Contributing factors are substances, contexts or conditions that have roles in the causation or promotion of hypothyroidism.

Oxidative stress is the condition in the body where the protective capacity of antioxidant molecules is exceeded by reactive oxygen species (free radicals).

• Oxidative stress is increasingly being associated with thyroid diseases (Kochman et al., 2021).
• Oxidative stress in the context of hypothyroidism can:
• cause lipid peroxidation (damage to fatty acids in cell membranes)
• cause DNA damage
• interfere with intracellular signalling
• promote autoimmune activity against thyroid cells

Nicotinamide Adenine Dinucleotide Phosphate (NADPH) is a coenzyme that plays a critical role in various biological reactions. A coenzyme is a non-protein compound that binds to an enzyme and is essential for the enzyme’s activity.

The NADPH system, oxidative stress, and autoimmunity

• The process of making T4 by the enzyme thyroid peroxidase generates hydrogen peroxide.
• NADPH provides electrons for the conversion of hydrogen peroxide  into water
• Hydrogen peroxide  generates free-radical production 
• Insufficient NADPH activity results in excessive free radical damage to thyroid cells
• Damage to the cells promotes autoimmune activity against the thyroid cells

Glutathione and the thyroid

• Glutathione and the thyroid
• Glutathione is a key protective antioxidant
• The presence of glutathione helps prevent excessive accumulation of H2O2 – protecting thyroid cells from oxidative damage.
• elevated levels of oxidative stress in the context of low levels of glutathione can damage thyroid cells and worsen autoimmune symptoms

Inflammation is a normal part of the body’s defense to injury or infection. However, inflammation is damaging when it occurs in healthy tissues or lasts too long (months or years).

Causes of chronic inflammation include (Inflammation, n.d.):

• environmental chemicals
• poor nutrition
• imbalanced microbiome
• sleep issues
• stress
• personal environment

T3 and inflammation

• An autoimmune response against the thyroid causes an increased release of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6).
• The onging inflammation damages thyroid tissue which results in decreased production of T4.
• Continued inflammation within the thyroid gland can result in fibrosis (formation of scar tissue). The scar tissue hinders thyroid functioning, disrupting hormone production and secretion.

T3 and immune balance

• T3 is vital for the proper development and activity of specific immune cells associdated with inflammation.
• Inflammatory processes can disrupt enzymes responsible for converting T4 to T3.
• In hypothyroidism, the ratio of T4 to T3 is often skewed, resulting in an increased production of reactive oxygen species and inflammation. 

Thyroid hormones and intestinal tract movement (gut motility)

• Thyroid hormones are known to affect gut motility by modulating neurological and smooth muscle function (8, 9) (Lauritano et al., 2007)
• Hypothyroidism may promote reduced rhythmic colonic activity and slower transit time (the time it takes for food to travel from the mouth through the digestive tract) (Lauritano et al., 2007).
• Constipation is a common gastrointestinal (GI) symptom of hypothyroidism. (Patil, 2014).
• Since hypothyroidism significantly reduces gut motility,  it is advisable to check thyroid function in patients with complaints of dyspepsia (pain or discomfort in the upper abdomen) (Patil, 2014).

Dysbiosis and hypothyroidism

• Dysbiosis is an imbalance of microorganisms in the digestive tract, typically manifesting as decreased beneficial bacteria, combined with an increase in pathogenic bacteria.
• Microorganisms can positively and negatively affect thyroid hormone levels by controlling iodine uptake, degradation, and  thyroid hormone cycling. (Fröhlich & Wahl, 2019)

SIBO and hypothyroidism

• Small Intestinal Bacterial Overgrowth (SIBO) refers to an excessively high bacterial count in the small intestine. 
• Hypothyroid increases SIBO
• Decreased thyroid hormone activity can lead to SIBO (Patil, 2014).
• A history of overt hypothyroidism is a risk factor for developing SIBO (Lauritano et al., 2007).
• The possible connection is that intestinal motor dysfunction in hypothyroidism decreases the small bowel’s ability to clear luminal bacteria. (Lauritano et al., 2007)
• Studies have shown that SIBO may affect more than half of hypothyroidism patients (Patil, 2014).

Lauritano et al. examined 90 subjects (50 with hypothyroidism and 40 as controls) and discovered that 54% of hypothyroidism patients tested positive for SIBO using the glucose breath test, compared to only 5% of the control group (P < 0.001). (Patil, 2014)

• Intestinal bacteria can decrease the availability of selenium. Selenium is essential for the activity of deiodinase enzymes and the protective antioxidant enzyme  glutathione peroxidase (Virili & Centanni, 2015),
• Intestinal bacteria affect neurotransmitters like dopamine in the brain and control the hypothalamus-pituitary axis (HPA) [43]. Since dopamine suppresses TSH secretion, it can also impact thyroid function. (Fröhlich & Wahl, 2019)

Secondary bile acids

• Secondary bile acids are a type of bile acids formed in the intestines through the action of gut bacteria on bile acids made by the body.
• SIBO can cause elevated levels of secondary bile acids in the context of hypothyroidism (Fröhlich & Wahl, 2019).
• Secondary bile acids can dysrupt the action of deiodinase enzymes in the intestines. REF

Lipopolysaccharides

• Lipopolysaccharides (LPS) are large molecules found in the outer membrane of Gram-negative bacteria. 
• When Gram-negative bacteria invade a host, LPS can trigger a strong immune response, including the production of inflammatory cytokines.
• LPS inhibits both intestinal and liver diodinase function, and reduces thyroid hormone receptor expression in the liver [49]. (Fröhlich & Wahl, 2019)

Dysbiosis and autoimmunity

• Changes in the composition gut microorganisms are associated with a higher occurrence of Hashimoto’s thyroiditis (autoimmunity against thyroid tissue)  (Fröhlich & Wahl, 2019)
• Autoimmune activity against the thyroid is marked by autoreactive T cells and antibodies – which target thyroid peroxidase and thyroglobulin, resulting in the destruction of the thyroid gland. (Fröhlich & Wahl, 2019)
• Autoimmune thyroid disease is the most common autoimmune condition, with both hypo- and hyper-thyroidism often having autoimmune origins linked to bacterial overgrowth and altered microbiota composition. (Virili & Centanni, 2015).

The Brassica family is a group of plants also known as the mustard family or cruciferous family.

Brassica family foods include (Cruciferous Vegetables, 2016):

• arugula
• bok choy
• broccoli
• Brussels sprouts
• cabbage
• cauliflower
• kale
• radish
• turnips

Cruciferous plants like cabbage, Brussels sprouts, legumes, and cassava contain substances that can interfere with (Köhrle, 2008): 

• iodine uptake by the thyroid, 
• the incorporation of iodine into the T4 moleculae
• other reactions within the thyroid system

Goitrogens and hypothyroidism

• Brassica family vegetables contain compounds known as goitrogens 
• Goitrogens are substances that can interfere with thyroid function by inhibiting the uptake of iodine, which is essential for the production of thyroid hormones. (Panduang et al., 2023)
• Consuming uncooked Brassica vegetables in large amounts can negatively impact thyroid system function – especially in people with hypothyroidism or iodine deficiency (Panduang et al., 2023)
• Glucosinolates are natural compounds, commonly found in Brassica famly vegetables are biologically inactive.
• When the plant cell wall are broken or chewed and enzyme called myrosinase converts the glucosinolates  to their active goitrogenic form (Conaway et al., 2000).

Mitigation of goitrogens

• Cooking brassica family vegetables can help reduce the levels of goitrogens, making them safer for consumption even for individuals with hypothyroidism.
• The deactivation of myrosinase through cooking significantly diminishes the breakdown of glucosinolates  (Conaway et al., 2000)
• In a study involving 12 male subjects in a crossover design, researchers compared the metabolic fate of glucosinolates after consuming steamed and fresh broccoli. They found that the bioavailability of glucosinolates  from fresh broccoli is approximately three times higher than that from cooked broccoli, where myrosinase is deactivated. (Conaway et al., 2000)
• Consuming other foods alongside broccoli at the time of ingestion may reduce myrosinase activity and hinder the production of goitrogens. (Conaway et al., 2000)
• the negative effects of goitrogens can be prevented or reduced by ensuring an adequate intake of iodine through a varied diet. (Köhrle, 2008)

Soy contains both beneficial compounds and others that can pose health concerns.

Some compounds in soy, known as  goitrogens can negatively affect thyroid system.

Soy goitrogens

• The compounds in soy that are problematic for the thyroid system are genestein and diadzen. 
• These compounds (Köhrle, 2008): 
  • interfere with the iodination and coupling reactions  of thyroid peroxidase a crucial enzyme for producing T4 hormones (Otun et al., 2019)
  • compete strongly with T4 and T3 for binding to the thyroid hormone transporter transthyretin
  • impede the conversion of thyroid hormones by deiodinases. 
  • The harmful effects of these goitrogens can contribute to the development of goiter, especially when iodine intake is insufficient. (Köhrle, 2008)

Genestein and the thyroid system

• Experiments have demonstrated that genistein strongly inhibits the activity of thyroid peroxidase, an enzyme essential for synthesizing thyroid hormones. (Marini et al., 2012).
• When  thyroid peroxidase is inhibited:
  • there is a reduction in thyroid hormone levels, leading to an increase in the release of thyroid-stimulating hormone (TSH). 
  • the increase in TSH then triggers the growth of the thyroid gland. 
  • Genistein also impacts the metabolism of thyroid hormones and the re-utilization of iodide by inhibiting sulfotransferase enzymes (Marini et al., 2012).

Genestein and T4

• Genestein displaces T4 from its binding protein – transthyretin, This results in a temporary increase in the amount of free thyroid hormones in the bloodstream, – which in turn, affects how tissues absorb and eliminate these hormones. (Köhrle, 2008)
• Genistein binds to  transthyretin as effectively as T4 (Köhrle, 2008), which means T4 and genestein compete for transport in the bloodstream. 
• A study by Hampl et al. (2008) examined the impact of short-term soy consumption on thyroid parameters in healthy male and female subjects. Following 7 days of soy consumption, there was an increase in the levels of both genistein and daidzein. (Marini et al., 2012).
• Soy may have a greater impact on individuals with pre-existing thyroid issues or those taking it for extended periods. (Otun et al., 2019)

Soy and iodine

• When iodine levels are low, soy’s ability to affect the thyroid becomes much stronger. (Doerge & Sheehan, 2002)
• Iodine supplementation can help counteract these effects (Doerge & Sheehan, 2002)
• It is important to note that cases of soy-induced goiter and other signs of hypothyroidism have been documented in humans even when there’s no evidence of iodine deficiency (24). (Doerge & Sheehan, 2002)
• A study by Divi et al. (1997) showed that the inhibition of thyroid peroxidase-catalyzed iodination of tyrosine by genistein depends on the dosage; however, the negative effects of  can be reversed by adding adequate amounts of iodide to the incubation mixtures. (Marini et al., 2012)

• Gluten is a general name for proteins found in wheat and related grains. Although many people are not affected by gluten, for a variety of reasons for others it can cause problems.
• Gluten can damage the digestive tract, resulting in decreased nutrient absorption, and increased inflammation

Gluten and hypothyroidism

• gluten can affect digestive tract integrity, nutrient absorption, and promote autoimmune activity against thryoid system components
• CD and NCGS are gluten-driven conditions that can affect the thyroid system by various mechanisms

Celiac disease, non-celiac gluten sensitivity (NCGS)

• Celiac disease is an autoimmune condition triggered by consumption of gluten (Naidoo, 2020; Anderson, n.d.; Jackson et al., 2011).
• NCGS does not involve the autoimmune destruction of the small intestine or an allergic reaction, but does cause gastrointestinal and other symptoms in response to gluten consumption.

Celiac disease and autoimmune thyroiditis

• Autoimmune thyroiditis is the most prevalent coexisting autoimmune disorder in patients with celiac disease (Krysiak et al., 2019).
• The association between autoimmune thyroid disease and celiac disease may be attributed to factors such as: 
• low selenium or vitamin D levels due to malabsorption
• cross reaction of anti-tissue transglutaminase antibodies with thyroid tissue (tissue transglutaminase  is a repair enzyme in the digestive tract)
• or a shared genetic-immune makeup (Krysiak et al., 2019).
• A pooled analysis involving 6024 patients with autoimmune thyroiditis revealed a notably higher prevalence of biopsy-confirmed coeliac disease (Krysiak et al., 2019).
• Consequently, it has been recommended that all patients with autoimmune thyroiditis undergo screening for the presence of coeliac disease. (Krysiak et al., 2019).

Gluten intake and thyroid antibodies

• gluten-free diet lowered the levels of thyroid antibodies   (Krysiak et al., 2019)
• adopting a gluten-free diet could be beneficial for these women, especially since having high levels of thyroid antibodies puts them at risk of developing hypothyroidism. (Krysiak et al., 2019)
• gluten-free diet reduced autoimmune activity against the thyroid and slightly boosted thyroid function in women with Hashimoto’s thyroiditis who had normal thyroid function otherwise. (Krysiak et al., 2019)

Gluten free diet and hypothyroid symptoms

• A study from 2017 looked into how different nutrients like iodine, selenium, vitamin D, and gluten impact the treatment of patients with Hashimoto’s thyroiditis. It found that following a gluten-free diet can help manage hypothyroid symptoms, even if the patient doesn’t have celiac disease. (Abbott et al., 2019.
• Gluten-free diet and vitamin D
• A gluten-free diet can lead to increased  levels of 25-hydroxyvitamin D (a marker of vitamin D) in the bloodstream. (Krysiak et al., 2019)
• When women with thyroid autoimmune conditions took additional vitamin D supplements, it led to a decrease in thyroid antibody levels, especially for TPOAb define this . (Krysiak et al., 2019)

>state relevance

Gluten-free diet and  autoimmune thyroid progression 

• It has been shown that following a gluten-free diet might help manage hypothyroid symptoms, even if the patient doesn’t have celiac disease. (Abbott et al., 2019.
• the gluten-free diet might slow down the progression to thyroid dysfunction in women with Hashimoto’s thyroiditis who still have normal thyroid function. (Krysiak et al., 2019)

Endocrine-Disrupting Compounds (EDCs) are compounds that  can interfere withe thyroid function and health.

Endocrine-disrupting chemicals (EDCs) have the ability to impact the thyroid system through a variety of mechanisms, including:

• Imitating or obstructing thyroid hormones: EDCs have the capacity to attach to thyroid hormone receptors, imitating the functions of natural hormones or impeding their normal effects.
• Disturbing hormone production: EDCs can disrupt the enzymes responsible for thyroid hormone synthesis, resulting in the production of hormones being altered.
• Influencing hormone metabolism: EDCs can modify the metabolism and elimination of thyroid hormones, thereby changing their concentrations within the body.
• Interfering with hormone transportation: EDCs can influence the proteins involved in transporting thyroid hormones in the bloodstream, which can impact the availability and functionality of these hormones.

Bromine (halogen)

Bromine sources:

• flame retardants
• some pesticides
• certain baked goods (as potassium bromate)
• medications – many prescription and over-the-counter drugs contain bromine. (Allain et al., 1993)
• Bromine effects on the thyroid system (Allain et al., 1993):
  • competes with iodine uptake by the thyroid gland
  • decreases conversion of iodide to iodine
  • can be incorporated bound to tyrosine instead of iodine leading to the formation of brominated compounds rather than T4. These analogs of thyroid hormones are not functional.

Fluorine (halogen)

Fluoride is a naturally occuring element. Fluoride is the salt form of fluorine – fluoride bound to another element. 

Fluoride is known to be more electronegative than iodine, which means it can easily replace iodine in the body. (Singh et al., 2014)

Fluoride sources:

• drinking water
• dental products (toothpaste, fluoride treatments)
• some processed foods
• some medications (Office of Dietary Supplements – Fluoride, n.d.)
• Fluoride effects on the thyroid system:
  • competes with iodine uptake by the thyroid gland
  • inhibits thyroid peroxidase which assembles the T4 molecule
  • decreases the production of TSH by the pituitary gland which decreases thyroid hormone production (Singh et al., 2014)

Study: Researchers conducted a study to investigate fluoride levels in the blood and urine of children aged 8 to 15 from areas with and without dental fluorosis. They also compared the levels of free T4, free T3, and thyroid-stimulating hormone (TSH) in these children. Significant differences were found in the levels of FT3, FT4, and TSH between the two groups. Fluoride levels in the blood and urine were elevated in both groups. There was a strong correlation between fluoride content in water and fluoride levels in urine and blood. Additionally, the concentration of fluoride in the blood was closely linked to the levels of thyroid hormones (FT3/FT4) and TSH (Singh et al., 2014).

Lead (heavy metal)

Common sources of lead exposure (Common Sources of Lead, n.d., Campbell, 1995):

• lead-based paint
• children’s toys and jewelry
• mini blinds
• imported candy
• lead water pipes
• drinking water
• newsprint
• organ meats
• tobacco
• cosmetics
• workplace and hobby hazards
• traditional home remedies and cosmetics
• lead-glazed ceramic ware, pottery and leaded crystal
• contaminated soil
• car batteries
• leaded gas (which may persist in the environment still) (Eschner, 2016)

Lead effects on the thyroid system:

• impacts the hypothalamic-pituitary axis, which controls the release of  TSH in response to different stimuli. (Doumouchtsis et al., 2009)
• disrupts the balance of growth, thyroid, and stress hormones in the body It does this by getting in the way of how these hormones are made, released, and used in the body’s biological processes. (Doumouchtsis et al., 2009)
• Researchers fhave ound that in teenagers exposed to low levels of lead over a long time, there was a connection between higher levels of lead in the blood and lower levels of free T4 (Doumouchtsis et al., 2009)

Addressing Lead Toxicity

• Environmental and dietary sources of toxic metal exposures need to be removed as much as possible.
• Many patients will improve with a basic protocol of a healthy diet, supplementation of essential nutrients, exercise, and rest. Sweating from exercise or sauna can also help remove toxic metals (Sears, 2018).
• Detoxification of toxic metals must be properly supported with a protocol tailored to the patient’s unique situation and toxic load, in order to minimize the risk of releasing, then depositing the metals back into tissues. The best approach for brain detoxification is conservatively, “with repeated, modest treatments, using multiple agents” (Sears, 2018).

Mercury (heavy metal)

Sources of mercury exposure (US EPA, 2015):

• fish and shellfish that contain higher levels of mercury
• thermometers
• Novelty jewelry
• Dental Amalgam Fillings
• fungicides, preservatives, antiseptics
• skin lighteners and anti-aging products for the skin (sold illegally)
• Mercury effects on the thyroid system (Chen et al., 2013):
• stops the thyroid gland from absorbing iodide
• can interfere with the function of thyroid hormone deiodinase
• increase thyroid antibodies

STUDY: A study found that only patients who were sensitive to mercury and had their dental amalgams replaced showed a significant drop in certain antibodies linked to thyroid problems. For those who didn’t replace their amalgams, regardless of mercury sensitivity, antibody levels didn’t change. This suggests that removing mercury-containing dental fillings in sensitive individuals might help treat autoimmune thyroid conditions. (Sterzl et al., 2006)

Bisphenol A (BPA) (chemical compound)

BPA sources(Bisphenol A (BPA), n.d.):

• epoxy resins that coat some metal food cans, bottle tops, 
• water bottles
• bottle tops
• water supply pipes
• shatterproof windows
• eyewear
• BPA effects on the thyroid system:
• can mimic thyroid hormones and disrupt their normal function

Phthalates (chemical compound)

Sources of phthalates:

• personal care products, 
• plasticizers (make plastics more flexible)
• leach into food from plastic packaging and processing materials (Most Foods Contain Toxic Phthalates. Now What?, n.d.)
• cash register tapes (Printed Receipts at Most Major Store Chains Contain “Toxic” Chemicals like BPA, Report Says – CBS News, n.d.)
• medical devices

Effects of phthalates on the thyroid system:

• interfere with the production, release, and metabolism of thyroid hormones. Proposed mechanisms are:
• inhibiting the enzymes responsible for producing thyroid hormones
• interfering with the attachment of thyroid hormones to transport proteins
• altering  the expression of receptors for thyroid hormones
• disrupting  the signaling pathways that control thyroid function

Organophosphate pesticides

Sources of pesticide exposure (Adeyinka et al., 2024):

• wheat, flour
• cooking oil
• ant and roach sprays 
• foods sprayed with pesticides including apples, corn, oranges, rice, and wheat (Chemicals in Food, 2019)
• household use of organophosphates (Jaga & Dharmani, 2003)

Organophosphate pesticides are now among the most commonly used nonpersistent pesticides globally for pest control in both residential and agricultural environments. (Lacasaña et al., 2010)

Effects of pesticides and the thyroid system

• may change how thyroid hormones bind to their receptors (Meeker et al., 2006). (Lacasaña et al., 2010)
• may disrupt the negative feedback mechanism that regulates the production of TSH and Thyrotropin-releasing hormone (TRH). THR regulates thyroid growth and function.
• exposure to organophosphate pesticides is linked to dose-dependent changes in serum levels of TSH, total T4, and total T3 in humans. (Lacasaña et al., 2010)