February 5, 2014

Thyroid-stimulating Hormone Fluctuates With Time of Day

Time of day matters when drawing blood for diagnosis
A diagnosis could be missed in 3 out of every 10 patients with subclinical hypothyroidism if the blood draw is done later in the day.


Sviridonova MA, Fadeyev VV, Sych YP, Melnichenko GA. Clinical significance of TSH circadian variability in patients with hypothyroidism. Endocr Res. 2012 Aug 2. [Epub ahead of print]


A prospective observational study in which thyroid hormone levels were assessed in the morning (8 am–9 am) and afternoon (2 pm–4 pm) for each participant.


A total of 42 participants were enrolled: 20 women with subclinical hypothyroidism (SH) caused by autoimmune thyroiditis (TSH>4.0 mU/L, FT4 9.0–22.0 pmol/L) and 22 patients (20 women and 2 men) with primary hypothyroidism (PH). Those with PH were all taking L-thyroxine. Of the 22 PH patients, 16 had Hashimoto’s thyroiditis and 6 had postsurgical hypothyroidism.

Outcome Measures

Serum levels of thyroid-stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3)

Key Findings

TSH levels were lower in the afternoon compared to morning values in 41 of the 42 participants. Median TSH in the subclinical hypothyroid group was 5.83 mU/L in the morning vs 3.79 mU/L in the afternoon (P<0.001). Median TSH in the primary hypothyroid group taking L-thyroxine was 3.27 mU/L in the morning vs 2.18 mU/L in the afternoon (P<0.001) Using the current reference range of TSH (0.4–4.0 mU/L), an afternoon blood sample would lead to a missed diagnosis in 50% of those with subclinical hypothyroidism (P<0.0001). Per participant, the range of TSH variability reached highs of 73% in the SH group and 64.7% in the PH group.

Practice Implications

That there is a circadian rhythm to thyroid hormones is not surprising as the hormonal milieu is associated with diurnal rhythms. Thirty-five years ago, fluctuating TSH levels were demonstrated and found to be at their highest in the middle of the night.1 Current research suggests that TSH serum levels peak at between 2 am and 4 am and decrease to their lowest levels at between 4 pm and 8 pm.2 Thus, the lower afternoon TSH levels found in the current abstract are consistent with previous research. Interestingly, the current abstract also found that higher morning TSH levels were associated with greater variability later in the day. The study’s authors also found that FT3, but not FT4, had a positive correlation with the TSH variability. The question they pose is whether a tighter range of TSH (0.4–2.5 mU/L) would be more sensitive in diagnosing hypothyroid patients whom would otherwise be missed using the current reference range (0.4–4.0 mU/L).
A diagnosis could be missed in 3 out of every 10 patients with subclinical hypothyroidism if the blood draw is done later in the day.
There is a continuing debate about what the upper end of the reference range for TSH should be.3,4 While the current study has a small sample size, the researchers note that 100% of the participants in the subclinical hypothyroid (SH) group had a TSH greater than 4.0 mU/L in the morning but only 50% had levels exceeding 4.0 mU/L in the afternoon. When an upper end of 2.5 mU/L was used for the afternoon samples, 80% of the SH group exceeded the upper limit. This implies that a diagnosis could be missed in 3 out of every 10 patients with subclinical hypothyroidism if the blood draw is done later in the day.
Compared to the SH group, the PH group did not have as great a fluctuation in TSH but all of them did have lower levels of TSH in the afternoon samples. This is somewhat expected, as all of these patients were taking L-thyroxine. The authors use the term “inadequate compensation of hypothyroidism” to define the existence of hypothyroidism despite the use of L-thyroxine. When the upper limit of TSH was set at 4.0 mU/L, 45% of patients had inadequate compensation in the morning and 9% had inadequate compensation in the afternoon. When this upper limit was changed to 2.5 mU/L, inadequate compensation was found in 54.5% of patients in the morning and 40% of patients in the afternoon. Not surprisingly, when the TSH upper limit is 2.5 mU/L, inadequate compensation (ie, underdosing of thyroxine) is found in a greater number of PH patients.
This study implies that it is best for patients to have their blood drawn in the morning. Currently, whether a clinician uses the 4.0 or 2.5 mU/L value as a cutoff is somewhat arbitrary. However, there is mounting evidence that a TSH of between 2.5 and 4.0 mU/L is associated with serious health risks, including metabolic syndrome,5 nonalcoholic fatty liver disease,6 and dysglycemia.7
This particular study did not assess quality-of-life parameters or signs and symptoms of hypothyroidism in any of the participants. Of course, clinically, this is useful information as it is often the reason we assess thyroid hormone status. It stands to reason that treatment of hypothyroid states may begin when the TSH is above 2.5 mU/L. Certainly, supporting possible deficiencies in nutrients necessary for thyroid hormone production such as selenium,8 iodine, and zinc9 is indicated as this presents no risk to the patient.

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3. Waise A, Price HC. The upper limit of the reference range for thyroid-stimulating hormone should not be confused with a cut-off to define subclinical hypothyroidism. Ann Clin Biochem. 2009;46(2):93-98.
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