Ketoconazole-induced increase in estradiol-testosterone ratio. Probable explanation for gynecomastia

Abstract

Ketoconazole, an antifungal drug, causes gynecomastia in some patients. It also inhibits androgen and glucocorticoid synthesis. In four volunteer male subjects, 600-mg doses of ketoconazole depressed serum testosterone concentrations markedly, but serum estradiol to a much lesser degree. The bound and free percentages of both hormones were not significantly altered. The net result was a significant elevation of the estradiol-testosterone ratio, expressed as either total circulating hormone or free hormone. In five male patients receiving long-term high-dose ketoconazole therapy, the testosterone concentrations fell, but the effect on estradiol was variable. In these patients the estradiol-testosterone ratio was persistently increased. Since gynecomastia appears to be the result of an elevated estradiol-testosterone ratio, the selective hormonal effect demonstrated may explain the side effect of gynecomastia after ketoconazole therapy.

In young men, a moderate inhibition of testosterone synthesis capacity is only partly compensated by increased activity of the pituitary and the hypothalamus

“…A larger decrease of E2 levels might have been expected knowing that plasma T is a major precursor for E2 synthesis. However, also in previous studies using KTZ, a mild or absent effect on E2 levels has been reported 29,30 . The E2 levels may have weakened the modulating effect of T on LH release in our subjects.…”

Adverse Drug Reactions to Systemic Antifungals Prevention and Management

“…In patients receiving higher dosages (800 to 1200 mg/day), the incidence approaches 21 % (Pont et al 1984). Pont et al (1985) have shown that ketoconazole, by virtue of its selective effect on testosterone synthesis, causes a significant rise in estradioltestosterone ratio in both male volunteers and men receiving long term therapy. This selective hormonal effect may explain the development of gynaecomastia.…”

Adverse Effects of Drugs Used in the Management of Opportunistic Infections Associated with HIV Infection

“…Ketoconazole is less specific in its action than some of the newer azoles. This accounts for some of its endocrine effects, including altered adrenal hormone and cholesterol metabolism, gynaecomastia (Pont et al 1985) and impotence. Nausea, vomiting, pruritus, abdominal pain, diarrhoea, headache, urticaria and dizziness have all been reported, but are all uncommon, with the exception of nausea (3 to 10%) [Van Tyle 1984].…”