Testosterone metabolism in brain cells and membranes

doi:10.1016/0960-0760(91)90289-H

The Journal of Steroid Biochemistry and Molecular Biology

Volume 40, Issues 4–6, 1991, Pages 673-678

https://doi.org/10.1016/0960-0760(91)90289-H Get rights and content

Abstract

The central nervous system (CNS) is considered a target structure for the action of all the classes of hormonal steroids produced by the organism. Well-characterized genomic and less well-understood membrane mechanisms of action are probably involved in the steroid modulation of brain activities. Moreover, some classes of steroids need to be converted into “active” metabolites before interacting with their effector systems. In particular, testosterone (T) exerts many of its effects after conversion to 5α-dihydrotestosterone (DHT) and estrogens. The CNS possesses both the 5α-reductase, the enzyme which produces DHT and the aromatase which transforms T into estrogens; however, the relative role and distribution of these enzymes in the various structural components of the CNS has not been clarified so far. The 5α-reductase has been found to be present in high concentrations in brain white matter structures because these are particularly rich in myelin membranes, to which the enzymatic activity appears to be associated. This membrane localization might suggest a possible involvement of steroidal 5α-reduced metabolites in membrane-mediated events in the CNS. Moreover, the distribution of 5α-reductase was studied in neurons, astrocytes and oligodendrocytes isolated from the brain of male rats by density gradient ultracentrifugation, as well as in neurons and glial cells grown in culture. The aromatase activity was also evaluated in neurons and glial cells grown in culture and in isolated oligodendrocytes. Among the three cell types isolated, neurons appear to be more active than oligodendrocytes and astrocytes, respectively, in converting T into DHT. Also, in cell culture experiments, neurons are more active in forming DHT than glial cells. Only neurons possess aromatase activity, while glial cells are apparently unable to aromatize T.

References (34)

I. Nenci et al.
The plasma membrane as an additional level of steroid-cell interaction
J. Steroid Biochem.
(1981)
D.E. Dluzen et al.
Progesterone effects upon dopamine release from corpus striatum of female rats. II. Evidence for a membrane site of action and the role of albumin
Brain Res.
(1989)
B.S. McEwen et al.
Steroid hormones: humoral signals which alter brain cell properties and functions
Recent Prog. Horm. Res.
(1982)
L.M. Garcia-Segura et al.
Astrocytic shape and glial fibrillary acidic protein immunoreactivity are modified by estradiol in primary rat hypothalamic cultures
Devl Brain Res.
(1989)
J.P. O'Callaghan et al.
Glucocorticoids regulate the concentration of glial fibrillary acidic protein throughout the brain
Brain Res.
(1989)
M. Palkovits
Isolated removal of hypothalamic or other brain nuclei of the rat
Brain Res.
(1973)
F. Celotti et al.
Is the 5α-reductase of the hypothalamus and of the anterior pituitary neurally regulated? Effects of hypothalamic deafferentations and of centrally acting drugs
J. Steroid Biochem.
(1983)
R.C. Melcangi et al.
Testosterone 5α-reductase in discrete hypothalamic nuclear areas in the rat: effect of castration
Steroids
(1985)
R.C. Melcangi et al.
Testosterone 5α-reductase activity in the rat brain is highly concentrated in white matter structures and in purified myelin sheaths of axon
J. Steroid Biochem.
(1988)
R.C. Melcangi et al.
The 5α-reductase activity of the subcortical white matter, the cerebral cortex, and the hypothalamus of the rat and the mouse: possible sex differences and effect of castration
Steroids
(1987)

F. Celotti et al.

Differential distribution of the 5α-reductase in the central nervous system of the rat and the mouse: are the white matter structures of the brain target tissue for testosterone action?

J. Steroid Biochem.

(1987)

A. Poletti et al.

Kinetics properties of the 5α-reductase of testosterone in purified myelin, in the subcortical white matter and in the cerebral cortex of the male rat brain

J. Steroid Biochem.

(1990)

R.C. Melcangi et al.

Ontogenetic development of the 5 alpha-reductase in the rat brain: cerebral cortex, hypothalamus, purified myelin and isolated oligodendrocytes

Devl Brain Res.

(1988)

R.C. Melcangi et al.

5α-Reductase activity in isolated and cultured neuronal and glial cells of the rat

Brain Res.

(1990)

L.N. Berti Mattera et al.

Isolation of oligodendroglial cells from young and adult whole rat brains using an in situ generated percoll density gradient

Neurochem. Int.

(1984)

J. Borg et al.

Selective cultures of neurons from rat cerebral cortex: morphological characterization, glutamate uptake and related enzymes during maturation in various culture media

Devl Brain Res.

(1985)

G. Labourdette et al.

S-100 protein in monolayer cultures of glial cells: basal level in primary and secondary cultures

Biochem. Biophys. Res. Commun.

(1978)

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Testosterone metabolism in brain cells and membranes

Abstract

J. Steroid Biochem.

Brain Res.

Recent Prog. Horm. Res.

Devl Brain Res.

Brain Res.

Brain Res.

J. Steroid Biochem.

Steroids

J. Steroid Biochem.

Steroids

J. Steroid Biochem.

J. Steroid Biochem.

Devl Brain Res.

Brain Res.

Neurochem. Int.

Devl Brain Res.

Biochem. Biophys. Res. Commun.