Epidermal growth factor receptor signaling is required for normal ovarian steroidogenesis and oocyte maturation

The midcycle luteinizing hormone (LH) surge triggers several tightly linked ovarian processes, including steroiclogenesis, oocyte maturation, and ovulation. We designed studies to determine whether epidermal growth factor receptor (EGFR)-mediated signaling might serve as a common regulator of these activities. Our results showed that EGF promoted steroiclogenesis in two different in vitro models of oocyte-granulosa cell complexes. Inhibition of the EGFR kinase prevented EGF-induced steroiclogenesis in these in vitro systems and blocked LH-induced steroiclogenesis in intact follicles primed with pregnant mare serum gonadotropin. Similarly, inhibition of the EGFR kinase attenuated LH-induced steroiclogenesis in MA-10 Leydig cells. Together, these results indicate that EGFR signaling is critical for normal gonadotropin-induced steroiclogenesis in both male and female gonads. Interestingly, inhibition of metalloproteinase-mediated cleavage of membrane-bound EGF moieties abrogated LH-induced steroiclogenesis in ovarian follicles but not MA-10 cells, suggesting that LH receptor signaling activates the EGFR by different mechanisms in these two models. Finally, steroids promoted oocyte maturation in several ovarian follicle models, doing so by signaling through classical steroid receptors. We present a model whereby steroid production may serve as one of many integrated signals triggered by EGFR signaling to promote oocyte maturation in gonadotropin-stimulated follicles.