抗氧化剂改善卵母细胞线粒体功能和不孕女性生育结局的研究进展

doi:10.12280/gjszjk.20210248

摘要/Abstract

摘要：

线粒体是体内产生能量的工厂,在产生三磷酸腺苷（adenosine triphosphate,ATP）的同时还会产生大量的活性氧（reactive oxygen species,ROS）。过多的ROS可诱导氧化应激并最终导致线粒体功能障碍。卵母细胞线粒体功能障碍可导致卵母细胞质量下降,影响胚胎发育和妊娠结局。最新的动物实验和临床试验均表明,白黎芦醇、辅酶Q10、褪黑素、叶酸和维生素E等抗氧化剂可通过改善线粒体功能、促进线粒体生物合成来提高人类卵母细胞和胚胎质量,改善多囊卵巢综合征、早发性卵巢功能不全等不孕患者的生育结局。辅助生殖助孕的患者在周期前口服抗氧化剂或在体外未成熟卵母细胞培养液中加入抗氧化剂可能改善助孕结局。综述抗氧化剂最新的动物实验结果和辅助生殖临床应用剂量、途径和效果。

关键词: 线粒体, 抗氧化剂, 氧化性应激, 活性氧, 卵母细胞, 胚胎质量

Abstract:

Mitochondria, as a factory that produces energy in the body, produce adenosine triphosphate (ATP) while also generate high amounts of reactive oxygen species (ROS). ROS at the high level is detrimental, leading to oxidative stress and ultimately to mitochondrial dysfunction. Oocyte mitochondrial dysfunction may also lead to poor oocyte quality and embryo development, and poor pregnancy outcomes. The newest animal experiments and clinical trials suggest that antioxidants such as resveratrol, coenzyme Q10, melatonin, folic acid and vitamin E may improve human oocyte and embryo quality via improving oocyte mitochondrial function. Antioxidants can improve the reproductive outcomes of patients with polycystic ovarian syndrome and premature ovarian insufficiency by promoting mitochondrial biogenesis. It is suggested that oral antioxidants supplement before assisted reproductive cycles or the antioxidants added into culture medium of in vitro immature oocytes may improve assisted reproductive outcomes. We reviewed the outcomes of antioxidants applied in animal experiments and clinical trials including its dose and administration route.

Key words: Mitochondria, Antioxidants, Oxidative stress, Reactive oxygen species, Oocytes, Embryo quality

武硕, 焦立媛, 侯海燕. 抗氧化剂改善卵母细胞线粒体功能和不孕女性生育结局的研究进展[J]. 国际生殖健康/计划生育, 2022, 41(1): 62-67.

WU Shuo, JIAO Li-yuan, HOU Hai-yan. Research Progress of Antioxidants Supplement on Improvement of Oocyte Mitochondrial Function and Reproductive Outcomes in Infertile Women[J]. Journal of International Reproductive Health/Family Planning, 2022, 41(1): 62-67.

参考文献 44

[1]	Zhao RZ, Jiang S, Zhang L, et al. Mitochondrial electron transport chain, ROS generation and uncoupling (Review)[J]. Int J Mol Med, 2019, 44(1):3-15. doi: 10.3892/ijmm.2019.4188. doi: 10.3892/ijmm.2019.4188
[2]	Gulcin İ. Antioxidants and antioxidant methods: an updated overview[J]. Arch Toxicol, 2020, 94(3):651-715. doi: 10.1007/s00204-020-02689-3. doi: 10.1007/s00204-020-02689-3 URL
[3]	Yang H, Kuhn C, Kolben T, et al. Early Life Oxidative Stress and Long-Lasting Cardiovascular Effects on Offspring Conceived by Assisted Reproductive Technologies: A Review[J]. Int J Mol Sci, 2020, 21(15):5175. doi: 10.3390/ijms21155175. doi: 10.3390/ijms21155175 URL
[4]	Showell MG, Mackenzie-Proctor R, Jordan V, et al. Antioxidants for female subfertility[J]. Cochrane Database Syst Rev, 2020, 8(8):CD007807. doi: 10.1002/14651858.CD007807.pub4. doi: 10.1002/14651858.CD007807.pub4
[5]	Ben-Meir A, Burstein E, Borrego-Alvarez A, et al. Coenzyme Q10 restores oocyte mitochondrial function and fertility during reproductive aging[J]. Aging Cell, 2015, 14(5):887-895. doi: 10.1111/acel.12368. doi: 10.1111/acel.12368 pmid: 26111777
[6]	Zhang M, ShiYang X, Zhang Y, et al. Coenzyme Q10 ameliorates the quality of postovulatory aged oocytes by suppressing DNA damage and apoptosis[J]. Free Radic Biol Med, 2019, 143:84-94. doi: 10.1016/j.freeradbiomed.2019.08.002. doi: 10.1016/j.freeradbiomed.2019.08.002 URL
[7]	Ben-Meir A, Kim K, McQuaid R, et al. Co-Enzyme Q10 Supplementation Rescues Cumulus Cells Dysfunction in a Maternal Aging Model[J]. Antioxidants (Basel), 2019, 8(3):58. doi: 10.3390/antiox8030058. doi: 10.3390/antiox8030058
[8]	Giannubilo SR, Orlando P, Silvestri S, et al. CoQ10 Supplementation in Patients Undergoing IVF-ET: The Relationship with Follicular Fluid Content and Oocyte Maturity[J]. Antioxidants (Basel), 2018, 7(10):141. doi: 10.3390/antiox7100141. doi: 10.3390/antiox7100141
[9]	Bentov Y, Hannam T, Jurisicova A, et al. Coenzyme Q10 Supplementation and Oocyte Aneuploidy in Women Undergoing IVF-ICSI Treatment[J]. Clin Med Insights Reprod Health, 2014, 8:31-36. doi: 10.4137/CMRH.S14681. doi: 10.4137/CMRH.S14681
[10]	Xu Y, Nisenblat V, Lu C, et al. Pretreatment with coenzyme Q10 improves ovarian response and embryo quality in low-prognosis young women with decreased ovarian reserve: a randomized controlled trial[J]. Reprod Biol Endocrinol, 2018, 16(1):29. doi: 10.1186/s12958-018-0343-0. doi: 10.1186/s12958-018-0343-0 URL
[11]	Florou P, Anagnostis P, Theocharis P, et al. Does coenzyme Q(10) supplementation improve fertility outcomes in women undergoing assisted reproductive technology procedures? A systematic review and meta-analysis of randomized-controlled trials[J]. J Assist Reprod Genet, 2020, 37(10):2377-2387. doi: 10.1007/s10815-020-01906-3. doi: 10.1007/s10815-020-01906-3 URL
[12]	El Refaeey A, Selem A, Badawy A. Combined coenzyme Q10 and clomiphene citrate for ovulation induction in clomiphene-citrate-resistant polycystic ovary syndrome[J]. Reprod Biomed Online, 2014, 29(1):119-124. doi: 10.1016/j.rbmo.2014.03.011. doi: 10.1016/j.rbmo.2014.03.011 URL
[13]	Ma L, Cai L, Hu M, et al. Coenzyme Q10 supplementation of human oocyte in vitro maturation reduces postmeiotic aneuploidies[J]. Fertil Steril, 2020, 114(2):331-337. doi: 10.1016/j.fertnstert.2020.04.002. doi: 10.1016/j.fertnstert.2020.04.002 URL
[14]	Kile R, Logsdon DM, Nathanson C, et al. Mitochondrial support of embryos from women of advanced maternal age during ART[J]. Fertil Steril, 2020, 114(3):e122. doi: 10.1016/j.fertnstert.2020.08.363. doi: 10.1016/j.fertnstert.2020.08.363
[15]	Chen ZG, Luo LL, Xu JJ, et al. Effects of plant polyphenols on ovarian follicular reserve in aging rats[J]. Biochem Cell Biol, 2010, 88(4):737-745. doi: 10.1139/O10-012. doi: 10.1139/O10-012 URL
[16]	Liu M, Yin Y, Ye X, et al. Resveratrol protects against age-associated infertility in mice[J]. Hum Reprod, 2013, 28(3):707-717. doi: 10.1093/humrep/des437. doi: 10.1093/humrep/des437 URL
[17]	Li N, Liu L. Mechanism of resveratrol in improving ovarian function in a rat model of premature ovarian insufficiency[J]. J Obstet Gynaecol Res, 2018, 44(8):1431-1438. doi: 10.1111/jog.13680. doi: 10.1111/jog.13680 URL
[18]	Wu M, Ma L, Xue L, et al. Resveratrol alleviates chemotherapy-induced oogonial stem cell apoptosis and ovarian aging in mice[J]. Aging(Albany NY), 2019, 11(3):1030-1044. doi: 10.18632/aging.101808. doi: 10.18632/aging.101808
[19]	Liu MJ, Sun AG, Zhao SG, et al. Bin Resveratrol improves in vitro maturation of oocytes in aged mice and humans[J]. Fertil Steril, 2018, 109(5):900-907. doi: 10.1016/j.fertnstert.2018.01.020. doi: 10.1016/j.fertnstert.2018.01.020 URL
[20]	Banaszewska B, Wrotyńska-Barczyńska J, Spaczynski RZ, et al. Effects of Resveratrol on Polycystic Ovary Syndrome: A Double-blind, Randomized, Placebo-controlled Trial[J]. J Clin Endocrinol Metab, 2016, 101(11):4322-4328. doi: 10.1210/jc.2016-1858. doi: 10.1210/jc.2016-1858 pmid: 27754722
[21]	Bahramrezaie M, Amidi F, Aleyasin A, et al. Effects of resveratrol on VEGF & HIF1 genes expression in granulosa cells in the angiogenesis pathway and laboratory parameters of polycystic ovary syndrome: a triple-blind randomized clinical trial[J]. J Assist Reprod Genet, 2019, 36(8):1701-1712. doi: 10.1007/s10815-019-01461-6. doi: 10.1007/s10815-019-01461-6 URL
[22]	Ochiai A, Kuroda K. Preconception resveratrol intake against infertility: Friend or foe?[J]. Reprod Med Biol, 2020, 19(2):107-113. doi: 10.1002/rmb2.12303. doi: 10.1002/rmb2.12303 pmid: 32273814
[23]	Tagliaferri V, Romualdi D, Scarinci E, et al. Melatonin Treatment May Be Able to Restore Menstrual Cyclicity in Women With PCOS: A Pilot Study[J]. Reprod Sci, 2018, 25(2):269-275. doi: 10.1177/1933719117711262. doi: 10.1177/1933719117711262 pmid: 28558523
[24]	Eryilmaz OG, Devran A, Sarikaya E, et al. Melatonin improves the oocyte and the embryo in IVF patients with sleep disturbances, but does not improve the sleeping problems[J]. J Assist Reprod Genet, 2011, 28(9):815-820. doi: 10.1007/s10815-011-9604-y. doi: 10.1007/s10815-011-9604-y URL
[25]	Batıoğlu AS, Sahin U, Gürlek B, et al. The efficacy of melatonin administration on oocyte quality[J]. Gynecol Endocrinol, 2012, 28(2):91-93. doi: 10.3109/09513590.2011.589925. doi: 10.3109/09513590.2011.589925 pmid: 21770829
[26]	Tamura H, Takasaki A, Miwa I, et al. Oxidative stress impairs oocyte quality and melatonin protects oocytes from free radical damage and improves fertilization rate[J]. J Pineal Res, 2008, 44(3):280-287. doi: 10.1111/j.1600-079X.2007.00524.x. doi: 10.1111/j.1600-079X.2007.00524.x URL
[27]	Abdelnour SA, Abd El-Hack ME, Swelum AA, et al. The Usefulness of Retinoic Acid Supplementation during In Vitro Oocyte Maturation for the In Vitro Embryo Production of Livestock: A Review[J]. Animals(Basel), 2019, 9(8):561. doi: 10.3390/ani9080561. doi: 10.3390/ani9080561
[28]	Rahimi S, Martel J, Karahan G, et al. Moderate maternal folic acid supplementation ameliorates adverse embryonic and epigenetic outcomes associated with assisted reproduction in a mouse model[J]. Hum Reprod, 2019, 34(5):851-862. doi: 10.1093/humrep/dez036. doi: 10.1093/humrep/dez036 URL
[29]	Espino J, Macedo M, Lozano G, et al. Impact of Melatonin Supplementation in Women with Unexplained Infertility Undergoing Fertility Treatment[J]. Antioxidants(Basel), 2019, 8(9):338. doi: 10.3390/antiox8090338. doi: 10.3390/antiox8090338
[30]	Takasaki A, Nakamura Y, Tamura H, et al. Melatonin as a new drug for improving oocyte quality[J]. Reprod Med Biol, 2003, 2(4):139-144. doi: 10.1111/j.1447-0578.2003.00035.x. doi: 10.1111/j.1447-0578.2003.00035.x pmid: 29699177
[31]	Fernando S, Wallace EM, Vollenhoven B, et al. Melatonin in Assisted Reproductive Technology: A Pilot Double-Blind Randomized Placebo-Controlled Clinical Trial[J]. Front Endocrinol (Lausanne), 2018, 9:545. doi: 10.3389/fendo.2018.00545. doi: 10.3389/fendo.2018.00545 URL
[32]	Willmott M, Bartosik DB, Romanoff EB. The effect of folic acid on superovulation in the immature rat[J]. J Endocrinol, 1968, 41(3):439-445. doi: 10.1677/joe.0.0410439. doi: 10.1677/joe.0.0410439 pmid: 5711115
[33]	Mohanty D, Das KC. Effect of folate deficiency on the reproductive organs of female rhesus monkeys: a cytomorphological and cytokinetic study[J]. J Nutr, 1982, 112(8):1565-1576. doi: 10.1093/jn/112.8.1565. doi: 10.1093/jn/112.8.1565 pmid: 7097366
[34]	Zheng M, Tong J, Li WP, et al. Melatonin concentration in follicular fluid is correlated with antral follicle count (AFC) and in vitro fertilization (IVF) outcomes in women undergoing assisted reproductive technology (ART) procedures[J]. Gynecol Endocrinol, 2018, 34(5):446-450. doi: 10.1080/09513590.2017.1409713. doi: 10.1080/09513590.2017.1409713 pmid: 29185361
[35]	Castillo-Martín M, Bonet S, Morató R, et al. Supplementing culture and vitrification-warming media with l-ascorbic acid enhances survival rates and redox status of IVP porcine blastocysts via induction of GPX1 and SOD1 expression[J]. Cryobiology, 2014, 68(3):451-458. doi: 10.1016/j.cryobiol.2014.03.001. doi: 10.1016/j.cryobiol.2014.03.001 pmid: 24657197
[36]	Nohalez A, Martinez CA, Parrilla I, et al. Exogenous ascorbic acid enhances vitrification survival of porcine in vitro-developed blastocysts but fails to improve the in vitro embryo production outcomes[J]. Theriogenology, 2018, 113:113-119. doi: 10.1016/j.theriogenology.2018.02.014. doi: S0093-691X(18)30068-2 pmid: 29477909
[37]	Paffoni A, Somigliana E, Sarais V, et al. Effect of vitamin D supplementation on assisted reproduction technology (ART) outcomes and underlying biological mechanisms: protocol of a randomized clinical controlled trial. The "supplementation of vitamin D and reproductive outcome" (SUNDRO) study[J]. BMC Pregnancy Childbirth, 2019, 19(1):395. doi: 10.1186/s12884-019-2538-6. doi: 10.1186/s12884-019-2538-6 URL
[38]	Olson SE, Seidel GE Jr. Culture of in vitro-produced bovine embryos with vitamin E improves development in vitro and after transfer to recipients[J]. Biol Reprod, 2000, 62(2):248-252. doi: 10.1095/biolreprod62.2.248. doi: 10.1095/biolreprod62.2.248 pmid: 10642559
[39]	Bahadori MH, Sharami SH, Fakor F, et al. Level of Vitamin E in Follicular Fluid and Serum and Oocyte Morphology and Embryo Quality in Patients Undergoing IVF Treatment[J]. J Family Reprod Health, 2017, 11(2):74-81.
[40]	Fatemi F, Mohammadzadeh A, Sadeghi MR, et al. Role of vitamin E and D(3) supplementation in Intra-Cytoplasmic Sperm Injection outcomes of women with polycystic ovarian syndrome: A double blinded randomized placebo-controlled trial[J]. Clin Nutr ESPEN, 2017, 18:23-30. doi: 10.1016/j.clnesp.2017.01.002. doi: 10.1016/j.clnesp.2017.01.002 URL
[41]	Hou HY, Wang X, Yu Q, et al. Evidence that growth hormone can improve mitochondrial function in oocytes from aged mice[J]. Reproduction, 2018, 157(4):345-358. doi: 10.1530/REP-18-0529. doi: 10.1530/REP-18-0529 URL
[42]	Xu W, Li L, Sun J, et al. Putrescine delays postovulatory aging of mouse oocytes by upregulating PDK4 expression and improving mitochondrial activity[J]. Aging(Albany NY), 2018, 10(12):4093-4106. doi: 10.18632/aging.101699. doi: 10.18632/aging.101699
[43]	Selesniemi K, Lee HJ, Tilly JL. Moderate caloric restriction initiated in rodents during adulthood sustains function of the female reproductive axis into advanced chronological age[J]. Aging Cell, 2008, 7(5):622-629. doi: 10.1111/j.1474-9726.2008.00409.x. doi: 10.1111/j.1474-9726.2008.00409.x pmid: 18549458
[44]	Zhang J, Chen Q, Du D, et al. Can ovarian aging be delayed by pharmacological strategies?[J]. Aging(Albany NY), 2019, 11(2):817-832. doi: 10.18632/aging.101784. doi: 10.18632/aging.101784