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

Annelyn Torres-Reverón, Jaydie M Valles Ortiz, Valles Ortiz JM, Myrella L Cruz, Cruz ML, Omar Velez-Lopez, Velez-Lopez O, Idhaliz Flores, Appleyard CB, Caroline B Appleyard
Biology of reproduction · 2026 · doi:10.1093/biolre/ioag107 · PMID:42172143 · W7162147340
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⚙ AI-generated summary by claude@2026-06, 2026-06-09 ⓘ

Antagonizing the corticotropin-releasing hormone receptor 1 with pexacerfont reduced endometriosis pain and associated adhesions by suppressing neuroinflammatory and proliferative pathways without disrupting gonadal endocrine signaling.

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Abstract

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.

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Condition tags

endometriosis

Citation neighborhood

Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. [ expand to 2 hops ] — adds papers reached through this work's immediate citers/citees. Heavier; up to 60 extra dots.

References (60)

SciLite annotations

chemicals 4
estrogen pexacerfont elagolix elagolix
organisms 2
zitter rats rattus sp.

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last seen: 2026-07-26T06:08:39.051465+00:00
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License: CC0 · commercial use OK