Should Thyroid Hormone Be Taken at Night?

A new study shows that TSH and Free T3 and Free T4 levels fluctuate during the day. Surprisingly, TSH levels start to rise around 9 pm, hitting bottom again around 9 am. T3 levels follow a similar pattern following TSH levels by around 90 minutes (as would be expected if the TSH stimulates T3 release from the thyroid). T4 variability was not associated with TSH variability. So what does this all mean?

Key interesting take home points:

1. Thyroid hormone levels are highest at night while we sleep—NOT while we're awake.
2. Even though TSH regulates T4 over the long term (days to weeks), TSH variability during the day mostly seems to play a role in fine tuning T3 levels during the day, having little to no effect on T4 hormone variations during the day. This suggests that fine tuning the timing of giving T3 is more important than T4.

Implications:

1. With TSH varying so widely during the day (increasing by 72% from its daily low to its daily high—almost 1 mU on average and sometimes over 2 units in some people in the study), strictly interpreting a TSH level as the sole determinant of whether someone needs thyroid hormone becomes an even more ridiculous approach than it has been in the past (unless they want to define the normal range based on a set time of day the test was done—even if one does, TSH is still horribly unreliable).
2. Earlier research has suggested that people do better taking their thyroid hormone at bedtime instead of in the morning, and clinical experience has shown this is also often the case. This study further suggests that thyroid (especially if it also contains T3) may best be taken at night instead of in the morning. I have often had patients take part of their thyroid later in the day. Years from now, we may find this to be the preferred approach (perhaps even giving the entire dose at bedtime). Even now, for those not doing well on thyroid, it is worth a try of taking all or part of the thyroid dose at bedtime for a few weeks to see which way feels best.
3. Giving T3 may be important as well as T4. It is interesting watching the authors tiptoe around this issue. One can almost feel the politics as they say "Following the first publication that a combination replacement therapy of T4 and T3 may improve quality of life for hypothyroid patients,¹³ there has been considerable debate as to actual benefits. Despite a large number of studies there is no conclusive evidence that combination therapy with T4 and T3 improves efficacy of therapy or health related quality of life."¹⁴ This statement, of course, ignores that there is no conclusive evidence that using only T4 (e.g., Synthroid) does so either. This simple observation is irrelevant to the politics of addressing an underactive thyroid though, and I suspect the authors were simply spouting the current dogma so they could avoid being attacked for proposing that perhaps T3 may be worth adding to therapy (as they hint at).

Overall this is an interesting article, which supports a trial of giving thyroid (preferably also containing T3) at bedtime.

Abstract

Free triiodothyronine has a distinct circadian rhythm that is delayed but parallels thyrotropin levels

*W. Russell,¹ *R.F. Harrison,² N. Smith,³ K. Darzy,⁴ S. Shalet,⁴ A.P. Weetman,¹ and R.J. Ross¹

¹Academic Unit of Diabetes, Endocrinology & Metabolism, and ²Department of Automatic Control & Systems Engineering, The University of Sheffield, Sheffield S1

3JD, UK. ³Chemical Pathology, Royal Hallamshire Hospital, Sheffield S10 2JF, UK.

⁴Department of Endocrinology, Christie Hospital, Manchester M20 4BX, United Kingdom.⁵

* These two authors made an equal contribution:

Corresponding author: Professor Richard JM Ross, University of Sheffield, Room 112, Floor M, Royal Hallamshire Hospital, Glossop Road, Sheffield, S10 2JF, UK. E-mail: r.j.ross@sheffield.ac.uk Short title: Circadian rhythm of FT3

J Clin Endocrin Metab. First published ahead of print March 25, 2008 as doi:10.1210/jc.2007-2674, Copyright (C) 2008 by The Endocrine Society

Abstract

Context: TSH is known to have a circadian rhythm but the relationship between this and any rhythm in T4 and T3 has not been clearly demonstrated.

Objective: With a view to optimising thyroid hormone replacement therapy we have used modern assays for FT4 and FT3 to investigate circadian rhythmicity.

Setting: University Hospital.

Design and subjects: Cross sectional study in 33 healthy individuals with 24 hour blood sampling (TSH in 33 and FT4 and FT3 in 29 individuals) and cosinor analysis.

Results: 100% of individuals showed a sinusoidal signal in TSH, for FT4 76% and for FT3 86% (p<0.05). For FT4 and FT3 the amplitude was low. For TSH the acrophase occurred at a clock time of 0240 h and for FT3 approximately 90 minutes later at 0404h. The group cosinor model predicts that TSH hormone levels remain above the mesor between 2020 h and 0820 h and for FT3 from 2200 h to 1000 h. Cross correlation of FT3 with TSH showed that the peak correlation occurred with a delay of 0.5-2.5 hours. When time adjusted profiles of TSH and FT3 were compared there was a strong correlation between FT3 and TSH levels (?=0.80, p<0.0001). In contrast, cross correlation revealed no temporal relationship between FT4 and TSH.

Conclusion: FT3 shows a circadian rhythm with a periodicity that lags behind TSH suggesting the periodic rhythm of FT3 is due to the proportion of T3 derived from the thyroid. Optimising thyroid hormone replacement may need to take these rhythms into account.