Clomiphene citrate elicits estrogen agonistic/antagonistic effects differentially via estrogen receptors α and β

Abstract

Clomiphene citrate (CC) is known to possess dual actions as an estrogen agonist and an estrogen antagonist. To see how the dual actions of CC are exerted through estrogen receptor α (ERα) and/or ERβ we developed a cell-based transcription assay system in which 293T cells were transfected with the luciferase reporter plasmid with estrogen responsive element and either human ERα or ERβ expression plasmid. CC at lower doses (10 -10 M and 10 -12 M), but not higher doses (10 -6 M and 10 -8 M) elicited estrogenic activity via ERα. However, CC at concentrations between 10 -6 M and 10 -12 M did not elicit any estrogenic activity via ERβ. In the presence of 17β-estradiol (E2), CC behaved either as an agonist or as an antagonist via ERα depending on the concentrations of E2, i.e., antagonistic when combined with the higher E2 concentrations, agonistic with the lower E2 concentrations. On the other hand, via ERβ, CC acted as an estrogen antagonist regardless of the concentration of E2 added together. In conclusion, CC acts as an estrogen agonist/antagonist via ERα in a coexisting estrogen concentration-dependent way whereas it acts as an estrogen antagonist via ERβ whether or not estrogen is present.