New steps forward in the neuroactive steroid field

• Neuroactive steroid levels are sex dimorphic.
• Neuroactive steroids as protective agents.
• Neuroactive steroids may also exert detrimental effects.
• Steroidogenesis modulators may represent an interesting therapeutic strategy.

Evidence accumulated in recent years suggests that the systemic treatment with neuroactive steroids, or the pharmacological modulation of its production by brain cells, represent therapeutic options to promote neuroprotection. However, new findings, which are reviewed in this paper, suggest that the factors to be considered for the design of possible therapies based on neuroactive steroids are more complex than previously thought. Thus, although as recently reported, the nervous system regulates neuroactive steroid synthesis and metabolism in adaptation to modifications in peripheral steroidogenesis, the neuroactive steroid levels in the brain do not fully reflect its levels in plasma. Even, in some cases, neuroactive steroid level modifications occurring in the nervous tissues, under physiological and pathological conditions, are in the opposite direction than in the periphery. This suggests that the systemic treatment with these molecules may have unexpected outcomes on neural steroid levels. In addition, the multiple metabolic pathways and signaling mechanisms of neuroactive steroids, which may change from one brain region to another, together with the existence of regional and sex differences in its neural levels are additional sources of complexity that should be clarified. This complexity in the levels and actions of these molecules may explain why in some cases these molecules have detrimental rather than beneficial actions for the nervous system.This article is part of a Special Issue entitled ‘Steroid Perspectives’.