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Stress Levels of Glucocorticoids Inhibit LHЯ-Subunit Gene Expression In ORIGINAL RESEARCH Stress Levels of Glucocorticoids Inhibit LH␤-Subunit Gene Expression in Gonadotrope Cells Kellie M. Breen, Varykina G. Thackray, Tracy Hsu, Rachel A. Mak-McCully, Djurdjica Coss, and Pamela L. Mellon Department of Reproductive Medicine and Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, California 92093-0674 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 length- ened the ovulatory cycle of female mice and acutely reduced GnRH-induced LH secretion and synthesis of LH ␤-subunit (LH␤) mRNA, coincident with increased circulating glucocorticoids. Ad- ministration 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 glu- cocorticoids. Supporting a pituitary action, glucocorticoid receptor (GR) is expressed in mouse gonadotropes and treatment with glucocorticoids reduces GnRH-induced LH␤ expression in im- mortalized mouse gonadotrope cells. Analyses revealed that glucocorticoid repression localizes to a region of the LH␤ 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 repres- sion of LH␤ 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␤ promoter during GnRH induction and GR repression. (Molecular Endocrinology 26: 1716–1731, 2012) NURSA Molecule Pages†: Ligands: Corticosterone. tress profoundly disrupts reproductive function. idence that the glucocorticoid receptor (GR) antagonist, SWhether the nature of the stressor is physical (e.g. RU486, attenuates the inhibitory effect of immobilization foot-shock, exercise), immunological (e.g. infection, ad- stress on LH secretion in male rats or psychosocial stress ministration of cytokines or endotoxins), or psychologi- on pituitary responsiveness to GnRH in ovariectomized cal (e.g. isolation, mental performance tasks), each has ewes implies a physiological role for glucocorticoids in been shown to decrease circulating levels of gonadotro- mediating the inhibitory effects of stress on LH secretion, pins in mammals (1–5). Associated with this reproductive although RU486 can also block the effects of progester- disturbance is an activation of the hypothalamic-pitu- one (6–8). itary-adrenal axis and an elevation in circulating gluco- Although there is little doubt that glucocorticoids sup- corticoids from the adrenal cortex, the final hormonal press gonadotropin secretion, the neuroendocrine mech- effectors of the hypothalamic-pituitary-adrenal axis. Ev- anism underlying this effect is not well understood. Inhi- ISSN Print 0888-8809 ISSN Online 1944-9917 † Annotations provided by Nuclear Receptor Signaling Atlas (NURSA) Bioinformatics Resource. Printed in U.S.A. Molecule Pages can be accessed on the NURSA website at www.nursa.org. Copyright © 2012 by The Endocrine Society Abbreviations: ChIP, Chromatin immunoprecipitation; DBD, DNA-binding domain; Egr1, early doi: 10.1210/me.2011-1327 Received November 18, 2011. Accepted July 2, 2012. growth response factor 1; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFP, green First Published Online July 31, 2012 fluorescent protein; GR, glucocorticoid receptor; GST, glutathione-S-transferase; ␣GSU, gly- coprotien hormone alpha-subunit; SF1, steroidogenic factor 1; TK, thymidine kinase. 1716 mend.endojournals.org Mol Endocrinol, October 2012, 26(10):1716–1731 Mol Endocrinol, October 2012, 26(10):1716–1731 mend.endojournals.org 1717 bition at the hypothalamic level is supported by evidence fers biological specificity (26). Synthesis of the ␤-subunit that glucocorticoids reduce the frequency of LH pulses in gene of each hormone is the rate-limiting step in the over- ovary-intact female sheep, ovariectomized female rats, all production of LH and FSH (26, 27). Because expres- and women during the follicular phase of the ovulatory sion of each ␤-subunit is tightly controlled by endocrine, cycle (9–11). Because LH pulse frequency is generally paracrine, and autocrine actions, including hypothalamic modulated by the GnRH neurosecretory system, these GnRH, the activin-inhibin-follistatin system, and steroid findings suggest an action of glucocorticoids to suppress hormones of gonadal origin (27, 28), it is possible that the frequency of GnRH pulses. A recent study in follicular GR regulation of transcriptional activity underlies the in- phase sheep provides the first definitive evidence that glu- hibitory effects of stress on the gonadotrope. cocorticoids inhibit GnRH pulses in pituitary portal Transcriptional effects of steroid hormones within the blood (12). GR is expressed within hypothalamic neurons gonadotrope have been shown for the gonadotropin implicated in GnRH regulation (13), and such neurons genes, including Cga, Fshb, and Lhb (29, 30). With regard provide a potential indirect target by which glucocortico- to Lhb, androgen repression of Lhb involves protein-pro- ids may inhibit GnRH secretion or GnRH synthesis (14); tein interactions between the androgen receptor and ste- however, a direct action within the GnRH neuron itself is roidogenic factor 1 (SF1) and is localized to a bipartite supported by evidence that glucocorticoids blunt GnRH SF1 element within the LH␤ proximal promoter, critical synthesis and release from immortalized GnRH neurons, for mediating GnRH responsiveness (31, 32). Progester- GT1–7 cells (15, 16). Thus, the mechanism whereby glu- one repression also involves indirect receptor binding but cocorticoids suppress GnRH and LH remains unclear and differs from androgen repression of LH␤ gene expression may involve direct actions upon the GnRH neuron itself, in that, rather than SF1 elements, progesterone repression indirect actions via another neuronal cell type, or actions involves two novel promoter regions located upstream of upon an extrahypothalamic site. the SF1 sites. Similar to progestins and androgens, gluco- With regard to a site outside of the central nervous corticoids have been shown to inhibit LH␤ gene expres- system, the most obvious possibility is that glucocortico- sion (29, 33), although the mechanism is unclear, raising ids act via GR located within gonadotrope cells of the the possibility that stress impairs fertility by way of dis- anterior pituitary gland. Evidence that glucocorticoids re- ruption of gene expression within the gonadotrope cell. duce the amplitude of the LH response to a GnRH chal- We initiated two lines of investigation in the mouse to lenge in rodents, pigs, cows, and women is consistent with tease apart the mechanisms whereby elevated glucocorti- this possibility (17–20). Further, suppression of respon- coids inhibit gonadotrope responsiveness during episodes siveness to GnRH in vitro has been observed in rodent, of stress. First, we tested the hypothesis that restraint porcine, and bovine pituitary cell cultures, indicating that stress, and/or an elevation in glucocorticoids mimicking glucocorticoids can act directly upon the gonadotrope cell the level induced by restraint stress, can disrupt reproduc- to inhibit responsiveness to GnRH (19–21). Consistent tive function and inhibit gonadotrope production of LH with an action upon the gonadotrope cell, GR has been in female mice. Second, we conducted a series of studies to identified in rat gonadotropes (22), and studies in rat and examine the molecular mechanisms underlying glucocor- pig primary cells suggest that glucocorticoids inhibit sig- ticoid regulation of the LH␤ promoter utilizing the im- naling mechanisms downstream of the GnRH receptor, ␤ including protein kinase C and cAMP (20, 23). It is not mortalized L T2 gonadotrope cell line. known, however, whether these nongenomic actions of glucocorticoids that inhibit intracellular signaling path- ways ultimately lead to a reduction in LH release. Alter- Materials and Methods natively, evidence suggests that glucocorticoids can act Animals genomically to suppress gonadotrope responsiveness by Female C57Bl/6 mice (6 wk of age) were purchased from The regulating transcription and translation of the GnRH re- Jackson Laboratory (Bar Harbor, ME), and housed in a UCSD ceptor gene (24, 25). vivarium animal facility under standard conditions. All animals Another potential mechanism whereby glucocortico- were housed under a 12-h light, 12-h dark cycle (lights on at ids could diminish GnRH responsiveness of the gonado- 0700 h) and provided with food and water ad libitum. Mice trope is via regulation of gonadotropin synthesis. At the were group housed (four females per cage) for 2 wk of acclima- tization. All experimentation was performed between 0900 and molecular level, LH and FSH are glycoprotein hormones 1300 h in a room within
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