Summary
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 5α-reductase (the enzyme that converts testosterone into dihydrotestosterone; DHT) and of 3α-hydroxy steroid dehydrogenase (the enzyme that converts DHT into 5α-androstane-3α,17β-diol; 3α-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 3α-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 5α-reductase activity. A completely different localization was observed for 3α-hydroxysteroid dehydrogenase; the formation of 3α-diol appears to be prevalently, if not exclusively, present in type-1 astrocytes; 3α-diol is formed in very low yields by neurons, type-2 astrocytes, and oligodendrocytes. Moreover, the results indicate that, in type 1 astrocytes, both 5α-reductase and 3α-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, 5α-reductase, which metabolizes progesterone into 5α-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 5α-reduce progesterone. On the contrary, 3α-hydroxysteroid dehydrogenase, the enzyme which converts DHP into 5α-pregnane-3α-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 3α-hydroxysteroid dehydrogenase activity, even if this is statistically lower than that present in type-1 astrocytes. The existence of isoenzymatic forms of the enzymes involved in androgen and progesterone metabolism is discussed.
Similar content being viewed by others
References
Andersson, S., and Russell, D. W. (1990). Structural and biochemical properties of cloned and expressed human and rat 5α-reductases.Proc. Natl. Acad. Sci. USA 873640–3644.
Andersson, S., Berman, D. M., Jenkins, E. P., and Russell, D. W. (1991). Deletion of steroid 5α-reductase-2 gene in male pseudohermaphroditism.Nature 354159–161.
Banker, G. A. (1980). Trophic interactions between astroglial cells and hippocampal neurons in culture.Science 209809–810.
Baulieu, E.-E., and Robel, P. (1990). Neurosteroids: A new brain function?J. Steroid Biochem. 37395–403.
Bonsall, R. W., Zumpe, D., and Michael, R. P. (1990). Comparisons of the nuclear uptake of (3H)-testosterone and its metabolites by the brains of male and female macaque fetuses at 122 days of gestation.Neuroendocrinology 51474–480.
Campbell, J. S., and Karavolas, H. J. (1989). The kinetic mechanism of the hypothalmic progesterone 5α-reductase.J. Steroid Biochem. 32283–289.
Celotti, F., Melcangi, R. C., Negri-Cesi, P., and Poletti, A. (1991). Testosterone metabolism in brain cells and membranes.J. Steroid Biochem. Mol. Biol. 40673–678.
Celotti, F., Melcangi, R. C., and Martini, L. (1992). The 5α-reductase in the brain: Molecular aspects and relation to brain function. InFrontiers in Neuroendocrinology (L. Martini and W. F. Ganong, Eds.), Raven Press, New York, Vol. 13, pp. 163–215.
Cheng, K.-C. (1992). Molecular cloning of rat liver 3α-hydroxysteroid dehydrogenase and identification of structurally related proteins from rat lung and kidney.J. Steroid Biochem. Mol. Biol. 431083–1088.
Cheng, K.-C., White, P. C., and Quin, K.-N. (1991). Molecular cloning and expression of rat liver 3α-hydroxysteroid dehydrogenase.Mol. Endocrinol. 5823–828.
Corvalan, V., Cole, R., de Vellis, J., and Hagiwara, S. (1990). Neuronal modulation of calcium channel activity in cultured rat astrocytes.Proc. Natl. Acad. Sci. USA 874345–4348.
Frankfurt, M., Gould, F., Woolley, C. S., and McEwen, B. S. (1990). Gonadal steroids modify dendritic spine density in ventromedial hypothalamic neurons: A Golgi study in adult rat.Neuroendocrinology 51530–535.
Frye, C. A., and DeBold, J. F. (1993). 3α-OH-DHP and 5α-THDOC implants to the ventral tegmental area facilitate sexual receptivity in hamsters after progesterone priming to the ventral medial hypothalamus.Brain Res. 612130–137.
Gasser, U. E., and Hatten, M. E. (1990). Neuron-glia interactions of rat hippocampal cells in vitro: Glial-guided neuronal migration and neuronal regulation of glial differentiation.J. Neurosci. 101276–1285.
George, F. W., and Peterson, K. G. (1988). 5α-Dihydrotestosterone formation is necessary for embryogenesis of the rat prostate.Endrocrinology 1221159–1164.
Hansson, E. (1989). Co-existence between receptors, carriers, and second messengers on astrocytes grown in primary cultures.Neurochem. Res. 14811–819.
Harrison, N. L., Majewska, M. D., Harrington, J. W., and Barker, J. L. (1987). Structure-activity relationships for steroid interaction with the gamma-amminobutyric acidA receptor complex.J. Pharmacol. Exp. Ther. 241346–353.
Hatten, M. E., Lynch, M., Rydel, R. E., Sanchez, J., Joseph-Silverstein, J., Moscateli, D., and Rifkin, D. B. (1988). In vitro neurite extension by granule neurons is dependent upon astroglial-derived fibroblast growth factor.Dev. Biol. 125280–289.
Imperato-McGinley, J., Shackleton, C., Orlic, S., and Stoner, E. (1990). C19 and C21 5β/5α metabolite ratios in subjects treated with the 5α-reductase inhibitor Finasteride: Comparison of male pseudohermaphrodites with inherited 5α-reductase deficiency.J. Clin. Endocrinol. Metab. 70777–78.
Jung-Testas, I., Renoir, M., Bugnard, H., Greene, G. L., and Baulieu, E. E. (1992). Demonstration of steroid hormone receptors and steroid action in primary cultures of rat glial cells.J. Steroid Biochem. Mol. Biol. 41621–631.
Kabbadj, K., El-Etr, M., Baulieu, E.-E., and Robel, P. (1993). Pregnenolone metabolism in rodent embryonic neurons and astrocytes.Glia 7170–175.
Kraulis, I., Foldes, G., Traikov, H., Dubrovsky, B., and Birmingham, M. K. (1975). Distribution, metabolism and biological activity of deoxycorticosterone in the central nervous system.Brain Res. 88114.
Krieger, N. R., and Scott, R. G. (1989). Non-neuronal localization for steroid converting enzyme: 3α-Hydroxysteroid oxidoreductase in olfactory tubercule of rat brain.J. Neurochem. 521866–1870.
Langub, M. C., and Watson, R. E. (1992). Estrogen receptor-immunoreactive glia, endothelia, and ependyma in guinea pig preoptic area and median eminence: Electron microscopy.Endocrinology 130364–372.
Leedy, M., Beattie, M. S., and Bresnahan, J. C. (1987). Testosterone-induced plasticity of synaptic inputs to adult mammalian motoneurons.Brain Res. 424386–390.
Lindsay, R. M. (1987). Adult rat brain astrocytes support survival of both NGF-dependent and NGF-insensitive neurons.Nature 28280–82.
LoPachin, R. M., Jr., and Aschner, M. (1993). Glial-neuronal interactions: Relevance to neurotoxic mechanisms.Toxidol. Appl. Pharmacol. 118141–158.
Maggi, R., Casulari, L. A., Martini, L., and Piva, F. (1992). Effects of sex steroids and steroidal compounds on the binding characteristics of brainμ-opiod receptors. In Mornex, R., Jaffiol, C., and Leclere, J. (eds.),Progress in Endocrinology Parthenon, New York, pp. 160–164.
Martini, L. (1978). The hypothalamus as an endocrine target organ. InPharmacology of the Hypothalamus (B. Cox and I. D. Morris, Eds.), AH Weston, Macmillan, London, pp. 227–245.
Martini, L. (1982). The 5α-reduction of testosterone in the neuroendocrine structures.Endocr. Rev. 31–25.
Martini, L., Celotti, F., and Serio, M. (1979). 5α-Reductase deficiency in humans: Support to the theory that 5α-reduction of testosterone is an essential step in the control of LH secretion.J. Endocrinol. Invest. 2463–464.
Martini, L., Zoppi, S., and Motta, M. (1986). Studies on the possible existence of two 5α-reductases in the rat prostate.J. Steroid Biochem. 24177–182.
Martini, L., Melcangi, R. C., and Maggi, R. (1993). Androgen and progesterone metabolism in the central and peripheral nervous system.J. Steroid Biochem. Mol. Biol. 47195–205.
Mearow, K. M., Mill, J. F., and Freese, E. (1990). Neuron-glial interactions involved in the regulation of glutamine synthetase.Glia 3385–392.
Melcangi, R. C., Celotti, F., Ballabio, M., Castano, P., Poletti, A., Milani, S., and Martini, L. (1988a). Ontogenetic development of the 5α-reductase in the rat brain: Cerebral cortex, hypothalamus, purified myelin and isolated oligodendrocytes.Dev. Brain Res. 44181–188.
Melcangi, R. C., Celotti, F., Ballabio, M., Poletti, A., Castano, P., and Martini, L. (1988b). Testosterone 5alpha-reductase activity in the rat brain is highly concentrated in white matter structures and in purified myelin sheaths of axon.J. Steroid Biochem. 31173–179.
Melcangi, R. C., Celotti, F., Ballabio, M., Castano, P., Massarelli, R., Poletti, A., and Martini, L. (1990). 5α-Reductase activity in isolated and cultured neuronal and glial cells of the rat.Brain Res. 516229–236.
Melcangi, R. C., Celotti, F., Castano, P., and Martini, L. (1992). Intracellular signalling systems controlling the 5α-reductase in glial cell cultures.Brain Res. 585411–415.
Melcangi, R. C., Celotti, F., Castano, P., and Martini, L. (1993). Differential localization of the 5α-reductase and the 3α-hydroxysteroid dehydrogenase in neuronal and glial cultures.Endocrinology 1321252–1259.
Melcangi, R. C., Celotti, F., and Martini, L. (1994). Neurons influence the metabolism of testosterone in cultured astrocytes via humoral signals.Endocrine 2709–713.
Mendelson, W. B., Martin, J. V., Perlis, M., Wagner, R., Majewska, M. D., and Paul, S. M. (1987). Sleep induction by an adrenal steroid in the rat.Psychopharmacology 93226–229.
Mendez-Otero, R., and Constantine-Paton, M. (1990). Granule cell induction of 9-O-acetyl gangliosides on cerebellar glia in microcultures.Dev. Biol. 138400–409.
Motta, M., Zoppi, S., Brodie, A. M., and Martini, L. (1986). Effect of 1,4,6-androstatriene-3,17-dione (ATD), 4-hydroxy-4-androstene-3,17-dione (4-OH-A) and 4-acetoxy-4-androstene-3,17-dione (4-Ac-A) on the 5α-reduction of androgens in the rat prostate.J. Steroid Biochem. 25593–600.
Naftolin, F., Garcia-Segura, L. M., Keefe, D., Leranth, C., Maclusky, N. J., and Brawer, J. R. (1990). Estrogen effects on the synaptology and neural membranes of the rat hypothalamic arcuate nucleus.Biol. Reprod. 4221–28.
Negri-Cesi, P., Celotti, F., and Martini, L. (1989). Androgen metabolism in the male hamster. II. Aromatization of androstenedione in the hypothalamus and in the cerebral cortex: Kinetic parameters and effect of exposure to different photoperiods.J. Steroid Biochem. 3265–70.
Negri Cesi, P., Melcangi, R. C., Celotti, F., and Martini, L. (1992). Aromatase activity in cultured brain cells: Difference between neurons and glia.Brain Res. 589327–332.
Olmos, G., Aguilera, P., Tranque, P., Naftolin, F., and Garcia-Segura, L. M. (1987). Estrogen-induced synaptic remodelling in adult rat brain is accompanied by the reorganization of neuronal membranes.Brain Res. 42557–64.
Perez, J., Naftolin, F., and Garcia-Segura, L. M. (1990). Sexual differentiation of synaptic connectivity and neuronal plasma membrane in the arcuate nucleus of the rat hypothalamus.Brain Res. 527116–122.
Pfaff, D. W., and McEwen, B. S. (1983). Actions of estrogens and progestins on nerve cells.Science 219808–814.
Roselli, C. E., Salsibury, R. L., and Resko, J. A. (1987). Genetic evidence for androgen-dependent and independent control of aromatase activity in the rat brain.Endocrinology 1212205–2210.
Santagati, S., Melcangi, R. C., Celotti, F., Martini, L., and Maggi, A. (1994). Estrogen receptor is expressed in different types of glial cells in culture.J. Neurochem. 632058–2064.
Sar, M., and Stumpf, W. E. (1975). Distribution of androgen-concentrating neurons in rat brain. InAnatomical Neuroendocrinology (W. E. Stumpf and L. D. Grant, Eds.), Karger, Basel, pp. 120–133.
Sheridan, P. J. (1984). Autoradiographic localization of steroid receptors in the brain.Clin. Neuropharmacol. 7281–295.
Shima, H., Tsuji, M., Young, P., and Cunha, G. R. (1990). Postnatal growth of mouse seminal vesicle is dependent on 5α-dihydrotestosterone.Endocrinology 1273222–3233.
Steward, O., Torre, E. R., Tomasulo, R., and Lothman, E. (1991). Neuronal activity up-regulates astroglial gene expression.Proc. Natl. Acad. Sci. USA 886819–6823.
Stupnicka, E., Massa, R., Zanisi, M., and Martini, L. (1977). Role of the anterior pituitary and hypothalamic metabolism of progesterone in the control of gonadotropin secretion.Prog. Reprod. Biol. 288–95.
Zanisi, M., and Martini, L. (1979). Interaction of oestrogen and of physiological progesterone metabolites in the control of gonadotropin secretion.J. Steroid Biochem. 11855–862.
Zanisi, M., Motta, M., and Martini, L. (1973). Inhibitory effect of the 5α-reduced metabolites of testosterone on gonadotrophin secretion.J. Endocrinol. 56315–316.
Zoppi, S., Cocconi, M., Lechuga, M. J., Messi, E., Zanisi, M., and Motta, M. (1988). Antihormonal activities of 5α-reductase and aromatase inhibitors.J. Steroid Biochem. 31677–683.
Zoppi, S., Lechuga, M., and Motta, M. (1992). Selective inhibition of the 5α-reductase of the rat epididymis.J. Steroid Biochem. Mol. Biol. 42509–514.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Martini, L., Celotti, F. & Melcangi, R.C. Testosterone and progesterone metabolism in the central nervous system: Cellular localization and mechanism of control of the enzymes involved. Cell Mol Neurobiol 16, 271–282 (1996). https://doi.org/10.1007/BF02088095
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02088095