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.