A Comprehensive Review of Selenium as a Key Regulator in Thyroid Health

Abstract

Selenium (Se) is an essential trace element crucial for thyroid function, participating in the production and metabolism of thyroid hormones and the immune system. It engages in synthesizing selenoproteins, which are essential for antioxidant defense and regulating thyroid hormone levels. It is crucial to convert thyroxine (T4) into the active thyroid hormone triiodothyronine (T3) via deiodinase activity and safeguard thyroid cells from oxidative damage. Therefore, thyroid dysfunction, including abnormalities in thyroid hormone synthesis and the emergence of autoimmune thyroid conditions such as Graves’ disease and Hashimoto’s thyroiditis, has been linked to Se deficiency. When evaluating the benefits of Se supplementation, it is crucial to recognize that excessive mineral intake may be detrimental and result in adverse consequences, including gastrointestinal disturbances and neurological problems. The effectiveness of Se-based therapies is influenced by individual characteristics, including hereditary anomalies in thyroid function and Se metabolism. Further research should be performed on personalized Se supplementation approaches using genetics and nanotechnology to optimize the bioavailability and efficacy of the supplements. This study aims to thoroughly examine Se’s role in thyroid health and how its therapeutic use in thyroid-related diseases may be optimized via appropriate dosing.

Introduction

The trace element selenium (Se) is vital to human health because of the many essential functions it plays in the body [1], such as antioxidant defense, immunological function, and thyroid hormone metabolism [2]. Selenium, cadmium (Cd), arsenic (As), and lead (Pb) in particular have attracted a lot of study due to their complex relationships with thyroid function and trace elements [3]. Selenium has a major impact on thyroid health maintenance, even though it is only needed in minute amounts [4]. A specialized collection of proteins called selenoproteins (SelPs) mediate its unique biological features via the enzymatic processes that rely on selenium [5]. In particular, the iodothyronine deiodinases (DIO) and glutathione peroxidases (GPX1) play an essential role in thyroid physiology and safeguard against diseases caused by immunological dysregulation and oxidative stress (OS) [6]. In areas with low soils in Se, the health risks associated with Se insufficiency continue to be a major issue. Diseases related to deficiencies, such as thyroid dysfunction, are more common among populations in some areas of Asia, Africa, and Europe [7]. The thyroid gland, a butterfly-shaped organ located at the base of the neck, is responsible for producing hormones critical to regulating metabolism, growth, and development [8]. Although the thyroid gland is not the organ that has the most significant overall amount of Se in the human body, it does have the highest concentration of Se among all endocrine organs and, in fact, among all tissues regarding the amount of Se that it contains per gram [9]. This uniquely high Se density reflects the gland’s critical dependence on SelPs, which are involved in antioxidant defense and thyroid hormone metabolism [10]. Low selenium consumption has been linked to a higher incidence of thyroid-related disorders such as goiter, autoimmune thyroiditis (AITDs), and hypothyroidism [11]. Reactive oxygen species (ROS) are generated as byproducts during thyroid hormone synthesis [12]. Thyroid cells may sustain OS from these ROS if they are not well controlled [13]. Selenium antioxidant function is crucial for scavenging ROS and protecting the gland’s cellular apparatus [14]. To create iodothyronine, the building block of thyroid hormones, thyroid peroxidase (TPO) catalyzes the iodination of tyrosyl residues in thyroglobulin during thyroid hormone production [15]. Hydrogen peroxide (H₂O_₂) is needed as a substrate for this process. Excess of the potent oxidizing agent H₂O_₂ may result in OS, which damages DNA, causes lipid peroxidation, and causes thyroid cells to undergo cellular death [13]. Enzymes that include Se detoxify excess lipid hydroperoxides and H₂O_₂ by turning them into alcohols and water. This defense mechanism maintains thyroid cells’ structural and functional integrity. To maintain enough H₂O_₂ levels for hormone production without causing oxidative damage, GPX activity is necessary [16]. Another Se-dependent enzyme, thioredoxin reductase (TXNRD), supports antioxidant defense by maintaining the redox balance in thyroid cells [17]. Figure 1 demonstrates that diminished Se levels and decreased thioredoxin reductase 1 (TXNRD1) expression compromise antioxidant defense in the thyroid gland. This results in heightened susceptibility to OS, which factors like NADPH oxidase activity, radiation, microbial absorption, enzymatic reactions, metabolic processes in peroxisomes, endoplasmic reticulum stress, and mitochondrial oxidative phosphorylation may induce. Together, these activities produce ROS, leading to thyroid dysfunction and possible cellular damage. It regenerates thioredoxin, which helps repair OS proteins [15]. Hashimoto’s thyroiditis and Graves’ disease are two examples of AITDs, that pose a serious threat to world health. Chronic inflammation and dysregulated immune responses to thyroid antigens are hallmarks of these disorders, which result in glandular malfunction [18]. Selenium’s immunomodulatory qualities, which are mediated via its effects on antioxidant systems, T cells, and cytokines, provide a prospective therapeutic approach for treating various illnesses [19]. According to clinical research, selenium supplementation may lower autoantibody titters and enhance the quality of life for autoimmune thyroiditis patients, highlighting its potential as an adjuvant treatment [20]. Additionally, illness presentation is significantly impacted by the redox state inside thyroid tissues, which is regulated by trace elements. The clinical and pathological features of thyroid illnesses may be influenced by disruptions in antioxidative cofactor metals, highlighting the need to maintain a balanced trace element profile for optimum thyroid health [21].

Fig. 1.

Effect of low Se and TXNRD1 deficiency on thyroid gland OS pathways. Particularly its impact on the expression of thioredoxin reductase 1 (TXNRD1), a fundamental selenoenzyme involved in redox control; this figure shows the molecular and cellular repercussions of Se deprivation. Low Se levels reduce TXNRD1 activity in the thyroid, upsetting antioxidant protection and raising OS susceptibility. Among the many sources of ROS shown are NADPH oxidase activation, microbial absorption, radiation exposure, endoplasmic reticulum (ER) stress, mitochondrial oxidative phosphorylation, and peroxisomal metabolism. In the lack of enough Se-mediated enzymatic detoxification, the buildup of ROS, including hydrogen peroxide (H₂O₂) and superoxide (O₂,⁻ causes cellular damage and thyroid malfunction. This route emphasizes the role TXNRD1 and selenium play in preserving redox balance and shielding thyroid tissue from oxidative damage

Selenium has physiological roles, effects on specific illnesses, and therapeutic uses are the main topics of this review, which examines the complex interaction between Se and thyroid problems (Table 1). This study attempts to fully comprehend Se’s function in thyroid health and illness management by looking at the most recent clinical data and discussing the prospects and problems in Se supplementation.

Table 1.

Selenium’s impact on thyroid disorders, mechanisms, supplementation strategies, and potential challenges

Thyroid disorder	Role of Se	Mechanisms of action	Recommended supplementation	Challenges and considerations	Reference
Hashimoto’s Thyroiditis	Reduces TPOAb and TgAb levels, decreases thyroid inflammation	Antioxidant activity (GPX), immune modulation (reduces pro-inflammatory cytokines), and inhibits OS-induced thyroid damage	200 µg/day of SeMet or sodium selenite as an adjunct to levothyroxine therapy	Variability in supplementation efficacy based on baseline Se levels; potential over-supplementation risks	[22]
Graves’ Disease	Mitigates thyroid hyperactivity and alleviates thyroid eye disease (TED)	Reduces OS and inflammation, modulate the immune response, and may stabilize thyroid hormone overproduction	200 µg/day Se supplementation improves TED symptoms	Limited data on long-term efficacy; efficacy in mild vs. severe TED not well-established	[23]
Subclinical Hypothyroidism	Improves thyroid function and TSH levels	Enhances deiodinase activity (DIO1, DIO2) for T4 to T3 conversion, reduces rT3 levels	100–200 µg/day Se supplementation in Se-deficient individuals	Requires careful monitoring to avoid excess Se intake	[23]
Thyroid Nodules and Goiter	Decreases nodule size, prevents goiter in deficient regions	Antioxidant protection (GPX, TXNRD), improves iodine utilization	SeMet supplementation (100–200 µg/day) in populations with Se and iodine deficiency	Limited evidence; not universally effective in populations with adequate Se levels	[24]
Non-Thyroidal Illness Syndrome (NTIS)	Normalizes thyroid hormone levels, reduces rT3	Reduces reverse T3 (rT3) production, enhances T3 bioavailability, stabilizes redox-sensitive signalling pathways (Nrf2, NF-κB)	100–200 µg/day Se dosage, with potentially higher needs during critical illness	Effects in critically ill patients are mixed; not all respond to supplementation	[25]
Thyroid Hormone Regulation in Pregnancy	Prevents hypothyroidism, supports fetal development	Enhances deiodinase activity and protects thyroid tissue from OS during high metabolic demand	60–200 µg/day, depending on baseline Se and iodine levels	Excess supplementation in pregnancy may cause harm; limited data on ideal dosing	[26]
Cognitive Development in Children	Supports normal brain and thyroid development	Ensures adequate T3 availability for neurogenesis and reduces OS in developing neurons	Sufficient food intake Se consumption; supplementation in areas with deficiencies	Long-term effects on cognitive outcomes are still under research; potential toxicity with over-supplementation	[27]
Se-Toxicity (Selenosis)	Causes gastrointestinal and neurological symptoms	Overproduction of methylated Se compounds, accumulation of reactive Se species	Avoid excessive intake (> 400 µg/day); monitor Se status	A narrow therapeutic window requires careful balancing of intake and systemic levels	[28]
Innovative Therapies	Enhances bioavailability, reduces toxicity	Se-nanoparticles improve tissue delivery and controlled release	Ongoing research into optimal dosing and nanoparticle formulations	Clinical validation required; potential long-term safety concerns	[29]

Clinical Evaluation of Se Status and Suggested Consumption

Plasma or serum Se concentration is the usual way to evaluate Se status in people. It shows what people have eaten recently [30]. Additional functional biomarkers such as GPX activity and SelPs levels are also used to evaluate Se-dependent enzymatic functions [2]. Levels below 70 µg/L are considered inadequate and can potentially hinder thyroid hormone metabolism and antioxidant protection, while normal blood Se levels are often seen in the 70–150 µg/L range [4]. Typically, serum Se concentrations of 90–100 µg/L are required to achieve optimal GPX activity, although values closer to 125 µg/L may be necessary to achieve complete saturation of SelP. Dietary recommendations state that individuals should consume no more than 55 µg of Se per day, with an increase to 60–70 µg per day during pregnancy and breastfeeding [31]. The tolerable upper intake level (UL) for Se is set at 400 µg/day in adults; exceeding this limit may lead to Se toxicity (selenosis), characterized by gastrointestinal disturbances, hair loss, and neurological dysfunction [2]. Regarding thyroid function, immunological modulation, and redox equilibrium, it’s essential to keep Se consumption within the physiological range, as both low and high levels might lead to adverse clinical effects [17].

Activation and Deactivation of Thyroid Hormones

The DIO family of SelPs is responsible for activating or deactivating thyroid hormones, and selenium plays a direct role in this process. Figure 2 shows that deiodinase type 1 (DIO1) transforms the inactive thyroid hormone thyroxine (T4) into the active form of thyroid hormone triiodothyronine (T3) [32]. DIO1 maintains sufficient blood T3 levels in peripheral organs such as the kidneys and liver. Brain, brown fat, and skeletal muscle are among the tissues that contain deiodinase type 2 (DIO2), an enzyme that converts T4 to T3 on a local level. As a result, the function of thyroid hormone in specific organs may be precisely regulated. [33]. By transforming them into diiodothyronine (T2) and reverse T3 (rT3), respectively, Deiodinase Type 3 (DIO3) renders T4 and T3 inactive. In some physiological or developmental settings, DIO3 aids in hormone regulation, avoiding hyperthyroid conditions [34]. Maintaining a balance between T4 and T3 requires proper Se levels. Reduced availability of T3 and the possibility of hypothyroid-like symptoms despite normal T4 levels are caused by insufficient Se, which impairs the operation of DIO1 and DIO2 [35]. Thyroxine (T4) and triiodothyronine (T3), the thyroid hormones, play an essential role in controlling metabolism, growth, and development [36]. Nevertheless, the level of biological activity is influenced by concentration and how they are activated and deactivated inside the body. Selenium is required for this regulation to take place via DIO [17]. In addition, rather than leading to an increase in rT3 levels directly caused by an imbalance in DIO3, the available data imply that Se deficit may indirectly cause these levels to rise via reduced clearance of DIO1 and changes in peripheral thyroid hormone metabolism [33]. Table 2 shows the roles of Se in thyroid hormone synthesis.

Fig. 2.

The relative functions of the thyroid and SelPs synthesis via SeMet’s metabolic routes. SelPs production and the metabolic fate of dietary Se molecules, especially SeMet, are shown in this graphic. To get to selenocysteine, the trans-sulfuration route converts SeMet via stages that include selenocystathionine. The synthesis of SelPs is subsequently facilitated by selnocysteine via Sec-tRNA. Melylselenol (CH₃SeH) is another possible intermediate in the Se homeostasis and excretion pathways; it may be further transformed to dimethyl selenide ((CH₃)₂Se) or trimethylselenonium ((CH₃)₃Se⁺). The glutathione system is shown to reduce inorganic Se forms like selenate (SeO₄²⁻) and selenite (SeO₃²⁻) to hydrogen selenide (H₂Se), a commonly used precursor for SelPs production. In addition, the graphic shows how selenium helps the thyroid gland’s SelPs with redox control and thyroid hormone metabolism, such as changing thyroxine (T₄) into triiodothyronine (T₃), the active form of thyroid hormone. This route shows the significance of SeMet as an endocrine regulator and antioxidant

Table 2.

Roles of Se in thyroid hormone synthesis

Component	Role in hormone synthesis	Se’s contribution	Impact of deficiency	References
TPO	It iodinates thyroglobulin to generate iodotyrosines	Se enzymes manage oxidative byproducts like H₂O₂	Accumulation of ROS leads to OS in cells	[37]
H₂O₂	Plays a role in hormone production by providing a substrate for TPO	Detoxified by Se-dependent GPX enzymes	Excess H₂O₂ causes lipid peroxidation and cellular apoptosis	[15]
GPX1	Converts H₂O₂ and lipid hydroperoxides into water and alcohols	It prevents OS and protects thyroid integrity	Increased OS and thyroid cell damage	[38]
GPX3	Antioxidants in plasma control the redox status outside of cells	Protects thyroid extracellular matrix and vasculature from OS	Increased OS in thyroid interstitial space	[39]
GPX4	Prevents lipid peroxidation in cell membranes	Protects thyroid follicular cells from damage	Lipid membrane damage, apoptosis	[39]
TXNRD1	Maintains redox balance and regenerates thioredoxin	Repairs proteins damaged by OS	Impaired protein repair and redox imbalance	[40]
DIO1	Converts T4 → T3 in peripheral tissues (liver, kidney)	Maintains circulating T3 levels	Reduced T3, increased rT3	[41]
DIO2	Converts T4 → T3 locally in the brain, pituitary, BAT	Optimize the availability of T3 in certain tissues	Local hypothyroidism despite normal serum T4	[42]
DIO3	Inactivates T3 and T4 (→ rT3 and T2)	Regulates hormone inactivation during stress or development	Imbalanced T3/rT3, potential hormone excess or deficiency	[43]

Physiological Effects of Se Deficiency on the Thyroid Gland

Impaired Conversion of T4 to T3

Selenium is essential in synthesizing T3 by DIO1 and DIO2 [44]. Se-dependent enzymes include DIO1, which is expressed in the kidneys and liver, and DIO2, present in the brain and brown adipose tissue, among other organs [27]. The conversion of T4 into the more physiologically active T3 form is lowered due to a reduction in the activity of these deiodinases, which occurs when Se is deficient [33]. This reduction in T3 can manifest as hypothyroid symptoms such as fatigue, weight gain, and cold intolerance, even though T4 levels may appear normal. This phenomenon is often seen in populations with Se deficiency, particularly in areas with low soil Se content [45].

Increased Ratio of Reverse T3 (rT3)

Selenium deficiency not only impairs the conversion of T4 to T3 but may also lead to increased levels of reverse T3 (rT3), an inactive form of the hormone [46]. Without adequate Se, there is an imbalance between the activation and inactivation of thyroid hormones [47]. In the condition known as “functional hypothyroidism,” the thyroid hormones cannot control metabolism efficiently because of the excessive synthesis of rT3 and the lack of T3. This syndrome, which is aggravated by selenium shortage, is often seen in patients who are in critical condition. It is also referred to as “non-thyroidal illness syndrome” (NTIS) or “euthyroid sick syndrome.” [25].

OS and Thyroid Gland Damage

Selenium’s function as a cofactor for GPX is essential for neutralizing ROS produced during the thyroid hormone production process. By cleansing H_₂O_₂, a byproduct of thyroid hormone production, GPX enzymes protect the thyroid gland from OS [48]. Thyroid cells suffer OS when there is a Se shortage because the antioxidant defense system is weakened. Numerous illnesses may be exacerbated by this injury, which can result in inflammation, fibrosis, and perhaps thyroid malfunction. Furthermore, since Se shortage reduces TXNRD activity, it compromises mitochondrial integrity [24]. This damages the electron transport chain in the mitochondria, which raises ROS production, aggravates OS, and encourages apoptosis. Selenium is also necessary for controlling redox-sensitive signaling pathways, such as the Nrf2 and NF-κB pathways [49].

Increased Probability of AITD Disorders

Selenium has a role in the modulation of immunological responses, and a lack of Se may raise the risk of Acute Immunological Deficiency Disorders (AITDs). Both OS and inflammation contribute to the development of autoimmune thyroiditis, and the antioxidant capabilities of Se control the immune system by lowering both of these components [50]. Inadequate Se levels can increase the production of pro-inflammatory cytokines and enhance the autoimmunity process, leading to the development or exacerbation of conditions such as Hashimoto’s thyroiditis and Graves’ disease [48]. Research has shown that supplementation with selenium in persons who are deficient in selenium and suffer from autoimmune thyroiditis may lower levels of thyroid autoantibodies and improve clinical results [51].

Role of Se on Impaired Thyroid Hormone Release during Stress

Selenium also plays a role in regulating thyroid hormones during stress [52]. When the body is under acute or chronic stress, it often reduces the action of the thyroid hormone as a defensive strategy to preserve electricity [26]. Through inhibiting the conversion of T4 to T3 and enhancing the generation of rT3, Se shortage might impede the body’s capacity to adjust to certain stress situations, worsening the symptoms of hypothyroidism [6]. This dysregulation is especially problematic in the case of critical illness when a lack of Se might worsen NTIS because thyroid hormones are not regulated adequately to meet the needs of metabolism [52].

Role of Se on the Microbiome and Gut-Thyroid Axis

The gut microbiome plays a pivotal role in the bioavailability of Se [53]. The gastrointestinal tract is responsible for the biotransformation of Se, whether it is in an organic or inorganic form. The absorption and integration of SelPs, which are essential for thyroid function, are improved when certain stomach bacteria metabolize Se into bioactive forms [54]. On the other hand, dysbiosis, which is an imbalance in the populations of microorganisms in the gut, may hinder Se absorption, resulting in suboptimal levels that may impact thyroid function [55]. Additionally, the gut microbiome affects the production of these SelPs by influencing the bioavailability of Se and its incorporation into metabolic pathways. It has been shown that beneficial microorganisms such as Lactobacillus and Bifidobacterium are associated with increased SelP activity.

On the other hand, populations of pathogenic or dysbiotic microbes may lower the amount of Se that is available for these essential processes [56]. One of the reasons for the higher occurrence of thyroid diseases in areas with soils that are deficient in Se is that the connection between the stomach and the thyroid is impaired. Selenium shortage worsens hyperthyroidism in the thyroid gland and upsets the microbial equilibrium essential for the gland to perform its functions correctly [57]. In addition, being deficient in Se has been associated with a decrease in the variety of microorganisms, which further hinders the absorption and utilization of Se in the metabolism of thyroid hormone. The growing knowledge of the gut-thyroid axis paves the way for novel treatment strategies targeting both Se levels and the microbiome’s health [58]. The combination of Se administration with probiotics or prebiotics has the potential to maximize the bioavailability of selenium and improve thyroid function. In addition, personalized techniques that make use of gut microbiome profiling have the potential to guide the identification of people who are most likely to benefit from therapies of this kind [59].

Effects of Se on Development and Cognitive Function

Selenium is needed for appropriate growth and neurodevelopment, especially during the fetal and early postnatal periods. Selenium is required for optimal growth and development. Thyroid hormone metabolism is an essential component in the development of the brain, mainly via T3-regulated neurogenesis, myelination, and synaptogenesis. Selenium shortage may hurt thyroid hormone metabolism. The principal plasma transporter of Se, SelPs-P, is responsible for transporting Se to the brain via receptors such as ApoER2. However, its primary purpose is to preserve neuronal antioxidants rather than to perform thyroid function directly [60]. A shortage of Se may cause disruptions in the metabolism of thyroid hormones, which can impact the development of fetuses and young children and contribute to cognitive impairments and developmental delays [61]. As a result of disruptions in thyroid hormone control throughout critical stages of brain development, studies have shown that being deficient in Se may hurt intellectual function and lower IQ levels in children [62]. Additionally, low levels of Se have been associated with both anxiety and depression, as well as a decrease in cognitive ability [60].

Interventions of Se in Combination with other Micronutrients

Selenium plays an important function in the thyroid's health, especially when paired with other micronutrients such as iodine, zinc, iron, vitamin D, and B vitamins (Table 3). Selenium combined with iodine improves the conversion of T4 to T3, a more active form of the hormone, hence facilitating the effective generation of thyroid hormone [64]. Zinc (Zn) and Selenium protect the thyroid from OS and inflammation, optimizing hormone synthesis and improving thyroid function [66]. It is critical to maintain a balance of harmful and necessary trace elements. According to studies, changes may influence thyroid function and illness progression in elements including Zn, Cu, and Mn, Cd [67]. Such deficiencies may play a role in the etiology of diseases; for example, multinodular goiter and thyroid adenomas are associated with these deficiencies [1]. One important finding highlighting the diagnostic potential of elemental profiling is the ability to discriminate between healthy persons and those with hypothyroidism via abnormalities of trace elements in serum [68]. According to these patterns, thyroid dysfunction may be detected by changes in selenium and cadmium levels, among other elements. These results add weight to the case for using trace element monitoring as part of clinical assessments and preventative measures for thyroid-related diseases [3]. Moreover, a decrease in Se levels and a rise in harmful metals like Cd and Pb are standard features of thyroid cancer, according to an analysis of thyroid tissue elements. This discord may aid the development of illness and OS. Results like this show how important it is to monitor trace element trends when diagnosing thyroid diseases [69]. According to the research that has been conducted, zinc, like Se, is an essential trace element that plays a role in the maintenance of thyroid endocrine function. It is an extremely important factor in manufacturing thyroid hormones, as well as their structural stabilization and receptor binding.

Table 3.

Showing the role of micronutrients in thyroid health and how their interaction with Se enhances the therapeutic effects on thyroid function

Micronutrient	Role in thyroid health	Synergistic effect with Se	Clinical benefits	References
Iodine	Iodine is a vital mineral required to synthesize thyroid hormones T3 and T4	Se’s participation in deiodinase enzymes optimizes thyroid hormone action by converting T4 to T3	Proper thyroid hormone production requires enough iodine. Combining Se optimizes T4-to-T3 conversion, boosting thyroid function and metabolism and avoiding hypothyroidism or goiter from inefficient iodine consumption	[63]
Zinc	Zinc is involved in thyroid hormone synthesis, the function of TPO Zinc deficiency impairs both the immune function and thyroid function	Se and zinc are antioxidants that prevent thyroid disorders Zinc and Se promote thyroid function by modulating the immune system and hormones	Se and zinc enhance thyroid function by protecting the gland from OS and immune-mediated damage Zinc ensures adequate thyroid hormone synthesis, while Se aids in thyroid protection, reducing inflammation and the risk of autoimmune thyroid diseases like Hashimoto’s and Graves’ disease	[64]
Iron	Iron is a critical component for synthesizing thyroid hormones and supports the activity of deiodinase enzymes, which convert T4 to the more active T3. Iron is essential for oxygen transport, which in turn supports the metabolic activity of the thyroid	Se helps enhance the activity of the deiodinase enzymes that require iron for efficient T4 to T3 conversion. Adequate Se levels improve iron’s effectiveness in supporting thyroid metabolism and hormone synthesis	Iron and Se boost thyroid hormone production and conversion, especially in iron-deficiency anemia patients. The combination improves thyroid hormone metabolism and deiodinase enzyme activity, reducing hypothyroid symptoms, including tiredness, poor energy, and cognitive difficulties	[65]
Vitamin D	Vitamin D regulates immunity and thyroid function. Vitamin D insufficiency, which regulates immunological function, is associated with autoimmune thyroid illnesses, including Hashimoto’s thyroiditis and Graves'disease	Se and vitamin D work synergistically to reduce inflammation and autoimmune responses within the thyroid. Se’s antioxidant properties complement vitamin D’s ability to modulate immune function, reducing autoimmune attacks on the thyroid	Combining Se and vitamin D can benefit individuals with autoimmune thyroid diseases by reducing inflammation, supporting immune system balance, and potentially improving thyroid hormone production. This combination may also help minimize goiter size and thyroiditis and stabilize thyroid function	[65]
Vitamin A	Vitamin A is essential for thyroid hormone metabolism and is key in regulating the balance between T4 (inactive) and T3 (active). It supports the differentiation and function of thyroid cells and directly impacts gene expression related to thyroid health	Se and vitamin A boost thyroid hormone function by improving T4 to T3 conversion. Vitamin A balances thyroid hormone metabolism, whereas Se lowers OS	Combining Se and vitamin A enhances thyroid hormone balance, optimizing the conversion of T4 to the active T3 form. This is essential for maintaining proper metabolism, preventing fatigue, and improving the health of individuals suffering from hypothyroidism or poor hormone conversion	[63]
B-Vitamins (B6, B12, Folate)	B vitamins, notably B6, B12, and folate, are essential for energy generation, thyroid hormone metabolism, and cell function. B6 and folate help cells regenerate and synthesize hormones, and hypothyroidism often lacks B12	Se and B vitamins boost thyroid hormone metabolism and energy generation. B vitamins and Se's antioxidants boost energy, regulate hormones, and minimize weariness. B6 and B12 boost Se's thyroid hormone production efficiency	The combination of Se and B vitamins improves thyroid function by enhancing thyroid hormone synthesis, supporting cellular regeneration, and boosting energy levels. This is especially beneficial for individuals experiencing fatigue, weakness, and other hypothyroid symptoms. Vitamin B12 helps correct deficiencies seen in hypothyroidism	[64]

Inadequate zinc levels have been linked to decreased blood levels of T3 and T4 and high levels of TSH. Zn is essential for the action of transcription factors and enzymes like TPO, and Zn deficiency has been linked to these conditions [25]. When controlling oral sphincter (OS) in thyroid tissue, the interaction between Se and zinc is especially crucial. In the same way that selenium acts as a cofactor for antioxidant enzymes like GPX and TXNRD, zinc plays a function in the activity of superoxide dismutase (SOD), which helps with antioxidant defense [70]. Furthermore, the combined deficits in Se and Zn may worsen thyroid dysfunction by restricting the synthesis of hormones and the enzymatic conversion of T4 to T3. This highlights the therapeutic significance of treating these micronutrients in thyroid health initiatives [25]. Iron, in addition to zinc, is required for the production of thyroid hormones. Combined with Sem, iron contributes to the enhancement of the thyroid’s overall function by assuring the correct activity of enzymes involved in the process of hormone conversion [71]. Vitamin D is renowned for its ability to modulate immunological function and works in conjunction with Sem to reduce inflammation. This provides a beneficial effect for autoimmune thyroid illnesses such as Hashimoto’s thyroiditis [72]. A synergistic relationship exists between Sem and vitamin A, which helps control thyroid hormone metabolism and improves the conversion of T4 to T3 [73]. In addition, the B vitamins are beneficial to thyroid function because they enhance the production of hormones and the metabolism of energy [74]. When it comes to resolving thyroid dysfunction, lowering symptoms, and encouraging tissue regeneration and repair, a holistic strategy that includes Se and these micronutrients is helpful. This is especially true in the case of autoimmune thyroid diseases [65].

Se and Specific Thyroid Disorders

Autoimmune Thyroiditis (Hashimoto’s Thyroiditis)

Hashimoto’s thyroiditis is an autoimmune disorder with chronic thyroid gland inflammation [44]. The immune system produces antibodies against thyroid proteins, such as TPO and thyroglobulin (Tg), leading to thyroid cell damage and eventual hypothyroidism [75]. Selenium’s anti-inflammatory properties may help suppress the production of these autoantibodies, reducing thyroid glandular damage and potentially improving thyroid function in affected individuals [64]. Various studies, including randomized controlled trials (RCTs), have shown that Se supplementation can significantly reduce levels of TPOAb and TgAb in individuals with Hashimoto’s thyroiditis [76]. A notable meta-analysis by Toulis et al. [22] demonstrated a significant reduction in TPOAb levels following Se supplementation, particularly in those with Se deficiency. In Se-deficient patients, Se supplementation (typically 200 µg/day) has been associated with improved clinical outcomes, including reducing the severity of hypothyroid symptoms and decreasing the need for levothyroxine therapy [22]. Selenium supplementation can be used alongside standard levothyroxine therapy to improve thyroid function and quality of life in Hashimoto’s thyroiditis patients. Clinical recommendations generally suggest 200 µg/day of Se as sodium selenite or SeMet [77].

Graves’ Disease

Graves’ disease is an autoimmune condition that causes hyperthyroidism, resulting from the production of TSH receptor autoantibodies that stimulate the thyroid gland to overproduce thyroid hormones [78]. The autoimmune response in Graves’ disease is often accompanied by increased OS, which exacerbates thyroid tissue damage and may contribute to the development of thyroid eye disease (TED) [79]. A key randomized trial conducted by the European Group for the Study of Graves’ Orbitopathy (EUGOGO) demonstrated that Se supplementation (200 µg/day) reduced the severity of TED and improved quality of life in patients [80]. Selenium may serve as an adjunct to antithyroid drugs in managing Graves’ disease, especially in individuals with mild TED [81]. It may improve clinical outcomes by reducing inflammation and OS, contributing to better management of thyroid function and eye-related symptoms in these patients [79].

Subclinical Hypothyroidism

Elevated TSH levels characterize subclinical hypothyroidism, while free T4 remains within the normal range. This condition often arises due to mild thyroid dysfunction or autoimmune thyroiditis [82]. Selenium plays an important role in regulating thyroid hormone metabolism and may improve the function of the thyroid gland in subclinical hypothyroidism by promoting better conversion of T4 to the active form T3 [23]. Supplementation studies indicate that Se can improve TSH levels in Se-deficient individuals with subclinical hypothyroidism. The benefits of Se supplementation are most prominent in individuals with concurrent autoimmune thyroiditis [83]. Another study showed that Se supplementation reduced TSH levels in individuals with subclinical hypothyroidism, improving thyroid function markers and symptoms of hypothyroidism. Selenium supplementation can be considered for Se-deficient individuals with subclinical hypothyroidism, mainly if there is a co-existing autoimmune component. It may help prevent the progression of overt hypothyroidism, especially in Se-deficient individuals [84].

Thyroid Nodules and Goiter

Selenium deficiency has been linked to thyroid nodules and goiter formation, commonly caused by impaired antioxidant defense mechanisms, leading to OS and subsequent thyroid cell damage [85]. Oxidative damage may promote the development of these structural thyroid abnormalities. The reduction in Se levels may also affect iodine utilization, further contributing to the enlargement of the thyroid gland and nodule formation [86]. Some observational studies have suggested a correlation between low Se levels and an increased risk of developing goiter or thyroid nodules. However, the evidence remains inconclusive, and more robust randomized controlled trials (RCTs) are needed to establish a definitive causal relationship. Selenium supplementation has been shown to reduce the size of thyroid nodules and goiter in specific Se-deficient individuals, but further studies are required to confirm these findings conclusively [76]. While Se supplementation is not yet a standard treatment for thyroid nodules or goiter, it may benefit Se-deficient individuals as a preventive measure or adjunctive therapy [87].

Myxedema

Myxedema refers to severe hypothyroidism and is usually caused by untreated or poorly managed hypothyroidism. In rare cases, Se deficiency can contribute to the development of myxedema. Severe Se deficiency may impair the thyroid’s ability to produce or convert thyroid hormones, potentially exacerbating hypothyroidism symptoms, such as fatigue, weight gain, and cold intolerance [88]. Selenium deficiency can also interfere with converting T4 to T3, further reducing thyroid hormone activity. When Se deficiency occurs in the context of already existing hypothyroidism, the symptoms of myxedema (such as puffiness of the skin, a hoarse voice, and slowness of mental function) may become more pronounced [73]. Addressing Se deficiency can sometimes improve symptoms in individuals with myxedema. Another condition known as Myxedema Coma is a life-threatening condition that occurs when hypothyroidism becomes severe [89]. While rare, Se deficiency may contribute to an increased risk of myxedema coma, which is marked by reduced consciousness, hypothermia, and respiratory failure.

Non-toxic Goiter

A non-toxic goiter is a condition where the thyroid becomes enlarged but does not cause overproduction of thyroid hormones (i.e., it is not related to hyperthyroidism). This condition can result from iodine deficiency or other nutritional factors, including Se deficiency [90]. Selenium deficiency may exacerbate the goiter by impairing the thyroid’s ability to function correctly, even in iodine-sufficient areas [91]. Selenium supplementation, particularly in individuals with low Se status, may lead to a reduction in the size of the goiter. This effect is often observed when Se deficiency contributes to the goiter’s development. By improving the thyroid’s ability to function correctly, Se helps restore a balance in thyroid hormone production, which may reduce the thyroid’s compensatory enlargement [92]. Some researchers have revealed that Pb and Se changes in thyroid tissue are linked to colloid goiter. An imbalance between these components may alter thyroid hormone production and redox equilibrium, causing glandular hypertrophy and functional abnormalities. This emphasizes the need for trace element balance for thyroid health and illness prevention [93]. In some cases, goiter size can shrink significantly with Se supplementation alone, especially in those with both iodine and Se deficiencies. Several studies have investigated the effect of Se supplementation on goiter and thyroid function [94]. Research has shown that Se supplementation can improve thyroid function in areas with iodine deficiency, suggesting that Se not only enhances the conversion of T4 to T3 but also supports overall thyroid health [91]. In populations with low selenium levels, supplementation with this element was associated with reduced thyroid volume and goiter size [94]. In some cases, Se’s anti-inflammatory and antioxidant effects may help reverse the enlargement of the thyroid, especially when Se deficiency is a significant factor in the development of goiter [63].

Thyroid Cell Protection and Regeneration

Selenium supports the regeneration of thyroid cells by improving the health of the thyroid gland at a cellular level. By reducing OS and inflammation, Se ensures that thyroid cells can function optimally and undergo regeneration [95]. Thyroid tissue regeneration involves repairing and replacing damaged cells, which is crucial for maintaining thyroid health. Selenium’s antioxidant and anti-inflammatory actions provide the conditions for effective cellular turnover and tissue repair [96]. In particular, Se may help protect thyroid follicular cells (the primary cells of the thyroid gland) from apoptosis (programmed cell death), which OS can trigger. By reducing the risk of apoptosis, Se helps preserve the functional capacity of thyroid tissue and encourages its regeneration [97]. Se influences gene expression in thyroid cells, helping regulate processes that support cell repair, regeneration, and survival. By affecting the expression of genes involved in the OS response, apoptosis, and cell cycle regulation, Se can promote tissue repair and prevent damage from accumulating over time. Studies suggest that Se can influence genes that are important for cellular differentiation and regeneration [98]. These include genes that regulate the growth of thyroid cells and their ability to repair or replace damaged tissue. Selenium may, therefore, act at a molecular level to facilitate improved thyroid function [99].

Challenges in Se-Based Thyroid Therapies

Narrow Therapeutic Window and Risk of Selenosis

Although it is beneficial in insignificant amounts, it has a narrow therapeutic window. Selenium deficiency and Se toxicity (selenosis) can result in significant health problems [100]. The clinical manifestation of selenosis includes symptoms such as gastrointestinal disturbances, hair loss, neurological dysfunction, and nail abnormalities [101]. It has been noted that the upper safe limit for Se intake is around 400 µg/day for adults, and exceeding this level, particularly in the long term, can lead to toxicity. This narrow margin between deficiency and excess necessitates careful monitoring of Se supplementation, especially in individuals who may be at risk of selenosis due to high dietary Se intake or excessive supplementation [77]. Clinicians must balance providing enough Se to correct deficiencies and prevent toxic effects [28].

Genetic Variability in Se Metabolism

The response to Se supplementation can vary significantly between individuals due to genetic differences in Se metabolism. Specific genetic variations in the enzymes responsible for Se’s antioxidant functions, such as GPX and deiodinases, may impact how effectively Se is utilized in the body [102]. Individuals with polymorphisms in these genes may have altered Se metabolism and, consequently, variable responses to supplementation. For instance, some individuals may experience more significant benefits from Se supplementation, while others may not see any improvements, even with high doses. This variability emphasizes the need for personalized medicine, where Se therapy is tailored according to an individual’s genetic makeup, metabolic profile, and thyroid health status [103]. Genetic polymorphisms in DIOs and other SelPs significantly influence individual susceptibility to thyroid dysfunction and response to Se supplementation. Among these, the DIO2 Thr92 Ala (rs225014) is one of the most extensively studied single nucleotide polymorphisms (SNPs) [104]. This variant leads to an amino acid substitution that may impair enzyme activity and alter local T3 availability, particularly in the brain and pituitary. Carriers of the Ala/Ala genotype have been associated with reduced psychological well-being, decreased responsiveness to levothyroxine therapy, and increased risk of hypothyroid symptoms despite normal serum TSH and T4 levels [82]. Similarly, DIO1 polymorphisms, such as rs11206244 and rs2235544, have been linked to altered serum FT3 and FT4 concentrations, influencing peripheral thyroid hormone conversion and metabolic rate. Beyond DIOs, genetic variants in SelPs (e.g., rs3877899 and rs7579) affect Se transport efficiency and the distribution of Se to target tissues like the thyroid. These variants can reduce the bioavailability of Se for SelPs synthesis, compromising antioxidant defense and thyroid hormone regulation [4]. Additionally, polymorphisms in GPX1 (e.g., Pro198Leu, rs1050450) have been associated with decreased enzymatic activity and increased OS, potentially exacerbating autoimmune thyroid conditions. Understanding these genetic variations is critical in precision medicine, as they affect baseline thyroid function and modulate the efficacy and safety of Se-based interventions [103].

Bioavailability of Se

The bioavailability of Se is another challenge in Se-based thyroid therapies. Selenium is available in several forms, such as Se salts (e.g., sodium selenite), Se-enriched yeast, and organic Se compounds (e.g., Selenomethionine (SeMet)) [105]. These different forms have varying degrees of bioavailability, with some forms being more easily absorbed and utilized by the body than others. For example, SeMet is better absorbed than inorganic Se compounds like sodium selenite, and it has a longer half-life in the body, making it a preferred form for supplementation [6]. However, despite its efficacy in raising Se levels, the challenge lies in ensuring consistent absorption and optimal distribution of Se in tissues such as the thyroid [4]. Recent studies have explored the use of Se nanoparticles to improve Se absorption and bioavailability. These advanced formulations may enhance Se’s ability to reach the thyroid gland more efficiently and potentially reduce toxicity risks by allowing for more controlled release. While promising, these innovations are still being researched and require further clinical validation [25].

Emerging Research in Se Nanoparticles and Precision Medicine

Recent advances in nanotechnology have introduced Se nanoparticles (SeNPs) as a promising form of Se supplementation, particularly within the context of precision medicine [106]. It is worth noting that Fig.3 highlights four major issues affecting the effectiveness and safety of Se-based treatments: (1) a narrow therapeutic window requiring precise dosing to avoid toxicity or ineffectiveness; (2) genetic variability in selenium metabolism, which influences patient response; (3) limited bioavailability of selenium depending on its source and form; and (4) emerging but complex use of selenium nanoparticles for targeted personalized thyroid therapy. SeNPs offer several advantages over conventional Se compounds, such as sodium selenite or SeMet [107]. Firstly, SeNPs exhibit enhanced bioavailability, allowing for more efficient uptake and targeted delivery of Se to tissues like the thyroid, while reducing nonspecific accumulation that could lead to toxicity [29]. Secondly, SeNPs can be engineered for controlled release, providing sustained Se levels over time, particularly valuable for patients with fluctuating metabolic demands or chronic thyroid disorders [108]. Their lower cytotoxicity profile compared to inorganic Se forms makes them suitable for long-term use, especially in individuals with increased sensitivity to OS [107]. In precision medicine, the ability to customize nanoparticle composition, size, surface charge, and functionalization allows individualized treatment strategies that align with patient-specific genetic and metabolic profiles. SeNPs also demonstrate the potential to synergize with other therapeutic agents or delivery systems, opening avenues for integrative treatment approaches in autoimmune thyroid diseases or thyroid cancers. These properties collectively support the growing preference for SeNPs as a next-generation therapeutic form of Se in targeted thyroid interventions. Along with SeNPs, the field of precision medicine is growing. Precision medicine tailors treatment based on an individual’s genetic, environmental, and lifestyle factors [7]. In selenium therapy, this could involve adjusting Se dosages based on the patient’s genetic makeup, which influences how they metabolize and respond to Se. This personalized approach may help optimize Se supplementation and minimize risks of both deficiency and toxicity [29].

Fig. 3.

Challenges in Se-based thyroid therapies. In terms of Se in thyroid treatments, this conceptual picture identifies four main drawbacks: (1) A narrow therapeutic window exists for selenium supplementation because toxic consequences or adverse effects on thyroid hormone control and redox balance may result from either a deficit or an excess of the mineral; (2) Individual variations in SeLPs gene expression, polymorphisms, and enzymatic activity impact Se usage and treatment response, making routine dosage regimens more complicated due to genetic variability in Se metabolism; (3) The effectiveness of Se supplements is very variable due to factors such as the chemical type of the supplement (organic vs. inorganic), the amount of Se in the food, and the amount of selenium in the environment; (4) By improving stability, cellular absorption, and site-specific antioxidant effects, new methods using SeNPs and tailored delivery systems seek to circumvent conventional obstacles in precision medicine. The future of tailored Se supplementation for thyroid and OS-related diseases lies in these approaches

Conclusion

Selenium plays an indispensable role in thyroid health, particularly in mitigating OS, regulating immune responses, and modulating hormone metabolism. Selenium supplementation offers therapeutic potential for autoimmune thyroiditis, Graves’ disease, and subclinical hypothyroidism, especially in Se-deficient populations. However, careful attention to dosage, baseline Se status, and individual variability is essential to maximize benefits while avoiding toxicity. Future research should focus on personalized approaches, leveraging advancements in genomics and nanotechnology to refine Se-based therapies. With its multifaceted role, Se remains a cornerstone in the evolving landscape of thyroid disorder management. However, to harness these benefits effectively, careful attention must be given to dosage, baseline Se levels, and individual metabolic variations to avoid potential toxicity. Future research should explore personalized approaches, leveraging cutting-edge advancements in genomics and nanotechnology to refine Se-based therapies further. Ultimately, Se’s multifaceted role in thyroid health positions it as a cornerstone in the evolving landscape of thyroid disorder management, offering great promise, particularly for individuals with Se deficiency. Further clinical studies are essential to define its full scope of benefits better and confirm its therapeutic potential across diverse populations.

Author Contribution

IB: collection and analysis of literature, writing – original draft; MFH: collection and analysis of literature; MK: writing-review and editing, revision and discussing. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Ethics Approval and Consent to Participate

Neither ethics approval nor consent is needed. According to local rules, it was not necessary to obtain ethical approval.

Conflict of Interest

The authors declare no competing interests.