to become pregnant for 6 to 36 months. They found that after 5 months, 33% of the women in the supplementation group were pregnant and none in the placebo group. They concluded that nutritional supplementation may play an important role in fertility increasing mean midluteal phase progesterone levels and number of days with basal temperatures >37˚C.

In 2012, another prospective RCT [34] demonstrated that in women undergoing ovulation induction for anovulatory or unexplained subfertility using standard ovulation-induction regimens and who were on multiple micronutrient nutritional (MMN) supplementations as an adjuvant therapy had significantly higher ongoing pregnancy and cumulative clinical pregnancy rates compared with those who were on folic acid alone. Further, women on MMN supplementation achieved pregnancy in significantly fewer attempts compared with control group. Ruder et al. [35] corroborated that female antioxidant intake and OS may influence the timing and the maintenance of a viable pregnancy. They observed that higher intakes of antioxidants b-carotene, vitamin C and vitamin E were associated with a shorter time to conception among couples being treated for unexplained infertility, but this effect varies with BMI and age. Our report, as well of those of Westphal et al., Mier-Cabrera et al., Agrawal et al. and Ruder et al., demonstrated that women who took antioxidant supplementation had a higher chance of pregnancy.

On the other hand, there are some trials that failed to report this beneficial effect of oral antioxidant supplementation in the treatment of female infertility. In a study by Youssef et al. [36] , oral antioxidants in the form of a combination of multivitamins and minerals did not improve oocyte quality and pregnancy rates in women with unexplained infertility undergoing IVF/ICSI treatment. The lack of significant differences between the study and control groups could be explained by a lack of follicular fluid antioxidants during in vitro fertilization that may disturb the oxidant-antioxidant balance, rendering the culture media less protected against oxidation. Furthermore, ROS may develop in an IVF culture media as a consequence of oocyte metabolism, increased oocyte number per dish, long incubation time with spermatozoa used for insemination (150 × 103 - 200 × 103 per dish), visible light and metallic cations acting as exogenous sources of OS [37] . Another limitation of this study was short duration of antioxidant treatment (2 and half months) and follow-up.

In 2013, the Cochrane Collaboration reviewed antioxidant use in subfertile women [11] . This review included 28 randomized controlled trials that compared antioxidants with placebo or no treatment/standard treatment, or with another antioxidant in a total of 3548 women. Antioxidants were not found to be effective for increasing rates of live birth or clinical pregnancy. The quality of the evidence in this review for live birth, clinical pregnancy and adverse effects was rated “very low” to “low” limited because of the lack of large randomized controlled studies and the heterogeneity between them regarding indications for subfertility and types of administered antioxidants.

Concerning the occurrence of spontaneous intrauterine pregnancies in our patient regardless of bilateral tubal occlusion detected at laparoscopy, we support the opinion that this technique should not be considered the “gold” standard in the diagnosis of tubal infertility. The false appearance of proximal tube occlusion may be actually related to technical problems: insufficient anesthesia, insufficient injection of a blue dye, or quick injection of the dye causing the cornual spasm [38] . Anyway, it’s worth taking into account that a diagnostic test for tubal patency could in itself be responsible for fertility enhancement. Indeed, a Cochrane review meta-analysis found some evidence that tubal flushing can increase pregnancy rates which were significantly higher with oil-soluble media than water-soluble media [39] . Theoretical mechanisms for this finding include an effect inside the pelvic cavity near the ovary that influences the environment in which eggs grow, or an improvement of endometrial receptivity after exposure to contrast agents. Since tubal testing with either HSG or laparoscopy was performed early as part of the work-up for infertility in this patient, it seems unlikely that spontaneous pregnancy with a 26-month delay to be associated to the potential therapeutic effects of these procedures, at least at the level of the endometrium.

An important limitation of our report is that the OS has not been determined in the peripheral blood and/or the peritoneal fluid, before and after the treatment, to assess its capacity to reduce oxidative stress markers and improve the chances for natural conception. In addition, inflammatory markers were not measured either in serum or in reproductive tract since OS is known to induce a local inflammation resulting in elevated levels of cytokines and other factors that promote endometriosis.

4. Conclusions

Current evidence supports the use of oral supplementation with antioxidants to overcome OS and boost the exhausted antioxidant defense of the female reproductive microenvironment. This approach seems especially plausible in light of the fact that oral antioxidant treatment in males has been proven to be effective to treat male infertility and is widely employed in current clinical practice.

In this case of woman with endometriosis, the establishment of a successful pregnancy is consistent with the hypothesis that a 5-month antioxidant intake is positively associated with changes in endometrial receptivity. Accordingly, such therapy could be suggested as an alternative or complement to conventional fertility therapies with the aim to enhance both natural and assisted conception.

Nevertheless, future work should include prospective randomized, controlled studies within a larger population to confirm these preliminary data in order to ascertain the potential efficacy and safety of that medication in the improvement of female fertility.

Acknowledgements

This work was carried out with the help of DCMG laboratories.

Conflict of Interests

The authors has declared that no conflict of interest exists

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