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

The FSHβ 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 FSHβ may be mediated by pituitary expression of activin, which stimulates FSHβ messenger RNA (mRNA), and follistatin, which blocks activin. Using a system of perifused male rat pituitary cells, a reciprocal relationship was observed between FSHβ and follistatin mRNAs in response to different patterns of GnRH treatment. Pulses of GnRH (5 min; 10 nM) applied every 60 min stimulated FSHβ 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 FSHβ mRNA, and continuous GnRH stimulated follistatin mRNA 4.1-fold, with no significant increase in FSHβ mRNA. Stimulation of FSHβ 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 FSHβ 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 FSHβ 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 μg/h), continuous GnRH suppressed FSHβ mRNA levels to 50% of the control value, and follistatin decreased expression to 61% of the control value. We conclude that GnRH stimulation of FSHβ mRNA is activin dependent, and pituitary follistatin production is a major pathway by which higher GnRH pulse frequencies suppress FSHβ 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.