INTERACTION OF INSULIN-LIKE GROWTH FACTOR-II AND ESTRADIOL DIRECTS STEROIDOGENESIS IN THE HUMAN FETAL ADRENAL TOWARD DEHYDROEPIANDROSTERONE-SULFATE PRODUCTION
S. Mesiano et Rb. Jaffe, INTERACTION OF INSULIN-LIKE GROWTH FACTOR-II AND ESTRADIOL DIRECTS STEROIDOGENESIS IN THE HUMAN FETAL ADRENAL TOWARD DEHYDROEPIANDROSTERONE-SULFATE PRODUCTION, The Journal of clinical endocrinology and metabolism, 77(3), 1993, pp. 754-758
We examined the regulation of steroid production in fetal zone cells f
rom midgestation (16-21 weeks) human fetal adrenal glands to elucidate
the mechanism by which these cells secrete large quantities of dehydr
oepiandrosterone sulfate (DHAS) and little cortisol in response to ACT
H. Our underlying hypothesis is that estrogen and insulin-like growth
factor-II (IGF-II) modulate the steroidogenic response of fetal zone c
ells to ACTH, driving steroid production toward DHAS rather than corti
sol. We also hypothesize that the effects of IGF-II and estrogen on st
eroidogenesis are achieved by modulating the expression of key enzymes
in the steroidogenic pathway. Basal cortisol secretion by cultured fe
tal zone cells was below the limit of assay sensitivity (< 0.54 pmol/1
0(5) cells . 24 h), whereas basal DHAS secretion was 210.8 +/- 41.0 pm
ol/10(5) cells . 24 h (mean +/- SE). ACTH-(1-24) increased the secreti
on of cortisol to 228.96 +/- 6.75 pmol/10(5) cells . 24 h and that of
DHAS to 2039.8 +/- 121.7 pmol/10(5) cells . 24 h. Neither IGF-II nor e
stradiol (E2) affected basal (no added ACTH) steroid secretion by feta
l zone cells. IGF-II increased ACTH-stimulated cortisol and DHAS secre
tion by fetal zone cells in a dose-dependent fashion. In contrast, E2
at high concentrations (1-10 mumol/L) decreased ACTH-stimulated cortis
ol production to basal levels, but increased ACTH-stimulated DHAS prod
uction 1.5- to 2-fold. Combinations of IGF-II (100 ng/mL) and E2 (1 mu
mol/L) increased ACTH-stimulated cortisol and DHAS secretion by 1.5- t
o 2-fold compared with control values. However, compared with cultures
exposed to IGF-II alone, inclusion of E2 decreased ACTH-stimulated co
rtisol secretion by about 60% and increased ACTH-stimulated DHAS secre
tion by about 50%. IGF-II increased the abundance of ACTH-stimulated m
RNAs encoding cholesterol side-chain cleavage cytochrome P450 (P450scc
), 17alpha hydroxylase/17,20 lyase P450 (P450c17), and 3beta-hydroxyst
eroid dehydrogenase (3betaHSD). In addition, IGF-II increased the abun
dance of mRNA encoding P450c17 under basal conditions, but did not aff
ect the basal expression of P450scc or 3betaHSD. E2 had no effect on b
asal expression of these steroidogenic enzymes, but increased the abun
dance of ACTH-stimulated mRNA encoding P450scc and P450c17. The abunda
nce of mRNA encoding 3betaHSD was not affected by E2. The effect of IG
F-II and E2 in combination on steroidogenic enzyme mRNA abundance was
not different from that of IGF-II alone. These data indicate that IGF-
II increases ACTH-stimulated steroid production in fetal zone cells by
increasing the expression of key steroidogenic enzymes. Estrogen may
increase ACTH-stimulated DHAS secretion by increasing the expression o
f P450scc and P450c17. Although the mechanism by which estrogen inhibi
ts cortisol production is uncertain, our data clearly show that this e
ffect is not due to an inhibition of 3betaHSD expression. These data i
ndicate that IGF-II and E2 can influence the steroidogenic activity of
fetal zone cells. As the human fetal adrenal is exposed to high conce
ntrations of these substances, it is likely that they influence the st
eroidogenic response of fetal zone cells to ACTH in vivo, resulting in
the production of DHAS rather than cortisol.