Endometrial expression of receptivity markers subject to ovulation induction agents
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Implantation rates differ according to ovulation induction agents in ART. This study investigates the different local endometrial effects of LH- versus hCG-induced ovulation.
Endometrial stromal cells from healthy patients were cultured with hCG or LH in different concentrations, supplemented with 250 ng/mL hCG and progesterone after 2 and 5 days. In addition after decidualization induction, cells were treated with hCG (50 or 250 ng/mL) or LH (10 or 50 ng/mL) for 3 days. Receptivity markers expression was evaluated by real-time quantitative PCR on day 3 and 6.
On day 3, non-decidualized cells treated with LH showed an increased expression of IGFBP1, IL-8 and CXCL12 compared to hCG. The expression pattern changed on day 6, where cells treated with hCG showed higher expression of implantation markers compared to LH-treated cells. Furthermore, on day 3, decidualized cells treated with hCG250 showed an increased IL8 and CXCL12 expression compared to LH10.
LH seems to modulate the local endometrial expression of receptivity markers earlier compared to hCG; however, the effect is not sustained over time in cells without prior decidualization. Though, in decidualized cells, pattern changed and an earlier positive effect of hCG was shown on IL-8 and CXCL12.
KeywordsEndometrium implantation hCG LH IGFBP1 IL8 CXCL12
Insulin-like growth factor binding protein 1
CXC-Motif-Chemokin ligand 1
CXC-Motif-Chemokin ligand 12, also stromal cell-derived factor 1 (SDF-1) or pre-B cell growth-stimulating factor (PBSF)
Human chorionic gonadotropin
We acknowledge financial support by Ruprecht-Karls-Universität Heidelberg for open-access publishing.
Conceptualization, AF, AG, AMW; and JJ; methodology, AF, AG, JJ, AMW; formal analysis, AF, AG, EC, AMW; investigation, JJ, AMW, MZ, AF; resources, AG, AF, TS; data curation, JJ, AMW; writing—original draft preparation, AF, AMW; writing—review and editing, AF, AG, AMW, EC; visualization, AF, AMW; supervision, AG; project administration, AG; funding acquisition, AG, AF.
This research was funded by Dres. Majic/Majic-Schlez-Stiftung, University of Heidelberg.
Compliance with ethical standards
Conflict of interest
The authors declare no conflict of interest regarding this paper.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. All patients provided written consent for the use of their tissue samples. The study was approved by the Ethics Committee of Ruprecht Karls University Heidelberg (S239/2005).
- 1.Bourdiec A, Shao R, Rao CV, Akoum A (2012) Human chorionic gonadotropin triggers angiogenesis via the modulation of endometrial stromal cell responsiveness to interleukin 1: a new possible mechanism underlying embryo implantation. Biol Reprod 87(3):66. https://doi.org/10.1095/biolreprod.112.100370 CrossRefPubMedGoogle Scholar
- 2.Horcajadas JA, Minguez P, Dopazo J, Esteban FJ, Dominguez F, Giudice LC, Pellicer A, Simon C (2008) Controlled ovarian stimulation induces a functional genomic delay of the endometrium with potential clinical implications. J Clin Endocrinol Metab 93(11):4500–4510. https://doi.org/10.1210/jc.2008-0588 CrossRefPubMedGoogle Scholar
- 8.Zarei A, Parsanezhad ME, Younesi M, Alborzi S, Zolghadri J, Samsami A, Amooee S, Aramesh S (2014) Intrauterine administration of recombinant human chorionic gonadotropin before embryo transfer on outcome of in vitro fertilization/intracytoplasmic sperm injection: a randomized clinical trial. Iran J Reprod Med 12(1):1–6PubMedPubMedCentralGoogle Scholar
- 10.Berndt S, Blacher S, Perrier d’Hauterive S, Thiry M, Tsampalas M, Cruz A, Pequeux C, Lorquet S, Munaut C, Noel A, Foidart JM (2009) Chorionic gonadotropin stimulation of angiogenesis and pericyte recruitment. J Clin Endocrinol Metab 94(11):4567–4574. https://doi.org/10.1210/jc.2009-0443 CrossRefPubMedGoogle Scholar
- 12.Berkkanoglu M, Isikoglu M, Aydin D, Ozgur K (2007) Clinical effects of ovulation induction with recombinant follicle-stimulating hormone supplemented with recombinant luteinizing hormone or low-dose recombinant human chorionic gonadotropin in the midfollicular phase in microdose cycles in poor responders. Fertil Steril 88(3):665–669. https://doi.org/10.1016/j.fertnstert.2006.11.150 CrossRefPubMedGoogle Scholar
- 16.Craciunas L, Tsampras N, Raine-Fenning N, Coomarasamy A (2018) Intrauterine administration of human chorionic gonadotropin (hCG) for subfertile women undergoing assisted reproduction. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.cd011537.pub3 CrossRefPubMedPubMedCentralGoogle Scholar
- 17.Maslova MA, Smol’nikova VY, Savilova AM, Burmenskaya OV, Bystritskii AA, Tabolova VK, Korneeva IE, Demura TA, Donnikov AE (2015) Profiles of mRNA expression for genes involved in implantation, early and middle phases of secretion stage in human endometrium. Bull Exp Biol Med 158(6):781–784. https://doi.org/10.1007/s10517-015-2861-5 CrossRefPubMedGoogle Scholar
- 22.Wirleitner B, Schuff M, Vanderzwalmen P, Stecher A, Okhowat J, Hradecky L, Kohoutek T, Kralickova M, Spitzer D, Zech NH (2015) Intrauterine administration of human chorionic gonadotropin does not improve pregnancy and life birth rates independently of blastocyst quality: a randomised prospective study. Reprod Biol Endocrinol 13:70. https://doi.org/10.1186/s12958-015-0069-1 CrossRefPubMedPubMedCentralGoogle Scholar
- 26.Karpovich N, Klemmt P, Hwang JH, McVeigh JE, Heath JK, Barlow DH, Mardon HJ (2005) The production of interleukin-11 and decidualization are compromised in endometrial stromal cells derived from patients with infertility. J Clin Endocrinol Metab 90(3):1607–1612. https://doi.org/10.1210/jc.2004-0868 CrossRefPubMedGoogle Scholar
- 27.Lathi RB, Hess AP, Tulac S, Nayak NR, Conti M, Giudice LC (2005) Dose-dependent insulin regulation of insulin-like growth factor binding protein-1 in human endometrial stromal cells is mediated by distinct signaling pathways. J Clin Endocrinol Metab 90(3):1599–1606. https://doi.org/10.1210/jc.2004-1676 CrossRefPubMedGoogle Scholar
- 29.Humaidan P, Van Vaerenbergh I, Bourgain C, Alsbjerg B, Blockeel C, Schuit F, Van Lommel L, Devroey P, Fatemi H (2012) Endometrial gene expression in the early luteal phase is impacted by mode of triggering final oocyte maturation in recFSH stimulated and GnRH antagonist co-treated IVF cycles. Hum Reprod 27(11):3259–3272. https://doi.org/10.1093/humrep/des279 CrossRefPubMedGoogle Scholar
- 32.Gnainsky Y, Granot I, Aldo PB, Barash A, Or Y, Schechtman E, Mor G, Dekel N (2010) Local injury of the endometrium induces an inflammatory response that promotes successful implantation. Fertil Steril 94(6):2030–2036. https://doi.org/10.1016/j.fertnstert.2010.02.022 CrossRefPubMedPubMedCentralGoogle Scholar
- 33.Han VK, Bassett N, Walton J, Challis JR (1996) The expression of insulin-like growth factor (IGF) and IGF-binding protein (IGFBP) genes in the human placenta and membranes: evidence for IGF-IGFBP interactions at the feto-maternal interface. J Clin Endocrinol Metab 81(7):2680–2693. https://doi.org/10.1210/jcem.81.7.8675597 CrossRefPubMedGoogle Scholar
- 34.Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, Simonovic M, Roth A, Santos A, Tsafou KP, Kuhn M, Bork P, Jensen LJ, von Mering C (2015) STRING v10: protein–protein interaction networks, integrated over the tree of life. Nucleic Acids Res 43(Database issue):D447–D452. https://doi.org/10.1093/nar/gku1003 CrossRefPubMedGoogle Scholar
- 35.Szklarczyk D, Morris JH, Cook H, Kuhn M, Wyder S, Simonovic M, Santos A, Doncheva NT, Roth A, Bork P, Jensen LJ, von Mering C (2017) The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res 45(D1):D362–D368. https://doi.org/10.1093/nar/gkw937 CrossRefGoogle Scholar
- 39.Casarini L, Lispi M, Longobardi S, Milosa F, La Marca A, Tagliasacchi D, Pignatti E, Simoni M (2012) LH and hCG action on the same receptor results in quantitatively and qualitatively different intracellular signalling. PLoS ONE 7(10):e46682. https://doi.org/10.1371/journal.pone.0046682 CrossRefPubMedPubMedCentralGoogle Scholar
- 40.Mostajeran F, Godazandeh F, Ahmadi SM, Movahedi M, Jabalamelian SA (2017) Effect of intrauterine injection of human chorionic gonadotropin before embryo transfer on pregnancy rate: a prospective randomized study. J Res Med Sci 22:6. https://doi.org/10.4103/1735-1995.199096 CrossRefPubMedPubMedCentralGoogle Scholar
- 41.Craciunas L, Tsampras N, Coomarasamy A, Raine-Fenning N (2016) Intrauterine administration of human chorionic gonadotropin (hCG) for subfertile women undergoing assisted reproduction. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.cd011537.pub2 CrossRefPubMedPubMedCentralGoogle Scholar
- 42.Youssef MA, Van der Veen F, Al-Inany HG, Mochtar MH, Griesinger G, Nagi Mohesen M, Aboulfoutouh I, van Wely M (2014) Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist-assisted reproductive technology. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.cd008046.pub4 CrossRefPubMedGoogle Scholar
- 44.Ujvari D, Jakson I, Babayeva S, Salamon D, Rethi B, Gidlof S, Hirschberg AL (2017) Dysregulation of in vitro decidualization of human endometrial stromal cells by insulin via transcriptional inhibition of forkhead box protein O1. PLoS ONE 12(1):e0171004. https://doi.org/10.1371/journal.pone.0171004 CrossRefPubMedPubMedCentralGoogle Scholar