Oral GnRH Antagonists with Add-Back Therapy for Endometriosis-Associated Pain: A Systematic Review of Efficacy and Safety
Keywords:
ENDOMETRIOSIS, GONADOTROPIN-RELEASING HORMONE ANTAGONISTS, ADD-BACK THERAPY, DYSMENORRHEA, PELVIC PAIN, BONE MINERAL DENSITYAbstract
In women with endometriosis, the use of oral gonadotropin-releasing hormone (GnRH) antagonists for pain control, combined with add-back therapy, would be one way to counteract hypoestrogenic effects. Screening resulted in the identification of 4 key randomized efficacy trials on the relugolix, elagolix and linzagolix programmes, and their corresponding extensions, and of 2 trials that were terminated early that supplemented this data in a limited way. Dysmenorrhea response criterion after 24 weeks assessed by SPIRIT 1/2 suggested that about 75% of relugolix combination therapy participants vs. 27-30% with placebo achieved a response. A synthesis that reviewed the data computed a risk ratio of 2.61 (95% CI, 2.22–3.07) for dysmenorrhea response and 1.51 (95% CI, 1.32–1.74) for nonmenstrual pelvic pain response only for these matching trials. Elagolix with add-back and linzagolix with add-back were also effective when compared with placebo for both pain outcomes, but due to use of different instruments, thresholds and time for assessing the outcomes, it was not possible to rank these treatments defensibly. Add-back with immediate initiation showed reduced decrease in mean BMD compared with initial high-dose antagonist monotherapy. It was noted that the 48-month elagolix report was primarily a report on safety; there was significant attrition and some eligibility restrictions regarding bone outcomes caused inference to be limited for the long-term. Rare adverse effects on the vascular, psychiatric and skeletal systems remained insufficiently quantified. Combination products have clinically important short-term pain-relieving properties; repeat applications will depend on the individual analysis and following of the corresponding product data. Conclusions can be trusted only if the ascertainment is exhaustive, which in this study is hindered by restricted source coverage and incomplete access to several journal reports, and by the lack of independent duplicate human verification.
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