Abstract

Endometriosis is a disorder in which endometrial tissue is found outside the uterus causing pain, infertility and stress. Finding effective, non-hormonal and long-term treatments for endometriosis still remains one of the most significant challenges in the field. Corticotropin releasing hormone (CRH) is one of the main signaling peptides within the hypothalamic pituitary adrenal (HPA) axis released in response to stress. CRH can affect nervous and visceral tissues such as the uterus and gut via activation of two types of CRH receptors: CRHR1 and CRHR2. Our aim was to determine if blocking CRHR1 with antalarmin will reduce endometriosis progression. In experiment 1 we induced endometriosis in female rats by suturing uterine horn tissue next to the intestinal mesentery and allowed to progress for 7 days. We determined that after 7 days, there was a significant increase in CRHR1 within endometriotic vesicles as compared to normal uterus. In Experiment 2, we induced endometriosis and administered either antalarmin (20 mg/kg, i.p.) or vehicle during the first 7 days after surgery. A separate group of sham surgery rats served as non-endometriosis controls. Endometriosis was allowed to progress until 60 days after surgery, at which time rats were tested for anxiety behaviors. At the time of sacrifice, endometriotic vesicles, uterus and blood were collected. Treatment with antalarmin significantly reduced the size (67% decrease) and number (30% decrease) of endometriotic vesicles. Antalarmin also prevented the increase in CRH and CRHR1 mRNA within endometriotic vesicles but not of glucocorticoid receptor. Endometriosis did not change anxiety behaviors in the open field and zero-maze tests and prior antalarmin administration did not modify this. Our data provides the first in-vivo demonstration for use of CRHR1 antagonist for the treatment of endometriosis opening the possibility for further exploring CRH signaling as a treatment target for this debilitating disease.

Highlights

  • Corticotropin releasing hormone (CRH) is one of the main signaling molecules of the hypothalamic pituitary adrenal (HPA) axis

  • We demonstrated that antalarmin prevented the increase in CRH and CRH receptors type 1 (CRHR1) mRNA within endometriosis vesicles as compared to vehicle treated rats, and this reduction was long lasting

  • A single week of antalarmin treatment, corresponding to an up regulation of CRHR1 within endometriotic vesicles, was effective in reducing endometriosis in the rat model by reducing the number of developed vesicles by 30% and the size of the vesicles that developed by 67%

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Summary

Introduction

Corticotropin releasing hormone (CRH) is one of the main signaling molecules of the hypothalamic pituitary adrenal (HPA) axis. CRH has a myriad of physiological effects that include behavioral, endocrine, autonomic and immune responses [1,2]. CRH acts mainly by binding to CRH receptors type 1 (CRHR1) and type 2 (CRHR2), with a 10-fold higher affinity for the CRHR1 versus CRHR2 [3]. CRH receptors belong to the superfamily of G-protein coupled receptors and typically effect cellular activity via coupling to adenylate cyclase [3]. Eleven splice variants of the CRHR1 receptor have been identified [8], with a tissue-specific expression pattern [9,10]. The CRH paralog, urocortin 1 (UCN1) can bind and activate both the CRHR1 and R2 [11]

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