卵泡液中生长因子对卵母细胞发育和质量的影响

doi:10.12280/gjszjk.20240527

摘要/Abstract

摘要：

卵泡液（follicular fluid）是由穿过血-卵泡屏障的血浆及颗粒细胞和卵泡膜细胞分泌的活性物质组合而成，其含有的多种生长因子对卵母细胞的发育和质量具有重要影响，这些生长因子包括转化生长因子-β超家族的生长因子、胰岛素样生长因子、肿瘤坏死因子-α、血管内皮生长因子和白细胞介素（interleukin，IL）等。它们通过与特异的、高亲和性的细胞膜受体结合，调节细胞生长和功能，进而影响卵母细胞的成熟和质量，以及随后的受精、胚胎发育和妊娠结局。卵泡液中生长因子的浓度可能与卵母细胞质量有关，其中骨形态发生蛋白-15（bone morphogenetic protein-15，BMP-15）、生长分化因子-9（growth differentiation factor-9，GDF-9）和IL-6等因子备受关注。尽管目前对于这些生长因子与卵母细胞质量间的关系尚存争议，但未来的研究有望揭示它们之间的确切联系，为临床提供更准确的卵母细胞质量和胚胎发育的预测方法。

关键词: 卵泡液, 胞间信号肽类和蛋白质类, 转化生长因子β, 白细胞介素类, 卵母细胞质量

Abstract:

Follicular fluid is composed of the plasma that crosses the blood-follicle barrier and the active substances secreted by granulosa cells and theca cells. It contains various growth factors that significantly influence the development and quality of oocytes, including members of the transforming growth factor-β superfamily, insulin-like growth factors, tumor necrosis factor-α, vascular endothelial growth factors, interleukins (IL) and others. They regulate cell growth and function by binding to specific, high-affinity receptors of membrane, thereby affecting oocyte maturation and quality, as well as subsequent fertilization, embryonic development, and pregnancy outcomes. The concentrations of growth factors in follicular fluid may be related to oocyte quality. These factors such as bone morphogenetic protein-15 (BMP-15), growth differentiation factor-9 (GDF-9) and IL-6 have garnered significant attention. Although the relationship between growth factors and oocyte quality remains controversial, future research will reveal their exact connection, providing more accurate methods for predicting oocyte quality and embryonic development in clinical practice.

Key words: Follicular fluid, Intercellular signaling peptides and proteins, Transforming growth factor beta, Interleukins, Oocyte quality

王云凤, 侯海燕, 王建梅. 卵泡液中生长因子对卵母细胞发育和质量的影响[J]. 国际生殖健康/计划生育杂志, 2025, 44(2): 137-143.

WANG Yun-feng, HOU Hai-yan, WANG Jian-mei. Effect of Growth Factors in Follicular Fluid on Oocyte Development and Quality[J]. Journal of International Reproductive Health/Family Planning, 2025, 44(2): 137-143.

参考文献 48

[1]	黄剑磊, 陈书强, 王明, 等. 卵泡液代谢标志物与多囊卵巢综合征患者卵母细胞质量的相关性[J]. 解剖学报, 2021, 52(2):289-294. doi: 10.16098/j.issn.0529-1356.2021.02.020.
[2]	Li Y, Lin YF, Zhou X, et al. Ablation of TGFBR3 (betaglycan) in oocytes does not affect fertility in female mice[J]. Reproduction, 2021, 161(3):289-294. doi: 10.1530/REP-20-0515.
[3]	Lau CP, Ledger WL, Groome NP, et al. Dimeric inhibins and activin A in human follicular fluid and oocyte-cumulus culture medium[J]. Hum Reprod, 1999, 14(10):2525-2530. doi: 10.1093/humrep/14.10.2525. pmid: 10527982
[4]	Wen X, Tozer AJ, Butler SA, et al. Follicular fluid levels of inhibin A, inhibin B, and activin A levels reflect changes in follicle size but are not independent markers of the oocyte's ability to fertilize[J]. Fertil Steril, 2006, 85(6):1723-1729. doi: 10.1016/j.fertnstert.2005.11.058. pmid: 16650414
[5]	Fried G, Remaeus K, Harlin J, et al. Inhibin B predicts oocyte number and the ratio IGF-I/IGFBP-1 may indicate oocyte quality during ovarian hyperstimulation for in vitro fertilization[J]. J Assist Reprod Genet, 2003, 20(5):167-176. doi: 10.1023/a:1023656225053.
[6]	Chang CL, Wang TH, Horng SG, et al. The concentration of inhibin B in follicular fluid: relation to oocyte maturation and embryo development[J]. Hum Reprod, 2002, 17(7):1724-1728. doi: 10.1093/humrep/17.7.1724.
[7]	Ocal P, Aydin S, Cepni I, et al. Follicular fluid concentrations of vascular endothelial growth factor, inhibin A and inhibin B in IVF cycles: are they markers for ovarian response and pregnancy outcome?[J]. Eur J Obstet Gynecol Reprod Biol, 2004, 115(2):194-199. doi: 10.1016/j.ejogrb.2004.01.034. pmid: 15262355
[8]	Bouzoni E, Gavriil E, Anastasilakis AD, et al. Embryo Quality May Be Associated With Serum Inhibin B Levels but Not With Serum or Follicular Fluid Levels of Other Components of the Activin-Follistatin-Inhibin Axis[J]. Endocr Pract, 2022, 28(10):1086-1090. doi: 10.1016/j.eprac.2022.08.001.
[9]	Mashiach R, Amit A, Hasson J, et al. Follicular fluid levels of anti-Mullerian hormone as a predictor of oocyte maturation, fertilization rate, and embryonic development in patients with polycystic ovary syndrome[J]. Fertil Steril, 2010, 93(7):2299-2302. doi: 10.1016/j.fertnstert.2009.01.125. pmid: 19261276
[10]	Kim JH, Lee JR, Chang HJ, et al. Anti-Müllerian hormone levels in the follicular fluid of the preovulatory follicle: a predictor for oocyte fertilization and quality of embryo[J]. J Korean Med Sci, 2014, 29(9):1266-1270. doi: 10.3346/jkms.2014.29.9.1266. pmid: 25246746
[11]	Sacha CR, Chavarro JE, Williams PL, et al. Follicular fluid anti-Müllerian hormone (AMH) concentrations and outcomes of in vitro fertilization cycles with fresh embryo transfer among women at a fertility center[J]. J Assist Reprod Genet, 2020, 37(11):2757-2766. doi: 10.1007/s10815-020-01956-7.
[12]	Fountas S, Petinaki E, Bolaris S, et al. The Roles of GDF-9, BMP-15, BMP-4 and EMMPRIN in Folliculogenesis and In Vitro Fertilization[J]. J Clin Med, 2024, 13(13):3775. doi: 10.3390/jcm13133775.
[13]	De Los Reyes M, Palomino J, Araujo A, et al. Cyclooxygenase 2 messenger RNA levels in canine follicular cells: interrelationship with GDF-9, BMP-15, and progesterone[J]. Domest Anim Endocrinol, 2021,74:106529. doi: 10.1016/j.domaniend.2020.106529.
[14]	Sanfins A, Rodrigues P, Albertini DF. GDF-9 and BMP-15 direct the follicle symphony[J]. J Assist Reprod Genet, 2018, 35(10):1741-1750. doi: 10.1007/s10815-018-1268-4.
[15]	Dumesic DA, Meldrum DR, Katz-Jaffe MG, et al. Oocyte environment: follicular fluid and cumulus cells are critical for oocyte health[J]. Fertil Steril, 2015, 103(2):303-316. doi: 10.1016/j.fertnstert.2014.11.015. pmid: 25497448
[16]	Wu YT, Tang L, Cai J, et al. High bone morphogenetic protein-15 level in follicular fluid is associated with high quality oocyte and subsequent embryonic development[J]. Hum Reprod, 2007, 22(6):1526-1531. doi: 10.1093/humrep/dem029.
[17]	Deveci D. Alterations in follicular fluid BMP-15 RNA expression in women undergoing controlled ovarian hyperstimulation[J]. Turk J Med Sci, 2020, 50(5):1247-1253. doi: 10.3906/sag-2002-208. pmid: 32304195
[18]	Kristensen SG, Kumar A, Mamsen LS, et al. Intrafollicular Concentrations of the Oocyte-secreted Factors GDF9 and BMP15 Vary Inversely in Polycystic Ovaries[J]. J Clin Endocrinol Metab, 2022, 107(8):e3374-e3383. doi: 10.1210/clinem/dgac272.
[19]	Yoon JD, Hwang SU, Kim M, et al. Growth differentiation factor 8 regulates SMAD2/3 signaling and improves oocyte quality during porcine oocyte maturation in vitro[J]. Biol Reprod, 2019, 101(1):63-75. doi: 10.1093/biolre/ioz066.
[20]	Fang L, Wang S, Li Y, et al. High GDF-8 in follicular fluid is associated with a low pregnancy rate in IVF patients with PCOS[J]. Reproduction, 2020, 160(1):11-19. doi: 10.1530/REP-20-0077.
[21]	Mehdizadeh A, Soleimani M, Amjadi F, et al. Implication of Novel BMP15 and GDF9 Variants in Unexpected Poor Ovarian Response[J]. Reprod Sci, 2024, 31(3):840-850. doi: 10.1007/s43032-023-01370-1.
[22]	Esencan E, Beroukhim G, Seifer DB. Age-related changes in Folliculogenesis and potential modifiers to improve fertility outcomes - A narrative review[J]. Reprod Biol Endocrinol, 2022, 20(1):156. doi: 10.1186/s12958-022-01033-x.
[23]	Stoecklein KS, Ortega MS, Spate LD, et al. Improved cryopreservation of in vitro produced bovine embryos using FGF2, LIF, and IGF1[J]. PLoS One, 2021, 16(2):e0243727. doi: 10.1371/journal.pone.0243727.
[24]	Peron R, Vatanabe IP, Manzine PR, et al. Alpha-Secretase ADAM10 Regulation: Insights into Alzheimer's Disease Treatment[J]. Pharmaceuticals(Basel), 2018, 11(1):12. doi: 10.3390/ph11010012.
[25]	Molka B, Gwladys B, Dorian B, et al. Follicular Fluid Growth Factors and Interleukin Profiling as Potential Predictors of IVF Outcomes[J]. Front Physiol, 2022,13:859790. doi: 10.3389/fphys.2022.859790.
[26]	Wang TH, Chang CL, Wu HM, et al. Insulin-like growth factor-II (IGF-II), IGF-binding protein-3 (IGFBP-3), and IGFBP-4 in follicular fluid are associated with oocyte maturation and embryo development[J]. Fertil Steril, 2006, 86(5):1392-1401. doi: 10.1016/j.fertnstert.2006.03.064.
[27]	Revelli A, Delle Piane L, Casano S, et al. Follicular fluid content and oocyte quality: from single biochemical markers to metabolomics[J]. Reprod Biol Endocrinol, 2009,7:40. doi: 10.1186/1477-7827-7-40.
[28]	Asimakopoulos B, Abu-Hassan D, Metzen E, et al. The levels of steroid hormones and cytokines in individual follicles are not associated with the fertilization outcome after intracytoplasmic sperm injection[J]. Fertil Steril, 2008, 90(1):60-64. doi: 10.1016/j.fertnstert.2007.05.054. pmid: 17980366
[29]	Currin L, Glanzner WG, Gutierrez K, et al. Optimizing swine in vitro embryo production with growth factor and antioxidant supplementation during oocyte maturation[J]. Theriogenology, 2022, 194:133-143. doi: 10.1016/j.theriogenology. pmid: 36244270
[30]	Sinderewicz E, Grycmacher K, Boruszewska D, et al. Expression of factors involved in apoptosis and cell survival is correlated with enzymes synthesizing lysophosphatidic acid and its receptors in granulosa cells originating from different types of bovine ovarian follicles[J]. Reprod Biol Endocrinol, 2017, 15(1):72. doi: 10.1186/s12958-017-0287-9.
[31]	许嘉绵, 毛丽华, 林春丽, 等. 卵泡液中sRAGE、Vit D和TNF-α的含量与卵母细胞质量的相关性研究[J]. 生殖医学杂志, 2023, 32(9):1387-1392. doi: 10.3969/j.issn.1004-3845.2023.09.014.
[32]	Lee KS, Joo BS, Na YJ, et al. Relationships between concentrations of tumor necrosis factor-alpha and nitric oxide in follicular fluid and oocyte quality[J]. J Assist Reprod Genet, 2000, 17(4):222-228. doi: 10.1023/a:1009495913119.
[33]	Monteleone P, Giovanni Artini P, Simi G, et al. Follicular fluid VEGF levels directly correlate with perifollicular blood flow in normoresponder patients undergoing IVF[J]. J Assist Reprod Genet, 2008, 25(5):183-186. doi: 10.1007/s10815-008-9218-1.
[34]	Chen HT, Wu WB, Lin JJ, et al. Identification of potential angiogenic biomarkers in human follicular fluid for predicting oocyte maturity[J]. Front Endocrinol(Lausanne), 2023,14:1173079. doi: 10.3389/fendo.2023.1173079.
[35]	Malamitsi-Puchner A, Sarandakou A, Baka SG, et al. Concentrations of angiogenic factors in follicular fluid and oocyte-cumulus complex culture medium from women undergoing in vitro fertilization: association with oocyte maturity and fertilization[J]. Fertil Steril, 2001, 76(1):98-101. doi: 10.1016/s0015-0282(01)01854-4. pmid: 11438326
[36]	Turienzo A, Lledó B, Ortiz JA, et al. Prevalence of candidate single nucleotide polymorphisms on p53, IL-11, IL-10, VEGF and APOE in patients with repeated implantation failure (RIF) and pregnancy loss (RPL)[J]. Hum Fertil(Camb), 2020, 23(2):117-122. doi: 10.1080/14647273.2018.1524935.
[37]	Barroso G, Barrionuevo M, Rao P, et al. Vascular endothelial growth factor, nitric oxide, and leptin follicular fluid levels correlate negatively with embryo quality in IVF patients[J]. Fertil Steril, 1999, 72(6):1024-1026. doi: 10.1016/S0015-0282(99)00442-2. pmid: 10593375
[38]	lhan G, Bacanakgil BH, Vuruskan AK, et al. The effect of individual oocyte matched follicular fluid oxidant, antioxidant status, and pro- and anti-inflammatory cytokines on IVF outcomes of patients with diminished ovarian reserve[J]. Medicine(Baltimore), 2023, 102(4):e32757. doi: 10.1097/MD.0000000000032757.
[39]	Stojanovic Gavrilovic AZ, Cekovic JM, Parandilovic AZ, et al. IL-6 of follicular fluid and outcome of in vitro fertilization[J]. Medicine(Baltimore), 2022, 101(29):e29624. doi: 10.1097/MD.0000000000029624.
[40]	Kocyigit A, Cevik M. Effects of leukemia inhibitory factor and insulin-like growth factor-I on the cell allocation and cryotolerance of bovine blastocysts[J]. Cryobiology, 2015, 71(1):64-69. doi: 10.1016/j.cryobiol.2015.05.068. pmid: 26025880
[41]	Reiter RJ, Tan DX, Manchester LC, et al. Melatonin reduces oxidant damage and promotes mitochondrial respiration: implications for aging[J]. Ann N Y Acad Sci, 2002, 959:238-250. doi: 10.1111/j.1749-6632.2002.tb02096.x.
[42]	Adamczak R, Ukleja-Sokołowska N, Lis K, et al. Progesterone-induced blocking factor 1 and cytokine profile of follicular fluid of infertile women qualified to in vitro fertilization: The influence on fetus development and pregnancy outcome[J]. Int J Immunopathol Pharmacol, 2022,36:3946320221111134. doi: 10.1177/03946320221111134.
[43]	Li Z, Zhu Y, Li H, et al. Leukaemia inhibitory factor in serum and follicular fluid of women with polycystic ovary syndrome and its correlation with IVF outcome[J]. Reprod Biomed Online, 2018, 36(4):483-489. doi: 10.1016/j.rbmo.2017.12.020. pmid: 29397316
[44]	Moreira MV, Vale-Fernandes E, Albergaria IC, et al. Follicular fluid composition and reproductive outcomes of women with polycystic ovary syndrome undergoing in vitro fertilization: A systematic review[J]. Rev Endocr Metab Disord, 2023, 24(6):1045-1073. doi: 10.1007/s11154-023-09819-z.
[45]	Zhang H, Wang X, Xu J, et al. IL-18 and IL-18 binding protein concentration in ovarian follicular fluid of women with unexplained infertility to PCOS during in vitro fertilization[J]. J Reprod Immunol, 2020,138:103083. doi: 10.1016/j.jri.2020.103083.
[46]	Lai TH, Chen HT, Wu PH, et al. The Presence of TGFβ3 in Human Ovarian Intrafollicular Fluid and Its Involvement in Thromboxane Generation in Follicular Granulosa Cells through a Canonical TGFβRI, Smad2/3 Signaling Pathway and COX-2 Induction[J]. Int J Mol Sci, 2024, 25(10):5558. doi: 10.3390/ijms25105558.
[47]	Hosseini E, Aghajanpour S, Chekini Z, et al. An Approach to Improve Endometrial Receptivity: Is It Beneficial to Flush The Uterine Cavity with Follicular Fluid and Granulosa Cells? A Phase III Randomised Clinical Trial[J]. Int J Fertil Steril, 2024, 18(Suppl 1):22-29. doi: 10.22074/ijfs.2023.2000897.1461. pmid: 39033367
[48]	Piccinni MP, Vicenti R, Logiodice F, et al. Description of the Follicular Fluid Cytokine and Hormone Profiles in Human Physiological Natural Cycles[J]. J Clin Endocrinol Metab, 2021, 106(2):e721-e738. doi: 10.1210/clinem/dgaa880.