerably lower than were in those with tubal infertility and control group ( 10). Another case-control study on 53 women with idiopathic infertility, tubal infertility, and mild endometriosis and 13 healthy controls revealed that those with unexplained infertility had a significantly lower total antioxidant status (049 ± 0.21 mmol/L) compared with both fertile women (0.67 ± 0.24 mmol/L; P = 0.02) and women with tubal infertility (0.76 ± 0.26 mmol/L; P = 0.001) ( 11). The antioxidant status of peritoneal fluid did not differ significantly between women with endometriosis (0.61 ± 0.2 mmol/L), those with tubal infertility, and control group (P > 0.05). A study on 50 women with unexplained infertility and 50 control women suggested that serum MDA and Hcys levels in the cases (2.29 ± 0.45 nmol/L and 13.24 ± 5.27 µmol/L, respectively) were significantly higher than those in control group were (1.76 ± 0.20 nmol/L and 6.65 ± 0.89 µmol/L, respectively; P < 0.001) ( 12). In a study on 12 idiopathic infertile women who had low red blood cells’ magnesium (RBC-Mg) levels, a daily intake of 600 mg vitamin C and 200 µg selenium as selenomethionine in a period of two months resulted in normalizing RBC-Mg levels. All 12 infertile women became pregnant within eight months of normalizing their RBC-Mg levels and have produced healthy babies ( 6). A randomized trial investigated 404 and 400 women with unexplained infertility as study and control groups, respectively. The study group was treated with clomiphene citrate (50-mg tablets) twice daily and with N-acetylcysteine (1200 mg, daily) for five days, starting on second day of the cycle, and the control group was treated with clomiphene citrate and sugar powder as placebo. No significant differences were observed between two groups in the number and size of follicles, mean estrogen levels, serum progesterone, and endometrial thickness (P > 0.05). In addition, the authors reported that pregnancy rates were comparable in both group (27% vs. 22.2%) (8). In another randomized trial, 34 women with endometriosis, receiving daily 343 mg of vitamin C and 84 mg of vitamin E or placebo, were studied in a period of six month ( 7). Plasma and peritoneal fluid of MDA and lipid hydroperoxide (LOOH) were assessed in all women before and after the intervention. After four month, the study group had lower levels of MDA and LOOH (16.89 ± 4.54 µmol/L and 8.45 ± 1.39 µmol/L, respectively.) compared to the control group (25.8 ± 7.22 µmol/L and 10.77 ± 1.82 µmol/L, respectively). The authors reported that there was a statistically significant difference in plasma concentration of LOOHs and MDA between study groups at four and six month (P < 0.05). However, when pregnancy rates taken into account, no significant differences were observed between two groups (19% vs. 12%). Another randomized trial was conducted on 53 women as the vitamin group and 50 women as placebo group, all with unexplained infertility ( 9). The vitamin group underwent ovulation induction with clomiphene citrate with a daily intake of 400 IU vitamin E, whereas the control group underwent controlled ovarian stimulation without vitamin E. Vitamin E administration had started from the third to fifth days of the menstrual cycle until the injection day of human chorionic gonadotropin (hCG) of the controlled ovarian stimulation. Receiving vitamin E was significantly correlated with endometrial thickness on the day of hCG administration (9.6 ± 2.1 and 8.2 ± 2 in vitamin E and placebo groups, respectively; P = 0.001), while, it had no association with the implantation and the ongoing pregnancy rates (P < 0.05). Moreover, researchers have shown that thin endometrium is associated with unexplained infertility ( 9). Hence, consuming vitamin E may enhance the endometrial response in this condition through antioxidants and anticoagulant effects. To conclude, the findings of different studies revealed that low antioxidant status might be involved in fertility disorders. Moreover, some antioxidant supplementation may improve this condition. Nevertheless, more randomized controlled trial is needed to investigate the efficacy of supplementation with antioxidants in female fertility disorders.