Are you taking Thyroxine but not feeling any better? Is your TSH still high despite increasing your dose? Do you have issues with low T3 or high reverse T3? Perhaps you’re not converting your thyroid hormone effectively!

Let’s back up a few steps.

When we take Thyroxine (also known as Oroxine, Eutroxsig or Eltroxin in Australia), we are taking a hormone called T4. This is the main hormone produced by our thyroid gland. Unfortunately, T4 is largely inactive, meaning we rely on our body to convert the medication into its active form. This active form is known as T3 and the conversion process is ESSENTIAL to ensuring you can benefit from your thyroid medication and reduce your symptoms of hypothyroidism.

Too often, patients come to me with thyroid issues and yet despite taking Thyroxine on a regular basis, they feel no better than when they started on their thyroid journey. Often, their doctor has only been monitoring TSH and in some cases T4, and yet no one has looked ‘further down the pathway’ to see if they are effectively converting this T4 through to its active form, T3. This is a major issue and a common cause of persistent hypothyroid symptoms like hair loss, fatigue, weight gain and constipation. This is why I am insistent on checking TSH, T4 AND T3 in my hypothyroid patients, as we need to see the whole feedback loop in order to determine where the issue might be arising.

In this article today, I’ll be exploring the many factors which can negatively affect our thyroid hormone conversion, as this is an essential topic for any individual with thyroid issues to understand. As always, if you have thyroid issues, I recommend you work with a qualified and thyroid-savvy healthcare professional to help you optimise your thyroid function, but hopefully this article can serve as a discussion point if you’re one of the many individuals who suffers from poor thyroid hormone conversion.

In the article, I’ll be covering:

Liver and kidney function
Nutritional factors
Stress, fasting and carbohydrate restriction
Medications
Alcohol and smoking
Heavy metals and environmental toxins
Inflammation
Blood sugar and insulin abnormalities
And lastly, other factors that might be relevant

Liver and Kidney Function

When we talk about T3, it’s important to know it comes from two main sources. Firstly, the thyroid itself produces a small amount of T3, which is released into the blood. The majority of our T3 however comes from a process called deiodination, which takes place in our peripheral tissues (such as the liver and kidney) via the activity of two enzymes called deiodinase 1 and 2. During this process, an iodine molecule is removed from the hormone T4, converting it into its active form, T3. For this reason, liver damage or chronic kidney disease are both associated with impaired thyroid hormone conversion, which can result in reduced circulating levels of T3. Interestingly, the relationship between thyroid and liver health is bi-directional: Poor thyroid health can compromise liver function, and compromised liver function can impair thyroid hormone metabolism. In the case of chronic kidney disease, low serum T3 is common, due to impaired peripheral metabolism. Chronic kidney disease also results in a build up of inflammatory molecules in the blood; the presence of which can further inhibit this conversion process.

Nutritional Factors: Selenium and Zinc

There are a number of key nutrients for thyroid function, but none more important than selenium and zinc when it comes to thyroid hormone conversion. In fact, a deficiency of either of these nutrients can significantly impair thyroid hormone conversion, resulting in low circulating levels of T3. Selenium in perhaps the most important of the two, as the enzymes that catalyse the conversion of T4 to T3 are selenium-dependant, meaning they can’t function in its absence. As mentioned above, these enzymes are called ‘deiodinases’ and they act in tissues like the liver, kidneys and muscles to convert T4 into its active form.

Whilst less research has been conducted on the specific role of zinc in thyroid health, studies show that zinc supplementation may improve T4 to T3 conversion, resulting in improved T3 to T4 ratios. This is because, similar to selenium, zinc is involved in the enzymatic processes that govern both the production and conversion of thyroid hormones in the body. Zinc is also required for thyroid hormone receptors to function effectively, meaning a zinc deficiency impairs the binding of T3 to your cellular receptor sites. Interestingly, iron deficiency has also been shown to impair T4 to T3 conversion and increase shunting of T4 towards the inactive form, reverse T3.

In the case of a selenium or zinc deficiency, we tend to see a higher ratio of T4 to T3, suggesting impaired conversion - aka, there is more T4 relative to T3, as it is not being converted down the T3 pathway. When reverse T3 is tested as well, we might also see this being ‘high’ relative to the amount of circulating free T3. Whilst selenium and zinc are both incredibly important for thyroid function, an excess of either of these nutrients can be just as problematic as a deficiency, so I strongly recommend you seek professional advice prior to commencing supplementation with either nutrient.

Stress, Fasting and Carbohydrate Restriction

The effect of chronic stress on thyroid health is well-recognised, with prolonged stress affecting almost every aspect of the thyroid hormone pathway. Not only can chronic stress suppress the pituitary gland (resulting in impaired TSH release), but it is also associated with reduced T4 production, impaired thyroid hormone conversion, and lastly, higher circulating levels of reverse T3. This last point is particularly telling - high levels of cortisol (our stress hormone) are associated with higher levels of reverse T3, the inactive form of our thyroid hormone. Depression has also been associated with higher levels of reverse T3, and optimising thyroid function in such cases has been shown to be highly beneficial, in particular for patients who were non-responsive to traditional anti-depressant therapy.

Similarly, prolonged fasting or very low carbohydrate diets are perceived as a form of stress by the body. For this reason, they are associated with impaired pituitary function and TSH release, in addition to reduced levels of T3 and higher circulating levels of reverse T3. Biologically, this makes sense; during times of chronic stress (like starvation or famine), our body reduces thyroid hormone activity so as to conserve energy and reduce our metabolic rate. As I said in my article on Reverse T3: “During times of stress, famine or starvation, reverse T3 production increases, to slow the metabolic rate and conserve energy. Back in the cavemen era, this would have been a clever, protective adaptation when food supplies were low. In today’s world though, this ‘stress’ may take the form of a crash diet or a stressful work environment, but the effect on our thyroid hormones is the same: increased conversion of T4 to reverse T3, and a lower metabolic rate as a result”. Note: Intense or prolonged exercise is also interpreted as a form of stress by the body, especially when combined with dieting. In such cases, we tend to see reduced T4 to T3 conversion and a corresponding rise in reverse T3 as well.

As a naturopath, I work with my patient’s to identify and address sources of stress in their life, so we can implement appropriate stress management strategies and use herbal or nutritional medicine to support the body’s stress response where necessary. For example, we have lovely herbal medicines such as Rehmannia glutinosa, Rhodiola rosea and Withania somnifera, which act on different aspects of the stress response to help support adrenal function during times of stress. In the case of Withania, this traditional herbal medicine has been shown to support both the production and conversion of thyroid hormones, in addition to exerting adaptogenic, anti-inflammatory and anxiolytic effects. When it comes to weight loss, I discourage crash diets or extreme fasting in favour of a healthier and more sustainable approach to weight management. After all, if a crash diet compromises thyroid function and slows the metabolism, it’s a very counter-productive approach to weight loss long-term!

Medications

Did you know, certain medications may impair thyroid function and alter thyroid hormone conversion? For example, glucocorticoid medications such as Prednisone or Methylprednisolone are chemically very similar to our stress hormone cortisol, and they exert similar detrimental effects on thyroid function. These medications increase activity of an enzyme called type 3 deiodinase (D3), which converts T4 into the inactive form, reverse T3. They also down-regulate type 1 and 2 deiodinase activity, resulting in reduced T3 production. Many patients with autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease and/or ankylosing spondylitis may be on varying doses of these steroid medications at different points in their health journey, and their thyroid health may be affected as a result. For this reason, I always adopt a holistic approach to their care, aiming to reduce autoimmunity, minimise disease activity, lessen the frequency or severity of flares, and of course, support thyroid function along the way.

Other medications known to alter thyroid function in various ways include Amiodarone, lithium, interferons, tyrosine kinase inhibitors, iodinated contrast media, amphetamines, dopamine agonists and more. The extent and duration of these effects is very much dependent on the drug, the dose and duration for which it is given and whether or not the individual has any pre-existing thyroid conditions. For this reason, if you are taking any of these medications, I encourage you to chat to your prescribing healthcare provider about whether monitoring of your thyroid function is warranted and, if you’re experiencing detrimental effects on your thyroid health, whether a suitable alternative might be available.

Alcohol and Smoking

Alcohol is a known toxicant to many body cells, including thyroid tissue. This means alcohol is known to have a direct toxic effect on thyroid cells, to the extent that alcohol-dependent individuals have been shown to have reduced thyroid volume and increased thyroid fibrosis compared to healthy controls. This reduced thyroid volume is often accompanied by a significant reduction in free T3 levels, along with a more moderate reduction in T4 levels. Chronic alcohol excess is also associated with liver damage, which may in part account for this impaired thyroid hormone conversion. Alcohol dependence has also been associated with euthyroid sick syndrome, which presents with low T3 levels, high reverse T3 levels and normal T4.

Similar to alcoholic drinks, cigarettes contain toxic compounds that may directly damage thyroid tissue. Cigarette smokers tend to have higher T4 relative to their T3 levels (suggesting impaired conversion), along with an increased risk of thyroid cancer. Smoking is also associated with a dose-dependent reduction in TSH, meaning heavy smokers (8-12 cigarettes daily) experience a greater TSH reduction than those smoking less than four cigarettes daily. This can be problematic, as it suggest smoking disrupts the communication between the brain and thyroid gland. Following cessation, it can take 5-10 years in women and up to 18 years in men for TSH to return to pre-smoking levels. As cigarettes are a major contributor to oxidative stress within the body, cigarette smoking also increases selenium requirements, as selenium is the primary antioxidant required to counter free radical damage within the thyroid.

Heavy Metal and Environmental Toxins

Heavy metals, such as mercury, lead and cadmium, are known to have a variety of deleterious effects on both thyroid function and thyroid hormone metabolism. For example, methylmercury (found in various species of fish) is known to impair conversion of T4 to T3 as it depletes selenium stores. Mercury also binds to iodine within the thyroid gland, reducing its availability for thyroid hormone synthesis. Cadmium has also been shown to impair peripheral thyroid hormone conversion.

Note: In some cases, heavy metal exposure can be difficult to quantify objectively, with little scientific consensus as to which body tissues or testing methods are most reflective of heavy metal exposure. For this reason, it’s important to correlate suspected or known exposure, with clinical signs and symptoms and data gleaned from tissue samples or excretion studies where possible.

In addition to heavy metals, various endocrine disruptors such as bisphenol-A, pesticides and flame retardants have been shown to impair T4 to T3 conversion. Specifically, they inhibit type 1 deiodinase (D1) activity; the enzyme responsible for converting T4 to T3 in the liver and kidneys. On the other hand, they don’t appear to inhibit type 2 deiodinase (D2) activity in the brain, meaning conversion continues as normal at a pituitary level. As a result, blood levels of T3 may be lower than usual, but the brain may not be responding and TSH levels are unaffected. This concept is referred to by researchers as tissue or cellular hypothyroidism, and it’s a topic I intend to explore further in future blog posts. The endocrine-disrupting effects of these chemicals is one of the primary resources I encourage my patients to use low-tox personal care products where possible, and to swap to glass or stainless steel food containers. For some examples, visit the Resources section of my website.

Inflammation

When the body is inflamed, due to injury, autoimmune conditions, systemic disease or other factors, type 1 deiodinase (D1) activity is down-regulated. This means the conversion of T4 to T3 in the liver and kidneys is impaired, resulting in a higher T4 to T3 ratio in the blood. One of the interesting ways in which our body responds to inflammation is to produce cortisol, our stress hormone. This is because cortisol has anti-inflammatory effects, however, as we discussed above, it is also known to impair thyroid hormone conversion.

In contrast, inflammation is known to up-regulate type 2 deiodinase (D2) activity in brain, meaning the pituitary receives higher levels of T3, whilst the rest of the body is experiencing reduced conversion. As a result, we are likely to see low T3 in the blood, accompanied by normal levels of TSH (as the normal feedback mechanisms have been interrupted). This is another instance of tissue hypothyroidism, and it is particularly problematic if practitioners are only testing TSH, as they are unlikely to pick-up the potential problem.

Blood Sugar Irregularities, Insulin Resistance and Diabetes

Numerous studies have shown an association between metabolic abnormalities (such as insulin resistance and diabetes) and a reduction in T4 to T3 conversion. In addition, such conditions are associated with increased shunting of T4 down the reverse T3 pathway. When insulin is elevated, D2 activity in the brain increases, resulting in increased intra-pituitary conversion of T4 to T3. Again, this may account for a normal TSH, despite low T3 levels in the blood. For example, when researchers compared T3 levels in diabetic versus non-diabetic individuals, they found that those with diabetes had significantly lower T3 levels, despite having similar TSH and T4 readings. This means that despite the reduction in T3, TSH levels had not responded appropriately, likely to due to the effect of elevated insulin on deiodinase activity in the brain.

From this perspective, irregularities with glucose metabolism may both contribute to thyroid dysfunction and arise as a result of thyroid dysfunction. For this reason, I work very closely with my patients to ensure healthy blood glucose and insulin metabolism, not only to optimise thyroid function but to support their energy levels and weight loss goals as well.

Other Factors

There are many other factors known to affect thyroid hormone conversion, however I would have to write a book in order to cover them all! These include chronic disease, depression, seasonal changes, sleep apnoea, chronic pain, leptin resistance and hormonal factors. Working with a thyroid-savvy health professional is your best chance of getting to the bottom of each of these factors, so you can optimise your thyroid hormone conversion and improve your health long-term.

As you can see, interpreting thyroid hormone results involves so much more than just a quick look at TSH. This is why I encourage a holistic approach to investigating and managing thyroid issues, so all relevant factors can be considered and accounted for where possible.

Niki x