RAT OVARIAN INSULIN-LIKE-GROWTH-FACTOR BINDING PROTEIN-4 - A HORMONE-DEPENDENT GRANULOSA CELL-DERIVED ANTIGONADOTROPIN

OBJECTIVE: To assess the in vivo regulation of ovarian insulin-like gr owth factor binding protein-4 (IGFBP-4) mRNA expression by gonadotropi ns and estrogen.METHODS: Whole ovarian RNA, obtained from two models o f follicular development, was extracted and analyzed by Northern blott ing. Immature rats were treated with pregnant mare serum gonadotropin (PMSG) followed 48 hours later with hCG, or alternatively were hypophy sectomized and treated with FSH and/or diethylstilbestrol (DES). Local ization of IGFBP-4 expression was assessed in the former study by in s itu hybridization. Finally, the ability of human IGFBP-4 to antagonize FSH-stimulated progesterone accumulation was assessed in vitro. RESUL TS: The ovarian content of IGFBP-4 transcripts increased threefold (P < .05) at 12 hours after PMSG but was near baseline at 24 and 48 hours . The abundance of IGFBP-4 mRNA increased (P < .05) again at 6 and 24 hours after hCG. The expression of IGFBP-4 was localized to granulosa cells of preantral (untreated) and small antral (12 hours after PMSG) follicles. No IGFBP-4 expression was noted in large (gonadotropin-prim ed) antral follicles. Hypophysectomy increased (P < .05) the ovarian c ontent of IGFBP-4 mRNA by 1.5-fold, an effect further enhanced (1.8-fo ld; P < .05) by the provision of FSH and DES. In vitro studies reveale d the ability of increasing concentrations (0.01-1 mu g/mL) of recombi nant human IGFBP-4 to inhibit the FSH-supported accumulation of proges terone. CONCLUSION: Increased expression after administration of PMSG, hCG, and FSH/DES suggests that IGFBP-4 is a dynamic and hormonally re sponsive component of the ovarian cycle. The lack of expression in pre ovulatory follicles and its antigonadotropic actions in vitro imply th at the attenuated expression of IGFBP-4 may constitute a requirement f or successful follicular maturation. Copyright (C) 1997 by the Society for Gynecologic Investigation.