Endometriosis affects an estimated one in ten women of reproductive age, yet the path from symptom onset to effective treatment often remains unnecessarily long. For many patients, a confirmed diagnosis is only the beginning and there is meaningful opportunity to shorten the time to effective, appropriately matched treatment.1,2
Nonsteroidal anti-inflammatory drugs (NSAIDs) and combined hormonal contraceptives are often first steps, but their limitations in moderate-to-severe disease are well established.3 Recognizing when first-line agents have reached their therapeutic ceiling allows clinicians to move patients toward more effective options without unnecessary delay. When an NSAID or hormonal contraceptive has not achieved adequate pain control, the clinical question is not typically whether to escalate, but how to do so effectively.3,4
Gonadotropin-releasing hormone (GnRH) receptor antagonists represent a mechanistically distinct and expanding approach to estrogen-dependent pain suppression.4 Unlike GnRH agonists, which may require add-back therapy to offset cumulative estrogen depletion effects, oral GnRH antagonists offer a more flexible framework as add-back can be integrated from initiation. Additionally, they can help mitigate vasomotor symptoms and attenuate bone mineral density loss while preserving meaningful estrogen suppression at the lesion level.4
Several oral GnRH antagonists have advanced through clinical development for endometriosis, reflecting growing confidence in this mechanistic class. 4 Among these, the combination of relugolix with low-dose estradiol and norethindrone acetate is the only once-daily oral GnRH antagonist regimen with FDA approval for endometriosis-related pain.4 In clinical trials, treated patients were less likely than those receiving placebo to require analgesics or opioids by end of treatment.5,6
Optimizing the prescribing decision requires equal attention to the initiation conversation. Patient selection, expectation setting, and co-pay program enrollment at the time of the visit are each part of ensuring the prescription translates into sustained treatment rather than early abandonment. As with all combination estrogen-progestogen therapies, individualized risk-benefit assessment and shared decision-making remain essential, particularly regarding thromboembolic risk and patient-specific contraindications.
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