Phytoestrogen Intake and Risk of Endometrial Cancer
Principal Investigator
Name
Michael Reger
Degrees
Ph.D., M.P.H
Institution
University of Notre Dame
Position Title
Associate Professor of the Practice
Email
mreger2@nd.edu
About this CDAS Project
Study
PLCO
(Learn more about this study)
Project ID
PLCO-1996
Initial CDAS Request Approval
Nov 13, 2025
Title
Phytoestrogen Intake and Risk of Endometrial Cancer
Summary
Endometrial cancer (EC) is the most common gynecologic malignancy in the United States, with rising incidence largely attributed to obesity, metabolic syndrome, and cumulative estrogen exposure. Estrogen plays a central role in endometrial carcinogenesis by promoting cell proliferation and inhibiting apoptosis in the uterine endometrium. However, the influence of dietary compounds with weak estrogenic or anti-estrogenic activity, specifically phytoestrogens, remains unclear.
Phytoestrogens (PEs) are naturally occurring, non-steroidal plant compounds structurally similar to 17-β estradiol. They are found in soy products, legumes, whole grains, nuts, and flaxseed, and include major subclasses such as isoflavones, lignans, and coumestans. Phytoestrogens can act as partial agonists or antagonists at estrogen receptor (ER) sites, potentially modifying endogenous estrogen signaling and influencing hormone-dependent cancer risk.
Previous case-control studies in Western and Asian populations suggest that women with higher dietary intake of phytoestrogens—particularly isoflavones and lignans—have lower risk of endometrial cancer. For example, women in the highest quartile of isoflavone intake had approximately a 40–50% reduction in risk compared to those in the lowest quartile. However, these studies were limited by small sample sizes, retrospective dietary recall, and lack of prospective follow-up. To date, there are no large-scale prospective analyses in a U.S. cohort with validated dietary and cancer outcome data to evaluate this relationship.
This study aims to evaluate whether higher dietary phytoestrogen intake is associated with reduced risk of endometrial cancer, overall and across biologically relevant subgroups. By leveraging the PLCO’s detailed dietary assessment and follow-up, the opportunity exists to produce the most comprehensive analysis to date of phytoestrogen exposure and endometrial cancer risk in a U.S. population.
Data Analysis Plan:
1. Describe participant characteristics by phytoestrogen quartile.
2. Apply multivariable Cox regression to estimate HRs for endometrial cancer.
3. Test for linear trend and proportional hazards.
4. Conduct stratified analyses by menopausal status and hormone therapy.
5. Exclude cases diagnosed within two years of baseline as sensitivity analysis.
Significance: This will be the first prospective PLCO analysis linking dietary phytoestrogens to endometrial cancer risk, providing novel insights into modifiable hormonal risk factors.
Aims
• Aim 1: To evaluate the association between total dietary phytoestrogen intake and the risk of incident endometrial cancer.
o Hypothesis: Higher total phytoestrogen intake will be associated with a statistically significant lower risk of endometrial cancer after multivariable adjustment.
• Aim 2: To assess associations between specific phytoestrogen subclasses (isoflavones, lignans, coumestans) and endometrial cancer risk.
o Hypothesis: Isoflavones and lignans will show the strongest inverse associations due to their higher affinity for ER-β and their role in modulating estrogen metabolism and cell proliferation.
• Aim 3 (Exploratory): To examine potential effect modification by menopausal status, hormone replacement therapy (HRT), and body mass index (BMI).
o Hypothesis: Protective effects of phytoestrogens will be more pronounced among postmenopausal women and those not using HRT.
Collaborators
Michael Reger University of Notre Dame