This paper discusses how TSH values can change within-person and the effect on diagnosis using TSH as the preferred diagnostic test.
REVIEW article
Front. Endocrinol., 24 February 2021 doi.org/10.3389/fendo.2021....
Within-Person Variation in Serum Thyrotropin Concentrations: Main Sources, Potential Underlying Biological Mechanisms, and Clinical Implications
Evie van der Spoel1*, Ferdinand Roelfsema2 and Diana van Heemst1
Thanks, a couple of possibilities come to mind: -
1. It could be that the thyroid declines with age and more TSH is needed to whack it into action, a bit like an old car needs a little more throttle. If this is the case logic suggests a higher TSH may be tolerated in older people before diagnosing primary hypothyroidism (but not other forms of hypothyroidism). It also follows on that when treating the elderly their failing thyroid is bypassed and so TSH should be similar to a young people with primary hypothyroidism. I don't advocate treating according to TSH although it is a useful initial marker.
2. It could be that the elderly produce 'weaker' TSH and so need more of it to produce the same thyroidal (and deiodinase) stimulation. TSH has many isoforms with differing potency. This should be studied because if the elderly secretes TSH with less bioactivity it will affect deiodinase (T4 to T3 conversion), especially in organs such as the brain which is highly reliant on type-2 deiodinase. TSH with low bioactivity would cause cognitive problems similar to dementia.
Why do we seem to assume that the thyroid becomes less able to secrete thyroid hormone with age while the pituitary secretes more TSH?
Unless we understand quite how ageing affects us, organ by organ, gland by gland, the simplistic view would be to suggest that all our organs deteriorate in the same direction and at broadly similar rate.
For a pituitary to manage to secrete significantly more TSH while itself being aged and working less well raises lots of questions.
What happens to pituitary size as we age? What happens to hypothalamic TRH secretion as we age.
Good point .. never though of that.
Very interesting - thank you.
".....In the current review we focus on biological variation, in particular on within-person biological variation. Within-person variation in TSH levels is caused by rhythms ranging from minutes to years, including pulsatile secretion, circadian rhythm, monthly changes, and seasonality (3, 4). Furthermore, TSH levels change with age, with in general higher levels with increasing age (5). Independent of time, within-person variation in TSH is also caused by effects of among others medication, illness, TPO antibody positivity, and iodine intake............. In this context, a lack of awareness among clinicians of variation in TSH levels within individual patients over time could lead to under- or overdiagnosis of (subclinical) thyroid diseases, or to inadequate prescription of thyroid medication to patients with thyroid disease. Furthermore, if the variation in TSH levels is not considered, this could lead to a distorted interpretation of outcomes and results in scientific research. ....."
Half of me is pleased to to see this written down and published.
The other half of me is still incredulous that 'TSH measurement' ever reached such a dominant place in research, diagnosis , and treatment monitoring , without anyone taking this amount of variation into account to begin with.
I mean, really ..... Imagine the stupidity of publishing guidelines telling people to follow the Sun to find their way to the Equator .. and letting them get on with it for decades, (and insisting anybody finding themselves in Russia was a fool) ...
and then waiting for someone else to publish a review decades later saying :
" oh , by the way .... the Sun is higher in Summer, lower in Winter, rises from the East, sets to the West, and sometimes you can't see it at all because of clouds ,and ... oh yeah.... it's only 'Due South' at Midday... sooo, you might want to take all this into account when trying to navigate .... "
The single worst factor of TSH adulation was the attachment of the adjectival phrase "exquisitely sensitive" to TSH tests at every opportunity.
Choice of that wording highlighted that the writer had no understanding of the words used. Even ultimate sensitivity at the level of measuring individual TSH molecules wouldn't make measuring TSH any more justified and appropriate.
Praise of the developers for managing to detect incredibly low levels of TSH needs to be tempered with things like the possibility of interference, as by macro-TSH, not being addressed. And the failure to harmonise tests across all testing platforms.
Also, that sensitivity only has any meaning at all at the hyperthyroid/over-medicated end of the scale. In particular, in seeking maximum thyroid hormone dose post-cancer. It does nothing whatsoever for the majority of hypothyroid patients.
Yes . that phrase has always annoyed me. I don't care how exquisitely accurate your measuring equipment is.. if you don't understand the factors affecting what you're measuring, then it's not much use . I'd rather have it measured by an Aborigine with an notched stick who understood what he was looking at .
or she? 
probably even better
The "exquisitely sensitive" comment reveals they should have paid attention to their school mathematics. TSH rises exponentially as fT3 and fT4 falls, it's just an exponential variable, it is no more sensitive than fT3 or fT4, possibly less sensitive. A simple plot of fT4 v. ln(TSH) reveals it's limitations.
TSH is useful in that when the thyroid fails the TSH / thyroid hormone relationship breaks down and TSH can elevate above its upper reference interval limit before fT3 or fT4 go low. TSH is useless when the pituitary underperforms, observation of posts on this forum reveals this is quite common.
The terms 'specific' and 'sensitive' are used in medicine in relation to false positives and false negatives. TSH is not 'sensitive' in this sense, using TSH as a marker leads to a large number of false negatives.
But the flush of "exquisitely sensitive" occurred more or less alongside the availability of the second and third generation TSH assays. So I've always believed it was actual laboratory biochemical sensitivity, being able to measure decreasing levels of TSH, that was being praised rather the full interpretation of the test in a clinical setting.
That "suppressed" wasn't below bottom of a validated scale that only went as low as 0.2, but was below 0.05 or whatever. But use of that word opens another worm can.
Adding:
Note how many TSH assays are described as "TSH Ultrasensitive" or similar by their manufacturers, by labs, etc. And that was entirely due to next generation improvements at the bottom end of their ability to detect TSH.
The original use of the term 'exquisite sensitivity' referred to the thyrotroph. When Dr Skinner responded to this paper bmj.com/content/326/7384/29... it was followed by a number of complaints to the GMC about his practice. These complaints were from doctors not patients and prompted by 'advice' from endocrinologists.
Dr Toft, who was chairman of BTA at the time now supports the use of TSH suppressive doses of levothyroxine and liothronine provided fT3 remains within its reference interval. (he provides no evidence to support this). When he gave a talk to the Thyroid Trust I pointed out that he is now doing what Dr Skinner did 20 years ago and was hounded for. Unfortunately the sound quality was very poor during this part of the talk and so it is missing from the video.
Can anyone help with results please?
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