Journal
MOLECULAR ENDOCRINOLOGY
Volume 26, Issue 10, Pages 1716-1731Publisher
ENDOCRINE SOC
DOI: 10.1210/me.2011-1327
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Funding
- National Institutes of Health (NIH) [R01 HD020377, R01 HD072754, R01 DK044838]
- Eunice Kennedy Shriver National Institute of Child Health and Human Development/NIH as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research [U54 HD012303]
- NIH [K99 HD060947, K01 DK080467, R01 HD067448, R01 HD057549, R21 HD058752, R03 HD054595]
- National Cancer Institute Cancer Support Grant [P30 CA023100]
- National Institute of Child Health and Human Development [U54 HD028934]
- [P30 DK063491]
- [P42 ES010337]
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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 beta-subunit (LH beta) 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 LH beta expression in immortalized mouse gonadotrope cells. Analyses revealed that glucocorticoid repression localizes to a region of the LH beta 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 LH beta 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 LH beta promoter during GnRH induction and GR repression. (Molecular Endocrinology 26: 1716-1731, 2012)
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