Public Health Recommendation

Suggested Termination of Practice (STOP): Zinc oxide supplementation should be discontinued in women with or at risk for endometriosis.

Rationale

Zinc is an essential trace element necessary for immune function, antioxidant defense, DNA synthesis, and reproductive health. However, the findings from a large cross-sectional study involving 4,315 American women completely challenges the assumption that zinc supplementation is universally beneficial in reproductive disorders. Analysis of NHANES data (1999–2006) revealed that women consuming more than 14 mg/day of zinc had a 60% higher likelihood of being diagnosed with endometriosis compared to those consuming 8 mg/day or less (adjusted OR 1.60; 95% CI 1.12–2.27; p = 0.009), while intake between 8 and 14 mg/day showed a non-significant trend (OR 1.19; 95% CI 0.92–1.54; p = 0.189), suggesting a threshold effect above which zinc may increase disease risk. These associations remained robust across diverse demographic and lifestyle subgroups in stratified and sensitivity analyses, reinforcing the consistency of the observed relationship. ^[1] Many zinc supplements contain between 15 and 80 mg of elemental zinc, which is well beyond the 14 mg per day threshold associated with increased endometriosis risk. This makes routine supplementation a potential contributor to disease pathogenesisrather than prevention.

Reconciliation with Contradictory Findings

While several earlier case-control studies reported low serum zinc levels in women with endometriosis and served as the clinical basis for zinc supplementation, these findings most likely reflect secondary phenomena rather than causal deficiency. Specifically, endometriosis is associated with chronic inflammation and immune dysfunction, conditions under which zinc sequestration via calprotectin functions as part of a nutritional immunity strategy to restrict zinc availability from invading pathogens.

Consider that elevated calprotectin is a hallmark of inflammatory states. Although the recent cross-sectional study by Muharam et al. found no correlation between calprotectin serum levels and endometriosis stage, there was a marked increase in calprotectin in women with endometriosis relative to healthy controls.^[2] The underlying inflammatory burden would still explain reduced serum zinc levels without implying true systemic deficiency.

But most importantly, the recent NHANES-based analysis, which examined dietary zinc intake rather than serum levels, provided stronger population-level evidence of a positive association between elevated zinc intake and increased endometriosis risk, adjusting for key demographic and lifestyle confounders.^[3] Together, these findings suggest that earlier observations of low zinc status may reflect inflammation-induced redistribution rather than insufficient intake, and that excess dietary zinc may actually exacerbate risk, likely through immune, microbiome, and hormone-related mechanistic pathways.

Zinc Supplementation in Endometriosis: Mechanistic Pathways

Emerging mechanistic insights suggest that excessive zinc intake may contribute to the pathophysiology of endometriosis through multiple interrelated pathways. Again, although zinc is essential for cellular function and reproductive health, its biological activity can become maladaptive in the context of estrogen-driven inflammatory conditions. Zinc may function as a metalloestrogen, stimulate matrix metalloproteinase activity, suppress immune responses at high doses, and disrupt microbial equilibrium. Each of these mechanisms has the potential to exacerbate lesion growth, inflammation, and immune evasion in endometriosis, highlighting the need for careful reconsideration of zinc supplementation practices in this population.

Conclusion

Excessive zinc intake from diet or supplementation may worsen endometriosis by activating estrogen receptors, disrupting immune function, and altering the microbiome. A large NHANES study found that intake above 14 mg/day significantly increases endometriosis risk. With many supplements exceeding this threshold, routine zinc supplementation may contribute to disease progression rather than prevention, prompting a Suggested Termination of Practice (STOP).

Research Feed

References

1. Exploring the link between dietary zinc intake and endometriosis risk: insights from a cross-sectional analysis of American women. Huang, Y., Wei, Y., Liang, F. et al.. (BMC Public Health (2024))
2. Correlation of calprotectin serum levels with degrees of endometriosis: A cross-sectional study.. Muharam R, Rizal MS.. (Int J Reprod Biomed. 2021)
3. Exploring the link between dietary zinc intake and endometriosis risk: insights from a cross-sectional analysis of American women. Huang, Y., Wei, Y., Liang, F. et al.. (BMC Public Health (2024))
4. Exploring the link between dietary zinc intake and endometriosis risk: insights from a cross-sectional analysis of American women. Huang, Y., Wei, Y., Liang, F. et al.. (BMC Public Health (2024))
5. The effects of zinc treatment on matrix metalloproteinases: a systematic review.. Nosrati, R., Kheirouri, S., & Ghodsi, R.. (ournal of Trace Elements in Medicine and Biology. 2019.)
6. Exploring the link between dietary zinc intake and endometriosis risk: insights from a cross-sectional analysis of American women. Huang, Y., Wei, Y., Liang, F. et al.. (BMC Public Health (2024))
7. Gut Microbiota as a Mediator of Essential and Toxic Effects of Zinc in the Intestines and Other Tissues.. Skalny AV, Aschner M, Lei XG, Gritsenko VA, Santamaria A, Alekseenko SI, Prakash NT, Chang J-S, Sizova EA, Chao JCJ, et al.. (International Journal of Molecular Sciences. 2021)