STOP Advisory: Reevaluating Zinc Supplementation in Endometriosis
Researched by:
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Karen Pendergrass
ID
Karen Pendergrass
Karen Pendergrass is a microbiome researcher specializing in microbiome-targeted interventions (MBTIs). She systematically analyzes scientific literature to identify microbial patterns, develop hypotheses, and validate interventions. As the founder of the Microbiome Signatures Database, she bridges microbiome research with clinical practice. In 2012, based on her own investigative research, she became the first documented case of FMT for Celiac Disease—four years before the first published case study.
Excessive zinc intake may worsen endometriosis by activating estrogen receptors, disrupting immune function, and altering the microbiome. A large HANES 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 (TOP).
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Karen Pendergrass
Researched by:
-
Karen Pendergrass
ID
Karen Pendergrass
Microbiome Signatures identifies and validates condition-specific microbiome shifts and interventions to accelerate clinical translation. Our multidisciplinary team supports clinicians, researchers, and innovators in turning microbiome science into actionable medicine.
Karen Pendergrass
Research Feed 
References 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.
| Mechanistic Pathway | Explanation |
|---|---|
| Estrogenic Activity via Metalloestrogen Pathways | Zinc can activate estrogen receptors similarly to other metalloestrogens like cadmium and nickel, raising concern in estrogen-sensitive conditions such as endometriosis.[4] |
| Disruption of Zinc-Matrix Metalloproteinase (MMP) Axis | Zinc is a cofactor for Matrix Metalloproteinases MMP-2 and MMP-9, which are upregulated in endometriosis and promote tissue invasion and fibrosis. [5] |
| Immunosuppression at High Zinc Doses | High levels of zinc inhibit lymphocyte function and reduce interferon-gamma production, compromising immune surveillance and enabling persistence of ectopic endometrial tissue.[6] |
| Microbiome Modulation and Dysbiosis | High-dose zinc intake alters gut microbiota by decreasing beneficial commensals and enriching opportunistic pathogens, which may worsen inflammation and disrupt estrogen metabolism through the estrobolome. [7] |
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
Exploring the link between dietary zinc intake and endometriosis risk: insights from a cross-sectional analysis of American women
October 23, 2024
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Endometriosis •
Endometriosis
Did you know?
Gut microbiota predict endometriosis better than vaginal microbiota.
STOPs •
STOPs
Did you know?
The radical mastectomy for breast cancer was standard practice for nearly 60 years before less invasive options were proven effective.
This study links higher dietary zinc intake with increased endometriosis risk among American women, highlighting zinc’s complex role in immune modulation and estrogen-related pathways. Findings emphasize the importance of balanced intake for managing endometriosis risk.
What was studied?
This study investigated the association between dietary zinc intake and the risk of endometriosis among American women. Using cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) collected between 1999 and 2006, the researchers aimed to evaluate whether zinc intake, as a key nutritional factor, was linked to the prevalence of endometriosis. Zinc is known for its essential roles in immune modulation, antioxidative defense, and regulation of matrix metalloproteinases (MMPs), all of which are implicated in endometriosis progression.
Who was studied?
The study included 4,315 American women aged 20–54 years, of whom 331 were diagnosed with endometriosis based on self-reported doctor diagnoses. Participants’ dietary zinc intake was assessed using 24-hour dietary recall interviews, with additional data on demographics, lifestyle, and health covariates collected. Women with extreme caloric intakes or incomplete data were excluded to ensure robustness of results.
What were the most important findings?
The study revealed a positive correlation between higher dietary zinc intake and the risk of endometriosis. Women consuming over 14 mg/day of zinc had a significantly higher adjusted odds ratio (1.60, 95% CI: 1.12–2.27, p = 0.009) compared to those with intake ≤8 mg/day. Zinc’s dual role in immune modulation and antioxidative defense was emphasized, particularly its regulation of matrix metalloproteinases (MMPs) like MMP-2 and MMP-9, which are key enzymes in tissue remodeling and endometriotic lesion invasion. Interestingly, despite zinc’s known antioxidative and anti-inflammatory roles, excessive intake appeared to have a counterproductive effect. These nuanced findings highlight zinc’s complex role in endometriosis pathophysiology.
What are the greatest implications of this study?
This research underscores the potential for dietary zinc as both a marker and modifiable factor in endometriosis risk. It raises questions about zinc’s dualistic effects, where optimal levels may support immune health, but excess intake could exacerbate estrogen-related pathways in endometriosis. Clinicians should be cautious when recommending zinc supplementation for reproductive health, particularly in populations at risk for endometriosis. Furthermore, this study strengthens the biological plausibility of microbiome involvement in endometriosis, as zinc is a crucial cofactor for microbial activity, and its imbalance may alter the gut and pelvic microbiota implicated in the disease.
Gut Microbiota as a Mediator of Essential and Toxic Effects of Zinc in the Intestines and Other Tissues
October 15, 2021
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Metals •
Metals
Lorem ipsum dolor sit amet, consectetur adipiscing elit. Proin ut laoreet tortor. Donec euismod fermentum pharetra. Nullam at tristique enim. In sit amet molestie
Zinc •
Zinc
Did you know?
Zinc is so critical to life that some pathogens, like Staphylococcus aureus, evolved specialized “zinc theft” systems to hijack it from human cells, while your immune system fights back by starving them with zinc-sequestering proteins like calprotectin. This nutrient tug-of-war is a microscopic battle that can determine the outcome of an infection!
This review illustrates zinc’s dose- and species-dependent impact on gut microbiota, linking both deficiency and excess to dysbiosis and systemic inflammation. Physiological Zn enhances barrier integrity and probiotic efficiency, while excess Zn favors pathogens. Zn–microbiota interactions extend beyond the gut, influencing neurodevelopmental and metabolic diseases.
What was reviewed?
This review comprehensively examined the bidirectional relationship between zinc (Zn) status—both deficiency and excess—and gut microbiota composition across multiple species, including poultry, pigs, rodents, and humans. It also explored how these microbiota changes modulate local (intestinal) and systemic (extraintestinal) physiological and pathological effects of zinc, including inflammation, metabolic disorders, and neurodevelopmental conditions.
Who was reviewed?
The review drew from both in vivo and in vitro studies involving chicks, piglets, mice, and human subjects, including genetic studies on human Zn transporters. It considered experimental Zn deficiency and supplementation using various Zn formulations (oxide, sulfate, nanoparticles) and reviewed probiotic co-supplementation studies.
Most Important Findings
Zinc plays a critical, dose-dependent role in shaping gut microbiota composition and function, with downstream effects on intestinal and systemic health. Zinc deficiency is consistently associated with gut dysbiosis, which is marked by decreased microbial diversity, shifts in phyla proportions (notably reduced Firmicutes and increased Proteobacteria), and compromised intestinal barrier function. Physiological zinc supplementation, in contrast, supports gut integrity by enhancing tight junction protein expression, reducing pathogen abundance, and promoting beneficial microbial metabolite production such as short-chain fatty acids (SCFAs).
However, zinc overexposure induces microbial shifts favoring pathogenic taxa, impairs gut barrier function, and promotes systemic inflammation and endotoxemia. Beyond the gut, zinc–microbiota interactions have been implicated in extraintestinal disorders including autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), severe acute pancreatitis, fetal alcohol syndrome, endometriosis, and obesity. Notably, co-supplementation with probiotics enhances zinc bioavailability and supports microbial-host homeostasis, with some probiotic strains (e.g., E. coli Nissle 1917) exploiting zinc-binding mechanisms to competitively inhibit pathogens. The review highlights a nuanced, dose-dependent role of zinc in gut microbiota regulation:
| Zinc Status / Intervention | Microbiota and Host Outcomes |
|---|
| Zinc Deficiency | ↓ Microbial diversity; ↓ Firmicutes; ↑ Proteobacteria; ↑ LPS translocation; ↑ systemic inflammation |
| Physiological Zinc Supplementation | ↑ Gut wall integrity; ↑ tight junction proteins; ↓ E. coli, Salmonella; ↑ SCFAs; ↑ mucosal immunity |
| Zinc Overexposure (esp. ZnO nanoparticles) | ↑ Enterobacteriaceae; gut dysbiosis; ↑ gut permeability; ↑ systemic LPS; ↑ risk of necrotizing enterocolitis, C. difficile |
| Zinc in Autism Spectrum Disorder (ASD) | ↓ Proteobacteria; partial correction of dysbiosis; improved intestinal gene expression profiles |
| Zinc in ADHD | ↓ Microbial diversity to healthy baseline levels; potential behavioral improvements |
| Zinc in Severe Acute Pancreatitis | ↓ E. coli translocation; ↓ IL-1β and TNFα; ↑ Bifidobacterium and Lactobacillus abundance |
| Zinc in Fetal Alcohol Syndrome / Obesity | Correlates with α-defensin levels, barrier integrity, and shifts in weight-associated microbiota |
| Zinc + E. coli Nissle 1917Probiotic Supplementation | ↑ Zinc bioavailability; ↑ mucosal integrity; antagonism of pathogens via Zn-binding siderophores |
Greatest Implications
This review underscores the critical role of microbial context in modulating zinc’s biological effects. While physiological zinc supports microbial homeostasis and host immunity, excess zinc undermines nutritional immunity, selects for virulence traits in pathogens, and disrupts host–microbe symbiosis. Importantly, the work highlights the importance of considering microbial responses to Zn when designing supplementation strategies, especially in vulnerable populations (e.g., children, ASD, chronic inflammation). It also opens avenues for microbiota-targeted zinc therapeutics in metabolic and neurodevelopmental diseases.
Correlation of calprotectin serum levels with degrees of endometriosis: A cross-sectional study
August 16, 2021
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Endometriosis •
Endometriosis
Did you know?
Gut microbiota predict endometriosis better than vaginal microbiota.
Nutritional Immunity •
Nutritional Immunity
Nutritional immunity restricts metal access to pathogens, leveraging sequestration, transport, and toxicity to control infections and immunity.
This study found no significant correlation between serum calprotectin levels and the severity of endometriosis. Despite its known role as an inflammatory biomarker, calprotectin did not differentiate between stages of disease, suggesting limited utility in clinical staging and reinforcing the need for localized biomarker assessment.
What was studied?
This cross-sectional study aimed to evaluate the correlation between serum calprotectin levels and the severity of endometriosis. The primary objective was to determine whether calprotectin could serve as a non-invasive biomarker to distinguish the different stages of endometriosis severity based on the revised American Society for Reproductive Medicine (ASRM) classification.
Who was studied?
A total of 46 women diagnosed with endometriosis undergoing laparoscopic or laparotomy procedures at three tertiary hospitals in Jakarta, Indonesia, between July 2017 and April 2018 were enrolled. Blood samples were collected one day prior to surgery, and serum calprotectin was measured using the Phical® ELISA method. Diagnosis and classification of endometriosis were confirmed via histopathological examination following surgery. Exclusion criteria included comorbidities such as diabetes, hypertension, infections, liver disease, or recent corticosteroid/immunosuppressant therapy.
Most important findings:
The distribution of endometriosis stages among participants was as follows: minimal (15.2%), mild (39.1%), moderate (34.8%), and severe (10.9%). Median serum calprotectin levels showed modest variation across groups, with the highest levels in the minimal group (138.98 ng/mL) and the lowest in the mild group (121.49 ng/mL). However, Spearman’s correlation analysis revealed no statistically significant correlation between serum calprotectin levels and the degree of endometriosis (r = –0.16; p = 0.278).
Interestingly, age and BMI showed a moderate positive correlation with endometriosis severity (r = 0.37 and 0.36, respectively; both p < 0.05), which could imply that these host factors are more predictive of disease progression than calprotectin levels.
Despite calprotectin’s recognized value as a biomarker in other chronic inflammatory conditions such as rheumatoid arthritis, obesity, and Crohn’s disease—where it reflects systemic inflammation and correlates with CRP and disease activity—the results of this study do not support its utility in endometriosis staging. The authors acknowledge that calprotectin's utility may be more pronounced in localized samples such as feces or peritoneal fluid rather than systemic circulation, where inflammation may not be as detectably elevated in endometriosis.
Implications:
This study provides evidence against the clinical utility of serum calprotectin as a non-invasive biomarker for grading endometriosis severity. While calprotectin is a well-established marker of inflammation in other systemic and localized inflammatory diseases, its lack of correlation with endometriosis stages underscores the complexity of the disease's inflammatory profile. The findings suggest that systemic markers may not adequately reflect the localized inflammatory microenvironment of endometriotic lesions. The authors recommend further research exploring calprotectin in peritoneal fluid or fecal samples, which may better capture localized inflammatory processes relevant to endometriosis pathogenesis.
STOPs
A STOP (Suggested Termination Of Practices) is a recommendation that advocates for the discontinuation of certain medical interventions, treatments, or practices based on emerging evidence indicating that these may be ineffective, harmful, or counterproductive in the management of specific conditions.
Endometriosis
Endometriosis involves ectopic endometrial tissue causing pain and infertility. Validated and Promising Interventions include Hyperbaric Oxygen Therapy (HBOT), Low Nickel Diet, and Metronidazole therapy.
Zinc
Zinc is an essential trace element vital for cellular functions and microbiome health. It influences immune regulation, pathogen virulence, and disease progression in conditions like IBS and breast cancer. Pathogens exploit zinc for survival, while therapeutic zinc chelation can suppress virulence, rebalance the microbiome, and offer potential treatments for inflammatory and degenerative diseases.
Nutritional Immunity
Nutritional immunity restricts metal access to pathogens, leveraging sequestration, transport, and toxicity to control infections and immunity.
Matrix Metalloproteinases (MMPs)
Matrix Metalloproteinases (MMPs) are zinc-dependent enzymes that regulate extracellular matrix remodeling, with critical roles in health, disease, and interactions with the microbiome.
References
- 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))
- Correlation of calprotectin serum levels with degrees of endometriosis: A cross-sectional study.. Muharam R, Rizal MS.. (Int J Reprod Biomed. 2021)
- 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))
- 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))
- 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.)
- 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))
- 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)
Huang, Y., Wei, Y., Liang, F. et al.
Exploring the link between dietary zinc intake and endometriosis risk: insights from a cross-sectional analysis of American womenBMC Public Health (2024)
Read ReviewMuharam R, Rizal MS.
Correlation of calprotectin serum levels with degrees of endometriosis: A cross-sectional study.Int J Reprod Biomed. 2021
Read ReviewHuang, Y., Wei, Y., Liang, F. et al.
Exploring the link between dietary zinc intake and endometriosis risk: insights from a cross-sectional analysis of American womenBMC Public Health (2024)
Read ReviewHuang, Y., Wei, Y., Liang, F. et al.
Exploring the link between dietary zinc intake and endometriosis risk: insights from a cross-sectional analysis of American womenBMC Public Health (2024)
Read ReviewNosrati, R., Kheirouri, S., & Ghodsi, R.
The effects of zinc treatment on matrix metalloproteinases: a systematic review.ournal of Trace Elements in Medicine and Biology. 2019.
Huang, Y., Wei, Y., Liang, F. et al.
Exploring the link between dietary zinc intake and endometriosis risk: insights from a cross-sectional analysis of American womenBMC Public Health (2024)
Read ReviewSkalny AV, Aschner M, Lei XG, Gritsenko VA, Santamaria A, Alekseenko SI, Prakash NT, Chang J-S, Sizova EA, Chao JCJ, et al.
Gut Microbiota as a Mediator of Essential and Toxic Effects of Zinc in the Intestines and Other Tissues.International Journal of Molecular Sciences. 2021
Read Review