Relugolix for Endometriosis Pain: What a 2025 Meta-Analysis Says About Relief, Quality of Life, and Side Effects

Living with endometriosis can mean dealing with persistent pelvic pain, painful periods, and the emotional toll of symptoms that affect work, relationships, and daily routines. Newer oral medications—like relugolix—are being studied and used to help reduce endometriosis-associated pain and improve quality of life.

This post summarizes patient-relevant findings from a 2025 systematic review and meta-analysis of randomized controlled trials (RCTs)published in Frontiers in Endocrinology that evaluated relugolix using the Endometriosis Health Profile-30 (EHP-30), a common endometriosis quality-of-life questionnaire.

What is endometriosis—and why can it hurt so much?

Endometriosis is often described as a chronic condition where tissue similar to the lining of the uterus is found outside the uterus. Many people experience pain that can be intense and life-disrupting. This meta-analysis focused on endometriosis-associated pain and how treatment affected pain and quality of life as captured by EHP-30 scores.

How does relugolix work?

Relugolix is an oral gonadotropin-releasing hormone (GnRH) receptor antagonist. In plain language: it works by reducing hormonal signals that contribute to endometriosis-related pain.

The review also discusses a key practical difference from some older GnRH-based treatments (like GnRH agonists such as leuprorelin): relugolix may provide comparable benefit without an initial “flare-up” of symptoms that can happen when starting a GnRH agonist. (The paper emphasizes non-inferiority vs leuprorelin and notes the lack of a flare-up as a potential advantage.)

Does relugolix reduce endometriosis pain? What the evidence shows

Across the included RCTs, relugolix was associated with meaningful improvements in EHP-30 pain-related outcomes—especially compared with placebo (no active treatment).

Key findings (vs placebo):

• Improved EHP-30 Pain domain scores: mean difference (MD) 6.77(95% CI 3.15 to 10.39, p=0.0002)
• Higher likelihood of being a “responder” on the EHP-30 Pain domain: odds ratio (OR) 3.245(95% CI 2.496 to 4.219, p < 0.0001)

What this means for patients: in these studies, people taking relugolix were more likely to report meaningful pain improvement than those taking placebo.

Beyond pain: quality-of-life improvements (EHP-30 domains)

Endometriosis isn’t only about pain levels—it can affect mood, relationships, and self-confidence. In this meta-analysis, relugolix also improved several quality-of-life areas compared with placebo:

• Emotional well-being: MD 5.71(95% CI 1.87 to 9.55, p=0.0036)
• Social support: MD 6.40(95% CI 0.88 to 11.93, p=0.0231)
• Self-image: MD 6.00(95% CI 1.03 to 10.96, p=0.0179)

If you’ve felt that endometriosis affects your mental health or sense of self, these findings are important: the research suggests relugolix may help improve how you feel and function, not just pain scores.

How does relugolix compare with leuprorelin (an older GnRH treatment)?

Some trials compared relugolix with leuprorelin (a GnRH agonist). The review concludes that:

• Relugolix is generally non-inferior (meaning “not worse”) compared with leuprorelin.
• It was not statistically superior (not clearly better) for overall efficacy or quality-of-life impact.
• In results summarized by the authors, relugolix showed a numerically smaller improvement than leuprorelin in at least one analysis (reported as MD -3.79, 95% CI -6.27 to -1.31), and the discussion notes the confidence intervals did not show clear superiority.

Patient takeaway: Relugolix may be an alternative option with similar overall benefit, and it may avoid the initial symptom flare associated with starting a GnRH agonist—an issue some patients find difficult.

Side effects and “add-back” therapy: what to know

Like many treatments that reduce estrogen activity, relugolix can cause hypoestrogenic side effects (symptoms related to lower estrogen).

The meta-analysis reports common adverse events such as:

• Hot flushes(noted as frequent and dose-dependent)
• Headache
• Fatigue
• Musculoskeletal pain
• Nasopharyngitis

The paper also highlights the role of combination (“add-back”) therapy—relugolix used with estradiol and norethisterone acetate—which is designed to help mitigate hypoestrogenic side effects while maintaining benefit.

Important note: The article indicates that add-back therapy helps with tolerability and management of hypoestrogenic effects, but the blog data provided here does not include specific numerical results for every side-effect rate or discontinuation rate by regimen—so we can’t quantify exactly how much add-back reduces each side effect from this summary alone.

Relugolix combination therapy vs relugolix alone: is one better?

In subgroup analyses:

• Combination therapy showed a numerically larger improvement (MD 8.86) than
• Monotherapy (MD 4.99)

However, the authors report the difference between subgroups was not statistically significant. In other words, combination therapy may look better in numbers, but this meta-analysis could not confirm it is definitively better for pain outcomes based on the available trial data.

Is relugolix effective long term?

This is one of the biggest unanswered questions. The review notes that:

• Benefits were most clearly demonstrated around 24 weeks
• For longer follow-up periods (including 52 and 104 weeks), the confidence intervals crossed zero, meaning the meta-analysis could not conclusively demonstrate continued significant benefit at those extended durations

What this means for you: If you and your clinician are considering relugolix beyond 6 months, it’s reasonable to ask about:

• symptom monitoring plans,
• side effect management (including add-back therapy),
• and what is known (and not known) about longer-term outcomes.

Actionable takeaways: questions to bring to your next appointment

If you’re considering relugolix for endometriosis-associated pain, these discussion points can help:

1. Am I a good candidate for an oral GnRH antagonist?

Ask how relugolix fits with your symptoms, prior treatments, and preferences.

2. Should I use relugolix alone or relugolix combination (add-back) therapy?

This review suggests add-back is important for managing hypoestrogenic effects; the pain benefit difference vs monotherapy wasn’t statistically definitive.

3. What side effects should I watch for, and how will we manage them?

Hot flushes, headache, fatigue, and muscle aches were commonly reported; hot flushes were dose-dependent.

4. What’s the plan for follow-up at 24 weeks—and beyond?

Long-term benefit past 24 weeks was not clearly established in this meta-analysis, so having a reassessment timeline matters.

Cautions and gaps: avoiding common misunderstandings

Based on the authors’ discussion, it’s worth keeping these points in mind:

• Don’t assume long-term benefit is guaranteed. Evidence beyond ~24 weeks is limited/inconclusive in this analysis.
• Don’t assume relugolix is “better than” leuprorelin. It appears comparable overall (non-inferior), but not clearly superior.
• Don’t minimize side effects. Many are tied to lower estrogen, and the paper highlights the importance of add-back therapy for tolerability.
• Results can vary between people and studies. The meta-analysis reported substantial heterogeneity (I² reported as 90.7%), suggesting responses may differ depending on regimen, comparator, and other study factors.