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Steroids which are synthesized within the nervous system, such as progesterone, have been termed 'neurosteroids'. Levels of progesterone are much larger in peripheral nerves of rats and mice than in plasma, and persist after removal of the steroidogenic endocrine glands. Schwann cells are a source of progesterone: when isolated from embryonic dorsal root ganglia, they can synthesize progesterone from pregnenolone, the obligate precursor of all steroids. Locally produced progesterone has been shown to play an important role in myelination of peripheral nerve. We show here that sensory neurons from embryonic dorsal root ganglia also express 3beta-hydroxysteroid dehydrogenase and can convert [3H]pregnenolone to [3H]progesterone. Moreover, when cultured under different conditions and incubated for 24 h in the presence of 100 nM [3H]pregnenolone, they produce 5-10 times more [3H]progesterone than Schwann cells. The conversion of pregnenolone to progesterone by neurons is further increased by a diffusible factor produced by Schwann cells. Sensory neurons can also metabolize progesterone to 5alpha-dihydroprogesterone, but unlike Schwann cells, they do not produce 3alpha,5alpha-tetrahydroprogesterone, a potent positive allosteric modulator of gamma-aminobutyric acid type A receptors. We also show that cells isolated from the adult nervous system still have the capacity to convert [3H]pregnenolone to progesterone and its 5alpha-reduced metabolites: neurons and Schwann cells purified from dorsal root ganglia of 6 week old male rats show a similar pattern of pregnenolone metabolism to cells isolated from 18 day old embryos. These findings further support the important role of progesterone in the development and regeneration of the peripheral nervous system.

Progesterone is shown here to be produced from pregnenolone by Schwann cells in peripheral nerves. After cryolesion of the sciatic nerve in male mice, axons regenerate and become myelinated. Blocking either the local synthesis or the receptor-mediated action of progesterone impaired remyelination. Administration of progesterone or its precursor, pregnenolone, to the lesion site increased the extent of myelin sheath formation. Myelination of axons was also increased when progesterone was added to cultures of rat dorsal root ganglia. These observations indicate a role for locally produced progesterone in myelination, demonstrate that progesterone is not simply a sex steroid, and suggest a new therapeutic approach to promote myelin repair.

Pregnenolone (PREG) and corticosterone were measured in sciatic nerves and plasma of adult male rats by radioimmunoassays. Concentrations of PREG were higher in nerves than in plasma, whereas those of corticosterone were lower. In contrast to corticosterone, PREG was not reduced by castration and adrenalectomy, strongly suggesting a local synthesis of this steroid independent of glandular sources. In fact, Schwann cells in culture produced PREG from 25-hydroxy-cholesterol. They also converted PREG and dehydroepiandrosterone to the respective 7 alpha-hydroxylated metabolites and to 5-androstene-3 beta,17 beta-diol. The metabolism of steroids was increased when Schwann cells were grown in the presence of insulin and forskolin. These findings may have important implications for understanding the regeneration of peripheral nerves.