We appreciate Dr. Goldsmith's suggestion that the mechanism of fluconazole-induced reversible alopecia may be related to increased endogenous levels of biologically active retinoic acid derivatives associated with an interaction between fluconazole and the P-450 cytochrome system. Moreover, as he suggests, some patients receiving long-term fluconazole therapy develop dry skin and dry lips, adverse effects reminiscent of retinoid toxicity. Unfortunately, we did not measure retinoid metabolite levels in any of these patients. Findings seem to support a viable explanation for fluconazole-associated toxicity, however; further investigation is warranted, given that fluconazole use, particularly at higher doses, has become increasingly common.

We disagree with Dr. Shear's contention that the reversible alopecia we reported is not related to fluconazole therapy but rather to telogen effluvium. We are aware that telogen effluvium can cause reversible alopecia but remain certain that our patients (or at least most of them) had hair loss resulting from exposure to long-term, high-dose fluconazole therapy. Several observations support this association. First, all the investigators are experienced clinical mycologists, and none recall having seen telogen effluvium commonly associated with superficial or invasive fungal disease. Several of these patients had had fungal disease for months before initiation of therapy, and none had hair loss. Second, ketoconazole, another azole compound, has also been associated with reversible alopecia [1], but we have recognized no significant hair loss related to ketoconazole compared with that related to fluconazole [2]. We have not seen a significant frequency of alopecia in patients subsequently managed with itraconazole or amphotericin B for these same disorders, even though we continue to check these patients for hair loss. Third, at least 10 of the patients we described had received previous antifungal therapy with a different agent; they either had relapse or progressed and subsequently received fluconazole. Among these patients, hair loss was not reported until after fluconazole therapy was initiated. Finally, we noted a striking correlation between cessation of fluconazole and resolution of alopecia. Only one patient had resolution of alopecia while continuing to receive high-dose fluconazole (800 mg/d).

These observations strongly support an association between long-term (> 3 months), high-dose ( 400 mg/d) fluconazole and reversible alopecia. Our collective experience in treating patients with superficial and invasive mycoses and the relative rarity of significant alopecia before the use of fluconazole for these disorders form a strong argument against telogen effluvium as a cause of alopecia in these patients.