Antisteroid hormones compete for hormone binding at the receptor level and prevent the hormonal response. A new concept is proposed for explaining the antiglucocorticosteroid activity of RU 486 in the chick oviduct system. It is based on the ability of the antisteroid to stabilize the hetero-oligomeric 8s-form of the glucocorticosteroid receptor (GR), which involves the interaction of the 94kreceptor and heat-shock protein MW 90,000 (hsp 90). It is proposed that hsp 90 caps the DNA binding site of the receptor, and this prevents it from binding to the DNA of hormone regulatory elements (HRE) and increasing transcription of regulated genes. This paper reviews other antiglucocorticosteroid and antiestrogen systems with reference to this hypothesis and also describes a four-step analysis of the molecular mechanism of antisteroid hormone action at the receptor level. Key words: steroid hormone antagonists, receptor antisteroids, antihormones, heat-shock protein MW 90,OOO (hsp W), RU 486, hormone regulatory elements (HRE), antiglucocorticosteroid, antiestrogen, tamoxifen
To suppress selectively and safely the effect(s) of a given hormone can be of medical usefulness. Antiprogesterone (to interrupt the luteal phase and early pregnancy), antiglucocorticosteroid (to decrease deleterious effects of corticosteroids produced in excess in some tumoral processes), antiestrogens (active in "receptor + " breast cancers), antialdosterone (used in many cases of high blood pressure), and antiandrogens (for treating hypersexualisms) have been successfully utilized in human beings.
By definition, antihormones are not drugs decreasing steroid production or availability to target cells. In other words, their targets are neither the biosynthetic mechanisms for steroids, nor their metabolism, nor their transport in the blood circulation. They also are not addressed to postreceptor events, since in this case they could probably not be specific enough, most cellular activities being under multihormonal controls. At the receptor level, presently we only consider analogues which