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The Population Council and Rockefeller University, New York, New York 10021
Address all correspondence and requests for reprints to: Dr. Matthew P. Hardy, The Population Council, 1230 York Avenue, New York, New York 10021. E-mail: hardy{at}popcbr.rockefeller.edu
Glucocorticoids directly regulate testosterone production in Leydig
cells through a glucocorticoid receptor (GR)-mediated repression of the
genes that encode testosterone biosynthetic enzymes. The extent of this
action is determined by the numbers of GR within the Leydig cell, the
intracellular concentration of glucocorticoid, and 11ß-hydroxysteroid
dehydrogenase (11ßHSD) activities that interconvert corticosterone
(in the rat) and its biologically inert derivative,
11-dehydrocorticosterone. As glucocorticoid levels remain stable during
pubertal development, GR numbers and 11ßHSD activities are the
primary determinants of glucocorticoid action. Therefore, in the
present study, levels of GR and 11ßHSD messenger RNA (mRNA) and
protein were measured in rat Leydig cells at three stages of pubertal
differentiation: mesenchymal-like progenitors (PLC) on day 21, immature
Leydig cells (ILC) that secrete 5
-reduced androgens on day 35, and
adult Leydig cells (ALC) that are fully capable of testosterone
biosynthesis on day 90. Numbers of GR, measured by
[3H]dexamethasone binding, in purified cells were
6.34 ± 0.27 (x103 sites/cell; mean ±
SE) for PLC, 30.45 ± 0.74 for ILC, and 32.54 ±
0.84 for ALC. Although GR binding was lower in PLC, steady state levels
for GR mRNA were equivalent at all three stages (P
> 0.05). Oxidative and reductive activities of 11ßHSD were measured
by assaying the conversion of radiolabeled substrates in incubations of
intact Leydig cells. Both oxidative and reductive activities were
barely detectable in PLC, intermediate in ILC, and highest in ALC. The
ratio of the two activities favored reduction in PLC and ILC and
oxidation in ALC (oxidation/reduction, 0.33 ± 0.33 for PLC,
0.43 ± 0.05 for ILC, and 2.12 ± 0.9 for ALC, with a ratio
of 1 indicating equivalent rates for both activities). The mRNA and
protein levels of type I 11ßHSD in Leydig cells changed in parallel
with 11ßHSD reductive activity, which increased gradually during the
transition from PLC to ALC, compared with the sharp rise that was seen
in oxidative activity. We conclude that Leydig cells at all
developmental stages have GR and that their ability to respond to
glucocorticoid diminishes as net 11ßHSD activity switches from
reduction to oxidation. This provides a mechanism for the Leydig cell
to regulate its intracellular concentration of corticosterone, thereby
varying its response to this steroid during pubertal development.
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