Steroids-dopamine interactions in the pathophysiology and treatment of CNS disorders

Abstract

Introduction: Dopamine cell loss is well documented in Parkinson's disease and dopamine hypofunction is proposed in certain depressive states. At the opposite, dopamine hyperactivity is an enduring theory in schizophrenia with extensive supporting evidence.

Aims: This article reviews the sex differences in these diseases that are the object of many studies and meta-analyses and could be explained by genetic differences but also an effect of steroids in the brain. This article then focuses on the extensive literature reporting on the effect of estrogens in these diseases and effects of the other ovarian hormone progesterone as well as androgens that are less documented. Moreover, dehydroepiandrosterone, the precursor of estrogens and androgens, shows effects on brain dopamine neurotransmission that are reviewed. To investigate the mechanisms implicated in the human findings, animal studies are reviewed showing effects of estrogens, progesterone, and androgens on various markers of dopamine neurotransmission under intact as well as lesioned conditions.

Discussion: For possible future avenues for hormonal treatments in these central nervous system diseases, we discuss the effects of selective estrogen receptor modulators (SERMs), the various estrogen receptors and their specific drugs as well as progesterone drugs.

Conclusion: Clinical and experimental evidence supports a role of steroid-dopamine interactions in the pathophysiology of schizophrenia, depression and Parkinson's disease. Specific steroidal receptor agonists and SERMs are available for endocrine and cancer treatments and could find other applications as adjunct treatments in central nervous system diseases.

Figure 1

Schematic steroidal synthetic pathways of steroids mostly investigated for their activities on brain DA. Dotted arrows indicate that several synthetic steps and intermediate steroids were involved in the biosynthesis of the product. P450scc, cytochrome P450 sidechain cleavage; P450c17, cytochrome P450 17α‐hydroxylase/C17,20‐lyase; 3α‐HSD, 3α‐hydroxysteroid dehydrogenase; 3β‐HSD, 3β‐hydroxysteroid dehydrogenase; 5α‐R, 5α‐reductase; 17β‐HSD, 17β‐hydroxysteroid dehydrogenase.