The Frequency of Gonadotropin-Releasing-Hormone Stimulation Differentially Regulates Gonadotropin Subunit Messenger Ribonucleic Acid Expression*

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Abstract
The hypothalamic decapeptide GnRH is known to regulate the synthesis and secretion of LH and FSH by pituitary gonadotrope cells. The frequency of pulsatile GnRH secretion changes and LH and FSH are differentially secreted in various physiological situations. To investigate the potential role of altered frequency of GnRH stimulation in regulating differential secretion of LH and FSH, we examined the effects of GnRH pulses (25 ng/pulse) were administered to castrate testosterone-replaced rats at intervals of 8-480 min to cover the range of physiological pulsatile GnRH secretion. Fast frequency GnRH pulses (8 min pulse intervals) increased .alpha.-subunit mRNA concentrations 3-fold above those in saline-pulsed controls (controls, 1.01 fmol cDNA bound/100 .mu.g pituitary DNA) and LH.beta. mRNA by 50% (controls, 0.18 fmol cDNA bound), but FSH.beta. mRNA was unchanged (controls, 0.38 fmol cDNA bound). GnRH pulses given every 30 min increased all three subunit mRNAs (.alpha., 3-fold, LH.beta., 2-fold; FSH.beta., 2-fold), and acute LH release and serum FSH concentrations were maximal after this frequency. Slower frequency GnRH stimuli (120- to 480-min pulse intervals) did not change .alpha. and LH.beta. mRNA levels, but increased FSH.beta. mRNA 2- to 2.5-fold, and FSH secretion was maintained. Equalization of the total dose of GnRH given at different intervals over 24 h confirmed the frequency dependence of subunit mRNA expression. Fast frequency GnRH stimuli (8 min) increased .alpha. mRNA 1.5 to 2.5-fold, while the same total GnRH doses were ineffective when given at slow frequency (480 min). Similarly, LH.beta. mRNA was only increased by GnRH pulses given at 8-min intervals. In contrast, FSH.beta. mRNA increased 2-fold after pulse given every 480 min, and the 8-min pulse interval was ineffective. The data show that the frequency of GnRH stimulation can differentially regulate gonadotropin subunit mRNA expression and may be a mechanism that enables a single GnRH peptide to selectively regulate gonadotropin subunit gene expression and hormone secretion.