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Why isn't there T2 thyroid hormone?

Why isn't there T2 thyroid hormone?



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The follicles in the thyroid, intake iodine and bind them onto the tyrosine rings (attached to the thyroglobulin). This produces either MIT or DIT (tyrosine rings with 1 or 2 iodines attached respectively).

Then the DIT joins with either another DIT or a MIT to form T3 or T4. This makes sense.

But it seems to me, that there could be a MIT attaching to another MIT, forming T2. Why doesn't T2 get created?


In fact, there are two T2 hormones, depending on the position of iodine atoms on the thyronine backbone molecule [5].

One of them, 3,5-diiodothyronine (3,5-T2) is the most active of all thyroid hormones with a relative T4 potency of 8 to 15. Thereby, it is 2 to 5 times as potent as T3. Its plasma concentration is rather low, however, being 0.2 to 0.37 nmol/l [1-3]. It is weakly bound to plasma proteins and has a short half-life [7, 8]. 3,5-T2 seems to be a risk factor for atrial fibrillation [3], and it is able to suppress pituitary thyrotropin (TSH) secretion [4]. It is upregulated in critical illness (NTIS/TACITUS) [1, 3, 6].

The second isomer, 3',5'-T2 is an inhibiting thyroid agent that is able to block the activity of deiodinases and receptors for thyroid hormones, similar to reverse-T3 (rT3) [5].

References

  1. Pinna G, Meinhold H, Hiedra L, Thoma R, Hoell T, Gräf KJ, Stoltenburg-Didinger G, Eravci M, Prengel H, Brödel O, Finke R, Baumgartner A. Elevated 3,5-diiodothyronine concentrations in the sera of patients with nonthyroidal illnesses and brain tumors. J Clin Endocrinol Metab. 1997 May;82(5):1535-42. PMID 9141546. https://pubmed.ncbi.nlm.nih.gov/9141546/
  2. Lehmphul I, Brabant G, Wallaschofski H, Ruchala M, Strasburger CJ, Köhrle J, Wu Z. Detection of 3,5-diiodothyronine in sera of patients with altered thyroid status using a new monoclonal antibody-based chemiluminescence immunoassay. Thyroid. 2014 Sep;24(9):1350-60. doi: 10.1089/thy.2013.0688. Epub 2014 Aug 1. PMID: 24967815. https://pubmed.ncbi.nlm.nih.gov/24967815/
  3. Dietrich JW, Müller P, Schiedat F, Schlömicher M, Strauch J, Chatzitomaris A, Klein HH, Mügge A, Köhrle J, Rijntjes E, Lehmphul I. Nonthyroidal Illness Syndrome in Cardiac Illness Involves Elevated Concentrations of 3,5-Diiodothyronine and Correlates with Atrial Remodeling. Eur Thyroid J. 2015 Jun;4(2):129-37. doi: 10.1159/000381543. PMID 26279999. https://pubmed.ncbi.nlm.nih.gov/26279999/
  4. Pietzner M, Lehmphul I, Friedrich N, Schurmann C, Ittermann T, Dörr M, Nauck M, Laqua R, Völker U, Brabant G, Völzke H, Köhrle J, Homuth G, Wallaschofski H. Translating pharmacological findings from hypothyroid rodents to euthyroid humans: is there a functional role of endogenous 3,5-T2? Thyroid. 2015 Feb;25(2):188-97. doi: 10.1089/thy.2014.0262. PMID 25343227. https://pubmed.ncbi.nlm.nih.gov/25343227/
  5. Hoermann R, Midgley JE, Larisch R, Dietrich JW. Homeostatic Control of the Thyroid-Pituitary Axis: Perspectives for Diagnosis and Treatment. Front Endocrinol (Lausanne). 2015 Nov 20;6:177. doi: 10.3389/fendo.2015.00177. PMID: 26635726; PMCID: PMC4653296. https://pubmed.ncbi.nlm.nih.gov/26635726/
  6. Langouche L, Lehmphul I, Perre SV, Köhrle J, Van den Berghe G. Circulating 3-T1AM and 3,5-T2 in Critically Ill Patients: A Cross-Sectional Observational Study. Thyroid. 2016 Dec;26(12):1674-1680. PMID 27676423. https://pubmed.ncbi.nlm.nih.gov/27676423/
  7. Louzada RA, Carvalho DP. Similarities and Differences in the Peripheral Actions of Thyroid Hormones and Their Metabolites. Front Endocrinol (Lausanne). 2018 Jul 19;9:394. doi: 10.3389/fendo.2018.00394. PMID: 30072951. https://pubmed.ncbi.nlm.nih.gov/30072951/
  8. Köhrle J, Lehmphul I, Pietzner M, Renko K, Rijntjes E, Richards K, Anselmo J, Danielsen M, Jonklaas J. 3,5-T2-A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action. Front Endocrinol (Lausanne). 2020 Jan 8;10:787. doi: 10.3389/fendo.2019.00787. PMID: 31969860; PMCID: PMC6960127. https://pubmed.ncbi.nlm.nih.gov/31969860/

Why Your Doctor Won’t Prescribe the T3 Thyroid Hormone

There is a simple reason why doctors typically refuse to prescribe the T3 thyroid hormone and it has nothing to do with science, side-effects, or potential dangers.

As with so many things in healthcare, it boils down to Big Pharma and money. The solution is to find a better-informed doctor.

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About Dr. William Davis

William Davis, MD, FACC is cardiologist and author of the #1 New York Times bestselling Wheat Belly series of books. He is also author of the new Undoctored: Why Health Care Has Failed You and How You Can Become Smarter Than Your Doctor.


How TSH Levels Change

TSH levels are not very intuitive. Why does a high TSH mean you have an underactive thyroid gland? Why do low levels means the gland is overactive?

Understanding exactly how the thyroid gland works can help.

Your thyroid gland produces thyroid hormone. When it functions properly, your thyroid is part of a feedback loop with your pituitary gland that involves several actions:

First, your pituitary gland senses the level of thyroid hormone that is released into the bloodstream.

Your pituitary then releases the special messenger hormone TSH, which makes the thyroid release more thyroid hormone. From there:

  • If your thyroid doesn't produce enough thyroid hormone, your pituitary triggers your thyroid to make more. (This might happen in cases of illness, stress, or surgery, for example.)
  • If your thyroid is overactive and producing too much thyroid hormone, your pituitary senses that and slows or shuts down TSH production.

Why Don’t Doctors Run T3?

Hey everybody, it’s Dr. Eric Balcavage, and we’re back for another addition of Thyroid Thursday, and today, we want to answer a question that many of my patients have, and that is, why do doctors not want to run T3 or free T3?

And the answer for this is, most conventional medical doctors and endocrinologists, are taught that T3 isn’t that valuable in hypothyroid cases. Matter of fact, the American Thyroid Association guidelines say that, “… T3 is rarely helpful in a hypothyroid patient since it’s the last test to become abnormal.” TSH and T4 will become abnormal before T3 will, so doctors just don’t run it. They don’t see a value in it. Most times, they’re looking to give you a T4 support and they’re looking for TSH and T4 values to normalize, so looking at a T3 really isn’t that important to them.

Why is it that T3 is the last marker to become abnormal?

One of the answers is that the biology of the body actually defends serum T3 to maintain a normal lab level. In most situations, T3 doesn’t really leave the lab range. Now lab ranges are a bit broader range than functional ranges. Functional ranges which we use in functional medicine or integrative medicine are the optimal ranges for health. We use this narrower, healthy range and the functional range is really the range that the body works best in. Lab ranges are just a broader range. T3 and free T3 rarely ever leave these ranges because the body fights to defend T3 within that range.

Unfortunately, sometimes that’s at the detriment to your cells. The T3 in your serum doesn’t necessarily equal the amount of T3 that’s in your cells. T3 can be normal in the serum, but it can be deficient in the cells. T3 may be out of the functional range, but most times, it stays within that lab range.

Is T3 still an important test to run?

In functional medicine, it is still really important to run T3 because if it is high or low, outside the lab range or the functional range, we want to know that so we can understand why that’s happening, and understand how that is impacting our patients. We can also use T3 and free T3 in conjunction with something called reverse T3 to find out what’s happening at the cellular level with something called the deiodinase enzymes. Now I’ve talked about Deiodinase enzymes on other videos. The deiodinase enzymes are the enzymes that convert T4 to either T3 or reverse T3 and T3 to T2. It is really important to understand what’s happening to the T4 that your doctor puts into your system.

If we just look at T4 and TSH, we don’t know if that T4 is being converted efficiently in our peripheral cells to active T3 inside the cells or is it converting to reverse T3. So it becomes really important. If you get our T3 tests done we can compare it to reverse T3. We use T3/rT3 or fT3/rT3 ratio to evaluate deiodinase activity. If T3 divided by reverse T3 is less than 10, then we know you’re making more reverse T3 in relationship to T3. That means cells are increasing their deiodinase-3 to get rid of T3, and there is less T3 getting to the nucleus to stimulate your metabolism. If we take free T3 and divide it by reverse T3, and that number is less than 0.2, again that indicates that you probably have more deactivation of your T4 to this inactive hormone, reverse T3.

It is really important in functional medicine to understand what’s happening at the cellular level because thyroid physiology is really defined by what’s happening at the cellular level. Your symptoms, your hypothyroid symptoms, your dry skin, your thinning hair, your tiredness, your fatigue, is really the result of how much T3 is getting into your peripheral tissues. Most of the conversion of T4 to T3 for the cells of your body occurs in the peripheral cells. Once T4 is transported into the cell, it can then be acted on by deiodinases that can convert it to T3, which can stimulate metabolism or it can be acted on by deiodinases that convert it to reverse T3 and push it back out of the cell.

Most doctors don’t look at T3 because they don’t think it’s going to change too much, and most doctors don’t run reverse T3 because it’s not as important to what they are trying to accomplish. The guidelines pretty much have doctors focusing on TSH and T4 levels coming into normal range. It’s assumed that if those two values come back into normal range, then you’re getting sufficient levels of active thyroid hormone into the nucleus of all your cells and your thyroid physiology is corrected or fixed. Many times that’s just not the case. I’ve talked about this on multiple videos.

So what do you do?

You want to get T3, free T3, reverse T3 done, and your doctor doesn’t want to do it, what do you do? Listen, it’s your health. Ask them, tell them you want it done. Tell them you’ll take the responsibility. If it doesn’t get paid, then you’ll have to pay it. If you come to a functional medicine practitioner like me, you can get a full thyroid panel done for about $100, and that includes nine or 10 tests regarding thyroid physiology TSH, T4, free T4, T3, free T3, reverse T3, T3 uptake, thyroid antibodies. You can get a lot of testing done for about $100. It’s your life, it’s your health, you want T3 done. Tell your doctor you want to get it done. Don’t just get T3 and free T3, make sure you get that reverse T3 number with it, and then make sure that you get the TSH, T4, free T4, T3 uptake, thyroid antibodies done as well. But it’s your health, ask your doctors or demand your doctors to run those tests, all right? Hopefully that helps. If you need help, give us a call at the office, I’d be more than happy to help you. Take care.


HYPOTHYROIDISM IN THE OLDER PATIENT

Hypothyroidism is very common in patients over 60 years of age and steadily increases with age (see Hypothyroidism brochure). Up to 1 in 4 patients in nursing homes may have undiagnosed hypothyroidism. Unlike symptoms of hyperthyroidism, the symptoms of hypothyroidism are very non-specific in all patients, even more so in the older patient. As with hyperthyroidism, the frequency of multiple symptoms decreases in the older patient. For example, memory loss or a decrease in cognitive functioning, often attributed to advancing age, may be the only symptoms of hypothyroidism present. Symptoms and signs of hypothyroidism may include weight gain, sleepiness, dry skin, and constipation, but lack of these symptoms does not rule out the diagnosis. To make this diagnosis in the elderly patient, a doctor often needs a high index of suspicion. Clues to the possibility of hypothyroidism include a positive family history of thyroid disease, past treatment for hyperthyroidism, or a history of extensive surgery and/or radiotherapy to the neck.

A decision to treat the patient with a new diagnosis of hypothyroidism will rest on several factors, including whether the patient is symptomatic from hypothyroidism, or just has an elevated thyroid-stimulating hormone (TSH) level. In the case of the latter finding, many doctors will repeat the test in 3-4 months and elect to begin thyroid hormone replacement when the TSH level stays above the normal range. The presence or absence, and severity, of thyroid-related symptoms and co-existing diseases such as coronary artery disease or heart failure will determine the dose of thyroid hormone replacement that is given.


How the thyroid influences the gut/digestive system

You’re in deep now, so let’s continue by exploring how the thyroid affects the gut and entire gastrointestinal/digestive system.

We’ll start with the most familiar players in your digestive symphony: your mouth and stomach.

As you probably remember from grade school biology, digestion begins in your mouth with the production of enzyme-rich saliva which initiates the breakdown of food, specifically starches. So, it’s really important to have enough saliva production to get this process started off right.

However, research has shown that a significant amount of people with autoimmune thyroid disease, such as Hashimoto’s, lack adequate amounts of saliva and experience “dry mouth”. 23 This is due in part to the over-production of pro-inflammatory cytokines which hinder normal production of saliva.

Your thyroid also plays a super important role in production of stomach acid which can result in symptoms like GERD, nutrient deficiencies, and other digestive ailments like SIBO (small intestinal bacterial overgrowth) and SIFO (small intestinal fungal overgrowth).

Research has also shown that hypothyroidism causes gastrointestinal dysfunction by significantly reducing gatroesophageal motility (aka: movement), and thus, it is recommended thyroid function be checked in patients with indigestion. 24

Studies also show the link between atrophic gastritis and autoimmune thyroid disease. 25

This is why many people with low thyroid function benefit from supplementation with Betaine Hcl. (If you want to learn more about this I suggest you read this article from my friend and colleague Izabella Wentz PharmD, aka The Thyroid Pharmacist.)

There are other organs that play a crucial role in the proper assimilation, break down, and absorption of macro and micronutrients which are also impacted by thyroid health.

For example, your liver produces enzymes and bile essential to digestion and assimilation of proteins, sugars, and fats. It also works hard to metabolize toxins (like pesticides or heavy metals), alcohol, and control the amount of glucose released into your bloodstream.

In other words: if your liver isn’t functioning properly your digestion will be off.

However, your liver cannot function optimally without (you guessed it!) a healthy thyroid, and research has shown the liver is the organ most affected by hyper- and hypothyroidism. 26

So, an unhealthy thyroid makes for an unhealthy liver which affects the gallbladder and hampers optimal digestion, nutrient absorption, and T4/T3 conversion (as discussed in the previous section)…not a pretty picture.

Further, your pancreas and thyroid share a connection, with the thyroid showing influence over pancreatic enzyme production and overall functional integrity. 27

Finally, there are the numerous connections to intestinal function, such as altered motility, which we’ve discussed previously. 28 . To bring it full circle, altered motility is a setup for constipation, but also bacterial overgrowth, which is one reason for the strong association between hypothyroidism and SIBO. 29


What Does Free T3 Tell You About your Thyroid?

There are many ways to assess thyroid function in your body and many different lab tests.

This lab test gives you an idea as to how responsive your thyroid is to your brain and if that connection is working properly.

But what does free T3 tell you about your thyroid?

The measurement of free T3 is telling you how much free and active thyroid hormone your body as available to work with.

Free T3, after all, is the single most important thyroid hormone in your body.

It's the hormone that is responsible for attaching onto the surface and the nucleus of your cells and making genetic changes to those cells.

This simple process is what makes your thyroid increase your energy, manage your weight, regulate your cycle and so on.

But what happens if you don't have a sufficient amount of free T3 in your body?

You WILL experience the symptoms of hypothyroidism.

If you aren't familiar with the thyroid conversion process or why it's so important for your body to go through this process please see this short video below which will bring you up to speed:

TSH vs Free T3, Total T3 & Free F4

Like most people, you are probably more familiar with the TSH as a marker for testing your thyroid.

And you wouldn't be alone in this understanding because Doctors also love to use this test.

But is it the single best test to assess thyroid function in your body? Did you know that there are many other thyroid function tests?

The answer may surprise you.

It turns out that in healthy individuals the TSH is probably a great way to assess thyroid function in the body.

But where it fails is when you use it as the only source to help manage patients who are already taking thyroid medication .

That's important, but what exactly does it mean?

It means that if you are taking thyroid medication (such as Levothyroxine or Synthroid) that you may have a completely normal TSH, but that doesn't mean that your free thyroid hormone levels are "normal".

This may explain why many patients on these types of medications don't feel optimal despite having "normal" thyroid levels.

That's where free T3 steps in.

Free T3 can, and should, be used in conjunction with the TSH to ensure that you are getting a sufficient amount of ACTIVE thyroid hormone to your cells.

And this way of looking at hormone shouldn't be surprising to you or Doctors.

Because for virtually all other hormone levels in the body, we ALWAYS check for the active hormone!

Well, the TSH is NOT that marker.

The TSH is a proxy marker for how well the pituitary is functioning but it does NOT tell you how much hormone is in the body.

When you break it down in this way it just becomes obvious that we would want to look at the active thyroid hormone (free T3 and free T4) but this logic is lost on many patients and doctors.

Avoid falling into this trap! The free T3 can give you seriously helpful information about how your thyroid is functioning.

Download my Free Resources:

Foods to Avoid if you have Thyroid Problems:

I've found that these 10 foods cause the most problems for thyroid patients. Learn which foods you should absolutely be avoiding if you have thyroid disease of any type.

How to Calculate "Optimal" Free T4, Free T3, & Reverse T3 Ratio:

Calculating these ratios is important because it can help you determine if your efforts are on the right track and whether or not your medications are working.

Download more free resources on this page.

Optimal Ranges for Free (What's a "Normal" Range?)

But what is a "normal" or "healthy" range? What levels should you look for when you test for this simple lab test?

This is a simple yet very important question.

The answer is that it varies based on which lab company is drawing and running your bloodwork.

And that happens for this reason:

Each lab company creates their own "reference ranges" that your result is compared to.

And they often include people of ALL ages and of varying health status.

That means the reference range is compiled of a bunch of both healthy and unhealthy people which can skew the range.

When you look at your results you want to be compared to HEALTHY individuals who are around your same age .

You don't want to be compared to someone who is in their 80's with multiple health conditions.

By looking at the reference range and ensuring that your result falls within the top 50% percentile of that reference range.

This isn't a perfect way to do it, but it is much better than potentially comparing yourself to unhealthy people.

Let's use this as an example:

This example shows a free T3 of 2.3 with a reference range of 1.7 to 3.7.

If we break down the difference between 3.7 and 1.7 we get 2.0.

That means that the top 50% of the "healthy" range is between 2.7 and 3.7 (3.7 being the top end of the healthy range).

That also means that the bottom 50% of the "less optimal" range is between 1.7 and 2.7 (1.7 being the bottom end of that range based on the reference range).

So you want your result to ideally fall between 2.7 and 3.7 (in this example!) .

You can apply this same methodology to your lab test.

Is having a High Free T3 Dangerous? (Symptoms of High Free T3)

In a perfect world, you want your lab test in just the "perfect" zone (the top 50% of the reference range listed above).

What you will find, however, is that your free T3 will vary based on when you take your thyroid medication, (8) the type of thyroid medication you are taking and when you check your blood work.

To prevent abnormalities in your blood work you will want to follow these basic rules:

#1. Make sure to test your blood work about 24 hours after you take your thyroid medication.

This will help prevent abnormal highs when testing.

You want to look at the lowest level of thyroid hormone that is in your body prior to your next dose.

Checking at hour 24 (assuming you take your thyroid medication every 24 hours) will show you the lowest that your free T3 will be right before you take your medication.

If this value is in the 50% of the reference range then you know that throughout the day you are maintaining at least that level .

#2. Don't check your blood work right after you take your thyroid medication.

This will give you a value which is falsely elevated and not indicative of what your levels will be throughout the day.

If you still have a high free T3, despite following these rules, then you might be in danger of taking too much thyroid hormone.

If you do, you will most likely notice it as you become symptomatic.

Symptoms that may accompany a high free T3 include:

  • Jittery sensation
  • Heart palpitations
  • Sweating
  • Hot flashes
  • Tremors of the hands
  • Diarrhea
  • Anxiety
  • Rapid heart rate

If you are experiencing any of these symptoms and you have a high free T3 then you may need to adjust your dose.

Symptoms of Low Free T3

Perhaps more common than high free T3 is the condition of having a low free T3.

Most people, due to a variety of reasons, tend to be undertreated as opposed to overtreated.

Undertreatment of hypothyroidism usually results in low free T3 levels which can be identified when these levels are in the bottom 50% of the reference range (see example above).

Because free T3 is the hormone responsible for all of the benefits of thyroid hormone.

So it makes sense that low levels may result in these symptoms.

Symptoms of low free T3 include:

  • Weight gain
  • Fatigue
  • Constipation
  • Cold intolerance
  • Slow heart rate
  • Lower than normal body temperature
  • Brain fog
  • Depression
  • Menstrual problems

If you have these symptoms and low free T3 on lab testing then you may need to make adjustments to your medication regimen.

This may include using supplements or medications designed to help improve your free T3.

What to do to Raise your Free T3 (Medications + Supplements)

There are two main ways that you can improve your free T3.

The first is through the use of medications and the second is through the use of targeted supplements.

Let's discuss medications first:

Low free T3 when you are already taking thyroid medication is usually an indication that your body is having trouble activating the thyroid hormone.

In addition, it may be a sign that you are either not absorbing your medication or that your dose is not high enough.

Either way, you may need to make changes to your medication regimen.

Medications such as liothyronine and Cytomel can be added to your regimen which will directly increase T3 levels.

The problem with this approach is that it requires your Doctor to be on board.

It can be difficult to convince a physician to provide these medications as they are usually not comfortable using them (even though they are safe!).

If you fall into this category then you may need to take the supplement route:

Certain supplements, available over the counter, can be used to help improve thyroid function and thyroid conversion.

These supplements may help your body by providing the necessary vitamins and nutrients involved in the thyroid conversion process.

My personal recommendation is to use a supplement such as this which contains zinc, selenium, Vitamin A and guggul, all of which are designed to help this process.

The great thing about supplements is that they can be combined with thyroid medications, they are easy to get and may help a great many people.

Conclusion

Hopefully, you appreciate the value that testing free T3 can give you when looking at your thyroid.

Free T3 is available as an easy and routine blood test which is covered by all insurances (I've ordered it thousands of times and have never had an issue so don't buy that excuse!).

Testing your free T3 will help you to understand if your body activating thyroid hormone in your body and should be used in conjunction with other lab tests such as TSH and free T4.

Whenever you make any changes to your treatment regimen make sure that you test afterward !

This will help guide your treatment and help you to know what is working and what isn't.

Now I want to hear from you:

Have you tested your free T3?

Do you know if you have a low free T3 or high free T3?

Do you feel that your body is converting or activating your thyroid hormone?


Testing for normal levels of T4 thyroid hormone is a common lab test along with TSH to diagnose thyroid issues. Dr. Muhammad Bader Hammami on Medscape says that total T4 (TT4) range and free T4 (FT4) range are as follows: 10

Total T4 (TT4) range:

  • Newborn babies up to 14 days old: 11.8 – 22.6 mcg/dL (152 – 292 nmol/L)
  • Babies and older children: 6.4 – 13.3 mcg/dL (83 – 172 nmol/L)
  • Adults: 5.4 – 11.5 mcg/dL (57 – 148 nmol/L)

Normal free T4 (FT4) range:

  • Children and adolescents: 0.8 – 2 ng/dL (10 – 26 pmol/L)
  • Adults: 0.7 – 1.8 ng/dL (9 – 23 pmol/L)
  • Pregnant women: 0.5 – 1.0 ng/dL (6.5 – 13 pmol/L)

Choosing Between Synthetic And Whole Natural Thyroid Supplements

At antiaging-systems.com we stock a comprehensive range of both synthetic and natural thyroids, but would strongly advocate taking a natural supplement over a synthetic because products such as Armour Thyroid contain the full spectrum of Thyroid hormones (T1, T2, T3 and T4) unlike synthetic thyroid products such as Titre or Tiromel, which typically only contain one. However most mainstream doctors only prescribe synthetic thyroids.


Making sense of it all

While there’s a lot of dissatisfaction with thyroid treatments online, the vast majority of patients find levothyroxine to be a simple and highly effective daily therapy. There are some true controversies in the treatment of hypothyroidism, but they’re buried in vast amounts of pseudoscience and bad treatment advice. So I advise my newly diagnosed patients against complicating treatment unless it’s necessary, and to start treatment with positive expectations: Synthroid is a top dispensed drug for a reason: It works. And despite the controversies, and the outlier opinions, the medical consensus on the treatment of hypothyroidism is quite strong. That means ignoring the noise, focusing on the relevant outcomes, and taking a stepwise, science-based approach to treatment.