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Dexamethasone attenuates the embryotoxic effect of endometriotic peritoneal fluid in a murine model

  • Reproductive Physiology and Disease
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

The in vitro fertilization (IVF) pregnancy rate of women with advanced stage endometriosis is nearly half that of the general population, suggesting incomplete targeting of the pathophysiology underlying endometriosis-associated infertility. Compelling evidence highlights inflammation as the etiologic link between endometriosis and infertility and a potential target for adjunctive treatment. The objective of this study was to examine the effect of dexamethasone on murine embryos exposed to human endometriotic peritoneal fluid (PF) using the established murine embryo assay model.

Methods

PF was obtained from women with and without severe endometriosis. Murine embryos were harvested and randomly allocated to five groups of culture media conditions: (1) human tubal fluid (HTF), (2) HTF and 10 % PF from women without endometriosis, (3) HTF and 10 % PF from women with endometriosis (PF-E), (4) HTF with PF-E and 0.01 mcg/mL dexamethasone, and (5) HTF with PF-E and 0.1 mcg/mL dexamethasone. Embryos were cultured in standard conditions and evaluated for blastocyst development.

Results

A total of 266 mouse embryos were cultured. Baseline blastulation rates were 63.6 %. The addition of peritoneal fluid from women with endometriosis decreased the blastocyst development rate to 38.9 % (P = 0.008). The addition of 0.1 mcg/mL of dexamethasone to the culture media restored the blastulation rate to near baseline levels (61.2 %; P = 0.019).

Conclusions

The results of our in vitro study demonstrate the capacity of dexamethasone to mitigate the deleterious impact of endometriotic PF on embryo development. If confirmed in vivo, dexamethasone may prove a useful adjunct for the treatment of endometriosis-associated infertility.

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References

  1. Eskenazi B, Warner ML. Epidemiology of endometriosis. Obstet Gynecol Clin N Am. 1997;24(2):235–58.

    Article  CAS  Google Scholar 

  2. Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of endometriosis on in vitro fertilization. Fertil Steril. 2002;77(6):1148–55.

    Article  PubMed  Google Scholar 

  3. Halis G, Arici A. Endometriosis and inflammation in infertility. Ann N Y Acad Sci. 2004;1034:300–15.

    Article  CAS  PubMed  Google Scholar 

  4. Ho HN, Wu MY, Chao KH, Chen CD, Chen SU, Chen HF, et al. Decrease in interferon gamma production and impairment of T-lymphocyte proliferation in peritoneal fluid of women with endometriosis. Am J Obstet Gynecol. 1996;175(5):1236–41.

    Article  CAS  PubMed  Google Scholar 

  5. Oral E, Olive DL, Arici A. The peritoneal environment in endometriosis. Hum Reprod Update. 1996;2(5):385–98.

    Article  CAS  PubMed  Google Scholar 

  6. Prough SG, Aksel S, Gilmore SM, Yeoman RR. Peritoneal fluid fractions from patients with endometriosis do not promote two-cell mouse embryo growth. Fertil Steril. 1990;54(5):927–30.

    CAS  PubMed  Google Scholar 

  7. Morcos RN, Gibbons WE, Findley WE. Effect of peritoneal fluid on in vitro cleavage of 2-cell mouse embryos: possible role in infertility associated with endometriosis. Fertil Steril. 1985;44(5):678–83.

    CAS  PubMed  Google Scholar 

  8. Wu MY, Chen SU, Chao KH, Chen CD, Yang YS, Ho HN. Mouse embryo toxicity of IL-6 in peritoneal fluids from women with or without endometriosis. Acta Obstet Gynecol Scand. 2001;80(1):7–11.

    CAS  PubMed  Google Scholar 

  9. Gomez-Torres MJ, Acien P, Campos A, Velasco I. Embryotoxicity of peritoneal fluid in women with endometriosis. Its relation with cytokines and lymphocyte populations. Hum Reprod. 2002;17(3):777–81.

    Article  PubMed  Google Scholar 

  10. Esfandiari N, Falcone T, Goldberg JM, Agarwal A, Sharma RK. Effects of peritoneal fluid on preimplantation mouse embryo development and apoptosis in vitro. Reprod BioMed Online. 2005;11(5):615–9.

    Article  PubMed  Google Scholar 

  11. Noordin L, San GT, Singh HJ, Othman MS, Hafizah W. Pyruvate reduces in vitro the embryotoxic effect of peritoneal fluid from infertile women with endometriosis. Eur J Obstet Gynecol Reprod Biol. 2008;136(1):67–73.

    Article  CAS  PubMed  Google Scholar 

  12. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids–new mechanisms for old drugs. N Engl J Med. 2005;353(16):1711–23.

    Article  CAS  PubMed  Google Scholar 

  13. Eyster KM, Klinkova O, Kennedy V, Hansen KA. Whole genome deoxyribonucleic acid microarray analysis of gene expression in ectopic versus eutopic endometrium. Fertil Steril. 2007;88(6):1505–33.

    Article  CAS  PubMed  Google Scholar 

  14. Verhoog NJ, Du Toit A, Avenant C, Hapgood JP. Glucocorticoid-independent repression of tumor necrosis factor (TNF) alpha-stimulated interleukin (IL)-6 expression by the glucocorticoid receptor: a potential mechanism for protection against an excessive inflammatory response. J Biol Chem. 2011;286(22):19297–310.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Bider D, Amoday I, Tur-Kaspa I, Livshits A, Dor J. The addition of a glucocorticoid to the protocol of programmed oocyte retrieval for in-vitro fertilization–a randomized study. Hum Reprod. 1996;11(8):1606–8.

    Article  CAS  PubMed  Google Scholar 

  16. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997;67(5):817-21.

  17. Fassbender A, Vodeolaskaia A, Saunders P, Lebovic D, Waelkens E, De Moor B, et al. Biomarkers of endometriosis. Fertil Steril. 2013;99(4):1135–45.

    Article  CAS  PubMed  Google Scholar 

  18. Noyes R, Hertig A, Rock J. Dating the endometrial biopsy. Am J Obstet Gynecol. 1975;122:262–3.

    CAS  PubMed  Google Scholar 

  19. Byers SL, Payson SJ, Taft RA. Performance of ten inbred mouse strains following assisted reproductive technologies (ARTs). Theriogenology. 2006;65(9):1716–26.

    Article  PubMed  Google Scholar 

  20. Nagy A, Gertsenstein M, Vintersten K, Behringer R. Manipulating the Mouse Embryo: a laboratory manual. New York: Cold Spring Harbor Laboratory Press; 2003.

    Google Scholar 

  21. Lane M, Gardner DK. Effect of incubation volume and embryo density on the development and viability of mouse embryos in vitro. Hum Reprod. 1992;7(4):558–62.

    CAS  PubMed  Google Scholar 

  22. Lawitts JA, Biggers JD. Culture of preimplantation embryos. Methods Enzymol. 1993;225:153–64.

    Article  CAS  PubMed  Google Scholar 

  23. Navarro J, Garrido N, Remohi J, Pellicer A. How does endometriosis affect infertility? Obstet Gynecol Clin N Am. 2003;30(1):181–92.

    Article  Google Scholar 

  24. Simon C, Gutierrez A, Vidal A, Santos MJ d l, Tarin JJ, Remohi J, et al. Outcome of patients with endometriosis in assisted reproduction: results from in-vitro fertilization and oocyte donation. Hum Reprod. 1994;9(4):725–9.

    CAS  PubMed  Google Scholar 

  25. Ding GL, Chen XJ, Luo Q, Dong MY, Wang N, Huang HF. Attenuated oocyte fertilization and embryo development associated with altered growth factor/signal transduction induced by endometriotic peritoneal fluid. Fertil Steril. 2010;93(8):2538–44.

    Article  PubMed  Google Scholar 

  26. Mansour G, Abdelrazik H, Sharma RK, Radwan E, Falcone T, Agarwal A. L-carnitine supplementation reduces oocyte cytoskeleton damage and embryo apoptosis induced by incubation in peritoneal fluid from patients with endometriosis. Fertil Steril. 2009;91(5 Suppl):2079–86.

    Article  CAS  PubMed  Google Scholar 

  27. Hauzman EE, Garcia-Velasco JA, Pellicer A. Oocyte donation and endometriosis: what are the lessons? Semin Reprod Med. 2013;31(2):173–7.

    Article  PubMed  Google Scholar 

  28. Simon C, Gomez E, Mir A, Santos MJ D l, Pellicer A. Glucocorticoid treatment decreases sera embryotoxicity in endometriosis patients. Fertil Steril. 1992;58(2):284–9.

    CAS  PubMed  Google Scholar 

  29. Bider D, Hourvitz A, Tur Kaspa I, Dirnfeld M, Dor J. Dexamethasone supplementation to gonadotropin stimulation for in vitro fertilization in polycystic ovarian disease. J Assist Reprod Genet. 1999;16(5):233–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Keay SD, Lenton EA, Cooke ID, Hull MG, Jenkins JM. Low-dose dexamethasone augments the ovarian response to exogenous gonadotrophins leading to a reduction in cycle cancellation rate in a standard IVF programme. Hum Reprod. 2001;16(9):1861–5.

    Article  CAS  PubMed  Google Scholar 

  31. Czock D, Keller F, Rasche FM, Haussler U. Pharmacokinetics and pharmacodynamics of systemically administered glucocorticoids. Clin Pharmacokinet. 2005;44(1):61–98.

    Article  CAS  PubMed  Google Scholar 

  32. Lamiable D, Vistelle R, Sulmont V, Millart H, Caron J, Choisy H. Pharmacokinetics of dexamethasone administered orally in obese patients. Therapie. 1990;45(4):311–4.

    CAS  PubMed  Google Scholar 

  33. Van Merris V, Van Wemmel K, Cortvrindt R. In vitro effects of dexamethasone on mouse ovarian function and pre-implantation embryo development. Reprod Toxicol. 2007;23(1):32–41.

    Article  PubMed  Google Scholar 

  34. Sasson R, Amsterdam A. Pleiotropic anti-apoptotic activity of glucocorticoids in ovarian follicular cells. Biochem Pharmacol. 2003;66(8):1393–401.

    Article  CAS  PubMed  Google Scholar 

  35. Kumar S, Allen DA, Kieswich JE, Patel NS, Harwood S, Mazzon E, et al. Dexamethasone ameliorates renal ischemia-reperfusion injury. J Am Soc Nephrol : JASN. 2009;20(11):2412–25.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Korgun ET, Dohr G, Desoye G, Demir R, Kayisli UA, Hahn T. Expression of insulin, insulin-like growth factor I and glucocorticoid receptor in rat uterus and embryo during decidualization, implantation and organogenesis. Reproduction (Cambridge, England). 2003;125(1):75–84.

    Article  CAS  Google Scholar 

  37. Siemieniuch MJ, Majewska M, Takahashi M, Sakatani M, Lukasik K, Okuda K, et al. Are glucocorticoids auto- and/or paracrine factors in early bovine embryo development and implantation? Reprod Biol. 2010;10(3):249–56.

    Article  PubMed  Google Scholar 

  38. Pampfer S, Wuu YD, Vanderheyden I, De Hertogh R. Expression of tumor necrosis factor-alpha (TNF alpha) receptors and selective effect of TNF alpha on the inner cell mass in mouse blastocysts. Endocrinology. 1994;134(1):206–12.

    CAS  PubMed  Google Scholar 

  39. Ben-Yair E, Less A, Lev S, Ben-Yehoshua L, Tartakovsky B. Tumour necrosis factor alpha binding to human and mouse trophoblast. Cytokine. 1997;9(11):830–6.

    Article  CAS  PubMed  Google Scholar 

  40. Kohchi C, Tanabe Y, Noguchi K, Mizuno D, Soma G. Induction of differentiation in embryonic stem cells by 26-kD membrane-bound tumor necrosis factor (TNF) and 17-kD free TNF. In vivo (Athens, Greece). 1996;10(1):19-27.

  41. Wuu YD, Pampfer S, Vanderheyden I, Lee KH, De Hertogh R. Impact of tumor necrosis factor alpha on mouse embryonic stem cells. Biol Reprod. 1998;58(6):1416–24.

    Article  CAS  PubMed  Google Scholar 

  42. Pampfer S, Vanderheyden I, McCracken JE, Vesela J, De Hertogh R. Increased cell death in rat blastocysts exposed to maternal diabetes in utero and to high glucose or tumor necrosis factor-alpha in vitro. Development (Cambridge, England). 1997;124(23):4827–36.

    CAS  Google Scholar 

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Correspondence to Richard O. Burney.

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The views expressed in this manuscript are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense or the United States Government.

Capsule The addition of dexamethasone mitigates the embryotoxic effects of endometriotic peritoneal fluid in a murine embryo model. Dexamethasone may represent an adjunctive therapy for endometriosis-associated infertility.

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Heitmann, R.J., Tobler, K.J., Gillette, L. et al. Dexamethasone attenuates the embryotoxic effect of endometriotic peritoneal fluid in a murine model. J Assist Reprod Genet 32, 1317–1323 (2015). https://doi.org/10.1007/s10815-015-0516-0

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  • DOI: https://doi.org/10.1007/s10815-015-0516-0

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