Role of oral gonadotropin-releasing hormone antagonists in the management of uterine adenomyosis: a narrative review

ABSTRACT: In women with uterine adenomyosis, bleeding and pain can have a major impact on quality of life. There is clearly widespread demand for effective long-term medical therapies. The objective of this narrative review was to investigate the efficacy of oral gonadotropin-releasing hormone (GnRH) antagonists in the management of uterine adenomyosis by analyzing data from two post hoc analyses of two prospective randomized trials (elagolix and relugolix), one retrospective study (relugolix) and one prospective study (linzagolix). All three GnRH oral antagonists were able to control the disease and uterine fibroid-related heavy menstrual bleeding, enhancing quality of life. When administered without add-back therapy, high doses of GnRH antagonist were found to significantly and rapidly reduce uterine volume and the severity of adenomyotic lesions. Nevertheless, some limitations should be addressed. The post hoc analyses were a retrospective look at two prospective randomized clinical trials. In the elagolix study, most women underwent both transvaginal ultrasound and magnetic resonance imaging (MRI). Some who opted out of MRI may have had concurrent adenomyosis that was undetected by ultrasound, so they were not included in the adenomyosis subset. In the relugolix study, baseline ultrasounds were not specifically performed to spot adenomyosis that may have been overlooked in case of large fibroids, as shadowing can partially or completely obscure the disease. While the linzagolix study is prospective and evaluates data from women with proven adenomyosis documented by MRI, the number of cases is limited and randomized controlled trials are needed to confirm and validate this concept. LAY SUMMARY: Uterine adenomyosis is characterized by the presence of endometrial glands inside the myometrium, the muscular layer of the uterus. Transvaginal ultrasound and magnetic resonance imaging now facilitate its diagnosis. The estimated prevalence of adenomyosis among patients of reproductive age is 20-30%. Rising rates in younger patients combined with a growing trend to postpone first pregnancy underscore the importance of understanding the mechanisms behind its development. We need novel strategies for treatment of typical but distressing symptoms of adenomyosis, which include pelvic pain, abnormal uterine bleeding, menstrual cramps, painful sex and infertility. There is a lack of approved pharmacological agents specifically indicated for treatment of adenomyosis, presenting a clear unmet need in this population. Oral gonadotropin-releasing hormone (GnRH) antagonists have recently emerged as a promising new therapeutic option. Their advantages over GnRH agonist depot formulations include an absence of the flare-up effect, hence avoiding initially worsening symptoms and rapid reversibility.