Insulin-like growth factor-I induces follicular development by stimulating ovarian production of angiotensin II

We evaluated the effects of insulin-like growth factor binding protein- 3 (IGFBP-3) on insulin-like growth factor I (IGF-I)-stimulated follicular growth, oocyte maturation ovarian steroidogenesis and angiotensin II (Ang II) production, and intrafollicular plasminogen activator (PA) activity using all in vitro perfused rabbit ovary preparation. Exposure to 10² ng/ml of IGF-I significantly stimulated follicular development, oocyte maturation, and the secretion rate of Ang II-like immunoreacivity (Ang II-IR) in perfused rabbit ovaries. The concomitant addition of IGFBP-3 (1 to 10³ ng/ml) to the perfusate blocked the stimulatory effects of IGF-I in a dose-dependent manner. The percent increase in follicle diameter in IGF-I-treated ovaries with or without IGFBP-3 for 12 h was significantly correlated with the secretion tale of Ang II-IR at 12 h after exposure to IGF-I. The secretion rate of estradiol (E₂), but not progesterone, was significantly increased in response to IGF-I administration, with IGFBP-3 reduced the IGF-I-induced secretion rate of E₂ in a dose-dependent manner. A monoclonal antibody recognizing the type I receptor, αIR-3, also significantly blocked IGF-I- stimulated follicular growth, oocyte maturation, and Ang II-IR secretion. The addition of either 10³ ng/ml of IGFBP-3 or 1 μg/ml of αIR-3 to the perfusate significantly inhibited the intrafollicular PA activity stimulated by IGF-I. In conclusion, these results indicate that IGF-I stimulates follicular growth, at least in part, by stimulating the ovarian production of Ang II. Thus, IGF-I and Ang II may interact in the mechanisms that control follicular development.