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Endocrinology. 2019 Nov 22. pii: bqz012. doi: 10.1210/endocr/bqz012. [Epub ahead of print]

Sex-dependent mechanisms of glucocorticoid regulation of the mouse hypothalamic corticotropin-releasing hormone gene.

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Department of Biomedical Sciences, Colorado State University, Fort Collins CO, USA.
Department of Basic Medical Sciences, University of Arizona, Phoenix, AZ.
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Tx USA.


To limit excessive glucocorticoid secretion following hypothalamic pituitary adrenal (HPA) axis stimulation, circulating glucocorticoids inhibit corticotropin-releasing hormone (CRH) expression in paraventricular nucleus (PVN) neurons. As HPA function differs between sexes and depends on circulating estradiol (E2) levels in females, we investigated sex/estrous stage-dependent glucocorticoid regulation of PVN Crh. Using NanoString nCounter technology, we first demonstrated that adrenalectomized (ADX'd) diestrous female (low E2), but not male or proestrous female (high E2), mice exhibited a robust decrease in PVN CRH mRNA following two-day treatment with the glucocorticoid receptor (GR) agonist RU28362. Immunohistochemical analysis of PVN CRH neurons in Crh-IRES-cre;Ai14 mice, where TdTomato fluorescence permanently tags CRH-expressing neurons, showed similarly abundant co-expression of GR-immunoreactivity in males, diestrous females, and proestrous females. However, we identified sex/estrous stage-related glucocorticoid regulation or expression of GR transcriptional co-regulators. Out of 17 co-regulator genes examined using nCounter multiplex analysis, mRNAs decreased by RU28362 in ADX'd mice in a sex/ estrous stage-dependent fashion included: GR (males = diestrous females > proestrous females), STAT3 (males < diestrous = proestrous), and HDAC1 (males < diestrous > proestrous). SRC-3, NCoR1, hnrnpu, CBP and CRTC2 mRNAs were lower in ADX'd diestrous and proestrous females versus males. Additionally, most PVN CRH neurons co-expressed MeCP2-immunoreactivity in diestrous female and male Crh-IRES-Cre;Ai14 mice. Our findings collectively suggest that GR's sex-dependent regulation of PVN Crh may depend upon differences in the GR transcriptional machinery and an underlying influence of E2 levels in females.


adrenalectomy; corticotropin releasing hormone (CRH); glucocorticoid receptor (GR); paraventricular nucleus (PVN); sex differences


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