Polycystic ovary syndrome (PCOS) and endometriosis are the leading ovarian causes of infertility in young women. Both PCOS and endometriosis are associated with oxidative stress [12].

Oxidative stress in PCOC patients is related to an increased serum prolidase activity, which also appears to be associated with increased cardiovascular risk and menstrual irregularities [13]. PCOS patients also show increased oxidative stress markers in follicular fluid and decreased oocyte and embryo quality [14], as well as a high level of chronic inflammation markers [15]. Little data are available as to the utility of externally administered antioxidants to reduce oxidative stress and improve fertility in PCOC patients (Table 1) [16]. The administration of an antioxidant cocktail containing vitamin A, vitamin B1, vitamin B6, vitamin B12, vitamin C, vitamin D3, vitamin E, nicotinamide, and folic acid significantly improved pregnancy rates in PCOS patients [17]. Two randomized controlled trials (RCTs) were performed with in vivo antioxidant treatment of PCOS patients, and they showed an improvement of oocyte and embryo quality after treatment with resveratrol [17], and an increase in implantation, pregnancy, and cumulative pregnancy rates after treatment with vitamins D and E [18], respectively (Table 1). Moreover, encouraging results were obtained in an animal model (rat) by using mitochondria-targeted antioxidant therapy [19]. Interestingly, administration of growth hormone (GH) during ovarian stimulation of young PCOS patients led to a significantly improved pregnancy, clinical pregnancy and spare embryo cryopreservation rate while reducing the total number of oocytes recovered and thus the patients’ discomfort (Table 1) [20]. However, factors other than antioxidant actions could also have contributed to these GH effects.

As to endometriosis, RCTs showed that in vivo treatment of patients with vitamins C and E reduced pelvic pain and decreased the concentration of peritoneal fluid inflammatory markers as compared with untreated patients (Table 1). The study failed to detect any positive effect of in vivo treatment of patients with endometriosis with vitamin C on in vitro fertilization (IVF) outcomes [21], while resveratrol supplementation during IVF cycles even appeared to be detrimental to pregnancy outcomes (Table 1) [22]. Further studies are needed to find out whether other combinations of antioxidant medicines could also improve IVF outcomes, in addition to reduce pain and inflammation, in patients with endometriosis.

Even though the causes of ovarian factor infertility present in young women usually persist until more advanced ages their relative importance decreases, while the main causes of infertility in older women are related to ovarian aging [7]. Diminished ovarian reserve (DOR), characterized by the decline in the quality and quantity of oocytes, is the most significant feature of ovarian aging and becomes the main reason for infertility and ART failure [7]. DOR is at the origin of primary ovarian insufficiency (POI) and can be accentuated by a variety of age-unrelated factors [7], including chromosome X structural abnormalities and X-autosome translocations [23], single-gene perturbations ( some located on the X-chromosome and others on autosomes [24,25]), mendelian disorders implicated in other pathologies [24], mutations of genes (both nuclear and mitochondrial ones) affecting mitochondrial function [26,27], and disturbances of cell signaling pathways, especially those involved in cell protection against oxidative stress [28,29]. Independently of the exact cause, DOR and POI converge to mitochondrial damage, oxidative stress, and diminished ATP production, leading to inflammation, apoptosis, and telomere shortening [30], in addition to a decrease in the production of estradiol by the granulosa cells [31], a condition known to reduce oocyte developmental potential by causing an imbalance between nongenomic effects of androgens and estrogens at the oocyte surface [32].

In view of the above considerations, the use of antioxidants appears justified to improve oocyte quantity and quality in older women. Different antioxidants were tested in animal models of ovarian aging [33], and most of them gave encouraging results (Table 2). In mice, oral administration of vitamins C and E prevented the aging-related negative effects on ovarian reserve, metaphase II oocyte chromosomal aberrations and oocyte apoptosis in mice [32], N-acetyl-L-cystein mitigated age-related reduction of litter size and increased telomerase activity and telomere length [33], coenzyme Q10 restored oocyte mitochondrial function and fertility of aged animals [34], and melatonin improved age-induced fertility decline by attenuating ovarian mitochondrial oxidative stress [35]. Based on these encouraging data, different antioxidants were introduced into the treatment protocols used for ART in older women (Table 2). However, data obtained in humans are scarce and inconsistent, mainly because of the superimposition of different effects of the agents used, the heterogeneity of the patient populations studied, and the paucity of randomized controlled trials with appropriate controls.

An RCT performed in older women showed that the treatment of women aged >40 years with growth hormone resulted in an improvement of delivery and live birth rates [36]. Numerous subsequently published studies confirmed these findings and extended the use of growth hormone to other female infertility indications [37], including some younger women with previous unexplained IVF failures [38,39,40,41]. Growth hormone was also shown to improve human oocyte in vitro maturation from the germinal vesicle to metaphase II stage [42]. On the other hand, growth hormone can also fail to improve IVF outcomes in some women, and several clues were suggested to distinguish those patients who would benefit from growth hormone treatment from those who would not [43]. Moreover, even though growth hormone is known to stimulate cell signaling pathways involved in the defense against oxidative damage [7], it is not known whether, and to what extent, this effect is responsible for the improvement of the oocyte developmental potential described in the above studies.

Melatonin was also used to improve reproductive function of aging women. In a randomized and placebo-controlled clinical study, the treatment of women 43–49 years old with melatonin for 6 months led to a significant decrement of serum FSH and LH levels, suggesting a recovery of pituitary function towards a more juvenile pattern of regulation [44]. The concentration of melatonin in the follicular fluid was shown to be positively correlated with antral follicle count, oocyte quality, and IVF outcomes [45,46]. A recent study, based on network pharmacology, demonstrated a multi-target mechanism of action of melatonin against DOR [47].

Antioxidants were also suggested to improve the corpus luteum function in animal models [48]. However, experience with the use of antioxidants to rescue the corpus luteum from premature luteolysis is still insufficient.