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Background
Endometriosis is a benign estrogen-dependent disease, in which tissue that is morphologically and functionally similar to the endometrium grows outside the uterine cavity. Its main clinical symptoms are pain, including menstrual pain (dysmenorrhea) and infertility. Patients with endometriosis frequently experience endometriosis-associated pain, as well as pain during sexual intercourse (dyspareunia), even at times other than during menstruation, which significantly impair their quality of life (QOL) [1, 2].
One treatment option for managing endometriosis symptoms involves lowering the blood concentration of sex hormones by suppressing the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) [3]. Gonadotropin-releasing hormone (GnRH) agonists have been administered to patients to suppress GnRH secretion by desensitization of GnRH receptors in the pituitary gland. However, this treatment may temporarily worsen symptoms caused by stimulated LH and FSH secretion (flare-up) at the beginning of treatments and, then, hypoestrogenic side effects such as accelerated bone loss [3, 4, 5–6].
Relugolix is a non-peptide oral GnRH antagonist that directly antagonizes GnRH receptor and suppresses LH and FSH secretion and therefore does not induce flare-ups like GnRH agonists, and rapidly lowers the concentrations of estradiol (E2) and progesterone [7, 8]. Relugolix was approved in Japan in January 2019 for the indications of uterine fibroid-related symptoms, menorrhagia, lower abdominal pain, lower back pain, and anemia, with addition of the further indication of endometriosis-associated pain in December 2021 [1, 4].
A phase 3, multicenter, randomized, double-blind, double-dummy, active-controlled study comparing the efficacy and safety of relugolix with the GnRH agonist leuprorelin was carried out in 335 Japanese patients with endometriosis-associated pain [1]. The primary endpoint, defined as change in maximum visual analog scale (VAS) score for pelvic pain from baseline until 28 days before the end of treatment in patients treated with 40 mg oral relugolix once daily for 24 weeks, was non-inferior to that in patients treated with subcutaneous leuprorelin administered every 4 weeks for 24 weeks (between-group difference, 4.9). The results demonstrated that the incidence of treatment-emergent adverse events (TEAEs) in the relugolix group was similar to that in the leuprorelin group. Drug-related TEAEs were reported in 79.5% of patients treated with relugolix, including hot flushes in 42.7% (73 patients), metrorrhagia in 31.0% (53 patients), and headache in 10.5% (18 patients) of patients...