Do you wonder if you need t3 (Cytomel, triiodothyronine, liothyronine) added to your thyroid hormone treatment to feel normal again? The answer could be in your genes.
Recent discoveries reviewed by Antonio C. Bianco, M.D., Ph.D. at the recent American Thyroid Association meeting, reveal how genetic differences influence the effectiveness of thyroid hormone replacement. Dr. Bianco’s lecture focused on studies pinpointing inborn differences in the way people metabolism thyroid hormone to explain why t3 treatment of hypothyroidism is probably required by some to restore normal functioning of their brain, muscle and heart.
The most frustrating problem for people with hypothyroidism is being unable to convince their doctor that treatment with Synthroid, Levoxyl or similar pure t4 product, isn’t working. Continued symptoms of fatigue, weakness, inability to concentrate or think clearly, and inability to lose weight despite really trying, result in tension between the doctor and the “complainer”. When assessing the adequacy of thyroid hormone replacement therapy most doctors rely on the blood tests known as the Thyroid Function Panel. Typically this includes a measurement of t4, t3, t3RU, and TSH. Some panels may also include free t4 or free t3 measurements. If the hormone levels on these tests are “within normal limits” the doctor will often insist that the treatment is a success but it is the patient who fails to recognize this. A minority of endocrinologists know many of these “failures” can be turned into success by the addition of t3, the less utilized but much more powerful form of thyroid hormone.
Most of the biological effects of thyroid hormone in the body are due to the action of t3. The most common forms of thyroid hormone replacement however, involve giving t4 in the form of Synthroid, Levoxyl, levothyroxine etc. The t3 required by our tissues is produced by specific enzymes which convert t4 to t3 in the cells of the liver, kidney, brain, muscle, heart etc. These converting enzymes are known as deiodinases and under normal conditions they are responsible for about 80% of the body’s t3. The process by which t3 is produced from t4 is known as peripheral conversion.
It has long been the contention of the leaders in thyroid disorders that based on their arithmetic, t4 replacement is sufficient to provide all the t3 the body needs via peripheral conversion and giving t3 supplementation doesn’t make good medical sense. Now, based on the new information provided by researchers like Dr. Bianco, the “arithmetic guys” will, in my opinion, need to revise their thinking finally allowing the way for acceptance of t3 replacement approaches.
I will continue the explanation of the new breakthrough in genetic control of thyroid hormone replacement treatment in Part 2 of this post.
Treatment of hypothyroidism (low thyroid function) is accomplished by administering thyroid hormone by mouth in sufficient amounts to restore levels back to normal. At first glance this might seem like a simple goal to achieve. The truth is hormone replacement therapy is complex because there exists two very different thyroid hormones and because levels of thyroid hormone in the blood do not always reflect the amount of thyroid hormone within the cells where the hormone exerts its effects. In Part One of this blog I began to discuss how genetic differences among individuals could explain why some people need a complex mix of thyroid hormones to adequately treat hypothyroidism. In Part 2, I want to explain the nature of the differences between individuals and how it determines what sort of thyroid hormone therapy may be needed.
In May 2009 a group of researchers (Panicker, V. et al) in the UK published the WATTS study, the largest and most comprehensive study to date, of hypothyroid patients treated with combination t4 and t3. The goal of the study was to discover whether genetic differences in the population of hypothyroid patients accounts for some individuals needing t3 in addition to traditional t4 therapy. The researchers looked at 697 hypothyroid individuals and analyzed their DNA for differences in the portions controlling crucial enzymes which process thyroid hormones known as deiodinases. These enzymes are found widely distributed in the body including the thyroid, brain, muscle, liver, kidney and pituitary gland. As explained above, deiodinases convert t4 to the much stronger form of thyroid hormone, t3. At the same time the researchers measured patients’ mood and sense of well being on t4 alone and when t3 was added to the therapy.
Key findings of the WATTS study are that there is a substantial difference among individuals in the genes that make the deiodinases. In other words, due to genetic differences (mutations), there are differences in the way individuals make t3 out of t4. In a group of people, mutations in the genes that make a particular protein (in this case, the deiodinase), are called polymorphisms. The researchers discovered that a certain mutation in the deiodinase gene is associated with a poor sense of well being on t4 only therapy, and in the presence of this mutation a significantly better response to adding t3 can be found compared to those without this mutation. Of the group of hypothyroid patients studied in the UK about 16% possessed the faulty deiodinase gene. In other groups in other countries the percentage of people with this mutation could be higher or lower.
The traditional treatment of hypothyroidism is to administer t4 (Synthroid, Levothyroxine, Levoxyl etc.). It is the conventional wisdom that inactive t4 is converted in the body to the active thyroid hormone t3 by “peripheral conversion†in sufficient amounts to restore normal thyroid balance. The recent breakthrough discoveries described in the WATTS study reveal for the first time that individuals differ in how their bodies process (metabolize) thyroid hormone. While some may convert enough t4 to t3 in the cells of the body to restore normal function, due to genetic differences some individuals will not be able to make enough t3 leaving them with persistent hypothyroid symptoms. Since the problem is a deficiency of t3 within the cells of the body, measuring thyroid hormone levels in the blood cannot adequately reveal the problem. T4 replacement treatment alone can result in thyroid levels that appear normal on blood tests so doctors conclude that persistent hypothyroid symptoms are not related to the hormone therapy.
Based on my personal experience and the documented experience of many of the members of Metabolism.com it is clear that endocrinologists and other physicians are often reluctant to consider combination therapy for hypothyroidism, either by using Armour thyroid or adding t3 (Cytomel, liothyronine) to t4 only therapy. With this new research in hand, hypothyroid individuals and their advocates can finally state with confidence that: Yes! There is a firm scientific foundation for combination t4/t3 therapy and; No! We are not just chronic complainers or kooks. If I had hypothyroidism and was going to request a change in my thyroid treatment I would say something like, “Due to polymorphism of the deiodinase gene I probably possess a defective D2 deiodinase and therefore my peripheral conversion of t4 to t3 is impaired. I need t3 added to t4 to compensate for reduced intracellular t3 levels which cannot be detected on blood tests. Without t3 I continue to suffer with cellular hypothyroidism which is the likely cause of my persistent symptoms.â€
If you try this approach and your doctor looks bewildered hand them a copy of the study by Panicker et al in the Journal of Clinical Endocrinology and Metabolism, 2009, 94(5): 1623-1629.
Gary Pepper, M.D.
Editor-in-Chief, Metabolism.com
Notice: This article is for informational purposes only and does not substitute for the advice or treatment of your own physician. The disclaimer for all blogs at metabolism.com, applies.
Do you wonder if you need t3 (Cytomel, triiodothyronine, liothyronine) added to your thyroid hormone treatment to feel normal again? The answer could be in your genes.
Recent discoveries reviewed by Antonio C. Bianco, M.D., Ph.D. at the recent American Thyroid Association meeting, reveal how genetic differences influence the effectiveness of thyroid hormone replacement. Dr. Bianco’s lecture focused on studies pinpointing inborn differences in the way people metabolism thyroid hormone to explain why t3 treatment of hypothyroidism is probably required by some to restore normal functioning of their brain, muscle and heart.
The most frustrating problem for people with hypothyroidism is being unable to convince their doctor that treatment with Synthroid, Levoxyl or similar pure t4 product, isn’t working. Continued symptoms of fatigue, weakness, inability to concentrate or think clearly, and inability to lose weight despite really trying, result in tension between the doctor and the “complainer”. When assessing the adequacy of thyroid hormone replacement therapy most doctors rely on the blood tests known as the Thyroid Function Panel. Typically this includes a measurement of t4, t3, t3RU, and TSH. Some panels may also include free t4 or free t3 measurements. If the hormone levels on these tests are “within normal limits” the doctor will often insist that the treatment is a success but it is the patient who fails to recognize this. A minority of endocrinologists know many of these “failures” can be turned into success by the addition of t3, the less utilized but much more powerful form of thyroid hormone.
Most of the biological effects of thyroid hormone in the body are due to the action of t3. The most common forms of thyroid hormone replacement however, involve giving t4 in the form of Synthroid, Levoxyl, levothyroxine etc. The t3 required by our tissues is produced by specific enzymes which convert t4 to t3 in the cells of the liver, kidney, brain, muscle, heart etc. These converting enzymes are known as deiodinases and under normal conditions they are responsible for about 80% of the body’s t3. The process by which t3 is produced from t4 is known as peripheral conversion.
It has long been the contention of the leaders in thyroid disorders that based on their arithmetic, t4 replacement is sufficient to provide all the t3 the body needs via peripheral conversion and giving t3 supplementation doesn’t make good medical sense. Now, based on the new information provided by researchers like Dr. Bianco, the “arithmetic guys” will, in my opinion, need to revise their thinking finally allowing the way for acceptance of t3 replacement approaches.
I will continue the explanation of the new breakthrough in genetic control of thyroid hormone replacement treatment in Part 2 of this post.
The mission of the The Thyroid Project is to encourage sharing of information and experience between the public and the medical community about the treatment of hypothyroidism (low thyroid function). For at least the past few decades there is a growing awareness of “something missing†in the way suffers of hypothyroidism are treated for their disease.
Too many patients, as documented in an on-line study of 12,000 individuals conducted by the American Thyroid Association published in June 2018, (https://doi.org/10.1089/thy.2017.0681) , complain of persistent symptoms of hypothyroidism despite what their doctors believe is successful treatment with levothyroxine (brands include Synthroid, Unithroid, Tirosent, Levoxl). We believe something needs to be done to resolve this conflict between patients and their doctors.
By Gary M. Pepper, M.D. Ozempic, Rybelsus, Trulicity, Wegovy, Saxenda are the central players in the weight loss craze sweeping across the globe. Metabolisim.com has been monitoring this phenomenon from its beginnings in 2008 with its report “Lizard Spit Reduces Blood Sugar and Appetite”, regarding the first drug in this class, Byetta (exenatide). Caught In the middle of the current chaos are the medical experts who treat diabetes and have been prescribing these medications for more than a decade. Here is a brief commentary from one such board certified endocrinologist; “I started treating Type 2 diabetics with GLP-1 agonists more than 10 years ago. In some respects, these medications have revolutionized the treatment of diabetes by lowering blood sugar effectively and promoting weight loss at the same time, a unique combination of benefits. Not everyone benefits from these drugs to the same degree unfortunately, and I have seen lots of patients experience unacceptable side effects from them. Nothing though, has prepared me for what is happening now. Too often, I find myself confronting someone who expects me to prescribe one of these drugs just so they can lose weight. Sadly, one extreme example was someone who, despite battling a life threatening medical condition, was insistent on getting a prescription. At the same time my diabetic patients are scrambling to find a place to buy their medications if they can even afford it. It is disheartening, to say the least, and I dread the negative interactions with some of my patients I now face almost daily.”
Off- Label Use
The FDA is the U.S. government’s department tasked with evaluating and approving drugs for specific medical conditions. When a new medication is approved for treating a medical condition by the FDA the agency will, at the same time, set strict guidelines for exactly which patients may use the newly approved drug. When a medication is used “off-label” it means that these limitations are being overridden by the provider for a potential benefit which outweighs the drugs risks. It is a general misconception that off-label means illegal; it does not. This practice has been going on for ages and more than 20% of prescriptions in the United States are prescribed off-label. A common example is the use of beta-blockers (approved for heart problems) for the treatment of performance anxiety.
GLP-1 agonist drugs, as discussed recently by metabolism.com. were originally approved for the treatment of Type 2 diabetes in adults. In the past few years most of these same medications have gained unprecedented popularity for their “off-label” weight loss benefit. Of the 5 GLP-1 agents presently in U.S. pharmacies only Wegovy (semaglutide) and Saxenda (liraglutide) are FDA approved for treating obesity. Of these two, Wegovy is the newer and had been much more popular that its sister drug Saxenda, probably due to being dosed only once weekly compared to daily for Saxenda and less likely to cause side effects. Due to Wegovy’s soaring popularity, its manufacturer, Novo Nordisk, increased the price of Wegovy two times since its initial release.
by Gary M. Pepper, M.D. and Sam Jeans, MSc The global anti-obesity drug market, in 2021was valued at over $2 billion. Within one year this figure had skyrocketed to $8 billion and is expected to climb to nearly $ 20 billion by 2027. This astounding growth is a reflection of soaring obesity rates, and the arrival of a new class of weight loss medication fueling a craze both in the USA and across the world.
The FDA and global health regulators, until very recently, had maintained a very tight ship when it comes to treating obesity with medication, placing the emphasis on diet and exercise rather than weight loss drugs. Since the 80s, anti-obesity drugs continued to be controversial, and a more stringent FDA implemented ongoing safety trials along with other precautions. There is some speculation that a shift in attitude toward approval of weight loss medication by the FDA , is underway
Weight loss drug controversies are far from over and, in fact, may soon rival the amphetamine crisis of the 70’s. For that reason, metabolism.com has felt it important to provide our guide to weight loss drug issues, past and present.
Anti-Obesity Drugs Timeline
Prescription drugs for lifestyle diseases such as obesity were marketed heavily throughout the 1950s to the 1970s. Amphetamines entered the public domain after the Second World War where they were used extensively in the military.
In the 50s, walk-in clinics prescribed diet pills with other medications almost at random, with or without genuine concern for one’s weight. These brightly colored pills became known as “rainbow pills”.
In the 1960s and 1970s, the so-called “rainbow pill diet” of pills was finally coming to an end as the FDA began to systematically ban many of the drugs involved. A high-profile expose by investigative journalist Susanna Mcbee, published in Life magazine, brought attention to this new modern public health crisis.
The rainbow pill diet combined amphetamines, laxatives, thyroid hormones, and even diuretics to produce extreme weight loss, combined with benzodiazepines, barbiturates, and steroids to reduce side effects, and antidepressants to suppress medication-induced insomnia and anxiety.
In 1968, rainbow pills were linked to over 60 deaths, with numerous accounts of their devastating impact surfacing in the news and media. Within just two months, 48 million pills were seized and destroyed. Nevertheless, amphetamine-based diet pills remained extremely popular throughout the 1970s. In 1978, some 3.3 million prescriptions for amphetamines were written each year, with some 50 million pills a year ending up in the black market.
In 1979, the FDA banned amphetamines as a weight loss aid, but that is hardly the end of the USA’s love affair with obesity medication.
Here’s a brief timeline of recent anti-obesity drugs:
Lack of energy and inability to lose weight are constant challenges for many people and are every day complaints encountered in the doctor’s office. Almost anyone can find some relief from these problems by accessing the healing properties of physical activity. Mentioning to a patient the need for ‘more exercise’ often causes rolling of the eyes, sighing, shrugging, snorting or worse yet, the hundred-yard stare. We all know exercise is important but who has the energy for that? It seems like a vicious cycle. Surprisingly, when done correctly, exercise can improve energy with the additional advantage of promoting weight loss and restoring tone and stamina. It is helpful to remember that the human body was designed for a lot more physical activity and a lot less food than we are privileged to experience in present day life. It therefore takes will power and knowledge to maintain the environment required for optimal health. Here are eight steps to get in the swing of regular exercise. Some suggestions may surprise you.
