Cancer is a major public health problem around the world. Currently, about 5% of women diagnosed with cancer are of reproductive age. These young survivors may face compromised fertility. The effects of chemotherapeutic agents on ovarian reserve and its clinical consequences are generally inferred from a variety of surrogate markers of ovarian reserve, all aiming to provide prognostic information on fertility or the likelihood of success of infertility treatment. Until recently, the mechanisms that are responsible for chemotherapy-induced ovarian damage were not fully elucidated. The understanding of these mechanisms may lead to targeted treatments to preserve fertility. In this manuscript, we will review the current knowledge on the mechanism of ovarian damage and clinical impact of chemotherapy agents on fertility.

Polycystic ovary syndrome represents 80% of anovulatory infertility cases. Treatment initially includes preconception guidelines, such as lifestyle changes (weight loss), folic acid therapy to prevent the risk of fetal neural tube defects and halting the consumption of tobacco and alcohol. The first-line pharmacological treatment for inducing ovulation consists of a clomiphene citrate treatment for timed intercourse. The second-line pharmacological treatment includes the administration of exogenous gonadotropins or laparoscopic ovarian surgery (ovarian drilling). Ovulation induction using clomiphene citrate or gonadotropins is effective with cumulative live birth rates of approximately 70%. Ovarian drilling should be performed when laparoscopy is indicated; this procedure is typically effective in approximately 50% of cases. Finally, a high-complexity reproduction treatment (in vitro fertilization or intracytoplasmic sperm injection) is the third-line treatment and is recommended when the previous interventions fail. This option is also the first choice in cases of bilateral tubal occlusion or semen alterations that impair the occurrence of natural pregnancy. Evidence for the routine use of metformin in infertility treatment of anovulatory women with polycystic ovary syndrome is not available. Aromatase inhibitors are promising and longer term studies are necessary to prove their safety.

The environmental contaminant arsenic causes cancer, developmental retardation, and other degenerative diseases and, thus, is a serious health concern worldwide. Paradoxically, arsenic also may serve as an anti-tumor therapy, although the mechanisms of its antineoplastic effects remain unclear. Arsenic exerts its toxicity in part by generating reactive oxygen species. We show that arsenic-induced oxidative stress promotes telomere attrition, chromosome end-to-end fusions, and apoptotic cell death. An antioxidant, N-acetylcysteine, effectively prevents arsenic-induced oxidative stress, telomere erosion, chromosome instability, and apoptosis, suggesting that increasing the intracellular antioxidant level may have preventive or therapeutic effects in arsenic-induced chromosome instability and genotoxicity. Embryos with shortened telomeres from late generation telomerase-deficient mice exhibit increased sensitivity to arsenic-induced oxidative damage, suggesting that telomere attrition mediates arsenic-induced apoptosis. Unexpectedly, arsenite did not cause chromosome end-to-end fusions in telomerase RNA knockout mouse embryos despite progressively damaged telomeres and disrupting embryo viability. Together, these findings may explain why arsenic can initiate oxidative stress and telomere erosion, leading to apoptosis and anti-tumor therapy on the one hand and chromosome instability and carcinogenesis on the other.