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Preservation of female fertility with chemotherapy by nicotinamide adenine dinucleotide (NAD+) repletion

Wing-Hong Jonathan Ho (1, 2), Dave Listijono (1, 2), Michael Bertoldo (1, 2), Angelique Riepsamen (2), Kaisa Selesniemi (3, 4), Yiqing Zhao (2, 5), Wei-Guo Nicholas Loh (2), Neil Youngson (1), Safaa Cabot (1), Ashley Wong (1), Dulama Richani (2), Catherine Li (1), Lynn-Jee Kim (1), Laurin Lau (2), Rachael Wu (6), Pawel Kordowitzki (7), Toshiyuki Araki (8), A. Stefanie Mikolaizak (9), Sonia Bustamante (10), Abhirup Das (1), Jayanthi Maniam (1), David Le Couteur (11), Nigel Turner (1), Lake-Ee Quek (12), Margaret Morris (1), Kirsty Walters (2), Robert Gilchrist (2), David Sinclair (1, 3), Hayden Homer (2, 13) and Lindsay Wu (1)

  1. School of Medical Sciences, UNSW Sydney, New South Wales, Australia

  2. School of Women’s and Children’s Health, UNSW Sydney, New South Wales, Australia

  3. Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, Boston MA, United States 

  4. Jumpstart Fertility Inc., Boston MA, United States

  5. Reproductive Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

  6. Graduate Entry Medical School, University of Limerick, Republic of Ireland

  7. Polish Academy of Science, Tuwima Street 10, 10-748 Olsztyn, Poland

  8. Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and sychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo, Japan

  9. Robert Bosch Krankenhaus, Stuttgart, Germany

  10. Mark Wainwright Analytical Centre, UNSW Sydney, Sydney, New South Wales, Australia

  11. ANZAC Medical Research Institute, The University of Sydney, Concord, New South Wales, Australia

  12. School of Mathematics and Statistics, The University of Sydney, Sydney, New South Wales, Australia

  13. Christopher Chen Oocyte Biology Laboratory, University of Queensland Centre for Clinical Research, Royal Brisbane & Women’s Hospital, Herston, Queensland, Australia

Maintaining female fertility during gonadotoxic chemotherapy treatment is a major challenge in the treatment of female cancer patients. The only interventions for maintaining fertility during cancer treatment rely upon the cryopreservation of oocytes, embryos or ovarian biopsies. What is needed are pharmacological options to maintain fertility. In this work, we have found in mouse studies that the metabolite nicotinamide adenine dinucleotide (NAD+) plays a critical role in protecting ovarian function from chemotherapy treatment. Mice were treated with a single dose of doxorubicin in the presence or absence of supplementation with the NAD+ precursor nicotinamide mononucleotide (NMN), which continued for 8 weeks before functional fertility was measured by assessing ovarian reserve, oocyte yield, and breeding trials. Co-treatment with NMN successfully prevented the loss of primordial follicles, mature follicles, and maintained breeding performance during doxorubicin treatment. A similar protection was observed when single dose of cisplatin was administrated into newborn mice, resulting in preserving the fertility performance. NMN treatment did not impair the oncological efficacy of chemotherapy, and in fact NMN alone slowed tumour growth in the MDA-MB-231 orthotopic xenograft breast cancer model more than either doxorubicin or cisplatin. The results of this study demonstrated that ovarian toxicity induced by doxorubicin and cisplatin treatment can be prevented by artificially elevating NAD+ through pharmacological or genetic means. Together, this work might represent a pharmacological alternative for maintaining fertility in female cancer patients.