Regulation of Estrogen Receptor (ER) Isoform Messenger RNA Expression by Different ER Ligands in Female Rat Pituitary

Net estrogen sensitivity in target tissues critically depends on the regulated expression of full-length and alternately processed estrogen receptor (ER) isoforms. However, the molecular mechanisms for the control of pituitary responsiveness to estrogen remain partially unknown. In the present communication, we report the ability of different ligands, with distinct agonistic or antagonistic properties at the ER, to modulate the expression of the transcripts encoding ER(alpha) and ER(beta) isoforms, as well as those for the truncated ER(alpha) product (TERP), and the variant ER(beta)2, in pituitaries from ovariectomized rats, i.e., a background devoid of endogenous estrogen. Compared with expression levels at the morning of proestrus, ovariectomy (OVX) resulted in increased pituitary expression of ER(beta) and ER(beta)2 mRNAs, whereas it decreased TERP-1 and -2 levels without affecting those of ER(alpha). Administration of estradiol benzoate (as potent agonist for (alpha)and (beta) forms of ER) or the selective ER(alpha) agonist, propyl pyrazole triol, fully reversed the responses to OVX, while the ER(beta) ligand, diarylpropionitrile, failed to induce any significant effect except for a partial stimulation of TERP-1 and -2 mRNA expression levels. To note, the ER(beta) agonist was also ineffective in altering pituitary expression of progesterone receptor-B mRNA, i.e., a major estrogen-responsive target. In all parameters tested, tamoxifen, a selective ER modulator with mixed agonist/antagonist activity, behaved as ER(alpha) agonist, although the magnitude of tamoxifen effects was significantly lower than those of the ER(alpha) ligand, except for TERP induction. In contrast, the pure antiestrogen RU-58668 did not modify the expression of any of the targets under analysis. Overall, our results indicate that endogenous estrogen differentially regulates pituitary expression of the mRNAs encoding several ER isoforms with distinct functional properties, by a mechanism that is mostly conducted through ER(alpha). Differential regulation of ER isoforms may represent a relevant system for the self-tuning of estrogen responsiveness in female pituitary.