The steroid hormone antagonist RU486. Mechanism at the cellular level and clinical applications

Abstract

The cellular and molecular mechanism of RU486, a steroid hormone antagonist, is discussed in detail. Principally, RU486 opposes the action of two types of hormones: progesterone and glucocorticosteroids. The clinical applications are also described, as well as the future outlook.

PIP: This review of the mechanism of action of the anti-progestational agent RU-486 concentrates on its interactions with the sub-molecular regions of the progesterone receptor, and implications for clinical applications. The progesterone receptor, like other steroid hormone receptors, has 4 distinct regions, the ligand-binding domain (LBD), the DNA-binding domain (DBD), a highly charged hinge region, and an N-terminal section thought to be involved in regulation of transactivation. The progesterone receptor occurs in 2 forms, A and B, and these are linked in dimers. The dimer binds to DNA at locations called hormone response elements (HREs). The receptor remains in the nucleus, prevented from binding by heat shock protein 90 (hsp90). DNA binding, which can occur separately from hormone in experimental conditions, first causes release of hsp90, and a shape change in the receptor, and then elicits an effect on the DNA chromatin, modification of transcription factors, and other effects such as phosphorylation or related proteins. When RU-486 is substituted for progesterone, DNA binding is tight, but the hsp-90-receptor complex is stabilized, and the receptor shape is abnormal, incompatible with subsequent hormone effects in the cell. The implications for research on the mechanism of action of the progesterone receptor were discussed. Examples include the suggestion that the 1% of women who do not respond to RU-486 with early abortion may be genetically distinct; that research of progesterone receptors in several types of cancer such an meningiomas and breast cancer are justified; and alto that use of RU-486 for local or systemic hypercorticism may be applicable. On the other hand, while new users of RU-486 for contraception are theoretically of interest, it is unlikely that any company will invest in another type of oral contraceptive.