The effect of Ketoconazole on pituitary ACTH secretion

Abstract

Ketoconazole is an imidazole derivative which is an inhibitor of adrenal steroidgenesis and is used to inhibit cortisol production in the treatment of Cushing's disease of any etiology. With a decrease in cortisol and loss of negative feedback, one expects a compensatory rise in ACTH. This was not found in several clinical studies which suggested that ketoconazole might have a direct effect on the pituitary gland. Measurements of ACTH in animals and humans while on ketoconazole have given disparate results. In all studies, there was the confounding variable of changing levels of plasma cortisol. To evaluate the effect of ketoconazole on ACTH independent of changes in plasma cortisol, we studied 6 patients with no adrenal function. Four patients had primary Addison's disease and two patients had bilateral adrenalectomy for treatment of Cushing's disease. Serial ACTH levels (IRMA assay with Nichol's kit) were measured over an 8 hour period after a single dose of ketoconazole (400mg) or placebo given at 8 AM in a double-blinded trial. Growth hormone levels were measured to insure specificity of the drug for ACTH and there was no difference of growth hormone in the two studies (p = 0.14). The usual dose of hydrocortisone replacement was given at 5 PM the day before the study but withheld the morning of the study. All patients had measurable ACTH levels with an expected wide range in baseline values among patients (12 to 399 pg/ml). No bias of increased or decreased baseline levels was detected during treatment compared to control studies. The data were analyzed by paired "t" test of area under the curve and analysis of variance for repeated measures. Ketoconazole did not significantly increase or decrease ACTH levels when compared to placebo (p = 0.93 and p = 0.48, respectively). No toxic effects were noted. In this study, there was no evidence that ketoconazole has a direct action on the pituitary gland in humans. We therefor conclude that ACTH levels can be reliably interpreted with respect to cortisol in patients on ketoconazole.