therapy in men. Suppression of testosterone levels by ketoconazole is generally partial and has often been found to be transient. Better effects on suppression of testosterone levels have been observed in men when ketoconazole is combined with a GnRH agonist to suppress the hypothalamic–pituitary–gonadal axis, which prevents compensatory upregulation of luteinizing hormone secretion and consequent activation of gonadal testosterone production. In premenopausal women with polycystic ovary syndrome, ketoconazole has been found to significantly decrease levels of androstenedione and testosterone and significantly increase levels of 17α-hydroxyprogesterone and estradiol. Studies in postmenopausal women with breast cancer have found that ketoconazole significantly decreases androstenedione levels, slightly decreases estradiol levels, and does not affect estrone levels. This indicates minimal inhibition of aromatase by ketoconazole in vivo in humans. Ketoconazole has also been found to decrease levels of endogenous corticosteroids, such as cortisol, corticosterone, and aldosterone, as well as vitamin D. Ketoconazole has been found to displace dihydrotestosterone and estradiol from sex hormone-binding globulin in vitro, but this was not found to be relevant in vivo. Other activities Ketoconazole has been found to inhibit the activity of the cation channel TRPM5. Pharmacokinetics When administered orally, ketoconazole is best absorbed at highly acidic levels, so antacids or other causes of decreased stomach acid levels will lower the drug's absorption. Absorption can be increased by taking it with an acidic beverage, such as cola. Ketoconazole is very lipophilic and tends to accumulate in fatty tissues. Chemistry Ketoconazole is a synthetic imidazole. It is a nonsteroidal compound. It is a racemic mixture of two enantiomers, levoketoconazole ((2S,4R)-(−)-ketoconazole) and dextroketoconazole ((2R,4S)-(+)-ketoconazole). Levoketoconazole is under development for potential clinical use as a steroidogenesis inhibitor with better tolerability and less toxicity than ketoconazole. Other steroidogenesis inhibitors besides ketoconazole and levoketoconazole include the nonsteroidal compound aminoglutethimide and the steroidal compound abiraterone acetate. History Ketoconazole was discovered in 1976 at Janssen Pharmaceuticals. It was patented in 1977, followed by introduction in the United States in July 1981. Following its introduction, ketoconazole was the only systemic antifungal available for almost a decade. Ketoconazole was introduced as the prototypical medication of the imidazole group of antifungals. Oral ketoconazole has been replaced with oral itraconazole for many mycoses. Due to incidence of serious liver toxicity, the use of oral ketoconazole was suspended in France in July 2011 following review. This event triggered an evaluation of oral ketoconazole throughout the rest of the European Union as well.