• Relugolix (REL) is an oral GnRH antagonist medication 
• Leuprorelin (LEU) is a sustained-released GnRH agonist that downregulates the GnRH receptor 
• Harada et al. (Fertility and Sterility 2021) evaluated the efficacy and safety of 40-mg REL vs LEU in women with endometriosis-associated pain 

• Phase 3, multicenter, randomized, double-blind, double-dummy, active-controlled study 
  • 42 centers in Japan  
• Participants 
  • ≥20 years  
  • Regular menstrual cycles (25 to 38 days)  
  • Endometriosis or ovarian endometrioma and pelvic pain 
• Interventions 
  • REL group: 40 mg of REL, orally administered once a day for 24 weeks 
  • LEU group: 3.75 or 1.88 (body weight <50 kg) mg of LEU, subcutaneously injected every 4 weeks for 24 weeks 
• Primary outcome 
  • Change in the maximum visual analog scale (VAS) score for pelvic pain from baseline until the end of treatment period (last 28 days of the treatment period including those who completed treatment up to 24 weeks or discontinued treatment early) 
• Secondary outcomes 
  • Change from baseline to the end of treatment for 
    • Mean VAS score | Menstrual pain | Nonmenstrual pelvic pain (NMPP) | Dyspareunia 

• REL group: 171 participants | LEU group: 164 participants 
• REL was found to be noninferior to LEU at reducing maximum visual analog scale score for pelvic pain  
  • Changes in the mean (±SD) maximum visual analog scale score 
    • REL: −52.6 ± 1.3 
    • LEU: −57.5 ± 1.4 
• Ovarian endometrioma also decreased among both treatment groups 
  • REL: –12.26 ± 17.52 cm³  
  • LEU: –14.10 ± 18.81 cm³ 
• Return of menses 
  • REL: Median, 38 days 
  • LEU: Median 68 days 
  • By approximately 4 months, menstruation had returned to almost all patients 
• Drug-related treatment emergent adverse events (TEAE) with an incidence of >10% for both groups  
  • Hot flushes 
  • Metrorrhagia 
  • Headache 
  • Genital hemorrhage 
• Discontinuations due to TEAE 
  • REL: 2.9% 
  • LEU: 4.3% 

• Relugolix was found to be noninferior to leuprorelin at reducing endometriosis-associated pelvic pain 
• Both treatment groups experienced similar levels of adverse events 
• Women in the relugolix group had their menses return earlier than those in the leuprorelin group 
• The authors state 

The recovery of the serum E2 levels and menstruation after EOT occurred earlier for REL than for LEU, a huge advantage for patients who plan to become pregnant 

In addition, because REL is an oral drug, patients often recover from a TEAE more quickly after stopping treatment 

Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, reduces endometriosis-associated pain compared with leuprorelin in Japanese women: a phase 3, randomized, double-blind, noninferiority study 

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