{"paper_id":"eda4bbc0-3588-4765-aaec-1fd210cce8e6","body_text":"Abstract\nA systematic review was conducted pertaining to the biologic processes of cumulus cells and measures of oocyte quality. The initial search yielded 18,549 articles, and after screening, 65 studies were included in this review. Extracted data were synthesized descriptively. Articles were categorized based on the biologic feature of cumulus cells addressed: genetic expression, biochemical activity, and morphologic characteristics. Manuscripts addressing cumulus cell function in association with gynecologic conditions and their impact on oocyte quality were also reviewed. Findings from six studies showed an association between increased expression of pathways related to extracellular matrix development (HAS2, VCAN) and improved oocyte quality. Six manuscripts reported improved oocyte quality related to genes involved in cumulus cell expansion (GREM1, PTGS2) and 6 articles noted patterns in expression of regulators of apoptotic pathways (BCL2, BIRC5, MDM2, PGAM5). Twelve studies examined biochemical features of cumulus cells, including cumulus mitochondrial membrane resistance, respirometric index, and acetyl-CoA levels, which have been associated with oocyte development. Morphologic assessment of cumulus cells was evaluated by 5 studies, demonstrating a relationship between mitochondrial dimensions, telomere length, and cumulus density/dispersion with oocyte quality. Twenty-two articles assessed cumulus cell function and its relationship with oocyte quality in diseases such as polycystic ovarian syndrome (PCOS) and endometriosis conditions, and increased maternal age (with or without decreased ovarian reserve). This comprehensive systematic review has integrated findings from studies investigating the relationship between cumulus cells and oocyte quality, identifying patterns in gene expression, biochemical features and morphologic assessments that may offer meaningful insight into this relationship.\nSimilar content being viewed by others\nData Availability\nThe data that support the findings of this study were derived from the following resources available in the public domain: PubMed, Embase, PsycINFO, and Cochrane Library databases.\nCode Availability\nN/A.\nReferences\nThoma ME, et al. Prevalence of infertility in the united States as estimated by the current duration approach and a traditional constructed approach. Fertil Steril. 2013;99(5):1324–31. https://doi.org/10.1016/j.fertnstert.2012.11.037.\nSirard M-A, Richard F, Blondin P, Robert C. Contribution of the oocyte to embryo quality. Theriogenology. 2006;65(1):126–36. https://doi.org/10.1016/j.theriogenology.2005.09.020.\nLasienë K, Vitkus A, Valanèiûtë A, Lasys V. Morphological criteria of oocyte quality. Med (B Aires). 2009;45(7):509.\nPatounakis G, Hill MJ. The preimplantation genetic testing debate continues: first the hype, then the tension, now the hypertension? Fertil Steril. Aug. 2019;112(2):233–4. https://doi.org/10.1016/j.fertnstert.2019.04.028.\nTurathum B, Gao E-M, Chian R-C. The function of cumulus cells in oocyte growth and maturation and in subsequent ovulation and fertilization. Cells. 2021;10(9). https://doi.org/10.3390/cells10092292.\nGilchrist RB, Lane M, Thompson JG. Oocyte-secreted factors: regulators of cumulus cell function and oocyte quality, Hum Reprod Update. 2008;14(2):159–177. https://doi.org/10.1093/humupd/dmm040\nMoher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med. 2009;6(7):e1000097. https://doi.org/10.1371/journal.pmed.1000097\nPeterson J, Welch V, Losos M, Tugwell P. The Newcastle-Ottawa scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ott Hosp Res Inst. 2011;2(1):1–12.\nCillo F, Brevini TAL, Antonini S, Paffoni A, Ragni G, Gandolfi F. Association between human oocyte developmental competence and expression levels of some cumulus genes. Reproduction. 2007;134(5):645–50. https://doi.org/10.1530/REP-07-0182.\nScarica C, et al. An integrated investigation of oocyte developmental competence: expression of key genes in human cumulus cells, morphokinetics of early divisions, blastulation, and euploidy. J Assist Reprod Genet. 2019;36(5):875–87. https://doi.org/10.1007/s10815-019-01410-3.\nMcKenzie LJ et al. Human cumulus granulosa cell gene expression: a predictor of fertilization and embryo selection in women undergoing IVF. Human Reproduction. 2004;19(12):2869–2874. https://doi.org/10.1093/humrep/deh535\nShen Q, Chen M, Zhao X, Liu Y, Ren X, Zhang L. Versican expression level in cumulus cells is associated with human oocyte developmental competence. Syst Biol Reprod Med. 2020;66(3):176–84. https://doi.org/10.1080/19396368.2020.1725685.\nAdriaenssens T, et al. Cumulus cell gene expression is associated with oocyte developmental quality and influenced by patient and treatment characteristics. Hum Reprod. 2010;25(5):1259–70. https://doi.org/10.1093/humrep/deq049.\nHuang X et al. Differences in the transcriptional profiles of human cumulus cells isolated from MI and MII oocytes of patients with polycystic ovary syndrome, Int J Fertil Steril. 2014;8:36. https://www.embase.com/search/results?subaction=viewrecord%26id=L71786129%26from=export\nZhang X, Jafari N, Barnes RB, Confino E, Milad M, Kazer RR. Studies of gene expression in human cumulus cells indicate pentraxin 3 as a possible marker for oocyte quality, Fertil Steril. 2005;83(4):1169–1179. https://doi.org/10.1016/j.fertnstert.2004.11.030\nShafienia H et al. Target gene repression mediated by miR-144 and miR-224 in cumulus cells is related to the success of oocyte in vitro maturation and fertilisation in patients with polycystic ovary syndrome (PCOS). Reprod Fertil Dev. 2022;34(17):1089–1098. https://doi.org/10.1071/RD22082\nAllegra A, et al. The gene expression profile of cumulus cells reveals altered pathways in patients with endometriosis. J Assist Reprod Genet. 2014;31(10):1277–85. https://doi.org/10.1007/s10815-014-0305-1.\nWyse BA, Fuchs Weizman N, Kadish S, Balakier H, Sangaralingam M, Librach CL. Transcriptomics of cumulus cells– a window into oocyte maturation in humans. J Ovarian Res. 2020;13(1):93. https://doi.org/10.1186/s13048-020-00696-7.\nAnderson RA, et al. Cumulus gene expression as a predictor of human oocyte fertilisation, embryo development and competence to Establish a pregnancy. Reproduction. 2009;138(4):629–37. https://doi.org/10.1530/REP-09-0144.\nFeuerstein P, Cadoret V, Dalbies-Tran R, Guerif F, Bidault R, Royere D. Gene expression in human cumulus cells: one approach to oocyte competence, Human Reproduction. 2007;22(12):3069–3077. https://doi.org/10.1093/humrep/dem336\nFilali M, et al. Oocyte in-vitro maturation: BCL2 mRNA content in cumulus cells reflects oocyte competency. Reprod Biomed Online. 2009;19:71–84. https://doi.org/10.1016/S1472-6483(10)61071-1.\nArtini PG et al. Cumulus cells surrounding oocytes with high developmental competence exhibit down-regulation of phosphoinositol 1,3 kinase/protein kinase B (PI3K/AKT) signalling genes involved in proliferation and survival. Human Reproduction. 2017;32(12):2474–2484. https://doi.org/10.1093/humrep/dex320\nHaraguchi H, et al. Mdm2-p53-SF1 pathway in ovarian granulosa cells directs ovulation and fertilization by conditioning oocyte quality. FASEB J. 2019;33(2):2610–20. https://doi.org/10.1096/fj.201801401R.\nLi C-J, Lin L-T, Tsai H-W, Wen Z-H, Tsui K-H. Phosphoglycerate mutase family member 5 maintains oocyte quality via mitochondrial dynamic rearrangement during aging. Aging Cell. 2022;21(2):e13546. https://doi.org/10.1111/acel.13546.\nAkino R, et al. Next-Generation sequencing reveals downregulation of the Wnt signaling pathway in human dysmature cumulus cells as a hallmark for evaluating oocyte quality. Reproductive Med. 2020;1(3):205–15. https://doi.org/10.3390/reprodmed1030016.\nDumesic DA, et al. Cumulus cell mitochondrial resistance to stress in vitro predicts oocyte development during assisted reproduction. J Clin Endocrinol Metab. 2016;101(5):2235–45. https://doi.org/10.1210/jc.2016-1464.\nAnderson SH, Glassner MJ, Melnikov A, Friedman G, Orynbayeva Z. Respirometric reserve capacity of cumulus cell mitochondria correlates with oocyte maturity. J Assist Reprod Genet. 2018;35(10):1821–30. https://doi.org/10.1007/s10815-018-1271-9.\nKedem-Dickman A, et al. Anti-Müllerian hormone is highly expressed and secreted from cumulus granulosa cells of stimulated preovulatory immature and atretic oocytes. Reprod Biomed Online. 2012;24(5):540–6. https://doi.org/10.1016/j.rbmo.2012.01.023.\nDević Pavlić S et al. Genes for anti-Müllerian hormone and androgen receptor are underexpressed in human cumulus cells surrounding morphologically highly graded oocytes, SAGE Open Med. 2019;7:2050312119865137. https://doi.org/10.1177/2050312119865137\nAnderson S, et al. Cumulus cell acetyl-CoA metabolism from acetate is associated with maternal age but only partially with oocyte maturity. Syst Biol Reprod Med. 2022;68(1):36–43. https://doi.org/10.1080/19396368.2021.2003479.\nMaman E, et al. High expression of luteinizing hormone receptors messenger RNA by human cumulus granulosa cells is in correlation with decreased fertilization. Fertil Steril. 2012;97(3):592–8. https://doi.org/10.1016/j.fertnstert.2011.12.027.\nZhang Y et al. Resolvin E1 in follicular fluid acts as a potential biomarker and improves oocyte developmental competence by optimizing cumulus cells. Front Endocrinol (Lausanne). 2020;11. https://www.frontiersin.org/articles/\nSuchanek E, Grizelj V, Kozaric Z, Simunic V, Casl M-T. Histochemical demonstration of a ∆5,3β-hydroxysteroid dehydrogenase activity of cumulus cells related to the maturity and developmental potential of recovered oocytes. Fertil Steril. 1990;54(5):873–8. https://doi.org/10.1016/S0015-0282(16)53949-1.\nBaratas A, et al. Cumulus cell DNA damage as an index of human oocyte competence. Reproductive Sci. 2022;29(11):3194–200. https://doi.org/10.1007/s43032-021-00817-7.\nBosco L, Chiarelli R, Roccheri MC, Matranga D, Ruvolo G. Relationship between apoptosis and survival molecules in human cumulus cells as markers of oocyte competence. Zygote. 2017;25(5):583–91. https://doi.org/10.1017/S0967199417000429.\nCorn CM, Hauser-Kronberger C, Moser M, Tews G, Ebner T. Predictive value of cumulus cell apoptosis with regard to blastocyst development of corresponding gametes. Fertil Steril. 2005;84(3):627–33. https://doi.org/10.1016/j.fertnstert.2005.03.061.\nGhobadi N et al. Increased telomeric repeat containing RNA (TERRA) levels in cumulus cells of infertile polycystic ovary syndrome patients. Iran J Reproductive Med, pp. 75–75, 2015.\nThanaboonyawat I, Makemaharn O, Petyim S, Laokirkkiat P, Choavaratana R. The correlation of cumulus mucification patterns with oocyte maturation rate in vitro in FSH + LH-primed IVM cycles: a prospective study. Arch Gynecol Obstet. 2016;293(3):681–6. https://doi.org/10.1007/s00404-015-3935-3.\nLeung PS, Lopata A, Kellow GN, Johnston WI, Gronow MJ. A histochemical study of cumulus cells for assessing the quality of preovulatory oocytes. Fertil Steril. 1983;39(6):853–855.\nMurakawa H, et al. Morphological evaluation and measurement of the respiration activity of Cumulus-oocyte complexes to assess oocyte quality. J Mamm Ova Res. 2009;26(1):32–41.\nLourenço B, Sousa AP, Almeida-Santos T, Ramalho-Santos J. Relation of cumulus cell status with single oocyte maturity, fertilization capability and patient age. J Reprod Infertil. 2014;15(1):15–21.\nRibeiro A, et al. Age-related expression of TGF beta family receptors in human cumulus oophorus cells. J Assist Reprod Genet. 2017;34(9):1121–9. https://doi.org/10.1007/s10815-017-0930-6.\nPacella-Ince L, Zander-Fox DL, Lane M. Mitochondrial SIRT3 and its target glutamate dehydrogenase are altered in follicular cells of women with reduced ovarian reserve or advanced maternal age. Human Reproduction. 2014;29(7):1490–1499. https://doi.org/10.1093/humrep/deu071\nAl-Edani T et al. Female aging alters expression of human cumulus cells genes that are essential for oocyte quality. Biomed Res Int. 2014;2014.\nMaraldi T, et al. NADPH oxidase-4 and MATER expressions in granulosa cells: relationships with ovarian aging. Life Sci. 2016;162:108–14. https://doi.org/10.1016/j.lfs.2016.08.007.\nMolinari E, Bar H, Pyle AM, Patrizio P. Transcriptome analysis of human cumulus cells reveals hypoxia as the main determinant of follicular senescence. Mol Hum Reprod. 2016;22(8):866–876.\nSun X, et al. The activated DNA double-strand break repair pathway in cumulus cells from aging patients May be used as a convincing predictor of poor outcomes after in vitro fertilization-embryo transfer treatment. PLoS ONE. 2018;13(9):e0204524.\nLee KS, Joo BS, Na YJ, Yoon MS, Choi OH, Kim WW. Clinical assisted reproduction: cumulus cells apoptosis as an Indicator to predict the quality of oocytes and the outcome of IVF–ET. J Assist Reprod Genet. 2001;18(9):490–8. https://doi.org/10.1023/A:1016649026353.\nLiu Z, et al. Aberrant expression of angiopoietin-like proteins 1 and 2 in cumulus cells is potentially associated with impaired oocyte developmental competence in polycystic ovary syndrome. Gynecol Endocrinol. Jul. 2016;32(7):557–61. https://doi.org/10.3109/09513590.2016.1138463.\nMa Y, et al. ADAMTS1 and HSPG2 mRNA levels in cumulus cells are related to human oocyte quality and controlled ovarian hyperstimulation outcomes. J Assist Reprod Genet. 2020;37(3):657–67. https://doi.org/10.1007/s10815-019-01659-8.\nGohariTaban S, et al. Abnormal expressions of ADAMTS-1, ADAMTS-9 and progesterone receptors are associated with lower oocyte maturation in women with polycystic ovary syndrome. Arch Gynecol Obstet. 2019;299(1):277–86. https://doi.org/10.1007/s00404-018-4967-2.\nLiu Q et al. Involvement of GJA1 and gap junctional intercellular communication between cumulus cells and oocytes from women with PCOS. Biomed Res Int. 2020;2020:1–6. https://doi.org/10.1155/2020/5403904\nGu B-X, et al. Abnormal expression of TLRs may play a role in lower embryo quality of women with polycystic ovary syndrome. Syst Biol Reprod Med. Sep. 2016;62(5):353–8. https://doi.org/10.1080/19396368.2016.1187683.\nHaouzi D, Assou S, Monzo C, Vincens C, Dechaud H, Hamamah S. Altered gene expression profile in cumulus cells of mature MII oocytes from patients with polycystic ovary syndrome. Human Reproduction. 2012;27(12):3523–3530. https://doi.org/10.1093/humrep/des325\nPolzikov M, Yakovenko S, Voznesenskaya J, Troshina M, Zatsepina O. Overexpression of ribosomal RNA in cumulus cells of patients with polycystic ovary syndrome. J Assist Reprod Genet. 2012;29(10):1141–5. https://doi.org/10.1007/s10815-012-9827-6.\nSalehi E, et al. Apoptotic biomarkers in cumulus cells in relation to embryo quality in polycystic ovary syndrome. Arch Gynecol Obstet. 2017;296:1219–27.\nMasoudi M, et al. Notch signaling pathway in cumulus cells reflecting zygote and embryo quality in polycystic ovary syndrome. Arch Gynecol Obstet. 2021;304:1097–105.\nAllegra A, et al. The gene expression profile of cumulus cells reveals altered pathways in patients with endometriosis. J Assist Reprod Genet. Oct. 2014;31(10):1277–85. https://doi.org/10.1007/s10815-014-0305-1.\nGilchrist R. Oocyte-cumulus cell-signaling systems regulating oocyte quality. Biol Reprod. 2008;78(Suppl_1):232\nSaeed-Zidane M et al. Hyaluronic acid and epidermal growth factor improved the bovine embryo quality by regulating the DNA methylation and expression patterns of the focal adhesion pathway. PLoS One. 2019;14(10):e0223753. https://doi.org/10.1371/journal.pone.0223753\nHuszar G, Ozkavukcu S, Jakab A, Celik-Ozenci C, Sati GL, Cayli S. Hyaluronic acid binding ability of human sperm reflects cellular maturity and fertilizing potential: selection of sperm for intracytoplasmic sperm injection. Curr Opin Obstet Gynecol. 2006;18(3). https://journals.lww.com/co-obgyn/Fulltext/2006/06000/Hyaluronic_acid_binding_ability_of_human_sperm.4.aspx\nLi Y, et al. Increased GDF9 and BMP15 mRNA levels in cumulus granulosa cells correlate with oocyte maturation, fertilization, and embryo quality in humans. Reproductive Biology Endocrinol. 2014;12(1):81. https://doi.org/10.1186/1477-7827-12-81.\nWoo J, et al. Effects of elevated progesterone levels on the day of hCG on the quality of oocyte and embryo. J Clin Med. 2022;11(15). https://doi.org/10.3390/jcm11154319.\nAlviggi C, Humaidan P, Howles CM, Tredway D, Hillier SG. Biological versus chronological ovarian age: implications for assisted reproductive technology. Reproductive Biology Endocrinol. 2009;7:1–13.\nSasaki H et al. Impact of oxidative stress on age-associated decline in oocyte developmental competence. Front Endocrinol (Lausanne). 2019;10. https://doi.org/10.3389/fendo.2019.00811https://www.frontiersin.org/articles/\nDunn JD, Alvarez LAJ, Zhang X, Soldati T. Reactive oxygen species and mitochondria: A nexus of cellular homeostasis. Redox Biol. 2015;6:472–85.\nFunding\nNot applicable.\nAuthor information\nAuthors and Affiliations\nContributions\nMR, JS, SD, PG, AH, SD, MS, MD, JS, and BS conceived of the presented idea and supervised the findings of this work. MS, SD, PG, AH searched the databases for review articles for the research questions. MR, JS, SD, PG, AH, SD, MD, JS and BS interpreted the data and wrote the manuscript with help from JS and BS. All authors discussed the results and contributed to the final manuscript.\nCorresponding author\nEthics declarations\nEthics Approval\nN/A.\nConsent to Participate\nN/A.\nConsent for Publication\nN/A.\nCompeting Interests\nThe authors report no conflicts of interest.\nAdditional information\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\nElectronic Supplementary Material\nBelow is the link to the electronic supplementary material.\nRights and permissions\nSpringer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.\nAbout this article\nCite this article\nRohn, M.C.H., Simeone, J.M., Doctorman, S. et al. The Functional Role of Cumulus Cells and Their Influence on Oocyte Quality: A Systematic Review. Reprod. Sci. 32, 2877–2902 (2025). https://doi.org/10.1007/s43032-025-01940-5\nReceived:\nAccepted:\nPublished:\nVersion of record:\nIssue date:\nDOI: https://doi.org/10.1007/s43032-025-01940-5","source_license":"public-domain-us","license_restricted":false}