Functional Modification of Pituitary Somatotropes in the Aromatase Knockout Mouse and the Effect of Estrogen Replacement

• Published in: Endocrinology (Philadelphia) 2004-02, Vol.145 (2), p.604-612
• Main Authors: Yan, Ming, Jones, Margaret E. E, Hernandez, Maria, Liu, Dongling, Simpson, Evan R, Chen, Chen
• Format: Article
• Language: English
• Subjects: 17β-Estradiol; Aging; Androgen receptors; Animals; Aromatase; Aromatase - deficiency; Aromatase - genetics; Aromatase - physiology; Biological and medical sciences; Biosynthesis; Body Weight; DNA-Binding Proteins - genetics; Down-regulation; Estradiol - pharmacology; Estrogens; Female; Females; Fundamental and applied biological sciences. Psychology; Gene Expression; Gene regulation; Glyceraldehyde-3-Phosphate Dehydrogenases - genetics; Growth Hormone - blood; Growth Hormone - genetics; Growth hormone-releasing hormone; Hormone replacement therapy; In vivo methods and tests; Mice; Mice, Knockout; Molecular modelling; Organ Size; Pit1 protein; Pituitary; Pituitary Gland - chemistry; Pituitary Gland - drug effects; Pituitary Gland - metabolism; Receptors; Receptors, Androgen - genetics; Receptors, Estrogen - genetics; Receptors, G-Protein-Coupled - genetics; Receptors, Ghrelin; Receptors, Neuropeptide - genetics; Receptors, Pituitary Hormone-Regulating Hormone - genetics; Receptors, Somatostatin - genetics; RNA, Messenger - analysis; Secretion; Sex hormones; Somatostatin; Somatostatin receptors; Transcription; Transcription Factor Pit-1; Transcription Factors - genetics; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2003-0646

Available data on the influence of estradiol (E2) on GH levels remains controversial. A factor contributing to this uncertainty is a lack of knowledge of both E2 action on somatotropes as well as the molecular mechanisms involved. In this study we investigated gene expression implicated in GH secretion in somatotropes derived from female aromatase knockout (ArKO) mice. In these mice E2 production is blocked due to disruption of the Cyp19 gene encoding aromatase, the enzyme responsible for estrogen biosynthesis. The effect of E2 replacement was also studied by in vivo treatment of mice with E2 for 3 wk. It was demonstrated that somatotropes from ArKO mice had a low expression of GH, GH secretagogue receptor, GHRH receptor (GHRH-R), and pituitary-specific transcription factor (Pit-1). On the other hand, the somatotropes exhibited elevated expression of somatostatin receptors (sst1–5). Overall, these effects resulted in a reduction in GH secretion. E2 replacement increased GHRH-R, Pit-1, and GH mRNA levels to 185%, 193%, and 157% and reduced the levels of sst1, sst2, sst4, and sst5 mRNA expression in ArKO mice, respectively. E2 replacement did not affect the levels of pituitary estrogen (α and β) and androgen receptor mRNA expression. It is concluded that the expression of important genes involved in GH synthesis in somatotropes of the female ArKO mouse are functionally down-regulated, and such a down-regulation is reversed to normal levels by E2 replacement. The levels of GH secretagogue receptor, GHRH-R, and Pit-1 mRNA expression were also reduced, and sst1 and sst3 mRNA expression enhanced in aging ArKO and wild-type mice, resulting in a decrease in GH mRNA expression. It is suggested that aging is another important impact factor for the pituitary expression and regulation of GH mRNA in female mice.