Endocrine effects of low dose aminoglutethimide alone in advanced postmenopausal breast cancer

The site of action of aminoglutethimide (AG) has been investigated. An initial study was performed on 10 postmenopausal patients with advanced breast cancer who had taken 1000 mg AG per day and 20 mg hydrocortisone (HC) twice daily (b.d.) for greater than 3 months. There was a 15.5 +/- 5.6 s.e.-fold rise in 17-OH progesterone and a 4.9 +/- 0.9 s.e.-fold rise in 4 delta androstenedione but no rise in cortisol or oestrone 30 min after short Synacthen tests. These results suggested that peripheral aromatisation was a more important site of AG action than adrenal desmolase, and that adrenal 11 beta hydroxylase was inhibited. Since aromatase is more sensitive than desmolase to AG in vitro, lower doses of AG alone (i.e. without HC) were assessed for endocrine effects in 13 further post-menopausal women with advanced breast cancer. All of these patients tolerated 125 mg AG b.d., but 3 could not tolerate the conventional maximum dose. Oestrone levels on 125 mg AG b.d. were suppressed below pretreatment levels and were not significantly different from those on 500 mg AG b.d. alone, or with the addition of HC. Oestradiol levels were suppressed to a similar extent. Dehydroepiandrosterone sulphate (DHA-S) levels were not suppressed by AG alone, but fell on addition of HC. The endocrine results show low dose AG alone is an effective and well tolerated inhibitor of the peripheral production of oestrogens in postmenopausal patients. Therapeutic trials are now possible. DHA-S is not a marker of AG effect.