Exploring the complex relationship between soy isoflavones and ischemic stroke risk based on the Shanghai Women's Health Study
August 22, 2025 By Science Research Team
For decades, women have turned to soy products as a natural alternative to hormone replacement therapy, seeking relief from menopausal symptoms without the risks associated with conventional treatments. The 2002 Women's Health Initiative study revealed that hormone replacement therapy increased the risk of breast cancer, stroke, and coronary heart disease in healthy postmenopausal women, sending millions in search of safer alternatives 26. Soy isoflavones, celebrated for their estrogen-like properties, became a popular choice, particularly because epidemiological studies showed that women in Asian countries who consumed more soy reported significantly fewer menopausal symptoms than their Western counterparts 6.
However, emerging research reveals a complex relationship between soy compounds and cardiovascular health, particularly when it comes to ischemic stroke risk in postmenopausal women. This article explores the fascinating science behind urinary isoflavonoids and their potential association with stroke risk.
Isoflavones belong to a broader class of compounds called phytoestrogens (plant estrogens) that structurally resemble human estrogen. The most common dietary isoflavones—genistein, daidzein, and glycitein—are predominantly found in soybeans and soy products, though they also appear in smaller quantities in other legumes 2.
When we consume soy foods, the innate isoflavones undergo metabolic transformation in the gut through the action of gastrointestinal enzymes, converting to their active forms 6.
To better understand the relationship between soy isoflavones and stroke risk, researchers conducted a comprehensive investigation as part of the Shanghai Women's Health Study, one of the largest cohort studies of women's health in Asia 1.
This ambitious project enrolled 74,941 Chinese women aged 40-70 between December 1996 and May 2000, collecting extensive data on their dietary habits, lifestyle factors, and health outcomes.
For this particular investigation, researchers excluded women with a history of cardiovascular disease or cancer at baseline, resulting in a final analytical cohort of 66,832 women 1. These participants were followed for an average of 10 years, during which any incident strokes were carefully documented and verified through medical records.
Women in final analytical cohort
Average follow-up period
The research team employed rigorous scientific methods to ensure their findings would be reliable and valid:
Participants completed in-person interviews using a validated food-frequency questionnaire that included 77 food items covering 90% of foods commonly consumed in urban Shanghai.
Researchers measured urinary levels of seven isoflavonoids using high-performance liquid chromatography coupled with mass spectrometry 1.
Possible stroke cases were identified during follow-up home visits every 2-3 years. Medical records were obtained and physicians blinded to exposure status confirmed these diagnoses.
The team used advanced statistical models to adjust for potential confounding factors including age, income, education, physical activity, and various health parameters 1.
The findings revealed a complex and somewhat paradoxical relationship between soy isoflavones and stroke risk:
During the follow-up period, 3,110 incident ischemic strokes were verified among the study participants 1. Analysis of dietary data showed that higher dietary isoflavone intake was associated with a modestly increased risk of ischemic stroke.
Compared to women in the lowest quintile of isoflavone consumption, those in the highest quintile had a 24% increased risk (HR: 1.24; 95% CI: 1.08, 1.42; P-trend = 0.002) after adjusting for multiple potential confounders 1.
Women in the highest quintile of total urinary isoflavonoids had virtually the same stroke risk as those in the lowest quintile (OR: 1.01; 95% CI: 0.77, 1.32) 1.
| Quintile | Hazard Ratio (Dietary) | 95% Confidence Interval | Odds Ratio (Urinary) | 95% Confidence Interval |
|---|---|---|---|---|
| 1 (Low) | 1.00 (Ref) | - | 1.00 (Ref) | - |
| 2 | 1.05 | 0.93-1.18 | 0.97 | 0.75-1.25 |
| 3 | 1.10 | 0.98-1.24 | 0.94 | 0.72-1.22 |
| 4 | 1.11 | 0.99-1.25 | 0.90 | 0.69-1.18 |
| 5 (High) | 1.24 | 1.08-1.42 | 1.01 | 0.77-1.32 |
P for trend (dietary) = 0.002. Based on nested case-control study of postmenopausal women who never used hormone therapy. Adjusted for matching factors and additional covariates. 1
To conduct sophisticated research like the Shanghai Women's Health Study, scientists rely on specialized reagents and methodologies:
Separates complex mixtures of compounds in biological samples. In this study, HPLC was used to separate various isoflavonoids in urine samples before quantification.
Precisely identifies and quantifies specific compounds based on their mass-to-charge ratio. The coupling of HPLC with MS/MS allowed for accurate measurement of even trace amounts of isoflavonoids and their metabolites.
These chemically identical but heavier versions of the target compounds are added to samples to correct for variations in extraction and analysis efficiency, improving measurement accuracy.
Standardized tool for assessing habitual dietary intake over an extended period. The FFQ used in this study was specifically developed and validated for the Shanghai population.
Measure creatinine concentration in urine samples to standardize isoflavonoid measurements for urine dilution variations.
Various specialized reagents were used to measure clinical biomarkers included in the analysis (e.g., blood lipids, inflammatory markers, metabolic parameters).
The relationship between soy isoflavones and stroke risk in postmenopausal women is far more complex than initially imagined. While the Shanghai Women's Health Study found a modest association between high dietary isoflavone intake and increased ischemic stroke risk, the lack of association with urinary isoflavonoid levels suggests that actual exposure and effects may depend heavily on individual metabolic factors 1.
This research challenges the simplistic notion that "natural" always means "safe" and highlights the importance of considering dosage, individual differences in metabolism, and the complex ways in which plant compounds interact with our bodies.
Future research should focus on identifying the factors that determine individual responses to isoflavones, including genetic factors, gut microbiota composition, and overall dietary patterns.
This article is based on scientific research published in peer-reviewed journals. Consult with a healthcare professional before making significant changes to your diet or supplementation regimen.