The proposed studies are intended to delineate the role of GnRH in the secretion of pituitary gonadotropins and the modulating effects of gonadal steroids. The mechanisms of GnRH action on the pituitary gland will be investigated. At the pituitary level GnRH can stimulate or inhibit gonadotropin secretion depending upon the manner of GnRH administration. The mechanisms of these paradoxical effects will be studied by measurement of plasma membrane GnRH receptors, mRNA concentrations for the gonadotropin subunits and LH and FSH secretion in different physiological and experimental circumstances. Additionally, as the nature of the intracellular transmission of the GnRH stimulus is unknown, the possibility that GnRH may act directly on the nucleus of the gonadotroph cell via a specific receptor will be determined. These studies will define the relative importance of plasma membrane and nuclear events in the control of gonadotropin synthesis and secretion and will allow insights into the intracellular site of steroid hormone feedback. The paradoxical effects of GnRH have led to clinical applications for both the induction of fertility and for contraception. Knowledge of the mechanisms of these actions is critical in order to provide the basis for rational future therapeutic uses of GnRH and its analogs.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Reproductive Biology Study Section (REB)
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University of Michigan Ann Arbor
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Ann Arbor
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Burger, Laura L; Haisenleder, Daniel J; Aylor, Kevin W et al. (2008) Regulation of intracellular signaling cascades by GNRH pulse frequency in the rat pituitary: roles for CaMK II, ERK, and JNK activation. Biol Reprod 79:947-53
Haisenleder, D J; Burger, L L; Walsh, H E et al. (2008) Pulsatile gonadotropin-releasing hormone stimulation of gonadotropin subunit transcription in rat pituitaries: evidence for the involvement of Jun N-terminal kinase but not p38. Endocrinology 149:139-45
Burger, Laura L; Haisenleder, Daniel J; Wotton, Gordon M et al. (2007) The regulation of FSHbeta transcription by gonadal steroids: testosterone and estradiol modulation of the activin intracellular signaling pathway. Am J Physiol Endocrinol Metab 293:E277-85
Haisenleder, Daniel J; Aylor, Kevin W; Burger, Laura L et al. (2006) Stimulation of FSHbeta transcription by blockade of endogenous pituitary follistatin production: Efficacy of adenoviral-delivered antisense RNA in the rat. Endocrine 29:399-404
Haisenleder, D J; Burger, L L; Aylor, K W et al. (2005) Testosterone stimulates follicle-stimulating hormone beta transcription via activation of extracellular signal-regulated kinase: evidence in rat pituitary cells. Biol Reprod 72:523-9
Prendergast, Kathleen A; Burger, Laura L; Aylor, Kevin W et al. (2004) Pituitary follistatin gene expression in female rats: evidence that inhibin regulates transcription. Biol Reprod 70:364-70
Burger, Laura L; Haisenleder, Daniel J; Aylor, Kevin W et al. (2004) Regulation of luteinizing hormone-beta and follicle-stimulating hormone (FSH)-beta gene transcription by androgens: testosterone directly stimulates FSH-beta transcription independent from its role on follistatin gene expression. Endocrinology 145:71-8
Burger, L L; Haisenleder, D J; Dalkin, A C et al. (2004) Regulation of gonadotropin subunit gene transcription. J Mol Endocrinol 33:559-84
Haisenleder, D J; Burger, L L; Aylor, K W et al. (2003) Gonadotropin-releasing hormone stimulation of gonadotropin subunit transcription: evidence for the involvement of calcium/calmodulin-dependent kinase II (Ca/CAMK II) activation in rat pituitaries. Endocrinology 144:2768-74
Burger, Laura L; Dalkin, Alan C; Aylor, Kevin W et al. (2002) GnRH pulse frequency modulation of gonadotropin subunit gene transcription in normal gonadotropes-assessment by primary transcript assay provides evidence for roles of GnRH and follistatin. Endocrinology 143:3243-9

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