Pharmacologic suppression of estrogens with aminoglutethimide as treatment of advanced breast carcinoma - Mechanistic, hormonal, and clinical studies

Recent studies suggest that estrogens are the predominant hormones required for the growth of hormonedependent breast cancers in women. Traditional methods of lowering estrogens as treatment of breast cancer involve surgical removal of the ovaries, adrenals, or pituitary. Newer investigative strategies utilize blockade of estrogen action with antiestrogens or inhibition of estrogen synthesis. As reviewed previously, a regimen for pharmacologic suppression of estrogen production was developed which utilizes the aromatase/steroidogenesis inhibitor aminoglutethimide (AG) and replacement hydrocortisone (HC). The current paper updates recent mechanistic, clinical, and hormonal data regarding AG. The preservation of plasma androstenedione levels concomitant with marked estrone and estradiol suppression suggests that AG lowers estrogen production predominantly by blocking aromatization. The mechanism for sustained androstenedione production in the face of suppressed ketosteroids, glucocorticoids, and mineralocorticoids during AG administration was evaluated in dogs fitted with arteriovenous adrenal cannulae. Inhibition of the adrenal secretion of androstenedione with preservation of peripheral plasma levels of this steroid suggests stimulation of extra-adrenal 3 β-ol-dehydrogenase, Δ⁵-Δ⁴-isomerase activity by AG. Clinical studies revealed a 32% objective response rate to AG/HC in unselected patients and a 52% response in women with estrogen receptor positive tumors. Randomized trials indicated similar response rates to AG/HC vs hypophysectomy (AG/HC 47% vs Hypox 21%, p = NS), surgical adrenalectomy (AG/HC 52% vs surgical adrenalectomy 43%, p = NS) and antiestrogen therapy (AG/HC 36% vs tamoxifen 38%, p = NS). Cross-over data revealed that 50% of 94 patients initially responding to tamoxifen later experienced an objective regression to AG/HC. Only 25% of 93 tamoxifen nonresponders benefited later from AG/HC. Trends indicate that bone metastases may respond better to AG/HC (33%) than to tamoxifen (15%). Use of a computer-based data matrix allowed determination of whether patients escape from AG/HC induced estrogen and androgen suppression at the time of disease relapse. No trends towards escape from estrogen inhibition were apparent. However, in the objective responders to AG/HC, the weak androgens dehydroepiandrosterone-sulfate (DHEA-S) and androstenedione appeared to increase prior to disease relapse. DHEA-S but not androstenedione levels remained lower in the objective responders than in nonresponders at all phases of AG/HC therapy. Thus, the estrogens, but not androgens, remain constant during all phases of AG/HC treatment.