Adrenal Suppression with Aminoglutethimide. III. Comparison of Plasma Δ4- and Δ5-Steroids in Postmenopausal Women Treated for Breast Carcinoma*

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Abstract
A regimen or aminoglutethimide in combination with replacement glucocorticoid has been used to suppress adrenal steroidogenesis in postmenopausal women with metastatic breast carcinoma. During acute and chronic treatment with aminoglutethimide, the levels of the Δ4-steroids [progesterone (P), 17α-hydroxyprogesterone (17-Δ4-P), and androstenedione (Δ4-A)] and the Δ5-steroids [dehydroepiandrosterone (DHEA), dehydroepiandrosterone- sulfate (DHEA-S), and 17α-hydroxypregnenolone (17-Δ5-P)] were determined. In the total group of women, the plasma levels of P and Δ4-A increased 2- to 3-fold (P < 0.05) while 17-Δ4-P rose 10-fold (P < 0.01) from basal concentrations of 0.65 ± 0.07 to 6.48 ± 1.46 ng/ml during the initial 2 weeks of therapy with aminoglutethimide (AG) and dexamethasone. These three steroids then fell to basal levels during chronic treatment (P and 17-Δ4-P) or were suppressed (Δ4-A; P < 0.001). In contrast, the levels of Δ5-steroids (17-Δ5-P, DHEA, and DHEA-S) were reduced 3- to 5-fold during the initial 2 weeks of therapy and remained suppressed throughout. The relative levels of certain Δ5-and Δ4-steroid pairs were then examined. The ratio of 17-Δ5-P to 17-Δ4-P decreased from baseline values of 2.15 ± 0.35 to 0.38 ± 0.21 ng/ml (P < .02) with the initiation of therapy and remained low thereafter. A similar pattern for the ratios between DHEA and Δ4-A, and DHEA-S and Δ4-A was observed. This may indicate that the regimen of AG treatment utilized may facilitate the activity of the 3β-ol-dehydrogenase, Δ5- to Δ4-isomerase, and accelerate the conversion of Δ5- to Δ4-steroids. The patterns of suppression of the plasma Δ4- and Δ5-steroids in oophorectomized and spontaneously postmenopausal patients with intact ovaries were analyzed separately. The plasma levels of progesterone were higher during the first 2 weeks of therapy in surgically castrate women than in spontaneously postmenopausal women (0.72 ± 0.25 vs. 0.47 ± 0.20 ng/ml). A similar pattern was observed for 17-Δ4-P, DHEA, and DHEAS, indicating that the adrenals might contribute to this increase. In contrast, during chronic treatment, the levels of all steroids were lower in surgically castrate women than in those with intact ovaries. This suggested residual ovarian steroid during AG administration.