Androgenic, Antiandrogenic, and Synandrogenic Actions of Progestins: Role of Steric and Allosteric Interactions with Androgen Receptors*

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Abstract
Progestins are known to mimic, potentiate, and/or antagonize the actions of androgens in various mammalian target tissues. Such androgenic, synandrogenic and antiandrogenic responses to progestins were not detected in mice with defective androgen receptors (Tfm/Y mice). This inference that the androgen receptor, rather than a progestin receptor, mediates these responses in normal animals was tested by in vivo and in vitro experiments in castrated mice and rats. 17.alpha.-Acetoxy-6.alpha.-methylprogesterone (MPA), a progestin with both androgenic and synandrogenic activities, stimulated the growth of mouse prostate-seminal vesicle, kidney, and submaxillary gland. The specific nuclear uptake of [3H]MPA or 3H-labeled androgens by these organs in vivo was reduced more effectively by 5.alpha.-dihydrotestosterone than by MPA. Similar results were obtained in rats. In contrast, there was no evidence of nuclear uptake in Tfm/Y mice. The androgen receptor may be involved in the nuclear retention of [3H]MPA. The hypothesis of shared receptors was supported by ultracentrifugal analysis of progestin and androgen binding to mouse kidney cytosol. [3H]MPA and [3H]-testosterone ([3H]T) were both bound to high affinity, low capacity macromolecules with sedimentation coefficients of about 8S. This binding was displaced by nonradioactive MPA or T in a dose-dependent fashion, and by 100-fold excesses of 6-chloro-6-dehydro-17.alpha.-acetoxy-1,2.alpha.-methylene progesterone and other progestins, T and estradiol, but not by dexamethasone, a glucocorticoid. There was no detectable binding of [3H]MPA or [3H]T to 8S components in kidney cytosol from Tfm/Y mice. High concentrations of 3-4S components that bound [3H]MPA but not [3H]T were found in kidney cytosols from both Tfm/Y and normal mice, but not in mouse plasma. The competition by various progestins for [3H]T binding to mouse kidney cytosol was studied by adsorption of steroid-receptor complexes to DEAE-cellulose filters. The apparent affinities of several progestins for the androgen receptor were not directly correlated with the magnitude or direction (agonist and antagonist) of their effects on renal .beta.-glucuronidase activity. The monotonic decrease in 3H-labeled androgen binding with increasing concentrations of synandrogenic progestins was inconsistent with the proposal that the synergistic response involves a cooperative increase in androgen binding to a multisite receptor. The data were analyzed in terms of a mathematical model for combined steric and allosteric interactions. Unlike the classical allosteric model for interactions between identical or dissimilar ligands this model includes the competitive binding of similar ligands to the same sites, as well as their effects on the putative equilibrium between active and inactive states of the receptor. The observation that androgen binding to mouse kidney cytosol was similarly inhibited by progestins with disparate physiological effects (androgenic, antiandrogenic, synandrogenic, or undetectable) was consistent with the predictions of the steric-allosteric model.