The aim of experiments in this proposal is to elucidate the intracellular mechanisms (2nd messengers) by which gonadotropin- releasing hormone (GnRH) stimulates expression of the alpha and LH beta subunit mRNAs required for LH synthesis by pituitary gonadotrope cells. The studies will be performed in vitro and physiologic pulses of GnRH used to stimulate pituitary gonadotropes. Gonadotrope responses will be assessed by measurement of GnRH receptors, alpha and LH beta mRNA concentration, LH storage and acute release. The effect of prolactin and gonadal steroids on cellular responses to GnRH will be determined. The intracellular mechanisms involved in transmitting the GnRH signal to stimulate LH subunit gene expression will be examined by measurement of mRNA responses to agents which bypass the GnRH receptor. The effects of both continuous and pulsatile elevation of intracellular calcium and cyclic nucleotides, and constant or intermittent stimulation of protein kinase C on LH subunit mRNA concentrations will be determined. By comparison of the effects of these stimuli with those following GnRH pulses, we aim to elucidate the intracellular mechanism(s) involved in transmission of the signal initiated by GnRH-receptor binding. Subsequent studies will examine if gonadal steroids regulate GnRH action by modifying LH subunit mRNA responses to the second messengers. Other studies will examine the mechanisms involved in desensitization of LH secretion by a continuous GnRH stimulus. The role of mRNA expression and the ability of GnRH to stimulate phosphoinositol hydrolysis in desensitized cells will be examined. The mechanisms of GnRH action have important implications for the regulation of fertility in humans and animals. A pulsatile GnRH stimulus is required to maintain LH secretion and continuous stimulation by GnRH desensitizes LH secretion. Specific syndromes of GnRH deficiency are recognized in humans and fertility can be restored by administration of GnRH in a pulsatile manner. Long acting GnRH agonists which desensitize LH release are being assessed as potential contraceptive agents. The elucidation of the exact mechanisms by which a pulsatile GnRH stimulus maintain LH synthesis and secretion are important for the development of future therapeutic regimens to both enhance or inhibit gonadotropin secretion.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
7R01HD023736-04
Application #
3323959
Study Section
Endocrinology Study Section (END)
Project Start
1988-02-01
Project End
1993-01-31
Budget Start
1991-02-01
Budget End
1992-01-31
Support Year
4
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Virginia
Department
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Kerrigan, J R; Yasin, M; Haisenleder, D J et al. (1995) Regulation of gonadotropin subunit messenger ribonucleic acid expression in gonadotropin-releasing hormone (GnRH)-deficient female rats: effects of GnRH, galanin, GnRH-associated peptide, neuropeptide-Y, and thyrotropin-releasing hormone. Biol Reprod 53:1-7
Haisenleder, D J; Yasin, M; Marshall, J C (1995) Regulation of gonadotropin, thyrotropin subunit, and prolactin messenger ribonucleic acid expression by pulsatile or continuous protein kinase-C stimulation. Endocrinology 136:13-9
Dalkin, A C; Gilrain, J T; Marshall, J C (1994) Ovarian regulation of pituitary inhibin subunit and activin receptor type II gene expression: evidence for a nonsteroidal inhibitory substance. Endocrinology 135:944-9
Kirk, S E; Dalkin, A C; Yasin, M et al. (1994) Gonadotropin-releasing hormone pulse frequency regulates expression of pituitary follistatin messenger ribonucleic acid: a mechanism for differential gonadotrope function. Endocrinology 135:876-80
Haisenleder, D J; Yasin, M; Yasin, A et al. (1993) Regulation of prolactin, thyrotropin subunit, and gonadotropin subunit gene expression by pulsatile or continuous calcium signals. Endocrinology 133:2055-61
Marshall, J C; Dalkin, A C; Haisenleder, D J et al. (1993) GnRH pulses--the regulators of human reproduction. Trans Am Clin Climatol Assoc 104:31-46
Lawson, D M; Haisenleder, D J; Marshall, J C (1993) A comparison of the temporal effects of estradiol and diethylstilbestrol on pituitary content of DNA, prolactin mRNA and prolactin and on serum prolactin levels in ovariectomized Holtzman rats. Life Sci 53:1267-72
Kerrigan, J R; Dalkin, A C; Haisenleder, D J et al. (1993) Failure of gonadotropin-releasing hormone (GnRH) pulses to increase luteinizing hormone beta messenger ribonucleic acid in GnRH-deficient female rats. Endocrinology 133:2071-9
Haisenleder, D J; Ortolano, G A; Yasin, M et al. (1993) Regulation of gonadotropin subunit messenger ribonucleic acid expression by gonadotropin-releasing hormone pulse amplitude in vitro. Endocrinology 132:1292-6
Haisenleder, D J; Yasin, M; Marshall, J C (1992) Enhanced effectiveness of pulsatile 3',5'-cyclic adenosine monophosphate in stimulating prolactin and alpha-subunit gene expression. Endocrinology 131:3027-33

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