Inhibitory effects of some steroidal 6-methylene derivatives on 5 alpha-reductase activity in human and rat prostate

Using a short-term organ culture assay, some 6-methylene derivatives of progesterone and testosterone have been evaluated for their effects on testosterone metabolism in rat and human prostatic tissues, and on DNA synthesis in explants from 7-day castrated rats. Comparative studies showed that the ability to inhibit 5 alpha-reductase activity was fairly specific with respect to structural requirements. Methylene substitution at the C6 position of the progesterone molecule was associated with high inhibitory activity. In explants prepared from human prostates, 6-methylene progesterone (II) had 70-85% (mean of 79% for 4 BPH tissues) of the potency of unmodified progesterone (I). Its 17 alpha-acetoxy-6-methylene analog (III), however, had only 32-73% (mean of 53% for 5 BPH specimens) of the activity of (I). The degrees of inhibition in rat and human prostatic tissues were similar. Inhibition of 5 alpha-reductase activity in cultured explants by 6-methylene progesterone (II) could not be reversed by change in media. The 6-methylene derivatives had little or no effect on DNA synthesis. Histological examination confirmed a lack of effect on basal cell proliferation. However, morphological alterations affecting epithelial cell height and secretory activity were clearly evident. These results indicate that, under our experimental conditions, the main effect of inhibition of 5 alpha-reductase activity in prostatic tissues by 6-methylene derivatives of progesterone is related to suppression of differentiated function.