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口服GnRH拮抗剂elagolix治疗子宫内膜异位症相关疼痛的研究
Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist


Hugh S. Taylor ... 妇产科和儿科 • 2017.07.06
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• 无癌子宫内膜异位症携带癌症相关基因突变的研究

elagolix:子宫内膜异位症疼痛治疗的新选择


沈雪,段华*

首都医科大学附属北京妇产医院

* 通讯作者

 

子宫内膜异位症(简称内异症)是育龄期女性的常见、多发疾病,典型临床症状是疼痛和不孕。内异症所致的疼痛,以其持久性和易复发性特征,已经成为临床难治性疾病和严重影响患者身心健康与生活质量的“慢病”1。近年来,聚焦内异症疼痛治疗的方法不断推陈出新,对于疼痛治疗的选择也愈发呈现多样化态势。

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摘要


背景

子宫内膜异位症是一种慢性、雌激素依赖的疾病,可以引起痛经和盆腔痛。elagolix是一种口服非肽类促性腺激素释放激素(GnRH)拮抗剂;在此前的研究中,该药物可以抑制雌激素,抑制程度可从部分抑制到几乎完全抑制。

 

方法

我们实施了两项相似的双盲、随机、为期6个月的3期试验(Elaris子宫内膜异位症Ⅰ和Ⅱ试验[EM-Ⅰ和EM-Ⅱ]),研究对象为手术确诊子宫内膜异位症并且有中度或重度子宫内膜异位症相关疼痛的妇女;目的是对两种剂量的elagolix(150 mg每日1次[小剂量组]和200 mg每日2次[大剂量组])与安慰剂的疗效进行比较。主要疗效终点有两项:在3个月时,痛经获得临床缓解的妇女比例以及非经期盆腔痛获得临床缓解的妇女比例。这些终点的测量方法为,根据妇女每日记录的电子日记,判断她们的疼痛评分出现有临床意义的下降,以及挽救性止痛药物的使用量下降或保持稳定。

 

结果

Elaris EM-Ⅰ和Elaris EM-Ⅱ试验分别有872名妇女和817名妇女接受随机分组。其中,两项试验分别有653人(74.9%)和632人(77.4%)完成了试验干预。在3个月时对两项主要终点进行判断,接受任一剂量elagolix治疗的妇女中,满足临床缓解标准的妇女比例显著高于接受安慰剂治疗的妇女。在Elaris EM-Ⅰ试验中,小剂量elagolix组和大剂量组分别有46.4%和75.8%妇女的痛经获得临床缓解,而安慰剂组为19.6%;在Elaris EM-Ⅱ试验中,相应的百分比分别为43.4%和72.4%,而安慰剂组则为22.7%(所有比较均P<0.001)。在Elaris EM-Ⅰ试验中,小剂量elagolix组和大剂量组分别有50.4%和54.5%妇女的非经期盆腔痛获得临床缓解,而安慰剂组为36.5%(所有比较均P<0.001);在Elaris EM-Ⅱ试验中,相应的百分比分别为49.8%和57.8%,而安慰剂组为36.5%(P值分别为P=0.003和P<0.001)。痛经和非经期盆腔痛的缓解可持续至6个月。与接受安慰剂治疗的妇女相比,接受elagolix治疗的妇女中,潮热的比例较高(主要是轻度或中度),血脂水平较高,而且骨密度较基线降低幅度较大;未见子宫内膜不良的检查结果。

 

结论

在患子宫内膜异位症相关疼痛的妇女中,大剂量和小剂量的elagolix在6个月期间均可有效改善痛经和非经期盆腔痛。两种剂量的elagolix均伴有低雌激素水平的不良反应(由艾伯维公司[AbbVie]资助;Elaris EM-Ⅰ和EM-Ⅱ在ClinicalTrials.gov注册号为NCT01620528和NCT01931670)。





作者信息

Hugh S. Taylor, M.D., Linda C. Giudice, M.D., Ph.D., Bruce A. Lessey, M.D., Ph.D., Mauricio S. Abrao, M.D., Jan Kotarski, M.D., Ph.D., David F. Archer, M.D., Michael P. Diamond, M.D., Eric Surrey, M.D., Neil P. Johnson, M.D., Nelson B. Watts, M.D., J. Chris Gallagher, M.D., James A. Simon, M.D., Bruce R. Carr, M.D., W. Paul Dmowski, M.D., Ph.D., Nicholas Leyland, M.D., Jean P. Rowan, M.B., Ch.B., W. Rachel Duan, M.D., Ph.D., Juki Ng, Pharm.D., Ph.D., Brittany Schwefel, Ph.D., James W. Thomas, M.S., Rita I. Jain, M.D., and Kristof Chwalisz, M.D., Ph.D.
From Yale School of Medicine, New Haven, CT (H.S.T.); University of California, San Francisco, San Francisco (L.C.G.); Greenville Health System, Greenville, SC (B.A.L.); University of São Paulo and Sirio Libanes Hospital, São Paulo (M.S.A.); Medical University, Lublin, Poland (J.K.); Eastern Virginia Medical School, Norfolk (D.F.A.); Augusta University, Augusta, GA (M.P.D.); Colorado Center for Reproductive Medicine, Lone Tree (E.S.); Robinson Research Institute, University of Adelaide, Adelaide, SA, Australia (N.P.J.); Repromed Auckland, Auckland, New Zealand (N.P.J.); Mercy Health Osteoporosis and Bone Health Services, Cincinnati (N.B.W.); Creighton University School of Medicine, Omaha, NE (J.C.G.); George Washington University, Washington, DC (J.A.S.); University of Texas Southwestern Medical Center, Dallas (B.R.C.); Institute for the Study and Treatment of Endometriosis, Oak Brook (W.P.D.), and AbbVie, North Chicago (J.P.R., W.R.D., J.N., B.S., J.W.T., R.I.J., K.C.) — both in Illinois; and McMaster University, Hamilton, ON, Canada (N.L.). Address reprint requests to Dr. Taylor at the Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, 333 Cedar St., New Haven, CT 06520, or at hugh.taylor@yale.edu.

 

参考文献

1. Giudice LC. Endometriosis. N Engl J Med 2010;362:2389-2398

2. Missmer SA, Hankinson SE, Spiegelman D, et al. Reproductive history and endometriosis among premenopausal women. Obstet Gynecol 2004;104:965-974

3. Johnson NP, Hummelshoj L. Consensus on current management of endometriosis. Hum Reprod 2013;28:1552-1568

4. Nnoaham KE, Hummelshoj L, Webster P, et al. Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertil Steril 2011;96:366-373.e8

5. Simoens S, Dunselman G, Dirksen C, et al. The burden of endometriosis: costs and quality of life of women with endometriosis and treated in referral centres. Hum Reprod 2012;27:1292-1299

6. Soliman AM, Yang H, Du EX, Kelley C, Winkel C. The direct and indirect costs associated with endometriosis: a systematic literature review. Hum Reprod 2016;31:712-722

7. Gao X, Outley J, Botteman M, Spalding J, Simon JA, Pashos CL. Economic burden of endometriosis. Fertil Steril 2006;86:1561-1572

8. Vercellini P, Meana M, Hummelshoj L, Somigliana E, Viganò P, Fedele L. Priorities for endometriosis research: a proposed focus on deep dyspareunia. Reprod Sci 2011;18:114-118

9. Du H, Taylor HS. Contribution of bone marrow-derived stem cells to endometrium and endometriosis. Stem Cells 2007;25:2082-2086

10. Bulun SE. Endometriosis. N Engl J Med 2009;360:268-279

11. Reis FM, Petraglia F, Taylor RN. Endometriosis: hormone regulation and clinical consequences of chemotaxis and apoptosis. Hum Reprod Update 2013;19:406-418

12. Brosens JJ, Gellersen B. The uterus under hormonal control — cycling for life. Mol Cell Endocrinol 2012;358:145-145

13. Bulun SE, Yang S, Fang Z, Gurates B, Tamura M, Sebastian S. Estrogen production and metabolism in endometriosis. Ann N Y Acad Sci 2002;955:75-85

14. Barbieri RL. Hormone treatment of endometriosis: the estrogen threshold hypothesis. Am J Obstet Gynecol 1992;166:740-745

15. Brown J, Pan A, Hart RJ. Gonadotrophin-releasing hormone analogues for pain associated with endometriosis. Cochrane Database Syst Rev 2010:CD008475-CD008475

16. Petta CA, Ferriani RA, Abrao MS, et al. Randomized clinical trial of a levonorgestrel-releasing intrauterine system and a depot GnRH analogue for the treatment of chronic pelvic pain in women with endometriosis. Hum Reprod 2005;20:1993-1998

17. Dragoman MV, Gaffield ME. The safety of subcutaneously administered depot medroxyprogesterone acetate (104mg/0.65mL): A systematic review. Contraception 2016;94:202-215

18. Burney RO, Talbi S, Hamilton AE, et al. Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis. Endocrinology 2007;148:3814-3826

19. Olive DL. Gonadotropin-releasing hormone agonists for endometriosis. N Engl J Med 2008;359:1136-1142

20. Guo SW. Recurrence of endometriosis and its control. Hum Reprod Update 2009;15:441-461

21. Ofer A, Shulman LP, Singh SS. Improving the treatment and management of endometriosis: an overview of current and novel approaches. Am J Obstet Gynecol 2016;214:672-672

22. Carr B, Dmowski WP, O’Brien C, et al. Elagolix, an oral GnRH antagonist, versus subcutaneous depot medroxyprogesterone acetate for the treatment of endometriosis: effects on bone mineral density. Reprod Sci 2014;21:1341-1351

23. Diamond MP, Carr B, Dmowski WP, et al. Elagolix treatment for endometriosis-associated pain: results from a phase 2, randomized, double-blind, placebo-controlled study. Reprod Sci 2014;21:363-371

24. Carr B, Giudice L, Dmowski WP, et al. Elagolix, an oral GnRH antagonist for endometriosis-associated pain: a randomized, controlled study. J Endometr Pelvic Pain Disord 2013;5:105-115

25. Ng J, Chwalisz K, Carter DC, Klein CE. Dose-dependent suppression of gonadotropins and ovarian hormones by elagolix in healthy premenopausal women. J Clin Endocrinol Metab 2017;102:1683-1691

26. Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1 — executive summary. J Clin Lipidol 2014;8:473-488

27. Farrar JT, Young JP Jr, LaMoreaux L, Werth JL, Poole RM. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain 2001;94:149-158

28. Stratton P, Berkley KJ. Chronic pelvic pain and endometriosis: translational evidence of the relationship and implications. Hum Reprod Update 2011;17:327-346

29. Watts NB, Leslie WD, Foldes AJ, Miller PD. 2013 International Society for Clinical Densitometry Position Development Conference: Task Force on Normative Databases. J Clin Densitom 2013;16:472-481

30. Surrey ES, Hornstein MD. Prolonged GnRH agonist and add-back therapy for symptomatic endometriosis: long-term follow-up. Obstet Gynecol 2002;99:709-719

31. Mu F, Rich-Edwards J, Rimm EB, Spiegelman D, Missmer SA. Endometriosis and risk of coronary heart disease. Circ Cardiovasc Qual Outcomes 2016;9:257-264

32. Hornstein MD, Surrey ES, Weisberg GW, Casino LA. Leuprolide acetate depot and hormonal add-back in endometriosis: a 12-month study. Obstet Gynecol 1998;91:16-24

33. Maggi R, Cariboni AM, Marelli MM, et al. GnRH and GnRH receptors in the pathophysiology of the human female reproductive system. Hum Reprod Update 2016;22:358-381

34. Prentice A, Deary AJ, Goldbeck-Wood S, Farquhar C, Smith SK. Gonadotrophin-releasing hormone analogues for pain associated with endometriosis. Cochrane Database Syst Rev 2000:CD000346-CD000346

35. Sagsveen M, Farmer JE, Prentice A, Breeze A. Gonadotrophin-releasing hormone analogues for endometriosis: bone mineral density. Cochrane Database Syst Rev 2003:CD001297-CD001297

36. Practice Committee of the American Society for Reproductive Medicine. Treatment of pelvic pain associated with endometriosis: a committee opinion. Fertil Steril 2014;101:927-935

37. Gylfason JT, Kristjansson KA, Sverrisdottir G, Jonsdottir K, Rafnsson V, Geirsson RT. Pelvic endometriosis diagnosed in an entire nation over 20 years. Am J Epidemiol 2010;172:237-243

38. Leyland N, Casper R, Laberge P, Singh SS. Endometriosis: diagnosis and management. J Obstet Gynaecol Can 2010;32:Suppl 2:S1-S32

39. Parazzini F, Esposito G, Tozzi L, Noli S, Bianchi S. Epidemiology of endometriosis and its comorbidities. Eur J Obstet Gynecol Reprod Biol 2017;209:3-7

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