J Menopausal Med.  2018 Dec;24(3):196-203. 10.6118/jmm.2018.24.3.196.

Establishment of Effective Mouse Model of Premature Ovarian Failure Considering Treatment Duration of Anticancer Drugs and Natural Recovery Time

• Lee EH
• Han SE
• Park MJ
• Kim HJ
• Kim HG
• Kim CW
• Joo BS
• Lee KS

• KMID: 2455894
• DOI: http://doi.org/10.6118/jmm.2018.24.3.196

Abstract

OBJECTIVES
This study was aimed to establish the most effective premature ovarian failure (POF) mouse model using Cyclophosphamide (CTX), busulfan (Bu), and cisplatin considering treatment duration of anticancer drugs and natural recovery time.
METHODS
POF was induced by intraperitoneally injecting CTX (120 mg/kg)/Bu (12 mg/kg) for 1 to 4 weeks or cisplatin (2 mg/kg) for 3 to 14 days to C57BL/6 female mice aged 6 to 8 weeks. Controls were injected with equal volume of saline for the same periods. Body weight was measured every week, and ovarian and uterine weights were measured after the last injection of anticancer drug. To assess ovarian function, POF-induced mice were superovulated with pregnant mare serum gonadotropin and human chorionic gonadotropin, and then mated with male. After 18 hours, zygotes were retrieved and cultured for 4 days. Finally, the mice were left untreated for a period of times after the final injection of anticancer drug, and the time for natural recovery of ovarian function was evaluated.
RESULTS
After 2 weeks of CTX/Bu injection, ovarian and uterine weights, and ovarian function were decreased sharply. Cisplatin treatment for 10 days resulted in a significant decrease in ovarian and uterine weight, and ovarian function. When POF was induced for at least 2 weeks for CTX/Bu and for at least 10 days for cisplatin, ovarian function did not recover naturally for 2 weeks and 1 week, respectively.
CONCLUSIONS
These results suggest that CTX/Bu should be treated for at least 2 weeks and cisplatin for at least 10 days to establish the most effective primary ovarian insufficiency mouse model.

Keyword

Busulfan; Cisplatin; Cyclophosphamide; Mice; Primary ovarian insufficiency

MeSH Terms

Animals
Body Weight
Busulfan
Chorionic Gonadotropin
Cisplatin
Cyclophosphamide
Female
Gonadotropins
Humans
Male
Mice*
Primary Ovarian Insufficiency*
Weights and Measures
Zygote
Busulfan
Chorionic Gonadotropin
Cisplatin
Cyclophosphamide
Gonadotropins

Reference

1. Welt CK. Primary ovarian insufficiency: a more accurate term for premature ovarian failure. Clin Endocrinol (Oxf). 2008; 68:499–509.

2. Norling A, Hirschberg AL, Rodriguez-Wallberg KA, Iwarsson E, Wedell A, Barbaro M. Identification of a duplication within the GDF9 gene and novel candidate genes for primary ovarian insufficiency (POI) by a customized high-resolution array comparative genomic hybridization platform. Hum Reprod. 2014; 29:1818–1827.

3. Cox L, Liu JH. Primary ovarian insufficiency: an update. Int J Womens Health. 2014; 6:235–243.

4. Nelson LM. Clinical practice. Primary ovarian insufficiency. N Engl J Med. 2009; 360:606–614.

5. Qin Y, Sun M, You L, Wei D, Sun J, Liang X, et al. ESR1, HK3 and BRSK1 gene variants are associated with both age at natural menopause and premature ovarian failure. Orphanet J Rare Dis. 2012; 7:5.

6. Ameratunga D, Weston G, Osianlis T, Catt J, Vollenhoven B. In vitro fertilisation (IVF) with donor eggs in post-menopausal women: are there differences in pregnancy outcomes in women with premature ovarian failure (POF) compared with women with physiological age-related menopause? J Assist Reprod Genet. 2009; 26:511–514.

7. Sills ES, Brady AC, Omar AB, Walsh DJ, Salma U, Walsh AP. IVF for premature ovarian failure: first reported births using oocytes donated from a twin sister. Reprod Biol Endocrinol. 2010; 8:31.

8. Hernández-Angeles C, Castelo-Branco C. Early menopause: A hazard to a woman's health. Indian J Med Res. 2016; 143:420–427.

9. Cartwright B, Robinson J, Seed PT, Fogelman I, Rymer J. Hormone replacement therapy versus the combined oral contraceptive pill in premature ovarian failure: A randomized controlled trial of the effects on bone mineral density. J Clin Endocrinol Metab. 2016; 101:3497–3505.

10. Slopień R, Warenik-Szymankiewicz A. Premature ovarian failure: diagnosis and treatment. Clin Exp Obstet Gynecol. 2014; 41:659–661.

11. Sun M, Wang S, Li Y, Yu L, Gu F, Wang C, et al. Adipose-derived stem cells improved mouse ovary function after chemotherapy-induced ovary failure. Stem Cell Res Ther. 2013; 4:80.

12. Terraciano P, Garcez T, Ayres L, Durli I, Baggio M, Kuhl CP, et al. Cell therapy for chemically induced ovarian failure in mice. Stem Cells Int. 2014; 2014:720753.

13. Lai D, Wang F, Yao X, Zhang Q, Wu X, Xiang C. Human endometrial mesenchymal stem cells restore ovarian function through improving the renewal of germline stem cells in a mouse model of premature ovarian failure. J Transl Med. 2015; 13:155.

14. Wang Z, Wang Y, Yang T, Li J, Yang X. Study of the reparative effects of menstrual-derived stem cells on premature ovarian failure in mice. Stem Cell Res Ther. 2017; 8:11.

15. Rebar RW. Premature ovarian “failure” in the adolescent. Ann N Y Acad Sci. 2008; 1135:138–145.

16. Qin Y, Jiao X, Simpson JL, Chen ZJ. Genetics of primary ovarian insufficiency: new developments and opportunities. Hum Reprod Update. 2015; 21:787–808.

17. Liu TE, Wang S, Zhang L, Guo L, Yu Z, Chen C, et al. Growth hormone treatment of premature ovarian failure in a mouse model via stimulation of the Notch-1 signaling pathway. Exp Ther Med. 2016; 12:215–221.

18. He L, Ling L, Wei T, Wang Y, Xiong Z. Ginsenoside Rg1 improves fertility and reduces ovarian pathological damages in premature ovarian failure model of mice. Exp Biol Med (Maywood). 2017; 242:683–691.

19. Jiang Y, Zhao J, Qi HJ, Li XL, Zhang SR, Song DW, et al. Accelerated ovarian aging in mice by treatment of busulfan and cyclophosphamide. J Zhejiang Univ Sci B. 2013; 14:318–324.

20. Zhang T, Yan D, Yang Y, Ma A, Li L, Wang Z, et al. The comparison of animal models for premature ovarian failure established by several different source of inducers. Regul Toxicol Pharmacol. 2016; 81:223–232.

21. Copelan EA, Biggs JC, Szer J, Thompson JM, Crilley P, Brodsky I, et al. Allogeneic bone marrow transplantation for acute myelogenous leukemia, acute lymphocytic leukemia, and multiple myeloma following preparation with busulfan and cyclophosphamide (BuCy2). Semin Oncol. 1993; 20:33–38.

22. de Magalhaes-Silverman M, Lister J, Rybka W, Wilson J, Ball E. Busulfan and cyclophosphamide (BU/CY2) as preparative regimen for patients with lymphoma. Bone Marrow Transplant. 1997; 19:777–781.

23. Han YS, Lee AR, Song HK, Choi JI, Kim JH, Kim MR, et al. Ovarian volume in Korean women with polycystic ovary syndrome and its related factors. J Menopausal Med. 2017; 23:25–31.

24. Kim HG, Song YJ, Na YJ, Yang J, Choi OH. A rare case of an autoamputated ovary with mature cystic teratoma. J Menopausal Med. 2017; 23:74–76.