oocyte quality; G-CSF; in vitro fertilization; pregnancy; follicular fluid
Abstract :
[en] BACKGROUND: Previous experiments have shown that granulocyte colony-stimulating factor (G-CSF), quantified in the follicular fluid (FF) of individual oocytes, correlates with the potential for an ongoing pregnancy of the corresponding fertilized oocytes among selected transferred embryos. Here we present a proof of concept study aimed at evaluating the impact of including FF G-CSF quantification in the embryo transfer decisions. METHODS: FF G-CSF was quantified with the Luminex XMap technology in 523 individual FF samples corresponding to 116 fresh transferred embryos, 275 frozen embryos and 131 destroyed embryos from 78 patients undergoing ICSI. RESULTS: Follicular G-CSF was highly predictive of subsequent implantation. The receiving operator characteristics curve methodology showed its higher discriminatory power to predict ongoing pregnancy in multivariate logistic regression analysis for FF G-CSF compared with embryo morphology [0.77 (0.69-0.83), P < 0.001 versus 0.66 (0.58-0.73), P = 0.01)]. Embryos were classified by their FF G-CSF concentration: Class I over 30 pg/ml (a highest positive predictive value for implantation), Class II from 30 to 18.4 pg/ml and Class III <18.4 pg/ml (a highest negative predictive value). Embryos derived from Class I follicles had a significantly higher implantation rate (IR) than those from Class II and III follicles (36 versus 16.6 and 6%, P < 0.001). Embryos derived from Class I follicles with an optimal morphology reached an IR of 54%. Frozen-thawed embryos transfer derived from Class I follicles had an IR of 37% significantly higher than those from Class II and III follicles, respectively, of 8 and 5% (P < 0.001). Thirty-five per cent of the frozen embryos but also 10% of the destroyed embryos were derived from G-CSF Class I follicles. Non-optimal embryos appear to have been transferred in 28% (22/78) of the women, and their pregnancy rate was significantly lower than that of women who received at least one optimal embryo (18 versus 36%, P = 0.04). CONCLUSIONS: Monitoring FF G-CSF for the selection of embryos with a better potential for pregnancy might improve the effectiveness of IVF by reducing the time and cost required for obtaining a pregnancy.
Disciplines :
Reproductive medicine (gynecology, andrology, obstetrics)
Author, co-author :
Ledee, N.
Gridelet, Virginie ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Embryologie
RAVET, Stéphanie ; Centre Hospitalier Universitaire de Liège - CHU > Gynécologie-Obstétrique CHR
JOUAN, Caroline ; Centre Hospitalier Universitaire de Liège - CHU > Gynécologie-Obstétrique CHR
GASPARD, Olivier ; Centre Hospitalier Universitaire de Liège - CHU > Gynécologie-Obstétrique CHR
WENDERS, Frédéric ; Centre Hospitalier Universitaire de Liège - CHU > Gynécologie-Obstétrique CHR
THONON, Fabienne ; Centre Hospitalier Universitaire de Liège - CHU > Gynécologie-Obstétrique CHR
Hincourt, Nadine ; Université de Liège - ULiège > Département des sciences cliniques > Gynécologie-Obstétrique-Sénologie
DUBOIS, Michel ; Centre Hospitalier Universitaire de Liège - CHU > Gynécologie-Obstétrique CHR
Foidart, Jean-Michel ; Université de Liège - ULiège > Département des sciences cliniques > Gynécologie - Obstétrique
Munaut, Carine ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Assou S, Haouzi D, Mahmoud K, Aouacheria A, Guillemin Y, Pantesco V, Reme T, Dechaud H, De Vos J, Hamamah S. A non-invasive test for assessing embryo potential by gene expression profiles of human cumulus cells: a proof of concept study. Mol Hum Reprod 2008; 14: 711-719.
Balaban B, Urman B. Effect of oocyte morphology on embryo development and implantation. Reprod Biomed Online 2006;12: 608-615.
Blake DA, Farquhar CM, Johnson N, Proctor M. Cleavage stage versus blastocyst stage embryo transfer in assisted conception. Cochrane Database Syst Rev 2007. CD002118.
Broer SL, Mol B, Dolleman M, Fauser BC, Broekmans FJ. The role of anti-Mullerian hormone assessment in assisted reproductive technology outcome. Curr Opin Obstet Gynecol 2010;22: 193-201.
Gebhardt KM, Feil DK, Dunning KR, Lane M, Russell DL. Human cumulus cell gene expression as a biomarker of pregnancy outcome after single embryo transfer. Fertil Steril 2011;96: 47-52; e42.
Guerif F, Le Gouge A, Giraudeau B, Poindron J, Bidault R, Gasnier O, Royere D. Limited value of morphological assessment at days 1 and 2 to predict blastocyst development potential: a prospective study based on 4042 embryos. Hum Reprod 2007;22: 1973-1981.
Hashimoto S, Kato N, Saeki K, Morimoto Y. Selection of high-potential embryos by culture in poly(dimethylsiloxane) microwells and time-lapse imaging. Fertil Steril 2012;97: 332-337.
Hill MJ, Levens ED. Is there a benefit in follicular flushing in assisted reproductive technology? Curr Opin Obstet Gynecol 2010;22: 208-212.
Kaushansky K. Lineage-specific hematopoietic growth factors. N Engl J Med 2006;354: 2034-2045.
Ledee N, Lombroso R, Lombardelli L, Selva J, Dubanchet S, Chaouat G, Frankenne F, Foidart JM, Maggi E, Romagnani S et al. Cytokines and chemokines in follicular fluids and potential of the corresponding embryo: the role of granulocyte colony-stimulating factor. Hum Reprod 2008;23: 2001-2009.
Ledee N, Munaut C, Serazin V, Perrier d'Hauterive S, Lombardelli L, Logiodice F, Wainer R, Gridelet V, Chaouat G, Frankenne F et al. Performance evaluation of microbead and ELISA assays for follicular G-CSF: a non-invasive biomarker of oocyte developmental competence for embryo implantation. J Reprod Immunol 2010; 86: 126-132.
Ledee N, Frydman R, Osipova A, Taieb J, Gallot V, Lombardelli L, Logiodice F, Petitbarat M, Fanchin R, Chaouat G et al. Levels of follicular G-CSF and interleukin-15 appear as noninvasive biomarkers of subsequent successful birth in modified natural in vitro fertilization/intracytoplasmic sperm injection cycles. Fertil Steril 2011;95: 94-98.
Marino VJ, Roguin LP. The granulocyte colony stimulating factor (G-CSF) activates Jak/STAT and MAPK pathways in a trophoblastic cell line. J Cell Biochem 2008;103: 1512-1523.
Meseguer M, Herrero J, Tejera A, Hilligsoe KM, Ramsing NB, Remohi J. The use of morphokinetics as a predictor of embryo implantation. Hum Reprod 2011;26: 2658-2671.
Patrizio P, Sakkas D. Fromoocyte to baby: a clinical evaluation of the biological efficiency of in vitro fertilization. Fertil Steril 2009;91: 1061-1066.
Pollard JW. Role of colony-stimulating factor-1 in reproduction and development. Mol Reprod Dev 1997;46: 54-60; discussion 60-51.
Revelli A, Delle Piane L, Casano S, Molinari E, Massobrio M, Rinaudo P. Follicular fluid content and oocyte quality: from single biochemical markers to metabolomics. Reprod Biol Endocrinol 2009;7: 40.
Rienzi L, Vajta G, Ubaldi F. Predictive value of oocyte morphology in human IVF: a systematic review of the literature. Hum Reprod Update 2010;17: 34-45.
Robertson SA. GM-CSF regulation of embryo development and pregnancy. Cytokine Growth Factor Rev 2007;18: 287-298.
Salmassi A, SchmutzlerAG, Huang L,Hedderich J, JonatW,Mettler L. Detection of granulocyte colony-stimulating factor and its receptor in human follicular luteinized granulosa cells. Fertil Steril 2004;81(Suppl. 1): 786-791.
Salmassi A, Schmutzler AG, Schaefer S, Koch K, Hedderich J, Jonat W, Mettler L. Is granulocyte colony-stimulating factor level predictive for human IVF outcome? Hum Reprod 2005a;20: 2434-2440.
Salmassi A, Zhang Z, Schmutzler AG, Koch K, Buck S, JonatW, Mettler L. Expression of mRNA and protein of macrophage colony-stimulating factor and its receptor in human follicular luteinized granulosa cells. Fertil Steril 2005b;83: 419-425.
Setti PE, Bulletti C. Strategies to improve embryo implantation to supraphysiological rates. Ann N Y Acad Sci 2011;1221: 75-79.
Sills ES, Palermo GD. Human blastocyst culture in IVF: current laboratory applications in reproductive medicine practice. Rom J Morphol Embryol 2010;51: 441-445.
Steyerberg EW, Eijkemans MJ, Harrell FE Jr, Habbema JD. Prognostic modelling with logistic regression analysis: a comparison of selection and estimation methods in small data sets. Stat Med 2000; 19: 1059-1079.
Wongtra-Ngan S, Vutyavanich T, Brown J. Follicular flushing during oocyte retrieval in assisted reproductive techniques. Cochrane Database Syst Rev 2010. CD004634.
Yanagi K, Makinoda S, Fujii R, Miyazaki S, Fujita S, Tomizawa H, Yoshida K, Iura T, Takegami T, Nojima T. Cyclic changes of granulocyte colony-stimulating factor (G-CSF) mRNA in the human follicle during the normal menstrual cycle and immunolocalization of G-CSF protein. Hum Reprod 2002;17: 3046-3052.
Zhao Y, Rong H, Chegini N. Expression and selective cellular localization of granulocyte-macrophage colony-stimulating factor (GM-CSF) and GM-CSF alpha and beta receptor messenger ribonucleic acid and protein in human ovarian tissue. Biol Reprod 1995;53: 923-930.