Female infertility following chemotherapy is one of the most pressing health issues facing cancer survivors. Ovarian follicles are exquisitely sensitive to genotoxic chemotherapy drugs, and currently the only strategy for preserving the fertility of female cancer patients is cryopreservation of either harvest oocytes following superovulation, or in the case of pre-pubertal girls, surgical biopsy of the ovary. These options require a delay in initiating chemotherapy, which may be unacceptable, and in the case of ovarian biopsies, later implantation risks the re-introduction of cancer. A pharmacological therapy that preserved female fertility would be highly advantageous to the survival of these patients.
Here, we have discovered that a major cause of follicle death during chemotherapy treatment is the precipitous decline in cellular levels of nicotinamide adenine dinucleotide (NAD+), a key metabolite that is required for reactions carried out by around 40% of all enzymes in the cell, including those involved in DNA repair, respiration, and mitochondrial function. Elevating NAD+ levels through administration of the NAD+ precursor nicotinamide mononucleotide (NMN) completely protects against infertility caused by the widely used chemotherapy drugs doxorubicin and cisplatin, as measured by protection against a loss in ovarian follicles, oocyte yield, and decreased litter size, as assessed by breeding trials. Genetic over-expression of the NAD+ biosynthetic enzymes NMNAT1 and NMNAT3 in transgenic mouse strains also protects against a loss of primordial follicles and oocyte yield caused by doxorubicin.
Importantly, we also assessed the ability of NMN to restore female fertility following cisplatin treatment. When delivered two weeks following cisplatin treatment, NMN resulted in a restoration of oocyte yield, and normal fertility, as assessed by the number of pups born per female in mating trials. These data, showing the restoration of fertility after chemotherapy treatment, challenge the current dogma that mammalian females are born with a defined and irreplaceable follicular pool, and add further evidence towards the existence of oogonial stem cells, whose identity and function remains highly controversial. We propose that this putative oogonial stem cell pool is dependent upon NAD+ for its mobilisation into primordial follicles, and that compounds such as NMN which elevate ovarian NAD+ levels could be used as a fertility preserving, or even fertility restoring, drug candidate for cancer patients undergoing genotoxic chemotherapy treatment.