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

Area of Science:

• Endocrinology
• Pharmacology
• Reproductive Health

Background:

• Ketoconazole is an antifungal medication with known side effects.
• Gynecomastia, or breast enlargement in males, is a potential side effect linked to hormonal imbalances.

Purpose of the Study:

• To investigate the specific effects of ketoconazole on serum testosterone and estradiol levels in men.
• To determine if ketoconazole alters the estradiol-testosterone ratio, potentially explaining its link to gynecomastia.

Main Methods:

• Administered a 600-mg dose of ketoconazole to four male volunteers.
• Measured serum concentrations of testosterone and estradiol, including bound and free percentages.
• Analyzed hormonal changes in five male patients undergoing long-term high-dose ketoconazole therapy.

Main Results:

• Ketoconazole significantly depressed serum testosterone levels in volunteers.
• Serum estradiol levels were less affected, with no significant alteration in bound/free percentages.
• The estradiol-testosterone ratio was significantly elevated, both in total and free hormone concentrations.

Conclusions:

• Ketoconazole selectively inhibits androgen synthesis more than estrogen synthesis.
• The persistent elevation of the estradiol-testosterone ratio induced by ketoconazole likely explains the occurrence of gynecomastia.
• This hormonal shift provides a mechanistic explanation for a known clinical side effect of ketoconazole.