Adrenal Suppression with Aminoglutethimide. II. Differential Effects of Aminoglutethimide on Plasma Androstenedione and Estrogen Levels12

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Abstract
A regimen of adrenal suppression using aminoglutethimide in combination with hydrocortisone was developed as treatment of women with metastatic breast carcinoma. In order to determine the degree of suppression and the site or sites of estrogen blockade, we measured androstenedione, estrone, and estradiol plasma levels in castrate and non-castrate postmenopausal women with metastatic breast carcinoma during this therapy. During the initial 2 weeks of treatment, plasma androstenedione levels increased significantly from 570 ± 70 to 950 ± 160 pg/ml (P < .05) and then gradually fell to a nadir of 230 ± 50 pg/ml (P < .001) during chronic therapy with 40 mg of hydrocortisone and 1000 mg of aminoglutethimide. In contrast, estrone levels decreased abruptly with the initiation of therapy from basal levels of 43.7 ±11.2 pg/ml to 13.5 ± 1.6 pg/ml (P < .02) and during chronic drug administration to 9.3 ± 1.0 pg/ml (P < .001). Similarly, estradiol fell from 17.5 ± 4.1 to 5.5 ± 1.0 pg/ml (P < .01) initially and to 5.0 ± 0.5 pg/ml (P < .01) over a 6-12 month period. The dichotomy between high androstenedione and suppressed estrone early in therapy suggested that aminoglutethimide might block the extra-adrenal conversion of androstenedione to estrone. Continued production of various steroids by the postmenopausal ovary could influence the degree of estrogen suppression in individual patients. To examine this possibility, a subgroup of 5 women with spontaneous menopause was compared to 8 surgically castrate postmenopausal patients. Although the basal levels of estrone and estradiol were slightly higher in spontaneously postmenopausal women, the concentrations of these estrogens were not statistically significantly different from those in castrate women with breast carcinoma or in control groups of normal postmenopausal women or women with endometrial carcinoma. Basal androstenedione levels were similar in all groups. However, during each phase of aminoglutethimide therapy in women with breast carcinoma, androstenedione concentrations appeared to be higher in patients with postmenopausal ovaries than in surgically castrate subjects. These observations suggested thai the postmenopausal ovaries contributed significantly to androstenedione secretion in patients receiving aminoglutethimide. On the other hand, estrone and estradiol were suppressed similarly during medical adrenalectomy in postmenopausal women with oi without ovaries. In these two patient groups, nadii levels of estrone were 9.4 ± 2.3 pg/ml and 9.3 ± 1.1 pg/ml and of estradiol, 4.0 ±1.3 and 5.3 ± 0.6 pg/ml. respectively. These observations demonstrate that estrogen production is inhibited before total adrenal blockade is accomplished during the initial phases ol therapy and suggest that aminoglutethimide might block the peripheral conversion of androstenedione to estrone. This factor may provide a margin of safety in patients who lack rigid compliance to the established drug regimen. Our data also indicate that the ovaries in postmenopausal women are capable of contributing to androstenedione production.