The Corpus Luteum Revisited: Are the Paradoxical Effects of RU486 a Clue to How Progesterone Stimulates its Own Secretion?1

The progesterone (P) antagonist RU486 (RU) both lowers and raises P secretion by an apparently direct action on the corpus luteum. P receptors, however, exist in more than one form, and under certain conditions of P's target tissues, RU can act as a P agonist when bound to one of them. RU's paradoxical effects, therefore, may support the theory that P stimulates its own secretion since the conditions under which RU raises P secretion are always different from those in which it lowers it. These effects, however, occur in at least one species, the rat, in which luteal P receptors cannot be found, and there are several excellent reasons to think that the autocrine action of P in no way resembles its action in its target tissues. The system through which P controls its own secretion in all mammals, in other words, is still undiscovered.