November 1984

High-Dose Ketoconazole Therapy and Adrenal and Testicular Function in Humans

Author Affiliations

From the Department of Medicine, Children's Hospital of San Francisco (Dr Pont); the National Institute of Allergy, Immunology and Infectious Diseases Mycoses Study Group, Bethesda, Md (Drs Graybill, Craven, Galgiani, Dismukes, and Stevens); the Departments of Medicine, San Antonio (Tex) Veterans Administration Medical Center and University of Texas Health Sciences Center, San Antonio (Drs Graybill and Craven); the Departments of Medicine, Tucson VA Medical Center and University of Arizona Health Sciences Center, Tucson (Dr Galgiani); the Department of Medicine, University of Alabama Medical School, Birmingham (Dr Dismukes); the Endocrine Metabolic Center, Oakland, Calif (Dr Reitz); the Departments of Medicine, Santa Clara Valley Medical Center, San Jose, Calif, and Stanford (Calif) University (Dr Stevens); and the Institute for Medical Research, San Jose (Dr Stevens).

Arch Intern Med. 1984;144(11):2150-2153. doi:10.1001/archinte.1984.04400020052007

• Ketoconazole, an oral antifungal, when given in conventional doses, transiently blocks testosterone synthesis and adrenal response to corticotropin. Higher therapeutic doses (ie, 800 to 1,200 mg/day), even once daily, caused more prolonged blockade. In some men, the serum testosterone concentrations were always subnormal. Bound and free testosterone values were equally diminished. Oligospermia and azospermia after prolonged therapy were noted. Impotence and decreased libido were found. Gynecomastia appeared more common than with lower doses. Depressed response to corticotropin was pronounced. Urine cortisol excretion was depressed. The blockade appeared related to the serum ketoconazole concentration. Instances of normal hormone levels or responsiveness were associated with low ketoconazole concentrations. The hormonal effects were generally unrelated to duration of therapy, although there may have been partial reversal with continued therapy. These effects appeared reversible with discontinuation of therapy. Patients receiving ketoconazole should be considered potentially unable to mount an adrenal stress response and may require testosterone supplementation.

(Arch Intern Med 1984;144:2150-2153)