Insulin-Like Growth Factor-Binding Protein (IGF-BP) Inhibition of Granulosa Cell Function: Effect on Cyclic Adenosine 3’5’-Monophosphate, Deoxyribonucleic Acid Synthesis, and Comparison with the Effect of an IGF-I Antibody*

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Abstract
The effects of insulin-like growth factor binding proteins (IGF-BPs) purified from porcine follicular fluid on granulosa cell function were examined using serum-free cultures of rat granulosa cells obtained from immature, diethylstilbestrol-treated rats. Both the so-called GH-dependent (IGF-BP3) and non-GH-dependent (IGF-BP2) proteins dose dependently inhibited granulosa cell estradiol and progesterone production with IC5Os of 4.1-7.6 nM for IGF-BP3 and 12.6-12.9 nM for IGF-BP2, the actual value depending upon the steroid being measured. A specific antiserum directed against IGF-I also dose dependently suppressed both estradiol and progesterone production, although the effect on the latter was more marked. Experiments using cells that were primed with FSH to induce functional LH receptors showed that the inhibitory action of IGF-BP3 was specific to FSH. However, both IGF-BP3 and IGF-BP2 were capable of inhibiting both forskolin- and chlorea toxin-stimulated steroidogenesis, confirming that neither compound was competing with FSH for binding to its receptor. Neither IGF-BP had any effect on either basal or FSH-stimulated cAMP production, while exogenously added IGF-I was stimulatory in this respect. However, both IGF-BP''s inhibited FSH-stimulated [3H]thymidine uptake by the granulosa cells, while IGF-I had no effect on this parameter, suggestive of an IGF-independent effect on granulosa cell proliferation. Our data suggest that IGF-BPs have a multifaceted mode of action on granulosa cell function, and may therefore be an important regulator of follicular growth and differentiation.