Aromatase is a cytochrome P-450 enzyme responsible for converting androgens to estrogens. The biosynthesis of estrogens requires three hydroxylation steps that ultimately convert androstenedione to estrone or testosterone to estradiol. 1 Aromatase is expressed in many organs, including the breast, ovary, placenta, hypothalamus, liver, muscle, adipose, and endometrium. 1 Aromatase inhibitors (AIs) interfere with aromatase activity by either reversible or irreversible inhibition. AIs are most commonly recognized as a first-line endocrine therapy for postmenopausal women with breast cancer, or as a sequential treatment for those postmenopausal breast cancer patients who have failed tamoxifen. More recently, given the therapeutic potential of AIs in clinical gynecology, their use has been proposed for other indications such as ovulation induction or treatment of endometriosis.AIs have two different mechanisms of action. Some AIs are steroidal and bind covalently to aromatase, caus-ing permanent inactivation of the enzyme. Synthesis of new aromatase enzyme is required to overcome this type of inhibition. Other AIs (which are nonsteroidal) bind competitively to the activating site of the aromatase enzyme, thereby blocking the conversion of androgen to estrogen in the last critical step of estrogen biosynthesis. 2
Classification of Aromatase InhibitorsAIs are categorized into first-, second-, and third-generation formulations reflecting their temporal clinical introduction. First-generation AIs, such as aminoglutethimide, were discovered more than 30 years ago and were developed as a possible treatment for metastatic breast cancer. However, these first-generation AIs were potent inhibitors of multiple P-450 enzymes in addition to aromatase and interfered with synthesis of cortisol, aldosterone and thyroid hormone as well. 1 The nonspecific actions associated with this drug caused a broad range of negative side effects such as lethargy, rash, nausea, and depression. 3 The clinical utility of aminoglutethimide was limited by these side effects, and the resulting commercial failure prompted development of second-generation AIs.The second-generation AIs, fadrozole and formestane (Lentaron; Novartis), had improved side-effect profiles. However, neither of these medications was better than tamoxifen, which had already been established as a mainstay in treatment of patients with advanced breast cancer, 4,5 and further commercial development of these second-generation AIs was halted.Current third-generation AIs are represented by anastrozole (Arimidex, Astra Zeneca); letrozole (Femara, Novartis); and exemestane (Aromasin, Pfizer). Anastrozole is the most widely studied of these third-generation AIs, and it was the first AI to be approved in the United States for the treatment of advanced breast cancer in postmenopausal women.Learning Objectives: After reading this issue, the participant should be able to: 1. Describe the action of aromatase in estrogen production.
Explain how to identify gynecologic patients who may benefit fro...