Extraglandular aromatization of androstenedione (Δ4-A) to estrone (E1) provides the primary source of estrogen production in spontaneously postmenopausal or surgically castrate women. Estrogens produced by this enzymatic reaction in peripheral tissues can be biologically important, particularly in women with metastatic breast carcinoma. In such patients, an aromatase inhibitor would have potential usefulness clinically. In vitro studies demonstrated that aminoglutethimide (AG), a drug previously used as an adrenal steroidogenesis inhibitor, is also a potent aromatase blocker. A similar in vivo effect of AG was suggested by clinical observations of suppressed plasma E1 without concomitant reductions in Δ4-A concentrations in postmenopausal women given this drug. Based upon these considerations, we examined the in vivo effects of AG on the rate of aromatization of Δ4-A to E1 by direct radioisotopic kinetic methods. AG inhibited the fractional conversion of Δ4-A to E1 in blood from 1.65 ± 0.28% (SE) before treatment to 0.04 ± 0.01% during AG therapy (P < 0.01). In two of the same patients, the [p] values measured in urine fell similarly from 1.91% and 1.08% before therapy to 0.1% and 0.08%, respectively, during AG administration. These data demonstrated that AG blocks aromatization by 95-98%. This effect could explain the nonparallel suppression of Δ4-A and E1 observed in previous studies. However, two other possibilities to explain this phenomenon required exclusion: a reduction in the metabolic clearance rate of Δ4-A or an enhanced metabolism of E1. The metabolic clearance rate of Δ4-A, determined in five patients before AG therapy, was 1572 ± 241 (SE) liters/24 h, and during treatment with AG was 1638 ± 234 liters/24 h (P = NS). The rate of E, metabolism was not altered uniformly in the five patients studied before and during therapy. Consequently, inhibition of aromatization provides the major explanation for the greater suppression of E1 than Δ4-A observed previously. AG would be expected to lower plasma E1 and estradiol (E2) to negligible levels on the basis of its potent aromatase inhibitory properties. To determine the extent of drug blockade, the degree of estrogen suppression produced by AG may be compared to the lowering accomplished by surgical adrenalectomy in postmenopausal women. Mean levels of E1 and E2 fell to similar concentrations in both groups as a result of treatment: after adrenalectomy, E1 levels were 12.0 ± 1.4 pg/ml (n = 12) and during AG therapy, E1 levels were 12.3 ± 1.1 pg/ml (n = 41). Similarly, E2 levels were 5.8 ± 0.55 pg/ml in the surgically treated patients and 5.6 ± 0.65 pg/ml (n = 12) in women receiving AG (n = 42; P = NS). As a result of its dual site of action upon both adrenal and extraadrenal tissues, AG provides a unique pharmacological agent to produce estrogen suppression in patients with metastatic breast carcinoma.
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Clinical Biochemistry
- Biochemistry, medical