Department of Medicine, Centre for Neuroscience, Imperial College London London, UK.
Front Endocrinol (Lausanne). 2011 Nov 30;2:82. doi: 10.3389/fendo.2011.00082. eCollection 2011.
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.
黑质纹状体多巴胺能（NSDA）通路在帕金森病（PD）中退化，男性的发病率约为女性的两倍。对女性系统性雌激素影响的研究表明，性激素促成了这些差异。在这篇综述中，我们分析了表明健康和受损的 NSDA 系统对激素影响反应具有极大复杂性的证据，并强调了中枢产生的雌激素的重要性。在生理水平下，循环雌激素（女性）或雌激素前体（男性的睾酮，在中枢被芳香化为雌激素）对实验性 PD 中的多巴胺能神经元存活几乎没有影响，但可以通过作用于存活细胞的活性或适应性反应来改变纹状体多巴胺水平。然而，这些影响具有性别二态性。在女性中，雌二醇促进部分受损的 NSDA 通路的适应性反应，从而维持纹状体多巴胺，而在男性中，性腺类固醇和外源性雌二醇几乎没有或甚至有抑制作用，实际上加剧了多巴胺的丧失。总的来说，性腺因素在男性和女性中的不同作用促成了实验性 PD 中的性别差异。大脑组织中基本的性别差异，包括调节 NSDA 活性的性别二态性网络，可能是这些反应的基础。相比之下，局部产生的雌激素似乎在两性中都能维持纹状体多巴胺。因此，现有数据突出表明需要了解 NSDA 系统对周围激素的性别特异性反应的生物学基础，以便实现 PD 中基于激素的性别特异性治疗的潜力。此外，它们表明靶向中枢类固醇生成可能同样有效地在两性中维持纹状体多巴胺。因此，澄清外周和中枢性激素的相对作用是未来研究的重要挑战。
