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Department of Reproductive Medicine, University of California-San Diego School of Medicine, La Jolla, California 92093-0633
Address all correspondence and requests for reprints to: Ismail Zwain, Ph.D., Department of Reproductive Medicine, BSB-5045, University of California-San Diego School of Medicine, 9500 Gilman Drive, La Jolla, California 92093-0633. E-mail: izwain{at}ucsd.edu
The brain is a steroidogenic organ that expresses steroidogenic enzymes
and produces neurosteroids. Although considerable information is now
available regarding the steroidogenic capacity of the brain, little is
known regarding the steroidogenic pathway and relative contributions of
astrocytes, oligodendrocytes, and neurons to neurosteroidogenesis. In
the present study, we investigated differential gene expression of the
key steroidogenic enzymes using RT-PCR and quantitatively evaluated the
production of neurosteroids by highly purified astrocytes,
oligodendrocytes, and neurons from the cerebral cortex of neonatal rat
brains using specific and sensitive RIAs. Astrocytes appear to be the
most active steroidogenic cells in the brain. These cells express
cytochrome P450 side-chain cleavage (P450scc),
17
-hydroxylase/C17–20-lyase (P450c17), 3ß-hydroxysteroid
dehydrogenase (3ßHSD), 17ß-hydroxysteroid dehydrogenase (17ßHSD),
and cytochrome P450 aromatase (P450arom) and produce pregnenolone (P5),
progesterone (P4), dehydroepiandrosterone (DHEA),
androstenedione (A4), testosterone (T), estradiol, and estrone.
Oligodendrocytes express only P450scc and 3ßHSD and produce P5, P4,
and A4. These cells do not express P450c17, 17ßHSD, or P450arom or
produce DHEA, T, or estrogen. Neurons express P450scc,
P450c17, 3ßHSD, and P450arom and produce P5, DHEA, A4,
and estrogen, but do not express 17ßHSD or produce T. By comparing
the ability of each cell type in the production of neurosteroids,
astrocytes are the major producer of P4, DHEA, and
androgens, whereas oligodendrocytes are predominantly the producer of
P5 and neurons of estrogens. These findings serve to define the
neurosteroidogenic pathway, with special emphasis on the dominant role
of astrocytes and their interaction with oligodendrocytes and neurons
in the genesis of DHEA and active sex steroids. Thus, we
propose that neurosteroidogenesis is accomplished by a tripartite
contribution of the three cell types in the brain.
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