First generation aromatase inhibitors--aminoglutethimide and testololactone

Aminoglutethimide and testololactone may be considered the first generation Aromatase inhibitors for the endocrine treatment of breast carcinoma. Initially, both of these agents were designed and used clinically based on different concepts of their mechanisms of action. Only later were they both demonstrated to inhibit Aromatase. Curiously, testololactone was earlier and more widely used than aminoglutethimide in treating advanced breast carcinoma. The discovery of the peripheral Aromatase inhibition as the proper mechanism of action was delayed for both the agents but was relatively more timely for aminoglutethimide. Paradoxically, the clinical use of testololactone has become already obsolete since its true mechanism of action was discovered. Aminoglutethimide is still the most widely used Aromatase Inhibitor in treating advanced breast carcinoma. Due to the initial misinterpretation of its mechanism of action, aminoglutethimide was used for a long time at a relative high daily dose, always combined with hydrocortisone. Subsequent phase II and then randomized phase III studies demonstrated an equivalent efficacy using half (500 mg) of the previous conventional daily dose (1000 mg), with hydrocortisone. Very recently, a randomized clinical trial demonstrated that administering this lower dose without hydrocortisone did not significantly decrease the clinical efficacy. By decreasing the dose of aminoglutethimide, the incidence of side effects has been reduced. So, the last paradoxical aspect of the aminoglutethimide story is that this agent seemed initially very toxic but finally, with the new schedules, shows a very low toxicity profile, especially after the first few weeks of treatment.