Chronic stress may induce changes in thyroid hormone activity that contribute to hypothyroid symptoms. Stress may contribute through altering important thyroid hormone transporters and enzymes. Weight gain or inability to lose weight, cold extremities, depression, poor memory and focus, and hair loss are common signs and symptoms of hypothyroidism. Serum TSH and T4 levels are often used to assess thyroid function; however, some experts believe that these symptoms of thyroid dysfunction are not always detected by standard thyroid tests.
Thyroid Hormone Control: Deodinases
Deiodinase enzymes help modulate thyroid function by creating thyroid hormones that increase and decrease thyroid activity. There are three different types of deiodinase enzymes: type I, II, and III, or D2, D2, and D3. D1 and D2 convert the inactive hormone thyroxine (T4) to the active hormone triiodothyronine (T3), thus increasing cellular thyroid activity. D3 lowers thyroid activity through converting T4 to Reverse triiodothyronine (reverse T3). Different physiological conditions, including stress, affect the activity of each deiodinase enzyme, in turn altering T3 and T4 levels in the body’s tissues. [2, 20, 27]
Deiodinase type I (D1)
D1 converts inactive T4 to active T3 throughout the body, but does not control T4 to T3 conversion in the pituitary. In both physiologic and emotional stress, D1 activity is downregulated. This suppression decreases conversion of T4 to T3. [6, 15, 27]
Along with stress, D1 can be suppressed by:
- Weight Gain
- Leptin Resistance
- Insulin Resistance
- Inflammation from Autoimmune
- Disease or Systemic Illness
- Chronic Fatigue Syndrome
- Chronic Pain
- Exposure to Toxins and Plastics
With the presence of chronic stress and/or the listed conditions above, active thyroid hormone levels are lower throughout the body, but may not be lower in the pituitary gland. Additionally, D1 activity is usually lower in females. Thus, females may be more likely to experience hypothyroidism. [18, 27]
Deiodinase type II (D2)
TSH is produced in the pituitary gland and modulated by T3 levels in the pituitary. However, pituitary T3 levels may not correlate with T3 levels in the rest of the body. As the pituitary gland does not contain D3 and only low levels of D1, T3 levels in the pituitary are dependent on D2 activity. [2, 23, 27]
D2 is much more efficient in converting T4 to T3 than the D1 enzyme. Additionally, D2 responds to stress differently from D1. Among other conditions, emotional and physiologic stress stimulates and increases the activity of D2, therefore increasing T4 to T3 conversion in the pituitary, while the rest of the body may have lowered levels of active T3. Higher T3 levels in the pituitary may lower TSH. Optimally, TSH should increase with low peripheral T3 levels. [2, 7, 27].
With lower T4 levels, as often seen in hypothyroidism, D2 activity increases. This is an attempt to increase cellular thyroid activity, as D2 creates more T3 to increase cellular thyroid activity. However, lower amounts of T4 also contribute to lowered D1 activity and efficacy, causing lower cellular T3 levels throughout the body. [12, 27]
As stated previously, peripheral tissue levels of T3 are dramatically decreased in conditions such as chronic emotional or physical stress. This may lead to hypothyroidism. [9, 20, 27]
Deiodinase type III (D3)
As described above, D3 converts T4 to reverse T3, competing with D1 (which converts T4 to T3). D3 is present throughout the body, except for the pituitary gland. [20, 27]
Reverse T3 competes with T3, meaning that reverse T3 can prevent the active hormone T3 from binding to the receptor, thus blocking its effect. Reverse T3 also reduces metabolism, suppresses D1, and blocks T4 and T3 uptake into cells. All these effects decrease intracellular T3 levels and thyroid activity. [17, 26, 27]
Reverse T3 is upregulated in conditions such as chronic stress and illness. Additionally, reverse T3 is a marker for low T4 to T3 conversion and low T3 levels – even if TSH is normal. [17,27]
How Stress Impacts D1, D2 & D3
Chronic physiologic stress decreases D1 activity and increases D3 activity. As D3 converts T4 into reverse T3, this results in lowered thyroid activity. [2, 6, 21, 27]
Stress stimulates D2 activity, increasing T4 to T3 conversion in the pituitary and decreasing TSH production. Increased cortisol levels in stress are also associated with discrepancies between the pituitary TSH levels and T3 levels in other body tissues. [6, 27]
Additionally, high cortisol levels in stress also play a role in hypothyroid conditions through lowering T3. The reduction of active T3 and increased production of reverse T3 that occurs with stress may contribute to hypothyroidism, as well as weight gain, fatigue, and depression. This can lead to a vicious cycle of increased stress, weight gain, fatigue, and depression, that further imbalances thyroid hormones, leading to worsened symptoms, worsened thyroid function, and so on. [5, 6, 27]
Stress & the Immune System
Excess stress has also been shown to decrease optimal immune system function. Low thyroid hormone levels in the body may contribute to stress-related lowered immunity. Additionally, thyroid supplementation may potentially improve immunity that has been lowered by stress. [5, 27]
Inflammation, Stress, and Thyroid Function
Decreased T4 to T3 conversion is seen in physical and emotional stress, as well as other inflammatory conditions such as obesity, diabetes, depression, menopause, heart disease, autoimmune disease, injury, chronic infection, and cancer. [16, 27]
Inflammatory cytokines, such as IL-1, Il-6, C-reactive protein (CRP), and TNF alpha are known to significantly decrease D1 activity and lower T3 levels in body tissues. On the other hand, the inflammatory cytokines increase D2 action and lower TSH levels even with decreased T3 levels throughout the body. [19, 27]
CRP and low tissue T3 correlate inversely; therefore, people with high levels of CRP or other inflammatory cytokines will have significantly lower T3 levels in cells. This correlation exists despite normal serum thyroid test results. Therefore, inflammation associated with stress may cause suboptimal thyroid function. [14, 27]
Inflammation also activates D3, leading to higher reverse T3 levels. This may further contribute to hypothyroidism through decreasing T4 to T3 production inside the cell and inhibiting the T3 receptor inside the cell. Many believe this suggests that people with stress and/or another inflammatory condition may present with signs and symptoms related to hypothyroidism, but typical thyroid tests may not reflect the low levels throughout the body due to higher pituitary T3’s suppression of TSH. [3, 27]
Thyroid Hormone Control: Transport
Thyroid hormone transport is an essential part of thyroid function. Optimal thyroid activity, however, depends on T3 and T4 hormones traveling from the serum, through the cell membrane, and reaching their receptors in the cell. This transportation process may influence thyroid hormone regulation.
The rate-limiting step in thyroid activity is the rate that the thyroid hormones cross into the cell. This transportation across the cell membrane requires energy; this is called active transport. [1, 8, 10, 11, 24, 25]
Stress and Thyroid Hormone Transport
As the transport of thyroid hormones into cells requires energy, conditions that relate to low cellular energy may contribute to decreased thyroid hormone transport. Stress and anxiety are associated with decreased cellular energy; therefore, stress may be associated with hypothyroidism. [4, 22, 25]
Other conditions associated with abnormal thyroid hormone transport may include:
- Insulin Resistance
- Chronic and Acute Dieting
- Depression and Bipolar Depression
- Neurodegenerative Diseases
- Chronic Fatigue Syndrome
- Chronic Infections
- Cardiovascular Disease
- High Cholesterol and Triglyceride Levels
- Chronic Illness
The exact mechanism behind reduced thyroid hormone transport is yet to be understood. However, some studies have found significantly lower T4 uptake in cells correlating with stress levels. [11, 25]
Furthermore, there are different types of transporters that move T3 and T4 into cells. The T4 transporter needs more energy to move than the transporter for T3. Lowered cellular energy can result in lower T4 transport. [10, 11, 25] Chronic emotional or physiologic stress may significantly reduce T4 transport into the body’s cells. Some studies show significant reductions in tissue T4 and T3 levels with excessive stress. [13, 25] Thus, in conditions such as stress, there may be reduced T4 transport that contributes to hypothyroidism.
Additionally, research has shown that T4 and T3 levels differ in various body tissues in different individuals. This discrepancy may potentially explain the variety of hypothyroidism symptoms that can occur even without abnormal TSH or T4 blood tests. [1, 25]
One possible explanation involves 3-carboxy-4-methyl-5-propyl-2-furna propanoic acid (CMPF), indoxyl sulfate, bilirubin and fatty acids. These substances are produced in response to stress. They have been shown to inhibit cell transport of T4 into the cells, but may not affect T4 or T3 levels in the pituitary. [8, 25]
Thyroid Hormone Transport in the Pituitary
The transporters in the pituitary are not energy-dependent. They maintain the uptake of T3 and T4 regardless of how much energy is available. These transporters in the pituitary, unlike the transporters in the rest of the body, are not affected by stress. [8, 25]
Stress may contribute to hypothyroidism through altering the function of deiodinase enzymes and thyroid hormone transport. Low thyroid function can be present with severe stress, resulting in a cycle of exacerbating symptoms that should be addressed with appropriate thyroid testing and treatment for the individual. Practitioners may consider implementing therapies and lifestyle changes that help to reduce stress for optimal HPA axis function and patient wellbeing.
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