Adrenal Suppression with Aminoglutethimide. I. Differential Effects of Aminoglutethimide on Glucocorticoid Metabolism as a Rationale for Use of Hydrocortisone12

Abstract

The morbidity resulting from surgical adrenalectomy in patients with metastatic breast carcinoma has limited the use of this procedure to highly selected patients. Consequently, a chemical method of adrenal inhibition was developed which used aminoglutethimide to block cholesterol to pregnenolone conversion and dexamethasone as replacement glucocorticoid. This regimen effectively lowered urinary free cortisol excretion but was complicated by a drug interaction in which aminoglutethimide accelerated the metabolism of dexamethasone and reduced its bioavailability. Theoretically, replacement of dexamethasone with a glucocorticoid not subject to drug altered degradation would eliminate this drug interaction and simplify therapy. In order to determine whether hydrocortisone could be used, the metabolism and biological activity of this glucocorticoid was evaluated before and during aminoglutethimide administration. The plasma half-life, volume of distribution and metabolic clearance rate of hydrocortisone as determined by the single injection technique were not significantly altered by aminoglutethimide. The biopotency of hydrocortisone as reflected by its ability to suppress ACTH below basal levels was also retained during aminoglutethimide administration while that of dexamethasone was not. In order to evaluate the effectiveness of hydrocortisone in the aminoglutethimide regimen, a method was required for monitoring adrenal cortical function which was independent of glucocorticoid secretion. Plasma dehydroepiandrosterone-sulfate (DHA-S) levels were highly correlated (r – 0.79, P < .001) with urinary free cortisol excretion under basal and suppressed conditions. Plasma DHA-S was therefore used to establish the adrenal inhibiting effects of various doses of dexamethasone and hydrocortisone in patients receiving aminoglutethimide. A fixed dosage combination of 40 mg of hydrocortisone and 1000 mg of aminoglutethimide appeared to produce maximum suppression of DHA-S to levels 93% lower than basal. Negative nitrogen balance was not observed in patients receiving 20-60 mg of hydrocortisone along with aminoglutethimide, indicating a lack of major pharmacologic side effects of the administered glucocorticoid. A regimen for adrenal suppression using hydrocortisone and aminoglutethimide was developed which is simple and effective and should allow wide applicability without extensive endocrine monitoring in patients with metastatic breast carcinoma.