Research Article| Volume 159, ISSUE 1, P184-189, November 2011

Download started.


Regression of endometrial autografts in a rat model of endometriosis treated with etanercept



      To determine the efficacy of anti-tumor necrosis factor therapy (etanercept) for treating endometriosis in the rat endometriosis model.

      Study design

      A randomized, placebo-controlled, blinded study using rat endometriosis model. After the peritoneal implantation of endometrial tissue, twenty-eight Wistar female rats were randomized to two equal intervention groups: the control group and the etanercept-treated group. After measuring implant volume, pretreatment blood and peritoneal fluid samples were obtained. A vehicle treatment of 2 mL saline to the rats in control group and 0. 4 mg/kg etanercept SC once weekly were administered in the etanercept-treated group. After four weeks treatment period, the volumes and histopathological properties of the implants were evaluated. A scoring system was used to evaluate preservation of epithelia. Endometrial explants were evaluated immunohistochemically for tumor necrosis factor receptor type 2 (TNFR2). A scoring system was used to evaluate expression grade of TNFR2.


      There was not a significant difference in spherical volume between control (131.0 (60.3–501.2)) and treatment groups (72.8 (31.2–149.6)) (p > 0.025). There was a significant change in between the volumes of implants before and after treatment in etanercept group (p < 0.05). At the end of the treatment significant differences among the groups were found in histopathological and immunohistochemical parameters (p < 0.05) also histologic scores and HSCORES were decreased in the treatment group significantly (p < 0.05).


      These results indicate that etanercept was found to effectively reduce the development of endometriosis in this experimental rat model.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


        • Bullimore D.W.
        Endometriosis is sustained by tumour necrosis factor alpha.
        Med Hypotheses. 2003; 60: 84-88
        • Falconer H.
        • Mwenda J.M.
        • Chai D.C.
        • et al.
        Effects of anti-TNF-mAb treatment on pregnancy in baboons with induced endometriosis.
        Fertil Steril. 2008; 89: 1537-1545
        • Güney M.
        • Oral B.
        • Karahan N.
        • Mungan T.
        Regression of endometrial explants in a rat model of endometriosis treated with melatonin.
        Fertil Steril. 2008; 89: 934-942
        • Lebovic D.I.
        • Mueller M.D.
        • Hornung D.
        • Taylor R.N.
        Immunology of endometriosis.
        Immunol Allergy Clin North Am. 2002; 22: 585-598
        • Wu M.Y.
        • Ho H.N.
        The role of cytokines in endometriosis.
        Am J Reprod Immunol. 2003; 49: 285-296
        • D’Hooghe T.M.
        • Nugent N.P.
        • Cuneo S.
        • et al.
        Recombinant human TNFRSF1A (r-hTBP1) inhibits the development of endometriosis in baboons: a prospective, randomized, placebo- and drug-controlled study.
        Biol Reprod. 2006; 74: 131-136
        • Lebovic D.I.
        • Mueller M.D.
        • Taylor R.N.
        Immunobiology of endometriosis.
        Fertil Steril. 2001; 75: 1-10
        • Bedaiwy M.A.
        • Falcone T.
        • Sharma R.K.
        • et al.
        Prediction of endometriosis with serum and peritoneal fluid markers: a prospective controlled trial.
        Hum Reprod. 2002; 17: 426-431
        • Richter O.N.
        • Dorn C.
        • Rosing B.
        • Flaskamp C.
        • Ulrich U.
        Tumor necrosis factor alpha secretion by peritoneal macrophages in patients with endometriosis.
        Arch Gynecol Obstet. 2005; 271: 143-147
        • Zhang R.J.
        • Wild R.A.
        • Ojago J.M.
        Effect of tumor necrosis factor alpha on adhesion of human endometrial stromal cells to peritoneal mesothelial cells: an in vitro system.
        Fertil Steril. 1993; 59: 1196-1201
        • Chen D.B.
        • Yang Z.M.
        • Hilsenrath R.
        • Le S.P.
        • Harper M.J.
        Stimulation of prostaglandin (PG) F2 alpha and PGE2 release by tumour necrosis factor-alpha and interleukin-1 alpha in cultured human luteal phase endometrial cells.
        Hum Reprod. 1995; 10: 2773-2780
        • Bulun S.E.
        • Gurates B.
        • Fang Z.
        • et al.
        Mechanisms of excessive estrogen formation in endometriosis.
        J Reprod Immunol. 2002; 55: 21-33
        • Haider S.
        • Knöfler M.
        Human tumour necrosis factor: physiological and pathological roles in placenta and endometrium.
        Placenta. 2009; 30: 111-123
        • Waller K.G.
        • Shaw R.W.
        Gonadotropin-releasing hormone analogues for the treatment of endometriosis: long-term follow-up.
        Fertil Steril. 1993; 59: 511-515
        • Barrier F.B.
        • Bates G.W.
        • Leland M.M.
        • Leach D.A.
        • Robinson R.D.
        • Propst A.M.
        Efficacy of anti-tumor necrosis factor therapy in the treatment of spontaneous endometriosis in baboons.
        Fertil Steril. 2004; 81: 775-779
        • D’ Hooghe T.M.
        • Cuneo S.
        • Nugent N.
        • Chai D.
        • Deer F.
        • Mwenda J.
        Recombinant human TNF binding protein-1 (r-h TBP-1) inhibits the development of endometriosis in baboons: a prospective randomized, placebo- and drug-controlled study.
        Fertil Steril. 2001; : 76-81
        • D’Antonio M.
        • Martelli F.
        • Peano S.
        • Papoian R.
        • Borrelli F.
        Ability of recombinant human TNF binding protein-1 (r- hTBP-1) to inhibit the development of experimentally-induced endometriosis in rats.
        J Reprod Immunol. 2000; 48: 81-98
        • Nash P.T.
        • Florin T.H.
        Tumour necrosis factor inhibitors.
        Med J Aust. 2005; 183: 205-208
        • Vernon M.W.
        • Wilson E.A.
        Studies on the surgical induction of endometriosis in the rat.
        Fertil Steril. 1985; 44: 684-694
        • Uygur D.
        • Aytan H.
        • Zergeroglu S.
        • Batioglu S.
        Leflunomide-an immunomodulator induces regression of endometrial explants in a rat model of endometriosis.
        J Soc Gynecol Investig. 2006; 13: 378-383
        • Keenan J.A.
        • Williams-Boyce P.K.
        • Massey P.J.
        • Chen T.T.
        • Caudleb M.R.
        • Bukovsky A.
        Regression of endometrial explants in a rat model of endometriosis treated with the immune modulators loxoribine and levamisole.
        Fertil Steril. 1999; 72: 135-141
        • McCarty Jr., K.S.
        • Miller L.S.
        • Cox E.B.
        • Konrath J.
        • Mc Carthy Ks.
        Estrogen receptor analyses. Correlation of biochemical and immunohistochemical methods using monoclonal antireceptor antibodies.
        Arch Pathol Lab Med. 1985; 109: 716-721
        • Budwit-Novotny A.
        • McCarty K.S.
        • Cox E.B.
        • et al.
        Immunohistochemical analyses of estrogen receptor in endometrial adenocarcinoma using a monoclonal antibody.
        Cancer Res. 1986; 46: 5419-5425
        • Arici A.
        • Oral E.
        • Attar E.
        • Tazukue S.I.
        • Olive D.L.
        Monocyte chemotactic protein-1 concentration in peritoneal fluid of women with endometriosis and its modulation of expression in mesothelial cells.
        Fertil Steril. 1997; 67: 1065-1072
        • Ding J.
        • Shen M.
        • Gogacz M.
        • Braun D.P.
        • Rana N.
        • Dmowski W.P.
        Endometrial apoptosis is inhibited invitro by TNF-α in healthy women.
        J Soc Gynecol Investig. 2000; 47: 218A
        • Kaushic C.
        • Frauendorf E.
        • Rossoll R.M.
        • Richardson J.M.
        • Wira C.R.
        Influence of the estrous cycle on the presence and distribution of immune cells in the rat reproductive tract.
        Am J Reprod Immunol. 1998; 39: 209-216
        • Sharpe K.L.
        • Zimmer R.L.
        • Griffin W.T.
        • Penney L.L.
        Polypeptides synthesized and released by human endometriosis differ from those of the uterine endometrium in cell and tissue explant culture.
        Fertil Steril. 1993; 60: 839-851
        • Vernon M.W.
        Experimental endometriosis in laboratory animals as a research model.
        Prog Clin Biol Res. 1990; 323: 49-60
        • Shakiba K.
        • Falcone T.
        Tumour necrosis factor-alpha blockers: potential limitations in the management of advanced endometriosis? A case report.
        Hum Reprod. 2006; 21: 2417-2420