Aromatase: Update and New Roles in Reproductive Disease

Serdar E. Bulun, M.D.

Over the past decade, publications on humans with mutations in estrogen receptor alpha (ERα) and aromatase P450 (P450arom) genes, and knockout mice with disrupted genes that encode ERα, ERβ, or P450arom revolutionized our understanding of the roles of estrogen in human physiology and disease. A single gene encodes P450arom, which is the essential and specific component of the aromatase enzyme complex responsible for estrogen formation in several human tissues. The product of this enzyme estrogen acts as a masterswitch and regulates a large variety of genes in various human tissues. Inhibition of the aromatase enzyme or disruption of the P450arom gene is sufficient to stop biosynthesis of estrogen and block ER-dependent or ER-independent actions of estrogen. The first three articles discuss the structure of the P450arom gene, its tissue-specific regulation by alternatively used promoters and signaling pathways, and the consequences of aromatase deficiency in humans and mice.

The remaining four articles are devoted to the established and emerging indications of aromatase inhibitors. Aromatase inhibitors have been used to treat breast caner since the 1970s. The recent introduction of specific and effective inhibitors, the so-called third-generation inhibitors, in the 1990s significantly improved the hormonal treatment of breast cancer and permitted the application of aromatase inhibition to treat new disorders. Most of these new indications are related to gynecology. These last four articles discuss the use of aromatase inhibitors to treat breast cancer, endometriosis, and uterine leiomyomas, and for ovulation induction.