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Diverse Effects of Tyrosine Kinase Inhibitors on Follicle-Stimulating Hormone-Stimulated Estradiol and Progesterone Production from Rat Granulosa Cells in Serum-Containing Medium and Serum-Free Medium Containing Epidermal Growth Factor

^a Reproductive Medicine, The R.W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey 08869

Epidermal growth factor (EGF) has been shown to influence FSH-stimulated estradiol (E₂) and progesterone (P₄) production from granulosa cells. RG 50810, a tyrosine kinase inhibitor (TKI), has previously been shown to inhibit the EGF-receptor tyrosine kinase. RG 50810 has also been shown to inhibit FSH-stimulated increases in mRNA for steroidogenic enzymes, implying a functional role of tyrosine kinases in FSH action in granulosa cells. However, inhibition of FSH-stimulated steroidogenesis by TKIs has not been evaluated in connection with the effects of EGF in granulosa cells. In the present studies, FSH-stimulated E₂ production was inhibited similarly by inhibitors of protein kinase A (H-89) and protein kinase C (calphostin C) and by TKIs, and none of the inhibitors were capable of reversing the EGF-induced inhibition of FSH-stimulated E₂ production. FSH-stimulated P₄ production was enhanced dramatically in serum-containing medium with concentrations of TKI that were near previously reported IC₅₀s. The enhancing effect of TKIs was less evident in serum-free medium. Addition of EGF to serum-free medium enhanced FSH-stimulated P₄ production, and the TKIs reversed EGF-enhanced P₄ production, but in a manner similar to that of protein kinase A inhibitor H-89. Compared to results in serum-free medium, the potency of RG 50810 and genistein to inhibit the effects of EGF on P₄ production was 3- to 8-fold greater relative to H-89. These studies have demonstrated that TKIs RG 50810 and genistein selectively inhibit the effects of EGF on FSH-stimulated P₄ production in granulosa cell cultures. In contrast, these studies have demonstrated nonselective inhibition of FSH-stimulated E₂ and P₄ production by TKIs in serum-free medium, in which it is not clear which enzyme system is affected by the compounds tested.

¹ Correspondence: Stephen Palmer, The RW Johnson Pharmaceutical Research Institute, 1000 Rt 202, PO Box 300, Raritan, NJ 08869. FAX: 908 526 6469; spalmer{at}prius.jnj.com

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