The Implication of Neuroactive Steroids in Tourette's Syndrome Pathogenesis: A Role for 5α‐Reductase?

Abstract

Tourette syndrome (TS) is a neurodevelopmental disorder characterized by recurring motor and phonic tics. The pathogenesis of TS is thought to reflect dysregulations in the signaling of dopamine (DA) and other neurotransmitters, which lead to excitation/inhibition imbalances in cortico-striato-thalamocortical circuits. The causes of these deficits may reflect complex gene × environment × sex (G×E×S) interactions; indeed, the disorder is markedly predominant in males, with a male-to-female prevalence ratio of ~4:1. Converging lines of evidence point to neuroactive steroids as likely molecular candidates to account for GxExS interactions in TS. Building on these premises, our group has begun examining the possibility that alterations in the steroid biosynthetic process may be directly implicated in TS pathophysiology; in particular, our research has focused on 5α-reductase (5αR), the enzyme catalyzing the key rate-limiting step in the synthesis of pregnane and androstane neurosteroids. In clinical and preclinical studies, we found that 5αR inhibitors exerted marked anti-DAergic and tic-suppressing properties, suggesting a central role for this enzyme in TS pathogenesis. Based on these data, we hypothesize that enhancements in 5αR activity in early developmental stages may lead to an inappropriate activation of the “backdoor” pathway for androgen synthesis from adrenarche until the end of puberty. We predict that the ensuing imbalances in steroid homeostasis may impair the signaling of DA and other neurotransmitters, ultimately resulting in the facilitation of tics and other behavioral abnormalities in TS.

Adverse effects of 5α-reductase inhibitors: What do we know, don’t know, and need to know?

“…In particular, initial clinical data from open trials and case reports point to the possibility that these therapies may be effective in reducing the severity of tics in Tourette syndrome [68,69] and may even be useful in decreasing the severity of iatrogenic problem gambling in Parkinson's disease patients [70]. These preliminary data, however, need be confirmed in double-blind, placebo-controlled trials.…”

“…This development may be particularly important vis-à-vis recent preclinical and clinical findings pointing to a therapeutic potential of 5α-RIs for neuropsychiatric conditions, including tic disorders and risk-taking behaviors [2,68,69]. In addition, defining potential links between specific alterations of the neurosteroid profile and behavioral changes may provide crucial knowledge on the specific role of these compounds in mental regulation, also in relation to the development of neurosteroid-related therapies for PFS and other related conditions.…”

“…Taken together, these data seem to indicate that, in vulnerable subjects, finasteride can facilitate the emergence of depressive symptoms, the severity and duration of which is likely to depend on specific genetic and/or neurobiological characteristic of the individuals. If confirmed, these effects may be underpinned by psycholeptic properties of finasteride, which may also account for anecdotal evidence indicating its effectiveness in reducing impulse-control problems [69].…”

Animal models of tic disorders: A translational perspective

“…MAO A KO, but not MAO A hypomorphic mice exhibit spontaneous aggression (Cases et al, 1995; Scott et al, 2008; Bortolato et al, 2011; Bortolato and Shih, 2011). In addition, recent analyses have ascertained that MAOA mutants feature a number of other phenotypic characteristics, some of which may be relevant to the pathogenesis of TS, such as a higher proclivity to manifest spontaneously repetitive behaviors (Bortolato et al, 2011, 2013a,b). The effects of treatments of TS on the repetitive behaviors in this line have not yet been tested.…”

“…On the other hand, emerging evidence suggests that the gender differences in TS may be supported by the implication of androgen hormones in the pathophysiology of tics (for further reading on this topic, see Bortolato et al, 2013a,b). …”