FOLLISTATIN ANTAGONIZES THE EFFECTS OF ACTIVIN-A ON STEROIDOGENESIS IN HUMAN LUTEINIZING GRANULOSA-CELLS

Activin-A decreases progesterone secretion and aromatase activity in c ultured human luteinizing granulosa cells. Follistatin is a binding pr otein for activin and inhibin produced by granulosa cells and present in follicular fluid. The present study examines the hypothesis that fo llistatin reverses the actions of activin-A on human granulosa cells. Granulosa cells from women undergoing ovarian stimulation for in vitro fertilization were cultured in defined medium with recombinant human (rh) activin-A and purified porcine follistatin. Follistatin completel y reversed the inhibition of basal progesterone production by rh-activ in-A, but only when added in a greater than 2:1 molar ratio to activin -A. Although variable effects of activin-A on aromatase activity were observed in these studies, follistatin also antagonized these effects. Follistatin had no effect in the absence of added activin-A. rh-Inhib in-A did not alter steroidogenesis by granulosa cells either with or w ithout added activin-A. Even when added in a 45-fold molar excess, inh ibin-A did not displace sufficient activin-A from follistatin to inhib it progesterone secretion. This suggests that the affinity of inhibin- A for follistatin is much lower than that of activin-A, and/or that ac tivin-A bound to follistatin dissociates slowly. alpha(2)-Macroglobuli n, another activin-binding protein, did not alter the inhibition of pr ogesterone production by activin-A. We conclude that in human granulos a cells, follistatin, but not alpha(2)-macroglobulin or inhibin-A, act s to modulate the actions of activin-A. Follistatin and activin may be viewed as components of an autocrine/paracrine system within the huma n follicle that regulate the differentiated functions of granulosa cel ls.