Differential effects of hormone therapy formulations on Parkinson's disease risk: a systematic review and meta-analysis

Clinical Snapshot

Key Findings

• P Value: Overall HT: not statistically significant; Combined EPT: statistically significant; ET: not statistically significant; Interaction between subgroups: p = 0.12 (non-significant)

• Effect Size: Overall HT: RR 1.08; Combined EPT subgroup: RR 1.40; Estrogen-only ET subgroup: RR 1.01

• Primary Outcome: Incident Parkinson's disease diagnosis in postmenopausal women using hormone therapy versus non-users

• Nnt Or Sensitivity: Absolute risk increase not calculable from abstract data alone; RR 1.40 for combined EPT represents a 40% relative increase in PD risk, but baseline PD incidence in postmenopausal women (~0.1–0.2% per decade) means absolute risk differences are likely small. No NNH reported.

• Confidence Interval: Overall: 95% CI 0.94–1.23; Combined EPT: 95% CI 1.07–1.82; Estrogen-only: 95% CI 0.81–1.27

Clinical Application

The findings are hypothesis-generating rather than practice-changing. Clinicians can note the signal around combined EPT but should not alter prescribing based on this evidence alone given the observational design, non-significant interaction test, and absence of GRADE-level certainty assessment. Individualised HT counselling should continue to weigh established benefits (vasomotor symptom relief, bone protection) against known risks (cardiovascular, thromboembolic, breast cancer) with PD risk remaining an area of ongoing investigation. In Australia, menopausal HT is regulated by the TGA and several formulations are PBS-listed. The RACGP and the Australasian Menopause Society (AMS) provide guidance on HT prescribing. Current AMS guidelines do not include PD risk as a contraindication or specific consideration for HT formulation choice. The findings of this meta-analysis, while intriguing, do not meet the evidentiary threshold to prompt a change in AMS or RACGP guidance. Australian clinicians should be aware of this emerging signal, particularly when counselling women with first-degree relatives with PD, but should await higher-certainty evidence before modifying practice. PBS-listed combined EPT products (e.g., estradiol/norethisterone, estradiol/dydrogesterone) are widely used; the progestin component and its specific neurological effects warrant further investigation in Australian cohort studies. Postmenopausal women being considered for or currently using menopausal hormone therapy, particularly those with additional neurological risk factors or family history of Parkinson's disease

Abstract

BACKGROUND: The relationship between menopausal hormone therapy (HT) and Parkinson's disease (PD) risk remains controversial, with inconsistent findings potentially driven by differences in hormonal formulations. METHODS: We conducted a systematic review and meta-analysis following PRISMA 2020 guidelines. MEDLINE/PubMed and EMBASE were searched between January 8 and March 14, 2026. Observational studies evaluating the association between menopausal HT and PD risk were included. Effect estimates were pooled using random-effects models. Subgroup analyses were performed according to HT formulation (estrogen-only vs. combined estrogen-progestin therapy). A multilevel meta-analysis was conducted to account for within-study dependence. RESULTS: Fourteen studies including 753,749 participants (4,433 PD cases) were analyzed. Overall, HT was not significantly associated with PD risk (RR 1.08; 95% CI 0.94-1.23; I² = 49.4%). In subgroup analyses, combined therapy was associated with an increased PD risk (RR 1.40; 95% CI 1.07-1.82), whereas estrogen-only therapy showed no significant association (RR 1.01; 95% CI 0.81-1.27). Multilevel analysis yielded consistent results (combined: RR 1.33; 95% CI 1.00-1.77; estrogen-only: RR 1.03; 95% CI 0.83-1.27), with no statistically significant interaction between formulations (p = 0.12). CONCLUSIONS: Combined menopausal HT was associated with an increased risk of PD, while estrogen-only therapy showed no significant association. Although differences between formulations were not statistically significant, these findings suggest that hormone composition may influence neurological outcomes and warrant further investigation into individualized HT strategies.

References

1. 1.Macedo, V. F. B., & de Melo Barboza, A. M. (2026). Differential effects of hormone therapy formulations on Parkinson's disease risk: a systematic review and meta-analysis. Neurological Sciences: Official Journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. Advance online publication. https://pubmed.ncbi.nlm.nih.gov/42481816