The effect of progesterone on 14C-testosterone metabolism and on 14C-lipid synthesis was studied in two animal sebaceous gland models, hamster flank organ and rat ear skin. Unilateral topical application of progesterone to the female hamster flank organ topically treated with testosterone propionate resulted in localized inhibition of both in vitro 14C-lipogenesis and in vitro conversion of 14C-testosterone to 5 alpha-reduced radio-metabolites. Topical progesterone did not inhibit in vitro 14C-lipogenesis in the male hamster flank organ. Progesterone added in vitro inhibited 14-C-lipogenesis and 14C-testosterone metabolism in male rat ear sebaceous glands. These results lend support to the hypothesis that inhibition of sebaceous gland lipogenesis by progesterone is a consequence of its inhibitory effect on testosterone metabolism. Such a rationale provides a valid explanation for the clinical findings with progesterone reported by other investigators.