title: Stress levels of glucocorticoids inhibit LHβ-subunit gene expression in gonadotrope cells.
abstract: Increased glucocorticoid secretion is a common response to stress and has been implicated as a mediator of reproductive suppression upon the pituitary gland. We utilized complementary in vitro and in vivo approaches in the mouse to investigate the role of glucocorticoids as a stress-induced intermediate capable of gonadotrope suppression. Repeated daily restraint stress lengthened the ovulatory cycle of female mice and acutely reduced GnRH-induced LH secretion and synthesis of LH β-subunit (LHβ) mRNA, coincident with increased circulating glucocorticoids. Administration of a stress level of glucocorticoid, in the absence of stress, blunted LH secretion in ovariectomized female mice, demonstrating direct impairment of reproductive function by glucocorticoids. Supporting a pituitary action, glucocorticoid receptor (GR) is expressed in mouse gonadotropes and treatment with glucocorticoids reduces GnRH-induced LHβ expression in immortalized mouse gonadotrope cells. Analyses revealed that glucocorticoid repression localizes to a region of the LHβ proximal promoter, which contains early growth response factor 1 (Egr1) and steroidogenic factor 1 sites critical for GnRH induction. GR is recruited to this promoter region in the presence of GnRH, but not by dexamethasone alone, confirming the necessity of the GnRH response for GR repression. In lieu of GnRH, Egr1 induction is sufficient for glucocorticoid repression of LHβ expression, which occurs via GR acting in a DNA- and dimerization-independent manner. Collectively, these results expose the gonadotrope as an important neuroendocrine site impaired during stress, by revealing a molecular mechanism involving Egr1 as a critical integrator of complex formation on the LHβ promoter during GnRH induction and GR repression.
authors.affiliation: Department of Reproductive Medicine/Neuroscience, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0674, USA.
authors.forename: Kellie M
authors.initials: KM
authors.lastname: Breen
authors.forename: Varykina G
authors.initials: VG
authors.lastname: Thackray
authors.forename: Tracy
authors.initials: T
authors.lastname: Hsu
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Mak-McCully
authors.forename: Djurdjica
authors.initials: D
authors.lastname: Coss
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Mellon
mesh_terms: D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D030762:Estrous Cycle; D005260:Female; D015870:Gene Expression; D005938:Glucocorticoids / Q000097:blood* / Q000502:physiology; D052681:Gonadotrophs / Q000378:metabolism* / Q000502:physiology; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism / Q000502:physiology; D037101:Luteinizing Hormone, beta Subunit / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D020218:Response Elements; D012149:Restraint, Physical; D013312:Stress, Physiological; D013315:Stress, Psychological / Q000097:blood*
chemical_list: D005938:Glucocorticoids; D037101:Luteinizing Hormone, beta Subunit; D011965:Receptors, Glucocorticoid; D007987:Gonadotropin-Releasing Hormone