Chronic Systemic Toxicity Study of Copper Intrauterine Devices in Female Wistar Rats
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Xia Zhao, Qian Liu, Haixiang Sun, Yali Hu and Zhaoxu Wang
Medical Science Monitor
August 16, 2017
BACKGROUND:
The copper intrauterine device (Cu-IUD) was first marketed in the early 1970s. It is widely used due to its great efficacy, low cost, and long-lasting action [1]. Women living in China constitute about two-thirds of global users. Cu-IUDs do not cause hormone-related adverse effects such as weight gain, altered libido, or mood changes [2]. Generally, Cu-IUDs are made of Cu wires/tubes around T- or U-shaped flexible polymer material. Up to 60% of users choose, for various reasons, to have their IUDs removed within 5 years after insertion [3].Sustained release of the corrosion products of Cu ions from a Cu-IUD is quite efficient for contraception through release of uterine inflammatory products – leukocytes and prostaglandins – by the endometrium in response to the inserted Cu-IUD. They also lead to changes in the composition of cells and uterine fluid in tissue, which reduces not only the viability of sperms, but also the receptivity of endometrium to implantation of embryos [4,5]. Copper is an essential trace element for living organisms; however, the tissue surrounding the Cu-IUD is exposed to toxic Cu ion levels. Cu-IUDs also induce adverse effects such as pelvic inflammatory disease, bleeding, and pain [6]. Cu ion toxicity has drawn much attention recently, especially regarding the chronic systemic exposure of the rest of the body [7,8]. Once the Cu ions uptake across a threshold limit, the cells become apoptotic and die [9,10]. Previous studies have focused on copper concentration in serum or in uterine cavity irrigation fluid. A study at the National University of La Platain, Argentina [8] demonstrated that Cu ions released from an inserted Cu-IUD have cytotoxic and genotoxic effects on mammalian cells in vitro. Reduction of mitochondrial activity was observed when the concentration Cu ions was more than 7.42 mg/L, and a significant decrease in cell viability was observed at 10.85 mg/L. The genital tract was exposed to 25–80 μg/day of Cu ions [5], resulting in uterine tissue damage. Furthermore, the sustained high concentration of Cu ions released can lead to accumulation of Cu, and also gives rise to chronic systemic exposure [11]. Most importantly, Cu ions released from Cu-IUDs produce cytotoxicity to the cells, not only in the implant site, but also in remote tissues such as liver, kidney, spleen, and lungs. There are surprisingly little data on the potential toxicity of Cu-IUDs because of the difficulty collecting specimens from humans, and these reports do not reveal the effect of copper at the organ level. In general, data on the potential systemic toxicity of Cu-IUDs are sparse, and more information is needed. The safety evaluation of Cu-IUDs is also expected to help its acceptance worldwide. Thus, the goal of our study was to evaluate the chronic systemic and local toxicity of the copper intrauterine device in different concentrations of Cu ions released, as well as to demonstrate the effect of copper at different organ levels.
CONCLUSION:
The aim of this study was to evaluate the chronic systemic and local toxicity of a copper intrauterine device in a rat model. These results obtained at different dosages and long-term implantation provide solid data confirming the safety of long-term use of Cu-IUDs. However, the elevated leucocyte levels found in this study warrant further investigation.
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An international, peer-reviewed scientific journal established in 1995 which publishes original articles in Clinical Medicine and related disciplines such as Epidemiology and Population Studies, Product Investigations, Development of Laboratory Techniques :: Diagnostics and Medical Technology which enable presentation of research or review works in overlapping areas of medicine and technology such us (but not limited to): medical diagnostics, medical imaging systems, computer simulation of health and disease processes, new medical devices, etc.
REFERENCES
1. Arrowsmith ME, Aicken CR, Saxena S, Majeed A. Strategies for improving the acceptability and acceptance of the copper intrauterine device. Cochrane Database Syst Rev. 2012;(3):CD008896. [PubMed] [Google Scholar]
2. Andersson K, Odlind V, Rybo G. Levonorgestrel-releasing and copper-releasing (Nova T) IUDs during five years of use: A randomized comparative trial. Contraception. 1994;49(1):56–72. [PubMed] [Google Scholar]
3. Xu XX, Ding MH, Zhang JX, et al. A novel copper/polydimethiylsiloxane nanocomposite for copper-containing intrauterine contraceptive devices. J Biomed Mater Res B Appl Biomater. 2013;101(8):1428–36. [PubMed] [Google Scholar]
4. Ortiz ME, Croxatto HB. Copper-T intrauterine device and levonorgestrel intrauterine system: biological bases of their mechanism of action. Contraception. 2007;75(6 Suppl):29. [PubMed] [Google Scholar]
5. Arancibia V, Peña C, Allen HE, Lagos G, et al. Characterization of copper in uterine fluids of patients who use the copper T-380A intrauterine device. Clin Chim Acta. 2003;332(1–2):69–78. [PubMed] [Google Scholar]
6. Hubacher D, Chen PL, Park S. Side effects from the copper IUD: Do they decrease over time? Contraception. 2009;79(5):356–62. [PMC free article] [PubMed] [Google Scholar]
7. Cao B, Xi T, Zheng Y. Release behavior of cupric ions for TCu380A and TCu220C IUDs. Biomed Mater. 2008;3(4):044114. [PubMed] [Google Scholar]
8. Grillo CA, Reigosa MA, de Mele MA. Does over-exposure to copper ions released from metallic copper induce cytotoxic and genotoxic effects on mammalian cells? Contraception. 2010;81(4):343–49. [PubMed] [Google Scholar]
9. Grillo CA, Reigosa MA, Lorenzo de Mele MF. Effects of copper ions released from metallic copper on CHO-K1 cells. Mutat Res. 2009;672(1):45–50. [PubMed] [Google Scholar]
10. Hayashi M, Fuse S, Endoh D, et al. Accumulation of copper induces DNA strand breaks in brain cells of Long-Evans Cinnamon (LEC) rats, an animal model for human Wilson disease. Exp Anim. 2006;55(5):419–26. [PubMed] [Google Scholar]
11. De la Cruz D, Cruz A, Arteaga M, et al. Blood copper levels in Mexican users of the T380A IUD. Contraception. 2005;72(2):122–25. [PubMed] [Google Scholar]
12. Hua Z, Zhaoxu W. [Local reaction of endometrium after the implantation of Cu-intrauterine device into the urterine horn: Early-and late-stage evaluation]. Chinese Journal of Tissue Engineering Research. 2012;16(8):1407–12. [in Chinese] [Google Scholar]
13. International Organization for Standardization, 2006 Biological evaluation of medical devices, in Part 11: Tests for systemic toxicity2006: Geneva
14. Andreollo NA, Santos EF, Araújo MR, Lopes LR, et al. Rat’s age versus human’s age: What is the relationship? Arq Bras Cir Dig. 2012;25(1):49–51. [PubMed] [Google Scholar]
15. Wildemeersch D, Goldstuck ND, Hasskamp T. Intrauterine systems: A frameless future? Expert Opin Drug Deliv. 2016;13(6):911–18. [PubMed] [Google Scholar]
16. Whitaker AK, Johnson LM, Harwood B, et al. Adolescent and young adult women’s knowledge of and attitudes toward the intrauterine device. Contraception. 2008;78(3):211–17. [PubMed] [Google Scholar]
17. Godfrey EM, Folger SG, Jeng G, et al. Treatment of bleeding irregularities in women with copper-containing IUDs: A systematic review. Contraception. 2013;87(5):549–66. [PubMed] [Google Scholar]
18. Morris AW. Nephrotic syndrome: PCSK9: A target for hypercholesterolaemia in nephrotic syndrome. Nat Rev Nephrol. 2016;12(9):18. [PubMed] [Google Scholar]
19. Galanis A, Karapetsas A, Sandaltzopoulos R. Metal-induced carcinogenesis, oxidative stress and hypoxia signalling. Mutat Res. 2009;674(1–2):31–35. [PubMed] [Google Scholar]
20. Haliloglu B, Celik A, Ilter E, et al. Comparison of uterine artery blood flow with levonorgestrel intrauterine system and copper intrauterine device. Contraception. 2011;83(6):578–81. [PubMed] [Google Scholar]
21. Lowe RF, Prata N. Hemoglobin and serum ferritin levels in women using copper-releasing or levonorgestrel-releasing intrauterine devices: A systematic review. Contraception. 2013;87(4):486–96. [PubMed] [Google Scholar]
22. Grimes DA, Lopez LM, Manion C, Schulz KF. Cochrane systematic reviews of IUD trials: Lessons learned. Contraception. 2007;75(6 Suppl):S55–59. [PubMed] [Google Scholar]
23. Sonalkar S, Kapp N. Intrauterine device insertion in the postpartum period: A systematic review. Eur J Contracept Reprod Health Care. 2015;20(1):4–18. [PubMed] [Google Scholar]
24. Imani S, Moghaddam-Banaem L, Roudbar-Mohammadi S, Asghari-Jafarabadi M. Changes in copper and zinc serum levels in women wearing a copper TCu-380A intrauterine device. Eur J Contracept Reprod Health Care. 2014;19(1):45–50. [PubMed] [Google Scholar]
25. Cao B, Xi T, Zheng Y. Release behavior of cupric ions for TCu380A and TCu220C IUDs. Biomed Mater. 2008;3(4):044114. [PubMed] [Google Scholar]
26. Shin DG, Kim TN, Lee W. Intrauterine device embedded into the bladder wall with stone formation: Laparoscopic removal is a minimally invasive alternative to open surgery. Int Urogynecol J. 2012;23(8):1129–31. [PMC free article] [PubMed] [Google Scholar]
27. O’Brien PA, Kulier R, Helmerhorst FM, et al. Copper-containing, framed intrauterine devices for contraception: A systematic review of randomized controlled trials. Contraception. 2008;77(5):318–27. [PubMed] [Google Scholar]