{"paper_id":"5549d353-a095-4a76-bd7c-e1884a6d50a3","body_text":"Abstract\nPurpose\nEndometriosis is a debilitating disease with high recurrence rates requiring long-term management. Progestins such as dienogest are used empirically when first symptoms occur and post-surgery to reduce recurrence. This retrospective, practice-based study assessed the efficacy and safety of dienogest in women with endometriosis treated for at least 60 months.\nMethods\n37 women (age 39 ± 8 years) with laparoscopically diagnosed endometriosis received dienogest 2 mg orally once daily. Endometriosis-associated pelvic pain (EAPP) was measured on a 0–100 mm visual analog scale at baseline and every 12 months. Laboratory measures of lipid and liver metabolism, hemostatic and hormonal parameters were investigated in a subgroup of 15 women. Adverse events including bleeding disturbances and depressive symptoms were recorded.\nResults\nIn 22 women, dienogest was begun after laparoscopy; median EAPP score was 70 mm pre-surgery and 10, 10, 20, 20, and 20 mm, respectively, after 12, 24, 36, 48, and 60 months of dienogest treatment. Another 15 women began dienogest without prior surgery; median EAPP score was 80 mm pretreatment and 20, 20, 30, 30, and 30 mm, respectively, after 12, 24, 36, 48, and 60 months. All laboratory parameters remained within the normal range. Mean serum estradiol was 28 ± 12 pg/ml after 60 months. Seven women experienced spotting episodes and four women presented with phases of depressed mood, which could all be clinically managed.\nConclusions\nLong-term (60-month) treatment with dienogest 2 mg once-daily in women with endometriosis effectively reduced EAPP and avoided pain recurrence post-surgery. Dienogest was well tolerated and adverse effects were clinically managed.\nSimilar content being viewed by others\nChange history\n22 November 2018\nIn the original publication of the article, the word laparotomy has been presented in the proofs instead of laparoscopy in the below places.\n22 November 2018\nIn the original publication of the article, the word laparotomy has been presented in the proofs instead of laparoscopy in the below places.\n22 November 2018\nIn the original publication of the article, the word laparotomy has been presented in the proofs instead of laparoscopy in the below places.\nReferences\nKoninckx PR, Meuleman C, Demeyere S, Lesaffre E, Cornillie FJ (1991) Suggestive evidence that pelvic endometriosis is a progressive disease, whereas deeply infiltrating endometriosis is associated with pelvic pain. Fertil Steril 55(4):759–765\nSinaii N, Plumb K, Cotton L, Lambert A, Kennedy S, Zondervan K, Stratton P (2008) Differences in characteristics among 1,000 women with endometriosis based on extent of disease. Fertil Steril 89(3):538–545. https://doi.org/10.1016/j.fertnstert.2007.03.069\nSoliman AM, Coyne KS, Zaiser E, Castelli-Haley J, Fuldeore MJ (2017) The burden of endometriosis symptoms on health-related quality of life in women in the United States: a cross-sectional study. J Psychosom Obstet Gynaecol 38(4):238–248. https://doi.org/10.1080/0167482X.2017.1289512\nGuo SW (2009) Recurrence of endometriosis and its control. Hum Reprod Update 15(4):441–461. https://doi.org/10.1093/humupd/dmp007\nDunselman GA, Vermeulen N, Becker C, Calhaz-Jorge C, D’Hooghe T, De Bie B, Heikinheimo O, Horne AW, Kiesel L, Nap A, Prentice A, Saridogan E, Soriano D, Nelen W, European Society of Human Reproduction and Embryology (2014) ESHRE guideline: management of women with endometriosis. Hum Reprod 29(3):400–412. https://doi.org/10.1093/humrep/det457\nFalcone T, Lebovic DI (2011) Clinical management of endometriosis. Obstet Gynecol 118(3):691–705. https://doi.org/10.1097/AOG.0b013e31822adfd1\nJohnson NP, Hummelshoj L, World Endometriosis Society Montpellier Consortium (2013) Consensus on current management of endometriosis. Hum Reprod 28(6):1552–1568. https://doi.org/10.1093/humrep/det050\nKuznetsov L, Dworzynski K, Davies M, Overton C, Committee Guideline (2017) Diagnosis and management of endometriosis: summary of NICE guidance. BMJ 358:j3935. https://doi.org/10.1136/bmj.j3935\nLeyland N, Casper R, Laberge P, Singh SS, SOCG (2010) Endometriosis: diagnosis and management. J Obstet Gynaecol Can 32(7 Suppl 2):S1–S32\nPractice Committee of the American Society for Reproductive Medicine (2014) Treatment of pelvic pain associated with endometriosis: a committee opinion. Fertil Steril 101(4):927–935. https://doi.org/10.1016/j.fertnstert.2014.02.012\nAngioni S, Cofelice V, Pontis A, Tinelli R, Socolov R (2014) New trends of progestins treatment of endometriosis. Gynecol Endocrinol 30(11):769–773. https://doi.org/10.3109/09513590.2014.950646\nBrown J, Kives S, Akhtar M (2012) Progestagens and anti-progestagens for pain associated with endometriosis. Cochrane Database Syst Rev 3:CD002122. https://doi.org/10.1002/14651858.cd002122.pub2\nGrandi G, Mueller M, Bersinger NA, Cagnacci A, Volpe A, McKinnon B (2016) Does dienogest influence the inflammatory response of endometriotic cells? A systematic review. Inflamm Res 65(3):183–192. https://doi.org/10.1007/s00011-015-0909-7\nHorie S, Harada T, Mitsunari M, Taniguchi F, Iwabe T, Terakawa N (2005) Progesterone and progestational compounds attenuate tumor necrosis factor alpha-induced interleukin-8 production via nuclear factor kappa B inactivation in endometriotic stromal cells. Fertil Steril 83(5):1530–1535. https://doi.org/10.1016/j.fertnstert.2004.11.042\nKatsuki Y, Takano Y, Futamura Y, Shibutani Y, Aoki D, Udagawa Y, Nozawa S (1998) Effects of dienogest, a synthetic steroid, on experimental endometriosis in rats. Eur J Endocrinol 138(2):216–226\nMita S, Shimizu Y, Notsu T, Imada K, Kyo S (2011) Dienogest inhibits Toll-like receptor 4 expression induced by costimulation of lipopolysaccharide and high-mobility group box 1 in endometrial epithelial cells. Fertil Steril 96(6):1485–1489 e1484. https://doi.org/10.1016/j.fertnstert.2011.09.040\nMiyashita M, Koga K, Takamura M, Izumi G, Nagai M, Harada M, Hirata T, Hirota Y, Fujii T, Osuga Y (2014) Dienogest reduces proliferation, aromatase expression and angiogenesis, and increases apoptosis in human endometriosis. Gynecol Endocrinol 30(9):644–648. https://doi.org/10.3109/09513590.2014.911279\nNirgianakis K, Grandi G, McKinnon B, Bersinger N, Cagnacci A, Mueller M (2016) Dienogest mediates midkine suppression in endometriosis. Hum Reprod 31(9):1981–1986. https://doi.org/10.1093/humrep/dew180\nHarada T, Momoeda M, Taketani Y, Aso T, Fukunaga M, Hagino H, Terakawa N (2009) Dienogest is as effective as intranasal buserelin acetate for the relief of pain symptoms associated with endometriosis–a randomized, double-blind, multicenter, controlled trial. Fertil Steril 91(3):675–681. https://doi.org/10.1016/j.fertnstert.2007.12.080\nKohler G, Faustmann TA, Gerlinger C, Seitz C, Mueck AO (2010) A dose-ranging study to determine the efficacy and safety of 1, 2, and 4 mg of dienogest daily for endometriosis. Int J Gynaecol Obstet 108(1):21–25. https://doi.org/10.1016/j.ijgo.2009.08.020\nStrowitzki T, Faustmann T, Gerlinger C, Seitz C (2010) Dienogest in the treatment of endometriosis-associated pelvic pain: a 12-week, randomized, double-blind, placebo-controlled study. Eur J Obstet Gynecol Reprod Biol 151(2):193–198. https://doi.org/10.1016/j.ejogrb.2010.04.002\nStrowitzki T, Marr J, Gerlinger C, Faustmann T, Seitz C (2010) Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: a 24-week, randomized, multicentre, open-label trial. Hum Reprod 25(3):633–641. https://doi.org/10.1093/humrep/dep469\nStrowitzki T, Marr J, Gerlinger C, Faustmann T, Seitz C (2012) Detailed analysis of a randomized, multicenter, comparative trial of dienogest versus leuprolide acetate in endometriosis. Int J Gynaecol Obstet 117(3):228–233. https://doi.org/10.1016/j.ijgo.2012.01.009\nMorotti M, Sozzi F, Remorgida V, Venturini PL, Ferrero S (2014) Dienogest in women with persistent endometriosis-related pelvic pain during norethisterone acetate treatment. Eur J Obstet Gynecol Reprod Biol 183:188–192. https://doi.org/10.1016/j.ejogrb.2014.10.036\nVercellini P, Bracco B, Mosconi P, Roberto A, Alberico D, Dhouha D, Somigliana E (2016) Norethindrone acetate or dienogest for the treatment of symptomatic endometriosis: a before and after study. Fertil Steril 105(3):734–743 e733. https://doi.org/10.1016/j.fertnstert.2015.11.016\nMomoeda M, Harada T, Terakawa N, Aso T, Fukunaga M, Hagino H, Taketani Y (2009) Long-term use of dienogest for the treatment of endometriosis. J Obstet Gynaecol Res 35(6):1069–1076. https://doi.org/10.1111/j.1447-0756.2009.01076.x\nPetraglia F, Hornung D, Seitz C, Faustmann T, Gerlinger C, Luisi S, Lazzeri L, Strowitzki T (2012) Reduced pelvic pain in women with endometriosis: efficacy of long-term dienogest treatment. Arch Gynecol Obstet 285(1):167–173. https://doi.org/10.1007/s00404-011-1941-7\nSchindler AE (2011) Dienogest in long-term treatment of endometriosis. Int J Womens Health 3:175–184. https://doi.org/10.2147/IJWH.S5633\nKim SA, Um MJ, Kim HK, Kim SJ, Moon SJ, Jung H (2016) Study of dienogest for dysmenorrhea and pelvic pain associated with endometriosis. Obstet Gynecol Sci 59(6):506–511. https://doi.org/10.5468/ogs.2016.59.6.506\nLeonardo-Pinto JP, Benetti-Pinto CL, Cursino K, Yela DA (2017) Dienogest and deep infiltrating endometriosis: the remission of symptoms is not related to endometriosis nodule remission. Eur J Obstet Gynecol Reprod Biol 211:108–111. https://doi.org/10.1016/j.ejogrb.2017.02.015\nMaiorana A, Incandela D, Parazzini F, Alio W, Mercurio A, Giambanco L, Alio L (2017) Efficacy of dienogest in improving pain in women with endometriosis: a 12-month single-center experience. Arch Gynecol Obstet. https://doi.org/10.1007/s00404-017-4442-5\nPark SY, Kim SH, Chae HD, Kim CH, Kang BM (2016) Efficacy and safety of dienogest in patients with endometriosis: a single-center observational study over 12 months. Clin Exp Reprod Med 43(4):215–220. https://doi.org/10.5653/cerm.2016.43.4.215\nLang J, Yu Q, Zhang S, Li H, Gude K, von Ludwig C, Ren X, Dong L (2017) Dienogest for treatment of endometriosis in Chinese women: a placebo-controlled, randomized, double-blind phase 3 study. J Womens Health (Larchmt). https://doi.org/10.1089/jwh.2017.6399\nOta Y, Andou M, Yanai S, Nakajima S, Fukuda M, Mi Takano, Kurotsuchi S, Ebisawa K, Hada T, Ota I (2015) Long-term administration of dienogest reduces recurrence after excision of endometrioma. J Endometr Pelvic Pain Disord 7(2):63–67. https://doi.org/10.5301/je.5000219\nYamanaka A, Hada T, Matsumoto T, Kanno K, Shirane A, Yanai S, Nakajima S, Ebisawa K, Ota Y, Andou M (2017) Effect of dienogest on pain and ovarian endometrioma occurrence after laparoscopic resection of uterosacral ligaments with deep infiltrating endometriosis. Eur J Obstet Gynecol Reprod Biol 216:51–55. https://doi.org/10.1016/j.ejogrb.2017.07.014\nStrowitzki T, Faustmann T, Gerlinger C, Schumacher U, Ahlers C, Seitz C (2015) Safety and tolerability of dienogest in endometriosis: pooled analysis from the European clinical study program. Int J Womens Health 7:393–401. https://doi.org/10.2147/IJWH.S77202\nRevised American society for reproductive medicine classification of endometriosis: 1996 (1997). Fertil Steril 67(5):817–821\nVisanne [prescribing information] (2016) Bayer AG: Leverkusen, Germany. Available at: http://www.bayerresources.com.au/resources/uploads/pi/file10142.pdf\nLang J, Zhang X, Zhou Y, Di W, Gude K, Dong L (2017) Efficacy and safety of dienogest in Chinese women with endometriosis: a 24-week, multicenter, randomized, placebo-controlled study with 28-week open-label phase. Presented at the 13th World Congress on Endometriosis, Vancouver, Canada, 17–20 May 2017\nGerlinger C, Schumacher U, Faustmann T, Colligs A, Schmitz H, Seitz C (2010) Defining a minimal clinically important difference for endometriosis-associated pelvic pain measured on a visual analog scale: analyses of two placebo-controlled, randomized trials. Health Qual Life Outcomes 8:138. https://doi.org/10.1186/1477-7525-8-138\nVercellini P, Fedele L, Pietropaolo G, Frontino G, Somigliana E, Crosignani PG (2003) Progestogens for endometriosis: forward to the past. Hum Reprod Update 9(4):387–396\nSepulcri Rde P, do Amaral VF (2009) Depressive symptoms, anxiety, and quality of life in women with pelvic endometriosis. Eur J Obstet Gynecol Reprod Biol 142(1):53–56. https://doi.org/10.1016/j.ejogrb.2008.09.003\nLorencatto C, Petta CA, Navarro MJ, Bahamondes L, Matos A (2006) Depression in women with endometriosis with and without chronic pelvic pain. Acta Obstet Gynecol Scand 85(1):88–92\nFuldeore MJ, Soliman AM (2017) Prevalence and symptomatic burden of diagnosed endometriosis in the United States: national estimates from a cross-sectional survey of 59,411 women. Gynecol Obstet Invest 82(5):453–461. https://doi.org/10.1159/000452660\nVitale SG, Petrosino B, La Rosa VL, Rapisarda AM, Lagana AS (2016) A systematic review of the association between psychiatric disturbances and endometriosis. J Obstet Gynaecol Can 38(12):1079–1080. https://doi.org/10.1016/j.jogc.2016.09.008\nBarbieri RL (1992) Hormone treatment of endometriosis: the estrogen threshold hypothesis. Am J Obstet Gynecol 166(2):740–745\nLee DY, Park HG, Yoon BK, Choi D (2016) Effects of different add-back regimens on hypoestrogenic problems by postoperative gonadotropin-releasing hormone agonist treatment in endometriosis. Obstet Gynecol Sci 59(1):32–38. https://doi.org/10.5468/ogs.2016.59.1.32\nAcknowledgements\nEditorial assistance was provided by Bill Wolvey of PAREXEL International, which was contracted by Bayer AG.\nFunding\nNo study funding was received.\nAuthor information\nAuthors and Affiliations\nContributions\nTR participated in the project development, data collection and management, data analysis, and manuscript editing.\nCorresponding author\nEthics declarations\nConflict of interest\nProf. Römer has received honoraria for lectures and advisory boards from: Bayer, MSD, Gedeon Richter, Dr. KADE, and Aristo Pharma.\nInformed consent\nInformed consent was obtained from all individual participants included in the study.\nRights and permissions\nAbout this article\nCite this article\nRömer, T. Long-term treatment of endometriosis with dienogest: retrospective analysis of efficacy and safety in clinical practice. Arch Gynecol Obstet 298, 747–753 (2018). https://doi.org/10.1007/s00404-018-4864-8\nReceived:\nAccepted:\nPublished:\nVersion of record:\nIssue date:\nDOI: https://doi.org/10.1007/s00404-018-4864-8","source_license":"CC0","license_restricted":false}