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Experimental Studies |
Reproductive Endocrinology Center, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, California 94143-0556
Address all correspondence and requests for reprints to: Dr. Robert B. Jaffe, Reproductive Endocrinology Center, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, California 94143-0556.
The fetal zone is a unique adrenal cortical compartment that exists
only during fetal life in humans and higher primates and produces large
amounts of the adrenal androgen dehydroepiandrosterone sulfate
(DHEA-S). Growth of the fetal zone is primarily regulated by ACTH, the
actions of which are mediated in part by locally produced
autocrine/paracrine growth factors. We previously demonstrated that one
of these growth factors, insulin-like growth factor II (IGF-II), is
mitogenic for cultured fetal zone cells and is produced in high
abundance by these cells in response to ACTH. In the present study, we
determined whether IGF-II also modulates the differentiated function of
fetal zone cells. We examined the effects of recombinant human IGF-II
and the closely related peptide, IGF-I, on 1) basal and
agonist-stimulated [ACTH-(1–24), forskolin, or 8-bromo-cAMP]
cortisol and DHEA-S production, 2) basal and ACTH-stimulated steady
state abundance of messenger ribonucleic acids (mRNAs) encoding the
steroidogenic enzymes cytochrome P450 side-chain cleavage (P450scc) and
cytochrome P450 17
-hydroxylase/17,20-lyase (P450c17), and 3) basal
and ACTH-stimulated steady state abundance of mRNA encoding the ACTH
receptor. Basal cortisol (23.93 ± 1.20 pmol/105
cells·24 h) and DHEA-S (548.87 ± 43.17 pmol/105
cells·24 h) productions were significantly (P <
0.05) increased by IGF-I (2.3- and 1.8-fold, respectively) and IGF-II
(2.8- and 1.8-fold, respectively). As expected, ACTH, forskolin, and
cAMP markedly increased the production of cortisol by 26-, 10-, and
13-fold, respectively, and that of DHEA-S by 5.4-, 4.6-, and 5.5-fold,
respectively, compared with basal levels. IGF-II (100 ng/mL)
significantly (P < 0.001) increased ACTH-,
forskolin-, and cAMP-stimulated production of cortisol by 2.4-, 4.3-,
and 3.2-fold, respectively, and that of DHEA-S by 1.4, 1.6-, and
1.4-fold, respectively. IGF-I (100 ng/mL) had similar effects as IGF-II
and significantly (P < 0.001) increased ACTH-,
forskolin-, and cAMP-stimulated production of cortisol by 2.8-, 3.9-,
and 3.1-fold, respectively, and that of DHEA-S by 1.3-, 1.6-, and
1.4-fold, respectively. The similar potencies of IGF-I and IGF-II
suggest that the actions of these factors were mediated via a common
receptor, most likely the type I IGF receptor. The effects of IGF-II
on ACTH-stimulated steroid production were dose-dependent
(EC50, 0.5–1.0 nmol/L), and IGF-II markedly increased the
steroidogenic responsiveness of fetal zone cells to ACTH. With respect
to cortisol production, IGF-II shifted the ACTH dose-response curve to
the left by 1 log10 order of magnitude. IGF-II also
increased ACTH-stimulated abundance of mRNA encoding P450scc (1.9-fold)
and P450c17 (2.2-fold). Basal expression of P450scc was not affected by
IGF-II. In contrast, basal expression of P450c17 was increased 2.2-fold
by IGF-II and IGF-I in a dose-responsive fashion. Neither IGF-I nor
IGF-II affected basal or ACTH-stimulated abundance of mRNA encoding the
ACTH receptor, suggesting that the increase in ACTH responsiveness was
not mediated by an increase in ACTH-binding capacity. Taken together,
these data indicate that activation of the type I IGF receptor
increases ACTH responsiveness in fetal zone cells by modulating ACTH
signal transduction at some point distal to ACTH receptor activation.
These data also indicate that locally produced IGF-II modulates fetal
adrenal cortical cell function by increasing responsiveness to ACTH and
possibly (based on its direct stimulation of P450c17 expression)
augmenting the potential for adrenal androgen synthesis. Thus,
activation of the type I IGF receptor on adrenal cortical cells may
play a pivotal role in adrenal androgen production, both
physiologically in utero and at adrenarche, and in
pathophysiological conditions of hyperandrogenemia, such as the
polycystic ovary syndrome.
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