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.