GnRH analogues and dienogest for second line treatment of endometriosis-associated pain: a systematic review, meta-analysis, and network meta-analysis

Aim: GnRH agonists and dienogest are well established treatments for Endometriosis associated pain. Recently, oral GnRH antagonists were introduced and shown to be effective for endometriosis treatment. Yet, superiority of either of those drugs is not yet known. We aimed to compare the efficacy and side effect profile of GnRH analogues and dienogest for the treatment of endometriosis associated pain. Methods: MEDLINE, Embase, and Cochrane were searched for randomized controlled trials evaluating the impact of dienogest and GnRH analogues on dysmenorrhea, dyspareunia and non-menstrual pelvic pain (NMPP). Adverse events studied included: headaches, hot flashes, amenorrhea, irregular vaginal bleeding and change in bone mineral density. Individual effect sizes were calculated with the pre-post differences for each treatment comparison as standardized mean differences (SMD). Network meta-analysis was conducted, incorporating direct and indirect comparisons of the different drugs. Risk Ratios (RR) and 95 % confidence intervals (CIs) for adverse events were calculated from the number of cases in the study arm, compared to the controls. Results: A total of 8 studies including 3259 patients were identified. Both doses of GnRH antagonist, as well as dienogest were found superior to placebo for NMPP. The intervention hierarchy model revealed that high dose GnRH antagonist had the strongest effect in reducing NMPP (p = 0.07). Both doses of GnRH antagonist (p = 0.64 and p = 0.36) and dienogest (p = 0.31) were superior to placebo in reducing dyspareunia. In the hierarchy model, Leuprolide was found to have the most substantial effect (p = 0.24), while dienogest was beneficial compared to both doses of GnRH antagonist in reducing dyspareunia. High dose GnRH antagonist had the strongest effect in reducing dysmenorrhea (p = 0.05). The network meta-analysis has shown that dienogest had the best safety profile with the least adverse effects. Conclusions: Oral GnRH antagonist has shown to be the most effective in improving dysmenorrhea and NMPP, as compared to the other drugs. However, dienogest was found more beneficial in the treatment of dyspareunia. These finding may serve clinical practitioners in electing medical therapy.