GnRH Antagonists in Endometriosis: Evaluating the Evidence for Sustained Pain Reduction

Key Takeaways:

• Antagonists cause immediate gonadotropin suppression, avoiding the “flare” effect often seen with GnRH agonists.
• Clinical trials confirm significant reductions in dysmenorrhea and non-menstrual pelvic pain comparable to standard therapies.
• Oral dosing offers rapid reversibility, and add-back therapy preserves bone mineral density during long-term use.

Endometriosis remains a challenging condition, characterized by chronic inflammation, pain, and a significant burden on patients' quality of life. For decades, medical management has relied heavily on nonsteroidal anti-inflammatory drugs (NSAIDs), combined oral contraceptives (COCs), and progestins. While effective for many, a substantial subset of patients experience resistance to these first-line therapies or find the side effect profiles intolerable.¹

Gonadotropin-releasing hormone (GnRH) agonists have served as a second-line option, yet their use is often limited by profound hypoestrogenic effects and the "flare" phenomenon. The emergence of oral GnRH antagonists represents a shift in the therapeutic landscape, offering a mechanism that allows for more controlled estrogen suppression.^1,2

This article evaluates the clinical evidence, pharmacology, and safety profile of this class to inform clinical decision-making.

The clinical context

The management of endometriosis-associated pain requires a balance between efficacy and long-term tolerability. Current guidelines typically recommend NSAIDs and COCs as first-line treatments.¹

Historically, when first-line therapies failed, clinicians turned to injectable GnRH agonists (e.g., leuprolide). While effective, agonists induce an initial gonadotropin surge – the "flare" effect – that can temporarily worsen symptoms before desensitization occurs.^1,2

Furthermore, GnRH agonists often suppress estradiol (E2) to postmenopausal levels (<20 pg/mL), necessitating add-back therapy to mitigate bone mineral density (BMD) loss and severe vasomotor symptoms. The limitations of these agents have underscored the need for oral alternatives that offer rapid onset, reversibility, and dose flexibility.^1,2

Pharmacology

GnRH antagonists, including elagolix, relugolix, and linzagolix, function through competitive blockade of the GnRH receptor in the anterior pituitary. Unlike agonists, which cause initial receptor stimulation and subsequent downregulation, antagonists produce an immediate, dose-dependent suppression of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).^1,2

This mechanism offers distinct clinical advantages:^1,2

• No flare effect – Serum gonadotropins and sex steroids decline rapidly within hours of administration, avoiding the initial symptom exacerbation seen with agonists.
• Dose-dependent suppression – Antagonists allow for partial suppression of E2. By titrating the dose, it is possible to maintain E2 levels within a "therapeutic window" (typically 30 to 60 pg/mL). This threshold is often sufficient to suppress endometriotic proliferation while minimizing severe hypoestrogenic side effects like bone loss and hot flushes.
• Rapid reversibility – Due to their shorter half-lives and lack of pituitary desensitization, ovarian function typically recovers quickly upon discontinuation.

Evidence for pain reduction

Clinical trials have demonstrated the efficacy of oral GnRH antagonists in reducing dysmenorrhea (DYS) and non-menstrual pelvic pain (NMPP).^1,3

Elagolix

The pivotal Phase 3 trials (SPIRIT 1 and 2) evaluated elagolix at 150 mg once daily and 200 mg twice daily. Both doses demonstrated statistically significant reductions in dysmenorrhea and non-menstrual pelvic pain compared to placebo at 3 months, with sustained efficacy over 6 months.³

In SPIRIT 1, 75 percent of women in the higher-dose group achieved clinical response for dysmenorrhea compared to 27 percent in the placebo group.³

Relugolix

The SPIRIT 1 and 2 trials investigated relugolix (40 mg) in combination with estradiol (1 mg) and norethindrone acetate (0.5 mg). This combination therapy demonstrated superiority over placebo in reducing DYS and NMPP. Notably, the combination regimen maintained efficacy comparable to relugolix monotherapy while significantly mitigating vasomotor symptoms and bone loss.³

Linzagolix

Investigational data suggests linzagolix also reduces endometriosis-associated pain. A once-daily 75 mg dose has been shown to maintain estradiol within the target range, potentially allowing for use without add-back therapy in some patients.⁴

Safety profile

GnRH antagonists are linked with the following adverse events and side effects:^1,2

Bone mineral density (BMD)

Prolonged estrogen suppression can lead to decreased BMD. In trials, high-dose elagolix (200 mg twice daily) was associated with greater BMD loss than the lower dose.^1,2

However, the use of add-back therapy (estradiol/progestin) with agents like relugolix has been shown to preserve bone health, resulting in BMD loss of less than 1 percent over 24 weeks – a difference not deemed clinically significant.^1,2

Vasomotor symptoms

Hot flushes and night sweats are common, dose-dependent adverse events. Hot flushes were reported more often by patients in the treatment groups compared to the placebo group.^1,2

Lipid profile

Mild increases in total cholesterol, LDL, and triglycerides have been observed in some studies, though lipid levels generally remained within acceptable clinical limits.^1,2

Patient selection and clinical positioning

GnRH antagonists are best positioned as a second-line therapy for premenopausal women with moderate-to-severe endometriosis-associated pain who have failed or cannot tolerate NSAIDs or hormonal contraceptives.²

Ideal candidates include:^1,2

• Patients with inadequate pain relief on combined oral contraceptives or progestins
• Women requiring rapid symptom control without the initial flare of agonists
• Patients concerned about the long-term reversibility of injectable depot formulations

Clinical considerations

Oral GnRH antagonists represent a significant advancement in the pharmacological management of endometriosis. Consider the following when prescribing to patients:^1,2

• Dosing strategy – Clinicians may select dosing regimens based on the severity of symptoms and tolerance. For example, lower doses may be sufficient for some patients and carry lower risks of BMD loss, whereas higher doses may require concurrent add-back therapy to ensure long-term safety and reduction of side effects.
• Contraindications – These agents are generally contraindicated in pregnancy and in patients with known hypersensitivity to GnRH antagonists.

By providing dose-dependent estrogen suppression without the initial flare associated with agonists, they offer a versatile option for patients with refractory pain.^1,2

The availability of regimens with add-back therapy further expands their utility, allowing for sustained treatment while protecting bone health. As with all hormonal therapies, patient selection and shared decision-making regarding the balance of efficacy and side effects remain paramount.^1,2