title: mTORC1/2 inhibition preserves ovarian function and fertility during genotoxic chemotherapy.
abstract: The ovary contains oocytes within immature (primordial) follicles that are fixed in number at birth. Activation of follicles within this fixed pool causes an irreversible decline in reproductive capacity, known as the ovarian reserve, until menopause. Premenopausal women undergoing commonly used genotoxic (DNA-damaging) chemotherapy experience an accelerated loss of the ovarian reserve, leading to subfertility and infertility. Therefore, there is considerable interest but little effective progress in preserving ovarian function during chemotherapy. Here we show that blocking the kinase mammalian/mechanistic target of rapamycin (mTOR) with clinically available small-molecule inhibitors preserves ovarian function and fertility during chemotherapy. Using a clinically relevant mouse model of chemotherapy-induced gonadotoxicity by cyclophosphamide, and inhibition of mTOR complex 1 (mTORC1) with the clinically approved drug everolimus (RAD001) or inhibition of mTORC1/2 with the experimental drug INK128, we show that mTOR inhibition preserves the ovarian reserve, primordial follicle counts, serum anti-Mullerian hormone levels (a rigorous measure of the ovarian reserve), and fertility. Chemotherapy-treated animals had significantly fewer offspring compared with all other treatment groups, whereas cotreatment with mTOR inhibitors preserved normal fertility. Inhibition of mTORC1 or mTORC1/2 within ovaries was achieved during chemotherapy cotreatment, concomitant with preservation of primordial follicle counts. Importantly, our findings indicate that as little as a two- to fourfold reduction in mTOR activity preserves ovarian function and normal birth numbers. As everolimus is approved for tamoxifen-resistant or relapsing estrogen receptor-positive breast cancer, these findings represent a potentially effective and readily accessible pharmacologic approach to fertility preservation during conventional chemotherapy.
authors.affiliation: Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY 10016.
authors.forename: Kara N
authors.initials: KN
authors.lastname: Goldman
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY 10016.
authors.forename: Devon
authors.initials: D
authors.lastname: Chenette
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY 10016.
authors.forename: Rezina
authors.initials: R
authors.lastname: Arju
authors.affiliation: Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
authors.forename: Francesca E
authors.initials: FE
authors.lastname: Duncan
authors.affiliation: Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY 10016.
authors.forename: David L
authors.initials: DL
authors.lastname: Keefe
authors.affiliation: Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY 10016.
authors.forename: Jamie A
authors.initials: JA
authors.lastname: Grifo
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY 10016; robert.schneider@nyumc.org.|Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016.
authors.forename: Robert J
authors.identifier: 0000-0001-5807-5564
authors.initials: RJ
authors.lastname: Schneider
mesh_terms: D000818:Animals; D054304:Anti-Mullerian Hormone / Q000097:blood; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology; D015415:Biomarkers; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D059247:Fertility Preservation; D007150:Immunohistochemistry; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000076225:Mechanistic Target of Rapamycin Complex 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D006080:Ovarian Follicle / Q000187:drug effects / Q000378:metabolism; D010053:Ovary / Q000187:drug effects* / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D047428:Protein Kinase Inhibitors; D054304:Anti-Mullerian Hormone; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2
keywords: chemotherapy; fertility; mTOR; ovarian function; ovary