title: Neural growth hormone: regional regulation by estradiol and/or sex chromosome complement in male and female mice.
abstract: BACKGROUND
  Sex differences in pituitary growth hormone (GH) are well documented and coordinate maturation and growth. GH and its receptor are also produced in the brain where they may impact cognitive function and synaptic plasticity, and estradiol produces Gh sex differences in rat hippocampus. In mice, circulating estradiol increases Gh mRNA in female but not in male medial preoptic area (mPOA); therefore, additional factors regulate sexually dimorphic Gh expression in the brain. Thus, we hypothesized that sex chromosomes interact with estradiol to promote sex differences in GH. Here, we assessed the contributions of both estradiol and sex chromosome complement on Gh mRNA levels in three large brain regions: the hippocampus, hypothalamus, and cerebellum.
  
  
  METHODS
  We used the four core genotypes (FCG) mice, which uncouple effects of sex chromosomes and gonadal sex. The FCG model has a deletion of the sex-determining region on the Y chromosome (Sry) and transgenic insertion of Sry on an autosome. Adult FCG mice were gonadectomized and given either a blank Silastic implant or an implant containing 17β-estradiol. Significant differences in GH protein and mRNA were attributed to estradiol replacement, gonadal sex, sex chromosome complement, and their interactions, which were assessed by ANOVA and planned comparisons.
  
  
  RESULTS
  Estradiol increased Gh mRNA in the cerebellum and hippocampus, regardless of sex chromosome complement or gonadal sex. In contrast, in the hypothalamus, females had higher Gh mRNA than males, and XY females had more Gh mRNA than XY males and XX females. This same pattern was observed for GH protein. Because the differences in Gh mRNA in the hypothalamus did not replicate prior studies using other mouse models and tissue from mPOA or arcuate nucleus, we examined GH protein in the arcuate, a subdivision of the hypothalamus. Like the previous reports, and in contrast to the entire hypothalamus, a sex chromosome complement effect showed that XX mice had more GH than XY in the arcuate.
  
  
  CONCLUSIONS
  Sex chromosome complement regulates GH in some but not all brain areas, and within the hypothalamus, sex chromosomes have cell-specific actions on GH. Thus, sex chromosome complement and estradiol both contribute to GH sex differences in the brain.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22908 USA ; Neuroscience Graduate Program, University of Virginia School of Medicine, Charlottesville, VA 22908 USA.
authors.forename: Kayla M
authors.initials: KM
authors.lastname: Quinnies
authors.affiliation: Department of Neurobiology and Anatomy, University of Utah, 20 North 1900 East, Salt Lake City, UT 84132-3401 USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Bonthuis
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22908 USA ; Neuroscience Graduate Program, University of Virginia School of Medicine, Charlottesville, VA 22908 USA.
authors.forename: Erin P
authors.initials: EP
authors.lastname: Harris
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22908 USA ; Neuroscience Graduate Program, University of Virginia School of Medicine, Charlottesville, VA 22908 USA.
authors.forename: Savera Rj
authors.initials: SR
authors.lastname: Shetty
authors.affiliation: Department of Biological Sciences, North Carolina State University, Raleigh, NC 27695 USA.
authors.forename: Emilie F
authors.initials: EF
authors.lastname: Rissman
keywords: Cerebellum; Estradiol; Growth hormone; Growth hormone-releasing hormone; Hypothalamus; Obesity; Sex chromosomes; Sex differences