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.