Antagonizing the corticotropin releasing hormone receptor 1 with antalarmin reduces the progression of endometriosis

Abstract

AbstractEndometriosis is a disorder in which endometrial tissue is found outside the uterus causing pain, infertility and stress. Finding an effective and long-term treatment 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. First, 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. A second group of rats received endometriosis but also antalarmin (20 mg/kg, i.p.) during the first 7 days after surgery. As separate group of sham surgery rats served as controls. Endometriosis was allowed to progress until 60 days after surgery. At time of sacrifice, rats were tested for anxiety behaviors and endometriotic vesicles, and uterus were collected. Rats with endometriosis that received antalarmin significantly reduced the size (67% decrease) and number (30% decrease) of endometriotic vesicles. Antalarmin also prevented the increase in CRH and CRHR1 within endometriotic vesicles but not of glucocorticoid receptor. Behaviorally, endometriosis increased anxiety in the zero-maze test but antalarmin did not modify it. Our data provides the first demonstration for the effective use on CRHR1 antagonist for the treatment of endometriosis with promising effects for long-term therapy of this debilitating disease.