O-173 Pro

Abstract

Estrogens play a critical role in the pathogenesis of endometriosis, so it is logical to assume that lowering estradiol levels with oral gonadotropin-releasing hormone (GnRH) antagonists would be effective, especially in women who fail to respond to progestogens. Indeed, due to progesterone resistance, oral contraceptives and progestogens are ineffective in one-third of women affected by endometriosis. Oral GnRH antagonists have therefore been evaluated for management of premenopausal women with endometriosis-associated pelvic pain. Oral GnRH antagonists bind to and block the GnRH receptor, resulting in a dose-dependent drop in luteinizing hormone and follicle-stimulating hormone production, which in turn leads to a dose-dependent decline in estrogen. High doses of GnRH antagonists promote full suppression of estradiol secretion to serum levels below 20 pg/ml, but add-back therapy (ABT) may then be needed to manage hypoestrogenic side effects. Lower doses of oral GnRH antagonists maintain estradiol values within the target range of 20-60 pg/ml, which could be ideal to alleviate symptoms linked to endometriosis. There is a place for GnRH antagonists in the management of symptomatic endometriosis, with different molecules available on the market (elagolix, relugolix, linzagolix) at different doses and with or without ABT. Multicenter, prospective, randomized, placebo-controlled, double-blind studies have shown that oral GnRH antagonists significantly reduce dysmenorrhea and non-menstrual pelvic pain (NMPP) by 6 months of therapy. -One of the first papers on this reported 6-month outcomes of high- and low-dose elagolix monotherapy. High-dose elagolix yielded higher dysmenorrhea and NMPP responder rates than low-dose treatment. The twice-daily 200 mg elagolix dose generated clinically meaningful responses in 75–78% of subjects for dysmenorrhea and 67–69% for NMPP. At 150 mg daily, clinically meaningful responses were seen in 52% of women for dysmenorrhea and 67% for NMPP. Patients given the 200 mg elagolix dose showed greater bone mineral density (BMD) loss, namely −3.6% and −3.9% at weeks 36 and 52 respectively. -In the relugolix extension study, sustained improvements in endometriosis-related pain were noted through 104 weeks among patients taking relugolix combination therapy. Responder rates at week 104 were 84.4% for dysmenorrhea and 75.8% for NMPP. After initial least square mean BMD loss of less than 1% at week 24, BMD plateaued by week 36 and was sustained for the entire 104 weeks of treatment. -In a population of 353 women with moderate-to-severe pain linked to endometriosis, once-daily oral 200 mg linzagolix+ABT or 75 mg linzagolix alone provided sustained and clinically meaningful reductions in dysmenorrhea and NMPP for up to 52 weeks, achieving the 2 co-primary endpoints. By the end of treatment at month 12, proportions of subjects with reduced dysmenorrhea, associated with stable or decreased use of analgesics, were 91% in the 200 mg+ABT linzagolix group and 55.9% in the 75 mg linzagolix group. Percentages of women gaining relief from NMPP, associated with stable or decreased use of analgesics, were 62.6% with 200 mg+ABT linzagolix and 59.5% with 75 mg linzagolix. In conclusion, oral GnRH antagonists exhibited better efficacy and safety than a placebo in the management of moderate-to-severe endometriosis-associated pain. Quality of life of patients was enhanced and risks of BMD loss and vasomotor symptoms were minimized thanks to ABT or administration of lower doses of GnRH antagonists. Extension studies show that efficacy in terms of reduction of dysmenorrhea, NMPP and overall pelvic pain is maintained during long-term treatment. Withdrawal studies demonstrate that relief from pain may be maintained after cessation of therapy in some women. Further research could clarify whether intermittent therapy may be an option for these women suffering from endometriosis-related symptoms.