ACTIVIN-A AND FOLLISTATIN ARE DYNAMICALLY REGULATED DURING HUMAN-PREGNANCY

Activin A (beta(A)-beta(A)) and activin B (beta(B)-beta(B)) are relate d dimeric proteins that regulate numerous cellular activities. Activin activity is bioneutralized by follistatin, a specific and high-affini ty binding protein. Recently, our group developed specific and sensiti ve enzyme-linked immunosorbent activin assays that do not detect eithe r activin isoform when bound to follistatin, therefore, the assays are specific for biologically relevant ligands. Activin A is measurable i n the serum of pregnant women (cross-sectional sample collection), whi le activin B is not detected in maternal serum. However, activin B is measurable in amniotic fluid and cord blood sera. The purpose of this study was to measure serum activin A, activin B, and follistatin prosp ectively in longitudinally collected samples during pregnancy. This st udy design offered observations of relative changes in serum hormone c oncentration with each person serving as an internal reference. Serum samples were collected bimonthly from seven pregnant women beginning w ithin the second month of gestation, and up to, but not including, the onset of labor. Six of the seven women had normal labor and delivery. One patient required pitocin (an oxytocin agonist) for induction of l abor which led to delivery. Activin A, activin B, total follistatin, f ree follistatin, human chorionic gonadotropin, estradiol, progesterone , FSH, and LH were measured in maternal serum samples using specific a ssays. Serum activin A levels increased in the final month of pregnanc y in the six patients who delivered following normal labor (<0.78 ng/m l (first trimester) to 1-6 ng/ml (term)). Activin B was not detected i n any serum sample (<0.78 pg/ml). Total serum follistatin (free follis tatin, follistatin-activin, and follistatin-inhibin) increased 10- to 45-fold in the final month of pregnancy in four of the women undergoin g normal labor (10 ng/ml (first trimester) to 100-450 ng/ml (final mon th)). Total follistatin was high and variable in two women throughout pregnancy. Total follistatin returned to basal serum concentration in three of the patients during the last 2 weeks of pregnancy. Free folli statin was detected throughout pregnancy (range <2-35 ng/ml). Free fol listatin represented a small percentage of the total follistatin throu ghout the time of pregnancy and did not rise coincident with the rise in total follistatin. Serum activin A and activin B were not detected during the entire course of pregnancy in the one patient who did not h ave normal labor and total follistatin did not rise in the last trimes ter of pregnancy. Gonadotropin and steroid hormones were measured in a ll patients and were within normative ranges for human pregnancy (incl usive of the non-laboring patient). The results suggest that immunodet ectable activin A is present in the third trimester of: pregnant women who have normal onset labor. The total follistatin assay results sugg est that follistatin-activin (or -inhibin) complexes are upregulated d uring the third trimester of pregnancy. Importantly, activin A product ion exceeds the binding capacity of circulating follistatin. Because b inding protein free activin A is biologically active we conclude that the activin A detected in late pregnancy is biologically relevant. The findings are consistent with our hypothesis that activin A is an endo crine factor during the last trimester of human pregnancy and may be i nvolved in normal labor.