Ketoconazole impairs early pregnancy and the decidual cell response via alterations in ovarian function

Abstract

Ketoconazole (KCZ) is an imidazole antifungal agent that also affects P450 enzymes of the mammalian steroidogenic system. Several steps in the ovarian steroidogenesis pathway are known to be inhibited by KCZ, but previous work has failed to address the ramifications of such inhibition with respect to early pregnancy. In initial studies, Holtzman rats (8-10/group) were administered 10-100 mg/kg KCZ during days 1-8 of pregnancy. On day 9, evaluations revealed a reduction at both 75 and 100 mg KCZ/kg in the number of implantation sites and serum progesterone levels as well as an increase in ovarian weight. The decidual cell response (DCR) was blocked by KCZ in parallel with decreased serum progesterone and increased ovarian weight, indicating direct interference with uterine function. KCZ had no effect when given to long-term-ovariectomized rats that were hormone supplemented to permit the DCR, indicating that the ovary was at least one site of KCZ action on early pregnancy. Measurement of ovarian progesterone production in vitro from ovaries removed from rats treated in vivo with KCZ indicated a decline in progesterone production, suggesting a direct effect of KCZ on ovarian steroidogenesis. These data demonstrate that KCZ can compromise early pregnancy and appears to do so by inhibiting progesterone synthesis in the ovary.