Clomiphene citrate elicits estrogen agonistic/antagonistic effects differentially via estrogen receptors alpha and beta.

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 alpha (ER alpha) and/or ER beta 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 ER alpha or ER beta 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 ER alpha. However, CC at concentrations between 10(-6) M and 10(-12) M did not elicit any estrogenic activity via ER beta. In the presence of 17beta-estradiol (E2), CC behaved either as an agonist or as an antagonist via ER alpha 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 ER beta, CC acted as an estrogen antagonist regardless of the concentration of E2 added together. In conclusion, CC acts as an estrogen agonist/antagonist via ER alpha in a coexisting estrogen concentration-dependent way whereas it acts as an estrogen antagonist via ER beta whether or not estrogen is present.