An investigation of the protective effects of Dehydroepiandrosterone (DHEA) in chemotherapatic Cyclophosphamide (CP) induced ovarian damage on rats

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Önder Sakin
Yasemin Alan
Ali Doğukan Anğın
Kahyan Basak
Murat Alan


Objective: We aimed to investigate whether cyclophosphamide-induced damage to rat ovary can be prevented by DHEA.

Material and Method: Group 1 (the control Group): no treatment was administered. Intact ovarian tissue was removed and blood samples were taken for anti-mullerian hormone (AMH) test. Group 2 (the Cyclophosphamide Group): Rats received Cyclophosphamide intraperitoneally at a single dose of 150 mg / kg. Group 3 (the Cyclophosphamide + DHEA Group): Rats received Cyclophosphamide intraperitoneally at a single dose of 150 mg / kg at baseline and DHEA subcutaneously for 10 days at a dose of 60 mg / kg daily. Rats in groups 2 and 3 were sacrificed at the end of 10 days, ovarian tissues were removed and blood samples were taken for AMH test.

Results: While normal ovarian tissue damage scores were zero, cyclophosphamide showed significant damage and histopathological changes in all rats. Cyclophosphamide group had higher vascular congestion (p=0.004) and total damage scores (p=0.010) than normal ovarian group. Cyclophosphamide + DHEA group had higher edema (p<0.001), vascular congestion (p<0.001) and total damage scores (p<0.001). Cyclophosphamide group had a decrease in primordial (p = 0.001), primary (p = 0.043) and preantral follicles(p = 0.006). Cyclophosphamide + DHEA group showed a decrease in primordial (p = 0.001) and antral follicles(p = 0.018). AMH levels did not decrease in both groups.

Conclusions: It was found that the use of DHEA to prevent Cyclophosphamide-induced ovarian damage in rats did not produce significant changes in antral follicle counts, ovarian volume, and AMH levels, which were important for clinical practice.


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Sakin, Önder, Alan, Y., Anğın, A. D., Basak, K., & Alan, M. (2019). An investigation of the protective effects of Dehydroepiandrosterone (DHEA) in chemotherapatic Cyclophosphamide (CP) induced ovarian damage on rats . Medical Science and Discovery, 6(12), 340–346.
Research Article
Received 2019-11-28
Accepted 2019-12-26
Published 2019-12-27


Nguyen QN, Zerafa N, Liew SH, Findlay JK, Hickey M, Hutt KJ. Cisplatin- and cyclophosphamide-induced primordial follicle depletion is caused by direct damage to oocytes. Molecular human reproduction. 2019.

Han M, Cheng H, Wang J, Yu Y, Wang F, Zhu R, et al. Abnormal aggregation of myeloid-derived suppressor cells in a mouse model of cyclophosphamide-induced premature ovarian failure. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. 2019:1-6.

D'Avila AM, Biolchi V, Capp E, Corleta H. Age, anti-mullerian hormone, antral follicles count to predict amenorrhea or oligomenorrhea after chemotherapy with cyclophosphamide. Journal of ovarian research. 2015;8:82.

Vural B, Duruksu G, Vural F, Gorguc M, Karaoz E. Effects of VEGF (+) Mesenchymal Stem Cells and Platelet-Rich Plasma on Inbred Rat Ovarian Functions in Cyclophosphamide-Induced Premature Ovarian Insufficiency Model. Stem cell reviews and reports. 2019;15(4):558-73.

Zhang BF, Hu Y, Liu X, Cheng Z, Lei Y, Liu Y, et al. The role of AKT and FOXO3 in preventing ovarian toxicity induced by cyclophosphamide. 2018;13(8):e0201136.

Zhang CW, Wang CZ, Tao R, Ye JZ. Separation of polyprenols from Ginkgo biloba leaves by a nano silica-based adsorbent containing silver ions. Journal of chromatography A. 2019;1590:58-64.

Helsby NA, Yong M, van Kan M, de Zoysa JR, Burns KE. The importance of both CYP2C19 and CYP2B6 germline variations in cyclophosphamide pharmacokinetics and clinical outcomes. 2019;85(9):1925-34.

Meng Y, Wang J, Wang Z, Zhang G, Liu L, Huo G, et al. Lactobacillus plantarum KLDS1.0318 Ameliorates Impaired Intestinal Immunity and Metabolic Disorders in Cyclophosphamide-Treated Mice. Frontiers in microbiology. 2019;10:731.

Liu X, Zhang Z, Liu J, Wang Y, Zhou Q, Wang S, et al. Ginsenoside Rg3 improves cyclophosphamide-induced immunocompetence in Balb/c mice. International immunopharmacology. 2019;72:98-111.

Meirow D, Epstein M, Lewis H, Nugent D, Gosden RG. Administration of cyclophosphamide at different stages of follicular maturation in mice: effects on reproductive performance and fetal malformations. Human reproduction. 2001;16(4):632-7.

Mark-Kappeler CJ, Hoyer PB, Devine PJ. Xenobiotic effects on ovarian preantral follicles. Biology of reproduction. 2011;85(5):871-83.

Gui T, Yuan G, Shen K, Cao D, Yang J, Wu M, et al. Protective effect of gonadotropin-releasing hormone analog on the ovarian reserve in rats receiving cyclophosphamide treatment. OncoTargets and therapy. 2015;8:661-7.

Dynes J, Osz K, Hooper A, Petrik J. Low-dose metronomic delivery of cyclophosphamide is less detrimental to granulosa cell viability, ovarian function, and fertility than maximum tolerated dose delivery in the mouse. Biology of reproduction. 2017;97(3):449-65.

Chen XY, Xia HX, Guan HY, Li B, Zhang W. Follicle Loss and Apoptosis in Cyclophosphamide-Treated Mice: What's the Matter? International journal of molecular sciences. 2016;17(6).

Healy MW, Patounakis G, Connell MT, Devine K, DeCherney AH, Levy MJ, et al. Does a frozen embryo transfer ameliorate the effect of elevated progesterone seen in fresh transfer cycles? Fertility and sterility. 2016;105(1):93-9.e1.

Al-Azemi M, Kyrou D, Kolibianakis EM, Humaidan P, Van Vaerenbergh I, Devroey P, et al. Elevated progesterone during ovarian stimulation for IVF. Reproductive biomedicine online. 2012;24(4):381-8.

Barad D, Brill H, Gleicher N. Update on the use of dehydroepiandrosterone supplementation among women with diminished ovarian function. Journal of assisted reproduction and genetics. 2007;24(12):629-34.

Yilmaz N, Uygur D, Inal H, Gorkem U, Cicek N, Mollamahmutoglu L. Dehydroepiandrosterone supplementation improves predictive markers for diminished ovarian reserve: serum AMH, inhibin B and antral follicle count. European journal of obstetrics, gynecology, and reproductive biology. 2013;169(2):257-60.

Zhang HH, Xu PY, Wu J, Zou WW, Xu XM, Cao XY, et al. Dehydroepiandrosterone improves follicular fluid bone morphogenetic protein-15 and accumulated embryo score of infertility patients with diminished ovarian reserve undergoing in vitro fertilization: a randomized controlled trial. Journal of ovarian research. 2014;7:93.

Casson PR, Lindsay MS, Pisarska MD, Carson SA, Buster JE. Dehydroepiandrosterone supplementation augments ovarian stimulation in poor responders: a case series. Human reproduction. 2000;15(10):2129-32.

Gleicher N, Weghofer A, Barad DH. Dehydroepiandrosterone (DHEA) reduces embryo aneuploidy: direct evidence from preimplantation genetic screening (PGS). Reproductive biology and endocrinology : RB&E. 2010;8:140.

Khedr NF. Protective effect of mirtazapine and hesperidin on cyclophosphamide-induced oxidative damage and infertility in rat ovaries. Experimental biology and medicine. 2015;240(12):1682-9.

Hassa H, Aydin Y, Ozatik O, Erol K, Ozatik Y. Effects of dehydroepiandrosterone (DHEA) on follicular dynamics in a diminished ovarian reserve in vivo model. Systems biology in reproductive medicine. 2015;61(3):117-21.

Wang YX, Zhu WJ, Xie BG. Expression of PPAR-gamma in adipose tissue of rats with polycystic ovary syndrome induced by DHEA. Molecular medicine reports. 2014;9(3):889-93.

Parlakgumus HA, Aka Bolat F, Bulgan Kilicdag E, Simsek E, Parlakgumus A. Atorvastatin for ovarian torsion: effects on follicle counts, AMH, and VEGF expression. European journal of obstetrics, gynecology, and reproductive biology. 2014;175:186-90.

Alarfaj AS, Khalil N. Fertility, ovarian failure, and pregnancy outcome in SLE patients treated with intravenous cyclophosphamide in Saudi Arabia. Clinical rheumatology. 2014;33(12):1731-6.

Liu T, Huang Y, Guo L, Cheng W, Zou G. CD44+/CD105+ human amniotic fluid mesenchymal stem cells survive and proliferate in the ovary long-term in a mouse model of chemotherapy-induced premature ovarian failure. International journal of medical sciences. 2012;9(7):592-602.

Liu T, Qin W, Huang Y, Zhao Y, Wang J. Induction of estrogen-sensitive epithelial cells derived from human-induced pluripotent stem cells to repair ovarian function in a chemotherapy-induced mouse model of premature ovarian failure. DNA and cell biology. 2013;32(12):685-98.

Liu T, Huang Y, Zhang J, Qin W, Chi H, Chen J, et al. Transplantation of human menstrual blood stem cells to treat premature ovarian failure in mouse model. Stem cells and development. 2014;23(13):1548-57.

Zhou L, Xie Y, Li S, Liang Y, Qiu Q, Lin H, et al. Rapamycin Prevents cyclophosphamide-induced Over-activation of Primordial Follicle pool through PI3K/Akt/mTOR Signaling Pathway in vivo. 2017;10(1):56.

Yuksel A, Bildik G, Senbabaoglu F, Akin N, Arvas M, Unal 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. Human reproduction. 2015;30(12):2926-35.

Ataya KM, Valeriote FA, Ramahi-Ataya AJ. Effect of cyclophosphamide on the immature rat ovary. Cancer research. 1989;49(7):1660-4.

Pydyn EF, Ataya KM. Effect of cyclophosphamide on mouse oocyte in vitro fertilization and cleavage: recovery. Reproductive toxicology. 1991;5(1):73-8.

Stefansdottir A, Fowler PA, Powles-Glover N, Anderson RA, Spears N. Use of ovary culture techniques in reproductive toxicology. Reproductive toxicology. 2014;49:117-35.

Epstein RJ. Drug-induced DNA damage and tumor chemosensitivity. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1990;8(12):2062-84.

Kilic S, Pinarli F, Ozogul C, Tasdemir N, Naz Sarac G, Delibasi T. Protection from cyclophosphamide-induced ovarian damage with bone marrow-derived mesenchymal stem cells during puberty. Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. 2014;30(2):135-40.

Song D, Zhong Y, Qian C, Zou Q, Ou J, Shi Y, et al. Human Umbilical Cord Mesenchymal Stem Cells Therapy in Cyclophosphamide-Induced Premature Ovarian Failure Rat Model. 2016;2016:2517514.

Nguyen QN, Zerafa N, Liew SH, Morgan FH, Strasser A, Scott CL. Loss of PUMA protects the ovarian reserve during DNA-damaging chemotherapy and preserves fertility. 2018;9(6):618.

Lande Y, Fisch B, Tsur A, Farhi J, Prag-Rosenberg R, Ben-Haroush A, et al. Short-term exposure of human ovarian follicles to cyclophosphamide metabolites seems to promote follicular activation in vitro. Reproductive biomedicine online. 2017;34(1):104-14.

Jayasinghe YL, Wallace WHB, Anderson RA. Ovarian function, fertility and reproductive lifespan in cancer patients. Expert review of endocrinology & metabolism. 2018;13(3):125-36.

Pascuali N, Scotti L, Di Pietro M, Oubina G, Bas D, May M, et al. Ceramide-1-phosphate has protective properties against cyclophosphamide-induced ovarian damage in a mice model of premature ovarian failure. Human reproduction. 2018;33(5):844-59.

Jayaprakasan K, Campbell B, Hopkisson J, Johnson I, Raine-Fenning N. A prospective, comparative analysis of anti-Mullerian hormone, inhibin-B, and three-dimensional ultrasound determinants of ovarian reserve in the prediction of poor response to controlled ovarian stimulation. Fertility and sterility. 2010;93(3):855-64.

Jayaprakasan K, Narkwichean A, Maalouf WE, Campbell BK. Efficacy of dehydroepiandrosterone to overcome the effect of ovarian ageing (DITTO): a proof of principle randomised controlled trial protocol. BMJ open. 2014;4(10):e005767.