Testosterone and progesterone metabolism in the central nervous system: cellular localization and mechanism of control of the enzymes involved

This paper summarizes the most recent data obtained in the authors' laboratory on the metabolism of testosterone and progesterone in neurons and in the glia. 1. The activities of 5 alpha-reductase (the enzyme that converts testosterone into dihydrotestosterone; DHT) and of 3 alpha-hydroxy steroid dehydrogenase (the enzyme that converts DHT into 5 alpha-androstane-3 alpha, 17 beta-diol; 3 alpha-diol) were first evaluated in primary cultures of neurons, oligodendrocytes, and type-1 and type-2 astrocytes, obtained from the fetal or neonatal rat brain. The formation of DHT and 3 alpha-diol was evaluated incubating the different cultures with labeled testosterone or labeled DHT as substrates. The results obtained indicate that the formation of DHT takes place preferentially in neurons; however, also type-2 astrocytes and oligodendrocytes possess considerable 5 alpha-reductase activity. A completely different localization was observed for 3 alpha-hydroxysteroid dehydrogenase; the formation of 3 alpha-diol appears to be prevalently, if not exclusively, present in type-1 astrocytes; 3 alpha-diol is formed in very low yields by neurons, type-2 astrocytes, and oligodendrocytes. Moreover, the results indicate that, in type 1 astrocytes, both 5 alpha-reductase and 3 alpha-HSD are stimulated by coculture with neurons and by the addition of neuron-conditioned medium, suggesting that secretory products released by neurons might intervene in the control of glial cell function. 2. Subsequently it was shown that, similarly to what happens when testosterone is used as the substrate, 5 alpha-reductase, which metabolizes progesterone into 5 alpha-pregnane-3,20-dione, (DHP), shows a significantly higher activity in neurons than in glial cells; however, also type-1 and type-2 astrocytes as well as oligodendrocytes possess some ability to 5 alpha-reduce progesterone. On the contrary, 3 alpha-hydroxysteroid dehydrogenase, the enzyme which converts DHP into 5 alpha-pregnane-3 alpha-ol-20-one (THP), appears to be present mainly in type-1 astrocytes; much lower levels of this enzyme are present in neurons and in type-2 astrocytes. At variance with the previous results obtained using androgens as precursors, oligodendrocytes show considerable 3 alpha-hydroxysteroid dehydrogenase activity, even if this is statistically lowe than that present in type-1 astrocytes. The existence of isoenzymatic forms of the enzymes involved in androgen and progesterone metabolism is discussed.