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History of Aromatase: Saga of an Important Biological Mediator and Therapeutic Target

Division of Endocrinology and Metabolism (R.J.S.), University of Virginia, Charlottesville, Virginia 22908; Emeritus Investigator (H.B.), Fulton, Maryland 20759; Prince Henry’s Institute of Medical Research (E.R.S.), Melbourne 3168, Australia; Department of Obstetrics and Gynecology (P.K.S.), University of California at San Francisco, San Francisco, California 94143; and Department of Pharmacology (A.B.), School of Medicine, University of Maryland, Baltimore, Maryland 21201

Correspondence: Address all correspondence and requests for reprints to: Dr. Richard J. Santen, University of Virginia Health System, Division of Endocrinology, P.O. Box 801416, Charlottesville, Virginia 22908. E-mail: RJS5Y{at}virginia.edu.

Aromatase is the enzyme that catalyzes the conversion of androgens to estrogens. Initial studies of its enzymatic activity and function took place in an environment focused on estrogen as a component of the birth control pill. At an early stage, investigators recognized that inhibition of this enzyme could have major practical applications for treatment of hormone-dependent breast cancer, alterations of ovarian and endometrial function, and treatment of benign disorders such as gynecomastia. Two general approaches ultimately led to the development of potent and selective aromatase inhibitors. One targeted the enzyme using analogs of natural steroidal substrates to work out the relationships between structure and function. The other approach initially sought to block adrenal function as a treatment for breast cancer but led to the serendipitous finding that a nonsteroidal P450 steroidogenesis inhibitor, aminoglutethimide, served as a potent but nonselective aromatase inhibitor. Proof of the therapeutic concept of aromatase inhibition involved a variety of studies with aminoglutethimide and the selective steroidal inhibitor, formestane. The requirement for even more potent and selective inhibitors led to intensive molecular studies to identify the structure of aromatase, to development of high-sensitivity estrogen assays, and to "mega" clinical trials of the third-generation aromatase inhibitors, letrozole, anastrozole, and exemestane, which are now in clinical use in breast cancer. During these studies, unexpected findings led investigators to appreciate the important role of estrogens in males as well as in females and in multiple organs, particularly the bone and brain. These studies identified the important regulatory properties of aromatase acting in an autocrine, paracrine, intracrine, neurocrine, and juxtacrine fashion and the organ-specific enhancers and promoters controlling its transcription. The saga of these studies of aromatase and the ultimate utilization of inhibitors as highly effective treatments of breast cancer and for use in reproductive disorders serves as the basis for this first Endocrine Reviews history manuscript.