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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

Division of Endocrinology, Department of Internal Medicine, and the Center for Research in Reproduction, University of Virginia, Charlottesville, Virginia 22908

Address all correspondence and requests for reprints to: Laura L. Burger University of Virginia, Department of Internal Medicine P.O. Box 801412, Charlottesville, Virginia 22908. E-mail: llb3k{at}virginia.edu.

We examined the time course of action of GnRH pulse frequency on gonadotropin subunit gene transcription and assessed the roles of GnRH, follistatin (FS), and activin on differential transcription of the LHß and FSHß genes. GnRH-deficient male rats were pulsed with 25 ng GnRH either every 30 min (fast frequency) or every 240 min (slow frequency) for 1–24 h.

Both GnRH frequencies increased primary transcript (PT) 5-fold within 6 h, but only fast frequency GnRH increased mRNA. Only fast frequency GnRH pulses affected LHß PT, resulting in 6- to 9-fold increases between 1–24 h. Fast frequency GnRH pulses transiently increased FSHß PT at 1 and 6 h (4- and 2-fold, respectively); but by 24 h FSHß PT had returned to control levels and was correlated to a 5- to 9-fold increase in FS mRNA. In contrast, slow GnRH pulses increased FSHß PT 3- and 6-fold at 8 and 24 h, respectively, which was correlated with a decline in FS mRNA. Activin mRNA did not change significantly after either GnRH frequency, but tended to fall after fast pulses.

To test whether activin was required for the effects of GnRH on FSHß transcription, rats were treated with GnRH pulses every 240 min for 8 h ± FS. FS treatment alone markedly decreased basal FSHß PT. GnRH in the presence of FS increased FSHß PT 8-fold but did not restore FSHß transcription to control or GnRH alone values.

In summary, whereas -subunit transcription is independent of frequency, an increase in mRNA requires fast frequency GnRH pulses. Fast frequency GnRH pulses increased both LHß and FSHß transcription, but the response of FSHß was transient. The sustained rise in FSHß transcription and mRNA expression required slow frequency GnRH pulses and was correlated to low FS mRNA. Neutralization of pituitary activin by exogenous FS markedly reduced basal FSHß PT and mRNA but did not prevent the stimulation of FSHß transcription by slow frequency GnRH pulses. These studies suggest that the frequency regulation of FSHß transcription involves both direct actions of GnRH and indirect effects, via changes in pituitary FS expression.

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