Gonadotropin-releasing hormone regulates follicle-stimulating hormone-beta gene expression through an activin/follistatin autocrine or paracrine loop

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 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 mu g/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.