西罗莫司在生殖领域的研究进展

doi:10.12280/gjszjk.20230438

摘要/Abstract

摘要：

西罗莫司作为常用的免疫抑制剂，现广泛用于预防器官移植受者发生免疫排斥反应。随着医学研究的不断发展，已证明西罗莫司在女性生殖过程中具有免疫调节作用。西罗莫司通过抑制哺乳动物雷帕霉素靶蛋白发挥免疫调节功能，可能会改善合并反复种植失败、复发性流产、子宫内膜异位症、慢性子宫内膜炎及多囊卵巢综合征等生殖系统疾病患者的生殖免疫状态。西罗莫司还可预防辅助生殖治疗过程中卵巢过度刺激综合征的发生，提高母胎界面免疫状态异常患者的胚胎种植率和临床妊娠率，实现更好的妊娠结局。综述西罗莫司在女性生殖相关疾病中的作用机制、研究现状及安全性。

关键词: 西罗莫司, 生殖技术, 辅助, 不育, 女（雌）性, 流产, 习惯性, 子宫内膜异位症, 多囊卵巢综合征, 卵巢过度刺激综合征

Abstract:

Nowadays, sirolimus as a popular immunosuppressant has been frequently used to shield the organ transplant recipients from immunological rejection. The immunomodulatory effects of sirolimus in the female reproductive process have been demonstrated by ongoing medical study. By blocking the immune-regulating action of mammalian target of rapamycin, sirolimus may help those patients with recurrent implantation failure, recurrent spontaneous abortion, endometriosis, chronic endometritis, polycystic ovary syndrome, and other illnesses of the reproductive system. Additionally, sirolimus can enhance the rates of embryo implantation and clinical pregnancy in individuals with aberrant immunological statuses at the mother-fetal interface, reduce ovarian hyperstimulation syndrome during assisted reproductive treatment, and improve the pregnancy outcomes. A review was conducted on the mode of action, research status and safety of sirolimus in female reproductive disorders.

Key words: Sirolimus, Reproductive techniques, assisted, Infertility, female, Abortion, habitual, Endometriosis, Polycystic ovary syndrome, Ovarian hyperstimulation syndrome

叶霖, 侯志金, 孟昱时. 西罗莫司在生殖领域的研究进展[J]. 国际生殖健康/计划生育杂志, 2024, 43(2): 132-137.

YE Lin, HOU Zhi-jin, MENG Yu-shi. Research Progress of Sirolimus in the Field of Reproduction[J]. Journal of International Reproductive Health/Family Planning, 2024, 43(2): 132-137.

参考文献 38

[1]	Ejzenberg D, Andraus W, Baratelli Carelli Mendes LR, et al. Livebirth after uterus transplantation from a deceased donor in a recipient with uterine infertility[J]. Lancet, 2019, 392(10165):2697-2704. doi: 10.1016/S0140-6736(18)31766-5. pmid: 30527853
[2]	Wang M, Jin L, Shi J, et al. Estradiol on trigger day: Irrelevant to live birth rates of fresh cycles but positively associated with cumulative live birth rates[J]. Int J Gynaecol Obstet, 2023, 163(2):627-638. doi: 10.1002/ijgo.14887.
[3]	Von Woon E, Greer O, Shah N, et al. Number and function of uterine natural killer cells in recurrent miscarriage and implantation failure: a systematic review and meta-analysis[J]. Hum Reprod Update, 2022, 28(4):548-582. doi: 10.1093/humupd/dmac006. pmid: 35265977
[4]	Ahmadi M, Abdolmohamadi-Vahid S, Ghaebi M, et al. Sirolimus as a new drug to treat RIF patients with elevated Th17/Treg ratio: A double-blind, phase Ⅱ randomized clinical trial[J]. Int Immunopharmacol, 2019,74:105730. doi: 10.1016/j.intimp.2019.105730.
[5]	Pantos K, Grigoriadis S, Maziotis E, et al. The Role of Interleukins in Recurrent Implantation Failure: A Comprehensive Review of the Literature[J]. Int J Mol Sci, 2022, 23(4):2198. doi: 10.3390/ijms 23042198.
[6]	Moldenhauer LM, Hull ML, Foyle KL, et al. Immune-Metabolic Interactions and T Cell Tolerance in Pregnancy[J]. J Immunol, 2022, 209(8):1426-1436. doi: 10.4049/jimmunol.2200362. pmid: 36192117
[7]	Coomarasamy A, Dhillon-Smith RK, Papadopoulou A, et al. Recurrent miscarriage: evidence to accelerate action[J]. Lancet, 2021, 397(10285):1675-1682. doi: 10.1016/S0140-6736(21)00681-4. pmid: 33915096
[8]	Huang N, Chi H, Qiao J. Role of Regulatory T Cells in Regulating Fetal-Maternal Immune Tolerance in Healthy Pregnancies and Reproductive Diseases[J]. Front Immunol, 2020,11:1023. doi: 10.3389/fimmu.2020.01023.
[9]	Li L, Ren AA, Gao S, et al. mTORC1 Inhibitor Rapamycin Inhibits Growth of Cerebral Cavernous Malformation in Adult Mice[J]. Stroke, 2023, 54(11):2906-2917. doi: 10.1161/STROKEAHA.123.044108. pmid: 37746705
[10]	Tsuji-Tamura K, Sato M, Fujita M, et al. The role of PI3K/Akt/mTOR signaling in dose-dependent biphasic effects of glycine on vascular development[J]. Biochem Biophys Res Commun, 2020, 529(3):596-602. doi: 10.1016/j.bbrc.2020.06.085.
[11]	Parhizkar F, Motavalli-Khiavi R, Aghebati-Maleki L, et al. The Impact of New Immunological Therapeutic Strategies on Recurrent Miscarriage and Recurrent Implantation Failure[J]. Immunol Lett, 2021, 236:20-30. doi: 10.1016/j.imlet.2021.05.008. pmid: 34090942
[12]	Royster GD, Harris JC, Nelson A, et al. Rapamycin Corrects T Regulatory Cell Depletion and Improves Embryo Implantation and Live Birth Rates in a Murine Model[J]. Reprod Sci, 2019, 26(12):1545-1556. doi: 10.1177/1933719119828110. pmid: 30782087
[13]	Makrigiannakis A, Makrygiannakis F, Vrekoussis T. Approaches to Improve Endometrial Receptivity in Case of Repeated Implantation Failures[J]. Front Cell Dev Biol, 2021,9:613277. doi: 10.3389/fcell.2021.613277.
[14]	Nakagawa K, Kwak-Kim J, Ota K, et al. Immunosuppression with tacrolimus improved reproductive outcome of women with repeated implantation failure and elevated peripheral blood TH1/TH2 cell ratios[J]. Am J Reprod Immunol, 2015, 73(4):353-361. doi: 10.1111/aji.12338.
[15]	Wang C, Guan D, Li R, et al. Comparative efficacies of different immunotherapy regimens in recurrent implantation failure: A systematic review and network meta-analysis[J]. J Reprod Immunol, 2021,148:103429. doi: 10.1016/j.jri.2021.103429.
[16]	Wang X, Geng S, Meng J, et al. Foxp3-mediated blockage of ryanodine receptor 2 underlies contact-based suppression by regulatory T cells[J]. J Clin Invest, 2023, 133(24):e163470. doi: 10.1172/JCI163470.
[17]	Wang WJ, Zhang H, Chen ZQ, et al. Endometrial TGF-β, IL-10, IL-17 and autophagy are dysregulated in women with recurrent implantation failure with chronic endometritis[J]. Reprod Biol Endocrinol, 2019, 17(1):2. doi: 10.1186/s12958-018-0444-9.
[18]	Busnelli A, Somigliana E, Cirillo F, et al. Efficacy of therapies and interventions for repeated embryo implantation failure: a systematic review and meta-analysis[J]. Sci Rep, 2021, 11(1):1747. doi: 10.1038/s41598-021-81439-6. pmid: 33462292
[19]	Luo L, Zeng X, Huang Z, et al. Reduced frequency and functional defects of CD4⁺CD25^highCD127^low/- regulatory T cells in patients with unexplained recurrent spontaneous abortion[J]. Reprod Biol Endocrinol, 2020, 18(1):62. doi: 10.1186/s12958-020-00619-7.
[20]	Lu H, Yang HL, Zhou WJ, et al. Rapamycin prevents spontaneous abortion by triggering decidual stromal cell autophagy-mediated NK cell residence[J]. Autophagy, 2021, 17(9):2511-2527. doi: 10.1080/15548627.2020.1833515.
[21]	Mohammadi S, Abdollahi E, Nezamnia M, et al. Adoptive transfer of Tregs: A novel strategy for cell-based immunotherapy in spontaneous abortion: Lessons from experimental models[J]. Int Immunopharmacol, 2021,90:107195. doi: 10.1016/j.intimp.2020.107195.
[22]	Walker ER, McGrane M, Aplin JD, et al. A systematic review of transcriptomic studies of the human endometrium reveals inconsistently reported differentially expressed genes[J]. Reprod Fertil, 2023, 4(3):e220115. doi: 10.1530/RAF-22-0115.
[23]	Madanes D, Bilotas MA, Bastón JI, et al. PI3K/AKT pathway is altered in the endometriosis patient′s endometrium and presents differences according to severity stage[J]. Gynecol Endocrinol, 2020, 36(5):436-440. doi: 10.1080/09513590.2019.1680627.
[24]	Driva TS, Schatz C, Sobočan M, et al. The Role of mTOR and eIF Signaling in Benign Endometrial Diseases[J]. Int J Mol Sci, 2022, 23(7):3416. doi: 10.3390/ijms23073416.
[25]	Guo Z, Yu Q. Role of mTOR Signaling in Female Reproduction[J]. Front Endocrinol(Lausanne), 2019,10:692. doi: 10.3389/fendo.2019.00692.
[26]	Cuesta R, Gritsenko MA, Petyuk VA, et al. Phosphoproteome Analysis Reveals Estrogen-ER Pathway as a Modulator of mTOR Activity Via DEPTOR[J]. Mol Cell Proteomics, 2019, 18(8):1607-1618. doi: 10.1074/mcp.RA119.001506. pmid: 31189691
[27]	Zhang X, Li S, Chen Z, et al. Tanshinone ⅡA participates in the treatment of endometriosis by regulating adhesion, invasion, angiogenesis and inhibition of PI3K/Akt/mTOR signaling pathway[J]. Mol Med Rep, 2023, 28(5):221. doi: 10.3892/mmr.2023.13108.
[28]	Alam MM, Fermin JM, Knackstedt M, et al. Everolimus downregulates STAT3/HIF-1α/VEGF pathway to inhibit angiogenesis and lymphangiogenesis in TP53 mutant head and neck squamous cell carcinoma (HNSCC)[J]. Oncotarget, 2023, 14:85-95. doi: 10.18632/oncotarget.28355.
[29]	Choi J, Jo M, Lee E, et al. Involvement of endoplasmic reticulum stress in regulation of endometrial stromal cell invasiveness: possible role in pathogenesis of endometriosis[J]. Mol Hum Reprod, 2019, 25(3):101-110. doi: 10.1093/molehr/gaz002. pmid: 30657961
[30]	Sun YZ, Liu L, Cai N, et al. Anti-angiogenic effect of rapamycin in mouse oxygen-induced retinopathy is mediated through suppression of HIF-1alpha/VEGF pathway[J]. Int J Clin Exp Pathol, 2017, 10(10):10167-10175.
[31]	Yang Y, Xia J, Yang Z, et al. The abnormal level of HSP70 is related to Treg/Th17 imbalance in PCOS patients[J]. J Ovarian Res, 2021, 14(1):155. doi: 10.1186/s13048-021-00867-0. pmid: 34781996
[32]	Li T, Dong G, Kang Y, et al. Increased homocysteine regulated by androgen activates autophagy by suppressing the mammalian target of rapamycin pathway in the granulosa cells of polycystic ovary syndrome mice[J]. Bioengineered, 2022, 13(4):10875-10888. doi: 10.1080/21655979.2022.2066608. pmid: 35485387
[33]	Liu J, Zhao Y, Chen L, et al. Role of metformin in functional endometrial hyperplasia and polycystic ovary syndrome involves the regulation of MEG3/miR-223/GLUT4 and SNHG20/miR-4486/GLUT4 signaling[J]. Mol Med Rep, 2022, 26(1):218. doi: 10.3892/mmr.2022.12734.
[34]	Estienne A, Bongrani A, Ramé C, et al. Energy sensors and reproductive hypothalamo-pituitary ovarian axis (HPO) in female mammals: Role of mTOR (mammalian target of rapamycin), AMPK (AMP-activated protein kinase) and SIRT1 (Sirtuin 1)[J]. Mol Cell Endocrinol, 2021,521:111113. doi: 10.1016/j.mce.2020.111113.
[35]	Zhang S, Ma Y, Zuo Q, et al. Repeated controlled ovarian stimulation-induced ovarian and uterine damage in mice through the PI3K/AKT signaling pathway[J]. Hum Cell, 2023, 36(1):234-243. doi: 10.1007/s13577-022-00829-8.
[36]	Wang H, Chen W, Huang Y, et al. EGR1 Promotes Ovarian Hyperstimulation Syndrome Through Upregulation of SOX9 Expression[J]. Cell Transplant, 2023,32:9636897231193073. doi: 10.1177/09636897231193073.
[37]	Liu W, Zhang C, Wang L, et al. Successful reversal of ovarian hyperstimulation syndrome in a mouse model by rapamycin, an mTOR pathway inhibitor[J]. Mol Hum Reprod, 2019, 25(8):445-457. doi: 10.1093/molehr/gaz033. pmid: 31329230
[38]	Andreescu M. The impact of the use of immunosuppressive treatment after an embryo transfer in increasing the rate of live birth[J]. Front Med(Lausanne), 2023,10:1167876. doi: 10.3389/fmed.2023.1167876.