多囊卵巢综合征氯米芬抵抗的预测及促排卵治疗

doi:10.12280/gjfckx.20211135

摘要/Abstract

摘要：

多囊卵巢综合征（polycystic ovary syndrome,PCOS）是无排卵性不孕症最常见的原因,对于有生育要求的PCOS患者,促排卵是其首选治疗方案。枸橼酸氯米芬（clomiphene citrate,CC）是目前国内外指南推荐治疗PCOS不孕症的传统一线促排卵药物,但CC的治疗反应性个体差异显著,其中约40%的患者对CC不反应,即CC抵抗。综述近年来CC抵抗的PCOS患者预测指标及替代的促排卵策略的研究进展,主要从表型、生化特征和基因组学角度阐述PCOS不孕症患者CC抵抗预测指标,从来曲唑（Letrozole,LE）、促性腺激素（gonadotropin,Gn）、腹腔镜卵巢打孔术（laparoscopic ovarian drilling,LOD）、体外受精（in vitro fertilization,IVF）及中医辅助治疗等治疗方式中选用单一或联合的方案阐述其替代促排卵策略,并比较各种方案或方案组合的优势与潜在不足,以期为临床PCOS不孕症患者提供更加精准、个体化的促排卵方案。

关键词: 多囊卵巢综合征, 不育,女（雌）性, 氯米芬, 排卵诱导, 治疗

Abstract:

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. Ovulation induction is the first choice of treatment for PCOS patients with fertility requirements. According to the current domestic and international treatment guidelines, clomiphene citrate (CC) is the traditional first-line drug to induce ovulation for infertile women with PCOS. However, the response of CC ovulation treatment varies significantly for different patients. It was reported that about 40% of PCOS patients cannot respond to CC, that is, CC resistance. This paper provides a review on the research progress of predictive indicators for PCOS infertile women with CC resistance as well as alternative ovulation induction strategies in recent years. This paper mainly expounds the predictive indicators for PCOS patients with CC resistance from the perspective of phenotype, biochemical characteristics and genetics. Single or combined schemes are selected in the treatment methods of letrozole (LE), gonadotropin (Gn), laparoscopic ovarian perforation (LOD), in vitro fertilization (IVF) and adjunctive therapy of traditional Chinese medicine to elaborate their alternative ovulation induction strategies, and the advantages and potential shortcomings of these single and combined schemes are discussed to provide more accurate and individualized ovulation induction schemes for PCOS infertile women.

Key words: Polycystic ovary syndrome, Infertility,female, Clomiphene, Ovulation induction, Therapy

马丽娜, 马红丽, 李建, 丛晶, 高敬书, 王宇, 吴效科. 多囊卵巢综合征氯米芬抵抗的预测及促排卵治疗[J]. 国际妇产科学杂志, 2022, 49(3): 256-260.

MA Li-na, MA Hong-li, LI Jian, CONG Jing, GAO Jing-shu, WANG Yu, WU Xiao-ke. Predictors and Ovulation Induction Therapy for Polycystic Ovary Syndrome Patients with Clomiphene Resistance[J]. Journal of International Obstetrics and Gynecology, 2022, 49(3): 256-260.

参考文献 34

[1]	Dadachanji R, Shaikh N, Mukherjee S. Genetic Variants Associated with Hyperandrogenemia in PCOS Pathophysiology[J]. Genet Res Int, 2018, 2018:7624932. doi: 10.1155/2018/7624932. doi: 10.1155/2018/7624932
[2]	中华医学会妇产科学分会内分泌学组及指南专家组. 多囊卵巢综合征中国诊疗指南[J]. 中华妇产科杂志, 2018, 53(1):2-6. doi: 10.3760/cma.j.issn.0529-567x.2018.01.002. doi: 10.3760/cma.j.issn.0529-567x.2018.01.002
[3]	ACOG Practice Bulletin No. Bulletin No. 194: Polycystic Ovary Syndrome[J]. Obstet Gynecol, 2018, 131(6):e157-e171. doi: 10.1097/AOG.0000000000002656. doi: 10.1097/AOG.0000000000002656
[4]	Smithson DS, Vause T, Cheung AP. No. 362-Ovulation Induction in Polycystic Ovary Syndrome[J]. J Obstet Gynaecol Can, 2018, 40(7):978-987. doi: 10.1016/j.jogc.2017.12.004. doi: S1701-2163(17)31217-3 pmid: 29921434
[5]	Yu Q, Hu S, Wang Y, et al. Letrozole versus laparoscopic ovarian drilling in clomiphene citrate-resistant women with polycystic ovary syndrome: a systematic review and meta-analysis of randomized controlled trials[J]. Reprod Biol Endocrinol, 2019, 17(1):17. doi: 10.1186/s12958-019-0461-3. doi: 10.1186/s12958-019-0461-3
[6]	Sachdeva G, Gainder S, Suri V, et al. Comparison of Clinical, Metabolic, Hormonal, and Ultrasound Parameters among the Clomiphene Citrate-Resistant and Clomiphene Citrate-Sensitive Polycystic Ovary Syndrome Women[J]. J Hum Reprod Sci, 2019, 12(3):216-223. doi: 10.4103/jhrs.JHRS_89_18. doi: 10.4103/jhrs.JHRS_89_18 pmid: 31576079
[7]	石伟龙, 赵云天, 赵荣生. 基因多态性对氯米芬药物代谢动力学及药效学影响的系统评价[J]. 临床药物治疗杂志, 2021, 19(1):50-53. doi: 10.3969/j.issn.1672-3384.2021.01.011. doi: 10.3969/j.issn.1672-3384.2021.01.011
[8]	Kim MJ, Byeon JY, Kim YH, et al. Effect of the CYP2D6*10 allele on the pharmacokinetics of clomiphene and its active metabolites[J]. Arch Pharm Res, 2018, 41(3):347-353. doi: 10.1007/s12272-018-1005-7. doi: 10.1007/s12272-018-1005-7
[9]	Quaas AM, Legro RS. Pharmacology of medications used for ovarian stimulation[J]. Best Pract Res Clin Endocrinol Metab, 2019, 33(1):21-33. doi: 10.1016/j.beem.2018.10.002. doi: 10.1016/j.beem.2018.10.002
[10]	Sachdeva G, Gainder S, Suri V, et al. Prediction of Responsiveness to Clomiphene Citrate in Infertile Women with PCOS[J]. J Reprod Infertil, 2019, 20(3):143-150. pmid: 31423417
[11]	Gülşen MS, Ulu İ, Yıldırım K, et al. The role of anti-Müllerian hormone in predicting clomiphene citrate resistance in women with polycystic ovarian syndrome[J]. Gynecol Endocrinol, 2019, 35(1):86-89. doi: 10.1080/09513590.2018.1499085. doi: 10.1080/09513590.2018.1499085
[12]	Rajendiran L, Nandeesha H, Chitra T. Reduced Angiopoietin-2 as a Predictive Biomarker for Clomiphene Citrate Resistance in Polycystic Ovary Syndrome[J]. J Hum Reprod Sci, 2021, 14(2):144-148. doi: 10.4103/jhrs.jhrs_179_20. doi: 10.4103/jhrs.jhrs_179_20
[13]	Peker N, Ege S, Bademkiran MH, et al. Can clomiphene citrate resistance be predicted by RDW-CV levels in infertile women with PCOS?[J]. Niger J Clin Pract, 2019, 22(11):1463-1466. doi: 10.4103/njcp.njcp_666_18. doi: 10.4103/njcp.njcp_666_18
[14]	Overbeek A, Kuijper EA, Hendriks ML, et al. Clomiphene citrate resistance in relation to follicle-stimulating hormone receptor Ser680Ser-polymorphism in polycystic ovary syndrome[J]. Hum Reprod, 2009, 24(8):2007-2013. doi: 10.1093/humrep/dep114. doi: 10.1093/humrep/dep114
[15]	Mohiyiddeen L, Salim S, Mulugeta B, et al. PCOS and peripheral AMH levels in relation to FSH receptor gene single nucleotide polymorphisms[J]. Gynecol Endocrinol, 2012, 28(5):375-377. doi: 10.3109/09513590.2011.633649. doi: 10.3109/09513590.2011.633649 pmid: 22429116
[16]	Robin C, Hennart B, Broly F, et al. Could Cytochrome P450 2D6, 3A4 and 3A5 Polymorphisms Explain the Variability in Clinical Response to Clomiphene Citrate of Anovulatory PCOS Women?[J]. Front Endocrinol (Lausanne), 2021, 12:718917. doi: 10.3389/fendo.2021.718917. doi: 10.3389/fendo.2021.718917
[17]	Mitwally MF, Casper RF. Use of an aromatase inhibitor for induction of ovulation in patients with an inadequate response to clomiphene citrate[J]. Fertil Steril, 2001, 75(2):305-309. doi: 10.1016/s0015-0282(00)01705-2. doi: 10.1016/s0015-0282(00)01705-2 pmid: 11172831
[18]	Rezk M, Shaheen AE, Saif El-Nasr I. Clomiphene citrate combined with metformin versus letrozole for induction of ovulation in clomiphene-resistant polycystic ovary syndrome: a randomized clinical trial[J]. Gynecol Endocrinol, 2018, 34(4):298-300. doi: 10.1080/09513590.2017.1395838. doi: 10.1080/09513590.2017.1395838
[19]	Abu Hashim H, Shokeir T, Badawy A. RETRACTED: Letrozole versus combined metformin and clomiphene citrate for ovulation induction in clomiphene-resistant women with polycystic ovary syndrome: a randomized controlled trial[J]. Fertil Steril, 2010, 94(4):1405-1409. doi: 10.1016/j.fertnstert.2009.07.985. doi: S0015-0282(09)02481-9 pmid: 19732888
[20]	Shi S, Hong T, Jiang F, et al. Letrozole and human menopausal gonadotropin for ovulation induction in clomiphene resistance polycystic ovary syndrome patients: A randomized controlled study[J]. Medicine (Baltimore), 2020, 99(4):e18383. doi: 10.1097/MD.0000000000018383. doi: 10.1097/MD.0000000000018383
[21]	Hassan A, Shehata N, Wahba A. Cost effectiveness of letrozole and purified urinary FSH in treating women with clomiphene citrate-resistant polycystic ovarian syndrome: a randomized controlled trial[J]. Hum Fertil (Camb),2017, 20(1):37-42. doi: 10.1080/14647273.2016.1242783. doi: 10.1080/14647273.2016.1242783
[22]	Palomba S, Falbo A, La Sala GB. Effects of metformin in women with polycystic ovary syndrome treated with gonadotrophins for in vitro fertilisation and intracytoplasmic sperm injection cycles: a systematic review and meta-analysis of randomised controlled trials[J]. BJOG, 2013, 120(3):267-276. doi: 10.1111/1471-0528.12070. doi: 10.1111/1471-0528.12070
[23]	Zhao Y, Ruan X, Mueck AO. Letrozole combined with low dose highly purified HMG for ovulation induction in clomiphene citrate-resistant infertile Chinese women with polycystic ovary syndrome: a prospective study[J]. Gynecol Endocrinol, 2017, 33(6):462-466. doi: 10.1080/09513590.2017.1292241. doi: 10.1080/09513590.2017.1292241 pmid: 28277124
[24]	Seow KM, Chang YW, Chen KH, et al. Molecular Mechanisms of Laparoscopic Ovarian Drilling and Its Therapeutic Effects in Polycystic Ovary Syndrome[J]. Int J Mol Sci, 2020, 21(21):8147. doi: 10.3390/ijms21218147. doi: 10.3390/ijms21218147
[25]	Sinha P, Chitra T, Papa D, et al. Laparoscopic Ovarian Drilling Reduces Testosterone and Luteinizing Hormone/Follicle-Stimulating Hormone Ratio and Improves Clinical Outcome in Women with Polycystic Ovary Syndrome[J]. J Hum Reprod Sci, 2019, 12(3):224-228. doi: 10.4103/jhrs.JHRS_161_18. doi: 10.4103/jhrs.JHRS_161_18
[26]	Rezk M, Sayyed T, Saleh S. Impact of unilateral versus bilateral laparoscopic ovarian drilling on ovarian reserve and pregnancy rate: a randomized clinical trial[J]. Gynecol Endocrinol, 2016, 32(5):399-402. doi: 10.3109/09513590.2015.1124262. doi: 10.3109/09513590.2015.1124262
[27]	Amer SA, Shamy T, James C, et al. The impact of laparoscopic ovarian drilling on AMH and ovarian reserve: a meta-analysis[J]. Reproduction, 2017, 154(1):R13-R21. doi: 10.1530/REP-17-0063. doi: 10.1530/REP-17-0063
[28]	Kamal N, Sanad Z, Elkelani O, et al. Changes in ovarian reserve and ovarian blood flow in patients with polycystic ovary syndrome following laparoscopic ovarian drilling[J]. Gynecol Endocrinol, 2018, 34(9):789-792. doi: 10.1080/09513590.2018.1459549. doi: 10.1080/09513590.2018.1459549
[29]	Seyam E, Hefzy E. Tumor necrosis factor alpha versus LH and androstendione as a reliable predictor of spontaneous ovulation after laparoscopic ovarian drilling for women with clomiphene citrate resistance polycystic ovarian disease[J]. Eur J Obstet Gynecol Reprod Biol, 2018, 222:126-133. doi: 10.1016/j.ejogrb.2018.01.011. doi: 10.1016/j.ejogrb.2018.01.011
[30]	Seyam E, Hefzy E. Laparoscopic ovarian drilling versus GnRH antagonist combined with cabergoline as a prophylaxis against the re-development of ovarian hyperstimulation syndrome[J]. Gynecol Endocrinol, 2018, 34(7):616-622. doi: 10.1080/09513590.2018.1425989. doi: 10.1080/09513590.2018.1425989
[31]	Mahey R, Gupta M, Bansiwal R, et al. Successful IVF outcome after repeat laparoscopic ovarian drilling in a case of resistant PCOS[J]. BMJ Case Rep, 2020, 13(9):e235628. doi: 10.1136/bcr-2020-235628. doi: 10.1136/bcr-2020-235628
[32]	夏桂成, 谈勇. 中医药治疗排卵障碍性不孕症临床研究进展述评[J]. 江苏中医药, 2019, 51(9):1-7. doi: 10.3969/j.issn.1672-397X.2019.09.001. doi: 10.3969/j.issn.1672-397X.2019.09.001
[33]	彭绍婵. 针刺联合LE+Gn治疗克罗米芬不敏感型多囊卵巢综合征不孕妇女的疗效观察[D]. 广州: 广州中医药大学, 2018.
[34]	张岩, 谈勇. 滋阴补阳中药序贯法联合rFSH低剂量递增方案治疗CC抵抗的临床观察[J]. 中国妇幼保健, 2015, 30(34):6099-6103. doi: 10.7620/zgfybj.j.issn.1001-4411.2015.34.62. doi: 10.7620/zgfybj.j.issn.1001-4411.2015.34.62