• Chronic Fatigue and Fibromyalgia look very like Hypothyroidism.
  • Thyroid Patients aren't happy with either the diagnosis or treatment of Hypothyroidism.
  • It is possible that lots of FMS/CFS cases are 'something wrong with the thyroid system that doesn't show up on laboratory hormone level tests'.
  • It's possible that it's not too difficult to fix these CFS/FMS cases with thyroid hormones.
  • I believe that there may have been a stupendous cock-up that's hurt millions.
  • Less Wrong should be interested, because it could be a real example of how bad inference can cause the sciences to come to false conclusions, as well as a good practice problem for the things we really care about.


I found a possible answer here:
I do not believe it, because I do not understand it, but contemplation of it seems to be enlightening. In particular, the problem is much broader than I originally thought.

A summary of the argument in the first two posts, together with links to lots of evidence in the literature:

And this is pretty much proof, I think:

At this point, I think I'm as confident as I can be without some sort of formal trial (so 25% maybe?)

But certainly, if you're suffering from Chronic Fatigue Syndrome/Fibromyalgia/Major Depression/Irritable Bowel Syndrome, or any of the many similar disorders which just seem to be different names for 'hypothyroidism with normal TSH', I reckon this is worth trying!

I have done, and it worked for me. For about four months now...


Original Post:

I believe that I've come across a genuine puzzle, and I wonder if you can help me solve it. This problem is complicated, and subtle, and has confounded and defeated good people for forty years. And yet there are huge and obvious clues. No-one seems to have conducted the simple experiments which the clues suggest, even though many clever people have thought hard about it, and the answer to the problem would be very valuable. And so I wonder what it is that I am missing.

I am going to tell a story which rather extravagantly privileges a hypothesis that I have concocted from many different sources, but a large part of it is from the work of the late Doctor John C Lowe, an American chiropractor who claimed that he could cure Fibromyalgia.

I myself am drowning in confirmation bias to the point where I doubt my own sanity. Every time I look for evidence to disconfirm my hypothesis, I find only new reasons to believe. But I am utterly unqualified to judge. Three months ago I didn't know what an amino acid was. And so I appeal to wiser heads for help.

Crocker's Rules on this. I suspect that I am being the most spectacular fool, but I can't see why, and I'd like to know.

Setting the Scene

Chronic Fatigue Syndrome, Myalgic Encephalitis, and Fibromyalgia are 'new diseases'. There is considerable dispute as to whether they even exist, and if so how to diagnose them. They all seem to have a large number of possible symptoms, and in any given case, these symptoms may or may not occur with varying severity.

As far as I can tell, if someone claims that they're 'Tired All The Time', then a competent doctor will first of all check that they're getting enough sleep and are not unduly stressed, then rule out all of the known diseases that cause fatigue (there are a very lot!), and finally diagnose one of the three 'by exclusion', which means that there doesn't appear to be anything wrong, except that you're ill.

If widespread pain is one of the symptoms, it's Fibromyalgia Syndrome (FMS). If there's no pain, then it's CFS or ME. These may or may not be the same thing, but Myalgic Encephalitis is preferred by patients because it's greek and so sounds like a disease. Unfortunately Myalgic Encephalitis means 'hurty muscles brain inflammation', and if one had hurty muscles, it would be Fibromyalgia, and if one had brain inflammation, it would be something else entirely.

Despite the widespread belief that these are 'somatoform' diseases (all in the mind), the severity of them ranges from relatively mild (tired all the time, can't think straight), to devastating (wheelchair bound, can't leave the house, can't open one eye because the pain is too great).

All three seem to have come spontaneously into existence in the 1970s, and yet searches for the responsible infective agent have proved fruitless. Neither have palliative measures been discovered, apart from the tried and true method of telling the sufferers that it's all in their heads.

The only treatments that have proved effective are Cognitive Behavioural Therapy / Graded Exercise. A Cochrane Review reckoned that they do around 15% over placebo in producing a measurable alleviation of symptoms. I'm not very impressed. CBT/GE sound a lot like 'sports coaching', and I'm pretty sure that if we thought of 'Not Being Very Good at Rowing' as a somatoform disorder, then I could produce an improvement over placebo in a measurable outcome in ten percent of my victims without too much trouble.

But any book on CFS will tell you that the disease was well known to the Victorians, under the name of neurasthenia. The hypothesis that God lifted the curse of neurasthenia from the people of the Earth as a reward for their courage during the wars of the early twentieth century, while well supported by the clinical evidence, has a low prior probability.

We face therefore something of a mystery, and in the traditional manner of my people, a mystery requires a Just-So Story:

How It Was In The Beginning

In the dark days of Victoria, the brilliant physician William Miller Ord noticed large numbers of mainly female patients suffering from late-onset cretinism.

These patients, exhausted, tired, stupid, sad, cold, fat and emotional, declined steeply, and invariably died.

As any man of decent curiosity would, Dr Ord cut their corpses apart, and in the midst of the carnage noticed that the thyroid, a small butterfly-shaped gland in the throat, was wasted and shrunken.

One imagines that he may have thought to himself: "What has killed them may cure them."

After a few false starts and a brilliant shot in the dark by the brave George Redmayne Murray, Dr Ord secured a supply of animal thyroid glands (cheaply available at any butcher, sautée with nutmeg and basil) and fed them to his remaining patients, who were presumably by this time too weak to resist.

They recovered miraculously, and completely.

I'm not sure why Dr Ord isn't better known, since this appears to have been the first time in recorded history that something a doctor did had a positive effect.

Dr Ord's syndrome was named Ord's Thyroiditis, and it is now known to be an autoimmune disease where the patient's own antibodies attack and destroy the thyroid gland. In Ord's thyroiditis, there is no goiter.

A similar disease, where the thyroid swells to form a disfiguring deformity of the neck (goiter), was described by Hakaru Hashimoto in 1912 (who rather charmingly published in German), and as part of the war reparations of 1946 it was decided to confuse the two diseases under the single name of Hashimoto's Thyroiditis. Apart from the goiter, both conditions share a characteristic set of symptoms, and were easily treated with animal thyroid gland, with no complications.

Many years before, in 1835, a fourth physician, Robert James Graves, had described a different syndrome, now known as Graves' Disease, which has as its characteristic symptoms irritability, muscle weakness, sleeping problems, a fast heartbeat, poor tolerance of heat, diarrhoea, and weight loss. Unfortunately Dr Graves could not think how to cure his eponymous horror, and so the disease is still named after him.

The Horror Spreads

Victorian medicine being what it was, we can assume that animal glands were sprayed over and into any wealthy person unwise enough to be remotely ill in the vicinity of a doctor. I seem to remember a number of jokes about "monkey glands" in PG Wodehouse, and indeed a man might be tempted to assume that chimpanzee parts would be a good substitute for humans. Supply issues seem to have limited monkey glands to a few millionaires worried about impotence, and it may be that the corresponding procedure inflicted on their wives has come down to us as Hormone Replacement Therapy.

Certainly anyone looking a bit cold, tired, fat, stupid, sad or emotional is going to have been eating thyroids. We can assume that in a certain number of cases, this was just the thing, and I think it may also be safe to assume that a fair number of people who had nothing wrong with them at all died as a result of treatment, although the fact that animal thyroid is still part of the human food chain suggests it can't be that dangerous.

I mean seriously, these people use high pressure hoses to recover the last scraps of meat from the floors of slaughterhouses, they're not going to carefully remove all the nasty gristly throat-bits before they make ready meals, are they?

The Armour Sausage company, owner of extensive meat-packing facilities in Chicago, Illinois, and thus in possession of a large number of pig thyroids which, if not quite surplus to requirements, at the very least faced a market sluggish to non-existent as foodstuffs, brilliantly decided to sell them in freeze-dried form as a cure for whatever ails you.

Some Sort of Sanity Emerges, in a Decade not Noted for its Sanity

Around the time of the second world war, doctors became interested in whether their treatments actually helped, and an effort was made to determine what was going on with thyroids and the constellation of sadness that I will henceforth call 'hypometabolism', which is the set of symptoms associated with Ord's thyroiditis. Jumping the gun a little, I shall also define 'hypermetabolism' as the set of symptoms associated with Graves' disease.

The thyroid gland appeared to be some sort of metabolic regulator, in some ways analogous to a thermostat. In hypometabolism, every system of the body is running slow, and so it produces a vast range of bad effects, affecting almost every organ. Different sufferers can have very different symptoms, and so diagnosis is very difficult.

Dr Broda Barnes decided that the key symptom of hypometabolism was a low core body temperature. By careful experiment he established that in patients with no symptoms of hypometabolism the average temperature of the armpit on waking was 98 degrees Fahrenheit (or 36.6 Celsius). He believed that temperature variation of +/- 0.2 degrees Fahrenheit was unusual enough to merit diagnosis. He also seems to have believed, in the manner of the proverbial man with a hammer, that all human ailments without exception were caused by hypometabolism, and to have given freeze-dried thyroid to almost everyone he came into contact with, to see if it helped. A true scientist. Doctor Barnes became convinced that fully 40% of the population of America suffered from hypometabolism, and recommended Armour's Freeze Dried Pig Thyroid to cure America's ills.

In a brilliant stroke, Freeze Dried Pig's Thyroid was renamed 'Natural Desiccated Thyroid', which almost sounds like the sort of thing you might take in sound mind. I love marketing. It's so clever.

America being infested with religious lunatics, and Chicago being infested with nasty useless gristly bits of cow's throat, led almost inevitably to a second form of 'Natural Desiccated Thyroid' on the market.

Dr Barnes' hypometabolism test never seems to have caught on. There are several ways your temperature can go outside his 'normal' range, including fever (too hot), starvation (too cold), alcohol (too hot), sleeping under too many duvets (too hot), sleeping under too few duvets (too cold). Also mercury thermometers are a complete pain in the neck, and take ten minutes to get a sensible reading, which is a long time to lie around in bed carefully doing nothing so that you don't inadvertently raise your body temperature. To make the situation even worse, while men's temperature is reasonably constant, the body temperature of healthy young women goes up and down like the Assyrian Empire.

Several other tests were proposed. One of the most interesting is the speed of the Achilles Tendon Reflex, which is apparently super-fast in hypermetabolism, and either weirdly slow or has a freaky pause in it if you're running a bit cold. Drawbacks of this test include 'It's completely subjective, give me something with numbers in it', and 'I don't seem to have one, where am I supposed to tap the hammer-thing again?'.

By this time, neurasthenia was no longer a thing. In the same way that spiritualism was no longer a thing, and the British Empire was no longer a thing.

As far as we know, Chronic Fatigue Syndrome was not a thing either, and neither was Fibromyalgia (which is just Chronic Fatigue Syndrome but it hurts), nor Myalgic Encephalitis. There was something called 'Myalgic Neurasthenia' in 1934, but it seems to have been a painful infectious disease and they thought it was polio.

Finally, Science

It turned out that the purpose of the thyroid gland is to make hormones which control the metabolism. It takes in the amino acid tyrosine, and it takes in iodine. It releases Thyroglobulin, mono-iodo-tyrosine (MIT), di-iodo-tyrosine (DIT), thyroxine (T4) and triiodothyronine (T3) into the blood. The chemistry is interesting but too complicated to explain in a just-so story.

I believe that we currently think that thyroglobulin, MIT and DIT are simply by-products of the process that makes T3 and T4.

T3 is the hormone. It seems to control the rate of metabolism in all cells. T4 has something of the same effect, but is much less active, and called a 'prohormone'. Its main purpose seems to be to be deiodinated to make more T3. This happens outside the thyroid gland, in the other parts of the body ('peripheral conversion'). I believe mainly in the liver, but to some extent in all cells.

Our forefathers knew about thyroxine (T4, or thyronine-with-four-iodines-attached), and triiodothyronine (T3, or thyronine-with-three-iodines-attached)

It seems to me that just from the names, thyroxine was the first one to be discovered. But I'm not sure about that. You try finding a history-of-endocrinology website. At any rate they seem to have known about T4 and T3 fairly early on.

The mystery of Graves', Ord's and Hashimoto's thyroid diseases was explained.

Ord's and Hashimoto's are diseases where the thryoid gland under-produces (hypothyroidism). The metabolism of all cells slows down. As might be expected, this causes a huge number of effects, which seem to manifest differently in different sufferers.

Graves' disease is caused by the thyroid gland over-producing (hyperthyroidism). The metabolism of all cells speeds up. Again, there are a lot of possible symptoms.

All three are thought to be autoimmune diseases. Some people think that they may be different manifestations of the same disease. They are all fairly common.

Desiccated thryoid cures hypothyroidism because the ground-up thyroids contain T4 and T3, as well as lots of thyroglobulin, MIT and DIT, and they are absorbed by the stomach. They get into the blood and speed up the metabolism of all cells. By titrating the dose carefully you can restore roughly the correct levels of the thyroid hormones in all tissues, and the patient gets better. (Titration is where you change something carefully until you get it right)

The theory has considerable explanatory power. It explains cretinism, which is caused either by a genetic disease, or by iodine deficiency in childhood. If you grow up in an iodine deficient area, then your growth is stunted, your brain doesn't develop properly, and your thyroid gland may become hugely enlarged. Presumably because the brain is desperately trying to get it to produce more thyroid hormones, and it responds by swelling.

Once upon a time, this swelling (goitre) was called 'Derbyshire Neck'. I grew up near Derbyshire, and I remember an old rhyme: "Derbyshire born, Derbyshire bred, strong in the arm, and weak in the head". I always thought it was just an insult. Maybe not. Cretinism was also popular in the Alps, and there is a story of an English traveller in Switzerland of whom it was remarked that he would have been quite handsome if only he had had a goitre. So it must have been very common there.

But at this point I am *extremely suspicious*. The thyroid/metabolic regulation system is ancient (universal in vertebrates, I believe), crucial to life, and it really shouldn't just go wrong. We should suspect either an infectious cause, or a recent environmental influence which we haven't had time to adjust to, an evolved defence against an infectious disease, or just possibly, a recently evolved but as yet imperfect defence against a less recent environmental change.

(Cretinism in particular is very strange. Presumably animals in iodine-deficient areas aren't cretinous, and yet they should be. Perhaps a change to a farming from a hunter-gatherer lifestyle has increased our dependency on iodine from crops, which crops have sucked what little iodine occurs naturally out of the soil?)

It's also not entirely clear to me what the thyroid system is *for*. If there's just a particular rate that cells are supposed to run at, then why do they need a control signal to tell them that? I could believe that it was a literal thermostat, designed to keep the body temperature constant at the best speed for the various biological reactions, but it's universal in *vertebrates*. There are plenty of vertebrates which don't keep a constant temperature.

The Fall of Desiccated Thyroid

There turned out to be some problems with Natural Desiccated Thyroid (NDT).

Firstly, there were many competing brands and types, and even if you stuck to one brand the quality control wasn't great, so the dose you'd be taking would have been a bit variable.

Secondly, it's fucking pig's thyroid from an abattoir. It could have all sorts of nasty things in it. Also, ick.

Thirdly, it turned out that pigs made quite a lot more T3 in their thyroids than humans do. It also seems that T3 is better absorbed by the gut than T4 is, so someone taking NDT to compensate for their own underproduction will have too much of the active hormone compared to the prohormone. That may not be good news.

With the discovery of 'peripheral conversion', and the possibility of cheap clean synthesis, it was decided that modern scientific thyroid treatment would henceforth be by synthetic T4 (thyroxine) alone. The body would make its own T3 from the T4 supply.

Alarm bells should be ringing at this point. Apart from the above points, I'm not aware of any great reason for the switch from NDT to thyroxine in the treatment of hypothyroidism, but it seems to have been pretty much universal, and it seems to have worked.

Aware of the lack of T3, doctors compensated by giving people more T4 than was in their pig-thyroid doses. And there don't seem to have been any complaints.

Over the years, NDT seems to have become a crazy fringe treatment despite there not being any evidence against it. It's still a legal prescription drug, but in America it's only prescribed by eccentrics. In England a doctor prescribing it would be, at the very least, summoned to explain himself before the GMC.

However, since it was (a) sold over the counter for so many years, and (b) part of the food chain, it is still perfectly legal to sell as a food supplement in both countries, as long as you don't make any medical claims for it. And the internet being what it is, the prescription-only synthetic hormones T3 and T4 are easily obtained without a prescription. These are extremely powerful hormones which have an effect on metabolism. If 'body-builders' and sports cheats aren't consuming all three in vast quantities, I am a Dutchman.

The Clinical Diagnosis of Hypothyroidism

We pass now to the beginning of the 1970s.

Hypothyroidism is ferociously difficult to diagnose. People complain of 'Tired All The Time' well, ... all the time, and it has literally hundreds of causes.

And it must be diagnosed correctly! If you miss a case of hypothyroidism, your patient is likely to collapse and possibly die at some point in the medium-term future. If you diagnose hypothyroidism where it isn't, you'll start giving the poor bugger powerful hormones which he doesn't need and *cause* hypermetabolism.

The last word in 'diagnosis by symptoms' was the absolutely excellent paper:

Statistical Methods Applied To The Diagnosis Of Hypothyroidism

by W. Z. Billewicz, R. S. Chapman, J. Crooks, M. E. Day, J. Gossage, Sir Edward Wayne, and J. A. Young

Connoisseurs will note the clever and careful application of 'machine learning' techniques, before there were machines to learn!

One important thing to note is that this is a way of separating hypothyroid cases from other cases of tiredness at the point where people have been referred by their GP to a specialist at a hospital on suspicion of hypothyroidism. That changes the statistics remarkably. This is *not* a way of diagnosing hypothyroidism in the general population. But if someone's been to their GP (general practitioner, the doctor that a British person likely makes first contact with) and their GP has suspected their thryoid function might be inadequate, this test should probably still work.

For instance, they consider Physical Tiredness, Mental Lethargy, Slow Cerebration, Dry Hair, and Muscle Pain, the classic symptoms of hypothyroidism, present in most cases, to be indications *against* the disease.

That's because if you didn't have these things, you likely wouldn't have got that far. So in the population they're seeing (of people whose doctor suspects they might be hypothyroid), they're not of great value either way, but their presence is likely the reason why the person's GP has referred them even though they've really got iron-deficiency anaemia or one of the other causes of fatigue.

In their population, the strongest indicators are 'Ankle Jerk' and 'Slow Movements', subtle hypothyroid symptoms which aren't likely to be present in people who are fatigued for other reasons.

But this absolutely isn't a test you should use for population screening! In the general population, the classic symptoms are strong indicators of hypothyroidism.

Probability Theory is weird, huh?

Luckily, there were lab tests for hypothyroidism too, but they were expensive, complicated, annoying and difficult to interpret. Billewicz et al used them to calibrate their test, and recommend them for the difficult cases where their test doesn't give a clear answer.

And of course, the final test is to give them thyroid treatment and see whether they get better. If you're not sure, go slow, watch very carefully and look for hyper symptoms.

Overconfidence is definitely the way to go. If you don't diagnose it and it is, that's catastrophe. If it isn't, but you diagnose it anyway, then as long as you're paying attention the hyper symptoms are easy enough to spot, and you can pull back with little harm done.

A Better Way

It should be obvious from the above that the diagnosis of hypothyroidism by symptoms is absolutely fraught with complexity, and very easy to get wrong, and if you get it wrong the bad way, it's a disaster. Doctors were absolutely screaming for a decisive way to test for hypothyroidism.

Unfortunately, testing directly for the levels of thyroid hormones is very difficult, and the tests of the 1960s weren't accurate enough to be used for diagnosis.

The answer came from an understanding of how the thyroid regulatory system works, and the development of an accurate blood test for a crucial signalling hormone.

Three structures control the level of thyroid hormones in the blood.

The thyroid gland produces the hormones and secretes them into the blood.

Its activity is controlled by the hormone thyrotropin, or Thyroid Signalling Hormone (TSH). Lots of TSH works the thyroid hard. In the absence of TSH the thyroid relaxes but doesn't switch off entirely. However the basal level of thyroid activity in the absence of TSH is far too low.

TSH is controlled by the pituitary gland, a tiny structure attached to the brain.

The pituitary itself is controlled, via Thyroid Releasing Hormone (TRH), by the hypothalamus, which is part of the brain.

This was thought to be a classic example of a feedback control system.


It turns out that the level of thyrotropin TSH in the blood is exquisitely sensitive to the levels of thyroid hormones in the blood.

Administer thyroid hormone to a patient and their TSH level will rapidly adjust downwards by an easily detectable amount.


In hypothyroidism, where the thyroid has failed, the body will be desperately trying to produce more thyroid hormones, and the TSH level will be extremely high.

In Graves' Disease, this theory says, where the thyroid has grown too large, and the metabolism is running damagingly fast, the body will be, like a central bank trying to stimulate growth in a deflationary economy by reducing interest rates, 'pushing on a piece of string'. TSH will be undetectable.

The original TSH test was developed in 1965, by the startlingly clever method of radio-immuno-assay.

[For reasons that aren't clear to me, rather than being expressed in grams/litre, or mols/litre, the TSH test is expressed in 'international units/liter'. But I don't think that that's important]

A small number of people in whom there was no suspicion of thyroid disease were assessed, and the 'normal range' of TSH was calculated.

Again, 'endocrinology history' resources are not easy to find, but the first test was not terribly sensitive, and I think originally hyperthyroidism was thought to result in a complete absence of TSH, and that the highest value considered normal was about 4 (milli-international-units/liter).

This apparently pretty much solved the problem of diagnosing thyroid disorders.


It's no longer necessary to diagnose hypo- and hyper-thyroidism by symptoms. It was error prone anyway, and the question is easily decided by a cheap and simple test.

Natural Desiccated Thyroid is one with Nineveh and Tyre.

No doctor trained since the 1980s knows much about hypothyroid symptoms.

Medical textbooks mention them only in passing, as an unweighted list of classic symptoms. You couldn't use that for diagnosis of this famously difficult disease.

If you suspect hypothyroidism, you order a TSH test. If the value of TSH is very low, that's hyperthyroidism. If the value is very high then that's hypothyroidism. Otherwise you're 'euthyroid' (greek again, good-thyroid), and your symptoms are caused by some other problem.

The treatment for hyperthyroidism is to damage the thyroid gland. There are various ways. This often results in hypothyroidism. *For reasons that are not terribly well understood*.

The treatment for hypothyroidism is to give the patient sufficient thyroxine (T4) to cause TSH levels to come back into their normal range.

The conditions hyperthyroidism and hypothyroidism are now *defined* by TSH levels.

Hypothyroidism, in particular, a fairly common disease, is considered to be such a solved problem that it's usually treated by the GP, without involving any kind of specialist.

Present Day

It was found that the traditional amount of thyroxine (T4) administered to cure hypothyroid patients, was in fact too high. The amount of T4 that had always been used to replace the hormones that had once been produced by a thyroid gland now dead, destroyed, or surgically removed appeared now to be too much. That amount causes suppression of TSH to below its normal range. The brain, theory says, is asking for the level to be reduced.

The amount of T4 administered in such cases (there are many) has been reduced by a factor of around two, to the level where it produces 'normal' TSH levels in the blood. Treatment is now titrated to produce the normal levels of TSH.

TSH tests have improved enormously since their introduction, and are on their third or fourth generation. The accuracy of measurement is very good indeed.

It's now possible to detect the tiny remaining levels of TSH in overtly hyperthyroid patients, so hyperthyroidism is also now defined by the TSH test.

In England, the normal range is 0.35 to 5.5. This is considered to be the definition of 'euthyroidism'. If your levels are normal, you're fine.

If you have hypothyroid symptoms but a normal TSH level, then your symptoms are caused by something else. Look for Anaemia, look for Lyme Disease. There are hundreds of other possible causes. Once you rule out all the other causes, then it's the mysterious CFS/FMS/ME, for which there is no cause and no treatment.

If your doctor is very good, very careful and very paranoid, he might order tests of the levels of T4 and T3 directly. But actually the direct T4 and T3 tests, although much more accurate than they were in the 1960s, are quite badly standardised, and there's considerable controversy about what they actually measure. Different assay techniques can produce quite different readings. They're expensive. It's fairly common, and on the face of it perfectly reasonable, for a lab to refuse to conduct the T3 and T4 tests if the TSH level is normal.

It's been discovered that quite small increases in TSH actually predict hypothyroidism. Minute changes in thyroid hormone levels, which don't produce symptoms, cause detectable changes in the TSH levels. Normal, but slightly high values of TSH, especially in combination with the presence of thyroid related antibodies (there are several types), indicate a slight risk of one day developing hypothyroidism.

There's quite a lot of controversy about what the normal range for TSH actually is. Many doctors consider that the optimal range is 1-2, and target that range when administering thyroxine. Many think that just getting the value in the normal range is good enough. None of this is properly understood, to understate the case rather dramatically.

There are new categories, 'sub-clinical hypothyroidism' and 'sub-clinical hyperthyroidism', which are defined by abnormal TSH tests in the absence of symptoms. There is considerable controversy over whether it is a good idea to treat these, in order to prevent subtle hormonal imbalances which may cause difficult-to-detect long term problems.

Everyone is a little concerned about accidentally over-treating people, (remember that hyperthyroidism is now defined by TSH<0.35).

Hyperthyroidism has long been associated with Atrial Fibrillation (a heart problem), and Osteoporosis, both very nasty things. A large population study in Denmark recently revealed that there is a greater incidence of Atrial Fibrillation in sub-clinical hyperthyroidism, and that hypothyroidism actually has a 'protective effect' against Atrial Fibrillation.

It's known that TSH has a circadian rhythm, higher in the early morning, lower at night. This makes the test rather noisy, as your TSH level can be doubled or halved depending on what time of day you have the blood drawn.

But the big problems of the 1960s and 1970s are completely solved. We are just tidying up the details.


Many hypothyroid patients complain that they suffer from 'Tired All The Time', and have some of the classic hypothyroid symptoms, even though their TSH levels have been carefully adjusted to be in the normal range.

I've no idea how many, but opinions range from 'the great majority of patients are perfectly happy' to 'around half of hypothyroid sufferers have hypothyroid symptoms even though they're being treated'.

The internet is black with people complaining about it, and there are many books and alternative medicine practitioners trying to cure them, or possibly trying to extract as much money as possible from people in desperate need of relief from an unpleasant, debilitating and inexplicable malaise.


Not good data, to be sure. But if ten people mention to you in passing that the sun is shining, you are a damned fool if you think you know nothing about the weather.

It's known that TSH ranges aren't 'normally distributed' (in the sense of Gauss/the bell curve distribution) in the healthy population.

If you log-transform them, they do look a bit more normal.

The American Academy of Clinical Biochemists, in 2003, decided to settle the question once and for all. They carefully screened out anyone with even the slightest sign that there might be anything wrong with their thyroid at all, and measured their TSH very accurately.

In their report, they said (this is a direct quote):

In the future, it is likely that the upper limit of the serum TSH euthyroid reference range will be reduced to 2.5 mIU/L because >95% of rigorously screened normal euthyroid volunteers have serum TSH values between 0.4 and 2.5 mIU/L.

Many other studies disagree, and propose wider ranges for normal TSH.

But if the AACB report were taken seriously, it would lead to diagnosis of hypothyroidism in vast numbers of people who are perfectly healthy! In fact the levels of noise in the test would put people whose thyroid systems are perfectly normal in danger of being diagnosed and inappropriately treated.

For fairly obvious reasons, biochemists have been extremely, and quite properly, reluctant to take the report of their own professional body seriously. And yet it is hard to see where the AACB have gone wrong in their report.

Neurasthenia is back.

A little after the time of the introduction of the TSH test, new forms of 'Tired All The Time' were discovered.

As I said, CFS and ME are just two names for the same thing. Fibromyalgia Syndrome (FMS) is much worse, since it is CFS with constant pain, for which there is no known cause and from which there is no relief. Most drugs make it worse.

But if you combine the three things (CFS/ME/FMS), then you get a single disease, which has a large number of very non-specific symptoms.

These symptoms are the classic symptoms of 'hypometabolism'. Any doctor who has a patient who has CFS/ME/FMS and hasn't tested their thyroid function is *de facto* incompetent. I think the vast majority of medical people would agree with this statement.

And yet, when you test the TSH levels in CFS/ME/FMS sufferers, they are perfectly normal.

All three/two/one are appalling, crippling, terrible syndromes which ruin people's lives. They are fairly common. You almost certainly know one or two sufferers. The suffering is made worse by the fact that most people believe that they're psychosomatic, which is a polite word for 'imaginary'.

And the people suffering are mainly middle-aged women. Middle-aged women are easy to ignore. Especially stupid middle-aged women who are worried about being overweight and obviously faking their symptoms in order to get drugs which are popularly believed to induce weight loss. It's clearly their hormones. Or they're trying to scrounge up welfare benefits. Or they're trying to claim insurance. Even though there's nothing wrong with them and you've checked so carefully for everything that it could possibly be.

But it's not all middle aged women. These diseases affect men, and the young. Sometimes they affect little children. Exhaustion, stupidity, constant pain. Endless other problems as your body rots away. Lifelong. No remission and no cure.

And I have Doubts of my Own

And I can't believe that careful, numerate Billewicz and his co-authors would have made this mistake, but I can't find where the doctors of the 1970s checked for the sensitivity of the TSH test.

Specificity, yes. They tested a lot of people who hadn't got any sign of hypothyroidism for TSH levels. If you're well, then your TSH level will be in a narrow range, which may be 0-6, or it may be 1-2. Opinions are weirdly divided on this point in a hard to explain way.

But Sensitivity? Where's the bit where they checked for the other arm of the conditional?

The bit where they show that no-one who's suffering from hypometabolism, and who gets well when you give them Desiccated Thyroid, had, on first contact, TSH levels outside the normal range.

If you're trying to prove A <=> B, you can't just prove A => B and call it a day. You couldn't get that past an A-level maths student. And certainly anyone with a science degree wouldn't make that error. Surely? I mean you shouldn't be able to get that past anyone who can reason their way out of a paper bag.

I'm going to say this a third time, because I think it's important and maybe it's not obvious to everyone.

If you're trying to prove that two things are the same thing, then proving that the first one is always the second one is not good enough.


It's possible, of course, that I've missed this bit. As I say, 'History of Endocrinology' is not one of those popular, fashionable subjects that you can easily find out about.

I wonder if they just assumed that the thyroid system was a thermostat. The analogy is still common today.

But it doesn't look like a thermostat to me. The thyroid system with its vast numbers of hormones and transforming enzymes is insanely, incomprehensibly complicated. And very poorly understood. And evolutionarily ancient. It looks as though originally it was the system that coordinated metamorphosis. Or maybe it signalled when resources were high enough to undergo metamorphosis. But whatever it did originally in our most ancient ancestors, it looks as though the blind watchmaker has layered hack after hack after hack on top of it on the way to us.

Only the thyroid originally, controlling major changes in body plan in tiny creatures that metamorphose.

Of course, humans metamorphose too, but it's all in the womb, and who measures thyroid levels in the unborn when they still look like tiny fish?

And of course, humans undergo very rapid growth and change after we are born. Especially in the brain. Baby horses can walk seconds after they're born. Baby humans take months to learn to crawl. I wonder if that's got anything to do with cretinism.

And I'm told that baby humans have very high hormone levels. I wonder why they need to be so hot? If it's a thermostat, I mean.

But then on top of the thyroid, the pituitary. I wonder what that adds to the system? If the thyroid's just a thermostat, or just a device for keeping T4 levels constant, why can't it just do the sensing itself?

What evolutionary process created the pituitary control over the thyroid? Is that the thermostat bit?

And then the hypothalamus, controlling the pituitary. Why? Why would the brain need to set the temperature when the ideal temperature of metabolic reactions is always 37C in every animal? That's the temperature everything's designed for. Why would you dial it up or down, to a place where the chemical reactions that you are don't work properly?

I can think of reasons why. Perhaps you're hibernating. Many of our ancestors must have hibernated. Maybe it's a good idea to slow the metabolism sometimes. Perhaps to conserve your fat supplies. Your stored food.

Perhaps it's a good idea to slow the metabolism in times of famine?

Perhaps the whole calories in/calories out thing is wrong, and people whose energy expenditure goes over their calorie intake have slow metabolisms, slowly sacrificing every bodily function including immune defence in order to avoid starvation.

I wonder at the willpower that could keep an animal sane in that state. While its body does everything it can to keep its precious fat reserves high so that it can get through the famine.

And then I remember about Anorexia Nervosa, where young women who want to lose weight starve themselves to the point where they no longer feel hungry at all. Another mysterious psychological disease that's just put down to crazy females. We really need some female doctors.

And I remember about Seth Robert's Shangri-La Diet, that I tried, to see if it worked, some years ago, just because it was so weird, where by eating strange things, like tasteless oil and raw sugar, you can make your appetite disappear, and lose weight. It seemed to work pretty well, to my surprise. Seth came up with it while thinking about rats. And apparently it works on rats too. I wonder why it hasn't caught on.

It seems, my female friends tell me, that a lot of diets work well for a bit, but then after a few weeks the effect just stops. If we think of a particular diet as a meme, this would seem to be its infectious period, where the host enthusiastically spreads the idea.

And I wonder about the role of the thyronine de-iodinating enzymes, and the whole fantastically complicated process of stripping the iodines and the amino acid bits from thyroxine in various patterns that no-one understands, and what could be going on there if the thyroid system were just a simple thermostat.

And I wonder about reports I am reading where elite athletes are finding themselves suffering from hypothyroidism in numbers far too large to be credible, if it wasn't, say, a physical response to calorie intake less than calorie output.

I've been looking ever so hard to find out why the TSH test, or any of the various available thyroid blood tests are a good way to assess the function of this fantastically complicated and very poorly understood system.

But every time I look, I just come up with more reasons to believe that they don't tell you very much at all.

The Mystery

Can anyone convince me that the converse arm has been carefully checked?

That everyone who's suffering from hypometabolism, and who gets well when you give them Desiccated Thyroid, has, before you fix them, TSH levels outside the normal range.

In other words, that we haven't just thrown, though carelessness, a long standing, perfectly safe, well tested treatment, for a horrible disabling disease that often causes excruciating pain, that the Victorians knew how to cure, and that the people of the 1950s and 60s routinely cured, away.

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This sounds like a job for Sarah Constantin, formerly of MetaMed...

1Adele Lopez3y
She's seems to agree there's an issue: (from
If anyone can stick this post and the follow-up in front of someone open-minded and competent, I'd love to hear their reactions to it!

There actually is a way to test for Chronic Fatigue Syndrome. Have someone exercise (to the extent they can) and have them try to repeat the performance the next day. Most people will do about as well; CFS sufferers will do about 20% worse.

One of the things John Lowe spent his life doing was to track down evidence that clinically, fibromyalgia and hypothyroidism are the same thing. He certainly thought he'd proved it, and wrote a review paper called Inadequate Thyroid Hormone Regulation as the Main Mechanism of Fibromyalgia: A Review of the Evidence You can find it here: I haven't followed up the references, but he gave four for exercise intolerance/fibromyalgia and four for exercise intolerance/hypothyroidism.
Yes, Sarah Myhill (an English doctor who specializes in chronic fatigue) has published a fabulous paper (really good actually, reads more like physics than the usual medical rubbish) attributing the whole thing to an inability of the mitochondria to recycle ATP. If your mitochondria were completely buggered, that would presumably cut your easily available energy by a factor of about 30, before you have to go into anaerobic respiration. Imagine that! Climbing the stairs in your house might feel like walking up to the top of a tower block, and significant exercise would shatter you like a marathon does, and leave lots of lactic acid behind, which sounds a bit like the muscle pain in fibromyalgia. So now we've got two competing explanations, which is the closest I've come to breaking my idea. But of course, the thyroid hormones have effects on the mitochondria! I think she thinks it's mostly environmental, and of course it could well be, but that doesn't mean the extra T3 might not alleviate the symptoms. I wrote to Doctor Myhill asking her if they could be the same thing, but no reply. I don't know if that means she's thinking about it or whether she gets enough crank letters as it is. I have an awful lot more to say about this, but the essay above is the bit that I'm fairly sure of. The rest is all wild speculation. But I intend to write it all down, and if Less Wrong is interested then this is a good place to post it. It occurred to me that we needed another Amanda Knox. This looks like one, if we can solve it. As well as the side effect of doing a terrific amount of good in the world. Part of me thinks, hang on, all this is just bloody obvious and there are loads of alternative medicine people and doctors talking about it. And part of me thinks, if it's so obvious, why has no-one bothered to refute it/been able to prove it? I have a feeling that the answer is actually going to be very complicated, and involve a lot of bad science and human feelings getting
...and there are mutations in mitochondrial DNA, which on one hand should have already been tested and rejected and don't seem very likely, given inheritance patterns, and on the other are linked to some relevant illnesses (although not fibromyalgia itself, if I understand Wiki right).

"I am going to tell a story .. "

Please, no.

Not to pick on you, as this is a pet peeve of mine, but I don't know how people are being taught to write anymore.

Three paragraphs in, and I don't know what you're talking about yet. And now it's story time! Somebody put a bullet in me!

Particularly if you're trying to convey a thesis, how about an abstract, or a brief description of the question you're trying to evaluate?

Give me a frame to start hanging information on as I read the article. What are we trying to accomplish here?

Otherwise, the article washes over me like a drive in the country. An annoying drive, because I spend my time wondering where the hell we're going.

EDIT: And whaddya know? Looks like it's all about thyroid hormones. I happen to be hypothyroid, am currently taking medication, and have done a bunch of reading about it.

Changed title to be less cryptic and put a summary of what it's about and why we should be interested. Is that better? If not, how should I fix it? Thanks for your help.

I'm still a bit at a loss for the specific thesis you're trying to sell. Or at least test. In your abstract, you're not giving me relevant facts to a specific thesis or conjecture.

Let me try. Mine is turning into a summary more than an abstract to more easily include elements of your story.

Here goes:

Pre 1900 there was a "tiredness" disease called neurasthenia. People died. On dissection, a doctor noticed that the cadavers had shrunken thyroid glands. "Hey, maybe if I chopped up pig's thyroids and give it to them, it would help." And it did. But people didn't really know what was going on. Armour (as in Armour ham) was slaughtering lots of pigs, so standardized the generation of pig thyroids in a desiccated form, known today as Armour Thyroid, or more generically from all manufactures as natural desiccated thyroid (NDT).

So, science marches on, and after WWII people investigated what was going on with NDT and neurasthenia and we learned that the thyroid gland produces hormones T3 and T4 from a TSH stimulus from the pituitary, from a TRH signal from the hypothalamus, which is controlled through a negative feedback loop by T3 and T4 levels in the blood.

And, whadd... (read more)

Dan, this post was a question, not a thesis. The thesis I am now trying to promote is 'there are type 2 versions of endocrine disorders, and this is very important indeed if it is true'. See follow up post:
It occurs that I could just delete the first three paragraphs. Anyone else think that's a good idea? All I'm trying to say there is 'don't trust me', 'this is interesting, important and hard', and 'it's mostly John Lowe's ideas'.
That's a good rule for editing in general; if you can remove something without losing any value, remove it. (Apply this on multiple levels: a chapter in a book, a paragraph in a chapter, a word in a sentence.) Sometimes instead of thinking too much when one writes, it is better to just write, and delete the unnecessary parts afterwards. Sometimes I reduce my e-mails to half or less, when I have enough time to write them. However, what gjm said: adding an abstract is even better. You can do both, of course.
It might be, but would be a much bigger improvement. Maybe some other signposts to help the reader grasp the structure of what you're doing, but I think most important is for the reader to go in with some idea of (1) what's at issue and (2) what you're suggesting might be true. And maybe also of (3) what the prevailing consensus is and (4) why you think it might be wrong. Of course laying out #3 and #4 is the purpose of the whole article, but maybe you can give a brief summary for readers to hang their thoughts on.
Yeah, signposts are good too. Where are we going, how are we getting there? Give the reader some structure up front to help him organize and consume the mass of info. And just know if he wants to read it too. There is a snide comment I got from somewhere, but it comes to mind often: Don't make me wonder.
Dan, thanks. (a) How can I do better? (b) If you're on thyroid meds, how is that working out? Can you tell me what works for you? If you don't want to talk about it publicly, I'd appreciate a private message, and I undertake to keep it anonymous. I'll just absorb it into my list of things thyroid patients say.
a) Early on, an abstract or thesis statement. Is there a particular question you're going to get to? If so, knowing it upfront would allow the reader to marshal the rest of the post as it relates to that question, as they read it. b) I'm not shy about the thyroid. I'm hypothyroid with high TSH (primary hypothyroid?) but not tremendously. I've chosen to use the dessicated thyroid for the various components it has which more closely mimics what a thyroid produces in response to TSH. I target TSH < 2.0, which leaves T3 and T4 in the normal ranges, but higher than they would be if I took no meds.
Cool, thanks. What was your original TSH? I had symptoms with TSH 2.53, then got much worse, My GP was absolutely brilliant and ruled out everything we could think of. Then a friend recommended iron supplements (Floradix, also contains many B vitamins), which shouldn't have worked since I wasn't Anaemic. I tried them just to pacify her, and made a miraculous recovery. Once I had my mind back I started researching, and convinced myself that it was likely hypothyroidism and it was worth trying desiccated thyroid. By Christmas the symptoms were back and my TSH 4.0. Against my doctor's advice I started taking very small doses of desiccated thyroid and for the last month I've been feeling absolutely wonderful. But I think the effect is now starting to fade, although I'm not symptomatic yet, just less bouncy. So I'm wondering what lies ahead. It wouldn't surprise me if my brain kept dialing my thyroid back to compensate for the NDT, which would mean that I'd have to keep raising the dose. That doesn't sound like it ends well.... Still, death in the cause of science is better than the ghastly half-life I've been living for the last year. How is it all working out for you?
TSH had been in the 3+ range, with T3,T4 in the low end of normal, probably for a decade before I started any treatment - I started with dessicated thyroid. Your experience with the iron is interesting - I checked ferritin levels and they were ok, so I didn't go in that direction. Two grains brought TSH down around 2, and brought T3,T4 to upper half of their ranges. One thing interesting. I was going through a bad time emotionally and financially when I started, and I went up to 3 grains to try to get TSH down to around 1.5. That brought TSH to 0, and brought me to the worst depression of my life. I tend toward anhedonia and flat emotions, and I kind of wonder if I was just finally "getting in touch with my feelings" - i.e., I had things to be unhappy about, and was finally actually feeling them. From my reading, apparently a depressive crash is common enough to be notice by people starting on thyroid hormones. I don't recall a doctor ever mentioning this, but I did see it at thyroid support sites. Something for you to be aware of, particularly if you're upping your doses on your own say so. I was off of any meds for a year, and when I next tested TSH was up to 5, though free T3, free T4, reverse T3 were technically still in the low normal range. I've started back on 2 grains. Last test that only brought TSH down to ~4, but I didn't test T3,T4 so I don't know how they're doing. I've got more fiddling around to do. Not indefinitely. If you pull back TSH levels < 2.0, and you still have symptoms, then maybe you have some other problem. My philosophy on hormones is to get them in a "good" (not just "normal") range. If you still have some issues, then you start looking around. Yeah. If you've got a health issue, do something about it. I regret the time I haven't spent doing something. No regrets, even when experiments went awry. Much better than doing nothing.
Hi Dan, I can confirm your observations and I thank you for them. Not a depressive crash, but a sudden and totally unexpected intensification of my normal emotions over the last few days, on 21mg/day of desiccated thyroid. It was quite obvious from the inside, thanks to your warning. No hyper symptoms at all. I've been watching for them. I contacted a friend with some experience of psychiatric diagnosis, and he and I agree that I'm showing some of the symptoms of a mild bipolar disorder. I may have caused it, or that may have been the problem all along. The down phase looks like CFS, apparently, and is quite common. But who knows? He's advised me to stop obsessing about this problem, and I'm going to try. For obvious reasons this should be my last comment on the matter for a while! Sorry to waste everyone's time. Pray for me, those of you who believe that it will help. Once I'm completely sure that I'm capable of thinking straight, I might come back and re-read what I've written to see how much sense it makes. How embarrassing to go mad in public. Thank you all. Talk about reasoning under uncertainty!
That's a better description of what I experienced. It was depression in the sense of an intensification of anxiety and sadness, not in the sense of lethargy and apathy. Also, I think I was having heart palpitations. The thing is, I think the symptoms you list are Hyper symptoms. I googled HYPERthyroid symptoms, and sometimes saw mentions of bipolar, crying fits, and mood swings, along with the usual heart palpitations and anxiety. I wonder if sudden increases in thyroid levels at low basal levels can have some of the same effects as long term high basal levels. That's consistent with some models of psychiatric meds - at low basal levels, you're upregulated to compensate, so that initial bumps are equivalent to high basal levels until your system downregulates. I don't mean to feed the obsession, but at the time the worst aspect was feeling in the grips of some psychological problem I didn't understand, instead of merely just having a reaction to meds. As I hazily recall, I think I backed off on the dosage and the symptoms went away a few days thereafter. Take care of yourself. Oh. Just got some lab work back. TSH down to 2.2. T3 mid range. DHEA/Progesterone/T/E2 all right where I want them (I'm big on life extension and HRT). Yay!
Dan, again I hear you and agree. I thought I was being so careful. What a fool I am. Good luck! Be careful. Note the awe-inspiring lack of smugness with which I pretend to greet your news.
In case anyone is worried, my attorney (who really really should know, and who spotted me going off the rails at almost the same time that I did) advises me that I am no longer any more mad than usual, and gives me permission once again to contemplate the question of the thyroid. I still have a feeling that I am experiencing my emotions full strength for the first time in ten years, and I have forgotten how to do that. Another bloody skill to learn. Personally, I have found not thinking about this to be a most relaxing hobby, and I intend to do more of it in future. I have found great solace in sport, history, literary theory, ancient mythology, and popular music. And much unexpected wisdom there! Those of you who prayed, thank you. It appears to have worked. Those of you who did not, well, I wouldn't have bothered either. But were you scared to try the experiment? If so, and you did not, you are far from the way. As are we all.
Hi Dan, thanks for this. (a) I haven't read anything about starting on thyroid hormones causing depression. I haven't noticed it myself. I know that depression is a symptom of hypothyroidism, and that hyperthyroidism often starts with a feeling of unusual well-being. I've recently learned that the thyroid hormones are sometimes used to treat depression, especially in people who don't respond to anti-depressants. Googling doesn't get me anywhere. Can you link me to a website where people are reporting that their use of thyroid hormones causes a depressive crash? This is very interesting. (b) 2 grains (120mg) per day of desiccated thyroid is a lot. I believe that 2-3 grains was once considered the full replacement dose, i.e., what you'd give to someone if their thryoid had completely failed or been removed. For comparison, I had a TSH of 4 when I started messing about. I weigh about 90kg, and around 21mg/day seems to be optimal for me, and +/-4mg to that causes very noticeable changes (either sluggishness or an over-stimulated anxious state) after a few days. I've felt completely brilliant doing this for about a month, now I think I feel the effect fading. If your thyroid system is just a bit on the low side, then I'd imagine that if you take that much you'll cause your own thyroid to back off as hard as it can. Obviously that's not consistent with a TSH of 4, but the TSH of 0 sounds right for that. There's too much T3 in desiccated thyroid. I'd imagine that lots of T3 and not much T4 is every bit as bad for you as the reverse. You should probably find an 'unconventional' endocrinologist to work with on this. If you can't, maybe start with very low doses and work up? And obviously, I'm not a doctor. I have no business giving this sort of advice, and I'm only experimenting on myself because I have no alternative. I suspect I'm going to end up doing myself major harm.
I believe it was a Yahoo Group: That 2-3 grains as full replacement may be about right for me, at least once upon a time. 2 grain brought my TSH under 2. When I went to 3, TSH went to 0. I did go from 1 to 2. 1 brought TSH down in the mid 2s, I think, so I took more, targeting < 2. Thanks for the tip on dessicated thyroid having too much T3. I'll look into it sometime. I appreciate the info, even if you're not a MD.
Hi Dan, I've tried to join that group pseudonymously, don't know if they'll let me in but I'm reluctant to give them my real e-mail address. From their front page, they're wrong about NDT. It doesn't contain T2 or T1, which are deiodination products of T3 and T4. It does contain MIT/DIT, but they're different things. NDT contains T3/T4 in 4:1 or 5:1 ratio, and T3 is better absorbed through the gut, I believe. Human thyroid is believed to secrete T3/T4 in 10:1 or 15:1 ratio, so a priori NDT is just as bad an idea as T4 monotherapy. None of these numbers are solid, research on this has just not been done carefully. On this, John Lowe and Kenneth Blanchard disagree. John Lowe loved NDT, Ken Blanchard thinks over-replacing T3 is just as bad as over-replacing T4. There are interesting papers about rats by Escobar-Morreale et al. My (excellent) GP thinks that around 2% of his patients are unhappy on T4 monotherapy. Obviously Blanchard, Lowe and others see the subset of patients for whom traditional T4 monotherapy doesn't work and that will have skewed their judgement even if they're inferring accurately. I have read reports claiming a 16% single-nucleotide polymorphism in the deiodinating enzyme 2 gene that controls T4->T3 conversion in the brain. I can square this with my GP's estimate by assuming that he only gets major complaints from those with the homozygote version of the DIO2 allele, which will have a prevalence of 0.16^2=0.0256 Also, for the love of God read up on the symptoms of hyperthyroidism/hypermetabolism, and make sure you take notice if you get any. If you screw around with this system you can make yourself hyper and hypo at the same time. I am so not a doctor. Do not believe a word I or anyone else says on this issue. We are all wrong. If it was easy, it would be properly understood. Hope this helps!

[Epistemic status: speculative. Definitely don't try to make a decision based on this without speaking to an endocrinologist first.]

So, let me see if I understand what you wrote, adding in a few things I read on Wikipedia and the interpretations that seem obvious to me.

T3 controls metabolic rate, by upregulating metabolic processes throughout the body. TSH controls the concentration of T3 by setting the rate at which T4 is converted to T3. TSH is tested for, T3 and T4 are usually not. The Wikipedia page for TSH lists diagnoses for the cross-product of T3 and TSH, with primary hyper- and hypothyroidism corresponding to the cases where they are mismatched: high TSH and low T3, or low TSH and high T3. Cases where T3 and TSH are both low indicate iodine deficiency, because iodine is also a necessary part of the conversion from T4 to T3. TSH is linked to the circadian rhythm.

Adding a bit of interpretation of my own, TSH represents the difference between the body's overall metabolic rate is, and what some mechanism thinks it should be. Under this model, symptoms of metabolic-rate-too-low would appear if:

  • That unspecified mechanism were disrupted such that TSH was targeting a level of ac
... (read more)
Jim, I think you've essentially got the standard picture, except that TSH is thought to be the thing controlling T4/T3 production. There are those that say that it also controls T4->T3 conversion. This paper: Homeostatic Control of the Thyroid–Pituitary Axis: Perspectives for Diagnosis and Treatment Rudolf Hoermann, John E. M. Midgley, Rolf Larisch and Johannes W. Dietrich Suggests that it's all a bit more complicated than that though. And I'd imagine that high TSH might make your thyroid swell, or what are goiters? Apparently goiters and cretinism used to be anticorrelated in areas where both were popular. I'm certainly not suggesting that anyone with CFS should start snorting pig thyroid! I think that's just sticking a screwdriver in a complicated control mechanism. You might well provoke a response..... I am saying that CFS/FMS/hypothyroidism look far too similar for it to be a coincidence, two different diseases with the exact same symptoms apart from TSH, and that CFS may well be related to some aspect of disturbed metabolic rate-control. And that I don't think that the normal TSH of CFS sufferers is enough to prove that CFS is something else entirely. And obviously, I wonder if pig-thyroid might not be a bad screwdriver to stick in. And I'm puzzled that no-one's tried it in a PCRT. There are occasional papers where someone's given T4 alone to tired people (well, I've read one). That doesn't seem to work, or at least if it did work on a couple of them it wasn't enough of them to make a statistically significant difference to the group as a whole. And there are other papers where people have given T4/T3 mixes to hypothyroid cases. There was a famous one where it measurably worked, and lots of attempts to replicate it with slightly different cocktails that didn't. And of course, scientific statistics being what it is that's gone down as 1 vote for, 7 votes against, so the initial interest has died down. I think it's pretty solid that some patients prefer
Buskila, Sarzi-Puttini and Ablin in their paper The genetics of fibromyalgia syndrome (Pharmacogenomics, 8(1) 67-74) say it is probably polygenic, so perhaps there is significant overlap in the genes making people more likely to get either of the disorders. (I only read the abstract.)
Damn, I can only see the abstract. I'd like to see that paper if anyone has a copy. They seem to be fingering endocrine genes, but adrenal rather than thyroid. A lot of alternative medicine people talk about 'adrenal fatigue' in this context, but I hadn't been paying much attention to that since 'real' doctors don't think it's a thing. But I don't know what I'm talking about! Can anyone who does read that paper and tell us what it means?
Both the paper and an update to it can be found quite easily on Library Genesis.
Ooh, that is an interesting site. Thankyou. Paper downloaded and will read.
Thanks, I'll have a look! Other minds finding reasons why I'm wrong is exactly why I stuck this on Less Wrong. (Also it's just quite a fun puzzle)
Meh, I don't think you are wrong, I just think you will have to incorporate genome sequencing in recommendations for future research (even if you won't conduct it yourself). Maybe some of the genes they found should go into the confounder bin?.. And of course, they mention 'additional comorbid conditions' (cretinism?), so it will be a very convoluted question. Not to mention that you should also look up any studies on 1) whether pig-thyroid-eating people had better or worse outcomes when compared to what is expected from an equivalent dose of pure hormones, and 2) what substances are found in the preparation (preferably something with mass-spectrometry as the method ofidentification) & how it was made (I don't know a thing about pigs, but they do have parathyroid glands - could those be included, too?), 3) how well do the respective forms of hormone store (under such freeze-drying conditions) - I bet that they decompose at different rates, which means... I can't even say what it wouldean right now, except that standardization of doses should be difficult. Er, hope that helps.
1) Can't find any data on this. 1970s experiments concluded pig-thyroid much worse than pure T4, but they were using very large doses of T4, and when they swapped some of it for T3, it might have over-ridden the conversion mechanism and produced hyper symptoms. Also I suspect that only a small number (ballpark 16% notice, 2% notice strongly) of people would be happier on T4/T3 mix. Also there's too much T3 in pig-thyroid, it is thought. T3 monotherapy generally believed to be a disaster. And I would suspect that to be right if I didn't have John Lowe's posthumous word that it works well for some people including him. 2) I'd love to see that if you know where it might be found. 3) Christ alone knows. One of the original concerns with pig-thyroid was inconsistency. I think they do it better now. Synthetic T4 also has a slightly patchy consistency record, according to some sources.
I wonder about this. A lot of things, including cancers, are caused by viruses / may be caused by undiscovered infective agents. If slow metabolism also slows your immune system, then a lot of horrid things might take advantage of that fact. Cochran said that on genetic load grounds alone, we should expect an awful lot of diseases we currently think are non-infective to be cryptically infective (e.g. ulcers) or recent broken infection defenses (e.g. sickle-cell).
Not sure if you're saying this, but to be clear, I don't think that your suggestion and user:jimrandomh's are mutually exclusive.

This post is 5 years old, but I just came across it and it's sent me off into a rabbit hole of learning about hypothyroidism and the community of rogue practitioners that argue for treating CFS as a thyroid problem. 

I've had CFS ever since a sinus infection 7 years ago. I've mostly given up on finding a solution, but periodically check to see if there's any new research. Somehow I'd totally missed the thyroid angle, presumably because I've been told so many times that my thyroid function (measured by TSH) is normal. 

Anyway, @johnlawrenceaspden , ... (read more)

Thank you, that is most interesting! I wouldn't call this nearly conclusive evidence, but I would certainly call it further weak evidence to stick on the pile.  My favourite in this line is Gordon Skinner's paper "Clinical Response to Thyroxine Sodium in Clinically Hypothyroid but Biochemically Euthyroid Patients". I did once make a subreddit devoted to this sort of thing: and stuck everything I found on it, but it's drawn remarkably little interest. I'll read this nice new paper and add it there. But you want to hear about my own experiences, so: In short, thyroid's been an almost perfect fix for me ever since I wrote all that, so much so that I've lost interest in the subject. I currently take 100ug of T4 and 1 grain of NDT every day, and that's been fairly stable for around four years now. My TSH is almost always suppressed (i.e. 0), but my only health problems are sports injuries, and I don't have any of the symptoms of hyperthyroidism. I don't feel *perfectly* well, occasionally I feel a bit more tired than seems reasonable, and sometimes I get depressed for no good reason, but usually fiddling around with the dose seems to sort that out.  (too hot, down a bit, too tired/sad, up a bit) I've never gone back to being the bouncy energetic person I was in my thirties, but it's nothing compared to the living hell of chronic fatigue syndrome. I play tennis three times a week and cycle to my office every day. However, I do know two or three people who had something CFS-like and bought my arguments and tried thyroid to fix it, and all they got was a feeling of overstimulation, like drinking far too much coffee, and they didn't think it was worth sticking with. So it clearly won't fix everybody or even a plurality of CFS people. That wasn't my experience, for me it was an excellent instant fix for everything that was wrong with me. Too good to be true.
Oops, went to post this paper on my little subreddit and it's already there! There's quite a lot of this sort of stuff in the literature, what we need is someone to give it a go in a proper trial and work out whether it really helps. I'm sure that it will work for some people, I'm fairly sure that it won't work for everyone.  If I take Gordon Skinner seriously, then a good 'diagnosis of hypothyroidism by symptoms' should be what would tell you in advance whether it would work or not. But honestly, if you're careful enough that you can try this on yourself without doing harm, just give it a go. Do tell your doctor what you're doing. He'll tell you not to, but he can keep an eye on you while you do it anyway.

I've only skimmed this but let me give a bunch of info that seems relevant. (As I understand it, the question is whether low thyroid levels could cause chronic fatigue and fibromyalgia). For background, I am a junior doctor with no specific experience in endocrinology and support healthy scepticism towards the medical establishment:

  • Thyroid hormones are of course the first thing that one thinks of in people with low mood. Sometimes one will check the T4 and T3 as well as the TSH.
  • it is also one of the first things that one would research and it looks like
... (read more)
A likelier solution would be that pain-sensitivity and vulnerability to demotivation and fatigue are just (mostly additive) polygenic traits. Look to partially confirm this in 0-5 years when the first GWAS come out and demonstrate that thousands of genes make these diseases more likely, similarly to IQ and height.
1Robert Miles3y
I just stumbled across this and see it is in fact 5 years later! Have you seen anything interesting from GWAS so far?
Hi Ryan, thanks. My point is that 'hypothyroidism' is defined by high TSH. I wonder if it's possible to have 'hypometabolism' or 'all the symptoms of hypothyroidism' whilst having a normal or even low TSH and maybe normal levels of the blood hormones too. to answer your points: (a) Yes, agreed. Only wrinkle here is that labs often refuse to check T4 if TSH is normal. This has happened to me twice despite my doctor specifically requesting an FT4 test. And I personally know someone who had CFS for years and lots of expensive NHS and BUPA and privately paid treatment without any thyroid test except for TSH. (b) Yes, but if you've already removed all the people with strange hormone levels (because they're hypothyroid, and so they don't have CFS or FMS), then of course you'll find normal levels in the remaining cases. (c) Agreed, because hypothyroidism is defined by TSH. My hypothesis is exactly that many cases of FMS/CFS are 'something wrong with the thyroid system that doesn't show up on laboratory hormone level tests'. (d) Hypothyroidism has lots of famously non-specific symptoms. Do hypothyroid patients sometimes complain of pains in the same way? (e) that's interesting and surprises me. I was under the impression that exactly that kind of widespread pain was one of the (many possible) symptoms of hypothyroidism. I'll go and look. Thanks ever so! I've added the explicit hypothesis to the summary. I'll go and see what I can find out about pain in hypothyroidism/fibromyalgia.
a) This is a bit misleading. I've never had a lab refuse to do any test as simple as T4. It's more a matter of how you communicate it. If you as for "thyroid function tests" or "TSH, T3, T4" without clearly explaining, then they will usually stop at a normal TSH. b) Most people diagnosed with CFS have had their thyroid levels checked but is this necessarily so for fibromyalgia? I don't think so. Also there are studies where they stimulate release of thyroid humans. There are literally hundreds of highly relevant studies here. c) Aren't there things like thyroid receptor abnormalities that have different biochemistry but similar presentation to hypothyroidism? (And wildly different to fibromyalgia?) One has to look into this. d) usually it's just tiredness and slowness isn't it? The fact that hypothyroidism presents so generally actually makes it less likely, not more likely to bear a specific connection here. e) people with fibromyalgia often recoil if you try to examine them, take blood etc in a trait that they largely share with people who are anxious or have mental health issues with psychosomatic complaints. What is needed here are similarities that are specific to these conditions and that are shared, whereas here it is the aspects that are the most general that are shared but the main facets of each condition are quite different and overall the two conditions don't blur together in an interesting way.
At the fourth attempt, my doctor managed to get the local lab to test TSH,T3 and T4 simultaneously. He had to ring them up and ask them in person, apparently. It turns out that I've currently got TSH~2.5, and FT4,FT3 low-in-range. Given that that looks like central hypothyroidism, and that's under the influence of 1 grain/day of desiccated thyroid, we've decided we that we have no clue, and I'm carrying on messing around with random thyroid drugs aiming for relief of symptoms (which are all gone, but I keep having to up the dose to keep it so). Basically Christ knows. If I'm not medically unique, there's something very funny going on.
Aren't you just taking thyroid hormones analogues (not T3/T4) that are - as expected - suppressing the pituitary production of TSH?
That's what I was expecting, but 2.5 isn't suppressed, it's actually quite high compared to the average for healthy people, (or at least normal, depending on what you think normal is). And roughly the same as it was at the start of all this. And both the free hormones look low. You'd think adding a fair bit of thyroid to a healthy system would have bumped up the free hormones and maybe lowered TSH to somewhere like the hyperthyroid range. What's really weird is that I've tripled the dose of NDT since the last time I had blood drawn, and my TSH has gone up slightly in response. I thought I'd be seriously suppressing my own system by now. It's possible that I've just developed a primary gland failure, but that's weird because there was no sign of it when I first showed severe symptoms.
Ok so your TSH is normal and your T3/T4 are low in the normal range because you've replaced them with some T1/T2. Every value is in the normal range. Problem? It makes no sense at all to call it pituitary failure (central hypothyroidism) - that would imply low TSH. You could argue that it's successfully medicated peripheral hypothyroidism if anything, though that's a stretch.
Ryan, this is great, I came here for an argument! Thanks. ("I wish to believe 'snow is blue' if and only if snow is blue") (a) OK, can we agree on "In most cases with 'normal' 0.3<TSH<5.5, TSH is the sole test performed"? (b1) I don't know, but given that FMS includes 'brain fog' and 'tiredness' I'd be surprised if many people with it haven't had a TSH test. I would be surprised by the existence of people who only have the tender points and no other hypometabolic symptoms. Do we know what proportion that is? (b2) "Also there are studies where they stimulate release of thyroid humans. There are literally hundreds of highly relevant studies here." I don't quite understand what you're saying here. Can you link to a couple? Google scholar "fibromyalgia and thyroid" gives top hit:, Neeck G , Riedel W "Thyroid function in patients with fibromyalgia syndrome.", in which they find abnormalities in a thyroid hormone releasing test in fibromyalgia patients. Doesn't that support me? (c) There are forms of hypothyroidism that don't show up on the TSH test certainly, 'central hypothyroidism' and 'peripheral resistance to thyroid hormone', which have the same presentation but normal TSH. 'Central' should give you normal TSH but low T4 and T3. 'Peripheral' should be normal in all respects. But they're thought to be vanishingly rare, and as far as I know, CFS/FMS people aren't tested for them. In fact presumably the only way to test for them would be a trial of thyroid hormones! That's kind of my point. (d) Not just tiredness and slowness. It's more of a general metabolic collapse. And which systems fail first seems to be random, which is why it's so difficult to diagnose clinically. (e) I'd expect anyone with widespread pain to recoil if you tried to touch them. "What is needed here are similarities that are specific to these conditions and that are shared, whereas here it is the aspects that are the most general that are shared but
Sorry this discussion is not interesting to me. It's only mildly surprising that fibromyalgia patients have lower temperature in one study, or that improvement was seen in one study with thyroid hormone. Fibromyalgia patient's having lower metabolic activity is a plausible component but does not necessarily implicate the thyroid. Taking anything with a stimulant effect would do similarly to thyroid hormone here. People with fibromyalgia present similarly to patients with other chronic pain syndromes, and other presumed multifactorial syndromes like irritable bowel syndrome. It is associated with childhood trauma, sexual abuse, etc (just as is IBS) It's likely a massive combination of metabolic, psychiatric/psychosonatic, social and physical factors at play here. That's because the gestalt of the condition is that someone is complaining of pain that you can't explain, which is apparent if you spend time seeing these people. Of course this is not going to be always caused by a problem in one hormonal controller of metabolism. Many (combinations of) problems can cause body pains! I apologise that this note is less carefully proofed than previous ones but spending more time on this investigation does not seem likely to bear fruit.
Ryan, thank you, I really appreciate your time, and that is exactly the sort of thing that someone needs to say to me. I have come to the conclusion that I must be trolling. My idea, which I have arrived at quite independently by a long chain of dodgy inferences from a minor puzzle to do with my own illness, it now seems to me can be summed up as: Almost all the remaining unexplained human ailments can be explained as disorders of the endocrine system. This idea seems to have been first thought of in the 1940s, and independently deduced, observed, or inferred many times since. If true, it would have a great number of disturbing implications. If untrue but widely believed, it would cause a catastrophe. Now I look for them, there are published books suggesting this, and an entire tradition of alternative medicine based on it. Which reports success. But then, they would say that, wouldn't they? And yet no one except a few quacks believes it. And so my mystery is now: Where is the obvious refutation that means that it is false? I apologise for wasting everyone's time. I am not being sarcastic. I realise that my argument is 'You cannot prove me wrong, and therefore I must be right' I realise just how bad that argument is. I realise that I have blundered into a complicated subject that I am not in the least qualified to discuss. I have already had to discard one simple obvious explanation for a complicated problem (they are almost always wrong). I do not like to believe in chocolate teapots. I am asking for help in discarding another one. What on earth is Less Wrong for, if it is not for this? I do not imply that you must waste your time helping me. But I am damned sure that someone needs to say it plainly. It has fooled me. It is causing havoc. Why is it not true?
I think you're underestimating the complexity of human biology. The condition of a human body is a function of a very large number of factors: internal and external, somatic and psychological, genetic and acquired, etc. etc. Moreover, these factors are interdependent and tend to form feedback loops. The situations where you have one clear cause for a problem certainly exist (e.g. infections, type 1 diabetes, etc.). But there are also situations where there are multiple factors in play. It would be a mistake either to believe that a single one of these factors explains everything, or to believe that this single factor is irrelevant, that is, "false". It is likely that some disorder of the hormonal system plays some role in some chronic illnesses for which we have no clear etiology. Can you fix those illnesses by tinkering with hormones? Maybe -- that's what medicine is trying to find out, with... various success so far. tl;dr: It's complicated :-)
Of course it's complicated! I'm saying, there's serious grounds for suspicion here. And the problem, if it exists at all, is likely to be gigantic. So we need to pay attention even though it doesn't look very likely. A genuine Pascal's Wager. We aren't allowed to shrug our shoulders in response. Scope insensitivity is one of the sins. All these funny diseases that look like mixtures of type 2 versions of well understood endocrine disorders. That I didn't know about until after I'd made up the idea. And a very simple hypothesis that explains them all and should be easy to refute. I predict low body temperature in every different group. Patterns of differently low body temperatures correlating with how much the disease looks like classical hypothyroidism. I have a hypothesis formed by whatever dodgy method I like, and which has turned out to have been commonly suspected by many different people, all starting from different observations, which I am now using to explain and predict lots of other facts that didn't figure in the original making-it-up process. Does the order in which I learned these facts matter? How should I adjust my conclusions to account, even given that I probably can't remember the precise order? I am going through periods of puzzlement, enlightenment, and then spectacular rewards of confirmation followed by terror at the implications. And the competing explanations all turn out to be philosophically suspect. This science business turns out to be quite hard. And we claim (and I believe us) that we are unnaturally good at this sort of thing. Where have I erred, Brothers in Bayes? What do you know that I don't know? What conclusions (that are safe to draw in public) do you draw from my idea and do they turn out to be true? What are the odds and why? What is a yes worth. What is a no worth? Are doctors actually trained to ignore these symptoms? Because they're everywhere? How common are these diseases? Are the patterns of occurrence the same in
That's still handwaving. Let's invoke Popper and ask for specific, testable, falsifiable statements. What exactly do you claim and want to test? What outcomes will prove you wrong? I don't think the details of how you came to formulate your hypothesis matter. Will they listen to you?
1johnlawrenceaspden8y I hope so!
Actually we are. Changing the status quo is hard even if you are right. I don't think mainling the original post to any medical statistician will get you anywhere. You would beforehand have to be clearer about your thesis and the evidence you have. It helps to cite the evidence. A prediction is something that has a credence value especially if you see yourself as Bayesian. At the moment you don't state those.
Shouldn't be. If I can sharpen my argument to the point where I believe it myself, then I can take it to the ivory towers of the wise and they will listen. I know these people, and I trust them. They will do the right thing. For the rest, see:
How much have you talked to people inside the system? From my conversations with stakeholders I have the impression that change is very hard.
Excellent - thanks for responding to this so positively. I wouldn't say you're necessarily trolling, rather than just arguing a little more forcefully than someone else might. I basically think that this is the absurd conclusion that demonstrates your chain of reasoning to be false. This is far wronger than the idea that Fibromyalgia could have an endocrine cause. And I think you've identified this problem with your argument even more acutely that I had. I think there are a lot of useful ways you can reason from here, such as: 1 - It has never been the case previously that almost all unexplained human ailments have shared a single simple explanation 2 - Many conditions that we discovered a long time ago had simpler 'single pathogen' explanations, whereas many newer ones are quite complex. 3 - Although many of these conditions will eventually be explained, the explanations are not likely to be visible to a non-expert. 4 - If they all shared an explanation, there's no major reason why it should lie in the endocrine system. An alternative 'catch-all' explanation for these would be 'psycho-neuro-immunology', another somewhat overambitious school of mostly scientific thinking that could potentially claim these conditions more credibly. My alternative explanation that collects this thinking is that most 'unexplained human ailments' are likely to be multifactorial. This is also the common wisdom. As to where to read and learn about this, by far the best place is This is very popular but also potentially expensive. So if you really must, you could instead look through medical textbooks like Harrison's or Kumar and Clarke, focussing specifically on unexplained conditions. I would warn that reading about conditions unexplained by medical science via textbooks of medical science might be a bit like pulling teeth, but truly it should be one way to abstract away the knowledge of these conditions. Another approach might be to learn more about the scores of "
Ryan, thank you again. Your concerns are my concerns, I am grateful to you for them. And I apologise. You have been talking to a raving lunatic, by the ICD10 diagnostic criteria as applied by my attorney and myself. See the exchange with buybuydandavis for details. I am apparently recovered now, in the opinion of one who should know. I am painfully aware that I have reasoned myself into a place where I prove too much. I am in the position of a philosopher who started out with a little detail, and is now claiming 'It is at least marginally possible that here is the light and the sacred cup'. Knowing that he is wrong. I was carefully and expensively trained to speak with certainty when and only when I was certain. The Lord knows I was never very good at it. I have used plausible reasoning where I only trust classical logic. I am forced to seek the Grail. But I cannot shake the suspicion that I might be right. And I know that my hopeless hardware will not let me find the reason why I am wrong. It has. The germ theory. I am claiming that the great killers of the past may have left their shadows in our genes, and those shadows still plague us today. I am claiming that the great changes we have made in our environment may have hurt us worse than we know. Here I stand, naked to the world. Afraid. I can do no other in good conscience. I do not believe my own conclusion. I hope that when I am shown to be wrong, I can retreat with no more than huge embarrassment, resolving to fail better next time. And it all depends on the TSH test. If I am wrong about that, I am just wrong. If the TSH test is flawed, then all our statistics are confounded, and we have some thinking to do. Still Crocker's Rules though! Let this cup pass from me!
Forget about being proved wrong and facing huge embarassment. Short-circuit that by getting some background domain knowledge then making claims that in light of that knowledge are reasonable.
OK, type 2 diabetics, suffering from a mysterious condition that prevents insulin (an endocrine hormone) acting on their cells, can achieve very good blood sugar control by overwhelming the resistance with exogenous insulin. And yet they still suffer horrible complications. Which look awfully like hypothyroidism. The simplest explanation is that this mysterious condition is interfering with other endocrine hormones as well. Desiccated thyroid, containing excessive T3, will overwhelm the hormone resistance, and clear up the complications of diabetes. T4 alone will not change the amount of T3 in the blood significantly, since it is subject to the body's T4->T3 conversion mechanism, which defends T3 levels. Therefore T4 will not help diabetics, but T4/T3 combinations will. Broda Barnes observed this empirically in the sixties. I predicted it independently before I read his book. Find a diabetic colleague, and explain this to him. I predict that he will suddenly take the idea very seriously indeed.
While I am very much not a medical professional, I do know that, while germs cause a lot of trouble, there are nonetheless quite a variety of things that can go wrong that have nothing to do with germs. There are even a lot of things that can go wrong that have nothing to do with the closely-related viruses. Examples include: * Physical trauma (e.g. broken legs) * Nutritional deficiencies * Genetic diseases (sickle-cell anemia?) * Hormonal imbalances * Cancer (I think a growth is different from a germ, right?) * Asphyxiation and/or drowning And I think it's possible to cause trouble for yourself by drinking too much water as well - it has to be seriously too much - and that's also not due to germs...
I know you're teasing, but physical trauma and drowning aren't unexplained, sickle-cell anaemia is very much explained by germ theory (malaria defense), controlling nutrition and energy usage is probably exactly what the thyroid system's for in adults, hormonal imbalances are what I'm talking about, and OK, I'll give you cancer. For now. In fact I think I'm trying to add a coda to the germ theory. One reason that ancient control systems would just spontaneously go horribly wrong is if they were in a continuous state of desperate patching and hacking to deal with an intelligent and adaptive enemy. And pathogen evolution is just that. That's why we see in living systems a combination of beautiful engineering and idiotic kludge. Like a BMW with a tin can lid riveted on one side. The explanation is likely to do with bullets. Therefore we expect infectious cause for this sort of horror. But we don't find it. Where is it? In the past. Today's fuckups are yesterday's hastily constructed defenses. Not of course to forget the environment. If we've got a hideously complicated and sensitive chemical control system that's been tested to death really well in the presence of all the usual chemicals, and suddenly we start adding new chemicals, what then? Notice that a lot of cancers are caused by novel chemicals, and a lot of them are caused by viruses. Presumably all the viruses and bacteria and fungi and cancer cells are themselves generating novel chemicals in order to screw the system up so it can't kill them. I'm not saying. I'm just saying.... Infectious cause, immune defence, recent environmental change, recent adaptation to environmental change. The four horsemen of unexplained diseases. One thing I don't claim is vitamin deficiencies. But they fit into Cochran's framework nicely. And I'll give you that if you deliberately drink far too much water even though you'd really like to stop and then it kills you, you've got a genuine 'somatoform' disorder. Except eve
Sickle-cell anemia may have been a bad choice. It was supposed to be an example of genetic factors causing trouble - which can happen even in the complete absence of germs, since random mutations are rare but possible. (The fact that one particular genetic factor is partially successful because it provides a higher resistance to certain germs is somewhat beside the point).
Absolutely, a famous example is Queen Victoria's mutation that caused haemophilia in some of her male descendants. The queen really does seem to have been the mutant, and it was just a rotten bit of luck! What needs explanation is how a harmful random mutation can spread to a significant proportion of the population. One way that can happen is if it's actually also a defence against something, and another is if the heterozygote version is good, but the homozygote is harmful. With a large fitness advantage, mutations can spread quickly! Consider a lightning plague like the black death. It wiped out a third of the population of Europe in a couple of years, and then simmered and flared for centuries. A 'harmful' gene that defended against that would have had a whale of a time, and you'd expect to see it in all Europeans. But if it's really harmful, you'd expect that over the last 600 years, better defenses might have evolved, and the previous defence might start evolving back out. About 500 years ago, all the old world plagues were introduced to the Americas at once, and they literally decimated the native population. I don't know if there are any 'pureblood' native americans left, but if there are, their genes should be a mass of defensive scars.
Easy. * The harm is easily avoided. For example, an allergy-against-bananas gene might not affect one's reproductive fitness at all in the modern world - one merely needs to avoid bananas. * The "harm" is to the society, not to the individual. For example, a mutation (in males) that causes all children born to be male will not harm the person carrying the gene, but will end up with fewer total greeding pairs in subsequent generations. * A guy with the harmful mutation just happens to have a lot of wealth of political power - and takes a few dozen wives.
(1) Sure, but that sort of thing will just random-walk, it would take ages to go from one mutation to 50% of the population. It has almost no fitness effect. It will probably get gambler's-ruined out. (2) Absolutely, and we see those things in animals. You can evolve to extinction. In the particular case of a male-causing gene, I think it would have to stabilize very low (because the more successful it is the more harmful it is to the carrier) , but you can certainly imagine (and find) driving genes that just become rapidly prevalent and wipe out the species. (3) Yes, but that's just the random walk walking. It has to get very lucky to become prevalent, and if it's actively harmful, it won't get that lucky, and that will kill it off eventually. A mutation needs an edge to spread fast.
In general, harmful mutations will die out. In order to spread to a significant proportion of the population, yes, a random mutation has to be lucky. It has to random-walk in a very rare way, and it is still more likely than not going to hit the gambler's ruin and be eventually eliminated from the population, even if it first spreads to 99% of said population (an extremely unlikely event). But the thing about random-walking is that it is random. One wouldn't bet on a given harmful mutation spreading fast (not if one wanted to win the bet)... but if there are a million harmful mutations, then one of them could reasonably be expected to have one-in-a-million luck.
I think we're pretty much on the same page. But have you actually calculated the odds? One in a million is no big deal. Twenty half-chances. I must say I haven't, and I don't know how to (especially since it's all screwed up by genes moving around and getting passed on together, and I don't understand the first thing about all that). But it feels more like 'thermodynamic entropy' than 'winning the lottery'. Also remember that nothing is perfectly neutral. Even the banana man might get fed banana-cake by a dastardly enemy.
No, I haven't actually calculated the odds. I wouldn't really have much of an idea how. (I could probably work it out on a basis of - if a gene has x% chance of preventing descendants as compared to not having that gene and a y% chance of being passed on to any descendants - and then do some overly-simplified calculations from the values of x and y - but I haven't, yet.) True, but his problem there isn't the banana gene. His problem there is that he has a dastardly enemy. If he didn't have the banana gene, the dastardly enemy could simply feed him arsenic cake instead, or just shoot him.
The official name of a mutation winning despite having no selection benefit is genetic drift. When I had genetics lessons in university the concept that was taught was that a significant amount of our genetic changes are due to gene drift but there's no exact way to quantify how many. Furthermore some genes aren't stable and can easily mutate. Evolution doesn't succeed in bringing color blindness to zero despite it being no useful mutation.
Yes, an obvious one is the inability to manufacture Vitamin C. Universal in great apes, including us, but every other animal and plant can do it, except guinea pigs. I imagine that at some point our ancestors lived in a vitamin C rich environment, so losing this was no immediate handicap. But even then, the random drift should have taken ages. Is there some reason why losing this pathway would be a benefit? Same for colour-blindness. Is it drifting, or is it actually good for something in an environment where it does no harm? (These poor children, none of them will ever be commercial pilots or qualified electricians....)
"Literally decimated" would have reduced the population by 10%. Some Native American groups were hit much harder than that. (I think the "mound builders" in what is now the southeastern US may have actually disappeared completely.)
Accepted. I have managed to use decimated in the wrong way. Sorry.
Minus the "literally", though, the word "decimated" in current English uses would include much more severe population declines. I'm just being unnecessarily pedantic.
Spectacular pedantry is sort of where I'm coming from here, though. And actually literally can be used metaphorically too, and has been for some centuries. I'm confidently expecting this to be the most controversial assertion in this entire discussion, so you can go look for your own references. [Openly trolling now]
In fact, how did any of them live through that? Did the vikings take some diseases and some genes over with them early doors?
Did the Vikings ever get out of Newfoundland? Is there any evidence they made it to the mainland?
According to Wikipedia, yes, the Norse made it to continental North America in pre-Columbian times and made multiple voyages there to obtain natural resources (primarily fur and timber), but did not establish any permanent colonies (perhaps due to hostile relations with the native Americans (which the Norse called the Skrælings)).
I asked about the mainland. The Vikings made it to Newfoundland, certainly, but Newfoundland is an island.
The Wikipedia article mentions that a Norwegian coin from King Olaf Kyrre's reign (1067–1093) was allegedly found in a Native American archaeological site in the state of Maine, but does not mention any definitive evidence that the Norse made it to the mainland.
Yes, I know. That's why I asked :-/
I have no clue. Is there a vikingologist in the house?
Tuberculosis keeps coming up. It was deadly and recent and widespread, and it's implicated in the 'plausible mechanism' paper, and in the one about rheumatoid arthritis, and the other day I met an old friend with bladder cancer. Apparently he's having tuberculosis drugs injected to try to kill it. No one knows why, but it works about 30% of the time! It would be way interesting if someone had statistics for ancient diseases and statistics for modern unexplained diseases. I've no idea what to predict, but I bet it's not 'no correlation'.
Have you seen Greg Cochran's paper on infections?
Yes, I based the entire second post on it, and referenced it. But thanks, that would have been really useful! I just emailed the address on the paper (paul ewald) to see what they thought of it. But no reply. If anyone knows one of them could you tell them there's someone wrong on the internet?
Physical trauma doesn't have to be explained, it's an explanation. In cases like broken legs it's a pretty straightforward explanation. In other cases like depression, it get's more complicated.
An explanation is a chain of causal links, where each one is verified under interventions. If I hit you with a sledgehammer, your leg will break, and we know why, and it's not that my anger causes 'stress', and that breaks your leg by magic stress-property, because I'm stressed too, and yet my leg never breaks. A vague correlation is not an explanation. It's a sign that you should look for one. Sure if I attacked you with a sledgehammer, you might get depressed. But why?
Depression in patients with acute traumatic brain injury : Major depression occurs in about one-quarter of patients after traumatic brain injury. This is the same frequency as in other major disorders such as stroke. Major depression appears to be provoked by one or more factors that include poor premorbid social functioning and previous psychiatric disorder or injury to certain critical brain locations. Depression among older adults after traumatic brain injury: a national analysis.: TBI significantly increased the risk of depression among older adults, especially among men and those discharged to a skilled nursing facility. Results from this study will help increase awareness of the risk of depression post-TBI among older adults. It's plausible that the trauma kills neurons and thus creates depression. It's also possible that some fascia tenses up and produces problems. It's possible that it produces Sensor Motor Amnesia. It's possible that it creates problematic inflammation. There are a lot of plausible mechanisms to choose from.
Agreed. Thanks. It was more a sort of philosophical point about the nature of explanation. We might be able to tell which of these counted as an explanation by intervening later on in the proposed causal chain and seeing if the same results obtain.
As far as the philosophy goes, for most successful interventions in health care we don't really know how they work. Depression usually comes along with increased inflamation of the gut. Depression medicine that's intented to target the brain because of chemical imbalance, also hit's targets in the gut. Does that mean I'm certain that those drugs fight depression by having positive effect on the gut? No, I'm not certain of that, but it's an open possibility. "Explanations" in general aren't good at predicting outcomes for drugs. That way so many clinical trials fail. The only way that seems to work is to gather empiric evidence for treatments. That way you know whether the treatment works but not why it works.
Trolling or eyerolling? You decide! X-D
90% of prospective drugs fail to produce positive clinical effects. That's even through theoretically they should work. The refutation comes with the clinical trial. That's usually how it goes.
Absolutely. The only good evidence is randomized controlled trial. But what can we deduce using the bad evidence? Remember Amanda Knox. We showed she must be innocent by thinking. And everyone laughed at us for believing it. As if it was some sort of cult badge.
Drug trials are incredibly expensive. There's a lot of money involved in reasoning about the likelihood that the drug will work before it's put to trial. At the same time those people still often put their chips on drugs that turn out not to work. That means that in many cases there's not an obvious refutation to be found that a drug doesn't work if you don't actually run a trial. Who do you think laughed at us? As far as I understand the US media in general thought Know to be innocent and most people don't care about the LW opinion on Amanda Knox.
I was reading RationalWiki about Less Wrong, to find out anything I should know about us, and they were in hilarious form about how the innocence of Amanda Knox was a compulsory belief. So I thought "Oh, I didn't realise we believed that.". I'm British, and as you'd expect since the victim was British, the British press thought Amanda Knox was some sort of sexy cartwheeling antichristette. And went and read the article in question, which said: "Think about this as if it were a problem in probability." So I did, for a couple of hours, and it was obvious that she was innocent. So for a while I went around telling everyone that she was innocent, and they reacted how you'd expect when a middle aged man gets interested in the innocence of a pretty youngster. And then it turned out she was, and they all think I'm a witch now. And that is the first and only time I have seen this purported method work on something real. It works on made-up theoretical problems, Bob's your uncle. And philosophically it's nice. But here we have a chance to find out something really important, or discredit something harmful. And then I'll know. Both things.
Sometimes the answer is "You have no evidence". (Or at least no good evidence.) Of course, if you have no evidence that an accused criminal is guilty, you should assume they are innocent. But if you have no evidence in some medical theory, you shouldn't be assuming the medical theory is true.
I hope I'm not assuming it. I certainly don't believe it.
I don't think you are wrong to have this discussion on LW. The fact that the main post got 23 upvotes also indicates that the community doesn't think you were wrong to post this here. I think most illnesses are based on a chain of things going wrong with the body. Various alternative treatments do sometimes produce positive results. On the other hand they often don't consistently produce results.
I think this too. I think the chain is (mysterious Cochran-type cause)->(mysterious endocrine transport disorder)->weird polymorphous syndrome. We don't find out this sort of thing by expensively trying random things. Especially since the tests are terrible. We have to work it out in theory, and then make predictions where we don't already know the answers, and then see whether they're true. And then adjust our beliefs. If I am sounding like a fanatic, I hope it is a Bayesian fanatic. Because that is what I am. And here I have a chance to test my beliefs on something real, and hard. And I haven't a clue how to go about doing it.
The start is getting clearer about your own theory and what you actually believe. If you claim to be a Bayesian fanatic, then actually reason in probabilities. Bring numbers. Be clear about how probably you consider various thesis that you made. Then it's worth noting that you being right means that a company might make a billion dollars of that knowledge. Especially if the solution is a special mix of hormones that could be patented to make a synthetic analog of the pig thyroid. That means that if you can convince the right person that there a 5% chance that you are right they might fund a 100,000$ trial to find out. Just be to clear, I'm not a person who's defending the status quo of the way the medical system works. In the last month I sat down with a person who had a cat allergy and did an NLP intervention to treat it. The next day he spent 30 minutes with a cat to test and didn't have any allergy symptoms. I put down 2:1 chances of success beforehand in our shared prediction database. Next month I'm at a workshops with 3-4 QS people a 3-4 academic scientists to talk about what Let's say it's: "A person shy's away from conflicts that arise when they speak up. As a result the fascia around the throat is tense. The tense fascia then presses on the thyroid. The thyroid doesn't work properly because there's pressure on it. Badly regulated hormones then do a mess elsewhere in the body." In my understanding the recent history of hormone supplementation generally isn't good, because the body stops to produce less of the hormone if it's supplemented. However let's spend more time investigating it here. Alexandra Carmichael who used to be one of the people at the head of the Quantified Self mothership build CureTogether as a database where people can report their results with different treatments. It has 137 treatments for Fibromyalgia. The most sensible treatments seem to be getting more sleep, resting and and hot bathes. But there are also drugs listed. The fir
That site's a wonderful idea! And it looks as though LDN has some effect on the immune system. So if we can trust it, it looks like the two things that attack the problem rather than the symptoms are LDN (suppresses immune reaction) and T3 (overwhelms my hypothesised immune-caused endocrine resistance). This is the problem I keep having. Every time I see something new, it supports me. Can anyone find something that I can't explain? And just for the avoidance of doubt, I think taking pure T3 is a terrible idea. But John Lowe thought it worked for him and for many of his patients, and I trust John Lowe much more than I trust myself.
Science isn't about explaining but about making successful predictions. Smart people can explain anything.
You're conflating two different meanings of "explain": * Construct a plausible narrative * Describe the underlying mechanism
I don't think I'm conflating something in the context of this discussion. I think johnlawrenceaspden does focus on providing a plausible narrative instead of making falsifiable statements.
Is fair, but surely those predictions can be about bits of the medical literature that I haven't seen yet, or haven't understood properly, otherwise history would not be a rational endeavour.
You admitted it yourself. You're using dodgy inferences! This is especially bad if you have a chain of them, as the errors accumulate--if your reasoning depends on five dodgy inferences each with a 60% chance of being correct, you're already down to 8%.
Right! So now I have an 8% chance of being right about something really serious. And so I need to make a prediction and work out whether it's true, and then adjust. You try it!
What kind of prediction could you possibly make about "almost all the remaining unexplained human ailments", that could be checked to see if it's true? And even if there was something, you haven't actually made or tested the prediction yet. So not only have you used dodgy inferences, you're putting the burden of proof on the wrong side. It's not up to other people to prove it false, it's up to you to prove it true, and if you haven't done that yet, you have no business believing it.
0johnlawrenceaspden8y Certainly not putting the burden of proof on the other side. Don't believe it myself.
(a) Actually, my wonderful GP confirms that whatever phrasing he uses, the local lab won't test FT4 unless TSH is abnormal. He's going to try 'FT4 IRRESPECTIVE of TSH result' and see what happens. Of course, this is England, and you may have a different experience. The T4 tests are badly standardized, apparently you can get high FT4 by one method and low FT4 by another from the same blood sample. I don't think they've ever been used for anything serious since TSH is a better test anyway, so the lab may not be acting insanely here.

All three/two/one are appalling, crippling, terrible syndromes which ruin people's lives. They are fairly common. You almost certainly know one or two sufferers. The suffering is made worse by the fact that most people believe that they're psychosomatic, which is a polite word for 'imaginary'.

I don't think that it's useful to treat imaginary the same as psychosomatic. Quite a lot of illnesses have psychosomatic parts and react to treatment on that level is the treatment is done right. Mostly it's difficult to get good treatment but that is no reason to equate it to imaginary suffering.

Up or downregulating hormones is something that the brain can do.

Without mechanism, I am suspicious of wise-sounding explanations. And so, quite rightly, are most people. That's what I meant. We observe a problem, we make up a 'problem-causation principle' and give it a name in ancient greek (actually I love this bit). We deceive ourselves, and the man in the street does not believe us.

"And the people suffering are mainly middle-aged women. Middle-aged women are easy to ignore. Especially stupid middle-aged women who are worried about being overweight and obviously faking their symptoms in order to get drugs which are popularly believed to induce weight loss. It's clearly their hormones. Or they're trying to scrounge up welfare benefits. Or they're trying to claim insurance. Even though there's nothing wrong with them and you've checked so carefully for everything that it could possibly be."

If you decide to delete everything a... (read more)

I might sound more rational. But I would not be able to explain the apparent contempt in which these terrible diseases seem to be widely held. I seek the truth. Political correctness often hinders that search. I can't resist saying at this point that some of my best friends are middle-aged women. Low, I'd imagine. What does that matter? An excellent point. It may be that we can alleviate these syndromes with amphetamine. But then we need to explain how that knowledge got forgotten. It is not as if doctors are reluctant to hand out ill-understood prescription drugs to the sufferers. As far as tranquillizers go, they might shut the sufferers up, but I'm not sure that's what I mean by alleviate.
Don't focus on explaining. Focus on providing arguments for the claims you are making. The claim that middle-aged woman are a class of patients that generally easy to ignore is a significant claim for which you provide no evidence.
What's the difference? Then as evidence I refer you to the site, which is largely devoted to middle-aged women complaining about displaying terrible symptoms, and being ignored. I predict that you will be tempted to ignore them. They are certainly doing a good job of looking like lunatics. It is a problem with what I am increasingly tempted to think of as 'my tribe'. If they're too mad for you, then try, where one brave and clever lady, who does not look mad at all to me, has comprehensively debunked the medical theory and treatment of hypothyroidism proper. I have not read the website, but I have recently read the book 'Tired Thyroid'. She has done a wonderful job and gone much deeper into the literature than I have. She debunks not only conventional medicine but all the lunatic alternative treatments too. She provides references from the literature for everything she says. The book is closely argued. It is heartbreaking. Its arguments affect the lives of millions. Tell me why she is ignored. The most open-minded thing I've read from "medical science" recently is called 'Dissatisfaction with thyroxine therapy — could the patients be right?' by John Walsh. This man is being ludicrously brave by sticking his neck out that far. 'Could the patients be right?'. About their own symptoms. This is not science. This is some pathetic parody of science, where idiots in white coats claim the glory of physics despite not being able to reason their way out of paper bags. I call bullshit.
Explaining is about providing a narrative. Adding additional detail can make a narrative more persuasive. On the other hand it also makes the whole story less likely to be true. I don't see how that's evidence for the fact that middle-aged women get treated differently than men or woman that aren't middle-aged. How do you know that you aren't simply ignoring people who aren't middle-aged women because they aren't complaining as loud as the people towards which you linked? If she has the same mentality as you, that mentality is a good recipe for getting ignored. This reminds me of a woman who thinks that a lot of women lose their needlessly lose their uterus because of operations to remove myomes. Because financial relations between stakeholders in Germany are different than in France, there are a lot more operations in Germany than in France and in France other treatments get used that don't remove the uterus. She was willing to make that case behind closed doors. In public she was using much more friendly language to be in a position where all-stakeholders would talk to her. As a result she's finds herself in a position where people listen to her. You seem to suffer from the just-world fallacy.
That all seems fair! Where am I falling for the just-world fallacy? That seems quite plausible, especially since I've lost my usual ability to see both sides of the argument. And I've come down in favour of nut-jobs and against science. That scares me very much.
You think that the fact that patient complains about symptoms should get the system to hear the complaint and fix them. In a just-world there would be people to look at every complained to see whether it's valid. We don't live in that world. The most common way treatment get's changed is when a corporation finds they can produce a new drug that can be protected by a patent that treats a disease. After the FDA approved the new drug, the corporation pays pharma representatives to run around the country and talk to doctors so that they learn about the virtues about the new drug and the new drug get's adopted. Most academic departments get pressured to seek third-party funding and thus try to do research that can help with the discovery of new drugs. Even if "Natural Desiccated Thyroid" is susperior the system is not designed to find that it's superior. That's not because anything went wrong in the specific case, but simply because the economics aren't there to push "Natural Desiccated Thyroid". There's still a possible way for change. Find out what makes "Natural Desiccated Thyroid" better. Create a synthetic analog and patent it. Pay 70 million to run the trials that prove that it's better. A company could then make billions if the new drug would successful treat Fibromyalgia. Take a look at Michael Vassar Tedx talk* The legend of healthcare. Michael Vassar was CEO of MIRI and then went to found MetaMed. *Just disregard Vassar's claims about life expectance of Jordan. It seems that Jordan publishes life expectancy statistics in a creative way, that's not in line with numbers of outside observers.
Oh, if by 'just-world' fallacy, you mean that medical science ought to be about understanding things and making things better, then I most certainly do believe that. I seem to be being rather forcefully rammed up against the fact that you can't get an 'is' from an 'ought'. But again, you have strengthened my position. I want to be defeated. Show me why I am wrong about type 2 endocrine disorders.
Medical science is about understanding things and making things better but it's not about understanding everything. Different organisations focus on trying to understand different things and focusing on whether different interventions work. In a world of very uncertain knowledge that's not to be expected. But if that's actually what you want you have to move to make more specific claims. You still haven't provided probability values for any of the claims you are making. As a result it's hard to argue that you are wrong about the probability of various claims.
Oh, most definitely. Endocrinology is only my third-favourite hobby, and I'd like to put this idea to bed and get back to the things I enjoy.
OK, I think I have to start drawing conclusions in public. Some of them terrify me, but I'll try a few of the safer ones. Thanks. Actually I've just read Broda Barnes (I was originally assuming he was a lunatic who'd confirmation-biased and placebo-effected himself to death), and his clinical observations agree pretty much with my predictions, although I'm not sure yet what I think of his theory, which isn't the same as mine.
Careful. Many things claiming to be science aren't. And science is a process, not a temple the high priests of which pronounce infallible truths.
Yes, I guess I've been believing that I believe that, while not actually believing it. If I'm right, medical science has, as a body, over the long run, managed to make the situation worse. Despite the fact that most of the people in it are good, clever people, trying their best and caring very much. I'm shocked by this conclusion, and it makes me distrust the reasoning by which I came to it. And yet I have a strong feeling that my reasoning is correct, and that my simple obvious hypothesis explains far too much to be entirely wrong. All I wanted was to be a bit less tired and stupid!
Wanting to be less stupid is a dangerous path to set on.
Yes, I have spent a fair bit of time thinking about how a mind might remain sane under self-improvement. That's why I felt such a fool when my 'less stupid' drugs sent me mad. Especially given that not a week before I'd come up with a theory that strongly suggests it might happen!
The track record of people who claim things like that is not good. Go one meta level up and consider the likelihood of all the endocrinologists being knaves or fools... A recent Yvain post might be relevant. Happens all the time X-) but still does not imply that "comprehensive debunkings" are correct. Reverse stupidity, y'know...
Read Yvain's post. As always brilliant. I can see the reason for Attitude 2, but I think you're only allowed to use it if your arrogant airy dismissal then results in a drill-down to find the real problem, which real problem then leads to an intervention that actually helps and clears up the original difficulty. One reason I think I'm a loony is that Yvain liked my first post, and sent me some clever questions which prompted the metamorphosis into the second post. So I sent him the second post wondering what he thought, and now he's stopped talking to me. Good evidence that I'm unhinged. My attorney thinks I'm sane (and he should know). And he thinks I'm wrong (and he should know). But he can't tell me why. (and he should be able to).
Absolutely agree, again. I must be wrong, for reasons I cannot see. But the fact that this idea is obvious (to a child!), widely believed, often believed by empirically-minded doctors, causes striking-offs of those doctors brave enough to act on the belief and yet has no obvious refutation in the literature or in any public place I can find, is itself a scandal. Can you imagine how easy it would be for a man to find the reason that his clever method of squaring the circle must be wrong? Or that his perpetual motion machine doesn't work? Or that he can't communicate faster than light? I might not be able to understand the refutation, if it exists. I accept that. I don't have the knowledge. But it should be in a public place, and someone should be pointing me at it while calling me a moron. And God help us all if I'm actually right.
You're at LW which is not inhabited by a large number of doctors or biomedical PhDs :-) I don't know the right places for you to go to, but watering holes for medical geeks must exist. LW is not it, though. Or you can start digging through PubMed X-)
I've been digging through it for the last three months. And I can't find what I'm looking for. That's why I'm asking for help. The author of Tired Thyroid has obviously been digging through it for years.
What are you looking for?
Evidence against my idea! Firstly I was looking for reasons to believe that the replacement of clinical diagnosis by the TSH test in the early 70s was done carefully. Now I'm looking for any attempt that has ever been made to refute the claims of Broda Barnes, or to investigate why there should be 'insulin resistance', but not resistance to other hormones. As far as I can tell, there aren't any. They've just assumed their stupid TSH test to be gospel, despite massive patient complaints, and ignored a seventy year old tradition of treatment that appears to work really well, and that seems to be working really well on me.

Does this have any immediate safe implications for people of my acquaintance who are tired all the time? Should I be offering them thyroids? How do you serve thyroid?

As I understand it, the most likely cause of tired all the time is lack of sleep. Easy to check: throw away your alarm clock. If you're habitually using a machine to shorten your sleep then you'll be tired, and getting rid should fix that. Apparently 'stress' is another common cause, but I don't know what 'stress' is. It just appears to be a word for 'bad stuff possibly including diseases and definitely including things that spoil your sleep'. After those two are ruled out, then you should go and see your doctor. Fatigue isn't normal, and there are about 200 different diseases that can cause it. Go pre-armed with arguments like 'I get twelve hours sleep every night and I still need an afternoon nap' and 'I've lost the ability to read, I can't concentrate', then she'll take you seriously. She should check for anaemia and thyroid function, plus loads of other things. If after having tested for anything she, you, the NICE guidlines and the internet in general and any medical friends can think of, you're still inexplicably tired but apparently perfectly well, then you're probably on the verge of a CFS diagnosis. I think up until that point, medicine and I are in agreement. Then the craziness starts: Apparently low iron can be 'low for you' rather than 'out of the population normal range'. If your iron levels are 'low normal', then there's a nice-tasting iron supplement that you can try called Floradix that gets good reviews on Amazon. Don't go overboard though, high iron levels are also a cause of fatigue and other nastiness. Also try making a list of symptoms, by which I mean 'everything about your state that isn't the same as it was the last time you remembered being unambiguously bouncy and enthusiastic'. A lot of it just looks like aging. Then work out what your score is according to Billewicz's test. If Billewicz would have thought you were hypothyroid, then it might be worth trying to find a doctor who is prepared to give you a trial of thyroid hormones. But
Easy unless you happen to need the income from your job and your employer cares when you get into work. (That is, unfortunately, the situation of a great many people.)
It's one thing to use an alarm clock as a safety net in case you oversleep. It's quite a different one to have it wrench you out of deep sleep every morning. If you need it to get up every morning, try going to bed earlier. People need different amounts of sleep. I think people complaining about being tired when they're just not getting enough is a large part of why doctors tend to need convincing that people's tiredness isn't self-inflicted.
Ah, but now we've replaced "throw away your alarm clock" with "make a possibly major change in your sleeping habits, and then use your alarm clock only as a safety net". That's not quite so easy.
No! That's the fix. The check is still 'throw away your alarm clock'. Or variants thereof adapted to specific circumstances. In fact you might just need to count how often you wake up before it goes off. Should be 'mostly'.
But the check isn't "easy" if doing it requires you also to implement a highly nontrivial fix. Imagine that you go to your doctor because you're worried you have Scary Disease X. He says "I have good news: there's a really easy test for this. We just take a drop of blood from your finger and put it in this machine and see which of these two lights light up." That sounds pretty good. "... Now, before we can do this you're going to have to eat a purely vegetarian diet for three months, and run a half-marathon every week during that time. And then we're all set."
g, we're getting hung up on a misunderstanding here. I don't think we disagree about anything. The check is 'get rid of your alarm clock, see if you can still wake up at the right time'. Nothing else needs doing. If you have a job pressing the world-not-explode button at precisely 9am every morning then you might need to do something ever-so-slightly more complicated to allow for that. But not much more complicated. You know my number, give me a ring if I'm not making sense.
And you aren't friends with your system I to the extend that it understands that it's important that you get up on time.
That's a bad sign. If you don't naturally wake up at the time you normally get up, you're forcing something.
Actually screw everything I said earlier. It now appears to me that poor mad placebo-effected confirmation-biased Broda Barnes was right all along, although I believe my reasons for his many years of careful clinical observations more than I believe his. I recommend Broda Barnes 'Hypothyroidism: The Unsuspected Illness'. It appears that NDT is good for what ails you, pretty much whatever that is. I love the bit where he says 'I'm not for a moment claiming that thyroid therapy is a panacea'. I can only hypothesise that we are using slightly different definitions of panacea.

I lack the expertise to judge any of this -- but I hope someone who does have the requisite expertise shows up in the comments. I have a friend with FMS/CFS and this would be relevant to him.

I second this, and would also be interested in explanations from downvoters.
I recommend Broda Barnes' book : 'Hypothyroidism: The Unsuspected Illness'. It's pretty much what you'd expect from a 1970s popular medical book, but the author was a real endocrinologist and a practising MD, and as far as I can tell, his observations agree with the predictions of my idea. (See second post, linked at top of this one). He's almost certainly wrong about a lot of stuff, but he's also probably the last best word we have from the world before the hormone blood tests sodded everything up.

I don't know that much about hormones, but from my reading of Inadiquite equilibria, This sort of thing happens. There are general game theoretic reasons why everyone seems to be inexplicably stupid. I don't know if this is a case of doctors ignoring an easy and effective medical treatment, but if it is, it would be far from the only case.

I think your post would benefit from you having a tl,dr and a proposal of what kind of study you would run to find out whether you are right.

I added a summary. How can I improve it? As far as falsifiability goes, I'm working on it, but so far: Take a load of CFS/FMS patients. Filter out those with abnormal TSH values (they're just normal hypothyroid cases, I'm sure there'll be some) Filter them for the clinical signs of hypometabolism (principally low metabolic rate, but use Billewicz criteria too) (1) That should do it, actually. Hypothyroidism in the presence of normal TSH values should be a surprise! (2) As a follow up, feed them small quantities of desiccated thyroid. Most of them should get better. (3) For a final flourish, feed the remainder who didn't respond T3 in increasing doses, and increase the doses until they either show signs of hypermetabolism (oops, stop) or get better. If there aren't any patients at (1), then I'm just wrong. I'll shut up, and anyone who wants to show that alternative medicine is badly mistreating people can point to the study. If there are a significant number of people at (1), then we know that the current understanding of thyroids is hopelessly wrong. More research is needed! If (2) works, then we have a major scandal. If it's only a temporary cure, then that's at least interesting. If it's a permanent fix then that's a huge win. If (3) works, then John Lowe was completely and utterly right about everything, and everyone in the world should apologise to his widow and he should get some sort of posthumous Nobel prize or something.
P.S. I have no idea how to design studies. Does anyone know how to put this into study-design-speak?

I wonder why [Seth Robert's Shangri-La Diet] hasn't caught on.

Because like every other dietary intervention, there's no rhyme or reason as to when it works for one person and fails for someone else. Recall:

But I don't think that Roberts has the whole story. There's something missing - something that would explain why the Shangri-La Diet lets some people control their weight as easily as a thermostat setting, and why others lose 30 pounds and then plateau well short of their goal, and why others simply find the Shangri-La diet ineffective. The Myster

... (read more)
I wonder if the rhyme or reason might be to do with the metabolism slowing down in response to low availability of calories. and maybe that happens more quickly in some people than in others. The mysterious bit would be if there were some people who could starve themselves without their metabolism slowing down. But we know that's not true for obese people because dieting and exercise don't work as treatments for obesity. So, all diets work for a bit, people tell their friends about them, write books, etc. They spread like wildfire for a bit and then they stop working and so people stop talking about them. And repeat. That leaves a fair number of people with slow metabolisms. So obviously they put on weight when they start eating properly again. Storing calories for future famines. But they're doing that at the expense of things they might rather be doing with their calories, like fighting off invading infectious agents. I guess I now have to predict that dieting fat people and anorexics get lots of symptoms associated with hypothyroidism. Anyone know if that's true? Is dieting part of this 'stress' that doesn't seem to be a real thing?

One of the commenters stated that no doctor would refuse to do a TSH, T4 and T3 panel. That's funny, because for six years, my doctors flatly refused to do anything but a TSH even when I told them that my TSH is always borderline normal while my T3 and T4 are abnormal. Because of this, I suffered without hormones for six years. Congrats on having good doctors, I guess...

I wonder if they just assumed that the thyroid system was a thermostat. The analogy is still common today.

While it's usually a safe bet that a biological system has complexities, it's entirely possible for it to be a simple control system, where the TSH levels serve as an control signal, and still have a failure mode where TSH is normal or low but thyroid output low.

That possible failure mode is that a problem in the hypothalamus or pituitary could lead to an underproduction of TSH. The properly-functioning thyroid would then dutifully lower production ... (read more)

Simon, failure of the hypothalamus and pituitary is known about, and referred to as 'central hypothyroidism', and it does indeed produce the same symptoms but normal TSH values. However you can detect it by other blood tests. But it's very rare. So rare that it's not cost-effective to test for it unless you've got some reason to look. Some undiagnosed cases will end up getting labelled as CFS, and that's a reason to test other hormone levels too if you can't explain someone's problems, but it's not nearly common enough to explain the whole thing (assuming very minimal levels of competence in those investigating).

Two other things come to mind: One: Smoking is also associated with these diseases, and smoking peaked in the 1970's Two: Iodine consumption.

Absolutely, but smoking causes everything, as does hypothyroidism. If there are interesting patterns of smoking prevalence (male/female ratio might be good) and CFS/FMS/hypothyroidism, that would be cool. Iodine is interesting, since it's very intimately part of all of this. And the other halogens. Please God, don't let me become an anti-fluorine nutter. Unless becoming an anti-fluorine nutter is the correct choice.
Smoking is associated with a lot of things, and in many cases, such as depression, the causation is very confused. It's possible people were self-medicating for these problems with cigarettes. Personally, I've switched from nicotine-and-flavoring-only e-cig juice to WTA juice following a comment in a Slate Star thread talking about the MAOI in tobacco, and the slow decline I've experienced with the effectiveness of vitamin D in correcting my emotional deadness seems to have largely, although not entirely, reverted. I hesitate to declare it a success, placebo effect and everything, but I certainly started smoking in a particularly deep depression, and my recovery, in retrospect, stalled out when I switched to e-cigs. (Which I was entirely not expecting, since I moved at the same time from a Northern state to a Southern one, explicitly for the increased hours of sunlight.) Gwern might have data on peak iodine consumption somewhere on his site. I feel like the sodium scare happened later, but that's hard to pin down. ETA: I'm also on absurd doses of iodine (usually used by paranoid people to flush out radiation or something), personally, because with a normal consumption level, iodine (which I have long used as a general-purpose antiseptic) would -visibly- absorb into my skin, which is apparently a sign that my levels are low.
Why do you think your levels are low if iodine absorbs into your skin? Biologically necessary doses have little relation to somewhat arbitrarily concentrated solutions! Or there have been studies on it, and I don't know something less obvious?

BTW, this is about a different gland (thymus), but I still thought you might find it interesting; a history of research: