High dose ketoconazole therapy and adrenal and testicular function in humans

Allan Pont, John R. Graybill, Philip C. Craven, John N. Galgiani, William E. Dismukes, Richard E. Reitz, David A. Stevens

Research output: Contribution to journalArticle

Abstract

Ketoconazole is an oral antifungal agent with reported efficacy against a variety of pathogenic fungi in humans. The development of gynecomastia in some patients taking the drug has prompted investigation of the effect of ketoconazole on steroid secretion. The present authors have studied testicular and adrenal function in patients receiving high dosages of the drug. Their results are given in this report. Six of nine patients studied has sperm counts below normal for the laboratory performing the test, and four counts were below the lowest standard used by any laboratory. Two patients were azospermic. Ketoconazole therapy was discontinued in one patient when azospermia was noted. Three weeks later, his count was 81,000 per ml. Three months later, it was 3.5 million per ml and rose steadily to 20 million per ml at 9 months. Because of his coccidoidal disease, therapy was reinstituted at 800 mg per day. Seven months later, his sperm count was again zero. All of the patients with decreased sperm counts had been receiving high dosages (800 mg or more/day) of ketoconazole for more than 4 months. Of three patients with normal sperm counts, two had been receiving the high dosage for less than 3 months. The third had low serum ketoconazole concentrations, presumably because of poor absorption, although altered disposition could not be ruled out. Five of 24 patients studied had easily detectable gynecomastia during therapy that had not been noted before treatment. This incidence is higher than that reported for lower ketoconazole doses. Five of the 24 patients reported impotence, and an additional three of the 24 noted decreased libido that reportedly had developed after initiation of ketoconazole therapy. Specific physiological tests for impotence were not performed. Sixty-five determinations for testosterone levels were made. Twenty-five serum testosterone concentrations were determined after an 800-mg dose. The concentration was below 300 ng/dl in six of eight patients 4 hours after the dose, in seven of seven patients at 8 hours, and in three of 10 patients 24 hours after the dose. The latter three had testosterone values of 56, 20, and 187 ng/dl at that time. Ketoconazole induced a parallel diminution in both total and unbound testosterone concentrations in five patients tested before and after 800 or 1200-mg doses. Four hours after the dose, the mean (±SD) total testosterone level was 37 ± 14 per cent of baseline, and the free testosterone level was 35 ± 15 per cent of baseline. The effect of high-dose ketoconazole on the cortisol response to corticotropin was observed in 20 patients. All had normal test results before initiation of therapy or 36 hours after the discontinuation of therapy. Two to 8 hours after an 800 or 1200-mg dose, however, there was a sharp diminution of cortisol response in most patients. Corticotropin increased serum cortisol concentration less than 7μg/dl in 10 of 14 studies in the 800-mg group and in nine of 11 in the 1200-mg group. Ketoconazole phar-macokinetic data were available in one of the two patients with cortisol increases of more than 7μg/dl in the latter group, and this patient appeared to have altered pharma-cokinetics also. In two separate studies after an 800-mg dose, his peak serum concentrations were 1.15 and 2.15 mg per liter. By contrast, in 34 patients studied after an 800-mg dose, the peak concentration was 9.7 +0.8 mg per liter. Although the baseline cortisol concentration was in the normal range in the 1200-mg group, even this value was significantly (P < 0.02) lower than that of the patient group studied when they were not receiving the drug. The duration of ketoconazole therapy in the patients with corticotropin studies was less than 1 week to 18 months. There was no apparent correlation between duration of therapy and adrenal responsiveness to corticotropin. An 800-mg dose of ketoconazole reduced urinary free cortisol values to approximately 50 per cent in the patients tested (65 to 33 μg per day, 36 to 13 μg per day, and 176 to 87 μg per day). Monitoring of the 111 patients in the study did not disclose symptoms, signs, or other laboratory findings suggestive of hypoadrenalism, e.g., there was no evidence of hypotension or pigment changes, and serum electrolytes were unaltered by ketoconazole therapy.

Original languageEnglish (US)
Pages (from-to)374-375
Number of pages2
JournalObstetrical and Gynecological Survey
Volume40
Issue number6
DOIs
StatePublished - Jun 1985

ASJC Scopus subject areas

  • Obstetrics and Gynecology

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    Pont, A., Graybill, J. R., Craven, P. C., Galgiani, J. N., Dismukes, W. E., Reitz, R. E., & Stevens, D. A. (1985). High dose ketoconazole therapy and adrenal and testicular function in humans. Obstetrical and Gynecological Survey, 40(6), 374-375. https://doi.org/10.1097/00006254-198506000-00019