Distinguishing androgen receptor agonists and antagonists: distinct mechanisms of activation by medroxyprogesterone acetate and dihydrotestosterone

Mol Endocrinol. 1999 Mar;13(3):440-54. doi: 10.1210/mend.13.3.0255.


Natural and pharmacological androgen receptor (AR) ligands were tested for their ability to induce the AR NH2-terminal and carboxyl-terminal (N/C) interaction in a two-hybrid protein assay to determine whether N/C complex formation distinguishes in vivo AR agonists from antagonists. High-affinity agonists such as dihydrotestosterone, mibolerone, testosterone, and methyltrienolone at concentrations between 0.1 and 1 nM induce the N/C interaction more than 40-fold. The lower affinity anabolic steroids, oxandrolone and fluoxymesterone, require concentrations of 10-100 nM for up to 23-fold induction of the N/C interaction. However no N/C interaction was detected in the presence of the antagonists, hydroxyflutamide, cyproterone acetate, or RU56187, at concentrations up to 1 microM, or with 1 microM estradiol, progesterone, or medroxyprogesterone acetate; each of these steroids at 1-500 nM inhibited the dihydrotestosterone-induced N/C interaction, with medroxyprogesterone acetate being the most effective. In transient and stable cotransfection assays using the mouse mammary tumor virus reporter vector, all ligands displayed concentration-dependent AR agonist activity that paralleled induction of the N/C interaction, with antagonists and weaker agonists failing to induce the N/C interaction. AR dimerization and DNA binding in mobility shift assays and AR stabilization reflected, but were not dependent on, the N/C interaction. The results indicate that the N/C interaction facilitates agonist potency at low physiological ligand concentrations as detected in transcription, dimerization/DNA binding, and stabilization assays. However the N/C interaction is not required for agonist activity at sufficiently high ligand concentrations, nor does its inhibition imply antagonist activity.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Androgen Antagonists / pharmacology*
  • Androgen Receptor Antagonists*
  • Androgens*
  • Animals
  • COS Cells / drug effects
  • COS Cells / metabolism
  • DNA / metabolism
  • Dihydrotestosterone / pharmacology*
  • Dimerization
  • Dose-Response Relationship, Drug
  • Imidazoles / pharmacology
  • Luciferases / drug effects
  • Luciferases / genetics
  • Luciferases / metabolism
  • Mammary Tumor Virus, Mouse / genetics
  • Medroxyprogesterone Acetate / pharmacology*
  • Metribolone / pharmacology
  • Mice
  • Nandrolone / analogs & derivatives
  • Nandrolone / pharmacology
  • Nitriles / pharmacology
  • Peptide Fragments / metabolism
  • Progesterone Congeners / pharmacology
  • Receptors, Androgen / physiology
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Testosterone Congeners / pharmacology
  • Transcription, Genetic
  • Transfection


  • Androgen Antagonists
  • Androgen Receptor Antagonists
  • Androgens
  • Imidazoles
  • Nitriles
  • Peptide Fragments
  • Progesterone Congeners
  • Receptors, Androgen
  • Recombinant Proteins
  • Testosterone Congeners
  • Dihydrotestosterone
  • 4-(3,4,4-trimethyl-5-oxo-2-thioxo-1-imidazolidinyl)-2-(trifluoromethyl)benzonitrile
  • Metribolone
  • Nandrolone
  • DNA
  • mibolerone
  • Medroxyprogesterone Acetate
  • Luciferases