Abstract

Background and Aims: Chemotherapy induced ovarian failure and infertility is an important concern in female cancer patients of reproductive age or younger, and non-invasive, pharmacological approaches to prevent chemotherapy induced infertility are urgently needed. Here we investigate whether pharmacological elevation of nicotinamide adenine dinucleotide (NAD+) ameliorates chemotherapy induced female infertility in mice. Method: 8-week-old C57BL6 female mice were treated +/- chemotherapy (doxorubicin, Dox; 10 mg/kg) and +/- nicotinamide mononucleotide (NMN; 200 mg/kg i.p. once and 2 g/L in drinking water on-going), an orally bioavailable metabolic precursor to NAD+. Effects on fertility were measured by impact on ovarian reserve and folliculogenesis, ovulation rates and breeding performance. Effects on the ovarian NAD+ metabolome were assessed by mass spectrometry. A potential adverse effect of NMN on the efficiency of chemotherapy was assessed using a xenograft model of mammary cancer. Results: NMN treatment did not prevent a decline in the ovarian reserve caused by chemotherapy but did maintain the health of the remaining primordial follicle and total follicle populations, leading to a restoration in oocyte yield in chemo-treated mice (Dox vs Dox+NMN; P<0.007), culminating in an increase in pups born/mating in chemo+NMN treated mice (P<0.05). Chemo caused ovarian NMN, NADP+ and NADPH depletion, and NADPH was restored by NMN, which likely contributes to Dox detoxification. Importantly, treatment of the breast cancer mouse model with NMN reduced tumour growth and did not impair the efficacy of chemotherapy drugs in vivo or in diverse cancer cell lines. Conclusion: Overall, these findings raise the possibility that NAD+ precursors could be a non-invasive strategy for maintaining ovarian function and fertility in cancer patients, with potential benefits in cancer therapy.