Tuesday, August 13, 2013

Thyroid Hormones and Heart Disease

"One of my recurring objects of thought has been the slowness with which raw knowledge is assimilated. For example, I have been thinking about Broda Barnes’s work on the prevention of heart disease with thyroid extract. He did solve much of ‘the riddle of heart attacks,’ but recent statements by the Heart Association show that the dominant forces in the health business haven’t learned anything at all from his work, which he began 50 years ago. His work is clearly presented, not hard to understand, and it is scientifically so sound that no one challenges it, at least not on the scientific level. It is ignored, rejected by people who choose not to be bothered to read it. How many people have died from heart disease, since his work first became available? (And how many more from cancer, tuberculosis, and other diseases he showed occur mainly among hypothyroid people?)"
- Raymond F. Peat

1. Introduction

This review addresses the hypothesis that thyroid insufficiency could be a significant cause of the heart disease and that the traditional thyroid medication (desiccated thyroid) could therefore be a logical strategy for an effective prophylaxis for heart disease. There is a considerable amount of studies carried out on this subject that aren’t very well-known despite their remarkable results.

In addition to describing these studies conducted mostly in the middle of the 20th century, some parts regarding diagnosis, causes, and treatment of hypothyroidism are included.

2. Regarding the current CVD treatments

In the last few decades, a large part of the discussion related to heart disease (CVD) has been about cholesterol levels. The modern theories of heart disease often focus on the effect of LDL cholesterol in the genesis of atheroma plaques (in the intima part of blood vessels).

This is also the reason why low-fat or low-saturated fat diets are recommended for the prevention of heart disease. Saturated fat is supposed to cause CVD by increasing the serum concentration of LDL cholesterol. It’s also the reason why a large amount of the western human population uses cholesterol-lowering drugs, statins.

These two methods, however, haven’t proved very effective. Especially, if we look at the recent meta-analyses compiling evidence from a large amount of fat-modification trials, they don’t support the view that saturated fat is an important cause of CVD. (Hooper 2011, Ramsden 2010, Skeaff&Miller 2009)

Statins, on the other hand, have proved effective. Meta-analysis published in 2012 revealed that in the context of secondary prevention, statins can decrease total mortality by 20 per cent in men, though no significant benefit was seen in women. Also, the Cochrane review published in 2011 showed that in primary prevention, statins can decrease total mortality by 16 per cent, and heart attacks by a few dozen per cent. (Gutierrez et al. 2012, Taylor et al. 2011)

These results are quite good, but since we want to maximize the effectiveness of medications and even statins do leave a majority of people vulnerable to CVD deaths, it's always good to think about alternative ways to minimize the harms of cardiovascular disease.

3. Desiccated thyroid and CVD, part I: William B. Kountz

In 1951, physician William B. Kountz published his monograph Thyroid function and its possible role in vascular degeneration, in which he introduced his 5-year study with 268 subjects.

As study subjects, Kountz had specifically chosen people with low basal metabolic rate (BMR; on average, 10 to 18 percent below normal). For the intervention groups he prescribed desiccated thyroid to raise their metabolic rate to the normal level. The control group did not get thyroid. Both groups got some B vitamins as well.

There were three intervention groups plus their corresponding control groups. Group 1 consisted of middle-aged businessmen, Group 2 consisted of middle-aged office workers, and Group 3 consisted of elderly infirmary patients.

The study results were promising. The rates of heart attacks were 85, 76 and 44 per cent lower in the intervention groups (group 1, 2 and 3). The reductions in mortality were similar, and are shown below.

The absolute values are shown here: Figure 6

4. Desiccated thyroid and CVD, part II: James C. Wren

Two decades after Kountz’s research, physician James Wren conducted two studies which gave additional support to Kountz’s results.

The first study, Thyroid function and coronary atherosclerosis, was published in 1968. During the two years, 74 CVD patients were given desiccated thyroid plus some vitamins. Forty-six controls were matched for the same number of intervention subjects.

The results were positive. The thyroid treatment decreased subjects’ pains, improved their ECGs and lowered their cholesterol levels 17 per cent on average. 95 per cent of the subjects reported subjective benefit from the treatment. The difference in the mortality rates between the intervention and control group was six-fold (2 vs 12).

The results of a second and a little big larger study, Symptomatic atherosclerosis: prevention or modification by treatment with desiccated thyroid were published 1971.

In this five-year study there were 347 CVD patients (1/3 of them were symptomatic), all of which were put on desiccated thyroid medication even though only 9 per cent of them had hypothyroidism based on the blood tests.

There was no control group, but during the five years of study there were half as many deaths as the statistics would have predicted for the people of the same age. When a rough adjustment for the risk factors (heart disease, hypertension etc) was made, it was clear that the subjects had a fortunate survival rate. Their mortality was only one fifth of the expected number (11 vs. 53).

Did they prevent ~40 unnecessary deaths in this study? (Wren 1971)

5. Desiccated thyroid and CVD, part III: Broda Barnes

Dr. Barnes

Physician Broda Otto Barnesdissertation, published in 1932, was related to the function of the thyroglobulin protein. In the beginning of his medical practice, he noticed that many of his patients had symptoms that were similar to mild hypothyroidism. After noticing this, he began prescribing desiccated thyroid to a large part of his patients.

Barnes didn’t diagnose hypothyroidism based on his patients’ blood tests or basal metabolism (BMR), but instead he claimed that basal temperature is a more accurate marker of thyroid hormone function and health. His essay on that subject, Basal temperature versus basal metabolism, was published in 1942 in The Journal of the American Medical Association. In that article, Barnes wrote that he told his patients to measure their axillary temperature immediately after waking up. Temperature lower than 36.5 celcius (97.8F) was an important indicator of hypothyroidism and thus, a need for a prescription of desiccated thyroid.

Thirty years later, in 1973, Barnes published some of his patient data in his article On the genesis of atherosclerosis. The occurrence of CVD in his 1500+ patients was 94% lower than Framingham statistics would have predicted. This is a remarkable result considering that Barnes didn’t advocate his patients to quit smoking or change their other habits.

"72 expected, 4 observed"

I think it’s wise to mention one of Barnes’ other papers too, Prophylaxis of ischaemic heart-disease by thyroid therapy (1959), published in Lancet. The paper shows that thyroid treatment lowers high cholesterol levels very reliably.

For his study, Barnes chose 80 persons who had high cholesterol (>200mg/dl). Usually the cholesterol levels fell to the range of 170-200mg/dl or 4.4-5.2 mmol/l after the patients had been on their thyroid medication for a sufficient duration. 

Even very high initial cholesterol levels could be lowered
 effectively with desiccated thyroid. (Barnes 1959)

6. Desiccated thyroid and CVD, part IV: Mark Starr, Lerman&White, Russek, Strisower, Moses&Danowski and Eaton

Physician Mark Starr (who has written a book Hypothyroidism Type 2: The Epidemic) has treated his patients according to Broda Barnes’ recommendations. In his book, he mentions that despite having treated over 1600 patients, only two have had a heart attack.

“I have treated over 1,600 patients during my 14 years of private practice and only two have had a heart attack while under my care.” - Mark Starr, MD

In 1946, Jacob Lerman and Paul D. White described how of 27 young CVD patients, 21 had BMR less than 10 per cent below normal. Desiccated thyroid raised their BMR and lowered their cholesterol levels. According to Lerman ja White, they couldn’t make any clear conclusions from their observations, but in all except two patients with angina pectoris a little amount of thyroid extract decreased or cured the pain. And the patients without previous angina pectoris symptoms didn’t suffer any adverse effects from thyroid extract either. (J Clin Invest 1946; 25:914)

In 1959, Henry I. Russek wrote in Circulation the following:
“To access the effects of thyroid therapy in patients with coronary artery disease, this hormone, or an identical placebo, was administered to 58 clinically proven cases of angina pectoris. All patients studied were determined to be euthyroid by appropriate tests (BMR, PBI, and cholesterol). [...]

Although all patients have been taking maximum doses [180mg] of thyroid extract for 6 to 15 months, no complications from therapy have been observed. Exercise-electrocardiographic tests have not demonstrated diminution in exercise tolerance and, in fact, have shown improved response in 6 patients. Forty-six patients reported subjective benefit as evidenced by an improved sense of well being, greater motivation, alertness and increased exercise tolerance. These observations are not only contrary to the traditional view that thyroid extract is dangerous in the presence of coronary heart disease, but also establish a rationale for its use in selected euthyroid patients with this disorder.” (Circulation 20: 761, 1959)

In 1957, Strisower et. reported about a two-year-study, in which subjects were given desiccated thyroid (up to 325mg) to lower their cholesterol levels (baseline 216mg/dl). The medication was most useful for those who had the highest initial cholesterol levels. Based on this finding, the group summarized: “The large falls in atherogenic-index values for patients with high initial atherogenic index values suggest that dried thyroid is worthy of consideration as a prophylactic agent against coronary heart-disease.” (Strisower et al. 1957)

(Strisower et al. 1957)

In 1958, Moses ja Danowski wrote about their 10-month trial in which desiccated thyroid (150-180mg) was given for elderly people institutionalized for custodial care. The report says:
“While maintaining a normal protein bound iodine level, statistically significant decreases in total cholesterol and [beta]-lipoprotein cholesterol were found in the great majority of subjects. [...] the data indicate that even in subjects euthyroid by the usual indices, a thyroid deficit exerting considerable effect on the cholesterol-lipoprotein partition may be present.” (Circulation 1958; 18: 761)

In 1954, C.D. Eaton, a physician from Detroit published an scientific paper about the remarkably high incidence of hypothyroid symptoms in diabetics. Eaton noted that the patients often responded positively to desiccated thyroid and that they also had less of the vascular complications associated with diabetes. (Eaton 1954)

7. Other human and animal studies regarding the link between CVD and thyroid hormones

Now we have gone through the clinical data regarding prevention of heart disease with thyroid. Next, we are going to look at some indirect evidence from other kinds of studies.

1) Clinical hypothyroidism causes heart disease, and thyroxine prevents this effect

In clinical hypothyroidism, LDL levels do increase and LDL also oxidizes much faster than usually (lag time 29min), but thyroxine (T4) restores LDL levels and oxidation rate to normal (lag time 77min). (Diekman et al. 1998) This phenomena is at least partially related to the physiological fact that triiodothyronine (T3) increases hepatic LDL receptor activity, which causes LDL to stay less time in the blood because of the increased uptake*. Serum free T3 is also inversely associated with heart disease. (Lopez et al. 2007, Bakker et al. 1998, Scarabottolo et al. 1986, Ertas et al. 2012)

Clinically and subclinically hypothyroid people have increased intima-media thickness (IMT), and thyroxine resolves this problem. (Nagasaki et al. 2003, Duman et al. 2007, Monzani et al. 2004, Adrees et al. 2009, Cakal et al. 2009)

Treating subclinical hypothyroidism with thyroxine reduced the total mortality of patients (age less than 70) 64% compared to the control group. The reduction in the total mortality was mainly due to reduced cardiovascular and cancer mortality. (Razvi et al. 2012)

On one study, subclinical hypothyroidism was quite strongly correlated with an increased risk of myocardial infarction in elderly women (OR 2.3). In other studies the link seems to be a little bit weaker. (Hak et al. 2000, Rodondi et al. 2010)

Clinical (and some studies, subclinical) hypothyroidism is associated with increased levels of homocysteine and Lp(a) and increased plasma viscosity. Increased levels of fibrinogen have also been found in subclinical hypothyroidism, but T4 didn’t lower it. (Kutluturk et al. 2013, Adrees et al. 2009, Caraccio et al. 2002, Hussein et al. 1999, Catargi et al. 1999, Erdem et al. 2008, Cakal et al. 2007).

2) Very often, people with heart disease have also thyroid (gland) problems

István Gáspár studied patients who died from atherosclerosis (n=55). Seventy-one per cent of them had abnormally small thyroid glands. Twenty-four patients also had signs of thyroid inflammation, fibrosis and other kinds of thyroid degeneration. (Gaspar 1968)

Gordon J. Azar noticed that in his group of 73 heart attack survivors, approximately half of the subjects had marginal or submarginal thyroid function according to the protein-bound iodine PBI test. (Azar 1965)

Unto Uotila’s group, here in Finland in the ’50s, noticed that 58% of men and 50% of women dying of CVD had goiter, while amongst people dying because of other cause, 28% of men and 22% of women had goiter. (Uotila et al. 1958)

Dean and Fowler found that women with coronary artery disease have exaggerated TSH response to TRH-stimulation. (Dean&Fowler 1985)

3) Higher TSH levels are correlated with raised cholesterol and heart disease even within normal range

The HUNT study included more than 25,000 Norwegians. The women with TSH in the range of 1.5-2.4, had 41 per cent higher CVD mortality the women whose TSH was in the range of 0.5-1.4. TSH of 2.5-3.5 was correlated with 69 per cent increased heart mortality. For men, the trend was not statistically significant. (Asvold et al. 2008)

It has also been shown that higher TSH is associated with less favourable serum lipids and higher blood pressure even in the normal TSH range. (Asvold et al. 2007, Boggio et al. 2014) We also know from the 30′s that cholesterol levels higher than 7mmol/L is strongly correlated with hypothyroidism, and usually thyroid extract lowers the cholesterol levels sufficiently. (Barnes 1959, Hurxthal 1934, Gildea et al. 1939, Michalopoulou et al. 1998 etc…)

The cholesterol levels increase to the left, correlating with 
hypothyroid symptoms (Clinical Myxedema) (Hurxthal, 1934)

In hypothyroid patients, the cholesterol levels go down
when basal metabolic rate goes up.(Gildea, 1939)

4) Lower free T4, even within reference ranges, is associated with poorer cardiovascular health

It has been noted in a couple of studies that even in clinically euthyroid people, lower FT4 levels are correlated with increased intima-media thickness, calcium scores and risk of hypertension. (Kim et al. 2012a, 2012b, Takamura et al. 2009, Dullaart et al. 2007, Gumieniak et al. 2004)

5) The herbivore cholesterol feeding studies

Pathologist Nikolai Anichkov is considered a very important person in the history of cholesterol theory. He showed that “without cholesterol there’s no atherosclerosis.” In 1912, he fed rabbits with cholesterol in vegetable oil medium, and because of this, rabbits developed atherosclerosis. In 1933 Anichkow stated that this rabbits’ atherosclerosis is similar to human atherosclerosis.

In the same year, Kenneth B. Turner and I.B. Friedland published their own studies on the same topic. Turner noticed that cholesterol feeding raised rabbits’ cholesterol levels to very high levels (13.45mmol/L), and feeding thyroid extract prevented this (4.60mmol/L). Iodine had a similar effect, but thyroxine prevented the rise in cholesterol levels only slightly. Friedland noticed the same thing: thyroid extract prevented cholesterol-induced rise in the serum cholesterol and atherosclerosis. (Turner 1933, Friedland 1933, Hoption Cann 2006)

In the beginning of ’60s, Bernick et al. studied the differences between cholesterol metabolisms of herbivores compared to omnivores. They noticed that the thyroid glands of omnivores expanded (hyperplasia) after cholesterol feeding, possibly due to increased thyroid hormone requirements in liver.** The thyroid glands of the herbivores became smaller (hypoplasia), and they developed atherosclerotic lesions. (Bernick et al. 1962)

In 1964, L.V. Malysheva noticed that feeding rabbits with cholesterol lowered their metabolic rate even in the important tissues such as liver and brain, and in the long term during the development of atherosclerosis this effect became even larger. The magnitude of this decrease in metabolism has been compared to the post-thyroidectomy decrease in metabolism. (Malysheva 1964, Duntas&Wartofsky 2007)

6) Hypertension

Hypertension is an important risk factor of CVD. Desiccated thyroid seems to be a quite potent medication for hypertension.

In 1952, Pericles Menof published his treatment results based on the data of 334 patients in South African Medical Journal. He had begun to treat essential hypertension with sole thyroid. Based on his 4-year experience, he reported that 69 per cent of his hypertensive patients benefited from the treatment, and that the lack of results in some patients can be explained by their renal hypertension which couldn’t be cured by thyroid. (Menof 1952)

Fifteen years later Menof had the same thoughts regarding hypertension and thyroid, and in the conclusions of his paper he stated that “relative thyroid insufficiency is the basic factor in the causation of essential hypertension”. (Menof 1967) Later, he also reported the cholesterol-lowering effect of thyroid extract based on his experience with over 100 patients. He also thought that benefits of thyroid hormones might be related to their antagonistic effect to hyperlipidemic effects of adrenaline and hypertensive effects of noradrenaline. (Menof 1973)

"If we are prepared to accept this view, then we must also accept the
 conclusion that in the timeous use of the thyroid hormone we have
 the solution to the Western world's most pressing medical problem
 - the prevention and control of atherosclerotic arterial disease."

- Pericles Menof (1973)

In 1971, Broda Barnes wrote in the Federation Proceedings, that during 20+ years and 1000+ patients, only twelve patients developed hypertension and of 127 hypertensive patients, 102 benefited from thyroid. He also stated that the reductions in blood pressure happen quite slowly and might take up to three years. (Fed Proc. Vol 31, Issue 2, s. A214)

Moreover, Fang and Reyes have also studied the usage of desiccated thyroid in the treatment of hypertension, but I haven’t managed to obtain the full text. According to a secondary source, “they were the first to report a coincident fall in the pulse rate in the majority of the cases successfully treated (68%).” (Fang&Reyes 1953, Menof 1967)

Fang also reported beneficial effects on total cholesterol: "Fourteen cases with hypercholesterolemia of various etiologies were treated with thyroid extract at the dosage of 2-6 grains daily for periods varying from 4 weeks to 16 months. Lowering of the serum cholesterol was noted in all cases. Elevation of the same was noted after the suspension of the therapy. There were no side effects noted". (Fang&Serrano 1960)

7) Thyroid hormone analogs

"Today, statins are used as the first treatment choice to lower plasma total and LDL cholesterol levels, but high-risk patients still experience further events of CHD. Thus, there is a need for novel pharmacological strategies. Preclinical and clinical studies using selective [thyroid hormone] analogs are promising and suggest TRβ1 as a potential target for treatment of dyslipidemia."

Various molecules that have similar properties to thyroid hormones are a relatively hot topic in the medical research, and there have been studies especially for treating high cholesterol levels and heart failure (Baxter&Webb 2009, Cioffi et al. 2010)

Thyroid hormone analogue eprotirome (KB2115) has been shown to decrease and improve cholesterol levels very effectivele. Some animal studies have shown it to cause cartilage damage, so the research regarding this drug was temporarily stopped. However, a more recent 3-month human study showed a beneficial effect on cholesterol levels with no evidence of adverse effects. (Berkenstam et al. 2008, Ladenson et al. 2010, Lin et al. 2012, Angelin et al. 2015)

Another thyroid analogue, sobetirome (GC-1), is provisionally a promising drug, but it hasn’t been tested on humans yet. (Grover et al. 2004, Baxter et al. 2004, Johansson et al. 2005, Venditti et al. 2009, Tancevski et al. 2011, Lin et al. 2012, Mitchell 2013)

Furthermore, neither of thyroid analogues MB07811 and KB-141 have been tested on humans, but in short-term animal studies, the results have been encouraging. (Erion et al. 2007, Cable et al. 2009, Ito et al. 2009 and Grover et al. 2005, Bryzgalova et al. 2008)

A very new drug, MGL-3196, has been Phase I tested with humans in a 2-week study, and the results showed a very beneficial effect on the cholesterol levels. (Taub et al. 2013)

8. Regarding the diagnostics: Is the incidence of hypothyroidism underestimated?

One important thing to remember now is that none of the physicians who saw reduced heart disease in their patients using desiccated thyroid (Kountz, Wren, Barnes, Starr) diagnosed their patients according to the typical guidelines, but instead they based their diagnoses on other markers such as basal metabolic rate, basal metabolism and heart disease.

Here in Finland, it’s generally accepted that no more than half a million Finns suffer from thyroid symptoms. That would equal nine percent of the Finnish population.

However, some doctors such as Broda Barnes have stated that there are probably a lot more people who would benefit from thyroid treatment. According to Barnes, in 1976 approximately 40% of Americans had symptoms of hypothyroidism. In 1989, Jacques Hertoghe estimated that in Belgium, up to 80 per cent of the population suffered from hypothyroid symptoms.

In common language, “hypothyroidism” refers mainly to primary hypothyroidism, in which the thyroid gland doesn’t produce thyroid hormones normally, and because of that TSH levels are high and T4 and/or T3 levels are low. The most common reason for primary hypothyroidism is Hashimoto’s thyroiditis. It's quite common especially in women.

However, in addition to actual hypothyroidism, some groups seem to suffer from a low metabolism and various symptoms which seem to be alleviated or cured by thyroid extract.

Two examples of this are polycystic ovary syndrome (PCOS) and fibromyalgia. In one study it was found that women with PCOS had remarkably low basal metabolic rates, yet in another study it was shown that the majority of these women had normal serum levels of thyroid hormones. In one study, they also got impressive results with thyroxine: "Of the 22 patients with mild hypothyroidism, 10 had polycystic ovaries before thyroxine therapy. In all these patients, the polycystic appearance of the ovaries regressed after euthyroidism was achieved for at least 3 months."  (Georgopoulos et al. 2009, Benetti-Pinto et al. 2013, Muderris et al. 2011)

Fibromyalgia, as a disease, shares many similarities with hypothyroidism. In fibromyalgia, both metabolic rate and basal temperature are reduced as in hypothyroidism. Lowe has reported that even “euthyroid” people (with normal serum levels of thyroid hormones) get good results with T3 medication. According to Broda Barnes, more common ailments such as migraine, recurring infections, acne, menstrual irregularities, and mental disturbances often go hand in hand with low basal metabolic rate and are often cured when the patient’s metabolic rate goes up with thyroid medication. (Lowe&Yellin 2008, Lowe et al. 2006, Barnes 1947, Barnes 1949, Foster 1939, Litzenberg 1937 etc…)

I think that some mechanism other than low thyroid hormone concentration in serum could cause hypothyroid symptoms. The mechanism is probably related to function of receptors and target tissues. Maybe many people have underlying metabolic problems caused by deficiencies, infections or other things, which inhibit thyroid hormone function and aerobic metabolism on the tissue level.

It has been observed that people with similar serum levels of thyroid hormones can have very different thyroid hormone levels in tissues. (Peeters 2005, check Fig 1 and Fig 2) Deiodinases can activate or inactivate thyroid hormones inside the cell, and therefore serum levels of thyroid hormones “do not faithfully reflect thyroid hormone signaling in cells.” (Bianco 2013, Gereben et al. 2008) Lowered thyroid hormone activity within the cell could be the reason why some people need TSH-suppressive doses of thyroid hormones in order to feel healthy. (Fraser et al. 1986)

9. Various thyroid medications (T4, T3, T4+T3 and desiccated thyroid)

In the above studies examining the possibility prophylaxis of heart disease with thyroid hormone, natural desiccated thyroid was used instead of synthetic hormones.

As a medication, NDT became popular in the ’30s, but after the sixties the synthetic hormones have replaced them almost completely. So nowadays most hypothyroid patients receive T4 monotherapy. Sometimes but still quite rarely patients are treated by synthetic combination therapy (T4+T3), sole triiodothyronine (T3) or desiccated thyroid (NDT; Armour Thyroid being the most popular trademark).

Can it be said that one of these medications is better than the others?

The question isn’t an easy one. In some studies combination therapy or NDT has brought clear benefits to the patients(+), but in many studies no benefit was found. However, in several studies the patients preferred the combination therapy to T4 therapy(#), even if there were no differences in symptom scores. In some studies, the addition of T3 was associated with the improvement of cholesterol levels(&). In one old study, the combination therapy led to worse results than T4 therapy(-). (Nygaard et al. 2009(+,#), Bunevicius et al. 1999(+,#), Bunevicius et al. 2002(+,#), Cooke et al. 1992(+), Solter&Solter 2012, Fadeyev et al. 2010(&), Celi et al. 2011(&), Hoang et al. 2013(#), Appelhof et al. 2005(#,&), Escobar-Morreale et al. 2005(#), Rodriguez et al. 2005(#), Slawik et al. 2007(+), Clyde et al. 2003, Walsh et al. 2003, Sawka et al. 2003, Regalbuto et al. 2007, Valizadeh et al. 2009, Smith et al. 1970(-), Pepper&Casanova-Romero 2014(#))

On the other hand, Baisier et al. compared T4 to NDT treatment and in their study, the desiccated thyroid seemed to outdo the synthetic treatment in every possible way. The authors also state that urine free T3 is a more worthy marker than the typical blood tests. NDT-treated patients had much higher urine free T3 than those who received synthetic treatment. (Baisier et al. 2001, pdf)

In this study, patients felt much better on desiccated
thyroid medication (Baisier 2001)

In a way it’s quite contradictory that in some studies, combination treatment is associated with better results while in other studies, no difference has been noted. Lowe (2006) has stated that the differing results are not due to chance, but because of differing methods between studies: combination treatments (incl. T3) could often be more effective than T4 treatment, but the effectiveness can’t usually be seen in typical replacement therapy in which the main goal is to normalize TSH. Instead, the dose should be adjusted by other markers such as symptoms or basal metabolic rate — in the most successful studies the results seem to have been achieved by such treatments. When the dose of thyroid hormone replacement is adjusted according to symptoms, sometimes sufficient treatment will suppress thyrotropin (TSH) to very low or even undetectable levels. (Lowe 2006, Fraser et al. 1986Cooper-Kazaz et al. 2007)

One reason why TSH-suppressive doses appear helpful, could be the fact that TSH by itself seems to be able to cause inflammation. The progression of Hashimoto's thyroiditis to hypothyroidism can sometimes be prevented with thyroxine, and one explanation for this could be the fact that the thyroid-stimulating effect of TSH might also cause or aggravate inflammation of the tissue. (Dardano 2007, Gavin et al. 2008, Padberg et al. 2001Takasu et al. 1992, Aksoy et al. 2005, Romaldini et al. 1996, Schumm-Draeger et al. 1996, Reinhardt et al. 1988, Braga et al. 2001, Gagnon et al. 2014Ericson et al. 1972)

There are a couple of differences between NDT and levothyroxine (synthetic T4) that aren’t discussed very often. In desiccated thyroid, the hormones are not free. Instead, they seem to be bound to thyroglobulin. Desiccated thyroid also seems to contain some other biologically active molecules such as T2 and calcitonin, both of which seem to have some potentially useful effects on animals. (Moreno et al. 2011, Mollica et al. 2009, Lombardi et al. 2009, Lanni et al. 2005, Lanni et al. 1998, Lanni et al. 1992 & Feigh et al. 2013, Robert et al. 1982)

Some studies have also been published on T3 monotherapy. Lowe reported that supraphysiological doses of T3 is an effective and safe treatment for fibromyalgia, even in euthyroid subjects. Celi et al. have reported that using T3 treatment for hypothyroidism, instead of T4, improves the body weight and cholesterol levels of the subjects. In some studies, T3 monotherapy has been useful for asthma, depression, and some types of bipolar disorder. However, many studies have also been unable to demonstrate any benefit for depression. (Lowe et al. 1996, Lowe et al. 1997, Lowe et al. 1998, Celi et al. 2011, adbel Khalek et al. 1991, Kelly&Lieberman 2009, Posternak et al. 2008, Iosifescu et al. 2005, Goodwin et al. 1982, Cooper-Kazaz et al. 2007)

In one large study with approximately one thousand subjects, dextro form of thyroxine (T4) was tried for atherosclerosis prophylaxis. However, the medication increased the total mortality a little bit. Nowadays, levothyroxine has completely replaced this less potent form of T4. (The Coronary Drug Project 1972, Barnes 1972)

There is also a huge amount of discussion about various types of thyroid therapy on the Internet (social media). I’m quite impressed about the numerous anecdotes of better results with NDT (or combination) therapy compared to T4 monotherapy. Many of these patients also report that their medication suppresses their TSH to about zero.

10. Possible causes of thyroid deficiency / lowered metabolic rate

The function of thyroid hormones is related to a large amount of metabolic processes, so it wouldn’t be very illogical to think that in some people, the inadequate metabolic rate (or thyroid function) could be related to their diet or lifestyle. Below I demonstrate some of the possible associations between diet, lifestyle, thyroid hormone function and CVD.

Nutritional deficiencies - Iodine deficiency is obviously the most well-known cause of hypothyroidism and goiter. Here in Finland, a large percentage of the population suffered from iodine deficiency goiter in the ’50s. However, salt and some other foods have been fortified with iodine since those times and therefore the deficiency is quite rare nowadays. (Lamberg 1986, Lamberg 2003)

Selenium is another trace mineral which is closely related to the thyroid function. In cholesterol-fed rabbits, the combination of selenium and vitamin E gives better protection from atherosclerosis than vitamin E alone. (Schwenke&Behr 1998) In Finland, soils were quite depleted of selenium until the beginning of 1980s. (Arthur 2003, Hoption Cann 2006)

I have been thinking that the additions of iodine and selenium to the Finnish food supply might have been one of the main contributors to the decline in coronary heart disease during the North Karelia project. The common view is that the project decreased CVD mortality by advocating people to eat less saturated fat (SFA) and to start exercising.

However, I think it’s quite probable that decreased SFA intake didn’t affect the mortality nearly as much as the changes in iodine and selenium consumption. Paavo Roine’s research group stated in 1958, that while there was higher CVD mortality in the eastern Finland, North Karelia in particular, fat consumption didn’t differ in the east, compared to the western Finland. However, iodine intake was a little bit lower in the eastern Fnland.*** So maybe we shouldn’t blame fat, but iodine deficiency instead. (Roine et al. 1958)

Another mineral related to thyroid hormone function and atherosclerosis is copper. Copper deficiency seems to cause cardiovascular disease and low dietary intake correlates with metabolic syndrome, which again is negatively correlated with metabolic rate and thyroid hormone levels (even in euthyroid subjects). Copper and zinc can attenuate the damage that cholesterol feeding causes to rabbits. (Shab-Bidar et al. 2013, Oliver 1975, Alissa et al. 2004, Roos et al. 2007)

Low intake of zinc tends to decrease basal metabolic rate. (Wada&King 1986)

Iron deficiency can also be a problem for some people, but on the other hand, excessive iron could also be a problem, as can be seen from the people with genes causing haemochromatosis (iron overload). (Dillman et al. 1980, Verdon et al. 2003, Edwards et al. 1983)

Obviously, there are plenty of associations between nutrients and thyroid function.

Stress - Those who have read Robert Sapolsky’s popular book Why Zebras Don’t Get Ulcers or any other similar work, are aware of the fact that chronic stress can make one more susceptible to a large amount of diseases. A popular health-blogger, Chris Kresser, has written about some mechanisms of stress-induced hypothyroid symptoms.

Endotoxemia, infections, metabolic syndrome and inflammation - When the lipopolysaccharides (LPS) of gram-negative gut bacteria end up in your bloodstream, the situation/condition is called “endotoxemia.” The most well-known problems caused by endotoxemia are sepsis and liver cirrhosis, but Robert McLeod has written an interesting blog post about how endotoxemia can also disturb the function of thyroid hormones, leading to the decrease of T3 levels and increase of rT3 levels. In rat studies, thyroid hormones protect from the harms of endotoxemia/sepsis. (van der Poll et al. 1999, Yildizdas et al. 2004, Inan et al. 2003)

Endotoxemia does also correlate with atherosclerosis. Inflammatory bowel disease (IBD) is also correlated with CVD, and this association can possibly be explained by the increased endotoxin levels associated with IBD. (Wiedermann et al. 1999, Yarur et al. 2011, Gardiner et al. 1995)

Lately, at least here in Finland, saturated fats have been blamed for TLR-4 activation (leading to inflammation), which seems to be caused by the digestion of fats, in which chylomicrons are featured, leading to postprandial endotoxemia. Clinical data seems to present saturated fats as quite harmless, but if there is some harm involved, endotoxemia could be one possible mechanism. However, quite paradoxically, numerous rodent studies have been conducted in which saturated fats of medium chain length seemed to protect animals from liver damage caused by endotoxemia and lipid peroxidation.**** (Nanji et al. 1997, Nanji et al. 2001, Nanji et al. 1989, Kirpich et al. 2012, Kirpich et al. 2013, You et al. 2005, Li et al. 2013, Ronis et al. 2004, Romestaing et al. 2007)

The composition of a meal might also affect whether the dietary fat causes TLR-4 activation. In one study, orange juice prevented the endotoxin-related inflammation caused by a high-fat meal. (Ghanim et al. 2010)

Fructose is another theoretical cause of endotoxemia. However, high amounts of pure fructose seems to be the real problem, not the moderate amounts of sucrose or fruits. As mentioned above, some forms of fruit (orange juice) might even be able to prevent endotoxemia. Bacterial overgrowth and increased intestinal permeability associated with fructose maldigestion is probably the mechanism for how excess fructose could cause endotoxemia in some people. (Stanhope et al. 2009, Kavanagh et al. 2013, Bergheim et al. 2008, Spruss et al. 2012, Yilmaz 2012, Chesta et al. 1991, Shanab et al. 2011, Miele et al. 2009, Gibson et al. 2007)

Some dietary factors such as dietary antioxidants, choline and glycine, can protect from endotoxemia. Choline can be obtained from liver, egg yolks, milk and meat while bones, cartilage and head cheese are good sources of glycine. Higher consumption of coffee is inversely correlated with liver cirrhosis, but it’s not known whether coffee prevents endotoxemia. (Rivera et al. 1998, Yilmaz et al. 2005, Ilcol et al. 2009, Ilcol et al. 2005, Tvarijonaviciute et al. 2012, Eastin et al. 1997 & Zhong et al. 2003, Yin et al. 1998, Ikejima et al. 1996, Xu et al. 2008, Wang et al. 2013 & Gallus et al. 2002, Klatsky et al. 2006)

There seem to be quite strong correlations between antibodies to certain pathogens (C. pneumoniae, Epstein-Barr virus, herpes simplex virus 2…) and atherosclerosis. (Espinola-Klein et al. 2002, Rupprecht et al. 2001, Taylor-Robinson&Thomas 2000)

Uncontrolled diabetes seems to be associated with significantly decreased T4->T3 conversion in liver, but insulin therapy seems to improve or normalize it. (Islam et al. 2008, Pittman et al. 1979, Saunders et al. 1978)

Many cytokines, protein complexes and other molecules related to inflammation, metabolic syndrome and stress can also have a negative impact on thyroid hormone levels (TNF, IL-1, IL-2, IL-6, IFN, interferon-gamma, cortisol). N-acetyl-cysteine (NAC) might prevent some of IL-6 induced harms, possibly by restoring glutathione levels. (Bartalena et al. 1998 (pdf)Westgren et al. 1977, Stouthard et al. 1994, Corssmit et al. 1995, Nagaya et al. 2000, van der Poll et al. 1990, Kung et al. 1992, Torpy et al. 1998, Bartalena et al. 1994, Abo-Zenah et al. 2008Boelen et al. 1993, Feelders et al. 1999 & Wajner et al. 2011)

Deficiency of red light and near-infrared radiation - I have written about the fact that red light and near-infrared radiation increase the tissue metabolism and decrease inflammatory cytokines in blood, by activating the mitochondrial enzyme cytochrome c oxidase.

It has been demonstrated in a vast amount of clinical human studies that near-infrared light is a very powerful treatment to various kinds of diseases. Excellent results have been achieved in hypothyroidism, fibromyalgia, osteoarthritis, macular degeneration and many other ailments. In two studies, almost 50% of hypothyroid patients did not require any thyroid medication after the treatment period. (Höfling et al. 2010, Höfling et al. 2013) Moreover, in a Russian study, the diabetic patients' total cholesterol was reduced from 7.98 to 5.31 in one month. (Kovalyova 2002) In cholesterol-fed rabbits, polarized light provides much a stronger protection from atherosclerosis than a statin drug. (Park et al. 2012)

Because higher exposure to near-infrared light seems to be beneficial to health, we can assume that a large percentage of population is getting too little of it. Some of the best sources of near-infrared radiation are sunlight, incandescent lamps, heat lamps and low-level laser therapy (LLLT), which is the most common treatment used in the studies.

11. Other potential benefits of desiccated thyroid therapy

In 1976, Broda Barnes published his book Hypothyroidism: The Unsuspected Illness. In the book he claims that there are numerous diseases which often can be cured or relieved with desiccated thyroid. The list includes health problems such as fatigue, migraine, mental health issues, frequent respiratory infections, menstrual irregularities, hypoglycemia, acne, and the vasculary complications of diabetes. Check the Appendix I for some studies about these ailments.

12. Conclusions

Desiccated thyroid, as a medication, has been studied a few times for prophylaxis of heart disease on clinically euthyroid (normal hormone levels) people. Without exception, the results have been very favourable: In the studies, the cardiovascular mortality in thyroid-treated patients has been less than a fourth of normal. The best effect was seen in people with no background of heart disease.

These studies also raise some questions concerning the diagnosis and treatment of hypothyroidism. Modern blood tests seem to leave a significant amount of people with hypothyroid symptoms undiagnosed, so maybe some other tests such as basal temperature, symptoms, basal metabolic rate and total cholesterol, could be useful in the diagnosis of thyroid hormone insufficiency. We should also consider that desiccated thyroid could be a more useful medication than thyroxine monotherapy, and that sometimes the optimal dosage of thyroid hormones will suppress TSH below the “normal” range.

The medical experts do not usually discuss the studies I’ve been talking about here. One plausible reason could be the fact that these studies do not follow the current RCT gold standard. On the other hand, lack of adequate data doesn’t imply lack of efficacy, and we are faced with the problem that to this date the clinical data on this subject seems to point to the direction that desiccated thyroid could be a very valuable tool in the prevention of the heart disease.

Scroll down past the endnotes to comment.


* Oxidized LDL (ox-LDL) seems to be an especially good marker for CVD, and better than the traditional markers such as age, total cholesterol HDL, blood pressure, diabetes and smoking. This seems to be quite logical, because immune cells degrade specifically ox-LDL, not unoxidized LDL. (Holvoet et al. 2011, Meisinger et al. 2005, Chris Masterjohn’s presentation, Chris Masterjohn’s cholesterol article, Sata&Walsh 1998, Henriksen et al. 1983, Steinbrecher et al. 1984, Watson et al. 1997, Nagy et al. 1998)

** I’ve been thinking whether this fact, combined with Eaton’s observation of diabetics’ hypothyroid symptoms and Islam et al. observation of lowered free T3 in diabetics, could explain why in some studies egg consumption is correlated with heart disease in diabetic subjects but not in non-diabetic subjects. (Rong et al. 2013, Islam et al. 2008)

*** The absolute difference was just 11-16µg depending on the time of the year, but even these minor amounts might have physiological significance because the total intake of iodine by Finns was as little as 51-71µg per day.

**** Even though dietary polyunsaturated fats (PUFA) can decrease the levels of LDL cholesterol, some of those fats seem to also increase the oxidation of LDL. Vitamin E and some phenolic compounds in the fat can reduce or prevent this increase. (Mata et al. 1996, Mata et al. 1997, Schwab et al. 1998, Palomäki et al. 2010, Kratz et al. 2002, Cicerale et al. 2010)

Appendix I: Extra citations from articles related to thyroid function and/or heart disease

1916: Bailey CH: Atheroma and other lesions produced in rabbits by cholesterol feeding. “Enlargement of the adrenals has been noted by several of the previously mentioned investigators and also by Rothschild (25), who reports experiments on the relationship of the adrenals to cholesterol metabolism and hypercholesterinemia. Enlargement of the adrenals appears to be a consistent finding, having been present in all rabbits except Nos. 2 and 3. In Rabbits 5 and 14 these organs were about four times the normal size.”

1929: Swaim LT: Chronic arthritis: Further metabolism studies “In 200 cases of chronic arthritis there was an abnormal metabolic rate in 39 per cent; 20 per cent were minus and 19 per cent plus. [...] An interesting drop in metabolic rate was noted in some cases after the administration of thyroid extract, with an improvement in the stability and regularity of the graphic metabolic chart.”

1935: Turner&Bidwell: Further observations on the blood cholesterol of rabbits in relation to atherosclerosis. “In thyroidectomized rabbits fed cholesterol and potassium iodide, both thyroid and thyroxin delayed but did not prevent a rise in blood cholesterol. Even with the hypercholesterolemia in these animals, however, the incidence of atherosclerosis was low.” “Page and Bernhard (4) also found that rabbits fed cholesterol and an organic iodide developed an average plasma cholesterol higher than those fed cholesterol alone. The animals given iodide, however, were largely protected from atherosclerosis”

1937: Litzenberg JC: The endocrines in relation to sterility and abortion “Since 1922 I have studied the relation of the basal metabolic rate to sterility, abortions and menstrual disturbances. In our first small series of sixty-nine consecutive women, in whom no other evidence of myxedema was present, 50 per cent had a low basal rate; adding those who had conceived but aborted, the figure was 56 per cent. Carefully supervised thyroid medication resulted in 33.3 per cent conception, 14 per cent of whom aborted. [...] Haines and Mussey of the Mayo Clinic confirmed our thyroid treatment of functional menstrual disturbances, saying: “Because of a desire to determine the effectiveness of thyroid medication alone, in the treatment of certain menstrual disturbances, no patient received any other treatment. All were definitely improved; amenorrhea, 72 per cent; oligomenorrhea, 55 per cent; menorrhagia, 73 per cent, and general health, 75 per cent.”"

1939: Foster&Thornton: Thyroid in the treatment of menstrual irregularities “Fifty patients with ages ranging from 16 to 34 years were seen because of dysmenorrhea, oligomenorrhea, amonerrhea, metrorrhagia and menorrhagia. All were apparently healthy individuals with normal pelvic findings. These patients had B.M.R. ranging from -1 to -33 with an average of -15. All were treated with desiccated thyroid. Of 25 cases of dysmenorrhea 17 had complete relief, 5 partial, and 3 no relief. Of 17 individuals with an oligomenorrhea all had complete relief. Of 4 patients with amenorrhea lasting from 8 months to 4 years only one had relief of her symptoms. Among 13 patients with metrorrhagia 12 had complete relief and of 7 with a menorrhagia 6 had complete relief.”

1939: Wharton GK: Unrecognized hypothyroidism “Many patients who could be helped by thyroid therapy are not recognized as hypothyroid. Standard textbooks subdivide hypothyroidism into myxcedema and cretinism, and refer to the basal metabolic rate as the significant diagnostic criterion. However, there are other important manifestations of hypothyroidism and methods of investigation based upon recent advances in the knowledge of the physiology of this gland. Endocrine factors are important in migraine, arthritis, acne vulgaris, hypertension, fatigue, growth and sexual disturbances, as these cases show.”

1942: Barnes BO: Basal temperature versus basal metabolism. “The blood cholesterol has been extensively used by some investigators but has been found useless in the present study. Since most of the present observations were carried out on college students, the failure of a correlation between metabolic rate and cholesterol content of the blood may be due to the age of the patient. Further work would be necessary to prove this point. The pulse rate has been suggested by some authors, but in college students many rapid pulses have slowed down on thyroid therapy.”

“The therapeutic results would leave no doubt in the mind of the physician or the patient that what had appeared to be a classic hyperthyroid syndrome was in reality hypothyroid in causation. The body temperature was the only criterion on which a correct diagnosis might have been made. That such cases are not rare is indicated by 6 additional cases that I have observed during the past twelve months. In 5 of these an operation had been performed, and  the subsequent history left no doubt of a mistaken diagnosis.”

1946: Popják G: The effect of feeding cholesterol without fat on the plasma-lipids of the rabbit. The role of cholesterol in fat metabolism. “During prolonged cholesterol feeding all plasma-lipids show a progressive increase.” “During the administration of cholesterol the iodine value of the phospholipid fatty acids decreased markedly, i.e. these phospholipids contained more saturated fatty acids than before the experiment.[...] There appears to be a selective ‘secretion’ into the blood by the liver of the phospholipids containing the more saturated fatty acids.”

1947: Barnes BO: Headache; etiology and treatment. “Practically all cases presented evidence of thyroid deficiency, and hence, were treated with thyroid extract. Within thirty days after medication was started, a marked decrease in both frequency and severity has been the rule. Many cases of migraine have been completely relieved”

1949: Kirk et al. The correlation between thyroid function and the incidence of arteriosclerosis. [This group didn't find strong correlations between PBI and atherosclerosis, but lowered basal metabolic rate was associated with peripheral atherosclerosis. "The findings suggest an influence of the thyroid gland on the development of medial arteriosclerosis in human subjects."]

Barnes BO: The treatment of menstrual disorders in general practice. [From Barnes' book: "In 1949, I published a report on 143 women with menstrual disorders whom I had seen in my practice and for whom, after taking a thorough history and carrying out a complete physical examination including examination of the pelvis, I had prescribed thyroid therapy. These were women without evidence of fibroids, ovarian cysts, or any other organic disease. In some, basal metabolism test indicated thyroid deficiency; in others, the basal temperature test was used.

Forty-eight of the women suffered from menstrual cramps. Only five failed to get some relief from thyroid therapy; thirty-five experienced complete relief.

Forty-five of the women had irregular cycles. Forty-three benefited, with the cycles becoming completely regular in forty-one.

Fifty women suffered from excessive bleeding. Two failed to benefit; two improved somewhat; forty-six resumed periods with normal flow."]

1950: Kountz WB: Vascular degeneration in hypothyroidism. “This work reveals that hypothyroidism and its associated metabolic deficiency in man may lead to advanced degeneration of the blood vessels when present over an extended period”

1951: Herbut et al: The effect of hepbisul (heptyl aldehyde-sodium bisulfite addition compound) and thyroxin on Walker rat carcinoma 256. “Hepbisul and natural [levo]thyroxin were administered subcutaneously to Sprague-Dawley rats bearing the Walker rat carcinoma 256. Of the 108 animals treated, 27 showed complete regression of the tumors and 12 others showed a favorable histologic response.” “Hepbisul and synthetic  [dextro]thyroxin resulted in a favorable response in 2 of 50 animals treated or a total of 4 per cent. The cause of this discrepancy is unknown.”

1953: Fang&Reyes: Thyroid extract in the management of hypertension. ["Fang and Reyes reported successful results in the treatment of 50 cases of hypertension. All received a uniform dose of thyroid gr.3 [180mg]. They were the first to report a coincident fall in the pulse rate in the majority of the cases successfully treated (68%).”]

Barnes BO: Etiology and treatment of lowered resistance to upper respiratory infections. “During the past 11 years over 150 patients susceptible to respiratory infections have been treated with thyroid, with gratifying results. In addition to feeling better, their incidence of colds and sore throats has been reduced to normal.”

1954: J. G. C. Spencer: The Influence of the Thyroid in Malignant Disease “A higher death rate from cancer was shown to exist in two Swedish counties, Kopparberg and Gefleborg[...] Those two counties (…) were found to have a higher incidence of goitre as compared with the rest of the country.”

“The association of goitre and malignant disease in the post-mortem room was strikingly illustrated by analysis of 1000 post mortems at the Middlesex Hospital (Stocks, 1924) [...] The final result of the survey showed that thyroid anomalities occurred in 18.7 per cent of 500 persons dying of cancer and only in 3.9 per cent of 500 persons dying of conditions other than cancer.” ”The presence of excess of thyroxine in the tissues appears to be prejudicial to the successful grafting of tumours from one mouse to another.”

“In an attempt to explain how this change in tissue is effective we are left with several possibilities : (a) That thyroxine encourages normal physiological tissue respiration rather than the so-called anaerobic type which appears to be the one demonstrable biochemical difference between normal and neoplastic tissue (Greenstein, 1947)”

Eaton CD: Co-existence of hypothyroidism with diabetes mellitus. [I couldn't find this paper so the citation is from a secondary source] 

“[...]when he sought to determine the incidence of hypothyroidism in diabetic patients by means of the basal metabolic rate, he found that even though that test is not very sensitive and may miss many cases of low thyroid function, it established that hypothyroidism was frequent in diabetics, more so than in the nondiabetic population. When he then began administration of thyroid in small, physiological doses to his hypothyroid diabetic patients, he found that the thyroid had no influence on the diabetes. [...] But there were other marked changes in his patients [...] They lost their fatigue, their skin problems, and other symptoms of thyroid deficiency which had not been controlled by the control of the diabetes. Their susceptibility to infections decreased greatly. Dr. Eaton also noted that there were fewer problems with thromboses, or blood clots, in the arteries, which he correctly interpreted as being due to improved circulation and less pooling and stagnation of blood. And he also noted that, as the result of increased circulation in the extremeties, there was less gangrene even in those with arteriosclerosis.”]

1955: Feinblatt et al: Treatment of arteriosclerosis and vague abdominal distress with niacinamide hydroiodide, without side-effects. [Feinblatt et al. [83], in a series of 59 arteriosclerosis patients, reported a reduction in dizziness (71%), headache (61%), disturbed orientation (50%), and fatigue (41%). Subjects were given both iodine and niacinamide.]

Uotila et al: Goitre and atherosclerosis. "In hypothyroidism an excessive amount of thyrotrophic hormone is secreted. In addition to its stimulating effect on the thyroid gland, thyrotrophin affects connective tissue directly by increasing its mucopolysaccharide content (Asboe-Hansen and Iversen 1951). It also prevents the maturation of granulation tissue whereas growth hormone promotes it (Saikku 1956). We think it likely that the acknowledged tendency of hypothyroid patients to arteriosclerosis is attributable not only to a raised serum-cholesterol level but also to the overproduction of thyrotrophin."

1961: Keating et al. Treatment of heart disease associated with myxedema. ["Keating et al. (68) reported a series of 1503 patients with hypothyroidism seen at the Mayo Clinic, 55 (3%) of whom had angina at the time of diagnosis. Among these patients with preexisting angina, improvement or no change in symptoms occurred in 84% after thyroid hormone replacement, with worsening of angina in only 16%. Thirty-five patients (2%) without preceding angina developed it after initiation of thyroid hormone therapy. The 1-yr cardiovascular mortality in those with preexisting angina and treated hypothyroidism was 3%, which is actually less than the 9–15% 1-yr cardiac mortality reported for angina patients during the same era (64)."]

1962: Myasnikov et al. The influence of thyroid hormones on cholesterol metabolism in experimental atherosclerosis in rabbits “It was found that desiccated thyroid produced an increase in the absorption of radioactive cholesterol by the blood and also produced an increase in the radioactivity present in the liver, the aorta, the adrenal glands and in the brain.”

Hay KM: The influence of thyroid on water metabolism in migraine. ”Patients subject to frequent attacks of migraine have a constitutional instability of their salt and water balances, with retention occurring in the prodromal phase, and a diuresis during and after the onset of the main symptoms. These changes do not in themselves account for migraine, but they serve as indicators of the state of flux in the background metabolism, which is part of the migraine syndrome. Evidence has been given to show that small doses of thyroid can modify the diumal weight changes in migraine, with clinical improvement in the majority of cases.”

1964: Dupertuis CW: The thyroid-vitamin approach to cholesterol atheromatosis and chronic disease. A ten year study. By Murray Israel, M.D. VIII & 132 pp. The George Press, Inc., New York, 1960 [book review] “According to this concept, hypofunction of the thyroid gland is fundamentally related to the deposition of cholesterol in the intima as well as to a chain of other commonly associated symptoms such as nervousness, irritability, depression and fatique.” Treatment for the alleviation of these conditions was based on the administration of a combination of thyroid extract in varying dosages with standaradized amounts of Vitamin Complex. [...] According to him, of the original 714, 443 remain under active treatment from seven months to more than 30 years later, but 202 are lost to follow-up for various reasons, especially economic. Others have died or moved away. The improvement rate of 92 per cent, however, is given on 655 patients. [...] As one reads this account of the results of the thyroid-vitamin therapy, one is impressed with the generally good results obtained. There seems to be no question that sluggish thyroids do contribute to a large number of clinical disorders and that these conditions can be improved by the thyroid-vitamin treatment.”

1971: Barnes BO: Physical Fitness in Military Personnel “Heart attacks have been always infrequent in Graz. In 1930, there were only 0.8% of the deaths from this cause. At the height of World War II, this fell to 0.3%. This drop was not the result of less atherosclerosis due to changes in the diet, since the coronary vessels showed approximately a fourfold increase in sclerosis in 1944. A marked rise in tuberculosis during the war was responsible for killing adult males with advancing coronary sclerosis before heart attacks could occur. The introduction of antibiotics at the end of the war curtailed deaths from infectious diseases; myocardial infarctions rose year by year until the incidence in 1966 was 7% of the total deaths.”

Barnes BO: The Coronary Drug Project “[...] the directors should be censored for selecting dextrothyroxine sodium, a synthetic preparation of variable activity, which has been listed as contraindicated in coronary disease by the Physicians Desk Reference. [...] The use of 6 mg of dextrothyroxine sodium by the Coronary Drug Project represented the calorigenic equivalent of 0.45 mg of levothyroxine sodium or 4.5 grains of desiccated thyroid. Since 1925 it has been repeatedly demonstrated that such dosages may be fatal in patients with coronary disease.”

Barnes BO: The role of hypothyroidism in hypertension “A 20-year follow-up on over 1000 patients receiving thyroid therapy reveals that new cases of hypertension are rare; only 12 new cases appeared in the interval. In 127 patients the blood pressure was elevated before thyroid was started. In 102 of these a marked reduction in pressure occurred; only a few required any other medication. In 19 others there was no change in the blood pressures, while 6 showed a mild further elevation over the years. [...] The reduction is very gradual, and in some cases may require as long as 3 years. [..] Basal Temperatures have been found more reliable than customary thyroid-function tests in selecting patients likely to respond to thyroid administration. [...] The improvement may be due to diuresis, increased renal blood flow and less atherosclerosis.”

1974: Dencla WD: Role of the pituitary and thyroid glands in the decline of minimal O2 consumption with age. “All the major endocrine ablations were performed in this and earlier work, and only pituitary ablation (a) restored in adults part of the responsiveness to thyroxine found in immature rats and (b) arrested the normal age-associated decrease in responsiveness to thyroxine in immature rats. Bovine pituitary extracts were found that decreased the responsiveness of immature rats to thyroxine.” [ks. myös Powers et al. 2006 ja Everitt 2003]

1976: Barnes BO: Thyroid Supplements and Breast Cancer “[...]they state that “a definite relationship between breast cancer and hypothyroidism has been established.” This is certainly true, and the most convincing evidence for it are some personal, unpublished observations on the routine autopsies performed in Graz, Austria. Graz is a goiter area; the entire population suffers from a relative thyroid deficiency. Thyroid replacement is rarely employed there. Yet the incidence of breast cancer is as high as ten times that seen in the United States.”

1978: Seino et al. Hypogastrinemia in hypothyroidism.“The decreased gastrin level in patients with hypothyroidism was significantly improved after the thyroid function was normalized by treatment.”

Saunders et al. Thyroid hormones in insulin requiring diabetes before and after treatment. ”“[Plasma T4 and T3 concentrations] were both low in diabetics, with T3 frequently in the hypothyroid range, while [...] [rT3 concentrations] were elevated. All three returned to normal following the treatment.”

1981: Lamberg et al. Further decrease in thyroidal uptake and disappearance of endemic goitre in children after 30 years of iodine prophylaxis in the east of Finland. “Endemic goitre of moderate severity was mainly found in the east of Finland in the 1930′s. Studies in the 1950′s showed an average daily iodine intake of 65-70 micrograms in the west and 50-65 micrograms in the east of the country. The use of iodized salt was introduced in the late 1940′s but added only 15 micrograms of iodine to the daily intake. In the late 1950′s iodine prophylaxis was intensified and the use of salt containing 25 mg KI/kg was recommended. In 1978 about 95% of all household salt used in the Savonlinna area was iodized. This region in the east of Finland has been used as an area of surveillance and studies have been carried out there in 1959, 1969 and 1979. During this period the thyroidal uptake decreased from 67 to 23% in non-goitrous subjects and from 62 to 28% in goitre patients the difference between the two last figures being statistically significant. The goitre patients also had significantly higher serum thyroxine and triiodothyronine levels. During the same period the urinary excretion of stable 127I increased from 45 micrograms to about 250 micrograms a day. Concomitantly the goitre prevalence among school children has decreased. Having been in the early 1950′s in most parts 15-30% it is generally now 1-4%. It seems that the iodine intake is now adequate and that the endemia is gradually subsiding.”

Estes NC: Mastodynia due to fibrocystic disease of the breast controlled with thyroid hormone. ”Nineteen patients were evaluated for breast pain and nodularity associated with fibrocystic disease. Rapid pain relief occurred in 73% of patients, with total relief in 47 percent after daily treatment with 0.1 mg of levothyroxine. Softening of breast tissue and decreased nodularity occurred within 3 months in many patients. Three patients had elevated levels of serum prolactin before treatment, with dramatic pain relief and normalization of prolactin levels after treatment.”
1983: Saito et al. Hypothyroidism as a cause of hypertension. “Adequate thyroid hormone replacement therapy for an average 14.8 months in 14 patients resulted in a normalization of thyroid function and a reduction of blood pressure (p less than 0.01). In four who showed no change in thyroid function due to inadequate replacement therapy, blood pressure remained elevated. These results suggest a close association between hypertension and hypothyroidism.”

1984: Leibel&Hirsch: Diminished energy requirements in reduced-obese patients. (1984) “The mean individual energy requirement of the reduced-obese subjects (2171 kcal/d) was less than that for the control subjects (2280 kcal/d) despite the fact that they still weighed 60% more than the controls.”

Sarne&Refetoff: Measurement of thyroxine uptake from serum by cultured human hepatocytes as an index of thyroid status: reduced thyroxine uptake from serum of patients with nonthyroidal illness. "In patients with NTI, the results of in vitro estimations of free T4 do not always correlate with the transfer of T4 to tissues, as assessed by T4 uptake in human hepatoma cells. In patients with NTI, equilibrium dialysis may overestimate and resin uptake measurements may underestimate the amount of T4 taken up by tissues. In some patients with severe NTI, tissue uptake of T4 is reduced."

1986: Brent&Hershman: Thyroxine therapy in patients with severe nonthyroidal illnesses and low serum thyroxine concentration. “A significant rise in serum T3 occurred in the control group on day 7, but was delayed until day 10 in the treatment group.”

Fraser et al: Are biochemical tests of thyroid function of any value in monitoring patients receiving thyroxine replacement? “It is clear from table IV, however, that serum thyroid hormone and thyroid stimulating hormone concentrations cannot be used with any degree of confidence to classify patients as receiving satisfactory, insufficient, or excessive amounts of thyroxine replacement.”

Brayshaw&Brayshaw: Thyroid hypofunction in premenstrual syndrome [54 women with PMS were studied. Various thyroid tests were done (TRH-stimulation test especially). The average TSH level of the women was within the "normal" range (<4.0) but still 51 of the women showed some cues of hypothyroidism. 34 of these patients were given T4 medication. All of these 34 women were cured from PMS symptoms.]

van der Heyden et al: Effects of caloric deprivation on thyroid hormone tissue uptake and generation of low-T3 syndrome. “In conclusion, during caloric restriction, transport of T4 and T3 into tissues is diminished, and this phenomenon is much more pronounced for T4 than for T3.”

1989: Escobar del Rey et al.: Generalized deficiency of 3,5,3′-triiodo-L-thyronine (T3) in tissues from rats on a low iodine intake, despite normal circulating T3 levels. “The present results show that, despite normal plasma T3, a deficiency of T3 occurs in more tissues of rats on a low iodine intake than previously assumed.”

Lindberg et al. The impact of 25 years of iodine prophylaxis on the adult thyroid weight in Finland. “In the 1950′s the iodine intake calculated both from urinary excretion of stable iodine and from food analysis data was 50-70 micrograms per day the intake being lower in the main endemic area in the eastern part of the country. [...] At the beginning of the 1980′s the iodine intake calculated in the same way was around 300 micrograms per day all over the country. [...] A significant decrease in thyroid weight from a mean of 44 to a mean of 34 g was observed.”

Wilansky&Greisman: Early hypothyroidism in patients with menorrhagia. “The functional status of the thyroid gland was evaluated in 67 apparently euthyroid menorrhagic women by a thyrotropin-releasing hormone test. Fifteen of 67 showed mild primary hypothyroidism characterized by a small but significant elevation of basal levels of thyroid-stimulating hormone (5.9 +/- 0.76 versus 2.4 +/- 0.24 mU/L) and lowering of serum thyroxine levels (85 +/- 4.2 versus 105 +/- 3.0 nmol/L) to levels that were nevertheless within the normal range [...] The terms early and potential hypothyroidism appear to better describe the preliminary phases of hypothyroidism than do other terms in current use. Menorrhagia disappeared within 3 to 6 months and did not reappear in 1 to 3 years of follow up in all patients with early hypothyroidism to whom L-thyroxine was given.”

Powell et al. Can thyroxine halt the progression of peripheral arterial disease? “Non-invasive assessment showed that three of the 15 (20%) women treated with thyroxine had progression of arterial disease, two in the legs and one in the legs and coronary arteries; two women showed improvement of ankle/brachial pressure indices. There was no accelerated angina, myocardial infarction, stroke or death in this group. Fifty-six of the 58 patients with normal levels of TSH were alive at follow-up and there was progression of distal disease in 24 (43%), coronary artery disease in 6 (11%), increasing carotid stenosis in four and two complained of transient ischaemic attacks. In this group, disease progression affected 32/56 (57%) of the women and this is significantly greater than in the thyroxine treated group chi 2 (P less than 0.05).” “The changes in apolipoprotein B and serum lipids may ameliorate the progression of arterial disease with only 20% of the treated women showing disease progression after one year compared with more than half of the cohort from whom they were selected.”

1990: Oster&Prellwitz: Selenium and cardiovascular disease“For humans, ecological and epidemiological results are reported that show a relationship between the serum selenium concentration and cardiovascular disease in populations where low serum selenium concentrations are found, e.g., in Eastern Finland. From clinical studies done in Germany (FRG and GDR), Finland, and Sweden, subnormal serum selenium and partially whole blood selenium concentrations are reported in patients with acute myocardial infarction.”

Witztum&Steinberg: Role of oxidized low density lipoprotein in atherogenesis. “The nature of the substrate for lipid peroxidation, mainly the polyunsaturated fatty acids in lipid esters and cholesterol, is a dominant influence in determining susceptibility. As noted by Esterbauer et al. (52), there is a vast excess of polyunsaturated fatty acids in LDL, in relationship to the content ofnatural, endogenous antioxidants. The importance ofthe fatty acid composition was impressively demonstrated by our recent studies of rabbits fed a diet high in linoleic acid (18:2) or in oleic acid (18:1) for a period of 10 wk. LDL isolated from the animals on oleic acid-rich diet were greatly enriched in oleate and low in linoleate. This LDL was remarkably resistant to oxidative modification, measured either by direct parameters oflipid peroxidation (i.e., TBARS and conjugated dienes) or by the indirect criterion of uptake by macrophages (53).”

1992: Nestler et al. Dehydroepiandrosterone: the “missing link” between hyperinsulinemia and atherosclerosis? “A well-established epidemiologic association exists between hyperinsulinemia and macrovascular disease. However, the mechanism or mechanisms by which hyperinsulinemia promotes atherogenesis is unknown. Recent evidence indicates that the adrenal steroid dehydroepiandrosterone (DHEA) exerts multiple antiatherogenic effects and also suggests that hyperinsulinemia may reduce serum DHEA and DHEA-sulfate levels by decreasing production and enhancing metabolic clearance.”

Kauf et al. Sodium selenite therapy and thyroid-hormone status in cystic fibrosis and congenital hypothyroidism. “The effectiveness of a peroral sodium selenite therapy (115 micrograms Se/m2 BSA/d) administered to cystic fibrosis patients (n = 32) could after three months be identified in a significant serum selenium increase (0.69–&gt;0.96 mumol/L), a significant malondialdehyde decrease (2.72–&gt;1.64 mumol/L), as well as in a significant serum vitamin E increase (4.31–&gt;5.72 micrograms/mL). Parallel to that, a serum T3 increase as well as a highly significant decrease in the serum T4/T3-ratio were found, too, which point to improved peripheral T4–&gt;T3 conversion during selenium medication.”

Staub et al: Spectrum of subclinical and overt hypothyroidism: effect on thyrotropin, prolactin, and thyroid reserve, and metabolic impact on peripheral target tissues. "In grade I subclinical hypothyroidism (basal TSH below 6 mU/L), we found significant changes in the clinical index (p less than 0.05), apoprotein A-I level (p less than 0.05), and stimulated prolactin level after oral TRH (p less than 0.001). The findings were similar in grade II (TSH 6 to 12 mU/L). Further changes could be demonstrated in grade III (TSH above 12 mU/L) with a definite elevation of ankle reflex time (p less than 0.001), serum myoglobin level (p less than 0.01), and, to a lesser extent, creatine kinase (p greater than 0.1). The mean low-density lipoprotein cholesterol (LDL-C) level showed an increase of 18%, which was not significant because of marked individual variations (p = 0.15)."

1993: Feingold et al. Effect of endotoxin on cholesterol biosynthesis and distribution in serum lipoproteins in Syrian hamsters. “Both low and high dose LPS increase hepatic cholesterol synthesis (low dose 85%, high dose 205%) and total HMG-CoA reductase activity (low dose 2.97-fold, high dose 9.96-fold).”

Hennemann et al. Decreased peripheral 3,5,3′-triiodothyronine (T3) production from thyroxine (T4): a syndrome of impaired thyroid hormone activation due to transport inhibition of T4- into T3-producing tissues. “Because T4 into T3 conversion efficiency in the REP (the main source of plasma T3 production) was normal, it was concluded that the lowered T3 production in the subject was caused by transport inhibition of T4 into the liver. Although the occurrence of the syndrome is rare, its significance is of general importance, in that it shows that transport of thyroid hormone may vary at the tissue level. Furthermore, as T3 is the principal biologically active thyroid hormone, regulation of transport of T4 into the REP may play a (patho)physiological role in the ultimate determination of thyroid hormone activity in the tissues.”

1995: Escobar-Morreale et al. Replacement therapy for hypothyroidism with thyroxine alone does not ensure euthyroidism in all tissues, as studied in thyroidectomized rats. “No single dose of T4 was able to restore normal plasma thyrotropin, T4 and T3, as well as T4 and T3 in all tissues, or at least to restore T3 simultaneously in plasma and all tissues. Moreover, in most tissues, the dose of T4 needed to ensure normal T3 levels resulted in supraphysiological T4 concentrations. Notable exceptions were the cortex, brown adipose tissue, and cerebellum, which maintained T3 homeostasis over a wide range of plasma T4 and T3 levels.”

Boelen et al. Soluble cytokine receptors and the low 3,5,3'-triiodothyronine syndrome in patients with nonthyroidal disease. "The variability in serum T3 was accounted for 35% by changes in ln (sTNF alpha R p75) and 14% by changes in ln (IL-6)."

Klemperer et al. Triiodothyronine therapy lowers the incidence of atrial fibrillation after cardiac operations. "Triiodothyronine-treated patients had a lower incidence of atrial fibrillation (24% versus 46%; p = 0.009), and fewer required cardioversion (0 versus 6; p = 0.012) or anticoagulation (2 versus 10; p = 0.013) during hospitalization. Six patients in the T3 group versus 16 in the placebo group required antiarrhythmic therapy at discharge (p = 0.019)."

1997: Zulewski et al: Estimation of tissue hypothyroidism by a new clinical score: evaluation of patients with various grades of hypothyroidism and controls. (1997) "In overt hypothyroid patients, the new score showed an excellent correlation with ankle reflex relaxation time and total cholesterol (r = 0.76 and r = 0.60; P &lt; 0.0001), but no correlation with TSH (r = 0.01)."

1998: Vine et al. Dietary oxysterols are incorporated in plasma triglyceride-rich lipoproteins, increase their susceptibility to oxidation and increase aortic cholesterol concentration of rabbits. “Seven animals received rabbit chow supplemented with 1.0% auto-oxidized cholesterol (containing 6% oxysterols), 8 rabbits received 1.0% purified cholesterol supplemented chow (control diet), and 5 rabbits received standard rabbit chow.”

“Oxidized cholesterol feeding increased total plasma cholesterol 8-fold, reflecting a greater proportion of apolipoprotein B containing lipoproteins [...] However, the increase in plasma cholesterol after supplementation with pure cholesterol was more than double that seen with the oxidized cholesterol-fed rabbits.”

“[...]the concentration of aortic total cholesterol in rabbits fed oxidized cholesterol was increased more than 2-fold (653 ± 131 μg/g versus 278 ± 39 μg/g aorta, respectively) compared to unsupplemented and purified cholesterol-fed rabbits (Fig. 6). Supplementation of the diet with pure cholesterol caused no significant increase in arterial cholesterol concentration (398 ± 41 μg/g aorta) compared to the unsupplemented group.”

“In addition, it has been suggested that arterial fatty lesions in cholesterol-fed rabbits are due to oxysterols associated with USP-grade cholesterol (16) [...] It is possible that the atherogenic basis of cholesterol-fed diets is positively related to the level of oxidized sterol products.“

1999: Monzani et al. Neuromuscular symptoms and dysfunction in subclinical hypothyroid patients: beneficial effect of L-T4 replacement therapy. “Neuromuscular symptoms were significantly more frequent in patients than in controls (P = 0. 0001), and correlated with TSH values (r = 0.52; P = 0.0001). Among patients showing three or more symptoms (n = 11), sEMG documented the presence of repetitive discharges in 8 patients. L-T4 therapy led to a significant improvement of symptoms (P = 0.0001); persistent repetitive discharges were no longer observed.” [Patients' average TSH at baseline was 5.39mIU/l. FT4 vas 11.1 (12.2 in controls) and FT3 was 4.8 (4.9 in controls)]

Carvalho et al. Thyroid peroxidase activity is inhibited by amino acids. “Normal in vitro thyroid peroxidase (TPO) iodide oxidation activity was completely inhibited by a hydrolyzed TPO preparation (0.15 mg/ml) or hydrolyzed bovine serum albumin (BSA, 0.2 mg/ml). A pancreatic hydrolysate of casein (trypticase peptone, 0.1 mg/ml) and some amino acids (cysteine, tryptophan and methionine, 50 microM each) also inhibited the TPO iodide oxidation reaction completely, whereas casamino acids (0.1 mg/ml), and tyrosine, phenylalanine and histidine (50 microM each) inhibited the TPO reaction by 54% or less. A pancreatic digest of gelatin (0.1 mg/ml) or any other amino acid (50 microM) tested did not significantly decrease TPO activity.”

Roberts WC: Twenty questions on atherosclerosis “The only way to produce atherosclerosis in a carnivore is to take out the thyroid gland”
2001: Umans-Eckenhausen et al: Low-density lipoprotein receptor gene mutations and cardiovascular risk in a large genetic cascade screening population. ”Patients with FH had CVD 8.5 times more often compared with their unaffected relatives (RR, 8.54; 95% CI, 5.29 to 13.80).”

Moreno et al. Are the effects of T3 on resting metabolic rate in euthyroid rats entirely caused by T3 itself? “These results seem to indicate that when T3 is injected into [euthyroid] animals, not all the effects on RMR are attributable to T3 itself, the early effect presumably being largely because of its in vivo deiodination to 3,5-T2.”

Hennemann et al. Plasma membrane transport of thyroid hormones and its role in thyroid hormone metabolism and bioavailability. “Thyroid hormone uptake in the intact rat and human liver is ATP dependent and rate limiting for subsequent iodothyronine metabolism. In starvation and nonthyroidal illness in man, T4 uptake in the liver is decreased, resulting in lowered plasma T3 production. Inhibition of liver T4 uptake in these conditions is explained by liver ATP depletion and increased concentrations of circulating inhibitors, such as 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid, indoxyl sulfate, nonesterified fatty acids, and bilirubin.”

Koyuncu et al: Effect of thyroid hormones on stress ulcer formation.  "It was found that both triiodothyronin and thyroxin reduce the length and depth of the stress ulcers (P < 0.001)."

Clejan et al. Blood histamine is associated with coronary artery disease, cardiac events and severity of inflammation and atherosclerosis. "Histamine and isoprostane levels increase in SCAD and ACS patients. Mast cell activation and lipid oxidation generated during atherosclerosis manifest this inflammatory response. Accelerated isoprostane formation and depleted ascorbate paired with histaminemia is active in CAD and predispose patients to acute coronary syndrome. Blood histamine alone may be a better risk factor for coronary events, and a better prognostic indicator than CRP even when combined with lipid indexes."

Solá et al. Massive triiodothyronine intoxication: efficacy of hemoperfusion? "A case of massive accidental triiodothyronine intoxication (1000-fold the usual therapeutic dose, for 8 days) is reported with important disturbances of cardiovascular and central nervous systems that required intensive care support. Serum free triiodothyronine levels were 4789 pmol L(-1) on admittance (normal values, 3.5-6.5 pmol x L(-1)). In the absence of a specific treatment, hemoperfusions were performed but failed to accelerate significantly the decay of blood levels of free triiodothyronine (apparent half-life 25.9 hours; 95% confidence interval: 19.8-37.4 hours). The patient, a young woman, made a satisfactory recovery, in spite of important clinical complications."

2003: Wilson et al. Hypocholesterolemia in sepsis and critically ill or injured patients “Hypocholesterolemia is an important observation following trauma. In a study of critically ill trauma patients, mean cholesterol levels were significantly lower (119 ± 44 mg/dl) than expected values (201 ± 17 mg/dl). In patients who died, final cholesterol levels fell by 33% versus a 28% increase in survivors. Cholesterol levels were also adversely affected by infection or organ system dysfunction. Other studies have illustrated the clinical significance of hypocholesterolemia. Because lipoproteins can bind and neutralize lipopolysaccharide, hypocholesterolemia can negatively impact outcome. New therapies directed at increasing low cholesterol levels may become important options for the treatment of sepsis.”

Stump et al. Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts. “Here we report increases in vastus lateralis muscle mitochondrial ATP production capacity (32-42%) in healthy humans (P &lt; 0.01) i.v. infused with insulin[...]“

2004: Gaby AR: Sub-laboratory hypothyroidism and the empirical use of Armour thyroid. “Research supporting the existence of sub-laboratory hypothyroidism is reviewed, and the author’s clinical approach to the diagnosis and treatment of this condition is described.”

Aviram et al: Pomegranate juice consumption for 3 years by patients with carotid artery stenosis reduces common carotid intima-media thickness, blood pressure and LDL oxidation. “PJ consumption resulted in a significant IMT reduction, by up to 30%, after 1 year. The patients’ serum paraoxonase 1 (PON 1) activity was increased by 83%, whereas serum LDL basal oxidative state and LDL susceptibility to copper ion-induced oxidation were both significantly reduced, by 90% and 59%, respectively, after 12 months of PJ consumption [...] Systolic blood pressure was reduced after 1 year of PJ consumption by 12%”

Nakahara et al: Association of antipituitary antibody and type 2 iodothyronine deiodinase antibody in patients with autoimmune thyroid disease. "[antipituitary antibody] was positive in 31.0% (13/42) of patients with Hashimoto's disease" "D2 peptide antibody was positive in 26.2% (11/42) of patients with Hashimoto's disease"

Staprans et al. The role of dietary oxidized cholesterol and oxidized fatty acids in the development of atherosclerosis. ”We hypothesize that diet-derived oxidized fatty acids in chylomicron remnants and oxidized cholesterol in remnants and LDL accelerate atherosclerosis by increasing oxidized lipid levels in circulating LDL and chylomicron remnants. This hypothesis is supported by our feeding experiments in animals. When rabbits were fed oxidized fatty acids or oxidized cholesterol, the fatty streak lesions in the aorta were increased by 100%. Moreover, dietary oxidized cholesterol significantly increased aortic lesions in apo-E and LDL receptor-deficient mice. A typical Western diet is rich in oxidized fats and therefore could contribute to the increased arterial atherosclerosis in our population.”
Casey et al. Subclinical hypothyroidism and pregnancy outcomes. “Pregnancies in women with subclinical hypothyroidism were 3 times more likely to be complicated by placental abruption (relative risk 3.0, 95% confidence interval 1.1-8.2). Preterm birth, defined as delivery at or before 34 weeks of gestation, was almost 2-fold higher in women with subclinical hypothyroidism (relative risk, 1.8, 95% confidence interval 1.1-2.9).”

Sato et al. Thyroid hormone targets matrix Gla protein gene associated with vascular smooth muscle calcification. “Our findings suggest that a physiological concentration of thyroid hormone directly facilitates MGP gene expression in smooth muscle cells via thyroid hormone nuclear receptors, leading to prevention of vascular calcification in vivo.”

Alevizaki et al. TSH may not be a good marker for adequate thyroid hormone replacement therapy. “We conclude that patients with T4-treated hypothyroidism have lower T3 levels, lower T3/T4 ratio and lower SHBG than normal individuals with the same TSH, perhaps indicating relative tissue hypothyroidism in the liver. TSH levels used to monitor substitution, mostly regulated by intracellular T3 in the pituitary, may not be such a good indicator of adequate thyroid hormone action in all tissues. The co-administration of T3 may prove more effective in this respect, provided novel suitable preparations are developed. Until this is accomplished, substitution in hypothyroidism should aim at low normal TSH, to ensure normal T3 levels.”

2006: Watanabe et al. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. ["In this study, mice that were fed a high-fat diet supplemented with bile acids were noted to be resistant to diet-induced obesity, but this protective effect of bile acids was lost in D2-knockout mice."]

Cohen et al: Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. “Of the 3363 black subjects examined, 2.6 percent had nonsense mutations in PCSK9; these mutations were associated with a 28 percent reduction in mean LDL cholesterol and an 88 percent reduction in the risk of CHD” “”Of the 9524 white subjects examined, 3.2 percent had a sequence variation in PCSK9 that was associated with a 15 percent reduction in LDL cholesterol and a 47 percent reduction in the risk of CHD”

Fukuyama et al. Thyroid hormone inhibits vascular remodeling through suppression of cAMP response element binding protein activity. “These results suggested that T3 inhibits CREB/CRE signaling pathway and suppresses cytokine expression and VSMCs proliferation, which may account for, at least in part, an anti-atherosclerotic effect of thyroid hormone.”

2007: Buscemi et al. A low resting metabolic rate is associated with metabolic syndrome. “The group with metabolic syndrome exhibited a significantly lower resting metabolic rate adjusted for fat-free mass with respect to the control group and the obese group without metabolic syndrome (respectively: 108+/-3 vs. 118+/-3, p<0.01 and 123+/-3 kJ/kg fat-free mass 24 h, p<0.01; mean+/-sem). The obese group with metabolic syndrome and type 2 diabetes (T2D) had a not different adjusted resting metabolic rate (114+/-6 kJ/kg fat-free mass 24h) with respect to other groups.”

Alvarez-Pedrerol et al. TSH concentration within the normal range is associated with cognitive function and ADHD symptoms in healthy preschoolers. "Children with TSH concentrations in the upper quartile of the normal range performed lower on McCarthy's scales and were at higher risk for attention deficit and hyperactivity/impulsivity symptoms. In the Menorca cohort, a decrease of 5.8 (P < 0.05) and 6.9 (P < 0.01) points was observed in memory and quantitative skills, respectively. In contrast, high T4 concentrations were associated with decreased risk of having 1-5 attention deficit symptoms (odds ratio: 0.25; P < 0.01);"

2008: Taubes G: Diabetes. Paradoxical effects of tightly controlled blood sugar. ”The obvious explanation for why the three studies came up negative is that the hypothesis that high blood sugar causes macrovascular complications in type 2 diabetes is simply wrong.” [At this point we ought to remember that Barnes and Eaton could prevent the complications of diabetes with desiccated thyroid.]

“Low resting metabolic rates of FMS patients. In the first study, patients’ mean resting metabolic rate was 29% below their predicted rate [...] The mean of the healthy control subjects’ metabolic rates was only 8% below their predicted rates. [...] In the second study, the mean resting metabolic rate for patients was 30% below the predicted rate. The mean metabolic rate of healthy controls was, again, 8% below the predicted rate.”

“Low basal body temperatures of FMS patients. In the first study, patients’ average basal temperature was 96.95/F. The average for healthy women was 97.54/F. In the second study, the average temperature of patients was 96.38/F. The average for healthy controls was 97.54/F. Statistically, the patients’ temperatures in both studies were significantly lower than those of controls.”

Wikland B: Redefining Hypothyroidism—A Paradigm Shift “A direct approach to demonstrate thyroid autoimmunity is to examine the gland by means of fineneedle aspiration cytology (FNA). For many years, this has been a routine procedure in our centre in Stockholm, Sweden. The diagnostic and therapeutic potential of FNA as a complement to conventional first-line tests is remarkable. In summary, we [1][2] found that no less than 40% of unselected patients with chronic fatigue (90% women) had definite evidence of lymphocytic invasion of the thyroid—the gold standard criterion of thyroid autoimmunity. 

What about TSH in patients with FNA-documented evidence of thyroid autoimmunity? We found that TSH values were scattered, ranging from less than 1 mU/L to over 30; the median TSH value was 3.8. (These were baseline values, and none of [1] the patients were on thyroid medication.) In patients with cytologically-demonstrated thyroid autoimmunity, the clinical response to thyroid medication was equally favourable, regardless of the presenting TSH value.

2009: Georgopoulos et al. Basal metabolic rate is decreased in women with polycystic ovary syndrome and biochemical hyperandrogenemia and is associated with insulin resistance. “Adjusted BMR was 1,868 +/- 41 kcal/day in the control group, 1,445.57 +/- 76 in all PCOS women, 1,590 +/- 130 in PCOS women without IR and 1,116 +/- 106 in PCOS women with IR.”

Kileĭnikov et al. [Pathogenesis of arterial hypertension in patients with primary hypothyroidism]. “These clinical and functional signs are supposed to reflect hypovolemia in patients with PH and concomitant AH.”

Ahlström et al. Correlation between plasma calcium, parathyroid hormone (PTH) and the metabolic syndrome (MetS) in a community-based cohort of men and women. “PTH and BMI (P &lt; 0.0001), waist circumference (P &lt; 0.0001), systolic blood pressure (P = 0.0034), diastolic blood pressure (P = 0.0008), serum triglycerides (P = 0.0003) and insulin resistance (P = 0.0003) were positively correlated, whereas serum high density lipoproteins (HDL) (P = 0.036) and PTH were negatively correlated.”

Lallès JP. Intestinal alkaline phosphatase: multiple biological roles in maintenance of intestinal homeostasis and modulation by diet. “In conclusion, IAP has a pivotal role in intestinal homeostasis and its activity could be increased through the diet. This is especially true in pathological situations (e.g., inflammatory bowel diseases) in which the involvement of commensal bacteria is suspected and when intestinal AP is too low to detoxify a sufficient amount of bacterial lipopolysaccharide.”

Ackay et al. T4 plus T3 treatment in children with hypothyroidism and inappropriately elevated thyroid-stimulating hormone despite euthyroidism on T4 treatment. “LDL-cholesterol decreased and ALP increased in the euthyrotropinemic state. [...] Our data strongly suggest that decreased negative feedback due to lower T3 levels at the pituitary level is the main reason for persistent hyperthyrotropinemia.”

Vogelzangs et al. Urinary cortisol and six-year risk of all-cause and cardiovascular mortality. “Persons in the highest tertile of urinary cortisol had a five times increased risk of dying of cardiovascular disease (hazard ratio = 5.00; 95% confidence interval = 2.02-12.37). This effect was found to be consistent across persons with and without cardiovascular disease at baseline (p interaction = 0.78).”

Celi et al. The pharmacodynamic equivalence of levothyroxine and liothyronine: a randomized, double blind, cross-over study in thyroidectomized patients. "This is the first study addressing the equivalency between L-T3 and L-T4 therapy measured by baseline and TRH-stimulated TSH. The therapeutic substitution of L-T3 for L-T4 was achieved at approximately 1:3 ratio."

Gullo et al: Levothyroxine Monotherapy Cannot Guarantee Euthyroidism in All Athyreotic Patients "Among the levothyroxine-treated patients 15.2% had lower serum FT3 and 7.2% had higher serum FT4 compared to euthyroid controls."

2012: Pagadala et al. Prevalence of hypothyroidism in nonalcoholic fatty liver disease. “Subjects with hypothyroidism were 2.1 (95% CI 1.1-3.9, P = 0.02) and 3.8 (95% CI 2-6.9, P &lt; 0.001) times more likely to have NAFLD and NASH, respectively.”

Farhangi et al. The effect of vitamin A supplementation on thyroid function in premenopausal women. [25 000 IU of vitamin A daily -> higher T3 levels, lower T4 and TSH levels. For some reason, control group also saw some similar changes. Another paper about the same study also tells that many of the participants (again, from the control group too) had worse cholesterol levels in the end of this study. Strange...]

McDermott MT: Does combination T4 and T3 therapy make sense? “One randomized controlled trial found that patients with the D2 Thr92Ala polymorphism had more baseline symptoms than those with the wild type D2 and experienced significantly greater symptomatic improvement in response to combined levothyroxine and liothyronine therapy.”

Goldberg et al: Thyroid hormone reduces cholesterol via a non-LDL receptor-mediated pathway. "We tested whether LDL receptor (LDLR) expression was required for cholesterol reduction by treating control and LDLR-knockout mice with two forms of thyroid hormone T(3) and 3,5-diiodo-l-thyronine. High doses of both 3,5-diiodo-l-thyronine and T(3) dramatically reduced circulating total and very low-density lipoprotein/LDL cholesterol (∼70%) and were associated with reduced plasma T(4) level. The cholesterol reduction was especially evident in the LDLR-knockout mice."

2013: Shab-Bidar et al. Dietary intakes of zinc and copper and cardiovascular risk factors in Tehranian adults: Tehran Lipid and Glucose Study “Comparing the highest versus the lowest intake categories of dietary copper, the multivariable adjusted odds ratios for HDL-C, fasting blood glucose(FBG), TG and MetS were 1.75 (1.43–2.25)(P for trend = 0.003), 0.90 (0.76–1.23)(P for trend = 0.017), 0.11(0.08–0.21) (P for trend = 0.042) and 0.19 (0.15–0.38)(P for trend = 0.023), respectively.”

Martucci et al. Overweight/obese women with primary acquired hypothyroidism in appropriate levothyroxine replacement therapy are characterized by impaired whole body energy metabolism ”TSH [...] and body composition [...] were not different between groups. REE was reduced in hypothyroid women when compared to the control group in absolute terms (1347±171 vs 1447±154 kcal [...] This study demonstrates that middle-aged, overweight/obese hypothyroid women in L-T4 replacement therapy, in spite of achieving an optimal serum TSH level, are characterized by altered whole body energy metabolism and substrate disposal supporting the view that additional interventions may be necessary to fully revert the entire set of hypothyroidism-related metabolic alterations.

Hoermann et al. Is pituitary TSH an adequate measure of thyroid hormone-controlled homoeostasis during thyroxine treatment? “Hence, the results indicate that the observed disjoint between the thyroid/pituitary FT4–TSH feedback mechanism and T3 production noted in hypothyroidism (whether inadequately or untreated) is not fully restored even when sufficient T4 is given to regain an apparently euthyroid state. In several cases, this results in a classification mismatch, for example placing ∼10% of patients on moderate T4 doses that are judged euthyroid according to their TSH measurements below the FT3 reference range. Higher L-T4 doses maintained FT3 within its reference limits, though frequently only in conjunction with suppressed TSH.”

Mdzinarishvili et al. Engineering triiodothyronine (T3) nanoparticle for use in ischemic brain stroke. “In MCAO model of ischemic stroke, significant benefit of administering T3 in nanoparticulate form was observed over injection of a T3 solution. A 34 % decrease in tissue infarction and a 59 % decrease in brain edema were seen upon administration of T3 solution in MCAO stroke model. Corresponding measurements for uncoated T3 nanoparticles were 51 % and 68 %, whereas for the glutathione coated were 58 % and 75 %.”

Kazanavicius et al. Effect of triiodothyronine on hyperandrogenism in women “Hirsutism, acne, androgens and ovarian volumes are decreased due to the increase of the triiodothyronine level in blood of women with hyperandrogenism signs.”

Buizert et al. PTH: A NEW TARGET IN ARTERIOSCLEROSIS? “Multivariate models showed that subjects in the highest quintile of serum PTH had a significantly higher risk of CVD as compared to subjects in the lowest quintile (OR = 2.22, CI = 1.39-3.56).”

Walter et al. Elevated thyroid stimulating hormone is associated with elevated cortisol in healthy young men and women “Results suggest a positive relationship between TSH and cortisol in apparently healthy young individuals. In as much as this relationship may herald a pathologic disorder, these preliminary results suggest that TSH levels &gt; 2.0 uIU/L may be abnormal.”

Nicolini et al. New Insights into Mechanisms of Cardioprotection Mediated by Thyroid Hormones “Experimental and clinical studies strongly support the concept that TH plays a fundamental role in cardiovascular homeostasis in both physiological and pathological conditions. 

Increasing evidence indicates that the low TH is not simply a consequence of cardiac disease evolution but a permissive state that favours adverse cardiac remodeling and failure.”

2014: Hoermann et al. Homeostatic Equilibria Between Free Thyroid Hormones and Pituitary Thyrotropin Are Modulated By Various Influences Including Age, Body Mass Index and Treatment. "FT3 levels were significantly lower in L-T4 treated versus untreated non-hypothyroid autoimmune thyroiditis (median 4.6 vs 4.9 pmol/l, p<0.001), despite lower TSH (1.49 vs 2.93 mU/l, p< 0.001) and higher FT4 levels (16.8 vs 13.8 pmol/l, p< 0.001) in the treated group."

Appendix II: Quotations from Mark Starr’s book Type 2 Hypothyroidism: The Epidemic

“In 1998, I recruited a Ph.D. exercise physiologist to perform basal metabolic rate testing for my pain patients. The doctor was very conscientious and tried to make certain the patients were relaxed and proper procedures followed. He performed basal metabolism tests on 50 consecutive pain patients. All of these patients had normal thyroid blood tests.

My 50 patients’ metabolism averaged 15% below normal. A significant number of their metabolic rates were in the 30 – 40% below-normal range. Several tests were above average as well. When a basal metabolism test was previously used to aid doctors in making the diagnosis of hypothyroidism, a test result of 10% less than normal or lower was considered strongly indicative of the illness.”

“Only one patient has developed diabetes while under my care. [...] No other patients have been diagnosed with diabetes while under my care. In addition, none of the many diabetic patients under my care have developed any of the common problems that afflict diabetics such as chronic renal failure, blindness, heart attacks, gangrene, or peripheral neuropathies. Dr. Eaton’s research remains just as valid as when it was first published in 1954.”

Appendix III: Quotations from William Kountz’ monograph Thyroid Function and its Possible Role in Vascular Degeneration

“Other observers as well have found that degenerative changes, which may result in debilitation of an individual, may cause a rise in the rate of oxygen consumption. This rise is not believed to be due to increased glandular activity but rather to an increase in the physiological strain that disease associated with degeneration imposes upon the organism.”

Appendix IV: Quotations from Broda Barnes' book Hypothyroidism: The Unsuspected Illness (1976)

“The hypothyroid patient may experience effects like those produced by anemia, including undue fatigue, for another reason. Thyroid deficiency tends to reduce the strength of the heartbeat, and the amount of blood pumped out to the body with each beat is reduced.

In severe hypothyroidism, studies have shown that the blood circulating per minute through the body may be reduced by as much as 40 percent, thus the effective oxygen-carrying capacity of the blood is only 60% of normal. In milder cases of reduced thyroid function, the reduction in circulation is, of course, not nearly that severe.”

“It could be only coincidence that among thousands of patients I have placed on thyroid therapy, not one has developed lung cancer and there have been only six deaths due to malignancies of any kind while in a similar number of people in the general population about twenty deaths from cancer would have been expected.”

Appendix V: Recommended reading (blog texts etc)