Aims: To determine the effects of a tumor necrosis factor inhibitor (etanercept) on pregnancy outcomes in patients with endometrioma who were treated with assisted reproductive technology. Methods: Sixty-eight infertile patients who had endometrioma were included in our retrospective case-control study. We administered etanercept (Enbrel, 50 mg in 1 mL intramuscularly) to 19 patients on the second day of their previous menstrual cycle. All patients were treated with assisted reproductive technology. Pregnancy and live birth rates (LBR) were documented. Results: When all other parameters (age, body mass index, infertility) are supposed to be constant, the clinical pregnancy rate was significantly higher in patients who used etanercept in an antagonist protocol than in patients who did not use etanercept (χ2 = 5.547; p = 0.019) but LBR did not reach a statistical significance (χ2 = 3.179; p = 0.075). The use of etanercept had an OR of 4.17 (95% CI 1.23–14.14) compared with not using etanercept for clinical pregnancy rate. The use of etanercept increased the rate of pregnancy (χ2 = 6.55; p = 0.01). The pregnancy rate with the use of etanercept had an OR of 4.23 (95% CI 1.35–13.25) compared with patients who did not use etanercept. In the same way, the use of etanercept increased LBR twofold, but it is not significant in the border line (χ2 = 3.771; p = 0.052). Conclusions: Etanercept may be a new non-hormonal therapy that may be an adjunct to treatment of infertile women with endometrioma. However, the safety of etanercept on embryos and fetuses has not been fully clarified.

Keywords:
Etanercept, Endometrioma, Assisted reproductive technology, Anti-tumor necrosis factor-alpha
1.
Dunselman GA, Vermeulen N, Becker C, Calhaz-Jorge C, D’Hooghe T, De Bie B, Heikinheimo O, Horne AW, Kiesel L, Nap A, Prentice A, Saridogan E, Soriano D, Nelen W: ESHRE guideline: management of women with endometriosis. Hum Reprod 2014; 29: 400–412.
2.
Chen DB, Yang ZM, Hilsenrath R, Le SP, Harper MJ: 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.
3.
Richter ON, 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.
4.
Idriss HT, Naismith JH: TNF alpha and the TNF receptor superfamily: structure-function relationship(s). Microsc Res Tech 2000; 50: 184–195.
5.
Valesini G, Iannuccelli C, Marocchi E, Pascoli L, Scalzi V, Di Franco M: Biological and clinical effects of anti-TNF-α treatment. Autoimmun Rev 2007; 7: 35–41.
6.
Gibellini L, De Biasi S, Bianchini E, Bartolomeo R, Fabiano A, Manfredini M, Ferrari F, Albertini G, Trenti T, Nasi M, Pinti M, Iannone A, Salvarani C, Cossarizza A, Pellacani G: Anti-TNF-α drugs differently affect the TNFα-sTNFR system and monocyte subsets in patients with psoriasis. PLoS One 2016; 11:e0167757.
7.
Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, Mak TW, Sakaguchi S: Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen. J Exp Med 2000; 192: 303–310.
8.
Roby KF, Weed J, Lyles R, Terranova PF: Immunological evidence for a human ovarian tumor necrosis factor-α. J Clin Endocrinol Metab 1990; 71: 1096–1102.
9.
Roby KF, Hunt JS: Mouse endometrial tumor necrosis factor-α ribonucleic acid and protein: localization and regulation by estradiol and progesterone. Endocrinology 1994; 135: 2780–2789.
10.
Hunt JS: Expression and regulation of tumor necrosis factor-α gene in the female reproductive tract. Reprod Fertil Dev 1993; 5: 141–153.
11.
Sharkey AM, Dellow K, Blayney M, Macnamee M, Charnock-Jones S, Smith SK: Stage-specific expression of cytokine and receptor messenger ribonucleic acids in human preimplantation embryos. Biol Reprod 1995; 53: 955–962.
12.
Beutler B, Milsark IW, Cerami AC: Passive immunization against cachectin/tumor -necrosis factor protects mice from lethal effect of endotoxin. Science 1985; 229: 869–871.
13.
Feldmann M, Main RN: TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases. Nat Med 2003; 9: 1245–1250.
14.
Sánchez-Cano D, Callejas-Rubio JL, Ruiz-Villaverde R, Ríos-Fernández R, Ortego-Centeno N: Off-label uses of anti-TNF therapy in three frequent disorders: Behçet’s disease, sarcoidosis, and noninfectious uveitis. Mediators Inflamm 2013; 2013: 286857.
15.
Quaas AM, Weedin EA, Hansen KR: On-label and off-label drug use in the treatment of endometriosis. Fertil Steril 2015; 103: 612–625.
16.
Peppel K, Crawford D, Beutler B: A tumor necrosis factor (TNF) receptor-IgG heavy chain chimeric protein as a bivalent antagonist of TNF activity. J Exp Med 1991; 174: 1483–1489.
17.
Islimye M, Kilic S, Zulfikaroglu E, Topcu O, Zergeroglu S, Batioglu S: Regression of endometrial autografts in a rat model of endometriosis treated with etanercept. Eur J -Obstet Gynecol Reprod Biol 2011; 159: 184–189.
18.
Jessica EM, Soo HA, Stephany PM, Kasra K, Madhuri K, Chandrakant T: Implications of immune dysfunction on endometriosis associated infertility. Oncotarget 2017; 8: 7138–7147.
19.
Opøien HK, Fedorcsak P, Omland AK, Abyholm T, Bjercke S, Ertzeid G, Oldereid N, Mellembakken JR, Tanbo T: In vitro fertilization is a successful treatment in endometriosis-associated infertility. Fertil Steril 2012; 97: 912–918.
20.
Hauzman EE, Garcia-Velasco JA, Pellicer A: Oocyte donation and endometriosis: what are the lessons? Semin Reprod Med 2013; 31: 173–177.
21.
Grandi G, Mueller MD, Papadia A, Kocbek V, Bersinger NA, Petraglia F, Cagnacci A, McKinnon B: Inflammation influences steroid hormone receptors targeted by progestins in endometrial stromal cells from women with endometriosis. J Reprod Immunol 2016; 117: 30–38.
22.
Chae U, Min JY, Kim SH, Ihm HJ, Oh YS, Park SY, Chae HD, Kim CH, Kang BM: Decreased progesterone receptor B/A ratio in endometrial cells by tumor necrosis factor-alpha and peritoneal fluid from patients with endometriosis. Yonsei Med J 2016; 57: 1468–1474.
23.
Dogan E, Saygili U, Posaci C: Regression of endometrial explants in rats treated with the cyclooxygenase-2 inhibitor rofecoxib. Fertil Steril 2004; 82: 1115–1120.
24.
Ceyhan ST, Onguru O, Fidan U, Ide T, Yaman H, Kilic S, Baser I: Comparison of aromatase inhibitor (letrozole) and immunomodulators (infliximab and etanercept) on the regression of endometriotic implants in a rat model. Eur J Obstet Gynecol Reprod Biol 2011; 154: 100–104.
25.
Mehmet G, Baha O, Nermin K, Tamer M: Regression of endometrial explants in a rat model of endometriosis treated with melatonin. Fertil Steril 2008; 89: 934–942.
26.
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.
27.
Lu D, Song H, Shi G: Anti-TNF-α treatment for pelvic pain associated with endometriosis. Cochrane Database Syst Rev 2013; 3: CD008088.
28.
Falconer H, Mwenda JM, Chai DC, Song XY, Cornillie FJ, Bergqvist A, Fried G, D’Hooghe TM: Treatment with anti-TNF monoclonal antibody (c5N) reduces the extent of induced endometriosis in the baboon. Hum Reprod 2006; 21: 1856–1862.
29.
Berthelot JM, De Bandt M, Goupille P, Solau-Gervais E, Lioté F, Goeb V, Azaïs I, Martin A, Pallot-Prades B, Maugars Y, Mariette X: Exposition to anti-TNF drugs during pregnancy: outcome of 15 cases and review of the literature. Joint Bone Spine 2009; 76: 28–34.
30.
Murashima A: Treatment of patients with rheumatoid arthritis who desire to become pregnant-successful pregnancy in three cases treated with etanercept. Nippon Rinsho 2008; 66: 2215–2220.
31.
Carman WJ, Accortt NA, Anthony MS, Iles J, Enger C: Pregnancy and infant outcomes including major congenital malformations among women with chronic inflammatory arthritis or psoriasis, with and without etanercept use. Pharmacoepidemiol Drug Saf 2017; 26: 1109–1118.
32.
Briggs GG, Roger KK, Sumner JY: Drugs in Pregnancy and Lactation, ed 7. Baltimore, Williams and Wilkins, 2005.
33.
Cush JJ: Biological drug use: US perspective on indications and monitoring. Ann Rheum Dis 2005; 64: 18–23.
© 2017 S. Karger AG, Basel
2017
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.