Gonadotropin releasing hormone analogue therapy alters signal transduction pathways involving mitogen-activated protein and focal adhesion kinases in leiomyoma

Abstract

Because gonadotropin releasing hormone analogue (GnRHa) therapy often causes leiomyoma regression, in part through alteration of growth factor and receptor expression, we determined whether GnRHa therapy alters the expression of extracellular signal-regulated kinase (ERK) and focal adhesion kinase (FAK), which are linked to intracellular signaling pathways activated by ovarian steroids, growth factors, and adhesion molecules. Leiomyoma and matched unaffected myometrium were collected from women who received GnRHa therapy (n = 5) and untreated women (n = 10). We determined the expression of ERK1, ERK2, FAK, phosphorylated ERK (pERK1/2), and pFAK using Western blotting and immunohistochemical analysis. Leiomyoma and myometrium expressed ERK1 (44 kD), ERK2 (42 kD), and FAK (125 kD) at variable levels with increased ERK2, pERK, and FAK expression in leiomyoma. We found that GnRHa therapy resulted in a noticeable decrease in ERK2 and FAK, with significant reduction in pERK1/2 and low or undetectable levels of pFAK in both leiomyoma and myometrium compared with the untreated group (P <.05). Immunohistochemically ERK1, ERK2, FAK, pERK1/2, and pFAK were localized in smooth muscle cells and connective tissue fibroblasts in GnRHa-treated and untreated leiomyoma and myometrium, with considerable reduction in their intensity as indicated by HScore in GnRHa-treated tissues. The data provide further evidence that leiomyoma regression induced by GnRHa is mediated in part through a mechanism involving suppression of signal transduction pathways involving growth factors or ovarian steroid and adhesion molecules.