We examined the relationship between TSH levels and cortisol in a preliminary study of young, healthy adults without known thyroid disease or other underlying health conditions. The positive relationship between serum TSH and cortisol levels in a healthy population is a compelling new finding that is consistent with and extends the observation that frankly hypothyroid patients have frankly elevated cortisol levels .
These preliminary results raise important questions – such as whether this relationship is pathologic or phy siologic and what the mechanism(s) involved in this relationship may be. While in frank hypothyroidism, it is hypothyroidism that causes elevation of cortisol by reducing peripheral disposal and blunting feedback of cortisol on the hypothalamic-pituitary-adrenal axis , our cross sectional data do not elucidate whether the same mechanisms hold true for TSH levels in the high normal and low elevated range. Thus more definitive population-based and intervention studies are now needed to confirm this finding and answer these questions.
Another potential explanation for the positive TSH-cortisol relationship is that hypothyroidism - subclinical or clinical - is associated with subtle metabolic stress. Metabolic stress could be imposing an effect on the adrenocorticotropin hormone-adrenal axis leading to an increase in stress hormone (i.e., cortisol) release and production. This hypothesis should be confirmed through the measurement of other stress hormones including the catecholamines, norepinephrine/epinephrine, and/or prolactin.
Although limited in sample size, our findings demonstrate that a positive relationship exists between TSH and cortisol that is maintained down to a TSH level of 2.5 uIU/L (but not below). This observation raises the possibility that negative health effects of mild, subclinical hypothyroidism with mild to modest elevations in TSH may begin at levels much lower than those currently considered abnormal based on assigned normal reference range values with an upper reference level of 4.5 uIU/L.
Chronic elevations in serum cortisol and hypothyroidism (including subclinical hypothyroidism) have been separately linked with increased rates of depression, anxiety, and poor cognitive functioning e.g., [15–17]. Thus, the association between TSH levels and cortisol suggests at least the possibility of a novel pathway through which hypothyroidism (both clinical and subclinical) may promote poor mental health; or hypothyroidism and an elevated cortisol level could be synergistic on mental health.
It is possible that the relationship described in this paper is physiologic rather than representative of pathology. Indeed, a failure to observe a relationship between TSH and cortisol for TSH < 2.5uIU/L may be a matter of methodology (assay accuracy at the lower levels, statistical power) rather than an indication that a relationship does not exist at those lower levels. Additional, larger clinical studies are needed that also include repeat TSH, FT3, FT4, cortisol, and catecholamine measurements to validate the reliability of the TSH-cortisol relationship.
A strength of this preliminary study is that we also measured FT3 and FT4 levels in this cohort of young, healthy individuals. Interestingly, while our results demonstrate that subtle elevations in TSH are associated with higher basal cortisol levels, this relationship is not apparent for FT3 or FT4 levels. One plausible explanation for the lack of an association between FT3 or FT4 and cortisol is that changes in FT3 and FT4 are slow to reflect subclinical hypothyroidism in the circulation because of adjustments made at the end organ level in both synthesis and metabolism of thyroid hormones . In addition, changes in TSH are 10 times more sensitive in reflecting an abnormality in thyroid hormone homeostasis compared to FT3 or FT4 . Similar to our finding, other studies of subclinical hypothyroidism typically report a relationship between the biomarker of interest (e.g., cholesterol) and TSH, but not FT3 or FT4 . However, it is still possible that mechanistically the relationship that we are here reporting is indeed between T3 and/or T4 and cortisol, but that measurement of FT4 and FT3 in blood is not sensitive enough to represent effects at the tissue level.
Our results and those of Iranmanesh et al.  for frank hypothyroidism suggest effects of the thyroid axis on the adrenal axis where hypothyroidism causes hypercortisolemia. It is of interest to consider these observations together with the well-established opposite effects, i.e. effects of the adrenal axis on thyroid function. Thus when cortisol levels are manipulated through pathologic as well as physiologic ranges, a negative relationship is found between cortisol and TSH. Both exogenous and endogenous (i.e. Cushing’s Syndrome, stress) corticosteroids suppress TSH [19–22] while low cortisol levels elevate TSH [23, 24]. These studies all taken together suggest a physiologic feedback loop where lower thyroid function increases cortisol, but cortisol feeds back to reduce TSH; this hypothesis is consistent with the observations that in the case of primary hypothyroidism (elevated TSH) cortisol is elevated, but in the setting of primarily elevated cortisol TSH is suppressed. Clearly further clinical studies, for instance studies that incrementally administer TSH and evaluate cortisol levels, are needed in order to better understand the mechanisms involved in the TSH-cortisol relationship.
In summary these initial data, that add to what is already known about frank hypothyroidism and cortisol, demonstrate a potentially important relationship between TSH and cortisol in apparently healthy young individuals. The finding that this relationship appears to hold in the controversial TSH range of 2.5-10 uIU/L, but not below, is compelling and requires further scientific and clinical investigation.