cyclophosphamide
; everolimus
; mammalian target of rapamycin complex 1
; mammalian target of rapamycin complex 2
; mammalian target of rapamycin inhibitor
; Muellerian inhibiting factor
; sapanisertib
; antineoplastic agent
; biological marker
; mammalian target of rapamycin complex 1
; mammalian target of rapamycin complex 2
; Muellerian inhibiting factor
; protein kinase inhibitor
; animal experiment
; animal model
; Article
; cancer chemotherapy
; controlled study
; enzyme inhibition
; female
; female fertility
; genotoxicity
; hormone blood level
; in vivo study
; mouse
; nonhuman
; ovarian reserve
; ovary follicle
; ovary function
; priority journal
; progeny
; reproductive toxicity
; animal
; antagonists and inhibitors
; blood
; disease model
; dose response
; drug effects
; fertility preservation
; immunohistochemistry
; metabolism
; ovary
; physiology
; Animals
; Anti-Mullerian Hormone
; Antineoplastic Agents
; Biomarkers
; Disease Models, Animal
; Dose-Response Relationship, Drug
; Female
; Fertility Preservation
; Immunohistochemistry
; Mechanistic Target of Rapamycin Complex 1
; Mechanistic Target of Rapamycin Complex 2
; Mice
; Ovarian Follicle
; Ovary
; Protein Kinase Inhibitors
英文摘要:
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.
Goldman, K.N., Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY 10016, United States; Chenette, D., Department of Microbiology, New York University School of Medicine, New York, NY 10016, United States; Arju, R., Department of Microbiology, New York University School of Medicine, New York, NY 10016, United States; Duncan, F.E., Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States; Keefe, D.L., Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY 10016, United States; Grifo, J.A., Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY 10016, United States; Schneider, R.J., Department of Microbiology, New York University School of Medicine, New York, NY 10016, United States, Perlmutter Cancer Center, New York University School of Medicine, New York, NY 10016, United States
Recommended Citation:
Goldman K.N.,Chenette D.,Arju R.,et al. MTORC1/2 inhibition preserves ovarian function and fertility during genotoxic chemotherapy[J]. Proceedings of the National Academy of Sciences of the United States of America,2017-01-01,114(12)