Abstract
Diminished ovarian reserve (DOR) and primary ovarian insufficiency (POI) are primary factors leading to infertility. However, there is a lack of appropriate animal models of DOR usable for assessing new therapeutic strategies. In this study, we aimed to evaluate whether chemotherapy treatment in mice could reproduce features similar of that observed in women with DOR. Twenty-one Nonobese diabetic/severe combined immunodeficiency (NOD/SCID) female mice were allocated to 3 groups (n = 7/group): control, single dose of vehicle (Dimethyl Sulfoxide [DMSO]); DOR, single reduced chemotherapy dose; and POI, single standard chemotherapy dose. After 21 days, mice underwent ovarian hyperstimulation and mating. Part of the animals were harvested to analyze ovarian reserve, ovulation and fertilization rates, and morphology, apoptosis, and vascularization of the ovarian stroma. The remaining mice underwent multiple matings to assess pregnancy rates and litter sizes. The DOR and POI mice showed an impaired estrous cyclicity and a decrease in ovarian mass, number of follicles, Metaphase II (MII) oocytes, and embryos as well as in ovarian stroma vascularization. Mice in both models showed also an increase in the percentage of morphologically abnormal follicles, stromal degeneration, and apoptosis. Similar to that observed in DOR and POI patients, these impairments were less severe in DOR than in POI mice. None of the POI females were able to achieve a pregnancy. Meanwhile, DOR females achieved several consecutive pregnancies, although litter size was decreased when compared to controls. In conclusion, a mouse model which displayed most of the ovarian characteristics and fertility outcomes of women with DOR has been established using a single dose of chemotherapy.
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10 November 2020
In the original article, Anna Buigues and Maria Marchante should have been listed as joint first authors.
References
Munne S, Cohen J, Sable D. Preimplantation genetic diagnosis for advanced maternal age and other indications. Fertil Steril. 2002;78(2):234–6.
Cohen J, Chabbert-Buffet N, Darai E. Diminished ovarian reserve, premature ovarian failure, poor ovarian responde—a plea for universal definitions. J Assist Reprod Genet. 2015;32(12):1709–12.
Goswami D, Conway GS. Premature ovarian failure. Hum Reprod Update. 2005;11(4):391–410.
Eggan K, Jurga S, Gosden R, Min IM, Wagers AJ. Ovulated oocytes in adult mice derive from non-circulating germ cells. Nature. 2006;441(7097):1109–14.
Zhai J, Yao G, Dong F, et al. In vitro activation of follicles and fresh tissue auto-transplantation in primary ovarian insufficiency patients. J Clin Endocrinol Metab. 2016;101(11):4405–12.
Kawamura K, Cheng Y, Suzuki N, et al. Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment. Proc Natl Acad Sci U S A. 2013;110(43):17474–9.
Jagarlamudi K, Reddy P, Adhikari D, Liu K. Genetically modified mouse models for premature ovarian failure (POF). Mol Cellular Endocrinol. 2010;315(1-2):1–10.
Danilovich N, Maysinger D, Sairam MR. Perspectives on reproductive senescence and biological aging: studies in genetically altered follitropin receptor knockout [FORKO] mice. Exp Gerontol. 2004;39(11-12):1669–78.
Abbott BD, Schmid JE, Pitt JA, et al. Adverse reproductive outcomes in the transgenic Ah receptor-deficient mouse. Toxicol Appl Pharmacol. 1999;155(1):62–70.
Benedict JC, Miller KP, Lin TM, et al. Aryl hydrocarbon receptor regulates growth, but not atresia, of mouse preantral and antral follicles. Biol Reprod. 2003;68(5):1511–7.
Lim J, Nakamura BN, Mohar I, Kavanagh TJ, Luderer U. Glutamate cysteine ligase modifier subunit (Gclm) null mice have increased ovarian oxidative stress and accelerated age-related ovarian failure. Endocrinology. 2015;156(9):3329–43.
Kalich-Philosoph L, Roness H, Carmely A, et al. Cyclophosphamide triggers follicle activation and “burnout” AS101 prevents follicle loss and preserves fertility. Sci Transl Med. 2013;5(185):185ra162.
Sonmezer M, Oktay K. Fertility preservation in young women undergoing breast cancer therapy. Oncologist. 2006;11(5):422–34.
Zhang T, Yan D, Yang Y, et al. The comparison of animal models for premature ovarian failure established by several different source of inducers. Regul Toxicol Pharmacol. 2016;81:223–32.
Lee HJ, Selesniemi K, Niikura Y, et al. Bone marrow transplantation generates immature oocytes and rescues long-term fertility in a preclinical mouse model of chemotherapy-induced premature ovarian failure. J Clin Oncol. 2007;25(22):3198–204.
Johnson J, Bagley J, Skaznik-Wikiel M, et al. Oocyte generation in adult mammalian ovaries by putative germ cells in bone marrow and peripheral blood. Cell. 2005;122(2):303–15.
Felicio LS, Nelson JF, Finch CE. Longitudinal studies of estrous cyclicity in aging C57BL/6 J mice: II. Cessation of cyclicity and the duration of persistent vaginal cornification. Biol Reprod. 1984;31(3):446–53.
Novella-Maestre E, Herraiz S, Rodriguez-Iglesias B, Diaz-Garcia C, Pellicer A. Short-Term PTEN inhibition improves in vitro activation of primordial follicles, preserves follicular viability, and restores AMH levels in cryopreserved ovarian tissue from cancer patients. PLoS One. 2015;10(5):e0127786.
Herraiz S, Buigues A, Diaz-Garcia C, et al. Fertility rescue and ovarian follicle growth promotion by bone marrow stem cell infusion. Fertil Steril. 2018;109(5):908-918.e2.
Herraiz S, Novella-Maestre E, Rodriguez B, et al. Improving ovarian tissue cryopreservation for oncologic patients: slow freezing versus vitrification, effect of different procedures and devices. Fertil Steril. 2014;101(3):775–84.
Johnson J, Canning J, Kaneko T, Pru JK, Tilly JL. Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature. 2004;428(6979):145–50.
Jiang Y, Zhao J, Qi HJ, et al. Accelerated ovarian aging in mice by treatment of busulfan and cyclophosphamide. J Zhejiang Univ Sci B. 2013;14(4):318–24.
Brydoy M, Fossa SD, Dahl O, Bjoro T. Gonadal dysfunction and fertility problems in cancer survivors. Acta Oncol. 2007;46(4):480–9.
Mayer LP, Dyer CA, Eastgard RL, Hoyer PB, Banka CL. Atherosclerotic lesion development in a novel ovary-intact mouse model of perimenopause. Arterioscler Thromb Vasc Biol. 2005;25(9):1910–6.
Romero-Aleshire MJ, Diamond-Stanic MK, Hasty AH, Hoyer PB, Brooks HL. Loss of ovarian function in the VCD mousemodel of menopause leads to insulin resistance and a rapid progression into the metabolic syndrome. Am J Physiol Regul Integr Comp Physiol. 2009;297(3):R587–92.
Van Kempen TA, Milner TA, Waters EM. Accelerated ovarian failure: a novel, chemically induced animal model of menopause. Brain Res. 2011;1379:176–87.
Ubaldi F, Vaiarelli A, D’Anna R, Rienzi L. Management of poorresponders in IVF: is there anything new? Biomed Res Int. 2014;2014:352098.
Ataya K, Rao LV, Lawrence E, Kimmel R. Luteinizing hormonereleasing hormone agonist inhibits cyclophosphamide-induced ovarian follicular depletion in rhesus monkeys. Biol Reprod. 1995;52(2):365–72.
Meirow D, Lewis H, Nugent D, Epstein M. Subclinical depletion of primordial follicular reserve in mice treated with cyclophosphamide: clinical importance and proposed accurate investigative tool. Hum Reprod. 1999;14(7):1903–7.
Grigg AP, McLachlan R, Zaja J, Szer J. Reproductive status in long-term bone marrow transplant survivors receiving busulfancyclophosphamide (120 mg/kg). Bone Marrow Transplant. 2000;26(10):1089–95.
Hassan M, Andersson BS. Role of pharmacogenetics in busulfan/cyclophosphamide conditioning therapy prior to hematopoietic stem cell transplantation. Pharmacogenomics. 2013;14(1):75–87.
Generoso WM, Stout SK, Huff SW. Effects of alkylating chemicals on reproductive capacity of adult female mice. Mutat Res. 1971;13(2):172–84.
Batchvarov IS, Taylor RW, Bustamante-Marin X, et al. A grafted ovarian fragment rescues host fertility after chemotherapy. Mol Hum Reprod. 2016;22(12):842–51.
Nelson JF, Felicio LS, Randall PK, Sims C, Finch CE. A longitudinal study of estrous cyclicity in aging C57BL/6J mice: I. Cycle frequency, length and vaginal cytology. Biol Reprod. 1982;27(2):327–39.
Skaznik-Wikiel ME, McGuire MM, Sukhwani M, et al. Granulocyte colony-stimulating factor with or without stem cell factor extends time to premature ovarian insufficiency in female mice treated with alkylating chemotherapy. Fertil Steril. 2013;99(7): 2045-2054 e2043.
Massin N, Gougeon A, Meduri G, et al. Significance of ovarian histology in the management of patients presenting a premature ovarian failure. Hum Reprod. 2004;19(11):2555–60.
Massin N, Meduri G, Bachelot A, Misrahi M, Kuttenn F, Touraine P. Evaluation of different markers of the ovarian reserve in patients presenting with premature ovarian failure. Mol Cell Endocrinol. 2008;282(1-2):95–100.
Jiang Y, Zhao J, Qi H-J, et al. Accelerated ovarian aging in mice by treatment of busulfan and cyclophosphamide. J Zhejiang Univ Sci B. 2013;14(4):318–24.
Pedersen T, Peters H. Proposal for a classification of oocytes and follicles in the mouse ovary. J Reprod Fertil. 1968;17(3):555–7.
Edwards RG, Fowler RE, Gore-Langton RE, et al. Normal and abnormal follicular growth in mouse, rat and human ovaries. J Reprod Fertil. 1977;51(1):237–63.
Gougeon A. Regulation of ovarian follicular development in primates: facts and hypotheses. Endocr Rev. 1996;17(2):121–55.
McGee EA, Hsueh AJ. Initial and cyclic recruitment of ovarian follicles. Endocr Rev. 2000;21(2):200–14.
Richardson RB, Allan DS, Le Y. Greater organ involution in highly proliferative tissues associated with the early onset and acceleration of ageing in humans. Exp Gerontol. 2014;55:80–91.
Pan HA, Wu MH, Cheng YC, Wu LH, Chang FM. Quantification of ovarian stromal Doppler signals in poor responders undergoing in vitro fertilization with three-dimensional power Doppler ultrasonography. Am J Obstet Gynecol. 2004;190(2):338–44.
Pellicer A, Ballester MJ, Serrano MD, et al. Aetiological factors involved in the low response to gonadotrophins in infertile women with normal basal serum follicle stimulating hormone levels. Hum Reprod. 1994;9(5):806–11.
Battaglia C, Genazzani AD, Regnani G, Primavera MR, Petraglia F, Volpe A. Perifollicular Doppler flow and follicular fluid vascular endothelial growth factor concentrations in poor responders. Fertil Steril. 2000;74(4):809–12.
Weiner Z, Thaler I, Levron J, Lewit N, Itskovitz-Eldor J. Assessment of ovarian and uterine blood flow by transvaginal color Doppler in ovarian-stimulated women: correlation with the number of follicles and steroid hormone levels. Fertil Steril. 1993;59(4):743–9.
Bassil S, Wyns C, Toussaint-Demylle D, Nisolle M, Gordts S, Donnez J. The relationship between ovarian vascularity and the duration of stimulation in in-vitro fertilization. Hum Reprod. 1997;12(6):1240–5.
Lopez SG, Luderer U. Effects of cyclophosphamide and buthionine sulfoximine on ovarian glutathione and apoptosis. Free Radic Biol Med. 2004;36(11):1366–77.
Plowchalk DR, Mattison DR. Reproductive toxicity of cyclophosphamide in the C57BL/6 N mouse: 1. Effects on ovarian structure and function. Reprod Toxicol. 1992;6(5):411–21.
Yuksel A, Bildik G, Senbabaoglu F, et al. The magnitude of gonadotoxicity of chemotherapy drugs on ovarian follicles and granulosa cells varies depending upon the category of the drugs and the type of granulosa cells. Hum Reprod. 2015;30(12):2926–35.
Herraiz S, Romeu M, Buigues A, et al. Autologous stem cell ovarian transplantation to increase reproductive potential in patients who are poor responders. Fertil Steril. 2018;110(3):496–505.
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Buigues, A., Marchante, M., Herraiz, S. et al. Diminished Ovarian Reserve Chemotherapy-Induced Mouse Model: A Tool for the Preclinical Assessment of New Therapies for Ovarian Damage. Reprod. Sci. 27, 1609–1619 (2020). https://doi.org/10.1007/s43032-020-00191-w
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DOI: https://doi.org/10.1007/s43032-020-00191-w