Abstract
Purpose
To evaluate the effect of medical or surgical treatment prior to embryo transfer in women with elevated endometrial BCL6 expression and suspected endometriosis in a prospective, cohort study design at a university-associated infertility clinic.
Methods
All subjects had at least 1 year of unexplained infertility (UI) and each prospectively underwent endometrial biopsy and immunostaining for the oncogene BCL6, prior to embryo transfer during an assisted reproductive technology (ART) cycle. To be included, subjects had to have an abnormal BCL6 result, defined by elevated HSCORE ≥ 1.4. Women that were pre-treated with laparoscopy or medical suppression with GnRH agonist (depot leuprolide acetate; Lupron®, Abbvie, Inc., Chicago, IL) for 2 months were compared to a group that went untreated (controls). Endpoints included implantation rate (IR), clinical pregnancy rate (CPR), and live birth rate (LBR), and as well as cycle characteristics. Miscarriage rate were also compared between treatment and control group.
Results
Women in each group had similar characteristics. Those treated by medical suppression and those undergoing laparoscopy for endometriosis had a significantly higher LBR, (5/10; 50%; 95%CI 23.7 to 76.3%) and (11/21; 52.4%; 95%CI 32.4 to 71.7), respectively, compared to controls (4/54; 7.4%; 95%CI 2.9 to 17.6). An absolute benefit of 44.2% (16/31; 95%CI 24.6 to 61.2) and a number need to treat of 3 for those that received treatment (medical suppression and laparoscopy), compared to no treatment. Miscarriages were significantly more common in the control group.
Conclusions
Women with suspected endometriosis and aberrant endometrial BCL6 expression have worse reproductive outcomes following embryo transfer, including a high miscarriage rate, poor IR, and low LBR and CPR compared to cycles pre-treated with medical and surgical management.
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References
Tsuji I, Ami K, Miyazaki A, Hujinami N, Hoshiai H. Benefit of diagnostic laparoscopy for patients with unexplained infertility and normal hysterosalpingography findings. Tohoku J Exp Med. 2009;219:39–42.
Nakagawa K, Ohgi S, Horikawa T, Kojima R, Ito M, Saito H. Laparoscopy should be strongly considered for women with unexplained infertility. J Obstet Gynaecol Res. 2007;33:665–70.
Meuleman C, Vandenabeele B, Fieuws S, Spiessens C, Timmerman D, D’Hooghe T. High prevalence of endometriosis in infertile women with normal ovulation and normospermic partners. Fertil Steril. 2009;92:68–74.
Littman E, Giudice L, Lathi R, Berker B, Milki A, Nezhat C. Role of laparoscopic treatment of endometriosis in patients with failed in vitro fertilization cycles. Fertil Steril. 2005;84:1574–8.
Mohamed AMF, Chouliaras S, Jones CJP, Nardo LG. Live birth rate in fresh and frozen embryo transfer cycles in women with endometriosis. Eur J Obstet Gynecol Reprod Biol. 2011;156:177–80.
Prapas Y, Goudakou M, Matalliotakis I, Kalogeraki A, Matalliotaki C, Panagiotidis Y, et al. History of endometriosis may adversely affect the outcome in menopausal recipients of sibling oocytes. Reprod BioMed Online. 2012;25:543–8.
Díaz I, Navarro J, Blasco L, Simón C, Pellicer A, Remohí J. Impact of stage III-IV endometriosis on recipients of sibling oocytes: matched case-control study. Fertil Steril. 2000;74:31–4.
Zullo F, Spagnolo E, Saccone G, Acunzo M, Xodo S, Ceccaroni M, et al. Endometriosis and obstetrics complications: a systematic review and meta-analysis. Fertil Steril 2017;108:667–72.e5.
National Summary Report [Internet] [cited 2017 Jul 21];Available from: https://www.sartcorsonline.com/rptCSR_PublicMultYear.aspx?reportingYear=2014.
D’Hooghe TM, Debrock S, Hill JA, Meuleman C. Endometriosis and subfertility: is the relationship resolved? Semin Reprod Med. 2003;21:243–54.
Senapati S, Sammel MD, Boudhar S, Morse CB, Barnhart KT. The impact of endometriosis on IVF: an evaluation using the society of assisted reproductive technologies (SART) database. Fertil Steril. 2014;102:e48–9.
Harton GL, Munné S, Surrey M, Grifo J, Kaplan B, McCulloh DH, et al. Diminished effect of maternal age on implantation after preimplantation genetic diagnosis with array comparative genomic hybridization. Fertil Steril. 2013;100:1695–703.
Pallacks C, Hirchenhain J, Krüssel J-S, Fehm TN, Fehr D. Endometriosis doubles odds for miscarriage in patients undergoing IVF or ICSI. Eur J Obstet Gynecol Reprod Biol. 2017;213:33–8.
Almquist LD, Likes CE, Stone B, Brown KR, Savaris R, Forstein DA, et al. Endometrial BCL6 testing for the prediction of in vitro fertilization outcomes: a cohort study. Fertil Steril. 2017;108:1063–9.
Evans-Hoeker E, Lessey BA, Jeong JW, Savaris RF, Palomino WA, Yuan L, et al. Endometrial BCL6 overexpression in eutopic endometrium of women with endometriosis. Reprod Sci. 2016;23:1234–41.
Yoo J-Y, Kim TH, Fazleabas AT, Palomino WA, Ahn SH, Tayade C, et al. KRAS activation and over-expression of SIRT1/BCL6 contributes to the pathogenesis of endometriosis and progesterone resistance. Sci Rep. 2017;7:6765.
World Health Organization. WHO Laboratory Manual for the Examination and Processing of Human Semen. 2010.
Noyes RW, Hertig AT, Rock J. Dating the endometrial biopsy. Fertil Steril. 1950;1:3–25.
Budwit-Novotny DA, McCarty KS, Cox EB, Soper JT, Mutch DG, Creasman WT, et al. Immunohistochemical analyses of estrogen receptor in endometrial adenocarcinoma using a monoclonal antibody. Cancer Res. 1986;46:5419–25.
Schoenfeld DA. Sample-size formula for the proportional-hazards regression model. Biometrics. 1983;39:499–503.
Kohl Schwartz AS, Wölfler MM, Mitter V, Rauchfuss M, Haeberlin F, Eberhard M, et al. Endometriosis, especially mild disease: a risk factor for miscarriages. Fertil Steril. 2017;108:806–14.e2.
Santulli P, Marcellin L, Menard S, Thubert T, Khoshnood B, Gayet V, et al. Increased rate of spontaneous miscarriages in endometriosis-affected women. Hum Reprod. 2016;31:1014–23.
Yang X, Huang R, Cai M, Liang X. Endometriosis has no negative impact on outcomes of in vitro fertilisation in women with poor ovarian response. BJOG. 2016;123 Suppl 3:76–81.
González-Comadran M, Schwarze JE, Zegers-Hochschild F, Souza M do CB, Carreras R, Checa MÁ. The impact of endometriosis on the outcome of assisted reproductive technology. Reprod Biol Endocrinol. 2017;15:8.
Brosens J, Verhoeven H, Campo R, Gianaroli L, Gordts S, Hazekamp J, et al. High endometrial aromatase P450 mRNA expression is associated with poor IVF outcome. Hum Reprod. 2004;19:352–6.
Miller PB, Parnell BA, Bushnell G, Tallman N, Forstein DA, Higdon HL 3rd, et al. Endometrial receptivity defects during IVF cycles with and without letrozole. Hum Reprod. 2012;27:881–8.
Fox C, Morin S, Jeong J-W, Scott RT Jr, Lessey BA. Local and systemic factors and implantation: what is the evidence? Fertil Steril 2016;105:873–884.
Bulun SE, Cheng Y-H, Yin P, Imir G, Utsunomiya H, Attar E, et al. Progesterone resistance in endometriosis: link to failure to metabolize estradiol. Mol Cell Endocrinol. 2006;248:94–103.
Bulun SE. Endometriosis. N Engl J Med. 2009;360:268–79.
Lessey BA, Lebovic DI, Taylor RN. Eutopic endometrium in women with endometriosis: ground zero for the study of implantation defects. Semin Reprod Med. 2013;31:109–24.
Burney RO, Talbi S, Hamilton AE, Vo KC, Nyegaard M, Nezhat CR, et al. Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis. Endocrinology. 2007;148:3814–26.
Website [Internet] . [cited 2018 Apr 19]. Available from: National Summary Report [Internet][cited 2017 Jul 21];Available from: https://www.sartcorsonline.com/rptCSR_PublicMultYear.aspx?reportingYear=2014.
Feinberg EC, Levens ED, DeCherney AH. Infertility surgery is dead: only the obituary remains? Fertil Steril. 2008;89:232–6.
Yu LP, Liu N, Liu Y. Effect of luteal-phase gonadotropin-releasing hormone agonist administration on pregnancy outcome in IVF/ICSI cycles: a systematic review and meta-analysis. Zhonghua Fu Chan Ke Za Zhi. 2016;51:850–8.
Siristatidis CS, Gibreel A, Basios G, Maheshwari A, Bhattacharya S. Gonadotrophin-releasing hormone agonist protocols for pituitary suppression in assisted reproduction. Cochrane Database Syst Rev 2015;CD006919.
Lensen S, Sadler L, Farquhar C. Endometrial scratching for subfertility: everyone’s doing it. Hum Reprod. 2016;31:1241–4.
van Hoogenhuijze NE, Torrance HL, Mol F, Laven JSE, Scheenjes E, Traas MAF, et al. Endometrial scratching in women with implantation failure after a first IVF/ICSI cycle; does it lead to a higher live birth rate? The SCRaTCH study: a randomized controlled trial (NTR 5342). BMC Womens Health. 2017;17:47.
Taylor HS, Giudice LC, Lessey BA, Abrao MS, Kotarski J, Archer DF, et al. Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist. N Engl J Med. 2017;377:28–40.
Funding
This study was supported by NICHD/NIH R01 HD067721 Grant 99999.003035/2015-08 (BAL) and by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior: CAPES/PROAP (RFS).
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Likes, C.E., Cooper, L.J., Efird, J. et al. Medical or surgical treatment before embryo transfer improves outcomes in women with abnormal endometrial BCL6 expression. J Assist Reprod Genet 36, 483–490 (2019). https://doi.org/10.1007/s10815-018-1388-x
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DOI: https://doi.org/10.1007/s10815-018-1388-x