Membrane receptor cross talk in steroidogenesis: recent insights and clinical implications

Steroid production by all three major steroidogenic tissues, the adrenals, testes, and ovaries, is critical for survival and reproduction of all animals. As such, the pathways that regulate steroidogenesis are conserved between these tissues, from the steroidogenic enzymes and cofactors that synthesize steroids, to the intracellular signaling molecules and Gαs-coupled receptors that mediate the activity of these enzymes. Recent work has revealed another important conserved pathway in steroidogenesis: crosstalk between membrane G protein-coupled receptors and membrane receptor tyrosine kinases. Luteinizing hormone (LH) or adrencorticotropic hormone (ACTH) binding to their cognate Gαs-coupled membrane receptors in the gonads and adrenals, respectively, leads to cAMP-induced trans-activation of the epidermal growth factor (EGF) receptor, followed by activation of Akt and Erk signaling. These kinase signals then activate Steroidogenic Acute Regulatory (StAR) protein, which promotes steroid production. Inhibition of this pathway abrogates both LH- and ACTH-induced steroidogenesis. Interestingly, LH-induced transactivation of the EGF receptor in the ovary uniquely requires matrix metalloproteinase-mediated release of EGF receptor ligands, and inhibition of these proteases blocks LH-induced steroidogenesis. Given this unique need for matrix metalloproteinases in ovarian steroidogenesis, MMP inhibition may prove to be useful when treating diseases of excess ovarian steroid production, such as polycystic ovary syndrome.