Abstract
Thyrotropin (TSH) secretion is regulated by the action of thyrotropin-releasing hormone on the thyrotrope and, in turn, is inhibited by thyroid hormone, this forming one of the well-known endocrine negative feedback loops that fine tune and balance the stimulatory response of the thyroid gland. In accordance with this principle, the homeostatic set point, also referred to as balance point, of the hypothalamic-pituitary-thyroid (HPT) axis translates as the individual's optimal range of TSH and free thyroxine (fT4), which is much narrower than the reference range of the general population. 1,2
It thus follows that the level of fT4 reflects the degree of TSH stimulation on the thyroid, which demonstrates that when measuring fT4 in conjunction with TSH, we do not determine two parameters independently of each other but instead ascertain their equilibrium, which is homeostatically regulated and strongly interdependent. 3
TSH reference ranges are age dependent, with a 97.5 percentile (upper limit of normal) of 3.6 mIU/L for patients under age 40 years and of 7.5 mIU/L for patients over age 80 years. 4 It is noteworthy that changes occur more often among older adults, with 32.3% of those aged >80 years but only 9.5% of those aged <60 years exhibiting thyroid function measurements in the highest and lowest quintiles. 5
Moreover, evaluation of TSH measurements should consider several other types of variation, including circadian and circannual rhythms, assay performance, and inter- and intraindividual variation. 6 Caution is required when determining the need for thyroid hormone treatment in populations of older adults due to age-related HPT axis alterations and altered pituitary responsiveness, as well as subtle and nonspecific symptoms in this elderly group.
In a Danish study including 140 patients with autoimmune hypothyroidism and a control group of 560 participants, although a good predictive value of a hypothyroidism composite symptom score was reported in patients younger than 50 years, it was of poor predictive value in older patients, and especially in females older than 60 years. 7
In a recent issue of the journal Thyroid, Yamada et al. reported the results of thyroid function study analyses from two Japanese centers. 8 A total of 14,860 participants underwent screening with a Siemens thyroid testing kit, while 8132 patients were screened with an Abbott kit. An additional 515 participants were evaluated at a thyroid-specialized hospital using Tosoh kits. In the first group, the median TSH level of females in their 30s amounted to 1.5 mIU/L (2.5th percentile, 0.5; 97.5th percentile, 4.6) and that of those in their 60s was 1.9 (0.7–7.8) mIU/L. In males, the corresponding TSH levels were lower and the increase with age was smaller, while the median serum fT4 levels of men gradually but significantly decreased with age.
Results were similar using the Abbott and the Tosoh kits, while, by using the Siemens kit and manufacturer-recommended reference, ∼60% (216/358) of women were diagnosed with subclinical hypothyroidism (SCH); these results, however, proved to be lower when age- and sex-specific reference ranges were applied in the interpretation of thyroid function testing (TFT). Τhe findings were most notable in postmenopausal females who, with increasing age, have a higher incidence of SCH.
A consequence of diagnosis of SCH may include prescription of levothyroxine (LT4) treatment. In the current issue of Thyroid, Toloza et al. reported on a multicenter electronic health records-based observational cohort study examining patients' and clinicians' determinants of LT4 treatment for SCH. 9 The study included 796 patients (65.2% females) with SCH, of whom 165 (20.7%) were treated with LT4 replacement therapy. The treated group was younger, with a higher proportion of females and positive thyroid autoimmunity compared with the untreated group.
It is of interest that 46.7% of patients in the treated group and 65.6% in the untreated group had confirmatory TFT before the decision to initiate LT4 treatment. One of the most interesting aspects of this study is its emphasis on the need to conduct a repeat set of TFT, usually after 2 to 3 months, to confirm the diagnosis: such a procedure may offer the opportunity to more frequently carry out assessment of thyroid autoimmunity as a diagnostic tool, thus critically supporting decision making.
The respective findings of Yamada et al. 8 and Toloza et al. 9 are of significance as they show that age and sex together with thyroid autoimmunity assessment are parameters of considerable importance for the diagnosis of SCH, as well as in consideration of its treatment. Lack of attention to these pivotal factors could well result in misinterpretation of the results, leading to application of unnecessary therapy.
Author's Contributions
L.H.D. is responsible for the conceptualization, writing, reviewing, and editing of this article.
Author Disclosure Statement
L.H.D. has no relevant financial disclosures. L.H.D. is an associate editor at Thyroid but was blinded to the review of this article.
Funding Information
No funding was received for this article.