氧化应激在卵巢相关生殖障碍疾病中的作用

doi:10.12280/gjszjk.20230028

摘要/Abstract

摘要：

活性氧（reactive oxygen species，ROS）在生理状态下作为第二信使发挥细胞信号转导作用，当机体受到缺氧、炎症反应等刺激时，体内ROS水平增加，诱导体内发生氧化应激（oxidative stress）反应。适量的ROS促进卵母细胞的第一次减数分裂，并诱导非优势卵泡进入细胞凋亡。研究表明，氧化应激与多囊卵巢综合征（polycystic ovary syndrome，PCOS）患者的高雄激素血症、胰岛素抵抗、排卵障碍和线粒体损伤等有密切联系；应用抗氧化剂控制氧化应激可能成为早发性卵巢功能不全（premature ovarian insufficiency，POI）的辅助治疗方式。氧化应激抑制DNA甲基化酶引起DNA低甲基化、引起微小RNA及相关活性因子的表达异常，参与卵巢肿瘤细胞增殖和耐药性发生。综述氧化应激在PCOS、POI和卵巢肿瘤等卵巢相关生殖障碍疾病中的作用，展望抗氧化应激治疗的可能应用前景。

关键词: 氧化性应激, 多囊卵巢综合征, 原发性卵巢功能不全

Abstract:

Reactive oxygen species(ROS) at the physiological level may play a role of the second messengers in signal transduction. When the body is stimulated by hypoxia, inflammatory response and others, the increased significantly level of ROS induces oxidative stress. ROS at an appropriate level promotes the first meiosis of oocytes, and induces the apoptosis of non-dominant follicles. Studies have shown that oxidative stress is closely related to hyperandrogenemia, insulin resistance, ovulation disorders and mitochondrial damage in the patients with polycystic ovary syndrome (PCOS). Controlling oxidative stress with antioxidants may be an adjunct therapy for the premature ovarian insufficiency(POI). Oxidative stress inhibits DNA methylase, which leads to DNA hypomethylation, and the abnormal expressions of microRNA and the factors related to the proliferation of ovarian cancer cells and the drug resistance. This article reviews the role of oxidative stress in ovary-related reproductive disorders such as PCOS, POI and ovarian tumors, and looks forward to the possible application of antioxidant therapy.

Key words: Oxidative stress, Polycystic ovary syndrome, Primary ovarian insufficiency

王甜, 莫少康, 黄冰雪, 魏璐晓, 王玲. 氧化应激在卵巢相关生殖障碍疾病中的作用[J]. 国际生殖健康/计划生育杂志, 2023, 42(4): 317-322.

WANG Tian, MO Shao-kang, HUANG Bing-xue, WEI Lu-xiao, WANG Ling. Oxidative Stress in Ovary-Related Reproductive Disorders[J]. Journal of International Reproductive Health/Family Planning, 2023, 42(4): 317-322.

参考文献 46

[1]	Chainy G, Sahoo DK. Hormones and oxidative stress: an overview[J]. Free Radic Res, 2020, 54(1):1-26. doi: 10.1080/10715762.2019.1702656. doi: 10.1080/10715762.2019.1702656 URL
[2]	Sies H. Oxidative stress: a concept in redox biology and medicine[J]. Redox Biol, 2015, 4:180-183. doi: 10.1016/j.redox.2015.01.002. doi: 10.1016/j.redox.2015.01.002 pmid: 25588755
[3]	Qi JH, Dong FX. The relevant targets of anti-oxidative stress: a review[J]. J Drug Target, 2021, 29(7):677-686. doi: 10.1080/1061186X.2020.1870987. doi: 10.1080/1061186X.2020.1870987 URL
[4]	Aitken RJ, Bromfield EG, Gibb Z. OXIDATIVE STRESS AND REPRODUCTIVE FUNCTION: The impact of oxidative stress on reproduction: a focus on gametogenesis and fertilization[J]. Reproduction, 2022, 164(6):F79-F94. doi: 10.1530/REP-22-0126. doi: 10.1530/REP-22-0126 URL
[5]	Agarwal A, Aponte-Mellado A, Premkumar BJ, et al. The effects of oxidative stress on female reproduction: a review[J]. Reprod Biol Endocrinol, 2012, 10:49. doi: 10.1186/1477-7827-10-49. doi: 10.1186/1477-7827-10-49 URL
[6]	Lu J, Wang Z, Cao J, et al. A novel and compact review on the role of oxidative stress in female reproduction[J]. Reprod Biol Endocrinol, 2018, 16(1):80. doi: 10.1186/s12958-018-0391-5. doi: 10.1186/s12958-018-0391-5
[7]	Lockwood CJ. Mechanisms of normal and abnormal endometrial bleeding[J]. Menopause, 2011, 18(4):408-411. doi: 10.1097/GME.0b013e31820bf288. doi: 10.1097/GME.0b013e31820bf288 pmid: 21499503
[8]	Belenkaia LV, Lazareva LM, Walker W, et al. Criteria, phenotypes and prevalence of polycystic ovary syndrome[J]. Minerva Ginecol, 2019, 71(3):211-223. doi: 10.23736/S0026-4784.19.04404-6. doi: 10.23736/S0026-4784.19.04404-6 pmid: 31089072
[9]	Sadeghi HM, Adeli I, Calina D, et al. Polycystic Ovary Syndrome: A Comprehensive Review of Pathogenesis, Management, and Drug Repurposing[J]. Int J Mol Sci, 2022, 23(2):538. doi: 10.3390/ijms23020583. doi: 10.3390/ijms23020583 URL
[10]	Mohammadi M. Oxidative Stress and Polycystic Ovary Syndrome: A Brief Review[J]. Int J Prev Med, 2019, 10:86. doi: 10.4103/ijpvm.IJPVM_576_17. doi: 10.4103/ijpvm.IJPVM_576_17 pmid: 31198521
[11]	Sun Y, Li S, Liu H, et al. Oxidative stress promotes hyperandrogenism by reducing sex hormone-binding globulin in polycystic ovary syndrome[J]. Fertil Steril, 2021, 116(6):1641-1650. doi: 10.1016/j.fertnstert.2021.07.1203. doi: 10.1016/j.fertnstert.2021.07.1203 pmid: 34433519
[12]	Yao Q, Zou X, Liu S, et al. Oxidative Stress as a Contributor to Insulin Resistance in the Skeletal Muscles of Mice with Polycystic Ovary Syndrome[J]. Int J Mol Sci, 2022, 23(19):11384. doi: 10.3390/ijms231911384. doi: 10.3390/ijms231911384 URL
[13]	Hu M, Zhang Y, Guo X, et al. Hyperandrogenism and insulin resistance induce gravid uterine defects in association with mitochondrial dysfunction and aberrant reactive oxygen species production[J]. Am J Physiol Endocrinol Metab, 2019, 316(5):E794-E809. doi: 10.1152/ajpendo.00359.2018. doi: 10.1152/ajpendo.00359.2018 URL
[14]	Victor VM, Rovira-Llopis S, Bañuls C, et al. Insulin Resistance in PCOS Patients Enhances Oxidative Stress and Leukocyte Adhesion: Role of Myeloperoxidase[J]. PLoS One, 2016, 11(3):e0151960. doi: 10.1371/journal.pone.0151960. doi: 10.1371/journal.pone.0151960 URL
[15]	Zeng X, Xie YJ, Liu YT, et al. Polycystic ovarian syndrome: Correlation between hyperandrogenism, insulin resistance and obesity[J]. Clin Chim Acta, 2020, 502:214-221. doi: 10.1016/j.cca.2019.11.003. doi: S0009-8981(19)32118-7 pmid: 31733195
[16]	Püschel GP, Klauder J, Henkel J. Macrophages, Low-Grade Inflammation, Insulin Resistance and Hyperinsulinemia: A Mutual Ambiguous Relationship in the Development of Metabolic Diseases[J]. J Clin Med, 2022, 11(15):4358. doi: 10.3390/jcm11154358. doi: 10.3390/jcm11154358 URL
[17]	Uçkan K, Demir H, Turan K, et al. Role of Oxidative Stress in Obese and Nonobese PCOS Patients[J]. Int J Clin Pract, 2022, 2022:4579831. doi: 10.1155/2022/4579831. doi: 10.1155/2022/4579831
[18]	Snider AP, Wood JR. Obesity induces ovarian inflammation and reduces oocyte quality[J]. Reproduction, 2019, 158(3):R79-R90. doi: 10.1530/REP-18-0583. doi: 10.1530/REP-18-0583
[19]	Wang F, Han J, Wang X, et al. Roles of HIF-1α/BNIP3 mediated mitophagy in mitochondrial dysfunction of letrozole-induced PCOS rats[J]. J Mol Histol, 2022, 53(5):833-842. doi: 10.1007/s10735-022-10096-4. doi: 10.1007/s10735-022-10096-4 pmid: 35951252
[20]	Song L, Yu J, Zhang D, et al. Androgen Excess Induced Mitochondrial Abnormality in Ovarian Granulosa Cells in a Rat Model of Polycystic Ovary Syndrome[J]. Front Endocrinol(Lausanne), 2022, 13:789008. doi: 10.3389/fendo.2022.789008. doi: 10.3389/fendo.2022.789008
[21]	Salahi E, Amidi F, Zahiri Z, et al. The effect of mitochondria-targeted antioxidant Mito Q10 on redox signaling pathway components in PCOS mouse model[J]. Arch Gynecol Obstet, 2022, 305(4):985-994. doi: 10.1007/s00404-021-06230-4. doi: 10.1007/s00404-021-06230-4
[22]	Olcese JM. Melatonin and Female Reproduction: An Expanding Universe[J]. Front Endocrinol(Lausanne), 2020, 11:85. doi: 10.3389/fendo.2020.00085. doi: 10.3389/fendo.2020.00085
[23]	Zheng B, Meng J, Zhu Y, et al. Melatonin enhances SIRT1 to ameliorate mitochondrial membrane damage by activating PDK1/Akt in granulosa cells of PCOS[J]. J Ovarian Res, 2021, 14(1):152. doi: 10.1186/s13048-021-00912-y. doi: 10.1186/s13048-021-00912-y pmid: 34758863
[24]	Panay N, Anderson RA, Nappi RE, et al. Premature ovarian insufficiency: an International Menopause Society White Paper[J]. Climacteric, 2020, 23(5):426-446. doi: 10.1080/13697137.2020.1804547. doi: 10.1080/13697137.2020.1804547 pmid: 32896176
[25]	Huhtaniemi I, Hovatta O, La Marca A, et al. Advances in the Molecular Pathophysiology, Genetics, and Treatment of Primary Ovarian Insufficiency[J]. Trends Endocrinol Metab, 2018, 29(6):400-419. doi: 10.1016/j.tem.2018.03.010. doi: 10.1016/j.tem.2018.03.010 URL
[26]	Ishizuka B. Current Understanding of the Etiology, Symptomatology, and Treatment Options in Premature Ovarian Insufficiency (POI)[J]. Front Endocrinol(Lausanne), 2021, 12:626924. doi: 10.3389/fendo.2021.626924. doi: 10.3389/fendo.2021.626924
[27]	Liu Y, Ao X, Ding W, et al. Critical role of FOXO3a in carcinogenesis[J]. Mol Cancer, 2018, 17(1):104. doi: 10.1186/s12943-018-0856-3. doi: 10.1186/s12943-018-0856-3 pmid: 30045773
[28]	马会明, 张永芳, 王蒙蒙, 等. 雌激素对卵巢颗粒细胞雌激素受体-β和转录因子叉头蛋白3表达的影响[J]. 山东大学学报(医学版), 2016, 54(5):50-55. doi: 10.6040/j.issn.1671-7554.0.2015.437. doi: 10.6040/j.issn.1671-7554.0.2015.437
[29]	He L, Long X, Yu N, et al. Premature Ovarian Insufficiency (POI) Induced by Dynamic Intensity Modulated Radiation Therapy via PI3K-AKT-FOXO3a in Rat Models[J]. Biomed Res Int, 2021, 2021:7273846. doi: 10.1155/2021/7273846. doi: 10.1155/2021/7273846
[30]	Abogresha NM, Mohammed SS, Hosny MM, et al. Diosmin Mitigates Cyclophosphamide Induced Premature Ovarian Insufficiency in Rat Model[J]. Int J Mol Sci, 2021, 22(6):3044. doi: 10.3390/ijms22063044. doi: 10.3390/ijms22063044 URL
[31]	Zheng S, Ma M, Chen Y, et al. Effects of quercetin on ovarian function and regulation of the ovarian PI3K/Akt/FoxO3a signalling pathway and oxidative stress in a rat model of cyclophosphamide-induced premature ovarian failure[J]. Basic Clin Pharmacol Toxicol, 2022, 130(2):240-253. doi: 10.1111/bcpt.13696. doi: 10.1111/bcpt.13696 URL
[32]	Bozkaya VÖ, Yumusak OH, Ozaksit G, et al. The role of oxidative stress on subclinical atherosclerosis in premature ovarian insufficiency and relationship with carotid intima-media thickness[J]. Gynecol Endocrinol, 2020, 36(8):687-692. doi: 10.1080/09513590.2020.1766439. doi: 10.1080/09513590.2020.1766439 pmid: 32429709
[33]	Zhou XY, Zhang J, Li Y, et al. Advanced Oxidation Protein Products Induce G1/G0-Phase Arrest in Ovarian Granulosa Cells via the ROS-JNK/p38 MAPK-p21 Pathway in Premature Ovarian Insufficiency[J]. Oxid Med Cell Longev, 2021, 2021:6634718. doi: 10.1155/2021/6634718. doi: 10.1155/2021/6634718
[34]	Guo L, Liu X, Chen H, et al. Decrease in ovarian reserve through the inhibition of SIRT1-mediated oxidative phosphorylation[J]. Aging(Albany NY), 2022, 14(5):2335-2347. doi: 10.18632/aging.203942. doi: 10.18632/aging.203942
[35]	Ma L, Li X, Li C, et al. Association of Coenzyme Q10 with Premature Ovarian Insufficiency[J]. Reprod Sci, 2023, 30(5):1548-1554. doi: 10.1007/s43032-022-01136-1. doi: 10.1007/s43032-022-01136-1
[36]	Feng J, Ma WW, Li HX, et al. Melatonin prevents cyclophosphamide-induced primordial follicle loss by inhibiting ovarian granulosa cell apoptosis and maintaining AMH expression[J]. Front Endocrinol(Lausanne), 2022, 13:895095. doi: 10.3389/fendo.2022.895095. doi: 10.3389/fendo.2022.895095
[37]	Huang B, Qian C, Ding C, et al. Fetal liver mesenchymal stem cells restore ovarian function in premature ovarian insufficiency by targeting MT1[J]. Stem Cell Res Ther, 2019, 10(1):362. doi: 10.1186/s13287-019-1490-8. doi: 10.1186/s13287-019-1490-8 pmid: 31783916
[38]	Ding C, Zou Q, Wu Y, et al. EGF released from human placental mesenchymal stem cells improves premature ovarian insufficiency via NRF2/HO-1 activation[J]. Aging(Albany NY), 2020, 12(3):2992-3009. doi: 10.18632/aging.102794. doi: 10.18632/aging.102794
[39]	Lu X, Bao H, Cui L, et al. hUMSC transplantation restores ovarian function in POI rats by inhibiting autophagy of theca-interstitial cells via the AMPK/mTOR signaling pathway[J]. Stem Cell Res Ther, 2020, 11(1):268. doi: 10.1186/s13287-020-01784-7. doi: 10.1186/s13287-020-01784-7 pmid: 32620136
[40]	Luo C, Hajkova P, Ecker JR. Dynamic DNA methylation: In the right place at the right time[J]. Science, 2018, 361(6409):1336-1340. doi: 10.1126/science.aat6806. doi: 10.1126/science.aat6806 pmid: 30262495
[41]	Brozovic A, Duran GE, Wang YC, et al. The miR-200 family differentially regulates sensitivity to paclitaxel and carboplatin in human ovarian carcinoma OVCAR-3 and MES-OV cells[J]. Mol Oncol, 2015, 9(8):1678-1693. doi: 10.1016/j.molonc.2015.04.015. doi: 10.1016/j.molonc.2015.04.015 pmid: 26025631
[42]	Boac BM, Xiong Y, Marchion DC, et al. Micro-RNAs associated with the evolution of ovarian cancer cisplatin resistance[J]. Gynecol Oncol, 2016, 140(2):259-263. doi: 10.1016/j.ygyno.2015.12.026. doi: 10.1016/j.ygyno.2015.12.026 pmid: 26731723
[43]	Deng X, Lin N, Fu J, et al. The Nrf2/PGC1α Pathway Regulates Antioxidant and Proteasomal Activity to Alter Cisplatin Sensitivity in Ovarian Cancer[J]. Oxid Med Cell Longev, 2020, 2020:4830418. doi: 10.1155/2020/4830418. doi: 10.1155/2020/4830418
[44]	Zhao F, Hong X, Li D, et al. Diosmetin induces apoptosis in ovarian cancer cells by activating reactive oxygen species and inhibiting the Nrf2 pathway[J]. Med Oncol, 2021, 38(5):54. doi: 10.1007/s12032-021-01501-1. doi: 10.1007/s12032-021-01501-1 pmid: 33811596
[45]	Sun C, Han B, Zhai Y, et al. Dihydrotanshinone I inhibits ovarian tumor growth by activating oxidative stress through Keap1-mediated Nrf2 ubiquitination degradation[J]. Free Radic Biol Med, 2022, 180:220-235. doi: 10.1016/j.freeradbiomed.2022.01.015. doi: 10.1016/j.freeradbiomed.2022.01.015 URL
[46]	Li Q, Tan Q, Ma Y, et al. Myricetin Suppresses Ovarian Cancer In Vitro by Activating the p38/Sapla Signaling Pathway and Suppressing Intracellular Oxidative Stress[J]. Front Oncol, 2022, 12:903394. doi: 10.3389/fonc.2022.903394. doi: 10.3389/fonc.2022.903394 URL