Long-term medical management of endometriosis with dienogest and with a gonadotropin-releasing hormone agonist and add-back hormone therapy

Endometriosis can recur after either surgical or medical therapy. Long-term medical therapy is implemented to treat symptoms or prevent recurrence. Dienogest and gonadotropin-releasing hormone (GnRH) analogues with hormone add-back therapy seem to be equally effective for long-term treatment of pain symptoms associated with endometriosis. There is insufficient evidence to support the superiority of one therapy over the other. However, add-back hormone therapy (HT) is recommended for patients using GnRH agonists. The treatment selection depends on therapeutic effectiveness, tolerability, drug cost, the physician's experience, and expected patient compliance. Endometriosis can recur after either surgical or medical therapy. Long-term medical therapy is implemented to treat symptoms or prevent recurrence. Dienogest and gonadotropin-releasing hormone (GnRH) analogues with hormone add-back therapy seem to be equally effective for long-term treatment of pain symptoms associated with endometriosis. There is insufficient evidence to support the superiority of one therapy over the other. However, add-back hormone therapy (HT) is recommended for patients using GnRH agonists. The treatment selection depends on therapeutic effectiveness, tolerability, drug cost, the physician's experience, and expected patient compliance. Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/14210-23389 Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/14210-23389 Endometriosis is a common gynecologic condition with a reported prevalence of 2% to 10% in the general population, up to 50% in the infertile patients (1Giudice L.C. Kao L. Endometriosis.Lancet. 2004; 364: 1789-1799Abstract Full Text Full Text PDF PubMed Scopus (2544) Google Scholar, 2Ilangavan K. Kalu E. High prevalence of endometriosis in infertile women with normal ovulation and normospermic partners [letter].Fertil Steril. 2010; 93: e10Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar), and more than 60% in patients with chronic pelvic pain (3Guo S.W. Wang Y. The prevalence of endometriosis in women with chronic pelvic pain.Gynecol Obstet Invest. 2006; 62: 121-130Crossref PubMed Scopus (115) Google Scholar). Endometriosis and its associated infertility and chronic pelvic pain (CPP) represents a challenge to health-care providers and a significant burden on the health-care system. The choice of medical management for endometriosis-associated pelvic pain depends on the patient's age and pain symptoms, the extent of the disease, the patient's reproductive plans, and the treatment risks, side effects, and cost considerations. In most cases, women with CPP due to presumptive endometriosis are initially treated empirically with nonsteroidal anti-inflammatory drugs (NSAIDs) and combined estrogen-progestin contraceptives (COCs). There is one placebo-controlled double-blind, randomized controlled trial (RCT) to support the beneficial effects of COCs on dysmenorrhea (4Harada 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: 1583-1588Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar). However, there is limited evidence to support a beneficial effect on COCs on noncyclic pelvic pain. Suppression of endogenous estrogen production is important for the successful treatment of endometriosis-associated pain (5Barbieri R.L. Hormone treatment of endometriosis: the estrogen threshold hypothesis.Am J Obstet Gynecol. 1992; 166: 740-745Abstract Full Text PDF PubMed Scopus (282) Google Scholar). Suppression of ovulation will in turn induce amenorrhea, thereby creating a relatively hypoestrogenic environment that will inhibit ectopic endometrial growth and prevent disease progression (5Barbieri R.L. Hormone treatment of endometriosis: the estrogen threshold hypothesis.Am J Obstet Gynecol. 1992; 166: 740-745Abstract Full Text PDF PubMed Scopus (282) Google Scholar). Discontinuation of the hormone suppressive therapy is usually followed by recurrence of pain symptoms due to the return of hormone stimulation of the endometriotic implants. Endometriosis can recur after either surgical or medical therapy, with reported recurrence rates of up to 45% after 5 years (6Evers J. Dunselman G. Land J. Bouckaert P. Is there a solution for recurrent endometriosis?.Br J Clin Pract Suppl. 1991; 72: 45-53PubMed Google Scholar). This rate is even higher reaching 56% for young women under the age of 21 years with surgically confirmed endometriosis (7Tandoi I. Somigliana E. Riparini J. Ronzoni S. Candiani M. High rate of endometriosis recurrence in young women.J Pediatr Adolesc Gynecol. 2011; 24: 376-379Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). Hence the need for long-term medical therapy. Dienoogest (DNG), a fourth generation progestin, and gonadotropin-releasing hormone agonists (GnRH-a) are frequently used medical treatment options. This article reviews the use of DNG and GnRH-a with hormone add-back in the medical management of endometriosis-associated pain. Progestin therapy is frequently used for patients with symptomatic endometriosis, and is typically considered when combined hormone contraceptives are contraindicated, lead to intolerable side effects, or fail to improve pain. A wide variety of oral, parenteral, intrauterine systems, and implantable progestins have been used for this purpose. Progestins inhibit the growth of endometriotic tissue by inducing decidualization followed by atrophy of the endometriotic implants and decreased peritoneal inflammatory markers (8Practice Committee of the American Society for Reproductive MedicineTreatment of pelvic pain associated with endometriosis: a committee opinion.Fertil Steril. 2014; 101: 927-935Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar). Additional proposed mechanisms of action include anovulation with reduced serum estrogen levels, suppression of matrix metalloproteinases–mediated growth and implantation of ectopic endometrium (9Olive D.L. Medical therapy of endometriosis.Semin Reprod Med. 2003; 21: 209-222Crossref PubMed Scopus (77) Google Scholar), inhibition of angiogenesis and immunomodulation (10Laschke M. Menger M. Anti-angiogenic treatment strategies for the therapy of endometriosis.Hum Reprod Update. 2012; 18: 682-702Crossref PubMed Scopus (124) Google Scholar). Dienogest (DNG) is the most recent member of this family, and its use in various countries has increased exponentially over the past decade. We will discuss clinically useful, evidence-based details about DNG pharmacotherapy for endometriosis-associated pain. Dienogest is a steroidal fourth-generation selective progestin that combines the pharmacologic properties of 19-nortestosterone and derivatives of progesterone. A nonethinylated progestin that is structurally related to testosterone (11Stanczyk F.Z. All progestins are not created equal.Steroids. 2003; 68: 879-890Crossref PubMed Scopus (173) Google Scholar), DNG has antiandrogenic activity and thus can improve androgenic skin-related side effects (12Foster R.H. Wilde M.I. Dienogest.Drugs. 1998; 56: 825-833Crossref PubMed Scopus (82) Google Scholar). At the pharmacokinetic level, DNG is absorbed rapidly after oral intake with approximately 90% bioavailability (13Bińkowska M. Woroń J. Progestogens in menopausal hormone therapy.Prz Menopauzalny. 2015; 14: 134-143PubMed Google Scholar), and it is exclusively bound to albumin (90%) and not to sex hormone-binding globulin or corticoid binding globulin (13Bińkowska M. Woroń J. Progestogens in menopausal hormone therapy.Prz Menopauzalny. 2015; 14: 134-143PubMed Google Scholar). Only 10% of absorbed DNG remains free, with a terminal half-life of 10 hours reaching a steady-state concentration after 2 days’ administration (13Bińkowska M. Woroń J. Progestogens in menopausal hormone therapy.Prz Menopauzalny. 2015; 14: 134-143PubMed Google Scholar). It is metabolized in the liver mainly by cytochrome P450 isoform 3A4 (CYP3A4) followed by rapid excretion of its inactive metabolites, and does not accumulate in the body (13Bińkowska M. Woroń J. Progestogens in menopausal hormone therapy.Prz Menopauzalny. 2015; 14: 134-143PubMed Google Scholar). Dienogest has a profound local effect on endometriotic lesions, with little androgenic, estrogenic, glucocorticoid, or mineralocorticoid activity and minimal impact on metabolic parameters (14Köhler G. Faustmann T.A. Gerlinger C. Seitz C. Mueck A.O. A dose-ranging study to determine the efficacy and safety of 1, 2, and 4mg of dienogest daily for endometriosis.Int J Gynecol Obstet. 2010; 108: 21-25Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar). Studies have shown that DNG has both an anovulatory and an antiproliferative effect, while inhibiting the secretion of cytokines in the stroma of endometrial cells (15Harada T. Momoeda M. Taketani Y. Aso T. Fukunaga M. Hagino H. 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: 675-681Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar). A systematic review evaluated 15 studies of the inflammatory response of endometriotic tissue to DNG therapy (16Grandi G. Mueller M. Bersinger N.A. Cagnacci A. Volpe A. McKinnon B. Does dienogest influence the inflammatory response of endometriotic cells?.Inflamm Res. 2016; 65: 183-192Crossref PubMed Scopus (40) Google Scholar). Dienogest modulated prostaglandin (PG) production and metabolism (PGE2, PGE2 synthase, cyclooxygenase-2, and microsomal PGE synthase-1) in a way that is anti-inflammatory. In addition, its use was associated with proinflammatory cytokine and chemokine production: interleukin-1β (IL-1β), IL-6, IL-8, tumor necrosis factor-α, monocyte chemoattractant protein-1, and stromal cell-derived factor-1. Moreover, it was associated with growth factor biosynthesis (vascular endothelial growth factor and nerve growth factor) and signaling kinases, responsible for the control of inflammation. There is evidence to support the anti-inflammatory effect of DNG at the epithelial and the stromal cell levels. This was mediated via progesterone receptor (PR) in PR-expressing epithelial cells; whether this is via a PR-mediated mechanism in stromal cells has yet to be determined (16Grandi G. Mueller M. Bersinger N.A. Cagnacci A. Volpe A. McKinnon B. Does dienogest influence the inflammatory response of endometriotic cells?.Inflamm Res. 2016; 65: 183-192Crossref PubMed Scopus (40) Google Scholar, 17Kocbek V. Grandi G. Blank F. Wotzkow C. Bersinger N.A. Mueller M.D. et al.TNFα-induced IKKβ complex activation influences epithelial, but not stromal cell survival in endometriosis.Mol Hum Reprod. 2016; 22: 768-777Crossref PubMed Scopus (15) Google Scholar). Treatment with DNG reduces endometriosis disease activity as measured by pretreatment and posttreatment surgical staging, and subjectively decreases pelvic pain as shown in multiple studies (Table 1). As an example, in an open-label, randomized, multicenter, 24-week comparative dose-finding trial, women with histologically confirmed endometriosis were assigned to 1, 2, or 4 mg of DNG. The efficacy of DNG was evaluated by second-look laparoscopy and patient-reported symptoms. The 1-mg dose arm was discontinued due to insufficient bleeding control. Dienogest reduced the mean revised American Fertility Society (AFS) scores from 11.4 to 3.6 in the 2-mg group and from 9.7 to 3.9 in the 4-mg group.Table 1Summary of clinical trials where dienogest was used to treat endometriosis-associated pain compared with no treatment, placebo, or other hormone treatment regimens.StudyDesignnInterventionDurationCommentsKöhler et al. 2010 14Köhler G. Faustmann T.A. Gerlinger C. Seitz C. Mueck A.O. A dose-ranging study to determine the efficacy and safety of 1, 2, and 4mg of dienogest daily for endometriosis.Int J Gynecol Obstet. 2010; 108: 21-25Abstract Full Text Full Text PDF PubMed Scopus (116) Google ScholarOpen-label, multicenter RCT68[1] DNG, 1 mg/d (n = 4)[2] DNG, 2 mg/d (n = 29)[3] DNG, 4 mg/d (n = 35)24 wkAt 1 mg, associated with irregular vaginal bleeding that led to discontinuation. In both 2- and 4-mg groups, statistically significant and equivalent reduction in clinical symptoms (dyspareunia, pelvic pain, dysmenorrhea) and revised ASRM score.Both 2 and 4 mg associated with irregular vaginal bleeding, which improved over time.Lowest effective dose is 2 mg/d.Strowitzki et al. 2010 18Strowitzki T. Faustmann T. Gerlinger C. 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: 193-198Abstract Full Text Full Text PDF PubMed Scopus (154) Google ScholarDouble-blind, placebo-controlled, multicenter RCT198[1] DNG, 2 mg/d (n = 102)[2] Placebo (n = 96)12 wkSignificantly superior to placebo in reduction of pelvic pain, dysmenorrhea, dyspareunia, and pelvic tenderness with remarkable improvement in QoL.Greater episodes of spotting associated with DNG.Petraglia et al. 2012 19Petraglia F. Hornung D. Seitz C. Faustmann T. Gerlinger C. Luisi S. et al.Reduced pelvic pain in women with endometriosis: efficacy of long-term dienogest treatment.Arch Gynecol Obstet. 2012; 285: 167-173Crossref PubMed Scopus (136) Google ScholarExtension for placebo-control study152DNG, 2 mg/d36 wk (n = 17) vs. 52 wk (n = 135)Improvement in pain for both groups previously treated with DNG or placebo.Adverse effects reported in 27 of 168 women, including breast discomfort, nausea, and irritability.Harada et al. 2009 15Harada T. Momoeda M. Taketani Y. Aso T. Fukunaga M. Hagino H. 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: 675-681Abstract Full Text Full Text PDF PubMed Scopus (174) Google ScholarProspective observational132DNG, 2 mg/d52 wkFurther reduction in VAS score for pelvic pain noted after 52 weeks of treatment.All patients experienced side effects as vaginal bleeding, headache, constipation, nausea, and hot flushes.Statistically significant reduction in BMD after 24 to 52 weeks of treatment.Strowitzki et al. 2015 20Strowitzki 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: 393-401Crossref PubMed Scopus (63) Google ScholarRCT332DNG, 2 mg/d65 wkWell tolerated, with a favorable safety profile extending over a period up to 65 weeks.Adverse events were generally of mild-to-moderate intensity (headache, breast discomfort, depressed mood, and acne), each occurring in <10% of women.Bleeding pattern associated with DNG was well tolerated.Estradiol levels maintained within the low-physiologic rangeAngioni et al. 2015 21Angioni S. Nappi L. Pontis A. Sedda F. Luisi S. Mais V. et al.Dienogest: a possible conservative approach in bladder endometriosis: results of a pilot study.Gynecol Endocrinol. 2015; 31: 406-408Crossref PubMed Scopus (42) Google ScholarPilot study6DNG, 2 mg/d12 moImprovement of pain symptoms, QoL, and decreased nodule size.Cosson et al. 2002 22Cosson M. Querleu D. Donnez J. Madelenat P. Konincks P. Audebert A. et al.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: 684-692Abstract Full Text Full Text PDF PubMed Scopus (124) Google ScholarMulticenter, open, randomized trial147[1] DNG, 2 mg/d (n = 68)[2] Triptorelin, 3.75 mg IM every 28 d (n = 74)16 wkSimilar reduction in revised ASRM implants and adhesion scores.Irregular vaginal bleeding more frequent in the DNG group (61.6% vs. 25.4%); hot flushes more frequent in the triptorelin group (61.2% vs. 9.6%).Vercellini et al. 2016 23Vercellini P. Bracco B. Mosconi P. Roberto A. Alberico D. Dhouha D. et al.Norethindrone acetate or dienogest for the treatment of symptomatic endometriosis: a before and after study.Fertil Steril. 2016; 105: 734-743.e3Abstract Full Text Full Text PDF PubMed Scopus (74) Google ScholarBefore and after study180[1] DNG, 2 mg/d (n = 90)[2] NETA, 2.5 mg/d (n = 90)24 wkSimilar improvement in both groups for pain scores, with statistical significance in favoring DNG.Side effects associated at a higher rate with NETA versus DNG: weight gain (32% vs. 16%), spotting (22% vs. 13%), and decreased libido (14% vs. 9%).Statistically significantly better tolerability with DNG, assessed by the numeric rating scale.Higher proportion of patient satisfaction with DNG.Strowitzki et al. 2010 24Strowitzki 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: 633-641Crossref PubMed Scopus (249) Google ScholarRandomized, multicenter, open-label trial229[1] DNG, 2 mg/d (n = 109)[2] LA, 3.75 mg/mo (n = 120)24 wkReduction in pelvic pain assessed by VAS similar between both groups.Main side effects were similar in both groups: headache, weight gain, and depression.Increased episodes of hot flushes in first week of treatment in LA group.Number of episodes per day of vaginal bleeding showed a tendency to decrease during treatment in both groups.Greater loss of BMD after treatment in LA group.Harada et al. 2009 15Harada T. Momoeda M. Taketani Y. Aso T. Fukunaga M. Hagino H. 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: 675-681Abstract Full Text Full Text PDF PubMed Scopus (174) Google ScholarDouble-blind, multicenter RCT271[1] DNG, 2 mg/d (n = 137)[2] BA, 900 mg/d intranasal (n = 134)24 wkDNG and BA showed similar results in reducing VAS scores.Frequency of reported adverse events similar in both groups.Statistically significant reduction in BMD in BA group.Granese et al. 2015 25Granese R. Perino A. Calagna G. Saitta S. De Franciscis P. Colacurci N. et al.Gonadotrophin-releasing hormone analogue or dienogest plus estradiol valerate to prevent pain recurrence after laparoscopic surgery for endometriosis: a multi-center randomized trial.Acta Obstet Gynecol Scand. 2015; 94: 637-645Crossref PubMed Scopus (35) Google ScholarMulticenter RCT78[1] E2V/DNG (n = 39)[2] GnRH-a (n = 39)[1] 9 mo[2] 6 moVAS and QoL improved with both treatments (no statistical significant difference).Morelli et al. 2013 26Morelli M. Sacchinelli A. Venturella R. Mocciaro R. Zullo F. Postoperative administration of dienogest plus estradiol valerate versus levonorgestrel-releasing intrauterine device for prevention of pain relapse and disease recurrence in endometriosis patients.J Obstet Gynaecol Res. 2013; 39: 985-990Crossref PubMed Scopus (43) Google ScholarProspective study92[1] E2V + DNG (n = 48)[2] LNG-IUD (n = 44)24 moStatistically significant improvement in VAS score in group 1; however, satisfaction rate higher in group 2 after 24 months of treatment.No difference in recurrence rate after laparoscopic surgery in either group.Grandi et al. 2015 27Grandi G. Xholli A. Napolitano A. Palma F. Cagnacci A. Pelvic pain and quality of life of women with endometriosis during quadriphasic estradiol valerate/dienogest oral contraceptive: a patient-preference prospective 24-week pilot study.Reprod Sci. 2015; 22: 626-632Crossref PubMed Scopus (28) Google ScholarProspective observational study34[1] E2V/DNG (n = 19)[2] NSAID (n = 15)24 wkGreater reduction in VAS scores for dysmenorrhea, intermenstrual pain, and dyspareunia with only minor adverse events, which did not cause withdrawal of treatment. in E2V/DNG group.No changes observed in NSAID group.Caruso et al. 2015 28Caruso S. Iraci M. Cianci S. Casella E. Fava V. Cianci A. Quality of life and sexual function of women affected by endometriosis-associated pelvic pain when treated with dienogest.J Endocrinol Invest. 2015; 38: 1211-1218Crossref PubMed Scopus (49) Google ScholarPlacebo-control study92[1] DNG, 2 mg/d (n = 54)[2] NSAID (n = 48)6 moStatistically significant improvement in QoL, VAS, Female Sexual Function Index (FSFI), and Female Sexual Distress Scale (FSDS) after 6 months of treatment with DNG.No changes observed in NSAID group.Caruso et al. 2016 29Caruso S. Iraci M. Cianci S. Fava V. Casella E. Cianci A. Comparative, open-label prospective study on the quality of life and sexual function of women affected by endometriosis-associated pelvic pain on 2 mg dienogest/30 μg ethinyl estradiol continuous or 21/7 regimen oral contraceptive.J Endocrinol Invest. 2016; 39: 923-931Crossref PubMed Scopus (55) Google ScholarOpen label prospective study99COC: DNG, 2 mg + EE, 30 μg, continuous (n = 63); 21/7 regimen (n = 33)6 moWith continued administration of COC, remarkable improvement of QoL, VAS, FSFI, and FSDS scores at 3 month follow-up visit. However, 21/7 regimen group had similar scores at 6 mo follow-up visit.Note: ASRM = American Society for Reproductive Medicine; BA = buserelin acetate; BMD = bone mass density; COC = combined oral contraceptive; DNG = dienogest; E2V = estradiol valerate; EE = ethinyl estradiol; FSDS = Female Sexual Distress Scale; FSFI = Female Sexual Function Index; GnRH-a = gonadotropin-releasing hormone agonist; LA = leuprolide acetate; LNG-IUD = levonorgestrel intrauterine device; NETA = norethindrone acetate; NSAID = nonsteroidal anti-inflammatory drug; QoL = quality of life; RCT = randomized controlled trial; VAS = visual analogue scale. Open table in a new tab Note: ASRM = American Society for Reproductive Medicine; BA = buserelin acetate; BMD = bone mass density; COC = combined oral contraceptive; DNG = dienogest; E2V = estradiol valerate; EE = ethinyl estradiol; FSDS = Female Sexual Distress Scale; FSFI = Female Sexual Function Index; GnRH-a = gonadotropin-releasing hormone agonist; LA = leuprolide acetate; LNG-IUD = levonorgestrel intrauterine device; NETA = norethindrone acetate; NSAID = nonsteroidal anti-inflammatory drug; QoL = quality of life; RCT = randomized controlled trial; VAS = visual analogue scale. Dienogest at 2 and 4 mg/day was also associated with symptom improvement in a substantial proportion of 54 women who completed the study. The rates of dyspareunia statistically significantly decreased from 51.7% at baseline to 6.9% at week 24 in the 2-mg group, and from 57.1% to 5.7% in the 4-mg group. Similar decreases were observed in both groups for diffuse pelvic pain, dysmenorrhea, and premenstrual pain. Consequently 2 mg daily was recommended as the optimal dose (14Köhler G. Faustmann T.A. Gerlinger C. Seitz C. Mueck A.O. A dose-ranging study to determine the efficacy and safety of 1, 2, and 4mg of dienogest daily for endometriosis.Int J Gynecol Obstet. 2010; 108: 21-25Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar), and that has been the dose of DNG used in most of the subsequent studies. However, reducing the revised AFS score is of limited clinical validity due to its poor correlation with pelvic pain. The 2-mg dose was shown to be effective in improving symptoms in another prospective observational study in 135 patients with endometriosis. The proportion of patients who showed marked or moderate improvement in their global scores went from 72.5% at 24 weeks to 90.6% (106 of 117 cases) at 52 weeks, indicating a cumulative response (30Momoeda M. Harada T. Terakawa N. Aso T. Fukunaga M. Hagino H. et al.Long-term use of dienogest for the treatment of endometriosis.J Obstet Gynaecol Res. 2009; 35: 1069-1076Crossref PubMed Scopus (134) Google Scholar). Dienogest was also shown to be superior to placebo in controlling pain symptoms in two independent studies (18Strowitzki T. Faustmann T. Gerlinger C. 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: 193-198Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar, 19Petraglia F. Hornung D. Seitz C. Faustmann T. Gerlinger C. Luisi S. et al.Reduced pelvic pain in women with endometriosis: efficacy of long-term dienogest treatment.Arch Gynecol Obstet. 2012; 285: 167-173Crossref PubMed Scopus (136) Google Scholar). When compared with prior use of norethindrone acetate (NETA) at 2.5 mg, DNG at 2 mg produced comparable improvements of symptoms and health-related quality of life (23Vercellini P. Bracco B. Mosconi P. Roberto A. Alberico D. Dhouha D. et al.Norethindrone acetate or dienogest for the treatment of symptomatic endometriosis: a before and after study.Fertil Steril. 2016; 105: 734-743.e3Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). Given the higher cost of DNG compared with NETA, the investigators suggested that DNG should be used in women who do not tolerate NETA. However, this study was limited by its serial design rather than head-to-head comparison, its relatively small sample size, and the variability of the medication cost in various settings. A recent systematic review of eight RCT between 2002 and 2011 comparing DNG with placebo or GnRH-a included 1,273 patients with symptomatic endometriosis. This review showed that DNG at 2 mg/day was superior to placebo in reducing pelvic pain, with results equivalent to GnRH agonists (buserelin, leuprorelin, leuprolide acetate, and triptorelin) in controlling the pain symptoms associated with endometriosis. Dienogest was also effective when used for prolonged durations up to 52 weeks with tolerable side effects (31de Paula Andres M. Lopes L.A. Baracat E.C. Podgaec S. Dienogest in the treatment of endometriosis: systematic review.Arch Gynecol Obstet. 2015; 292: 523-529Crossref PubMed Scopus (87) Google Scholar). In another study, statistically significant improvement in pain and health-related quality of life (QoL) was observed at 3 and 6 months in patients treated with DNG (54 women) compared with those treated with NSAIDs (48 women). The DNG group experienced an improvement in pain syndrome and QoL at the first follow-up evaluation, and in sexual life by the second follow-up evaluation of DNG usage as compared with the NSAIDs group. The women treated with DNG continued to improve over the treatment period (28Caruso S. Iraci M. Cianci S. Casella E. Fava V. Cianci A. Quality of life and sexual function of women affected by endometriosis-associated pelvic pain when treated with dienogest.J Endocrinol Invest. 2015; 38: 1211-1218Crossref PubMed Scopus (49) Google Scholar). Dienogest alone is available for the treatment endometriosis in Europe, Australia, Canada, and Japan but not in the United States. In combination with estradiol valerate (E2V) and ethinyl estradiol (EE), DNG is used as a contraceptive in the United States. Few studies have evaluated DNG containing combined oral contraceptives for treatment of endometriosis. In a multicenter RCT, DNG + E2V was compared with GnRH-a in patients with chronic pelvic pain due to laparoscopically diagnosed and treated endometriosis. Both therapies were shown to be equally efficacious in preventing pain recurrence in the first 9 months of follow-up observation (25Granese R. Perino A. Calagna G. Saitta S. De Franciscis P. Colacurci N. et al.Gonadotrophin-releasing hormone analogue or dienogest plus estradiol valerate to prevent pain recurrence after laparoscopic surgery for endometriosis: a multi-center randomized trial.Acta Obstet Gynecol Scand. 2015; 94: 637-645Crossref PubMed Scopus (35) Google Scholar). In a retrospective study, DNG + E2V was found to be statistically significantly more effective than a levonorgestrel intrauterine device (LNG-IUD) in reducing pelvic pain and more effective in reducing recurrence rate but not at a statistically significant level. However, LNG-IUD has statistically significantly higher patient satisfaction (26Morelli M. Sacchinelli A. Venturella R. Mocciaro R. Zullo F. Postoperative administration of dienogest plus estradiol valerate versus levonorgestrel-releasing intrauterine device for prevention of pain relapse and disease recurrence in endometriosis patients.J Obstet Gynaecol Res. 2013; 39: 985-990Crossref PubMed Scopus (43) Google Scholar). In another prospective observational study, 24-week administration of the association of DNG-E2V decreased pelvic pain and improved quality of life in patients with endometriosis compared with NSAIDs (27Grandi G. Xholli A. Napolitano A. Palma F. Cagnacci A. Pelvic pain and quality of life of women with endometriosis during quadriphasic estradiol valerate/dienogest oral contraceptive: a patient-preference prospective 24-week pilot study.Reprod Sci. 2015; 22: 626-632Crossref PubMed Scopus (28) Google Scholar). A recent study showed that DNG-EE combined continuous therapy led to a statistically significant reduction of endometriosis-associated pelvic pain. In addition, the improvement in sexual activity and QoL was better in the continuous than the 21/7 conventional regimen (29Caruso S. Iraci M. Cianci S. Fava V. Casella E. Cianci A. Comparative, open-label prospective study on the quality of life and sexual function of women affected by endometriosis-associated pelvic pain on 2 mg dienogest/30 μg ethinyl estradio