Sunday, February 19, 2012

Seasonal Variations in Thyroid Hormones

Just a little bit of an information post to get a handle on things and to open up some more lines of questions…in that vein:

This Head I Hold by Electric Guest (right click to open in new tab)

(Oh, be sure to look at the initial post for a short thyroid primer if you aren't up on your T4s, T3s, and TSHs).  

I'm having a little trouble nailing down consistent reports in the literature of seasonal hormonal variation.  The papers are old and often the studies were awfully small, and I'm also trying to get a handle on variations of thyroid hormones within the menstrual cycle, which might invalidate some of the results in the women in the studies if they were not controlled for stage of menstrual cycle. I'm not sure how important that is, however, as I can't find any consistent recommendations to measure TSH at a particular time of the menstrual cycle.  Estrogen will increase the amount of thyroid binding globulin, which will tend to bind up more T4 and T3.  With thyroid function especially the newest studies use far more accurate hormonal assays, but we just have to look at what the results say and keep an eye out for new studies.  One of the better papers is from the American Journal of Clinical Nutrition; "Seasonal variation in plasma glucose and hormone levels in adult men and women." 

According to some other papers linking this one, the results seem to be fairly consistent in several different studies of normal controls but not in folks with seasonal depression (1).  In short:

Fasting glucose levels are lowest in the spring and summer and highest in the fall and winter.  Accordingly, there are more diagnoses of new cases of type II diabetes in the fall and winter.  Fasting insulin was also significantly lower in the spring than in the fall.

Among the thyroid hormones, all people had normal levels through all seasons, but there were significant differences between the levels from season to season, and the levels also seemed to differ by sex.  All the measurements were taken in the morning after an overnight fast.

Total T4 was highest in the summer.  Free T4 was highest in summer and fall and lowest in the spring, with men having higher levels than women during the fall and winter and women having higher levels than men during the summer.  Total T3 was highest in the winter.  

There was a negative correlation between glucose and free T4, and a significant positive correlation between T4 and the amount of carbohydrate and sugar consumed.  The only major differences in eating across the seasons was an increase in sugar intake among men in the spring, and a lower fiber intake in men in the fall and in women in the winter.

The interesting thing is that in a study of 148 untreated men and women with depression, there were no differences in the thyroid hormones across seasons (though they did not measure the same people across seasons as it wouldn't pass the IRB to merely follow depressed people for a year without trying to treat them somehow).  

What does it all mean?  Well, let's start with going over how T4 becomes T3.  Both are made and released by the thyroid, though humans release about 15 times as much T4 as T3 from the thyroid (2).  In addition, some enzymes called deiodinases change T4 into T3 in the body, and this mechanism is the major one by which active thyroid hormone (T3) is made.   The deiodinases have a little pocket in them with a selenium molecule where the transformations occur.  Iron is also required along the way to make thyroid hormone.  

There are three types of deiodinases.  D1 and D3 live on the plasma (outer) membrane of cells.  D2 is within the endoplasmic reticulum within a cell.  D2 therefore creates active thyroid hormone much closer to the nucleus of the cell, where thyroid hormones exert most of their effects.  D2 is the most important deiodinase in the nerves and brain.  D2 has a very short half life (40 minutes) and its expression is tightly controlled.  Both high levels of T4 and reverse T3 can downregulate D2.  D2 is also the important go-between in how T4 levels regulate the amount of TSH secretion from the anterior pituitary (I know.  All endocrinology is like this, and understanding it is a bit like being a card counter in Vegas.)

D1 and D3, on the other hand, have longer half lives and seem to be more responsible for the serum (blood) circulating levels of thyroid hormones.  D1 makes T4 into T3 (though it can also inactivate T3), and D3 preferentially inactivates T3 by making it into reverse T3.  In times of iodine shortage or hypothyroidism, the brain can decrease the activity of D3 by about 90% while increasing the activity of D2, which leaves more T3 around a lot longer to protect the brain from an iodine deficiency.  Pretty cool.  In rats, when they are made iodine deficient, their serum and tissue T4 become almost unmeasureable, while brain T3 levels decreased only by 50%.  

A quick recap to solidify the facts in your brain:  D1 and D2 can make T4 into the active T3.  D3 makes T3 into inactive reverse T3.  D2 is found within the cell near the nuclear action, D1 and D3 on the surface of cells. 

So systemically, T3 and T4 levels remain pretty stable throughout the body, but intracellularly, depending on the actions of D2, T3 can be much higher.    In the liver and kidneys, without much D2, T3 at normal physiologic levels occupies about 50% of the nuclear thyroid hormone receptors (TRs).  In the central nervous system where there is a lot of D2, nuclear thyroid hormone receptor occupancy can be close to 95%.

D2 is also found in brown fat (which helps to regulate body temperature).  At room temperature, around 70% of the TRs are occupied by thyroid hormone.  In the cold, 100% of TRs are occupied.  Heat is generated in brown fat in part by uncoupling protein 1 (UCP-1), which is made in response to T3.  T3 also seems to increase the activity of fat-burning enzymes in response to cold.  It's important, however, to know that in these animal studies, the serum levels of T3 were relatively unchanged whether it was cold or room temperature.  All the action seemed to be happening intracellularly, with D2 then having tissue-specific metabolic effects by affecting the levels of T3 within the cells.  T3 changes within the cells may also explain changes in basal metabolic rate in response to different diets.  High carbohydrate diets in the context of eating too much (3), for example, may increase D2 activity in humans, who may have more brown fat than previously thought, and who also might have more D2 activity in skeletal muscle than previously thought.  Thyroid hormone is one of the few truly potent stimulators of metabolic rate.

All these findings elucidate an elegant system, wherein individual cells and tissues can respond to relatively wide variations in normal serum T3 and T4 levels.  It also shows us how we can preserve thyroid hormone function in times of iodine shortage.  On the other hand, it is hard to interpret some of these small variations in thyroid hormone function as the serum levels may have very little to do with what is going on within the cell, where all the action is.  Certainly in cases of severe iodine deficiency or thyroid disease or pituitary disease we can see the large and predictable changes in hormone levels and decipher their meaning and see how they will affect the physiology of the body.

The much smaller seasonal and nonthyroidal or euthyroid sick syndrome changes are much trickier.  What do we make of no significant seasonal differences in (serum) thyroid hormone levels in folks with seasonal depression, but a normal mild variation in healthy people?  Is that difference (a higher T3, perhaps) what makes us survive the winter with a smile?  I don't know.  We do know that in critically ill patients, tissue D3 expression is increased, thus reducing T3 and increasing reverse T3.  In fasting, a continuous administration of TRH can reverse the dropping T3 and T4 levels, suggesting that perhaps the central hypothalamic mechanism of reduced TRH in response to fasting (which can be reversed by leptin and feeding) may be more important than the peripheral mechanism.

Got that?  Heh.  There are consistent changes in summer and winter in thyroid hormone activity (but not in the disease state of seasonal depression).  These changes were not dependent on carbohydrate intake, though increasing carbohydrate does increase active thyroid hormone and fasting will decrease it.  If one thinks of an abundant summer and a lean winter, perhaps the increases in T3 in the winter is meant to compensate.  Would it compensate for a diet presumably lower in carbohydrate/plant matter in the winter?  Would it matter if humans evolved for most of the time near the equator?  Much of the study of thyroid hormone is done in reptiles (thyroid hormone is very important in stages of metamorphasis and reptilian development)--are these seasonal changes remnants of even earlier evolutionary signals? I don't think I have the breadth of knowledge to properly contemplate these questions.  

But I'll keep looking.  

8 comments:

  1. Great post. Thanks for putting that together.

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  2. Very interesting info.

    Seasonal effect in BGT is probably due to seasonal variation in dopamine sensitivity + level, with spring & summer being higher. This is related to recent research into D2 receptor agonists for DMII patients, and the general physiological overlap between seasonally obese/ hibernating animals and the metabolic syndrome in humans. (I tend to think this is very much the right direction and that many forms of human obesity/glucose intolerance are an evolutionarily conserved seasonal nutrient capitalization mechanism being triggered 24/7 by constant carbohydrate and abnormal light patterns, i.e. hunter gathers are genetically incompatible with an agricultural society, but yes I realize this is crazy person on internet level stuff in that few others agree).

    Cortisol also follows a seasonal pattern, with lowest cortisol being the warmer months, and cold stress increasing cortisol (higher in winter). This may play a particularly influential role in seasonal late fall/winter depression, which is related to hypersensitive negative feedback inhibition of CRH from cortisol (and of course diminished serotonin + dopamine neurotransmission, and augmented melatonin, due to lower levels of light, also suppress CRH in seasonal depressives).


    Insulin and leptin will increase the activity of thyroid axis, as these nutrient signals suggest generous energy intake, so I would expect thyroid activity to be highest when glucose tolerance is most poor (fall, winter). Many tend to think obesity is related to low metabolic rate and low thyroid by actually garden variety obesity features simultaneous fat tissue anabolism occuring with hypermetabolic states (this is all expected of pathological hyperinsulinemia).
    Note, increased thyroid activity is not the goal, this is not necessarily a good thing; evidence suggests hypermetabolic states lead to shorter life spans and insulin seems to control lifespan in many animals; I tend to think juicing ones metabolism with high insulin is probably related to the onset of disease so chronic in western society, at least somewhat.

    What I found not so expected was to see T4 highest in the milder months.

    Of course, another endocrine effect may even be stronger than seasonal insulin/glucose trends - that would be of seasonal trends of sex steroids. Testosterone reaches a seasonal peak late summer /early fall, presumably to promote summer births (more favorable for neonates), which could account for the seasonal trend of T4, and would explain why men exhibit the effect more strongly (males obviously have more testosterone and women have more estrogen to antagonize the trend of seasonal T4 increase in fall/summer). Testosterone reduces TBG, oppositional to estrogen.

    Winter births (which would occur with the lowest levels of T4, spring, and suggest evolution does not encourage spring conceptions) are well noted to be rife with developmental problems particularly mentally. I would speculate winter births are purely a modern phenomena, at odds with evolution, and are facilitated only by modern society.


    Anyway, more specifically to the topic at hand, I would not expect thyroid hormone abnormalities to relate to most depression all that much; while some depressed patients may have thyroid complicating things, in general depression is not related to abnormal thyroid functioning. I think the HPA axis + circadian rhythm (which also affects HPA) is a better place to look when trying to understand depression and I would expect big time SNAFUS there for all forms of depressive patients, whether seasonal, atypical, unipolar or bipolar. Stress response powerfully affects (and is affected by) monoamine system and endorphin system. These things are very closely regulated physiologically suggesting a defect in one can screw the other.

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  3. @thewoo-

    t4 levels alone tell you nothing about thyroid function. thyroid hormone protects you from just about every westertn disease. Your opinions could not be more off base. Carbohydrates increase thyroid because glycogen is the rate limiting factor for t4->t3, if leptin raised thyroid high fat diets which chronically raise leptin would raise thyroid higher than say a fructose diet and it doesn't.

    The so-called longevity aspect you speak of is bunk as well considering they are measuring the thyroid hormone of people who are very old and have low metabolisms, if they measured them early in life that might indicate something.

    In regards to obesity and t3-
    "Median serum concentration of free T3 (4.5 pmol/l) and total T3 (1.80 nmol/l) in the obese patients were not significantly (P greater than 0.10) different from free T3 (4.6 pmol/l) and total T3 (1.84 nmol/l) in the normal persons"
    http://www.ncbi.nlm.nih.gov/pubmed/7160956

    "Treatment with small doses of T3 may be considered to ameliorate some of the risk factors associated with abdominal obesity, particularly in some subgroups of obese women with a relative resistance to thyroid hormones possibly dependent on decreased peripheral deiodination of thyroxine."
    http://www.nature.com/?file=/ijo/journal/v21/n10/abs/0800493a.html

    Higher metabolic rate=higher longevity
    "Here we show that increased mitochondrial uncoupling activity of different tissues predicts longer lifespan of rats compared with mice"
    http://ajpendo.physiology.org/content/296/4/E621

    Thyroid hormone increases your need for nutrients which is a major co-founding variable in these studies imo.

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  4. I have been supplementing with thyroid supplement and adrenal supplement since April and this is the first winter in 20 years I have not had SAD. I take thyroxine at a lower dose than I used to as well. Have wanted to hibernate as long as I can remember in winter, still not hyperactive but not down or not coping this year. I find all this very confusing and very interesting, thanks for this blog.

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  5. In addition to the other innovations I've mentioned previously, my endo found early on that hypothyroid patients need more thyroid hormone supplementation in the winter and less in the summer, with the other seasons in between. This pattern is so consistent that he uses it when making dose recommendations. For example, if I seem a little overdosed (by labs and/or how I feel) in September or October, he might suggest keeping the doses constant since I will very likely need a little more soon anyway.

    He has told me that be believes any doctor who reviews his or her records will easily find this pattern in their own hypothyroid patients. The academic endos will have none of it, however, as one might expect.

    "On the other hand, it is hard to interpret some of these small variations in thyroid hormone function as the serum levels may have very little to do with what is going on within the cell, where all the action is."

    This is why my endo doesn't slavishly rely on lab work to make recommendations. He uses them mainly to make sure dosing isn't grossly off one way or the other and to provide hints to the optimal direction of dose adjustments, particularly in the context of an individual patient's historical sense of well being at different levels. And it varies a lot. Some, for example, feel their best with very low TSH below 1, but some need a TSH of 3. T3 levels are so uncorrelated with well being that he does not measure them at all.

    He always emphasizes that what really matters, hormone levels in the tissues, is unmeasurable and relying rigidly on what can be measured in the serum makes no sense when patients are perfectly capable of reporting how they feel and how their thyroid related symptoms and signs are doing.

    Concerning depression, this is one of the most rewarding areas of his practice, since so many people improve dramatically after stabilizing on the appropriate, seasonally-adjusted T3/T4 combo therapy. He has had people make incredible recoveries, though not all do since of course hypothyroidism is not the only contributor to depression. But I believe it is an extremely common and important one. My own experience, and that of several people I know under his care or using his methods, is very consistent with this.

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  6. R&C -
    Pathological hypothyroidism is different from physiologic hyperthyroid compensation secondary to excessive insulin/glucose/leptin. You are taking evidence , case studies of patients and articles who have diseased thyroid, who improve when they have their thyroid treated, and then you are irrationally concluding that "the more the better" when it comes to thyroid function. That conclusion is not justified. That's like saying "addisons patients improve on cortisol - DEXAMETHASONE FOR EVERYONE!"

    Furthermore, as Dr. Deans mentioned several times, the physiological stress response (activated in illness) conserves energy by stress hormones converting T4 to rT3. So when you say "thyroid hormone problems correlate with illness", is it because thyroid cures/prevents disease or is it because part of the physiologic adaptation to stress involves turning off the thyroid? Yes, thyroid is going to correlate with disease, for the same reason erythema + swelling is going to correlate with localized infections. It is the natural response to a disease process. Sun tanning is not going to prevent abscesses, and trying to become hypermetabolic is not going to make you disease resistant.


    I do not preface my statements based on thyroid hormone measurements of old people (huh?). I make my statements based on scientific evidence.
    In the real world, scientific evidence is clear that insulin signalling seems to control lifespan in simple organisms, almost all animals have some kind of life span extension if they are maintained at low insulin levels (via either food restriction or protein restriction), and actually higher metabolic rates = shorter life spans, in all life forms in general. The dauer state of worms is only accomplished via arresting metabolism completely like a living death ; they then can live forever, pretty much. While this is a far cry from PROVED@! in people, it does at least suggest that running metabolism faster + hotter (with high insulin and maximal thyroid and glucose/protein galore) is probably not as good of a bet as erring toward less. (FYI, insulin, leads to leptin, and both lead to maximal thyroid activity assuming there is no underlying disease in the system.)


    (PS, regarding Ray Peat, and "where he is wrong"... it took but 5 minutes to read his blog and find an OMG WTF worthy statement:
    http://raypeat.com/articles/articles/tissue-bound-estrogen.shtml
    This whole article is ridiculous. It's like he is ignoring that menopause involves the arrest of the HPO axis which is the primary source of estrogen. Tissue bound, free plasma, who cares if the ovaries are kaput (as they are after menopause, literally the PAUSE of MENSES, as in no follicles?)
    1% of deficient is still deficient; 100% of deficient is still deficient. The issue in menopause is the endocrine organ - ovaries - stop working, normal aging. There is absolutely estrogen deficiency. To say otherwise is ... there isn't a word, crazy, ridiculous, gimmicky, I don't even know.
    Goes back to what I said before about altie quacks and how they just basically ignore established basic endocrinology and charge bravely into the night with crazy theories totally disregarding science and common sense along the way.

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  7. I wonder, does it matter a lot where are you live for the effect to manifest? I live in the Northern Florida, days are shorted in Winter, but it is still sunny and often warm in winter.

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  8. Galina - I would say it matters MASSIVELY!

    I live at 57 north, trust me, only 6 hours of daylight during the darkest months has a marked effect on mood and I'm pretty certain on eating patterns, fat storage and metabolism in general.

    Emily - you touch on the paucity of studies that consider menstrual cycles; this I think is a huge area to be investigated. As far as I understand it most drugs are not dispensed dosage-wise in terms of gender (other than if you considered weight where I assume men will on average be heavier than women). I know from the anecdotal evidence over at MDA on the forums that females certainly experience a change to 'Primal' eating a great deal differently from men.

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