Role of estradiol metabolism in asthma

Emerging data suggest a significant involvement of estrogens in the development and clinical course of asthma. Yet, little is known regarding the effects of 17β-estradiol (estradiol; E2) metabolism in asthma. E2 is metabolized by 2-hydroxylation and subsequent O-methylation to 2-methoxyestradiol (2ME) and by 16-hydroxylation to estriol (16α-hydroxyestradiol; 16HE2) and to 16α-estrone (16HE1). 2ME is a non-estrogenic metabolite which exhibits anti-mitogenic, anti-inflammatory and anti-angiogenic effects, whereas 16HE2 and 16HE1 are estrogenic metabolites with mitogenic, pro-inflammatory, and angiogenic properties.We hypothesize that estradiol metabolites from the 2-hydroxylation and 16-hydroxylation pathways have opposing effects in asthma, and that the net effect of E2 in asthma reflects the balance of these two metabolic pathways. In this regard, we propose that 2ME and E2/16HE1 divergently affect mitogenic and synthetic activity of cells involved in airway inflammation, angiogenesis and remodeling. Finally, we suggest that an “anti-cancer approach”, i.e., the use of anti-inflammatory, anti-angiogenic and anti-mitogenic agents such as 2ME, may have therapeutic effects in asthma.