Endometrial receptivity under hormone replacement therapy in oocyte-donation recipient patients: transcriptomic approach

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Delphine Haouzi http://orcid.org/0000-0002-4740-8404


Purpose: Few studies have investigated the endometrial receptivity status of oocyte-donation (OD) recipient patients at the specific hormone replacement therapy (HRT)-cycle timing (5 to 6 days after progesterone administration) where embryos at blastocyst stage were mostly replaced. The aim of our study was to analyse, during the implantation window, (i) the global endometrial gene expression profile, and (ii) the endometrial receptivity exploration by the Win-Test® in OD recipient patients under HRT compared to spontaneous cycle in patients awaiting for IVF.

Material and methods: This study included OD recipient patients without (n=7) or with (OD RIF, n=20) repeated implantation failures and 12 normal responder patients in spontaneous cycles used as control. Endometrial biopsies were performed during the peri-implantation phase. Samples were analysed using DNA microarrays and the endometrial gene expression profiles of HRT-treated OD recipient patients and of patients in spontaneous cycles were compared. Then, specific biomarkers of endometrial receptivity were assessed in the two groups of HRT-treated OD patients in comparison to control patients

Results: The global gene expression profile of peri-implantation endometrial samples from HRT-treated OD recipients and from patients in spontaneous cycles was different with  significant alterations in the oestrogen receptor signalling [GTF2H2B, POLR2B, POLR2E], VEGF family ligand-receptor interactions [VEGFR1, VEGFB] and integrin signalling [ITGAL, PAK7, ILK]. Using specific biomarkers of human endometrial receptivity, we found that endometrium was non-receptive (29 % and 43 % in OD and RIF OD patients, respectively) or partially receptive (71 and 43 % in OD and RIF OD patients, respectively), at Pg+5/+6, in majority of HRT-treated patients. In OD RIF patients, a delay of the implantation window was observed. However, by targeting personalized embryos transfer by identifying for each patient the HRT-cycle day where endometrium is receptive, with respect of the synchronization of embryo-endometrium dialogue, high pregnancy rate per frozen-thawed embryo replacement (50%) was obtained in OD RIF patients.

Conclusion: This study underlines the need to take into account the individual patient’s response to HRT cycles and to move to a patient-tailored care management.

Article Details

How to Cite
HAOUZI, Delphine. Endometrial receptivity under hormone replacement therapy in oocyte-donation recipient patients: transcriptomic approach. Medical Research Archives, [S.l.], v. 2, n. 1, july 2015. ISSN 2375-1924. Available at: <https://www.journals.ke-i.org/index.php/mra/article/view/242>. Date accessed: 19 july 2018.
Endometrial receptivity, HRT, oocyte donation recipients, gene expression, implantation window, Win-Test
Research Articles


Afify AM, Craig S, Paulino AF. Temporal variation in the distribution of hyaluronic acid, CD44s, and CD44v6 in the human endometrium across the menstrual cycle. Appl Immunohistochem Mol Morphol. 2006;14(3):328-333.

Bourgain C, Devroey P, Van Waesberghe L, Smitz J, Van Steirteghem AC. Effects of natural progesterone on the morphology of the endometrium in patients with primary ovarian failure. Hum Reprod. 1990;5(5):537-543.

Ceyhan ST, Basaran M, Kemal Duru N, Yilmaz A, Göktolga U, Baser I. Use of luteal estrogen supplementation in normal responder patients treated with fixed multidose GnRH antagonist: a prospective randomized controlled study. Fertil Steril. 2008;89(6):1827-1830.

Check JH, Nowroozi K, Choe J, Lurie D, Dietterich C. The effect of endometrial thickness and echo pattern on in vitro fertilization outcome in donor oocyte-embryo transfer cycle. Fertil Steril. 1993;59(1):72-75.

de Hoon MJ, Imoto S, Nolan J, Miyano S. Open source clustering software. Bioinformatics 2004;20:1453-1454.

Díaz-Gimeno P, Horcajadas JA, Martínez-Conejero JA, Esteban FJ, Alamá P, Pellicer A, Simón C. A genomic diagnostic tool for human endometrial receptivity based on the transcriptomic signature. Fertil Steril. 2011;95(1):50-60, 60.e1-15.
Engmann L, DiLuigi A, Schmidt D, Benadiva C, Maier D, Nulsen J. The effect of luteal phase vaginal estradiol supplementation on the success of in vitro fertilization treatment: a prospective randomized study. Fertil Steril. 2008;89(3):554-561.

Farhi J, Weissman A, Steinfeld Z, Shorer M, Nahum H, Levran D. Estradiol supplementation during the luteal phase may improve the pregnancy rate in patients undergoing in vitro fertilization-embryo transfer cycles. Fertil Steril. 2000;73(4):761-766.

Fatemi HM, Kolibianakis EM, Camus M, Tournaye H, Donoso P, Papanikolaou E, Devroey P. Addition of estradiol to progesterone for luteal supplementation in patients stimulated with GnRH antagonist/rFSH for IVF: a randomized controlled trial. Hum Reprod. 2006;21(10):2628-2632.

Garcia-Velasco JA, Motta L, López A, Mayoral M, Cerrillo M, Pacheco A. Low-dose human chorionic gonadotropin versus estradiol/progesterone luteal phase support in gonadotropin-releasing hormone agonist-triggered assisted reproductive technique cycles: understanding a new approach. Fertil Steril. 2010;94(7):2820-2823.

Gleicher N, Brown T, Dudkiewicz A, Karande V, Rao R, Balin M, Campbell D, Pratt D. Estradiol/progesterone substitution in the luteal phase improves pregnancy rates in stimulated cycles—but only in younger women. Early Pregnancy 2000;4:64-73.
Glujovsky D, Pesce R, Fiszbajn G, Sueldo C, Hart RJ, Ciapponi A. Endometrial preparation for women undergoing embryo transfer with frozen embryos or embryos derived from donor oocytes. Cochrane Database Syst Rev. 2010;(1):CD006359.

Gorkemli H, Ak D, Akyurek C, Aktan M, Duman S. Comparison of pregnancy outcomes of progesterone or progesterone + estradiol for luteal phase support in ICSI-ET cycles. Gynecol Obstet Invest. 2004;58(3):140-144.

Haouzi D, Bissonnette L, Gala A, Assou S, Entezami F, Perrochia H, Dechaud H, Hugues JN, Hamamah S. Endometrial receptivity profile in patients with premature progesterone elevation on the day of HCG administration. Biomed Res Int. 2014;2014:951937.

Haouzi D, Dechaud H, Assou S, De Vos J, Hamamah S. Insights into human endometrial receptivity from transcriptomic and proteomic data. Reprod Biomed Online. 2012;24(1):23-34.

Haouzi D, Dechaud H, Assou S, Monzo C, de Vos J, Hamamah S. Transcriptome analysis reveals dialogues between human trophectoderm and endometrial cells during the implantation period. Hum Reprod. 2011;26(6):1440-1449.

Haouzi D, Mahmoud K, Fourar M, Bendhaou K, Dechaud H, De Vos J, Rème T, Dewailly D, Hamamah S. Identification of new biomarkers of human endometrial receptivity in the natural cycle. Hum Reprod. 2009;24(1):198-205.
Huhtinen K, Desai R, Ståhle M, Salminen A, Handelsman DJ, Perheentupa A, Poutanen M. Endometrial and endometriotic concentrations of estrone and estradiol are determined by local metabolism rather than circulating levels. J Clin Endocrinol Metab. 2012;97(11):4228-4235.

Jung H, Roh HK. The effects of E2 supplementation from the early proliferative phase to the late secretory phase of the endometrium in hMGstimulated IVF-ET. J Assist Reprod Genet 2000;17:28-33.

Kolibianakis EM, Venetis CA, Papanikolaou EG, Diedrich K, Tarlatzis BC, Griesinger G. Estrogen addition to progesterone for luteal phase support in cycles stimulated with GnRH analogues and gonadotrophins for IVF: a systematic review and meta-analysis. Hum Reprod. 2008;23(6):1346-1354.

Lewin A, Benshushan A, Mezker E, Yanai N, Schenker JG, Goshen R. The role of estrogen support during the luteal phase of in vitro fertilization–embryo transplant cycles: a comparative study between progesterone alone and estrogen and progesterone support. Fertil Steril 1994;62:121-125.

Liekens AM, De Knijf J, Daelemans W, Goethals B, De Rijk P, Del-Favero J. BioGraph: unsupervised biomedical knowledge discovery via automated hypothesis generation. Genome Biol. 2011;12(6):R57.
Lukaszuk K, Liss J, Lukaszuk M, Maj B. Optimization of estradiol supplementation during the luteal phase improves the pregnancy rate in women undergoing in vitro fertilization-embryo transfer cycles. Fertil Steril. 2005;83(5):1372-1376.

Marchais-Oberwinkler S, Henn C, Möller G, Klein T, Negri M, Oster A, Spadaro A, Werth R, Wetzel M, Xu K et al. 17β-Hydroxysteroid dehydrogenases (17β-HSDs) as therapeutic targets: protein structures, functions, and recent progress in inhibitor development. J Steroid Biochem Mol Biol. 2011;125(1-2):66-82.

Meduri G, Bausero P, Perrot-Applanat M. Expression of vascular endothelial growth factor receptors in the human endometrium: modulation during the menstrual cycle. Biol Reprod. 2000;62(2):439-47.

Mirkin S, Arslan M, Churikov D, Corica A, Diaz JI, Williams S, Bocca S, Oehninger S. In search of candidate genes critically expressed in the endometrium during the window of implantation. Hum Reprod 2005;20:2104-1217.

Nawroth F, Ludwig M. What is the 'ideal' duration of progesterone supplementation before the transfer of cryopreserved-thawed embryos in estrogen/progesterone replacement protocols? Hum Reprod. 2005;20(5):1127-34.

Nikas G, Drakakis P, Loutradis D, Mara-Skoufari C, Koumantakis E, Michalas S, Psychoyos A. Uterine pinopodes as markers of the 'nidation window' in cycling women receiving exogenous oestradiol and progesterone. Hum Reprod. 1995;10(5):1208-1213.

Ruiz-Alonso M, Blesa D, Díaz-Gimeno P, Gómez E, Fernández-Sánchez M, Carranza F, Carrera J, Vilella F, Pellicer A, Simón C. The endometrial receptivity array for diagnosis and personalized embryo transfer as a treatment for patients with repeated implantation failure. Fertil Steril. 2013;100(3):818-824.

Ruiz-Alonso M, Galindo N, Pellicer A, Simón C. What a difference two days make: "personalized" embryo transfer (pET) paradigm: A case report and pilot study. Hum Reprod. 2014;29(6):1244-1247.

Serna J, Cholquevilque JL, Cela V, Martínez-Salazar J, Requena A, Garcia-Velasco JA. Estradiol supplementation during the luteal phase of IVF-ICSI patients: a randomized, controlled trial. Fertil Steril. 2008;90(6):2190-2195.

Shapiro DB, Pappadakis JA, Ellsworth NM, Hait HI, Nagy ZP.Progesterone replacement with vaginal gel versus i.m. injection: cycle and pregnancy outcomes in IVF patients receiving vitrified blastocysts. Hum Reprod. 2014;29(8):1706-11.

Sidell N, Feng Y, Hao L, Wu J, Yu J, Kane MA, Napoli JL, Taylor RN. Retinoic acid is a cofactor for translational regulation of vascular endothelial growth factor in human endometrial stromal cells. Mol Endocrinol. 2010;24(1):148-160.

Smitz J, Bourgain C, Van Waesberghe L, Camus M, Devroey P, Van Steirteghem AC. A prospective randomized study on oestradiol valerate supplementation in addition to intravaginal micronized progesterone in buserelin and HMG induced superovulation. Hum Reprod 1993;8:40-45.

Talbi S, Hamilton AE, Vo KC, Tulac S, Overgaard MT, Dosiou C, Le Shay N, Nezhat CN, Kempson R, Lessey BA et al. Molecular phenotyping of human endometrium distinguishes menstrual cycle phases and underlying biological processes in normo-ovulatory women. Endocrinology 2006;147:1097-1121.

Tusher VG, Tibshirani R, Chu G. Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA 2001; 98:5116-5121.

van der Linden M, Buckingham K, Farquhar C, Kremer JA, Metwally M. Luteal phase support for assisted reproduction cycles. Cochrane Database Syst Rev. 2011;(10):CD009154.

Van Vaerenbergh I, Van Lommel L, Ghislain V, In't Veld P, Schuit F, Fatemi HM, Devroey P, Bourgain C. In GnRH antagonist/rec-FSH stimulated cycles, advanced endometrial maturation on the day of oocyte retrieval correlates with altered gene expression. Hum Reprod. 2009;24(5):1085-1091.

Wu J, Hansen JM, Hao L, Taylor RN, Sidell N. Retinoic acid stimulation of VEGF secretion from human endometrial stromal cells is mediated by production of reactive oxygen species. J Physiol. 2011;589(Pt 4):863-875.

Younis JS, Mordel N, Ligovetzky G, Lewin A, Schenker JG, Laufer N. The effect of a prolonged artificial follicular phase on endometrial development in an oocyte donation program. J In Vitro Fert Embryo Transf. 1991;8(2):84-88.

Zenke U, Chetkowski RJ. Transfer and uterine factors are the major recipient-related determinants of success with donor eggs. Fertil Steril. 2004;82(4):850-856.

Zhao Y, Garcia J, Kolp L, Cheadle C, Rodriguez A, Vlahos NF. The impact of luteal phase support on gene expression of extracellular matrix protein and adhesion molecules in the human endometrium during the window of implantation following controlled ovarian stimulation with a GnRH antagonist protocol. Fertil Steril. 2010;94(6):2264-2271.

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