RELUGOLIX AND ENDOMETRIOSIS: HOW CAN THIS NEW DRUG COUNTERACT IT?

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Endometriosis is a chronic oestrogen-dependent inflammatory disease that affects 6-10% of women of reproductive age and is responsible for 50-60% of pelvic pain and up to 50% of infertility. The pain associated with endometriosis, in terms of dysmenorrhoea, chronic pelvic pain and dyspareunia, significantly debilitates patients' physical and psychological well-being. Guidelines recommend long-term treatment of endometriosis to inhibit ovulation and reduce oestrogen production. First-line drug therapy for endometriosis-associated pain includes non-steroidal anti-inflammatory drugs (NSAIDs) combined with oral contraceptives (COCs) and progestins. As second-line drug therapy, we have available GnRh agonists, in injectable depot formulations, whose use is limited in time as the hypoestrogenic effect related to complete oestrogen suppression limits their long-term use.

GnRH antagonists, orally administered, short-acting drugs with a good controlling effect on pain associated with endometriosis, have been studied and introduced in recent years. Relugolix falls into this pharmaceutical category; it is a non-peptide GnRh antagonist, approved for the treatment of endometriosis in 2022. Relugolix is able to bind competitively to pituitary GnRH receptors, blocking the binding of endogenous GnRH with reversible, dose-dependent suppression of luteinising hormone and follicle-stimulating hormone. In women, reduced concentrations of follicle-stimulating hormone prevent natural follicular development by suppressing ovarian oestrogen production and, together with reduced LH concentrations, prevent ovulation, corpus luteum formation and, thus, progesterone production. By reducing circulating concentrations of oestradiol and progesterone, relugolix has effects on moderate to severe pain associated with endometriosis, including dysmenorrhoea, non-menstrual pelvic pain and dyspareunia. Relugolix acts rapidly, with no flare-up effects, and with rapid reversal of effects after discontinuation of the drug. Recent studies have reported that long-term use of relugolix 40 mg is well tolerated, but the dose-dependent decrease in bone mineral density and the increase in vasomotor symptoms make it unsuitable for long-term use. Combination therapy with Relugolix (40 mg relugolix, 1 mg oestradiol and 0.5 mg norethisterone acetate) was developed as a daily single-dose treatment to achieve efficacy and minimise vasomotor symptoms and loss of bone mineral density while keeping oestradiol concentrations within a certain therapeutic range. Recent studies have shown that women with moderate to severe endometriosis taking relugolix combination therapy had significantly less endometriosis-related pain than women taking placebo. This oral therapy has the potential to address the clinical need for long-term medical treatment for endometriosis by reducing the need for opioid use or repeated surgical treatment in those cases of uncontrollable pain.

 

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