Follistatin antagonizes the effects of activin-A on steroidogenesis in human luteinizing granulosa cells.
Activin-A decreases progesterone secretion and aromatase activity in cultured human luteinizing granulosa cells. Follistatin is a binding protein for activin and inhibin produced by granulosa cells and present in follicular fluid. The present study examines the hypothesis that follistatin 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 completely reversed the inhibition of basal progesterone production by rh-activin-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-Inhibin-A did not alter steroidogenesis by granulosa cells either with or without added activin-A. Even when added in a 45-fold molar excess, inhibin-A did not displace sufficient activin-A from follistatin to inhibit progesterone secretion. This suggests that the affinity of inhibin-A for follistatin is much lower than that of activin-A, and/or that activin-A bound to follistatin dissociates slowly. alpha 2-Macroglobulin, another activin-binding protein, did not alter the inhibition of progesterone production by activin-A. We conclude that in human granulosa cells, follistatin, but not alpha 2-macroglobulin or inhibin-A, acts to modulate the actions of activin-A. Follistatin and activin may be viewed as components of an autocrine/paracrine system within the human follicle that regulate the differentiated functions of granulosa cells.
Cataldo
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Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco 94143-0556.
Rabinovici
J
J
Fujimoto
V Y
VY
Jaffe
R B
RB
D028341:Activins; D001141:Aromatase / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D005307:Fertilization in Vitro; D038681:Follistatin; D006023:Glycoproteins / Q000494:pharmacology*; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007265:Inhibins / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000494:pharmacology; D011374:Progesterone / Q000096:biosynthesis* / Q000378:metabolism; D000511:alpha-Macroglobulins / Q000494:pharmacology
D038681:Follistatin; D006023:Glycoproteins; D007328:Insulin; D008077:Lipoproteins, LDL; D000511:alpha-Macroglobulins; D028341:Activins; D011374:Progesterone; D007265:Inhibins; D001141:Aromatase