Besecke L M, Guendner M J, Schneyer A L, Bauer-Dantoin A C, Jameson J L, Weiss J
Center for Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Medical School, Chicago, Illinois 60611, USA.
Endocrinology. 1996 Sep;137(9):3667-73. doi: 10.1210/endo.137.9.8756531.
The FSH beta gene is stimulated by low frequency pulses of GnRH, but is unaffected or suppressed when GnRH is applied at higher frequencies or continuously. The current studies explored the hypothesis that GnRH frequency-dependent regulation of FSH beta may be mediated by pituitary expression of activin, which stimulates FSH beta messenger RNA (mRNA), and follistatin, which blocks activin. Using a system of perifused male rat pituitary cells, a reciprocal relationship was observed between FSH beta and follistatin mRNAs in response to different patterns of GnRH treatment. Pulses of GnRH (5 min; 10 nM) applied every 60 min stimulated FSH beta mRNA 14.0-fold with no change in follistatin mRNA. Pulses of GnRH applied every 30 and 15 min elicited stepwise increases in follistatin mRNA and decreases in FSH beta mRNA, and continuous GnRH stimulated follistatin mRNA 4.1-fold, with no significant increase in FSH beta mRNA. Stimulation of FSH beta mRNA by hourly GnRH pulses (3.7-fold) was blocked in the presence of 30 ng/ml recombinant follistatin (0.8-fold), suggesting that GnRH stimulation of FSH beta mRNA requires endogenous activin. Treatment of plated pituitary cells with continuous GnRH for 24 h confirmed that secretion of follistatin protein rises (1.5-fold) coincident with follistatin mRNA (1.7-fold) under conditions that suppress FSH beta mRNA (9% of the control value). When male rats were infused through arterial cannulas for 6 h with continuous GnRH (100 nM) or recombinant follistatin (5 micrograms/h), continuous GnRH suppressed FSH beta mRNA levels to 50% of the control value, and follistatin decreased expression to 61% of the control value. We conclude that GnRH stimulation of FSH beta mRNA is activin dependent, and pituitary follistatin production is a major pathway by which higher GnRH pulse frequencies suppress FSH beta mRNA. Changes in activin or follistatin tone, therefore, provide a mechanism by which LH and FSH can be differentially regulated by GnRH in a variety of physiological and pathophysiological conditions.
促卵泡激素β（FSHβ）基因受促性腺激素释放激素（GnRH）低频脉冲刺激，但当以较高频率或持续应用GnRH时，该基因不受影响或被抑制。目前的研究探讨了以下假说：GnRH对FSHβ的频率依赖性调节可能由垂体中激活素的表达介导，激活素可刺激FSHβ信使核糖核酸（mRNA），而卵泡抑素则可阻断激活素。利用灌流雄性大鼠垂体细胞系统，在不同模式的GnRH处理下，观察到FSHβ和卵泡抑素mRNA之间存在反向关系。每60分钟给予一次GnRH脉冲（5分钟；10 nM）可使FSHβ mRNA增加14.0倍，而卵泡抑素mRNA无变化。每30分钟和15分钟给予一次GnRH脉冲可使卵泡抑素mRNA逐步增加，FSHβ mRNA减少，持续给予GnRH可使卵泡抑素mRNA增加4.1倍，而FSHβ mRNA无显著增加。在存在重组卵泡抑素（30 ng/ml）的情况下，每小时一次的GnRH脉冲对FSHβ mRNA的刺激作用（3.7倍）受到阻断（0.8倍），这表明GnRH对FSHβ mRNA的刺激需要内源性激活素。用持续GnRH处理培养的垂体细胞24小时证实，在抑制FSHβ mRNA（为对照值的9%）的条件下，卵泡抑素蛋白的分泌增加（1.5倍），与卵泡抑素mRNA增加（1.7倍）同时出现。当通过动脉插管给雄性大鼠持续输注GnRH（100 nM）或重组卵泡抑素（5微克/小时）6小时时，持续GnRH可使FSHβ mRNA水平降至对照值的50%，卵泡抑素可使表达降至对照值的61%。我们得出结论，GnRH对FSHβ mRNA的刺激依赖于激活素，垂体卵泡抑素的产生是较高GnRH脉冲频率抑制FSHβ mRNA的主要途径。因此，激活素或卵泡抑素水平的变化提供了一种机制，通过该机制，在各种生理和病理生理条件下，GnRH可对黄体生成素（LH）和FSH进行差异调节。
