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.
Similar content being viewed by others
References
Eskenazi B, Warner ML. Epidemiology of endometriosis. Obstet Gynecol Clin N Am. 1997;24(2):235–58.
Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of endometriosis on in vitro fertilization. Fertil Steril. 2002;77(6):1148–55.
Halis G, Arici A. Endometriosis and inflammation in infertility. Ann N Y Acad Sci. 2004;1034:300–15.
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.
Oral E, Olive DL, Arici A. The peritoneal environment in endometriosis. Hum Reprod Update. 1996;2(5):385–98.
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.
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.
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.
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.
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.
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.
Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids–new mechanisms for old drugs. N Engl J Med. 2005;353(16):1711–23.
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.
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.
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.
Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997;67(5):817-21.
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.
Noyes R, Hertig A, Rock J. Dating the endometrial biopsy. Am J Obstet Gynecol. 1975;122:262–3.
Byers SL, Payson SJ, Taft RA. Performance of ten inbred mouse strains following assisted reproductive technologies (ARTs). Theriogenology. 2006;65(9):1716–26.
Nagy A, Gertsenstein M, Vintersten K, Behringer R. Manipulating the Mouse Embryo: a laboratory manual. New York: Cold Spring Harbor Laboratory Press; 2003.
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.
Lawitts JA, Biggers JD. Culture of preimplantation embryos. Methods Enzymol. 1993;225:153–64.
Navarro J, Garrido N, Remohi J, Pellicer A. How does endometriosis affect infertility? Obstet Gynecol Clin N Am. 2003;30(1):181–92.
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.
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.
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.
Hauzman EE, Garcia-Velasco JA, Pellicer A. Oocyte donation and endometriosis: what are the lessons? Semin Reprod Med. 2013;31(2):173–7.
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.
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.
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.
Czock D, Keller F, Rasche FM, Haussler U. Pharmacokinetics and pharmacodynamics of systemically administered glucocorticoids. Clin Pharmacokinet. 2005;44(1):61–98.
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.
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.
Sasson R, Amsterdam A. Pleiotropic anti-apoptotic activity of glucocorticoids in ovarian follicular cells. Biochem Pharmacol. 2003;66(8):1393–401.
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.
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.
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.
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.
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.
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.
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.
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.
Author information
Authors and Affiliations
Corresponding author
Additional information
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.
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10815-015-0516-0