title: Both estrogen receptor α and β stimulate pituitary GH gene expression.
abstract: 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 (E2) directly affects GH synthesis in somatotrophs. Somatotroph GH3 and MtT/S cells were used as in vitro models. At physiological doses of E2 stimulation, GH mRNA levels were increased and the ER antagonist ICI 182,780 completely abolished this effect. Estrogen receptor (ER) α- and ERβ-selective agonists, propylpyrazole triol (PPT), and 2,3-bis(4-hydroxyphenyl) propionitrile (DPN), respectively, augmented GH mRNA expression and secretion, whereas E2 and PPT, but not DPN increased prolactin (PRL) mRNA levels. E2, PPT, and DPN stimulated expression of the pituitary transcription factor Pou1f1 and increased its binding to the GH promoter. In vivo evidence of E2 effects on GH synthesis was obtained from the generation of the somatotroph-specific ERα knockout (sERα-KO) mouse model. Basal pituitary GH, PRL, POU1F1, and ERα mRNA expression levels were lower in sERα-KO mice compared with those in controls; whereas ERβ mRNA levels remained unchanged. E2 and DPN stimulated pituitary GH mRNA expression and serum GH levels in control and sERα-KO ovariectomized mice; however, serum GH levels were unchanged in PPT-treated ovariectomized sERα-KO mice. In these animal models, PRL mRNA levels increased after either E2 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 ERα in the lactotroph, these results support a role for both ERα and ERβ in the transcriptional control of Gh in the somatotroph and illustrate important differences in ER isoform specificity in the anterior pituitary gland.
authors.affiliation: Department of Pediatrics (D.A., H.J.N., S.W., C.J.R., S.R.), Division of Endocrinology, and Department of Pediatrics (F.W.), Division of Metabolism, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; and Research and Development Division (R.K., R.M.L.), Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612.
authors.forename: Dimiter
authors.initials: D
authors.lastname: Avtanski
authors.forename: Horacio J
authors.initials: HJ
authors.lastname: Novaira
authors.forename: Sheng
authors.initials: S
authors.lastname: Wu
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Romero
authors.forename: Rhonda
authors.initials: R
authors.lastname: Kineman
authors.forename: Raul M
authors.initials: RM
authors.lastname: Luque
authors.forename: Fredric
authors.initials: F
authors.lastname: Wondisford
authors.forename: Sally
authors.initials: S
authors.lastname: Radovick
mesh_terms: D000818:Animals; D002460:Cell Line; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000502:physiology*; D047629:Estrogen Receptor beta / Q000819:agonists / Q000502:physiology*; D005260:Female; D000077267:Fulvestrant; D015870:Gene Expression; D005786:Gene Expression Regulation; D013006:Growth Hormone / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009570:Nitriles / Q000494:pharmacology; D010636:Phenols; D010902:Pituitary Gland / Q000166:cytology / Q000378:metabolism; D011388:Prolactin / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D052683:Somatotrophs / Q000378:metabolism*; D050817:Transcription Factor Pit-1 / Q000235:genetics / Q000378:metabolism; D011422:Propionates
chemical_list: D004958:Estradiol; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D000077267:Fulvestrant; D013006:Growth Hormone; D009570:Nitriles; D010636:Phenols; D011388:Prolactin; D011720:Pyrazoles; D050817:Transcription Factor Pit-1; C486182:2,3-bis(4-hydroxyphenyl)-propionitrile; D011422:Propionates; C494185:Pou1f1 protein, mouse; C486184:4,4',4''-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol