Reduced pelvic pain in women with endometriosis: efficacy of long-term dienogest treatment

Felice Petraglia, Daniela Hornung, Christian Seitz, Thomas Faustmann, Christoph Gerlinger, Stefano Luisi, Lucia Lazzeri, Thomas Strowitzki, Felice Petraglia, Daniela Hornung, Christian Seitz, Thomas Faustmann, Christoph Gerlinger, Stefano Luisi, Lucia Lazzeri, Thomas Strowitzki

Abstract

Purpose: To investigate the efficacy and safety of dienogest as a long-term treatment in endometriosis, with follow-up after treatment discontinuation. The study included women with endometriosis, who had previously completed a 12-week, placebo-controlled study of dienogest, who participated in an open-label extension study for up to 53 weeks. Thereafter, a patient subgroup was evaluated in a 24-week follow-up after treatment discontinuation.

Methods: A multicenter study performed in Germany, Italy and Ukraine. Women with endometriosis were enrolled at completion of the placebo-controlled study (n = 168). All women received dienogest (2 mg once daily, orally) and changes in pelvic pain (on a visual analog scale), bleeding pattern, adverse events and laboratory parameters were evaluated during and after treatment.

Results: The completion rate among women who entered the open-label extension study was 90.5% (n = 152). A significant decrease in pelvic pain was shown during continued dienogest treatment (P < 0.001). The mean frequency and intensity of bleeding progressively decreased. Adverse events, rated generally mild or moderate, led to withdrawal in four patients (2.4%). No clinically relevant changes in laboratory parameters were observed. During treatment-free follow-up (n = 34), the reduction in pelvic pain persisted, while bleeding frequency and intensity returned to normal patterns.

Conclusions: Long-term dienogest showed a favorable efficacy and safety profile, with progressive decreases in pain and bleeding irregularities during continued treatment; the decrease of pelvic pain persisted for at least 24 weeks after treatment cessation.

Figures

Fig. 1
Fig. 1
Patient disposition during the extension study and the treatment-free follow-up period
Fig. 2
Fig. 2
Mean (±SEM) VAS scores for EAPP during the extension study (FAS) in the total, prior-dienogest and prior-placebo groups. Mean VAS score was statistically significantly reduced by 43.2 (±21.7) mm over the total treatment period of 65 weeks (i.e., placebo-controlled plus extension study; P < 0.001). EAPP endometriosis-associated pain, FAS full analysis set, SEM standard error of the mean, VAS visual analog scale
Fig. 3
Fig. 3
Frequencies of maximal intensity of bleeding in 90-day reference periods 1 and 4 during dienogest treatment in the extension study (FAS) FAS full analysis set

References

    1. Guo SW. Recurrence of endometriosis and its control. Hum Reprod Update. 2009;15:441–461. doi: 10.1093/humupd/dmp007.
    1. Batzer FR. GnRH analogs: options for endometriosis-associated pain treatment. J Minim Invasive Gynecol. 2006;13:539–545. doi: 10.1016/j.jmig.2006.07.007.
    1. Jee BC, Lee JY, Suh CS, Kim SH, Choi YM, Moon SY. Impact of GnRH agonist treatment on recurrence of ovarian endometriomas after conservative laparoscopic surgery. Fertil Steril. 2009;91:40–45. doi: 10.1016/j.fertnstert.2007.11.027.
    1. Practice Committee of American Society for Reproductive Medicine Treatment of pelvic pain associated with endometriosis. Fertil Steril. 2008;90(5 Suppl):S260–S269.
    1. Harada T, Momoeda M, Taketani Y, Hoshiai H, Terakawa N. Low-dose oral contraceptive pill for dysmenorrhea associated with endometriosis: a placebo-controlled, double-blind, randomized trial. Fertil Steril. 2008;90:1538–1583. doi: 10.1016/j.fertnstert.2007.08.051.
    1. Luciano AA. Danazol treatment of endometriosis-associated pain. J Minim Invasive Gynecol. 2006;13:523–524. doi: 10.1016/j.jmig.2006.06.026.
    1. Razzi S, Luisi S, Calonaci F, Altomare A, Bocchi C, Petraglia F. Efficacy of vaginal danazol treatment in women with recurrent deeply infiltrating endometriosis. Fertil Steril. 2007;88:789–794. doi: 10.1016/j.fertnstert.2006.12.077.
    1. Vercellini P, Somigliana E, Viganò P, Abbiati A, Barbara G, Crosignani PG. Endometriosis: current therapies and new pharmacological developments. Drugs. 2009;69:649–675. doi: 10.2165/00003495-200969060-00002.
    1. Rahman M, Berenson AB. Predictors of higher bone mineral density loss and use of depot medroxyprogesterone acetate. Obstet Gynecol. 2010;115:35–40. doi: 10.1097/AOG.0b013e3181c4e864.
    1. Crosignani PG, Olive D, Bergqvist A, Luciano A. Advances in the management of endometriosis: an update for clinicians. Hum Reprod Update. 2005;12:179–189. doi: 10.1093/humupd/dmi049.
    1. Lockhat FB, Emembolu JO, Konje JC. The evaluation of the effectiveness of an intrauterine-administered progestogen (levonorgestrel) in the symptomatic treatment of endometriosis and in the staging of the disease. Hum Reprod. 2004;19:179–184. doi: 10.1093/humrep/deh004.
    1. Cosson M, Querleu D, Donnez J, Madelenat P, Konincks P, Audebert A, Manhes H. Dienogest is as effective as triptorelin in the treatment of endometriosis after laparoscopic surgery: results of a prospective, multicenter, randomized study. Fertil Steril. 2002;77:684–692. doi: 10.1016/S0015-0282(01)03270-8.
    1. Köhler G, Faustmann TA, Gerlinger C, Seitz C, Mueck AO. 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. 2010;108:21–25. doi: 10.1016/j.ijgo.2009.08.020.
    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. doi: 10.1093/humrep/dep469.
    1. Momoeda M, Harada T, Terakawa N, Aso T, Fukunaga M, Hagino H, Taketani Y. Long-term use of dienogest for the treatment of endometriosis. J Obstet Gynaecol Res. 2009;35:1069–1076. doi: 10.1111/j.1447-0756.2009.01076.x.
    1. Strowitzki T, Faustmann A, Christoph G, Seitz C. Dienogest in the treatment of endometriosis-associated pelvic pain: a 12-week, randomized, double-blind, placebo-controlled study. Eur J Obstet Gynecol Reprod Biol. 2010;151:193–198. doi: 10.1016/j.ejogrb.2010.04.002.
    1. American Society for Reproductive Medicine Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997;67:817–821. doi: 10.1016/S0015-0282(97)81391-X.
    1. Gerlinger C, Endrikat J, Kallischnigg G, Wessel J. Evaluation of menstrual bleeding patterns: a new proposal for a universal guideline based on the analysis of more than 4500 bleeding diaries. Eur J Contracept Reprod Health Care. 2007;12:203–211. doi: 10.1080/13625180701441121.
    1. Harada T, Momoeda M, Taketani Y, Aso T, Fukunaga M, Hagino H, Terakawa N. 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. doi: 10.1016/j.fertnstert.2007.12.080.
    1. Katsuki Y, Takano Y, Futamura Y, Shibutani Y, Aoki D, Udagawa Y, Nozawa S. Effects of dienogest, a synthetic steroid, on experimental endometriosis in rats. Eur J Endocrinol. 1998;138:216–226. doi: 10.1530/eje.0.1380216.
    1. Okada H, Nakajima T, Yoshimura T, Yasuda K, Kanzaki H. The inhibitory effect of dienogest, a synthetic steroid, on the growth of human endometrial stromal cells in vitro. Mol Hum Reprod. 2001;7:341–347. doi: 10.1093/molehr/7.4.341.
    1. Horie P, Harada T, Mitsunari M, Taniguchi F, Iwabe T, Terakawa N. 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. 2005;83:1530–1535. doi: 10.1016/j.fertnstert.2004.11.042.
    1. Schindler AE, Henkel A, Moore C, Oettel M. Effect and safety of high-dose dienogest (20 mg/day) in the treatment of women with endometriosis. Arch Gynecol Obstet. 2009;282:507–514. doi: 10.1007/s00404-009-1301-z.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere