KETOCONAZOLE IMPAIRS EARLY-PREGNANCY AND THE DECIDUAL CELL RESPONSE VIA ALTERATIONS IN OVARIAN-FUNCTION

Ketoconazole (KCZ) is an imidazole antifungal agent that also affects P450 enzymes of the mammalian steroidogenic system. Several steps in t he ovarian steroidogenesis pathway are known to be inhibited by KCZ, b ut previous work has failed to address the ramifications of such inhib ition with respect to early pregnancy. In initial studies, Holtzman ra ts (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 1 00 mg KCZ/kg in the number of implantation sites and serum progesteron e levels as well as an increase in ovarian weight. The decidual cell r esponse (DCR) was blocked by KCZ in parallel with decreased serum prog esterone and increased ovarian weight, indicating direct interference with uterine function. KCZ had no effect when given to long-term-ovari ectomized rats that were hormone supplemented to permit the DCR, indic ating that the ovary was at least one site of KCZ action on early preg nancy. Measurement of ovarian progesterone production in vitro from ov aries removed from rats treated in vivo with KCZ indicated a decline i n progesterone production, suggesting a direct effect of KCZ on ovaria n steroidogenesis. These data demonstrate that KCZ can compromise earl y pregnancy and appears to do so by inhibiting progesterone synthesis in the ovary.