MTHFR, Undermethylation and Overmethylation

As we have discussed in our other posts, the MTHFR gene is responsible for the MTHFR enzyme which regulates the methyl cycle (aka all of the important functions our body needs to survive). When this gene is mutated it can lead to the methyl cycle functioning abnormally. These abnormal functions can be related to highly efficient methylation or poor methylation.


As the name suggests, undermethylation is when there is too little methyl. Undermethylation is related to perfectionism, high levels of self-motivation and desire for high achievement. I bet you’re thinking ‘wow, how can I be an undermethylator?’…but before you get a head of yourself, undermethylation has also been associated with negative health issues such as:

  • Addiction/Addictive personalities
  • Competitive nature
  • Delusions
  • Obsessive compulsive disorders
  • Inner tension
  • Ritualistic behaviour
  • Social isolation
  • Phobias
  • Higher levels of allergies
  • Low serotonin
  • Heavy metal toxicity
  • Depression

Undermethylation can also result in a number of nutritional deficiencies including low levels of calcium, methionine, vitamin B6, magnesium, zinc, homocysteine and SAMe.


Overmethylation is the opposite of undermethylation. It is when the MTHFR enzyme produces too much methyl. Overmethylation has been associated with:

  • ADHD
  • Depression
  • Anxiety
  • Frustration/Anger
  • Low motivation
  • Paranoia
  • Self-harm
  • Food sensitivities
  • Sleep disorders

Overmethylation can also lead to elevated levels of serotonin (which is not always a good thing), low levels of histamine, low levels of zinc and high levels of copper.

Testing for Under or Overmethylation

As with anything, it’s important not to rely on Dr Google, or the internet, for diagnosis. MTHFR gene mutations and Under or Overmethylation can be tested by your doctor or by 23andMe.

Treatment for Under or Overmethylation

Once you have been medically diagnosed with a MTHFR gene mutation and a methylation problem, you can look to nutritional supplement regimes for treatment. The goal of these supplement programs is to offset the effects of the Under or Overmethylation. Addressing the methylation imbalance is a good start to improving your health.


Medication for the treatment of Hypothyroidism/Hashimoto’s Thyroiditis

Having felt tired and lacking zing for most of my life, seeing dozens of practitioners looking for answers and being told by my GP I should wait a little longer! to see what my thyroid antibodies were brewing, I was finally trialled on a low dose of thyroid medication – thyroxine (T4) to be exact. You may know what is coming but bear with me while I tell you about treatment options – sadly I wasn’t given this information.

Many thyroid patients who require thyroid hormone replacement to treat their hypothyroidism are never told that there is more than one medication. Here is a brief overview of the options available:-

Levothyroxine, a synthetic form of the T4 hormone, is the drug of choice for the mainstream and conventional medical world – commonly known here in Australia as Thyroxine. Generally a GP will prescribe only this drug for their hypothyroid patients.

However, as discussed previously, T4 is considered a storage hormone and must be converted in the body to the active T3. Therefore if your body cannot make this conversion, as mine couldn’t, when I started taking thyroxine I felt worse than when I was taking nothing! My body was converting the extra T4 into RT3 and I was like a bear heading into hibernation, every bodily function was slowing even further.

What next! After a great deal of research I found a doctor who knew a little about Natural Desiccated Thyroid, also known as NDT. NDT is a prescription drug derived from the dried thyroid glands of pigs. NDT is natural and gives you what your own thyroid would be giving you: T4, T3, T2, T1 and calcitonin. Most endocrinologists and many mainstream physicians do not support or prescribe the use of natural desiccated thyroid drugs.

For many, NDT is the answer and they live well on it. However, once again, I did not thrive on NDT – due to the fact that it still contains T4 and my body continued to convert this to RT3. My reverse T3 level continued to rise and I continued to feel unwell.

Life had become all about research, knowing there must be an answer out there!

Thankfully I found, for me, there was – in the form of Liothyronine. Liothyronine is a synthetic form of the active T3 hormone. Here in Australia it is called Tertroxin and generally not prescribed by mainstream GPs but nutritional doctors do – thank goodness! T3 takes more care to use as it has a short half-life, meaning its affects run out after 4-5 hours. I have alarms set on my phone to sound every 4 hours of daylight! but it is worth it. My body gets the active T3 I need to feel well for the first time in my life!

Hypothyroidism, and its associated health issues, is a complex disorder that requires understanding and help from people who really know – these may be fully qualified practitioners or people who have lived with it and found answers.

If you feel unwell and know something is wrong but can seem to find help, please contact us. We can point you in the right direction, provide contact details for practitioners who understand and don’t just tell you to ‘eat less exercise more’ or ‘it’s all in your head’. There is a wonderful, healthfull life to be lived out there for us all!

Testing for Thyroid Dysfunction

So how do you test for thyroid dysfunction?

Here is where things got a little tricky for me. I went to my GP and expected they would do all of the necessary tests needed to see if my thyroid was functioning correctly. My GP tested my TSH (Thyroid Stimulating Hormone), FT4 (Free Thyroxine) and the thyroid antibodies – anti-TPO and TgAb. Below are the tests you should have in order to gain a full picture of your endocrine health – do not take no for an answer!


TSH is like a messenger, it knocks on the door of the thyroid, telling your thyroid to produce more or less of the required thyroid hormones. If you are healthy, the message is determined by your blood levels, and if you have too little thyroid hormone to meet the demands of your body, then TSH knocks on the thyroid door and more hormone is produced or too much and TSH doesn’t knock as often and less hormone is produced.TSH

However, when the thyroid gland is not functioning correctly, theoretically  the TSH knocks and knocks on the door to no avail, the thyroid gland is unable to respond and the required hormones are not produced/released. When this happens your TSH blood level will be high.

However, based on normal medical training, a doctor will interpret your results as completely normal if your TSH is within the healthy range. In Australia the “healthy range” for TSH blood levels is ( 0.5 -4.0mIU/L). The problem is with the “healthy range” – a TSH level of 1 to 1.5mIU/L is better for optimum health (provided you are not on any thyroid medication – as optimum levels vary dependent upon you type of medication). My TSH was 3.86 and I was told I was absolutely fine despite a raft of clinical symptoms!

Free T4 and Free T3

The thyroid gland makes two main hormones – thyroxine (T4) and tri-iodothyronine (T3). T4 is produced in significantly greater quantities (a ratio of 17:1) than T3 whilst T3 is the more active hormone of the two. In fact T4 functions as a pro or storage hormone, it does not enter the cells and is biologically inert.  In circulation, most T4 is bound to specific transport proteins.

These transport proteins, produced by the liver – thyroid binding globulin (TBG), transthyretin and albumin – carry T4 and T3 to the tissues, where they are cut from their protein-carriers to become free T4 and free T3 and bind to thyroid hormone receptors (THRs) and thus exert their metabolic effect. Therefore it is critical that your doctor tests both free T4 and T3, as it is the unbound hormones that are able to do their job.

Unfortunately many GPs will only test for T4, total or possibly free and, like me if your body cannot convert T4 to T3 then a true picture of your thyroid health will not be obtained. You may have a normal blood level of T4, total or free, but it can’t be utilized by your body. The optimum levels for these tests should be roughly mid-range, however if either or both are high/low or a combination of the two there generally is an issue.

Remember we are looking for optimum health – not ‘within range’ which in mainstream medical terms can often translate to near enough is good enough despite clinical symptoms!

Reverse T3

A healthy thyroid produces T4, T3, and in smaller amounts T2, T1 and calcitonin. As discussed, T4, the storage hormone is meant to convert to T3 the active hormone.

However there is another substance produced by the thyroid called Reverse T3, it also comes from the conversion of the storage hormone T4 and it is quite normal to have some RT3.

Your liver can constantly be converting T4 to RT3 as a way to get rid of any unneeded T4 and maintain homeostasis (balance of all critical bodily functions).  In any situation where your body needs to conserve energy and focus on something else, for example during illness, injury, high levels of stress or a dramatic lowering of environmental temperature, the conversion rate of T4 to T3 or RT3 will change.

Additionally, certain physiological conditions cause T4 to be converted to RT3, including adrenal dysfunction (low cortisol, high cortisol), low or high iron levels, low B12 and chronic inflammation.

Given that RT3 is a ‘mirror molecule’ of normal T3, is intrinsically inactive and prevents proper activation of receptor sites, which in simple terms stops the active T3 from entering the cells where it is needed for all metabolic functions, it is critical that the level of RT3 remains in correct balance with T4 and T3. Therefore testing for RT3 levels at the same time as FT4 and FT3 is vital.

When testing for RT3 you are not necessarily looking for a blood level high in the range, but a problem in the ratio between RT3 and Free T3.  By dividing the Free T3 by the Reverse T3 (Free T3 ÷ RT3), all in the same measurement unit, the ratio should be 20 or greater. If using the total T3, the ratio should be greater than 10.

Remember, it is vital that you be tested for RT3, do not take no from your doctor who doesn’t believe in such witchcraft!

Here is a fun fact to reiterate the importance of rebalancing the conversion of T4 to T3 instead of RT3. When bears prepare for hibernation, in order to survive the long cold winter of their environment, their bodies produce RT3. By doing so their systems shut down to a point of barely functioning – very low heart rate, low body temperature, impaired digestive function, increased sleep requirements, and the list goes on. This is akin to our bodies preparing for famine, every function reduces to the most basic level in order to conserve energy and survive the dire period ahead.

Now we, as humans do not need to hibernate and generally, in the western world at least, do not face periods of famine so we definitely do not want our metabolic systems to slow down, we want to live life to the fullest!

Thyroid Antibodies

I have discussed the causes of hypothyroidism earlier and mentioned that one of those causes is Hashimoto’s Thyroiditis. Hashimoto’s, which I have, is an autoimmune disease (just like Type 1 diabetes, multiple sclerosis, alopecia, rheumatoid arthritis, vitilgo, celiac disease to name a few).

As with any autoimmune disease, a dysfunctional immune system produces antibodies which attack our own bodies, in this case the thyroid gland. In many cases this attack is virtually silent, initial symptoms mimic other illnesses and it is not until real damage has been done and the thyroid gland can barely function that we look for answers.

For this reason it is very important that thyroid antibodies blood tests be conducted along with the other thyroid tests. Generally Hashimoto’s is confirmed with two antibodies tests, anti-TPO and TgAb. Anti-TPO attacks an enzyme in our thyroid gland, the Thyroid peroxidase, which is vital in the production of all thyroid hormones and TgAb attacks our thyroglobulin, a key protein in the thyroid gland, which is essential for the production of T4 and T3.

The ranges for each antibodies test in Australia are: –

– anti-TPO <60IU/ml, and

– TgAb <60UI/ml.

When I was first tested my anti-TPO level was >1300! (the lab could not record anything higher) against a normal range of <60. The GP I was being treated by at the time basically scoffed at the tests, saying only that “something was going on, but we do not really know what” and did not want to help me with any form of treatment despite the fact that my test results were awful and I felt like the living dead!


As mentioned, the vital conversion of storage T4 to active T3 depends upon a number of factors including correct levels, neither too high nor too low, of iron in the blood.

Therefore it is important to test four iron labs:

  • Ferritin,
  • % Saturation,
  • TIBC, and
  • Serum iron.

Each provides an important and exact picture of how your body is functioning.

Adrenal Cortisol Levels

Healthy adrenal glands produce the correct level of cortisol, based on a diurnal curve, to increase blood sugar through gluconeogenesis, to suppress the immune system, and to aid the metabolism of fat, protein, and carbohydrate.

Correctly functioning adrenals and thus good cortisol levels, neither too high nor too low, are essential to healthy thyroid function. Cortisol raises your cellular level of glucose which works with your cell receptors, ATP (our energy source) and mitochondria to receive T3 from the blood into the cells.adrenal-gland-chart

Clues that you may have low cortisol levels include difficulty both falling asleep at night and waking up in the morning early, or feeling refreshed, waking frequently during the night, bright lights bother you more than they should, you startle easily due to noise (loud cars and motorbikes are awful!), when standing from sitting or from lying down, you feel lightheaded or dizzy, you take things too seriously and feel that you don’t cope well with certain people or events in your life.

For me getting my adrenals functioning as they should, (I am on specialized medication for this due to the severity of my adrenal insufficiency – however this step may not be necessary for much of the population) was a turning point in my life. Once my cortisol levels improved the uptake of my thyroid medication improved dramatically and so did my health. I work very hard in keeping all factors balanced as any small deviation can have a terribly detrimental effect on how I feel. Therefore testing for cortisol levels is a necessary piece of the health puzzle.

Adrenal Cortisol levels should be tested via a 24 hour saliva test, NOT blood, in order to determine if your cortisol production follows the diurnal curve that it should. Our highest levels of cortisol are required in the morning in order for us to carry on with our normal activities and then fall progressively towards night so that we can sleep.

Unfortunately, doctors tend to recommend a one-time blood test, which measures both your bound and unbound cortisol–not how much cortisol is produced at different times of the day. Ideally, you will need to be off all cortisol containing supplements for two weeks before testing.

Tests results for optimum health should look like these numbers below:-

8 am: At the literal top of the range.

11 am-noon: In the upper quarter, and often about a quarter below the top.

4-5 pm: Mid-range

11 pm to midnight: At the very bottom.

Sex Hormones

It is important to have your sex hormone levels tested too, as high or low levels/ imbalances can prevent optimum metabolic and endocrine health.

Estrogen dominance has been linked to an increased risk of hormonal cancers, adrenal fatigue and thyroid dysfunction – among other things. I have estrogen dominance and need to work carefully with my nutritional doctor in order to balance this with bio-identical progesterone and testosterone in order to feel well.

The sex hormones that should be tested are:

  • Estradiol,
  • Progesterone,
  • Free testosterone, and
  • DHEA.

Testing should be 7 days after ovulation, which is usually days 19-21 for most women.