What is the role of Relugolix (generic name: Relugolix) in the treatment of adenomyosis?

Relugolix Combination Therapy in Adenomyosis

Relugolix combination therapy (relugolix 40 mg with estradiol 1 mg and norethindrone acetate 0.5 mg) is highly effective for treating adenomyosis, achieving 83.8% treatment response rates for heavy menstrual bleeding and 64.9% amenorrhea rates, with superior uterine volume reduction (43%) compared to fibroids alone (27%). 1, 2

Evidence for Efficacy

Heavy Menstrual Bleeding Control

• In women with concomitant adenomyosis and uterine fibroids, relugolix combination therapy achieved treatment response (menstrual blood loss <80 mL with ≥50% reduction) in 83.8% of patients versus 27.6% with placebo. 1
• Amenorrhea was achieved in 64.9% of women with adenomyosis treated with relugolix combination therapy compared to only 6.9% with placebo. 1
• These efficacy outcomes in women with adenomyosis were comparable to the overall study population, demonstrating consistent benefit regardless of adenomyosis presence. 1

Volume Reduction

• Adenomyotic lesions show superior response to relugolix compared to uterine fibroids, with adenomyotic lesion volume decreasing by 61% versus fibroid reduction. 2
• Uterine volume decreased by 43% in women with adenomyosis coexisting with fibroids, significantly greater than the 27% reduction in women with fibroids alone (p = 0.00972). 2
• The least square mean uterine volume in women with adenomyosis decreased by 22.2% with relugolix combination therapy versus 5.8% with placebo. 1

Symptom Relief

• Relugolix effectively relieves pelvic pain and anemia associated with adenomyosis, with no significant difference in symptom mitigation between adenomyosis with fibroids versus fibroids alone. 2
• The rapid reduction in adenomyotic lesion volume occurs within approximately 16-20 weeks of treatment. 2

Clinical Positioning in Treatment Algorithm

First-Line Medical Management

• Per American College of Radiology guidelines, levonorgestrel-releasing intrauterine system (LNG-IUD) remains first-line medical management for adenomyosis symptoms. 3, 4
• Combined oral contraceptives are recommended as second-line options for symptom control. 3, 4

Second-Line Medical Management

• GnRH antagonists (including relugolix) are positioned as effective second-line therapy for heavy menstrual bleeding, particularly with concomitant adenomyosis. 3, 4
• This aligns with ACR guidelines that list oral GnRH antagonists (elagolix, linzagolix, and relugolix) as second-line medical management for fibroid-related bleeding. 5

Pre-Surgical Use

• Relugolix can serve as effective pre-surgical therapy to reduce adenomyotic lesion size and improve anemia before minimally invasive procedures. 2, 6
• Combined approach using uterine artery embolization followed by relugolix combination therapy has demonstrated effectiveness in reducing fibroid size and vascularity before surgery. 6

Mechanism and Formulation

• Relugolix is an oral, non-peptide GnRH receptor antagonist that competitively binds to GnRH receptors, preventing follicle-stimulating hormone and luteinizing hormone release. 7
• The combination formulation with estradiol 1 mg and norethindrone acetate 0.5 mg achieves therapeutic estradiol concentrations that mitigate bone mineral density loss and vasomotor symptoms, enabling longer-term treatment. 7
• This add-back therapy approach allows for extended use beyond the limitations of traditional GnRH agonists. 7

Important Caveats and Pitfalls

Side Effect Management

• Hot flushes and headaches may occur with relugolix therapy; traditional Japanese Kampo medicine (kamishoyosan) has been reported to help manage these menopausal symptoms. 8
• The combination formulation specifically addresses hypoestrogenic effects that occur with monotherapy. 7

Fertility Considerations

• Fertility is suppressed during relugolix treatment, and cessation of therapy leads to rapid recurrence of symptoms. 5
• Comprehensive data on fertility and pregnancy outcomes after relugolix treatment for adenomyosis is lacking, and patients must be counseled accordingly. 3, 9
• No medical therapy has been proven to eradicate adenomyosis lesions, providing only temporary symptom relief. 3

Long-Term Outcomes

• Relugolix is approved for longer-term use compared to traditional GnRH agonists due to the add-back hormone therapy component. 7
• Surgical recurrence remains common with adenomyosis, with up to 44% of women experiencing symptom recurrence within one year after conservative surgery. 3

Regulatory Status

• In the United States, relugolix combination therapy is approved as MYFEMBREE for management of heavy menstrual bleeding associated with uterine fibroids and moderate to severe pain associated with endometriosis. 7
• In the European Union and United Kingdom, it is approved as RYEQO for management of symptoms associated with uterine fibroids. 7
• In Japan, relugolix 40 mg monotherapy (RELUMINA) is approved to improve symptoms associated with uterine fibroids or pain associated with endometriosis. 7