Antagonizing the corticotropin-releasing hormone receptor 1 with an orally bioavailable drug reduces endometriosis pain and associated adhesions†

Estrogen stimulates corticotropin-releasing hormone (CRH) expression in endometrial tissue, and CRH signaling contributes to inflammation and pain, suggesting a mechanistic role in endometriosis pathophysiology. We previously identified elevated CRH receptor-1 (CRHR1) levels in endometriotic lesions in a rat model. Here, we tested the hypothesis that antagonizing CRHR1 with pexacerfont, an orally bioavailable small-molecule antagonist, would reduce endometriosis-associated pain and lesion activity. Beginning 25 days after disease induction, rats received pexacerfont (10 mg/kg), vehicle, or elagolix (14 mg/kg) in 7-day treatment cycles separated by 7-day drug-free intervals up to day 60 after endometriosis onset. Pexacerfont significantly reduced mechanical and inflammatory pain (34% and 38% decreases, respectively) and decreased nerve growth factor (NGF), vascular endothelial growth factor (VEGF), Ki67, and IL-6 and TNF-α mRNA expression within lesions. Unlike elagolix, pexacerfont did not alter peritoneal leptin-to-weight or serum FSH-to-LH ratios, indicating minimal disruption of gonadal endocrine signaling. Notably, pexacerfont reduced macroscopic adhesion scores by half, a therapeutic effect not observed with either vehicle or elagolix. CRHR1 antagonism, therefore, suppressed neuro-inflammatory and proliferative pathways while limiting lesion-associated angiogenesis and postoperative adhesion development. These findings position CRHR1 as a mechanistically distinct, non-hormonal therapeutic target for endometriosis and highlight pexacerfont's potential to reduce both pain and adhesions.