Characterization of LH-EGF Receptor Crosstalk During Steroidogenesis in the Ovary.

Recent evidence shows that cross talk between G protein-coupled receptors and EGF receptors is critical for steroidogenesis in all three major steroid-producing tissues. We recently characterized the intracellular signals regulating LH-induced steroid production in Leydig cells, demonstrating a linear pathway whereby LH receptor activation stimulates cAMP production and PKA signaling. PKA then triggers EGF receptor activation, which activates the MAPK cascade to promote StAR phosphorylation and translocation to the mitochondria. Once active and in the mitochondria, StAR promotes steroid production. Interesting, LH-mediated trans-activation of the EGF receptor occurs via both intracellular, ligand-independent signaling, and extracellular, ligand-dependent activation that requires MMP-mediated release of membrane-bound EGF receptor ligands. However, only intracellular signaling is required for LH-induced steroid production. Furthermore, the LH-EGF receptor pathway appears to be important only for early steroidogenesis in Leydig cells, as LH-induced steroid production beyond 60 minutes no longer requires EGF receptor and MAPK signaling. Here we characterize the LH-induced signals that regulate steoridogenesis in the ovary. We demonstrate that, similar to Leydig cells, activation of the EGF receptor is important for gonadotropin-induced steroid production in the ovary. Furthermore, as in Leydig cells, trans-activation of the EGF receptor is mediated by cAMP and PKA signaling. However, unlike in the testes, steroidogenesis in the ovary requires extracellular ligand-dependent activation of the EGF receptor, as inhibition of MMP-mediated release of EGF receptor ligands abrogates LH-induced steroid production. This result is consistent with the concept that paracrine signaling between outer theca/mural granulosa cells expressing LH receptors and the inner cumulus granulosa cells lacking LH receptors is required for steroid production. Furthermore, unlike in Leydig cells, EGF receptor and MAPK signaling are necessary for both short and long term gonadotropin-induced steroid production in the ovary, again emphasizing the importance of chronic paracrine signaling for steroidogenesis in ovarian follicles. Finally, in vivo studies demonstrate the requirement of EGF receptor signaling in regulating steroidogenesis, as serum progesterone levels are significantly reduced in female mice injected with EGF receptor inhibitors. These findings demonstrate the physiologic importance MMP-mediated LH/EGF receptor cross talk in the ovary, and suggest potential treatment targets for women with diseases of excess ovarian steroid production such as polycystic ovarian syndrome (PCOS).

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