难治性薄型子宫内膜的发病因素及处理策略

doi:10.12280/gjszjk.20210037

摘要/Abstract

摘要：

子宫内膜容受性是影响胚胎种植率的主要因素之一,而子宫内膜厚度是评价子宫内膜容受性的重要指标,薄型子宫内膜（thin endometrium,TE）患者的临床妊娠结局不良。大部分TE患者在接受雌激素治疗后子宫内膜能够达到胚胎种植需要的厚度,然而部分TE患者给予超生理剂量的雌激素后仍未能达到该厚度,这种情况被称为难治性薄型子宫内膜（treatment-resistant thin endometrium,TTE）。TTE的发病机制尚不明确,目前研究认为与雌激素受体不敏感、相关因子表达异常或内膜血供不足等因素有关。TTE的主要病因包括感染、宫腔操作和血流不足等,仍存在一部分TTE患者缺乏明确的病因。目前临床上TTE的治疗主要包括药物治疗、再生医学治疗及中医治疗等。尽管目前对于TTE的治疗方法多种多样,但治疗效果仍不尽满意。综述TTE的流行病学、高危因素和治疗方法等,为临床处理提供参考。

关键词: 子宫内膜, 受体, 雌激素, 血管内皮生长因子类, 基质金属蛋白酶11, 生殖技术, 辅助, 治疗

Abstract:

Endometrial receptivity is one of the main factors affecting embryo implantation rate, and endometrial thickness is an important index to evaluate endometrial receptivity. Patients with thin endometrium (TE) have poor clinical pregnancy outcome. The endometrium of most TE patients can reach a suitable thickness required for embryo implantation after estrogen treatment. However, some of TE patients cannot reach suitable thickness even though giving super-physiological dose of estrogen, which is called treatment-resistant thin endometrium (TTE). The pathogenesis of TTE is not clear. It is believed that the related factors of TTE are the insensitivity to estrogen receptor, abnormal expression of related factors and insufficient intimal blood supply. The main causes of TTE include infection, uterine cavity operation and insufficient blood flow. The causes of some patients with TTE are still unknown. At present, the clinical treatment of TTE mainly includes drug treatment, regenerative medicine and traditional Chinese medicine. Although there are a variety of treatment methods for TTE, the efficiency is still not satisfactory. This article reviews the epidemiology, high risk factors and treatment of TTE in order to provide reference for clinical treatment.

Key words: Endometrium, Receptor, estrogen, Vascular endothelial growth factors, Matrix metalloproteinase 11, Reproduction technique, assisted, Therapy

王丽燕, 符晓倩, 李华, 杨一华. 难治性薄型子宫内膜的发病因素及处理策略[J]. 国际生殖健康/计划生育, 2021, 40(4): 314-318.

WANG Li-yan, FU Xiao-qian, LI Hua, YANG Yi-hua. Pathogenic Factors and Management Strategies of Treatment-Resistant Thin Endometrium[J]. Journal of International Reproductive Health/Family Planning, 2021, 40(4): 314-318.

参考文献 41

[1]	Sarvi F, Arabahmadi M, Alleyassin A, et al. Effect of Increased Endometrial Thickness and Implantation Rate by Granulocyte Colony-Stimulating Factor on Unresponsive Thin Endometrium in Fresh In Vitro Fertilization Cycles: A Randomized Clinical Trial[J]. Obstet Gynecol Int, 2017, 2017:3596079. doi: 10.1155/2017/3596079. doi: 10.1155/2017/3596079
[2]	Kasius A, Smit JG, Torrance HL, et al. Endometrial thickness and pregnancy rates after IVF: a systematic review and meta-analysis[J]. Hum Reprod Update, 2014, 20(4):530-541. doi: 10.1093/humupd/dmu011. doi: 10.1093/humupd/dmu011 URL
[3]	Zhong Y, Zeng F, Liu W, et al. Acupuncture in improving endometrial receptivity: a systematic review and meta-analysis[J]. BMC Complement Altern Med, 2019, 19(1):61. doi: 10.1186/s12906-019-2472-1. doi: 10.1186/s12906-019-2472-1 URL
[4]	丁唤飞, 田莉. 薄型子宫内膜诊断阈值方法研究[J]. 中国妇产科临床杂志, 2018, 19(4):291-294. doi: 10.13390/j.issn.1672-1861. 2018.04.002. doi: 10.13390/j.issn.1672-1861. 2018.04.002
[5]	Miralaei S, Ashrafi M, Arabipoor A, et al. The incidence rate of unresponsive thin endometrium in frozen embryo transfer cycles: A case-series of therapy with granulocyte colony stimulating factor[J]. Int J Reprod Biomed, 2019, 17(12):923-928. doi: 10.18502/ijrm.v17i12.5797. doi: 10.18502/ijrm.v17i12.5797
[6]	Mishra VV, Choudhary S, Sharma U, et al. Effects of Granulocyte Colony-Stimulating Factor (GCSF) on Persistent Thin Endometrium in Frozen Embryo Transfer (FET) Cycles[J]. J Obstet Gynaecol India, 2016, 66(Suppl 1):407-411. doi: 10.1007/s13224-015-0775-9. doi: 10.1007/s13224-015-0775-9 URL
[7]	Hewitt SC, Winuthayanon W, Korach KS. What′s new in estrogen receptor action in the female reproductive tract[J]. J Mol Endocrinol, 2016, 56(2):R55-R71. doi: 10.1530/JME-15-0254. doi: 10.1530/JME-15-0254 URL
[8]	Gargett CE, Schwab KE, Deane JA. Endometrial stem/progenitor cells: the first 10 years[J]. Hum Reprod Update, 2016, 22(2):137-163. doi: 10.1093/humupd/dmv051. doi: 10.1093/humupd/dmv051
[9]	Hapangama DK, Kamal AM, Bulmer JN. Estrogen receptor β: the guardian of the endometrium[J]. Hum Reprod Update, 2015, 21(2):174-193. doi: 10.1093/humupd/dmu053. doi: 10.1093/humupd/dmu053 pmid: 25305176
[10]	Yuan R, Le AW. A study on the estrogen receptor α gene polymorphism and its expression in thin endometrium of unknown etiology[J]. Gynecol Obstet Invest, 2012, 74(1):13-20. doi: 10.1159/000334174. doi: 10.1159/000334174 URL
[11]	袁瑞, 乐爱文, 耿力, 等. 雌激素受体β基因RsaⅠ和AluⅠ多态性与原因不明月经过少的关系[J]. 中华医学遗传学杂志, 2007, 24(4):425-427. doi: 10.3760/j.issn:1003-9406.2007.04.014. doi: 10.3760/j.issn:1003-9406.2007.04.014
[12]	Gao M, Cao C, Zhang X, et al. Abnormal expression of estrogen receptor is associated with thin endometrium[J]. Gynecol Endocrinol, 2019, 35(6):544-547. doi: 10.1080/09513590.2018. 1554035. doi: 10.1080/09513590.2018. 1554035 URL
[13]	Gupta K, Sirohi VK, Kumari S, et al. Sorcin is involved during embryo implantation via activating VEGF/PI3K/Akt pathway in mice[J]. J Mol Endocrinol, 2018, 60(2):119-132. doi: 10.1530/JME-17-0153. doi: 10.1530/JME-17-0153 URL
[14]	Chakraborty C, Mitra S, Roychowdhury A, et al. Deregulation of LIMD1-VHL-HIF-1α-VEGF pathway is associated with different stages of cervical cancer[J]. Biochem J, 2018, 475(10):1793-1806. doi: 10.1042/BCJ20170649. doi: 10.1042/BCJ20170649 URL
[15]	Takasaki A, Tamura H, Taketani T, et al. A pilot study to prevent a thin endometrium in patients undergoing clomiphene citrate treatment[J]. J Ovarian Res, 2013, 6(1):94. doi: 10.1186/1757-2215-6-94. doi: 10.1186/1757-2215-6-94 pmid: 24369731
[16]	王一飞, 宋阳, 关永格, 等. 基于HOXA10调控网络探讨骨髓间充质干细胞移植治疗大鼠薄型子宫内膜[J]. 中国组织工程研究, 2019, 23(9):1397-1402. doi: 10.3969/j.issn.2095-4344.1605. doi: 10.3969/j.issn.2095-4344.1605
[17]	Bashiri A, Halper KI, Orvieto R. Recurrent Implantation Failure-update overview on etiology, diagnosis, treatment and future directions[J]. Reprod Biol Endocrinol, 2018, 16(1):121. doi: 10.1186/s12958-018-0414-2. doi: 10.1186/s12958-018-0414-2 URL
[18]	Gaide Chevronnay HP, Selvais C, Emonard H, et al. Regulation of matrix metalloproteinases activity studied in human endometrium as a paradigm of cyclic tissue breakdown and regeneration[J]. Biochim Biophys Acta, 2012, 1824(1):146-156. doi: 10.1016/j.bbapap.2011.09.003. doi: 10.1016/j.bbapap.2011.09.003 pmid: 21982799
[19]	周晓曦. 原因不明月经过少子宫内膜中血管内皮生长因子及基质金属蛋白酶-11的研究[D]. 重庆:重庆医科大学, 2007.
[20]	卢琼洁, 杜毅力, 曹永政, 等. 原因不明月经过少者经阴道彩色多普勒超声表现及分析[J]. 中国医学影像技术, 2009, 25(12):2264-2267. doi: 10.3321/j.issn:1003-3289.2009.12.033. doi: 10.3321/j.issn:1003-3289.2009.12.033
[21]	Li JY, Ren KK, Zhang WJ, et al. Human amniotic mesenchymal stem cells and their paracrine factors promote wound healing by inhibiting heat stress-induced skin cell apoptosis and enhancing their proliferation through activating PI3K/AKT signaling pathway[J]. Stem Cell Res Ther, 2019, 10(1):247. doi: 10.1186/s13287-019-1366-y. doi: 10.1186/s13287-019-1366-y URL
[22]	Dastgiri S, Yoosefian M, Garjani M, et al. Induced Abortion: a Systematic Review and Meta-analysis[J]. Mater Sociomed, 2017, 29(1):58-67. doi: 10.5455/msm.2017.29.58-67. doi: 10.5455/msm.2017.29.58-67 pmid: 28484357
[23]	Grace GA, Devaleenal DB, Natrajan M. Genital tuberculosis in females[J]. Indian J Med Res, 2017, 145(4):425-436. doi: 10.4103/ijmr.IJMR_1550_15. doi: 10.4103/ijmr.IJMR_1550_15
[24]	Wang Y, Lyu W, Xu W, et al. Asherman syndrome in adenomyosis treated with uterine artery embolization: incidence predictive factors[J]. Radiol Med, 2020, 125(5):437-443. doi: 10.1007/s11547-020-01136-8. doi: 10.1007/s11547-020-01136-8 URL
[25]	Talukdar N, Bentov Y, Chang PT, et al. Effect of long-term combined oral contraceptive pill use on endometrial thickness[J]. Obstet Gynecol, 2012, 120(2 Pt 1):348-354. doi: 10.1097/AOG.0b013e31825ec2ee. doi: 10.1097/AOG.0b013e31825ec2ee pmid: 22825095
[26]	Takasaki A, Tamura H, Miwa I, et al. Endometrial growth and uterine blood flow: a pilot study for improving endometrial thickness in the patients with a thin endometrium[J]. Fertil Steril, 2010, 93(6):1851-1858. doi: 10.1016/j.fertnstert.2008.12.062. doi: 10.1016/j.fertnstert.2008.12.062 pmid: 19200982
[27]	Zhong Y, Zeng F, Liu W, et al. Acupuncture in improving endometrial receptivity: a systematic review and meta-analysis[J]. BMC Complement Altern Med, 2019, 19(1):61. doi: 10.1186/s12906-019-2472-1. doi: 10.1186/s12906-019-2472-1 URL
[28]	Shen MS, Wang CW, Chen CH, et al. New horizon on successful management for a woman with repeated implantation failure due to unresponsive thin endometrium: use of extended estrogen supplementation[J]. J Obstet Gynaecol Res, 2013, 39(5):1092-1094. doi: 10.1111/j.1447-0756.2012.02070.x. doi: 10.1111/j.1447-0756.2012.02070.x URL
[29]	Zhong Y, Zeng F, Liu W, et al. Acupuncture in improving endometrial receptivity: a systematic review and meta-analysis[J]. BMC Complement Altern Med, 2019, 19(1):61. doi: 10.1186/s12906-019-2472-1. doi: 10.1186/s12906-019-2472-1 URL
[30]	Gutarra-Vilchez RB, Bonfill Cosp X, Glujovsky D, et al. Vasodilators for women undergoing fertility treatment[J]. Cochrane Database Syst Rev, 2018, 10(10):CD010001. doi: 10.1002/14651858.CD010001.pub3. doi: 10.1002/14651858.CD010001.pub3
[31]	张加能, 王冲. 盆底仿生物电刺激治疗薄型子宫内膜的Meta分析[J]. 中国现代医生, 2019, 57(20):64-68.
[32]	郑嘉华, 周寒, 张丹, 等. 子宫内膜微刺激对改善内膜容受性的作用[J]. 中国妇幼保健, 2018, 33(14):3355-3358. doi: 10.7620/zgfybj.j.issn.1001-4411.2018.14.77. doi: 10.7620/zgfybj.j.issn.1001-4411.2018.14.77
[33]	Yang JH, Chen CD, Chou CH, et al. Intentional endometrial injury increases embryo implantation potentials through enhanced endometrial angiogenesis?[J]. Biol Reprod, 2019, 100(2):381-389. doi: 10.1093/biolre/ioy205. doi: 10.1093/biolre/ioy205 URL
[34]	翟俊英, 王孜涵, 范宏芳. 高压氧对薄型子宫内膜患者冻融胚胎移植妊娠结局的疗效[J]. 广东医学, 2020, 41(19):1995-1998. doi: 10.13820/j.cnki.gdyx.20201211. doi: 10.13820/j.cnki.gdyx.20201211
[35]	Xie Y, Zhang T, Tian Z, et al. Efficacy of intrauterine perfusion of granulocyte colony-stimulating factor (G-CSF) for Infertile women with thin endometrium: A systematic review and meta-analysis[J]. Am J Reprod Immunol, 2017, 78(2):e12701. doi: 10.1111/aji.12701. doi: 10.1111/aji.12701 URL
[36]	白春梅, 土增荣, 王丽媛, 等. 宫腔内灌注粒细胞集落刺激因子联合低分子肝素在薄型子宫内膜患者冻融胚胎移植周期中的研究[J]. 国际生殖健康/计划生育杂志, 2020, 39(3):185-189. doi: 10.3969/j.issn.1674-1889.2020.03.002. doi: 10.3969/j.issn.1674-1889.2020.03.002
[37]	Zhao G, Cao Y, Zhu X, et al. Transplantation of collagen scaffold with autologous bone marrow mononuclear cells promotes functional endometrium reconstruction via downregulating ΔNp63 expression in Asherman′s syndrome[J]. Sci China Life Sci, 2017, 60(4):404-416. doi: 10.1007/s11427-016-0328-y. doi: 10.1007/s11427-016-0328-y URL
[38]	Tan J, Li P, Wang Q, et al. Autologous menstrual blood-derived stromal cells transplantation for severe Asherman′s syndrome[J]. Hum Reprod, 2016, 31(12):2723-2729. doi: 10.1093/humrep/dew235. doi: 10.1093/humrep/dew235 URL
[39]	Cao Y, Sun H, Zhu H, et al. Allogeneic cell therapy using umbilical cord MSCs on collagen scaffolds for patients with recurrent uterine adhesion: a phase I clinical trial[J]. Stem Cell Res Ther, 2018, 9(1):192. doi: 10.1186/s13287-018-0904-3. doi: 10.1186/s13287-018-0904-3 URL
[40]	郭杉, 刘英. 干细胞治疗宫腔粘连及薄型子宫内膜的研究进展[J]. 国际生殖健康/计划生育杂志, 2020, 39(6):504-508,513. doi: 10.3969/j.issn.1674-1889.2020.06.014. doi: 10.3969/j.issn.1674-1889.2020.06.014
[41]	袁丝丝, 刘文娥, 杨宇航, 等. 尤昭玲教授对薄型子宫内膜的认识[J]. 亚太传统医药, 2018, 14(1):139-140. doi: 10.11954/ytctyy.201801050. doi: 10.11954/ytctyy.201801050