ArticleProceedings of the National Academy of Sciences of the United States of America2017
mTORC1/2 inhibition preserves ovarian function and fertility during genotoxic chemotherapy.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 92 papers.
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Who cites it
92 citing papers in PubMed, 171 citations in OpenAlex.
- The role of anti-Müllerian hormone as a therapeutic agent to preserve the ovarian follicle pool during chemotherapy.Journal of assisted reproduction and genetics · 2026Review
- Rapamycin co-exposure fails to reduce cisplatin-induced damage in GC6-spg spermatogonial cell line.Reproduction & fertility · 2026Article
- Cumulus Expansion and Oocyte Quality Across the Pubertal Transition in Mice: Implications for Modeling Fertility Preservation in Adolescents.Research square · 2026Article
- From Maternal Exposure to F1 Development: Unveiling Cyclophosphamide-Induced Reproductive Toxicity.Biomedicines · 2026Article
- Article
- Retinoic Acid and Calcitriol Protect Mouse Primordial Follicles from Cyclophosphamide Treatment-Induced Apoptosis.Antioxidants (Basel, Switzerland) · 2026Article
- The role of mammalian target of rapamycin inhibitors in mitigating cyclophosphamide-induced ovarian damage in a murine model.Clinical and experimental reproductive medicine · 2025Article
- Childbearing in women diagnosed with cancer during reproductive age.Acta obstetricia et gynecologica Scandinavica · 2025Article
- The Effect of AMH on Folliculogenesis.Reproductive sciences (Thousand Oaks, Calif.) · 2025Review
- Reproductive Toxicity and Transgenerational Effects of Anesthetic Etomidate in Zebrafish: PCOS-like Ovarian Changes, Oxidative Stress, and Metabolism Disruption.Environment & health (Washington, D.C.) · 2025Article
- Nicotinamide mononucleotide protects ovarian function and oocyte developmental competence during chemotherapy.Journal of ovarian research · 2025Article
- Fertility Protection in Female Cancer Patients: From Molecular Mechanisms of Gonadotoxic Therapies to Pharmacotherapeutic Possibilities.International journal of molecular sciences · 2025Review
- Bushen Jianpi Tiaoxue Decoction (BJTD) inhibits the LIF-mTOR signaling axis to regulate mitochondrial function and alleviate cyclophosphamide-induced diminished ovarian reserve.Apoptosis : an international journal on programmed cell death · 2025Article
- Fertility Preservation in Female Children and Adolescent Cancer Patients.Children (Basel, Switzerland) · 2025Review
- Does gonadotoxic chemotherapy deplete the ovarian reserve through activation of primordial follicles?Human reproduction (Oxford, England) · 2025Article
- Intrinsic differences in mTOR activity mediates lineage-specific responses to cyclophosphamide in mouse and human granulosa cells.Journal of ovarian research · 2025Article
- Bridging tradition and innovation: electroacupuncture's impact on premature ovarian insufficiency.Frontiers in endocrinology · 2025Review
- Novel direct effect of CCR2 receptor on follicle activation process.Frontiers in endocrinology · 2025Article
- mTOR inhibitors potentially preserve fertility in female patients with haematopoietic malignancies: a narrative review.Annals of hematology · 2024Review
- An overview of different methods to establish a murine premature ovarian failure model.Animal models and experimental medicine · 2024Review
32 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
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.
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