The Role of HCG in Implantation: A Mini-Review of Molecular and Clinical Evidence

Antonis Makrigiannakis, Thomas Vrekoussis, Emmanouel Zoumakis, Sophia N Kalantaridou, Udo Jeschke, Antonis Makrigiannakis, Thomas Vrekoussis, Emmanouel Zoumakis, Sophia N Kalantaridou, Udo Jeschke

Abstract

Embryo implantation is a complex process involving continuous molecular cross-talk between the embryo and the decidua. One of the key molecules during this process is human chorionic gonadotropin (HCG). HCG effectively modulates several metabolic pathways within the decidua contributing to endometrial receptivity. Herein, a brief overview of the molecular mechanisms regulated by HCG is presented. Furthermore, we summarize the existing evidence regarding the clinical impact on reproductive outcomes after endometrial priming with HCG prior to embryo transfer. Although promising, further evidence is needed to clarify the protocol that would lead to beneficial outcomes.

Keywords: human chorionic gonadotropin (HCG); implantation; infertility.

Conflict of interest statement

The authors declare no conflict of interest.

References

    1. Herington J.L., Guo Y., Reese J., Paria B.C. Gene profiling the window of implantation: Microarray analyses from human and rodent models. J. Reprod. Health Med. 2016;2:S19–S25. doi: 10.1016/j.jrhm.2016.11.006.
    1. Salamonsen L.A., Evans J., Nguyen H.P., Edgell T.A. The microenvironment of human implantation: Determinant of reproductive success. Am. J. Reprod. Immunol. 2016;75:218–225. doi: 10.1111/aji.12450.
    1. Sharma S., Godbole G., Modi D. Decidual control of trophoblast invasion. Am. J. Reprod. Immunol. 2016;75:341–350. doi: 10.1111/aji.12466.
    1. Jurisicova A., Antenos M., Kapasi K., Meriano J., Casper R.F. Variability in the expression of trophectodermal markers β -human chorionic gonadotrophin, human leukocyte antigen-G and pregnancy specific β -1 glycoprotein by the human blastocyst. Hum. Reprod. 1999;14:1852–1858. doi: 10.1093/humrep/14.7.1852.
    1. Bonduelle M.L., Dodd R., Liebaers I., Van Steirteghem A., Williamson R., Akhurst R. Chorionic gonadotrophin-β mrna, a trophoblast marker, is expressed in human 8-cell embryos derived from tripronucleate zygotes. Hum. Reprod. 1988;3:909–914. doi: 10.1093/oxfordjournals.humrep.a136808.
    1. Lopata A., Hay D.L. The potential of early human embryos to form blastocysts, hatch from their zona and secrete hCG in culture. Hum. Reprod. 1989;4:87–94. doi: 10.1093/humrep/4.suppl_1.87.
    1. Hoshina M., Boothby M., Hussa R., Pattillo R., Camel H.M., Boime I. Linkage of human chorionic gonadotrophin and placental lactogen biosynthesis to trophoblast differentiation and tumorigenesis. Placenta. 1985;6:163–172. doi: 10.1016/S0143-4004(85)80066-7.
    1. Shikone T., Yamoto M., Kokawa K., Yamashita K., Nishimori K., Nakano R. Apoptosis of human corpora lutea during cyclic luteal regression and early pregnancy. J. Clin. Endocrinol. Metab. 1996;81:2376–2380.
    1. Crochet J.R., Shah A.A., Schomberg D.W., Price T.M. Hyperglycosylated human chorionic gonadotropin does not increase progesterone production by luteinized granulosa cells. J. Clin. Endocrinol. Metab. 2012;97:E1741–E1744. doi: 10.1210/jc.2012-2027.
    1. Cole L.A. hCG, five independent molecules. Clin. Chim. Acta. 2012;413:48–65. doi: 10.1016/j.cca.2011.09.037.
    1. Sasaki Y., Ladner D.G., Cole L.A. Hyperglycosylated human chorionic gonadotropin and the source of pregnancy failures. Fertil. Steril. 2008;89:1781–1786. doi: 10.1016/j.fertnstert.2007.03.010.
    1. Evans J., Salamonsen L.A., Menkhorst E., Dimitriadis E. Dynamic changes in hyperglycosylated human chorionic gonadotrophin throughout the first trimester of pregnancy and its role in early placentation. Hum. Reprod. 2015;30:1029–1038. doi: 10.1093/humrep/dev016.
    1. Cole L.A. Hyperglycosylated hCG, a review. Placenta. 2010;31:653–664. doi: 10.1016/j.placenta.2010.06.005.
    1. Guibourdenche J., Handschuh K., Tsatsaris V., Gerbaud P., Leguy M.C., Muller F., Brion D.E., Fournier T. Hyperglycosylated hCG is a marker of early human trophoblast invasion. J. Clin. Endocrinol. Metab. 2010;95:E240–E244. doi: 10.1210/jc.2010-0138.
    1. Shi Q.J., Lei Z.M., Rao C.V., Lin J. Novel role of human chorionic gonadotropin in differentiation of human cytotrophoblasts. Endocrinology. 1993;132:1387–1395. doi: 10.1210/endo.132.3.7679981.
    1. Keay S.D., Vatish M., Karteris E., Hillhouse E.W., Randeva H.S. The role of hCG in reproductive medicine. BJOG. 2004;111:1218–1228. doi: 10.1111/j.1471-0528.2004.00412.x.
    1. Fazleabas A.T., Donnelly K.M., Srinivasan S., Fortman J.D., Miller J.B. Modulation of the baboon (Papio anubis) uterine endometrium by chorionic gonadotrophin during the period of uterine receptivity. Proc. Natl. Acad. Sci. USA. 1999;96:2543–2548. doi: 10.1073/pnas.96.5.2543.
    1. Toth B., Roth K., Kunert-Keil C., Scholz C., Schulze S., Mylonas I., Friese K., Jeschke U. Glycodelin protein and mrna is downregulated in human first trimester abortion and partially upregulated in mole pregnancy. J. Histochem. Cytochem. 2008;56:477–485. doi: 10.1369/jhc.2008.950600.
    1. Han S.W., Lei Z.M., Rao C.V. Treatment of human endometrial stromal cells with chorionic gonadotropin promotes their morphological and functional differentiation into decidua. Mol. Cell. Endocrinol. 1999;147:7–16. doi: 10.1016/S0303-7207(98)00240-8.
    1. Licht P., Losch A., Dittrich R., Neuwinger J., Siebzehnrubl E., Wildt L. Novel insights into human endometrial paracrinology and embryo-maternal communication by intrauterine microdialysis. Hum. Reprod. Update. 1998;4:532–538. doi: 10.1093/humupd/4.5.532.
    1. Fluhr H., Bischof-Islami D., Krenzer S., Licht P., Bischof P., Zygmunt M. Human chorionic gonadotropin stimulates matrix metalloproteinases-2 and -9 in cytotrophoblastic cells and decreases tissue inhibitor of metalloproteinases-1, -2, and -3 in decidualized endometrial stromal cells. Fertil. Steril. 2008;90:1390–1395. doi: 10.1016/j.fertnstert.2007.08.023.
    1. Fluhr H., Carli S., Deperschmidt M., Wallwiener D., Zygmunt M., Licht P. Differential effects of human chorionic gonadotropin and decidualization on insulin-like growth factors-i and -ii in human endometrial stromal cells. Fertil. Steril. 2008;90:1384–1389. doi: 10.1016/j.fertnstert.2007.07.1357.
    1. Tapia-Pizarro A., Argandona F., Palomino W.A., Devoto L. Human chorionic gonadotropin (hCG) modulation of TIMP1 secretion by human endometrial stromal cells facilitates extravillous trophoblast invasion in vitro. Hum. Reprod. 2013;28:2215–2227. doi: 10.1093/humrep/det136.
    1. Fogle R.H., Li A., Paulson R.J. Modulation of hoxa10 and other markers of endometrial receptivity by age and human chorionic gonadotropin in an endometrial explant model. Fertil. Steril. 2010;93:1255–1259. doi: 10.1016/j.fertnstert.2008.11.002.
    1. Yang H., Lei C.X., Zhang W. Human chorionic gonadotropin (hCG) regulation of galectin-3 expression in endometrial epithelial cells and endometrial stromal cells. Acta Histochem. 2013;115:3–7. doi: 10.1016/j.acthis.2011.05.002.
    1. Kajihara T., Uchino S., Suzuki M., Itakura A., Brosens J.J., Ishihara O. Human chorionic gonadotropin confers resistance to oxidative stress-induced apoptosis in decidualizing human endometrial stromal cells. Fertil. Steril. 2011;95:1302–1307. doi: 10.1016/j.fertnstert.2010.05.048.
    1. Tapia-Pizarro A., Archiles S., Argandona F., Valencia C., Zavaleta K., Cecilia Johnson M., Gonzalez-Ramos R., Devoto L. hCG activates epac-Erk1/2 signaling regulating progesterone receptor expression and function in human endometrial stromal cells. Mol. Hum. Reprod. 2017;23:393–405. doi: 10.1093/molehr/gax015.
    1. Evans J., Salamonsen L.A. Too much of a good thing? Experimental evidence suggests prolonged exposure to hCG is detrimental to endometrial receptivity. Hum. Reprod. 2013;28:1610–1619. doi: 10.1093/humrep/det055.
    1. Schumacher A., Brachwitz N., Sohr S., Engeland K., Langwisch S., Dolaptchieva M., Alexander T., Taran A., Malfertheiner S.F., Costa S.D., et al. Human chorionic gonadotropin attracts regulatory t cells into the fetal-maternal interface during early human pregnancy. J. Immunol. 2009;182:5488–5497. doi: 10.4049/jimmunol.0803177.
    1. Diao L.H., Li G.G., Zhu Y.C., Tu W.W., Huang C.Y., Lian R.C., Chen X., Li Y.Y., Zhang T., Huang Y., et al. Human chorionic gonadotropin potentially affects pregnancy outcome in women with recurrent implantation failure by regulating the homing preference of regulatory T cells. Am. J. Reprod. Immunol. 2017;77:e12618. doi: 10.1111/aji.12618.
    1. Khan N.A., Khan A., Savelkoul H.F., Benner R. Inhibition of diabetes in nod mice by human pregnancy factor. Hum. Immunol. 2001;62:1315–1323. doi: 10.1016/S0198-8859(01)00368-8.
    1. Dong M., Ding G., Zhou J., Wang H., Zhao Y., Huang H. The effect of trophoblasts on T lymphocytes: Possible regulatory effector molecules--A proteomic analysis. Cell. Physiol. Biochem. 2008;21:463–472. doi: 10.1159/000129639.
    1. Akoum A., Metz C.N., Morin M. Marked increase in macrophage migration inhibitory factor synthesis and secretion in human endometrial cells in response to human chorionic gonadotropin hormone. J. Clin. Endocrinol. Metab. 2005;90:2904–2910. doi: 10.1210/jc.2004-1900.
    1. Wan H., Versnel M.A., Cheung W.Y., Leenen P.J., Khan N.A., Benner R., Kiekens R.C. Chorionic gonadotropin can enhance innate immunity by stimulating macrophage function. J. Leukoc. Biol. 2007;82:926–933. doi: 10.1189/jlb.0207092.
    1. Kayisli U.A., Selam B., Guzeloglu-Kayisli O., Demir R., Arici A. Human chorionic gonadotropin contributes to maternal immunotolerance and endometrial apoptosis by regulating Fas-Fas ligand system. J. Immunol. 2003;171:2305–2313. doi: 10.4049/jimmunol.171.5.2305.
    1. Kane N., Kelly R., Saunders P.T., Critchley H.O. Proliferation of uterine natural killer cells is induced by human chorionic gonadotropin and mediated via the mannose receptor. Endocrinology. 2009;150:2882–2888. doi: 10.1210/en.2008-1309.
    1. Dehghani Firouzabadi R., Janati S., Razi M.H. The effect of intrauterine human chorionic gonadotropin injection before embryo transfer on the implantation and pregnancy rate in infertile patients: A randomized clinical trial. Int. J. Reprod. Biomed. 2016;14:657–664.
    1. Mansour R., Tawab N., Kamal O., El-Faissal Y., Serour A., Aboulghar M., Serour G. Intrauterine injection of human chorionic gonadotropin before embryo transfer significantly improves the implantation and pregnancy rates in in vitro fertilization/intracytoplasmic sperm injection: A prospective randomized study. Fertil. Steril. 2011;96:1370–1374. doi: 10.1016/j.fertnstert.2011.09.044.
    1. Navali N., Gassemzadeh A., Farzadi L., Abdollahi S., Nouri M., Hamdi K., Mallah F., Jalilvand F. Intrauterine administration of hCG immediately after oocyte retrieval and the outcome of ICSI: A randomized controlled trial. Hum. Reprod. 2016;31:2520–2526. doi: 10.1093/humrep/dew236.
    1. Santibanez A., Garcia J., Pashkova O., Colin O., Castellanos G., Sanchez A.P., De la Jara J.F. Effect of intrauterine injection of human chorionic gonadotropin before embryo transfer on clinical pregnancy rates from in vitro fertilisation cycles: A prospective study. Reprod. Biol. Endocrinol. 2014;12:9. doi: 10.1186/1477-7827-12-9.
    1. Wirleitner B., Schuff M., Vanderzwalmen P., Stecher A., Okhowat J., Hradecky L., Kohoutek T., Kralickova M., Spitzer D., Zech N.H. 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. 2015;13:70. doi: 10.1186/s12958-015-0069-1.
    1. Zarei A., Parsanezhad M.E., Younesi M., Alborzi S., Zolghadri J., Samsami A., Amooee S., Aramesh S. 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. 2014;12:1–6.
    1. Ye H., Hu J., He W., Zhang Y., Li C. The efficacy of intrauterine injection of human chorionic gonadotropin before embryo transfer in assisted reproductive cycles: Meta-analysis. J. Int. Med. Res. 2015;43:738–746. doi: 10.1177/0300060515592903.
    1. Osman A., Pundir J., Elsherbini M., Dave S., El-Toukhy T., Khalaf Y. The effect of intrauterine hCG injection on IVF outcome: A systematic review and meta-analysis. Reprod. Biomed. Online. 2016;33:350–359. doi: 10.1016/j.rbmo.2016.05.010.
    1. Craciunas L., Tsampras N., Coomarasamy A., Raine-Fenning N. Intrauterine administration of human chorionic gonadotropin (hCG) for subfertile women undergoing assisted reproduction. Cochrane Database Syst. Rev. 2016 doi: 10.1002/14651858.cd011537.pub2.
    1. Strug M.R., Su R., Young J.E., Dodds W.G., Shavell V.I., Diaz-Gimeno P., Ruiz-Alonso M., Simon C., Lessey B.A., Leach R.E., et al. Intrauterine human chorionic gonadotropin infusion in oocyte donors promotes endometrial synchrony and induction of early decidual markers for stromal survival: A randomized clinical trial. Hum. Reprod. 2016;31:1552–1561. doi: 10.1093/humrep/dew080.
    1. Makrigiannakis A., BenKhalifa M., Vrekoussis T., Mahjub S., Kalantaridou S.N., Gurgan T. Repeated implantation failure: A new potential treatment option. Eur. J. Clin. Investig. 2015;45:380–384. doi: 10.1111/eci.12417.
    1. Yoshioka S., Fujiwara H., Nakayama T., Kosaka K., Mori T., Fujii S. Intrauterine administration of autologous peripheral blood mononuclear cells promotes implantation rates in patients with repeated failure of IVF-embryo transfer. Hum. Reprod. 2006;21:3290–3294. doi: 10.1093/humrep/del312.
    1. Li S., Wang J., Cheng Y., Zhou D., Yin T., Xu W., Yu N., Yang J. Intrauterine administration of hCG-activated autologous human peripheral blood mononuclear cells (PBMC) promotes live birth rates in frozen/thawed embryo transfer cycles of patients with repeated implantation failure. J. Reprod. Immunol. 2017;119:15–22. doi: 10.1016/j.jri.2016.11.006.
    1. Yu N., Zhang B., Xu M., Wang S., Liu R., Wu J., Yang J., Feng L. Intrauterine administration of autologous peripheral blood mononuclear cells (PBMCS) activated by hCG improves the implantation and pregnancy rates in patients with repeated implantation failure: A prospective randomized study. Am. J. Reprod. Immunol. 2016;76:212–216. doi: 10.1111/aji.12542.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe