E-Poster 63rd Endocrine Society of Australia Annual Scientific Meeting 2020

NMN supplementation rescues fertility and bone strength in chemotherapy-treated mice (#53)

Maria B Marinova 1 2 , Wing-Hong Jonathan Ho 1 3 , Michael J Bertoldo 1 2 , Vedran Lovric 4 , Kaisa Selesniemi 5 , William R Walsh 4 , David A Sinclair 5 , Kirsty Walters 2 , Robert B Gilchrist 2 , Lindsay E Wu 1
  1. School of Medical Sciences, UNSW Sydney, Sydney, NSW
  2. School of Women's and Children's Health, UNSW Sydney, Sydney, NSW
  3. Garvan Institute of Medical Research, Sydney
  4. Prince of Wales Clinical School, UNSW Sydney, Sydney, NSW
  5. Department of Genetics, Harvard Medical School, Boston, MA

Cancer survivors who have undergone chemotherapy often face infertility. Chemotherapy drugs such as cisplatin trigger a cascade of events ultimately causing exhaustion of the follicular reserve and endocrine disruption. Apart from infertility, this can have severe consequences on women’s health such as early-onset menopause and a decline in bone health.

For girls with cancer, ovarian tissue cryopreservation is the only available option for fertility preservation, which while providing options for future parenting, does not protect from endocrine failure and osteoporosis.

We hypothesise that the NAD+ booster nicotinamide mononucleotide (NMN) protects the ovarian reserve from the chemotherapy. The aim of this study is to assess NMN’s effects on fertility and late-life bone health.

Female mice at 7-days of age were treated with cisplatin (2mg/kg) and then 2 weeks later NMN (2g/L) delivered in drinking water. NMN treatment was sustained until animals were sacrificed at 24 months of age. Animals were bred at 6 weeks of age. NMN increased litter size, total pups per mouse 5-fold (p=0.015), and the cumulative rate of pregnancy compared to non-NMN, chemo-treated animals. Aside from improving fertility, we sought to determine the impacts of these interventions on bone strength, related to loss of ovarian function. Bones were subject to mechanical and structural analysis to determine changes in bone function, which is related to the increased risk of osteoporosis observed following ovarian failure and menopause. NMN treatment rescued cisplatin-induced reductions in cortical bone thickness (femur diaphysis -p<0.0001, femur metaphysis - p=0.0081, and tibia - p=0.0072), volume (femur - p=0.0015, and tibia – p=0.0102), and density (femur - p=0.0463) to control levels, as well as the increased physical strength of tibia (p=0.0024). These results infer that long-term NMN treatment protects against chemotherapy-induced bone fragility by preventing premature ovarian failure and maintaining estrogen levels sufficient to support healthy bone maintenance.