Objective: To address key methodological challenges in the methodology of meta-analysis of age at menopause, reproductive lifespan and the risk of Parkinson’s Disease (PD).

Background: The potential neuroprotective effects of endogenous estrogens have elicited increasing interest in reproductive history as a possible modifiable factor in the risk of PD development. (Subramanian et al. 2022) Previous systematic studies investigating reproductive factors in relation to dementia and PD (Georgakis et al. 2016, Unda et al. 2022) have identified several methodological limitations that impede robust conclusions on the association between age at menopause, reproductive lifespan and PD risk.

Method: Two independent reviewers screened 1054 publications derived from a search strategy from Pubmed and Web of Science, through April 2024. A total of 23 studies met our inclusion criteria: 6 cohort, 11 case-control and 6 cross-sectional studies.

Results: Several methodological challenges have been recognized. First, there is significant heterogeneity in variables definitions, particularly regarding menopause classification, distinctions between natural and surgical menopause, and the inclusion of hormone replacement therapy users. Second, confounding factors such as smoking and genetic predisposition are inconsistently adjusted across studies, contributing to variations in study populations and methodologies, ultimately leading to high statistical heterogeneity. Finally, differences in study designs further complicate quantitative synthesis, limiting the comparability of findings.

Conclusion: Meta-analysing reproductive factors and PD risk presents substantial methodological complexities. In our study, we focused on age at menopause and reproductive lifespan as key indicators of lifetime endogenous estrogen exposure, identifying 23 relevant studies. The quantitative analysis of these studies aims to provide the most comprehensive findings to date and generate robust evidence on this topic. By addressing methodological limitations, we seek to guide future research toward a more standardized and rigorous approach in this field.

References: Georgakis, M. K., E. I. Kalogirou, A. A. Diamantaras, S. S. Daskalopoulou, C. A. Munro, C. G. Lyketsos, A. Skalkidou & E. T. Petridou (2016) Age at menopause and duration of reproductive period in association with dementia and cognitive function: A systematic review and meta-analysis. Psychoneuroendocrinology., 73:224-243., 10.1016/j.psyneuen.2016.08.003. Epub 2016 Aug 3.
Subramanian, I., S. Mathur, A. Oosterbaan, R. Flanagan, A. M. Keener & E. Moro (2022) Unmet Needs of Women Living with Parkinson’s Disease: Gaps and Controversies. Mov Disord, 37, 444-455.
Unda, S. R., S. Marciano, T. A. Milner & R. Marongiu (2022) State-of-the-art review of the clinical research on menopause and hormone replacement therapy association with Parkinson’s disease: What meta-analysis studies cannot tell us. Front Aging Neurosci, 14, 971007.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/unraveling-the-estrogen-parkinsons-disease-link-methodological-challenges-in-meta-analyzing-reproductive-factors-and-pd-risk/