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

Objective: To evaluate the effects of a gonadotropin-releasing hormone agonist (GnRH-a) on plasminogen activator (PA), matric: metalloprotei nase (MMP), plasminogen activator inhibitor (PAI) and matrix metallopr oteinase inhibitor (MMPI) activities in peritoneal fluid relative to G nRH-a-induced reduction of adhesion formation. Design: Continuation of prospective randomized study using surgical models for adhesion forma tion. Setting: Department of Obstetrics and Gynecology research labora tory at the University of Missouri School of Medicine. Patient(s): For ty reproductively cycling female Sprague-Dawley rats. Intervention(s): Female rats were injected with depot GnRH-a or diluent and randomly a ssigned 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, M MP, 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 tim e 2, GnRH-a-treated mts showed an increase in PAI and MMPI activities without significant changes in PA or MMP activities, whereas rats rece iving diluent showed a significant increase in PAI and MMP activities but no significant changes in PA or MMPI activities. At time 2, rats r eceiving GnRH-a had less PA and MMP activities than those receiving di luent. Adhesion scores showed a positive correlation with MMP activity . Conclusion(s): In the absence of GnRH-a therapy, surgical tissue man ipulation increased peritoneal fluid MMP and PAI activity. Gonadotropi n-releasing hormone agonist therapy decreased PA and MMP activities an d also increased PAI and MMPI activities. This GnRH-a-induced shift to a less invasive phenotype may alter fibrinolysis and extracellular ma trix remodeling and thereby play a role in the mechanism of GnRH-a-ind uced reduction in adhesion formation. (C) 1998 by American Society for Reproductive Medicine.