Wednesday, March 27, 2013

Thyroid Hormones and Heart Disease

EN - Here is the translated version of my Finnish Thyroid-CVD essay.

I got the original inspiration to write about this topic after reading some nice blog posts by Matt Stone and Chris Masterjohn. There just were some studies these guys didn't mention about, so I decided to try to write a larger article on this topic.

Thyroid Hormones and Heart Disease

1. Introduction
This essay is about the possibility of using traditional thyroid medication, desiccated thyroid, as a strategy for an efficient prophylaxis for heart disease. There is a considerable amount of studies carried out on this subject that, for some reason, aren't very well-known despite their notable 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 decades, a large part of the discussion related to heart disease (CVD) has been about cholesterol levels. According to the modern knowledge, some of the LDL cholesterol in the blood causes atheroma plaques to the intima part of blood vessels.

This is also the reason why low-fat or low-SFA 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, 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 of course we want to maximize the effectiveness of medications and even statins do leave a majority of people vulnerable to CVD deaths. That's the reason why we should consider if some other treatment could give better results than the statins.
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). 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' research, physician James Wren conducted two studies which gave additional support to Kountz' 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 much 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? (Kountz 1971)
5. Desiccated thyroid and CVD, part III: Broda Barnes

Physician Broda Otto Barnes' dissertation was related to the function of thyroid gland. 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 (98.6F) was an important indicator of hypothyroidism and thus, a need for 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 results considering that Barnes didn't advocate his patients to quit smoking or change their other habits.
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 cholesteroli (>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.

6. Desiccated thyroid and CVD, part IV: Mark Starr, Lerman&White and Henry Russek

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)

7. Desiccated thyroid and CVD, part V: Other human and animal studies.

So, that was all the clinical data regarding prevention of heart disease with thyroid. Now 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*. (Lopez et al. 2007, Bakker et al. 1998, Scarabottolo et al. 1986)

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)
2) Quite often, people with heart disease have also problems with their thyroids

István Gáspár studies 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)

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

Subclinical hypothyroidism is correlated with increased risk of myocardial infarction in elderly women (OR 2.3). (Hak et al. 2000)

HUNT study included more than 25 000 Norwegians. Those with TSH in the range of 1.5-2.4, had 41 per cent higher CVD mortality than those with TSH in the range of 0.5-1.4. TSH of 2.5-3.5 was correlated with 69 per cent increased heart mortality. (Asvold et al. 2008)

HUNT also revealed that higher TSH was correlated with worse serum lipids even in the normal TSH range. (Asvold et al. 2007) 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. (Hurxthal 1934, Gildea et al. 1939 etc...)
(Hurxthal, 1934)
(Gildea, 1939)
4) The classic "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 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)

5) 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 benefitted 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)

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

One important thing to remember now is that none of the above physicians (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. Still they had excellent treatment results.
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 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 population suffer 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. Especially in men, it's quite rare. Despite this, many people seem to suffer from low metabolism and various symptoms which seem to be alleviated or cured by thyroid extract.

It's probable that Barnes' results can't be explained by primary hypothyroidism. I think that some other thing than low thyroid hormone blood concentration would explain why some people are susceptible to CVD if they are not given thyroid extract. I think that the mechanism is more likely related to function of receptors and target tissues (liver etc). Maybe many people have some other underlying metabolic problems caused by deficiencies, infections or other causes, that inhibit thyroid hormone function and aerobic metabolism on the cellular level. This could be reason why some people need some extra thyroid hormones, which often leads to extremely low TSH levels.**

9. Synthetic Hormones VS Natural Desiccated Thyroid

Nowadays the medication of thyroid patients is almost completely based on the synthetic hormones, most usual prescription being Synthroid (levothyroxine, T4). However, all of those positive results of Barnes and others were achieved with natural desiccated thyroid (NDT).

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).

T4 treatment has often been compared to the combination therapy. I haven't compiled the research on the subject, but from what I have seen, it seems to me that for many people the combination therapy works better than the monotherapy.

Baisier et al. have compared T4 and NDT treatments, and according to their results, NDT is utterly superior to the T4 treatment (see the diagram below). They 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)
T4 got really PWNT by NDT :)
I think that no relevant studies on the efficacy of levothyroxine on prevention of CVD, but in the seventies one very large study was conducted, in which they used dextrothyroxine. Those who received the synthetic hormone, had a slightly elevated total mortality. (The Coronary Drug Project 1972)

In the social media there are a lot of discussions regarding thyroid medications, and I think that very many people on various health forums also believe that the natural thyroid treatment is often better than the synthetic treatment.

10. Possible causes of inadequate thyroid hormone function

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 Finland, soils were quite depleted of selenium until the beginning of 1980s. (Arthur 2003, Hoption Cann 2006)

I have been thinking that he 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 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 that seems to be related to thyroid hormone function and atherosclerosis is copper, whose deficiency seems to cause cardiovascular disease. Copper and zinc can attenuate the damage that cholesterol feeding causes to rabbits. (Alissa et al. 2004) Iron deficiency can also be problem for some people, but on the other hand, excessive iron can also be a problem, as can be seen from the people with genes causing haemochromatosis (iron overload). (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 and infections - When the lipopolysaccharides (LPS) of gram-negative gut bacteria end up in your bloodstream, the condition is called "endotoxemia". Robert McLeod on has written an interesting blog post about how endotoxemia can disturb the function of thyroid hormones. Endotoxemia does also correlate with CVD. (Wiedermann et al. 1999)

11. Other potential targets 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, hypoglycemia, acne and the vasculary complications of diabetes.
12. Conclusions

Desiccated thyroid, as a medication, has been studied a few times for prophylaxis of heart disease on clinically euthyroid (no hypothyroidism) people. Without exception, the results have been very favourable: In the studies, the cardiovascular mortality in thyroid-treated patients has been less than a fifth 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.

I see that the professionals do not talk much about the studies I've been talking about here. I'm not really sure what are the reasons. One could be that these studies do not follow the current RCT gold standard, but 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 every clinical trial 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.


* 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)

** In many people, successful thyroid treatment does lower their TSH levels to almost zero.

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

Appendix I: Extra citations from articles related to thyroid function 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.""

1938: Turner et al: The role of the thyroid in the regulation of the cholesterol of rabbits.

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.

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."

1952: Menof P: The thyroid treatment of essential hypertension; report on 334 cases. (pdf) "On the assumption that thyroid insufficiency is the basic factor in the causation of essential hypertension, 334 cases of hypertension were treated with thyroid extract. About 70% responded favourably" "Renal hypertension does not respond to thyroid treatment."

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 secundary 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.]

1958: Wallach et al: Cardiac disease and hypothyroidism; complications induced by initial thyroid therapy.

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)."]

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." [Huom. arvostelija kuitenkin moittii Israelia puutteellisesta datan antamisesta.]

1967: Menof P: High blood pressure and thyroid insufficiency--recent developments. (pdf) "The clinical and experimental evidence in support of the view that a relative thyroid insufficiency is the basic factor in the causation of essential hypertension is summarized."

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."

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."

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."

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."

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."

1991: abdel Khalek et al: Effect of triiodothyronine on cyclic AMP and pulmonary function tests in bronchial asthma. "Twenty-three children clinically euthyroid and complaining of chronic bronchial asthma were given a triiodothyronine (T3) supply for a period of 30 days. [...] All patients tolerated well the T3 regimen without any adverse effect. They all reported at the end of the 30 days an obvious subjective improvement of their asthmatic conditions with a decrease in the number of exacerbations. Seven patients stopped their usual antiasthmatic medicines, being maintained on T3 only and 3 have decreased the amount of bronchodilators needed."

Witztum&Steinberg: Role of exodized 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)."

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."

1996: Escobar-Morreale et al. Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat.

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."

2000: Downing D: Hypothyroidism: Treating the Patient not the Laboratory (pdf)

Taylor-Robinson&Thomas: Chlamydia pneumoniae in atherosclerotic tissue. "71% of atheromatous arteries taken at autopsy from white South African subjects were C. pneumoniae positive compared with 9% of nonatheromatous arteries."

2002: Espinola-Klein et al: Impact of infectious burden on progression of carotid atherosclerosis. "Infectious burden, divided into 0 to 3, 4 to 5, and 6 to 8 seropositivities, was significantly associated with progression of atherosclerosis, with odds ratios of 1.8 (95% confidence interval, 1.1 to 2.9) for 4 to 5 and 3.8 (95% CI, 1.6 to 8.8) for 6 to 8 compared with 0 to 3 seropositivities after adjustment."

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)."

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."

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."]

Lowe et al. Female fibromyalgia patients: lower resting metabolic rates than matched healthy controls.

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"

2007: Roos et al. Thyroid function is associated with components of the metabolic syndrome in euthyroid subjects. "A total of 2703 adult inhabitants of a middle-sized city in The Netherlands participated in this cross-sectional study. Subjects who were not euthyroid were excluded, as were subjects taking thyroid medication, medication for diabetes, and subjects for whom medication data were not available (n = 1122). [...] After adjustment for age and sex, free T4 (FT4) was significantly associated with total cholesterol [standardized beta (beta) = -0.059; P = 0.014], low-density lipoprotein cholesterol (beta = -0.068; P = 0.004), high-density lipoprotein cholesterol (beta = 0.100; P < 0.001), and triglycerides (beta = -0.102; P < 0.001). Both FT4 and TSH were significantly associated with HOMA-IR (beta = -0.133; P < 0.001 and beta = 0.055; P = 0.024, respectively). Median HOMA-IR increased from 1.42 in the highest tertile of FT4 to 1.66 in the lowest tertile of FT4."

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.]

Lowe JC: Inadequate Thyroid Hormone Regulation as the Main Mechanism of Fibromyalgia: A Review of the Evidence

"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."

Lowe JC: Stability, Effectiveness, and Safety of Desiccated Thyroid vs Levothyroxine: A Rebuttal to the British Thyroid Association

2010: Kuppens et al. Maternal thyroid function during gestation is related to breech presentation at term.

2011: Yarur et al. Inflammatory bowel disease is associated with an increased incidence of cardiovascular events. "The unadjusted hazard ratio (HR) for developing CAD in the IBD group was 2.85 [...] IBD patients had significantly lower rates of selected traditional CAD risk factors (hypertension, diabetes, dyslipidemia, and obesity [...] Adjusting for these factors, the HR for developing CAD between groups was 4.08"

2012: Ertaş et al. Low serum free triiodothyronine levels are associated with the presence and severity of coronary artery disease in the euthyroid patients: an observational study. "Continuous variables are expressed as mean±standard deviation [...] the FT3 levels remained as a significant predictor of CAD (OR: 0.266, 95% CI: 0.097-0.731, p=0.01) [...] FT3 remained as a significant predictor of the severity of CAD (OR: 0.238, 95% CI: 0.083-0.685, p=0.008) (Table 3)."

Appendix II: Some citations 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: Citations 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."

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