Risk factors for non-response and discontinuation of Dienogest in endometriosis patients: A cohort study

Konstantinos Nirgianakis, Cloé Vaineau, Lia Agliati, Brett McKinnon, Maria L Gasparri, Michael D Mueller, Konstantinos Nirgianakis, Cloé Vaineau, Lia Agliati, Brett McKinnon, Maria L Gasparri, Michael D Mueller

Abstract

Introduction: Progestins are commonly prescribed first-line drugs for endometriosis. High rates of non-response and intolerance to these drugs have been previously reported. However, no study to date has investigated the characteristics and comorbidities of patients taking progestins in relation to treatment outcomes, so identifying which patients will respond to or tolerate the treatment is currently impossible. The purpose of this study, therefore, was to identify risk factors for non-response and discontinuation of Dienogest (DNG) in women with endometriosis.

Material and methods: This is a retrospective cohort study including women currently taking, or newly prescribed, DNG for endometriosis-associated pain presenting in the Endometriosis Clinic of the University Hospital of Bern between January 2017 and May 2018. Women with initiation of treatment directly after surgery for endometriosis were excluded. For all participants the symptoms and comorbidities were documented. Effectiveness, tolerability and discontinuation of DNG were the primary end points. Univariate and multivariate binary logistic regression models were carried out to identify risk factors for non-response, intolerance and discontinuation of DNG.

Results: A sufficient or excellent treatment response was reported by 85/125 (68%) participants. Genital bleeding during the DNG treatment was negatively (OR 0.185, 95% CI 0.056-0.610, P = .006) and rASRM endometriosis stages III and IV were positively (OR 3.876, 95% CI 1.202-12.498, P = .023) correlated with the DNG response. When accounting for exclusively pretreatment factors, primary dysmenorrhea (OR 0.236, 95% CI 0.090-0.615, P = .003) and suspicion of adenomyosis (OR 0.347, 95% CI 0.135-0.894, P = .028) were inversely correlated with DNG response, and the latter was also correlated with treatment discontinuation (OR 3.189, 95% CI 1.247-8.153, P = .015).

Conclusions: Genital bleeding during the DNG treatment and low rASRM stages are independent risk factors for DNG non-response. Before treatment initiation, primary dysmenorrhea and suspicion of adenomyosis correlate with DNG non-response. The results could assist the clinician first to provide detailed information to women before treatment initiation, second to identify and possibly modify in-therapy factors correlated to treatment effectiveness and lastly to switch treatment on time if needed.

Keywords: Dienogest; endometriosis; hormonal treatment; medical treatment; progestin; progestin-only pill; response; side effects.

© 2020 Nordic Federation of Societies of Obstetrics and Gynecology (NFOG). Published by John Wiley & Sons Ltd.

References

REFERENCES

    1. Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364:1789-1799.
    1. Ahn SH, Singh V, Tayade C. Biomarkers in endometriosis: challenges and opportunities. Fertil Steril. 2017;107:523-532.
    1. Practice bulletin no. 114: management of endometriosis. Obstet Gynecol. 2010;116:223-236.
    1. Lee SR, Yi KW, Song JY, et al. Efficacy and safety of long-term use of dienogest in women with ovarian endometrioma. Reprod Sci. 2018;25:341-346.
    1. Somigliana E, Vercellini P, Vigano P, Benaglia L, Busnelli A, Fedele L. Postoperative medical therapy after surgical treatment of endometriosis: from adjuvant therapy to tertiary prevention. J Minim Invasive Gynecol. 2014;21:328-334.
    1. Strowitzki T, Marr J, Gerlinger C, Faustmann T, Seitz C. Dienogest is as effective as leuprolide acetate in treating the painful symptoms of endometriosis: a 24-week, randomized, multicentre, open-label trial. Hum Reprod. 2010;25:633-641.
    1. Harada T, Momoeda M, Taketani Y, et al. 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. 2009;91:675-681.
    1. Becker CM, Gattrell WT, Gude K, Singh SS. Reevaluating response and failure of medical treatment of endometriosis: a systematic review. Fertil Steril. 2017;108:125-136.
    1. von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007;370:1453-1457.
    1. Chapron C, Lafay-Pillet M-C, Monceau E, et al. Questioning patients about their adolescent history can identify markers associated with deep infiltrating endometriosis. Fertil Steril. 2011;95:877-881.
    1. Strowitzki T, Faustmann T, Gerlinger C, Schumacher U, Ahlers C, Seitz C. Safety and tolerability of dienogest in endometriosis: pooled analysis from the European clinical study program. Int J Womens Health. 2015;7:393-401.
    1. Zigler RE, McNicholas C. Unscheduled vaginal bleeding with progestin-only contraceptive use. Am J Obstet Gynecol. 2017;216:443-450.
    1. Strowitzki T, Marr J, Gerlinger C, Faustmann T, Seitz C. Detailed analysis of a randomized, multicenter, comparative trial of dienogest versus leuprolide acetate in endometriosis. Int J Gynaecol Obstet. 2012;117:228-233.
    1. McKinnon B, Mueller M, Montgomery G. Progesterone resistance in endometriosis: an acquired property? Trends Endocrinol Metab. 2018;29:535-548.
    1. Flores VA, Vanhie A, Dang T, Taylor HS. Progesterone receptor status predicts response to progestin therapy in endometriosis. J Clin Endocrinol Metab. 2018;103:4561-4568.
    1. Romer T. Long-term treatment of endometriosis with dienogest: retrospective analysis of efficacy and safety in clinical practice. Arch Gynecol Obstet. 2018;298:747-753.
    1. Murji A, Biberoğlu K, Leng J, et al. Use of dienogest in endometriosis: a narrative literature review and expert commentary. Curr Med Res Opin. 2020;36:895-907.
    1. Tantiwattanakul P, Taneepanichskul S. Effect of mefenamic acid on controlling irregular uterine bleeding in DMPA users. Contraception. 2004;70:277-279.
    1. Kohler G, Faustmann TA, Gerlinger C, Seitz C, Mueck AO. A dose-ranging study to determine the efficacy and safety of 1, 2, and 4mg of dienogest daily for endometriosis. Int J Gynaecol Obstet. 2010;108:21-25.
    1. Kitawaki J, Kusuki I, Yamanaka K, Suganuma I. Maintenance therapy with dienogest following gonadotropin-releasing hormone agonist treatment for endometriosis-associated pelvic pain. Eur J Obstet Gynecol Reprod Biol. 2011;157:212-216.
    1. Barbieri RL, Evans S, Kistner RW. Danazol in the treatment of endometriosis: analysis of 100 cases with a 4-year follow-up. Fertil Steril. 1982;37:737-746.
    1. Techatraisak K, Hestiantoro A, Ruey S, et al. Effectiveness of dienogest in improving quality of life in Asian women with endometriosis (ENVISIOeN): interim results from a prospective cohort study under real-life clinical practice. BMC Women's Health. 2019;19:68.
    1. Treloar SA, Bell TA, Nagle CM, Purdie DM, Green AC. Early menstrual characteristics associated with subsequent diagnosis of endometriosis. Am J Obstet Gynecol. 2010;202(6):534.e1-534.e6.
    1. Aredo JV, Heyrana KJ, Karp BI, Shah JP, Stratton P. Relating chronic pelvic pain and endometriosis to signs of sensitization and myofascial pain and dysfunction. Sem Reprod Med. 2017;35:88-97.
    1. As-Sanie S, Harris RE, Harte SE, Tu FF, Neshewat G, Clauw DJ. Increased pressure pain sensitivity in women with chronic pelvic pain. Obstet Gynecol. 2013;122:1047-1055.
    1. Brawn J, Morotti M, Zondervan KT, Becker CM, Vincent K. Central changes associated with chronic pelvic pain and endometriosis. Hum Reprod Update. 2014;20:737-747.
    1. Lazorwitz A, Aquilante CL, Oreschak K, Sheeder J, Guiahi M, Teal S. Influence of genetic variants on steady-state etonogestrel concentrations among contraceptive implant users. Obstet Gynecol. 2019;133:783-794.
    1. Lazzeri L, Di Giovanni A, Exacoustos C, et al. Preoperative and postoperative clinical and transvaginal ultrasound findings of adenomyosis in patients with deep infiltrating endometriosis. Reprod Sci. 2014;21:1027-1033.
    1. Kunz G, Beil D, Huppert P, Noe M, Kissler S, Leyendecker G. Adenomyosis in endometriosis-prevalence and impact on fertility. Evidence from magnetic resonance imaging. Hum Reprod. 2005;20:2309-2316.
    1. Andres MP, Borrelli GM, Ribeiro J, Baracat EC, Abrão MS, Kho RM. Transvaginal ultrasound for the diagnosis of adenomyosis: systematic review and meta-analysis. J Minim Invasive Gynecol. 2018;25:257-264.
    1. Champaneria R, Abedin P, Daniels J, Balogun M, Khan KS. Ultrasound scan and magnetic resonance imaging for the diagnosis of adenomyosis: systematic review comparing test accuracy. Acta Obstet Gynecol Scand. 2010;89:1374-1384.
    1. Osuga Y, Fujimoto-Okabe H, Hagino A. Evaluation of the efficacy and safety of dienogest in the treatment of painful symptoms in patients with adenomyosis: a randomized, double-blind, multicenter, placebo-controlled study. Fertil Steril. 2017;108:673-678.
    1. Gallagher CS, Mäkinen N, Harris HR, et al. Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis. Nat Commun. 2019;10:4857.
    1. Shigesi N, Kvaskoff M, Kirtley S, et al. The association between endometriosis and autoimmune diseases: a systematic review and meta-analysis. Hum Reprod Update. 2019;25:486-503.

Source: PubMed

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