Beyond depression and anxiety; a systematic review about the role of corticotropin-releasing hormone antagonists in diseases of the pelvic and abdominal organs

Joshua E. Pagán-Busigó, Jonathan López-Carrasquillo, Caroline B. Appleyard, Annelyn Torres-Reverón
In: PLoS ONE, Vol 17, Iss 3 (2022) · 2022 · W4226365915
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This systematic review of preclinical studies found corticotropin-releasing hormone receptor 1 antagonists show beneficial effects in abdominal and pelvic diseases, though outcomes vary with administration details and animal models.

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This systematic review compiled preclinical animal studies (40 total over the last 15 years) assessing corticotropin-releasing hormone (CRH) receptor antagonists for diseases of pelvic and abdominal organs, with the authors using PRISMA to structure the search and ARRIVE 10 essential guidelines to appraise study quality. Across included conditions such as irritable bowel syndrome, inflammatory bowel disease, and endometriosis, the review found that blocking CRH receptor 1 was mostly associated with beneficial effects, whereas blockade of CRH receptor 2 tended to worsen outcomes, but effects varied by timing, route of administration, and animal model. A key limitation highlighted was substantial quality and design bias, including failure to randomize or blind in many studies and a predominance of male animal models despite the clinical context. This paper is centrally about endometriosis — it is included among the pelvic organ diseases reviewed for CRH antagonist effects, with endometriosis explicitly part of the analyzed evidence base.

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Abstract

Evidence for beneficial effects of corticotropin releasing hormone (CRH) antagonists in abdominal and pelvic organs is emerging in preclinical studies. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement a compilation of preclinical studies using CRH receptor antagonists as a treatment for abdominal and pelvic disease was carried out. The Animal Research: Reporting of In Vivo Experiments (ARRIVE) essential 10 guidelines were used to determine quality of the included studies. A total of 40 studies from the last 15 years studying irritable bowel syndrome, inflammatory bowel disease, endometriosis, enteritis, stress impact on gastrointestinal processes and exogenous CRH administration effects were included. Blockage of the CRH receptor 1 was mainly associated with beneficial effects while that of CRH receptor 2 worsened studied effects. However, time of administration, route of administration and the animal model used, all had an impact on the beneficial outcomes. Frequency of drugs administered indicated that astressin-2B, astressin and antalarmin were among the most utilized antagonists. Of concern, studies included were predominantly carried out in male models only, representing a gender discrepancy in preclinical studies compared to the clinical scenario. The ARRIVE score average was 13 with ~60% of the studies failing to randomize or blind the experimental units. Despite the failure to date of the CRH antagonists in moving across the clinical trials pipeline, there is evidence for their beneficial effects beyond mood disorders. Future pre-clinical studies should be tailored towards effectively predicting the clinical scenario, including reduction of bias and randomization.
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PLoS ONE (Jan 2022) Beyond depression and anxiety; a systematic review about the role of corticotropin-releasing hormone antagonists in diseases of the pelvic and abdominal organs Abstract Evidence for beneficial effects of corticotropin releasing hormone (CRH) antagonists in abdominal and pelvic organs is emerging in preclinical studies. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement a compilation of preclinical studies using CRH receptor antagonists as a treatment for abdominal and pelvic disease was carried out. The Animal Research: Reporting of In Vivo Experiments (ARRIVE) essential 10 guidelines were used to determine quality of the included studies. A total of 40 studies from the last 15 years studying irritable bowel syndrome, inflammatory bowel disease, endometriosis, enteritis, stress impact on gastrointestinal processes and exogenous CRH administration effects were included. Blockage of the CRH receptor 1 was mainly associated with beneficial effects while that of CRH receptor 2 worsened studied effects. However, time of administration, route of administration and the animal model used, all had an impact on the beneficial outcomes. Frequency of drugs administered indicated that astressin-2B, astressin and antalarmin were among the most utilized antagonists. Of concern, studies included were predominantly carried out in male models only, representing a gender discrepancy in preclinical studies compared to the clinical scenario. The ARRIVE score average was 13 with ~60% of the studies failing to randomize or blind the experimental units. Despite the failure to date of the CRH antagonists in moving across the clinical trials pipeline, there is evidence for their beneficial effects beyond mood disorders. Future pre-clinical studies should be tailored towards effectively predicting the clinical scenario, including reduction of bias and randomization.

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