Can follicular Emmprin and BMP 4 levels predict ICSI outcome?

Purpose To evaluate the relationship of clinical pregnancy rates with bone morphogenetic proteins 2-4-7 (BMP 2, 4, 7), growth differentiation factor 9 (GDF 9), and Emmprin levels in follicular fluid of intracytoplasmic sperm injection patients.

Follicular fluid of 77 patients who underwent ICSI procedure was collected during the oocyte retrieval procedure. And follicular fluid levels of BMP 2, BMP 4, BMP 7, GDF 9, and Emmprin (Basigin) were measured and compared for clinical pregnancy rates.

Follicular levels of BMP 4 was significantly higher whereas Emmprin levels were lower in patients who had achieved clinically diagnosed pregnancy compared with those who did not achieve clinical pregnancy after ICSI procedure (P = 0.007 and P = 0.035, respectively). BMP 2, BMP 7, and GDF 9 levels were comparable for both groups.

Clinical pregnancy rates after ICSI may be associated with follicular fluid levels of Emmprin and BMP 4. Follicular levels of Emmprin and BMP 4 can be used as a marker (as markers for predicting ICSI outcomes) for a better ICSI outcome. Similar content being viewed by others

Burdge GC, Hanson MA, Slater-Jefferies JL, Lillycrop KA. Epigenetic regulation of transcription: a mechanism for inducing variations in phenotype (fetal programming) by differences in nutrition during early life? Br J Nutr. 2007;97(6):1036–46. https://doi.org/10.1017/S0007114507682920. Leroy JL, Vanholder T, Delanghe JR, Opsomer G, Van Soom A, Bols PE, et al. Metabolic changes in follicular fluid of the dominant follicle in high-yielding dairy cows early post partum. Theriogenology. 2004;62(6):1131–43. https://doi.org/10.1016/j.theriogenology.2003.12.017. Gougeon A. Regulation of ovarian follicular development in primates: facts and hypotheses. Endocr Rev. 1996;17(2):121–55. https://doi.org/10.1210/edrv-17-2-121. Knight PG, Glister C. TGF-beta superfamily members and ovarian follicle development. Reproduction. 2006;132(2):191–206. https://doi.org/10.1530/rep.1.01074. Juengel JL, Reader KL, Bibby AH, Lun S, Ross I, Haydon LJ, et al. The role of bone morphogenetic proteins 2, 4, 6 and 7 during ovarian follicular development in sheep: contrast to rat. Reproduction. 2006;131(3):501–13. https://doi.org/10.1530/rep.1.00958. Persani L, Rossetti R, Di Pasquale E, Cacciatore C, Fabre S. The fundamental role of bone morphogenetic protein 15 in ovarian function and its involvement in female fertility disorders. Hum Reprod Update. 2014;20(6):869–83. https://doi.org/10.1093/humupd/dmu036. da Cunha EV, de Souza GB, Passos JRS, Silva AWB, Dau AM, Saraiva MVA, et al. Effects of bone morphogenetic protein 4 (BMP4) on in vitro development and survival of bovine preantral follicles enclosed in fragments ovarian tissue. Zygote. 2017;25(3):256–64. https://doi.org/10.1017/S0967199417000089. Israel DI, Nove J, Kerns KM, Kaufman RJ, Rosen V, Cox KA, et al. Heterodimeric bone morphogenetic proteins show enhanced activity in vitro and in vivo. Growth Factors. 1996;13(3–4):291–300. Peng J, Li Q, Wigglesworth K, Rangarajan A, Kattamuri C, Peterson RT, et al. Growth differentiation factor 9:bone morphogenetic protein 15 heterodimers are potent regulators of ovarian functions. Proc Natl Acad Sci U S A. 2013;110(8):E776–85. https://doi.org/10.1073/pnas.1218020110. Kaivo-Oja N, Mottershead DG, Mazerbourg S, Myllymaa S, Duprat S, Gilchrist RB, et al. Adenoviral gene transfer allows Smad-responsive gene promoter analyses and delineation of type I receptor usage of transforming growth factor-beta family ligands in cultured human granulosa luteal cells. J Clin Endocrinol Metab. 2005;90(1):271–8. https://doi.org/10.1210/jc.2004-1288. Kuno N, Kadomatsu K, Fan QW, Hagihara M, Senda T, Mizutani S, et al. Female sterility in mice lacking the basigin gene, which encodes a transmembrane glycoprotein belonging to the immunoglobulin superfamily. FEBS Lett. 1998;425(2):191–4. Igakura T, Kadomatsu K, Kaname T, Muramatsu H, Fan QW, Miyauchi T, et al. A null mutation in basigin, an immunoglobulin superfamily member, indicates its important roles in peri-implantation development and spermatogenesis. Dev Biol. 1998;194(2):152–65. Chang H, Ni H, Ma XH, Xu LB, Kadomatsu K, Muramatsu T, et al. Basigin expression and regulation in mouse ovary during the sexual maturation and development of corpus luteum. Mol Reprod Dev. 2004;68(2):135–41. https://doi.org/10.1002/mrd.20060. Bastu E, Gokulu SG, Dural O, Yasa C, Bulgurcuoglu S, Karamustafaoglu Balci B, et al. The association between follicular fluid levels of cathepsin B, relaxin or AMH with clinical pregnancy rates in infertile patients. Eur J Obstet Gynecol Reprod Biol. 2015;187:30–4. https://doi.org/10.1016/j.ejogrb.2015.02.009. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248–54. Little SC, Mullins MC. Bone morphogenetic protein heterodimers assemble heteromeric type I receptor complexes to pattern the dorsoventral axis. Nat Cell Biol. 2009;11(5):637–43. https://doi.org/10.1038/ncb1870. Valera E, Isaacs MJ, Kawakami Y, Izpisua Belmonte JC, Choe S. BMP-2/6 heterodimer is more effective than BMP-2 or BMP-6 homodimers as inductor of differentiation of human embryonic stem cells. PLoS One. 2010;5(6):e11167. https://doi.org/10.1371/journal.pone.0011167. Young JM, McNeilly AS. Theca: the forgotten cell of the ovarian follicle. Reproduction. 2010;140(4):489–504. https://doi.org/10.1530/rep-10-0094. Tanwar PS, McFarlane JR. Dynamic expression of bone morphogenetic protein 4 in reproductive organs of female mice. Reproduction. 2011;142(4):573–9. https://doi.org/10.1530/rep-10-0299. Nilsson EE, Skinner MK. Bone morphogenetic protein-4 acts as an ovarian follicle survival factor and promotes primordial follicle development. Biol Reprod. 2003;69(4):1265–72. https://doi.org/10.1095/biolreprod.103.018671. Bertoldo MJ, Duffard N, Bernard J, Frapsauce C, Calais L, Rico C, et al. Effects of bone morphogenetic protein 4 (BMP4) supplementation during culture of the sheep ovarian cortex. Anim Reprod Sci. 2014;149(3–4):124–34. https://doi.org/10.1016/j.anireprosci.2014.07.010. Childs AJ, Kinnell HL, Collins CS, Hogg K, Bayne RA, Green SJ, et al. BMP signaling in the human fetal ovary is developmentally regulated and promotes primordial germ cell apoptosis. Stem Cells. 2010;28(8):1368–78. https://doi.org/10.1002/stem.440. Davidson B, Goldberg I, Berner A, Kristensen GB, Reich R. EMMPRIN (extracellular matrix metalloproteinase inducer) is a novel marker of poor outcome in serous ovarian carcinoma. Clin Exp Metastasis. 2003;20(2):161–9. Muramatsu T, Miyauchi T. Basigin (CD147): a multifunctional transmembrane protein involved in reproduction, neural function, inflammation and tumor invasion. Histol Histopathol. 2003;18(3):981–7. https://doi.org/10.14670/HH-18.981. Biswas C, Zhang Y, DeCastro R, Guo H, Nakamura T, Kataoka H, et al. The human tumor cell-derived collagenase stimulatory factor (renamed EMMPRIN) is a member of the immunoglobulin superfamily. Cancer Res. 1995;55(2):434–9. Fan QW, Yuasa S, Kuno N, Senda T, Kobayashi M, Muramatsu T, et al. Expression of basigin, a member of the immunoglobulin superfamily, in the mouse central nervous system. Neurosci Res. 1998;30(1):53–63. Smedts AM, Lele SM, Modesitt SC, Curry TE. Expression of an extracellular matrix metalloproteinase inducer (basigin) in the human ovary and ovarian endometriosis. Fertil Steril. 2006;86(3):535–42. https://doi.org/10.1016/j.fertnstert.2006.01.042. Smedts AM, Curry TE Jr. Expression of basigin, an inducer of matrix metalloproteinases, in the rat ovary. Biol Reprod. 2005;73(1):80–7. https://doi.org/10.1095/biolreprod.104.036145. Shimizu T, Kayamori T, Murayama C, Miyamoto A. Bone morphogenetic protein (BMP)-4 and BMP-7 suppress granulosa cell apoptosis via different pathways: BMP-4 via PI3K/PDK-1/Akt and BMP-7 via PI3K/PDK-1/PKC. Biochem Biophys Res Commun. 2012;417(2):869–73. https://doi.org/10.1016/j.bbrc.2011.12.064. Acknowledgments We are thankful for all procedural help of the Infertility Department of Istanbul School of Medicine staff. Funding This study was funded by authors. Author information Authors and Affiliations Corresponding author Ethics declarations Institutional review boards approved the study and informed consent forms had been obtained from all participants included in the study. All procedures performed in this study were in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Conflict of interest The authors declare that they have no conflict of interest. Additional information Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions About this article Cite this article Takmaz, O., Yozgatli, D., Ozaltin, S. et al. Can follicular Emmprin and BMP 4 levels predict ICSI outcome?. J Assist Reprod Genet 36, 1127–1133 (2019). https://doi.org/10.1007/s10815-019-01459-0 Received: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s10815-019-01459-0