Relugolix in Treatment of Uterine Fibroids
Relugolix combination therapy (40 mg relugolix with 1 mg estradiol and 0.5 mg norethindrone acetate) is an FDA-approved, effective second-line oral treatment for heavy menstrual bleeding associated with uterine fibroids, reducing bleeding in 71-73% of patients while preserving bone mineral density through hormonal add-back therapy. 1
Role in Treatment Algorithm
Relugolix functions as a second-line medical therapy, positioned after first-line options (NSAIDs, oral contraceptives, progestin-containing IUDs, and tranexamic acid) but before surgical or interventional procedures. 2
Key Clinical Indications
Heavy menstrual bleeding reduction: Relugolix combination therapy achieves a menstrual blood loss response (<80 ml with ≥50% reduction from baseline) in 71-73% of patients versus 15-19% with placebo. 1
Fibroid volume reduction: Both GnRH agonists and antagonists like relugolix effectively reduce tumor volume by 18-30%, making them valuable for short-term preoperative use to decrease fibroid size before surgery. 2, 3
Symptom improvement: Relugolix significantly improves six of seven key secondary endpoints including amenorrhea rates, pain scores, distress from bleeding and pelvic discomfort, anemia correction, and uterine volume reduction. 1
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, thereby suppressing ovarian estrogen and progesterone production. 4
The critical advantage of combination therapy: The addition of 1 mg estradiol and 0.5 mg norethindrone acetate mitigates hypoestrogenic side effects (headaches, hot flushes, hypertension, bone mineral density loss) that occur with GnRH monotherapy, enabling longer-term treatment. 2, 5
Clinical Efficacy Evidence
The two replicate LIBERTY phase 3 trials (L1 and L2) provide the strongest evidence:
Primary endpoint achievement: 73% (L1) and 71% (L2) response rates with combination therapy versus 19% (L1) and 15% (L2) with placebo (P<0.001). 1
Bone preservation: Bone mineral density remained similar to placebo with combination therapy but decreased significantly with relugolix monotherapy, demonstrating the protective effect of hormonal add-back. 1
Safety profile: Adverse event incidence was similar between relugolix combination therapy and placebo, with vasomotor symptoms being the most common adverse reaction. 5, 1
Duration of use: Treatment for up to 2 years did not induce clinically meaningful bone loss in the majority of women. 5
Positioning Relative to Other Treatments
Compared to parenteral GnRH agonists (leuprolide): Relugolix offers the convenience of once-daily oral administration versus injections every 4 weeks, with faster reduction in heavy menstrual bleeding and potentially greater fibroid shrinkage. 6
Compared to surgical options: While hysterectomy provides definitive resolution and UAE shows 53% fibroid diameter reduction with lower reintervention rates than MRgFUS, relugolix offers a non-invasive option for patients desiring uterus preservation or avoiding procedural risks. 2, 7
Critical Limitations and Pitfalls
Fertility suppression during treatment: Although chosen by patients interested in uterus-preserving therapy or future fertility preservation, fertility is actively suppressed during treatment. 2
Rapid symptom recurrence: Cessation of therapy leads to rapid recurrence of symptoms, limiting its role as a definitive long-term solution. 2, 7
Not first-line therapy: Relugolix should be reserved as second-line treatment after failure of or contraindications to hormonal contraceptives, IUDs, or tranexamic acid. 2
Preoperative use: When used short-term before surgery to reduce fibroid size, the goal is to decrease intraoperative blood loss and operative time, though evidence for this specific indication with relugolix is still emerging. 8
Practical Implementation
For patients with moderate-severe symptoms desiring uterus preservation: Start relugolix combination therapy (40 mg/1 mg/0.5 mg) once daily, taken before a meal. 3, 8
Monitor for: Vasomotor symptoms (most common adverse effect), bone mineral density if treatment extends beyond 6 months, and hemoglobin improvement in anemic patients. 5, 1
Treatment duration: FDA-approved for up to 24 months based on trial data, with bone density monitoring recommended for extended use. 5, 1
When to transition to definitive therapy: If symptoms recur rapidly after discontinuation or if patient desires permanent resolution, consider surgical options (myomectomy if fertility desired, hysterectomy if not) or UAE for longer-lasting symptom control. 2, 7