Highlights
1. No Significant Impact on Remission
The Graves’ Selenium Supplementation (GRASS) trial demonstrated that daily 200 µg selenium supplementation did not lower the rate of non-remission compared to placebo. The odds ratio (OR) of 1.0 clearly indicates a lack of therapeutic advantage in achieving euthyroidism after antithyroid drug withdrawal.
2. Quality of Life Remains Unchanged
Serial assessments using the ThyPRO patient-reported outcome tool revealed no improvements in any quality-of-life scales for patients receiving selenium compared to those on placebo.
3. Immunological Neutrality
Thyrotropin receptor antibody (TRAb) levels, a hallmark of Graves’ disease activity, showed no significant difference between groups at the 18-month or end-of-study follow-up visits.
Background: The Role of Selenium in Thyroid Health
Graves’ disease is an autoimmune condition characterized by the production of antibodies against the thyrotropin receptor (TRAb), leading to hyperthyroidism. Beyond the systemic effects of excess thyroid hormone, the disease often places a significant burden on patient quality of life (QoL) and carries a risk of Graves’ orbitopathy. Standard treatment typically involves antithyroid drugs (ATD) such as methimazole or propylthiouracil. However, relapse rates after ATD withdrawal remain high, often exceeding 50%.
Selenium, an essential trace element, is highly concentrated in the thyroid gland. It serves as a critical component of selenoproteins, including glutathione peroxidases (GPx), thioredoxin reductases, and iodothyronine deiodinases. These enzymes play vital roles in antioxidant defense and thyroid hormone metabolism. Given that oxidative stress is a known component of Graves’ pathogenesis, clinicians have long hypothesized that selenium supplementation might exert an immunomodulatory effect, potentially increasing remission rates or improving the patient’s sense of well-being.
While the European Group on Graves’ Orbitopathy (EUGOGO) has previously recommended selenium for mild Graves’ orbitopathy based on clinical evidence, its efficacy in general Graves’ hyperthyroidism—specifically regarding remission of the hyperthyroid state itself—remained a subject of debate. The GRASS trial was designed to address this clinical uncertainty with high-level evidence.
Study Design: The GRASS Trial Methodology
The Graves’ Selenium Supplementation (GRASS) trial (NCT01611896) was a double-blind, placebo-controlled, multi-centre randomized clinical trial conducted in Denmark. The study recruited 430 individuals with newly diagnosed Graves’ hyperthyroidism between December 2012 and December 2018.
Intervention and Comparators
Participants were randomized to receive either 200 µg of selenium yeast daily or a matching placebo tablet. This intervention was administered as an add-on to standard antithyroid drug therapy. The duration of the intervention ranged from 24 to 30 months, depending on the specific timing of ATD withdrawal, ensuring that the effects of selenium could be observed through the critical post-medication period.
Endpoints and Definitions
The primary outcome was the proportion of participants with “non-remission.” This was rigorously defined as:
- The continued need for ATD during the last 12 months of the intervention.
- Remaining hyperthyroid (TSH < 0.1 mIU/L).
- Referral to definitive ablative therapy, such as radioactive iodine or thyroidectomy.
Secondary outcomes included health-related quality of life, measured by the thyroid-specific ThyPRO questionnaire, and biochemical markers including TRAb levels. The ThyPRO tool assesses multiple domains, including goiter symptoms, hyperthyroid symptoms, tiredness, and emotional impact.
Key Findings: Neutral Results Across All Domains
The trial results were remarkably consistent in showing a lack of benefit for selenium supplementation in this cohort.
Remission Rates
Of the 430 recruited participants, non-remission was observed in 118 (54.6%) of the selenium group and 114 (53.3%) of the placebo group. The calculated odds ratio (OR) was 1.0 (95% CI 0.7 to 1.5; p=0.98), demonstrating that selenium provided no statistically significant or clinically meaningful improvement in remission rates. This suggests that the underlying autoimmune process driving Graves’ hyperthyroidism is not sufficiently modified by selenium at this dosage to alter the disease course.
Quality of Life (QoL)
The ThyPRO assessments provided a detailed look at the patient experience throughout the study. Interestingly, while the QoL of participants improved significantly from the time of diagnosis as they reached a euthyroid state, there was no difference between the selenium and placebo arms. By the end of the study, the QoL of participants in both groups was comparable to that of the general population. This indicates that while standard treatment is effective at restoring QoL, selenium does not provide an additional boost to this recovery.
Biochemical and Immunological Markers
A key secondary interest was whether selenium could accelerate the clearance of thyrotropin receptor antibodies. However, TRAb levels remained similar between both groups at the 18-month mark and the end-of-study visit. This aligns with the primary clinical outcome, as TRAb levels are a strong predictor of relapse risk in Graves’ disease.
Expert Commentary: Contextualizing the Results
The findings of the GRASS trial are pivotal for endocrinology practice. For years, many patients and some clinicians have turned to selenium as a “natural” adjunct to thyroid therapy. The lack of efficacy seen here is particularly striking given that Denmark is traditionally considered a region with relatively low selenium intake. One might expect that if selenium were to work anywhere, it would be in a population with borderline selenium status. The fact that it failed in this setting strongly suggests that selenium is not a therapeutic silver bullet for Graves’ hyperthyroidism.
Distinction from Graves’ Orbitopathy
It is essential to distinguish these results from the management of Graves’ orbitopathy (GO). Previous research (notably by Marcocci et al.) has shown that selenium can improve eye symptoms and quality of life in patients with mild GO. The GRASS trial does not necessarily contradict those findings, as its primary focus was the hyperthyroid state and thyroidal remission rather than specific ocular outcomes. However, for the majority of Graves’ patients who do not have significant orbitopathy, the routine use of selenium is now clearly unsupported by high-quality evidence.
Safety and Public Health
While selenium is generally safe, chronic high-dose supplementation is not without risks, including potential links to type 2 diabetes and selenosis symptoms (such as hair and nail changes). In the absence of benefit, the potential for even minor side effects or the financial burden on patients makes the recommendation of selenium supplementation difficult to justify.
Conclusion: Shifting Clinical Practice
The GRASS trial provides high-quality, randomized evidence that daily 200 µg selenium supplementation, when added to standard antithyroid drug therapy, does not improve remission rates or quality of life in individuals with newly diagnosed Graves’ hyperthyroidism. The study was well-powered and rigorously conducted, offering a definitive answer to a long-standing clinical question.
For clinicians, the takeaway is clear: selenium should not be routinely recommended for the purpose of improving thyroid function or increasing the likelihood of remission in Graves’ disease. While it remains a tool for mild Graves’ orbitopathy, its use in general hyperthyroidism management should be discouraged. Future research may focus on whether specific subgroups with profound selenium deficiency might benefit, but for the general patient population, standard ATD therapy remains the cornerstone of medical management.
Funding and ClinicalTrials.gov
The GRASS trial was supported by various grants, including those from the Danish Council for Independent Research and the Novo Nordisk Foundation. The study is registered at ClinicalTrials.gov with the identifier NCT01611896.
References
- Cramon PK, et al. Selenium supplementation in individuals with newly diagnosed Graves’ hyperthyroidism: A double-blind, multi-centre RCT. Eur Thyroid J. 2025. doi: 10.1530/ETJ-25-0264.
- Marcocci C, et al. Selenium and the course of mild Graves’ orbitopathy. N Engl J Med. 2011;364(20):1920-1931.
- Watt T, et al. The thyroid-related quality of life measure ThyPRO has good responsiveness and ability to detect relevant clinical changes. J Clin Endocrinol Metab. 2014;99(10):3708-3717.
- Winther KH, et al. Selenium in thyroid disorders — essential knowledge for clinicians. Nat Rev Endocrinol. 2020;16(3):165-176.
