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SUMMARYIntroduction: 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.

Parkinson’s disease (PD) is an age‐related neurodegenerative disorder with a higher incidence in the male population. In the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) mouse model of PD, 17β‐oestradiol but not androgens were shown to protect dopamine (DA) neurones. We report that oestrogen receptors (ER)α and β distinctly contribute to neuroprotection against MPTP toxicity, as revealed by examining the membrane DA transporter (DAT), the vesicular monoamine transporter 2 (VMAT2) and tyrosine hyroxylase in ER wild‐type (WT) and knockout (ERKO) C57Bl/6 male mice. Intact ERKOβ mice had lower levels of striatal DAT and VMAT2, whereas ERKOα mice were the most sensitive to MPTP toxicity compared to WT and ERKOβ mice and had the highest levels of plasma androgens. In both ERKO mice groups, treatment with 17β‐oestradiol did not provide neuroprotection against MPTP, despite elevated plasma 17β‐oestradiol levels. Next, the recently described membrane G protein‐coupled oestrogen receptor (GPER1) was examined in female Macaca fascicularis monkeys and mice. GPER1 levels were increased in the caudate nucleus and the putamen of MPTP‐monkeys and in the male mouse striatum lesioned with methamphetamine or MPTP. Moreover, neuroprotective mechanisms in response to oestrogens transmit via Akt/glycogen synthase kinase‐3 (GSK3) signalling. The intact and lesioned striata of 17β‐oestradiol treated monkeys, similar to that of mice, had increased levels of pAkt (Ser 473)/βIII‐tubulin, pGSK3 (Ser 9)/βIII‐tubulin and Akt/βIII‐tubulin. Hence, ERα, ERβ and GPER1 activation by oestrogens is imperative in the modulation of ER signalling and serves as a basis for evaluating nigrostriatal neuroprotection.

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