Background: Past research indicates a higher prevalence, incidence, and severe clinical manifestations of alpha-synucleinopathies in men, leading to a suggestion of neuroprotective properties of female sex hormones (especially estrogen). The potential pathomechanisms of any such effect on alpha-synucleinopathies, however, are far from understood. With that aim, we undertook to systematically review the literature on sex differences in alpha-synucleinopathies, broadening our scope to sex-lineated assessments of prevalence, demographics, biomarkers, genetic factors, clinical features, neuroinflammatory and neurochemical responses, interventions, and quality of life themes.
Methods: In this systematic review, studies investigating sex and gender differences in alpha-synucleinopathies (Rapid Eye Movement (REM) Behavior Disorder (RBD), Parkinson’s Disease (PD), Dementia with Lewy Bodies (DLB), Multiple System Atrophy (MSA)) from 2012 to 2022 were identified using electronic database searches of PubMed, Embase and Ovid.
Results: 162 studies were included; 5 RBD, 6 MSA, 20 DLB and 131 PD studies. Overall, there is conclusive evidence to suggest sex-and gender-specific manifestation in demographics, biomarkers, genetics, clinical features, interventions, and quality of life in alpha-synucleinopathies. Only limited data exists on the effects of distinct sex hormones, with majority of studies concentrating on estrogen and its speculated neuroprotective effects. Similarly, there are several methodological caveats that should be considered while evaluating preclinical and clinical studies, all of which are rarely systematically considered in their translational importance. For example, in majority, if not in all, analysed clinical and preclinical studies, there is a lack of focus on the synergistic and antagonistic effects of different sex hormones on various aspects of alpha-synucleinopathies. Most studies predominantly focus on one specific hormone (i.e., estrogen/progesterone), which makes it impossible to fully understand the pathomechanistic complexity.
Conclusion: There is urgent need for future studies to disentangle the underlying sex-specific mechanisms of alpha-synucleinopathies to systematically account for (1) a specific subtype and distinct phenotype of alpha-synucleinopathies (2) ethnicity and geographical location, (3) disease progression, rate and severity (i.e., early versus late onset), (4) monitoring menstrual cycle and endocrinology health in women, (5) direct quantification of sex hormones in both sexes, (6) medication history and responses (i.e., hormones replacement therapy) and (7) consideration of societal, cultural and gender factors that could impact treatment of alpha-synucleinopathies. A comprehensive assessment of sex and gender differences in alpha-synucleinopathies holds promise for improving diagnosis and management, implementing prevention strategies, and developing treatments with optimal efficacy in both men and women.