Evidence that the insulin-like growth factor binding protein-4 protease inhuman ovarian follicular fluid is pregnancy associated plasma protein-A

Ovarian insulin-like growth factor binding protein-4 (IGFBP-4) proteolysis is involved in the regulation of follicular development, but until now the identity of the responsible enzyme was unknown. Ln this study, we identify the IGFBP-4 protease in human follicular fluid as pregnancy associated plas ma protein-A (PAPP-A) based on distinctive IGFBP-4 cleavage pattern, the sa me protease inhibitor profile, specific inhibition and immunodepletion of I GFBP-4 protease activity with PAPP-A polyclonal antibodies, and immunorecog nition by PAPP-A monoclonal antibodies in ELISA. Furthermore, PAPP-A levels in estrogen-dominant and androgen-dominant follicular fluids reflect their IGFBP-4 proteolytic activity. PAPP-A was also secreted by human granulosa cells, the reputed source of IGFBP-4 protease activity in follicular fluid. We have the molecular and biochemical tools to begin to delineate the regu lation and biological function of PAPP-A in normal and dysregulated follicu lar development and atresia.