Peripheral vs. Central Sex Steroid Hormones in Experimental Parkinson?s Disease

Simon Mcarthur,Glenda E Gillies

doi:10.3389/fendo.2011.00082

Simon Mcarthur, Glenda E Gillies

Open Access

https://doi.org/10.3389/fendo.2011.00082

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Abstract

The nigrostriatal dopaminergic (NSDA) pathway degenerates in Parkinson’s disease (PD), which occurs with approximately twice the incidence in men than women. Studies of the influence of systemic estrogens in females suggest sex hormones contribute to these differences. In this review we analyze the evidence revealing great complexity in the response of the healthy and injured NSDA system to hormonal influences, and emphasize the importance of centrally generated estrogens. At physiological levels, circulating estrogen (in females) or estrogen precursors (testosterone in males, aromatized to estrogen centrally) have negligible effects on dopaminergic neuron survival in experimental PD, but can modify striatal dopamine levels via actions on the activity or adaptive responses of surviving cells. However, these effects are sexually dimorphic. In females, estradiol promotes adaptive responses in the partially injured NSDA pathway, preserving striatal dopamine, whereas in males gonadal steroids and exogenous estradiol have a negligible or even suppressive effect, effectively exacerbating dopamine loss. On balance, the different effects of gonadal factors in males and females contribute to sex differences in experimental PD. Fundamental sex differences in brain organization, including the sexually dimorphic networks regulating NSDA activity are likely to underpin these responses. In contrast, estrogen generated locally appears to preserve striatal dopamine in both sexes. The available data therefore highlight the need to understand the biological basis of sex-specific responses of the NSDA system to peripheral hormones, so as to realize the potential for sex-specific, hormone-based therapies in PD. Furthermore, they suggest that targeting central steroid generation could be equally effective in preserving striatal dopamine in both sexes. Clarification of the relative roles of peripheral and central sex steroid hormones is thus an important challenge for future studies.

Highlights

Sex steroid hormones produced by activation of the hypothalamopituitary–gonadal (HPG) axis have profound effects on brain development and function
A wealth of evidence documents notable sex differences in the epidemiology, clinical features, molecular pathology, and treatment outcomes in Parkinson’s disease (PD), with women being relatively protected from, and having a more benign pre-clinical phase of the disease compared with men (Haaxma et al, 2007; Pavon et al, 2010)
In this review we have focused on the precise contributions of sex steroid hormones, and estrogens in particular

Summary

INTRODUCTION

Sex steroid hormones produced by activation of the hypothalamopituitary–gonadal (HPG) axis have profound effects on brain development and function. There is a growing realization that estrogens are important physiological regulators in males where they can be synthesized locally in many tissues either de novo or from steroid precursors, such as circulating testosterone (Sharpe, 1998; Jones et al, 2006) This includes the brain (Do Rego et al, 2009), where estrogens may act via their classical nuclear receptors, (ERα and ERβ), which are widely distributed in the brains of males as well as females, or via rapid membrane effects (Toran-Allerand, 2005; Balthazart and Ball, 2006; Brann et al, 2007; Micevych and Dominguez, 2009). We shall consider the evidence that this pathway, whether intact or injured, exhibits sexual dimorphisms www.frontiersin.org

McArthur and Gillies

Findings

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