Cortisol Suppresses TSH, Not TRH Directly
Cortisol suppresses TSH secretion at the pituitary level, with chronic hypercortisolism causing more pronounced suppression than acute elevations. 1, 2
Mechanism of Suppression
Cortisol acts primarily on pituitary thyrotrophs to suppress TSH secretion, rather than directly suppressing TRH release from the hypothalamus. 2, 3
Acute elevations in cortisol (such as from single-dose ACTH or hydrocortisone infusions) produce no significant effect on either basal or TRH-stimulated TSH secretion in healthy subjects. 2
Chronic hypercortisolism is required for clinically significant TSH suppression—patients with Cushing's syndrome demonstrate both suppressed basal TSH levels and impaired TSH response to TRH stimulation. 2, 3
Evidence from Cushing's Syndrome
In untreated Cushing's syndrome, 54% of patients have a "flat" TSH response to TRH (increment <2 mU/L), with the degree of suppression directly correlating with cortisol levels (morning cortisol, midnight cortisol, and 24-hour urinary free cortisol). 3
The correlation between cortisol excess and TSH suppression is strongest (r = -0.73 for midnight cortisol and stimulated TSH) when confounding factors like diabetes, goiter, or severe systemic illness are excluded. 3
TSH secretion becomes diminished and irregular during hypercortisolism, with decreased pulsatile TSH release and increased secretory irregularity (measured by approximate entropy), indicating glucocorticoid-induced dysregulation of hypothalamic control mechanisms. 1
Physiological Cortisol-TSH Relationship
Even physiological variations in cortisol affect TSH secretion—the normal early morning cortisol surge causes the characteristic daytime decrease in TSH levels. 4
When cortisol synthesis is blocked with metyrapone (reducing cortisol by 39-47%), daytime TSH levels increase by 35%, abolishing the normal circadian TSH variation and equalizing day and night TSH levels. 4
Cross-correlation analysis shows cortisol and TSH are negatively correlated with a 2.5-hour lag time (cortisol leading TSH), reflecting the negative glucocorticoid effect on the hypothalamic-pituitary-thyroid axis under physiological conditions. 5
Reversibility After Treatment
Successful treatment of Cushing's syndrome normalizes both basal TSH levels and TRH-stimulated TSH response as cortisol levels return to normal, demonstrating the reversibility of cortisol-induced TSH suppression. 2, 3
After surgical cure, TSH secretion increases primarily through elevated nonpulsatile (basal) TSH release during daytime, while TSH secretory regularity returns to normal. 1
Clinical Implications
The TSH suppression in hypercortisolism can mimic central hypothyroidism—patients with secondary adrenal insufficiency from hypophysitis will have low ACTH with low cortisol, and may also have low or normal TSH with low free T4. 6, 7
When replacing multiple hormones in hypopituitarism, corticosteroids must always be started first before thyroid hormone replacement to avoid precipitating adrenal crisis. 6, 7
Long-term exogenous steroid use suppresses the hypothalamic-pituitary-adrenal axis, and patients require education about not abruptly stopping therapy and recognizing symptoms of adrenal insufficiency. 8