Parkinson's disease (PD) is a common progressive neurological disorder characterized by motor symptoms of bradykinesia, rigidity, rest tremor and postural imbalance and non-motor symptoms including urinary, sexual dysfunction and neuropsychiatric symptoms (psychosis, anxiety, depression).1 The molecular pathologies comprise oxidative stress, mitochondrial dysfunction, proteasomal impairment, abnormal protein aggregation and neuroinflammation.2 The incidence of PD is slightly lower in women compared to men, possibly suggesting a neuroprotective effect of estrogen.1 The effect of estrogen on the prevalence of PD amongst the general population is unclear. Recent clinical studies have revealed the beneficial effect of estrogen on PD prognosis. A pooled analysis found that estrogen replacement therapy reduced the risk of PD and Alzheimer's disease compared to the control group.3 It has been postulated that estradiol receptors may play a role in mediating neuroprotection via modulating apoptosis and oxidative-related pathways.4 To study the effects of estrogen on α-synuclein (α-SYN) homeostasis and pathophysiology, investigators utilized an α-SYN tetramer-abrogating PD mouse model that amplifies a familial α-SYN PD mutation and demonstrated that brain-selective estrogen treatment in symptomatic mice elevated the tetramer-to-monomer ratio, and improved turnover of aggregate-prone monomers, and these correlated with improvement in the motor phenotype.5

Breast cancer (prevalent in post-menopausal women) is the most common cancer among women. A vast majority of breast cancers are estrogen receptor (ER) positive6 and ER can promote tumor growth in breast cancer. This provides the biological basis for ER inhibition therapies (such as aromatase inhibitors and selective estrogen receptor modulators) for breast cancer. Tamoxifen is a selective estrogen receptor modulator (SERM) and has been the drug of choice to treat estrogen receptor positive breast cancer for many decades.6 Tamoxifen competes with 17β-estradiol (E2) at the receptor site and inhibits E2 activity in breast cancer. It is also thought to bind DNA to precipitate malignant change.7 Some have suggested that it can function as an agonist-antagonist of the estrogen receptor depending on the cell types.8 It is currently unclear if tamoxifen is an agonist or antagonist of the estrogen receptors in the brain tissues. The occurrence of hot flashes, a side effect of tamoxifen, suggests that tamoxifen acts as an estrogen antagonist.6,9 Some studies suggest that it can exert an estrogen-like neuroprotective effect while others found tamoxifen to antagonize estrogenic effects.9 This has led to discussions regarding its effects on dopaminergic neurons in PD.

Findings from studies evaluating the association between tamoxifen use and PD risk have produced conflicting results.10, 11, 12, 13, 14, 15 It is not clear if these divergent observations were due to methodological differences or actual changes.10, 11, 12, 13, 14, 15 To date, no meta-analysis has been conducted to study the relationship between the use of tamoxifen and the risk of PD. To address the hypothesis that there is a possible link between tamoxifen and PD risk, we conducted a systematic review and meta-analysis (with a larger sample size and greater power of analysis) to determine the association between tamoxifen use and the risk of PD.