PHYSIOLOGICAL-ROLE OF INSULIN-LIKE-GROWTH-FACTOR-BINDING PROTEIN-4 INHUMAN FOLLICULOGENESIS

Insulin-like growth factor (IGF)-I and IGF-II, and their binding prote ins (IGFBPs) have been demonstrated to play important roles in follicu lar development as intraovarian regulators. Previous studies have demo nstrated that the follicular fluid of atretic follicles contains high levels of IGFBP-2 and IGFBP-4, which are known to inhibit the action o f IGFs. In this study, we identified IGFBP-4 protease activity in the follicular fluid of developing but not atretic follicles. To elucidate the regulation mechanism of IGFBP-4 proteolytic activity in the ovary , cultured luteinized granulosa cells (GCs) were incubated with variou s hormones, and proteolyzed IGFBP-4 in the medium was analyzed. IGFBP- 4 proteolytic activity was increased when GCs were incubated with IGFs , estradiol or follicle-stimulating hormone (FSH) but not with testost erone. We also showed that IGFBP-4 inhibited IGF-I-induced estradiol r elease by GCs while proteolyzed IGFBP-4 did not. These results suggest that human luteinized GCs produce IGFBP-4 protease, and that FSH and IGFs may stimulate folliculogenesis by modulating IGFBP-4 degradation in the ovary.