Gonadotropin-Releasing Hormone Agonist (GnRH-a) Therapy Alters Activity of Plasminogen Activators, Matrix Metalloproteinases, and Their Inhibitors in Rat Models for Adhesion Formation and Endometriosis: Potential GnRH-a–Regulated Mechanisms Reducing Adhesion Formation

Abstract

Objective: To evaluate the effects of a gonadotropin-releasing hormone agonist (GnRH-a) on plasminogen activator (PA), matrix metalloproteinase (MMP), plasminogen activator inhibitor (PAI) and matrix metalloproteinase inhibitor (MMPI) activities in peritoneal fluid relative to GnRH-a–induced reduction of adhesion formation. Design: Continuation of prospective randomized study using surgical models for adhesion formation. Setting: Department of Obstetrics and Gynecology research laboratory at the University of Missouri School of Medicine. Patient(s): Forty reproductively cycling female Sprague-Dawley rats. Intervention(s): Female rats were injected with depot GnRH-a or diluent and randomly assigned to adhesion and endometriosis surgeries. Peritoneal fluid was collected prior to (time 1) and 7 weeks from (time 2) initial surgery. Main Outcome Measure(s): Peritoneal fluid was analyzed for PA, PAI, MMP, and MMPI activities. Result(s): At time 1, MMP and MMPI activities were similar in all rats; however, PA and PAI activities were less in rats pretreated with GnRH-a than with diluent. Between time 1 and time 2, GnRH-a–treated rats showed an increase in PAI and MMPI activities without significant changes in PA or MMP activities, whereas rats receiving diluent showed a significant increase in PAI and MMP activities but no significant changes in PA or MMPI activities. At time 2, rats receiving GnRH-a had less PA and MMP activities than those receiving diluent. Adhesion scores showed a positive correlation with MMP activity. Conclusion(s): In the absence of GnRH-a therapy, surgical tissue manipulation increased peritoneal fluid MMP and PAI activity. Gonadotropin-releasing hormone agonist therapy decreased PA and MMP activities and also increased PAI and MMPI activities. This GnRH-a–induced shift to a less invasive phenotype may alter fibrinolysis and extracellular matrix remodeling and thereby play a role in the mechanism of GnRH-a–induced reduction in adhesion formation.