Why might excessive drinking produce a false hypercortisolism reading in a urinary free cortisol (UFC) test?

Question

From "Diagnosis of Cushing's Syndrome in the Modern Era" by L.K. Nieman, 2018:

A urine free cortisol (UFC) result may incorrectly exclude hypercortisolism in patients with a glomerular filtration rate less than 30 mL/min but might falsely diagnose hypercortisolism in individuals drinking more than 5 L of fluid daily. In the former situation, UFC should not be chosen as a screening test." In the latter group of individuals, urinary cortisone and cortisol both increase, so that the effect may be more accentuated in immunoassays in which cortisone cross-reacts with the antibody. Thus, 2 ways of addressing this are to use tandem mass spectroscopy assays (or immunoassays with minimal cross-reactivity) and to ask patients to restrict fluids to 2 L/d.

Why is that so? Is it because the body would naturally need to produce more cortisol in order to expel all this water?

Answer 1

Most of the cortisol entering the kidney is reabsorbed by the proximal tubule; only a small amount escapes and is eventually excreted in the urine.

When large amounts of fluid is taken, the re-absorption is less efficient, and more cortisol ends up in the urine. See following quote:

increased UFF excretion (when fluid intake is high) is mainly due to the escape of F from reabsorption/metabolism in the proximal tubule

(Fenske, 2006; here UFF/F is referring to urinary free cortisol and cortisol, respectively; words in parentheses are mine added for context)

Separately, this loss doesn't cause much of a change in systemic cortisol since passage through the urine is only a minor contributor to overall cortisol levels.

The Fenske paper referenced below talks more about this issue, and is cited by the paper referred to in the OP. Overall, I think it's important to mark carefully the author's specific words: they indicate that one might falsely diagnose hypercortisolism with heavy fluid intake, but they only caution against use of UFC if the glomerular filtration rate is very low (i.e., in patients with kidney problems). It seems that they simply mean to caution about the potential of abnormally high UFC in the case of an individual with high fluid intake, without an actual systemic increase in cortisol.

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Fenske, M. (2006). Urinary free cortisol and cortisone excretion in healthy individuals: influence of water loading. Steroids, 71(11-12), 1014-1018.