A Mechanism for the Antiandrogenic Action of Medrogestone1

Abstract

The antiandrogenic action of the progestin, medrogestone, in rat and man was ascribed initially to an alteration in testosterone biosynthesis and metabolism rather than to a direct effect via the androgen receptor. However in previous studies we had found that many progestins bind directly to the androgen receptor in mouse kidney and have androgenic, antiandrogenic or synandrogenic activity. It was thus of interest to characterize the effect of medrogestone on androgen action in mouse kidney and to determine if this progestin was bound by the androgen receptor. Medrogestone inhibited the growth response and increase in the activity of β‐glucuronidase and alcohol dehydrogenase induced by exogenous testosterone in the kidney of castrate male mice. It also inhibited the growth response of preputial gland and seminal vesicle. This progestin suppressed nuclear uptake of [3H]androgen in kidney, seminal vesicle and submaxillary gland following the in vivo administration of [3H] testosterone. In vitro, medrogestone directly inhibited [3H]testosterone binding by the androgen receptor in mouse kidney cytosol. To insure that these effects were not unique to the mouse, similar studies were repeated in the rat. In this species, medrogestone also inhibited nuclear androgen accumulation and receptor binding in prostate and seminal vesicle. Thus medrogestone can affect androgen action directly via binding to the androgen receptor in the mouse and rat.