Both Estrogen Receptor α and β Stimulate Pituitary GH Gene Expression

Although sex steroids have been implicated in the control of mammalian growth, their direct effect on GH synthesis is less clear. The aim of this study was to establish whether estradiol (E-2) directly affects GH synthesis in somatotrophs. Somatotroph GH(3) and MtT/S cells were used as in vitro models. At physiological doses of E-2 stimulation, GH mRNA levels were increased and the ER antagonist ICI 182,780 completely abolished this effect. Estrogen receptor (ER) alpha- and ER beta-selective agonists, propylpyrazole triol (PPT), and 2,3-bis(4-hydroxyphenyl) propionitrile (DPN), respectively, augmented GH mRNA expression and secretion, whereas E-2 and PPT, but not DPN increased prolactin (PRL) mRNA levels. E-2, PPT, and DPN stimulated expression of the pituitary transcription factor Pou1f1 and increased its binding to the GH promoter. In vivo evidence of E-2 effects on GH synthesis was obtained from the generation of the somatotroph-specific ER alpha knockout (sER alpha-KO) mouse model. Basal pituitary GH, PRL, POU1F1, and ER alpha mRNA expression levels were lower in sER alpha-KO mice compared with those in controls; whereas ER beta mRNA levels remained unchanged. E-2 and DPN stimulated pituitary GH mRNA expression and serum GH levels in control and sER alpha-KO ovariectomized mice; however, serum GH levels were unchanged in PPT-treated ovariectomized sER alpha-KO mice. In these animal models, PRL mRNA levels increased after either E-2 or PPT, but an increase was not seen after DPN treatment. Thus, we propose a mechanism by which estrogen directly regulates somatotroph GH synthesis at a pretranslational level. In contrast to the predominant effect of ER alpha in the lactotroph, these results support a role for both ER alpha and ER beta in the transcriptional control of Gh in the somatotroph and illustrate important differences in ER isoform specificity in the anterior pituitary gland.