PITUITARY FOLLISTATIN REGULATES ACTIVIN-MEDIATED PRODUCTION OF FOLLICLE-STIMULATING-HORMONE DURING THE RAT ESTROUS-CYCLE

Follistatin, an activin-binding protein, plays a key role in the modul ation of activin-dependent functions. In the anterior pituitary, activ in stimulates the synthesis and secretion of FSH. In the current study , we assessed the roles of locally produced activin and follistatin in the control of FSH gene expression and secretion. The anterior pituit ary gland follistatin content was measured at frequent intervals durin g the rat estrous cycle. Follistatin protein levels were high before t he primary gonadotropin surges, decreased by 50% on proestrous evening , and rebounded to a peak at midnight on proestrus before returning to presurge levels on estrus morning. Changes in pituitary follistatin p rotein content were preceded by parallel changes in pituitary follista tin messenger RNA (mRNA). The trough in follistatin protein content on proestrus coincided with a peak in circulating levels of free activin A (not bound to follistatin) and a sharp rise in FSH beta mRNA levels , suggesting that decreased pituitary follistatin leads to increased a vailable activin. To quantitate the contribution of pituitary free act ivin to pituitary expression of FSH beta mRNA and the primary and seco ndary serum FSH surges, rats were infused through carotid catheters wi th saline or recombinant human follistatin (288-amino acid isoform; rh FS-288) at different times during the estrous cycle. Infusion of rhFS- 288 on diestrus did not affect FSH production. In contrast, infusion o f rhFS-288 during the secondary FSH surge decreased the peaks in FSH b eta mRNA and serum FSH by 63% and 47%, respectively, relative to those in saline-infused control animals. Infusion of rhFS-288 during the pr imary FSH surge decreased serum FSK to a lesser degree (24%). These da ta indicate a physiological role for pituitary follistatin in the cont rol of activin-mediated FSH synthesis and secretion during the rat est rous cycle.