Divergent mechanisms regulate proliferation/survival and steroidogenesis of theca-interstitial cells.

Luteinizing hormone (LH) and insulin-like growth factor I (IGF-I) are recognized as major regulators of ovarian theca-interstitial (T-I) function. This study was designed to compare the effects of LH and IGF-I on T-I proliferation and steroidogenesis. Purified rat T-I cells were cultured in chemically-defined media. DNA synthesis was evaluated by a radiolabelled thymidine incorporation assay. The cells were also directly counted. Progesterone production was assessed using a specific radioimmunoassay. DNA synthesis of T-I cells was stimulated by IGF-I (10 nM) but modestly inhibited by LH (100 ng/ml). The inhibitory effect of LH was mimicked by 8Br-cAMP (10(-4) to 10(-3) M); forskolin (10(-5) M), cholera toxin (10 ng/ml) and 3-isobutyl-methylxanthine (10(-5) M). Stimulation of protein kinase C with phorbol 12-myristate 13-acetate (10(-7) M) had no significant effect on DNA synthesis. Furthermore, DNA synthesis was not affected by testosterone (10(-10) to 10(-9) M) or progesterone (10(-9) to 10(-8) M). Accumulation of progesterone was co-operatively stimulated by LH and IGF-I. These results suggest that LH-induced inhibition of T-I proliferation and/or survival is mediated via the cAMP system. IGF-I may be viewed as a co-gonadotrophin with respect to steroidogenesis but not with respect to proliferation/survival. The divergence of the effects on proliferation/survival versus steroidogenesis underscores the complexity of the interactions between LH and IGF-I signalling pathways.