The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 6 2258-2259
Copyright © 1999 by The Endocrine Society
Lack of Specificity of Urinary Free Cortisol Determinations: Why Does It Continue?
Beverley E. Pearson Murphy
McGill University
Montreal, Canada H3G 1A4
Values for urinary free (i.e. unconjugated) cortisol (UFC)
vary widely in the literature (Table 1
). Although it was shown 19 years
ago that the true mean value in healthy subjects is about 20–30
µg/day (2, 3), three recent articles in this journal
demonstrate that the gap between reported values is widening rather
than narrowing.
In their article "Obesity and gender influence cortisol secretion and
metabolism in man" (12), Andrew et al. report the highest
values yet! They found mean levels of urinary free cortisol in urine of
95 µg/day for men and 218 µg/day for women—values that far exceed
the established values of about 45 µg/day for the crude assay (1, 5, 6, 8)—and 25 µg/day after Sephadex LH-20 (3) or high-performance
liquid chromatography (HPLC) (2, 9). Their data probably include
conjugated cortisol in addition to UFC. If there are such large
discrepancies between the cortisol conjugates in men and women, these
are of interest and should be explored further. In the initial paper
describing the human CBG competitive binding assay, no differences in
UFC were found between obese and nonobese subjects, either men or women
(1). Because the difference between the crude assays (1, 5, 6) and the
specific ones (2, 3, 7) is mainly due to cross-reactions with still
unidentified polar metabolites, it is important to assess UFC in obese
subjects using a specific method. Most studies have found that UFC in
men exceeds that found in women (1, 3, 5, 7, 8) in a ratio of about
1.4:1.
Why do the reported UFC levels vary so widely? One reason is that the
producers of commercial assays have continued to use the term UFC
without pointing out the fact that half or less of what is being
measured is actually cortisol. Indeed, clinical relevance has been
demonstrated for what is measured in some assays (1, 3, 9). Lin
et al. (9) compared competitive protein-binding to human
corticosterone-binding globulin (1, 2) with an HPLC method specific for
cortisol and found them to be equally effective in diagnosing
Cushing’s syndrome. However, that the cross-reacting material is
behaving like cortisol in all radioimmunoassays is an assumption;
although kit manufacturers provide specific data for known steroid
competitors, the bulk of the competing material is never identified.
While this assumption may hold true for some diseases, it may not hold
true for others.
Recently, Mericq et al. (10) have raised the possibility
that high fluid intake increases UFC excretion. Because their values at
normal urine volumes (77 µg/day) are about four times higher than
those after HPLC, as they themselves pointed out, this should be
investigated with more specific assays.
Although the crude assays have been shown to be clinically useful
provided they are carefully validated (1, 3, 9), all competitive
binding assays (including all radioimmunoassays) overestimate true UFC,
and in order to measure cortisol alone, it is necessary to employ
chromatography. Laboratories that rely on crude assays should designate
their material by some term other than UFC, such as urinary free
corticoids (suggested in ref. 3), cortisol-like material, RIA-reactive
material, or some such, and should not express it as nmol/L, as the
molecular weights of the other reacting materials are not known.
Specific assays are particularly important when exploring physiological
problems such as obesity (1, 12) or pathological entities such as those
of fibromyalgia (11), depression (6), and chronic fatigue syndrome
(4).
Footnotes
Received October 8, 1998. Revision received November
4, 1998. Address correspondence to: Dr. B.E. Pearson Murphy, Montreal
General Hospital, R. C6268, 1650 Cedar, Montreal, Canada H3G 1A4.
References
-
Murphy BEP. 1968 Clinical evaluation of
urinary cortisol determinations by competitive protein-binding
radioassay. J Clin Endocrinol Metab. 28:343–348.[Abstract/Free Full Text]
-
Schöneshöfer M, Fenner A. Dulce
JK. 1980 Interferences in the radioimmunological determination of
urinary free cortisol. Clin Chim Acta. 101:125–134.[CrossRef][Medline]
-
Murphy BEP, Okouneff L, Klein GP, Ngo SC. 1981 Lack of specificity of cortisol determinations in human urine. J Clin Endocrinol Metab. 53:91–99.[Abstract/Free Full Text]
-
Demitrack MA, Dale JK, Straus SE, et al. 1991 Evidence for impaired activation of the hypothalamic-pituitary-adrenal
axis in patients with chronic fatigue syndrome. J Clin Endocrinol
Metab. 73:1224–1234.[Abstract/Free Full Text]
-
Lamb EJ, Noonan KA, Burrin JM. 1994 Urine-free
cortisol excretion: evidence of sex-dependence. Ann Clin Biochem. 31:455–458.
-
Michelson D, Stratakis C, Hill L, et al. 1996 Bone
mineral density in women with depression. N Eng J Med. 335:1176–1181.[Abstract/Free Full Text]
-
Palermo M, Shackleton CH, Mantero F, Stewart PM. 1996 Urinary free cortisone and the assessment of
11-beta-hydroxysteroid dehydrogenase activity in man. Clin Endocrinol. 45:605–611.[CrossRef][Medline]
-
Morineau G, Gosling J, Patricot M-C, et al. 1997 Convenient chromatographic prepurification step before measurement of
urinary cortisol by radioimmunoassay. Clin Chem. 43:786–793.[Abstract/Free Full Text]
-
Lin C-L, Wu T-J, Machacek DA, Jiang N-S. 1997 Urinary free cortisol and cortisone determined by high performance
liquid chromatography in the diagnosis of Cushing’s syndrome. J
Clin Endocrinol Metab. 82:151–155.[Abstract/Free Full Text]
-
Mericq MV, Cutler Jr GB. 1998 High fluid intake
increases urine free cortisol excretion in normal subjects. J Clin
Endocrinol Metab. 83:681–684.
-
Griep EN, Boersma JW, Lentjes EGWM, Prins APA, van der
Korst JK, Kloet ER. 1998 Function of the
hypothalamic-pituitary-adrenal axis in patients with fibromyalgia and
low back pain. J Rheumatol. 25:1374–1381.[Medline]
-
Andrew R, Phillips DI, Walker BR. 1998 Obesity and gender influence cortisol secretion and metabolism in man. J Clin Endocrinol Metab. 83:1806–1809:1998.[Abstract/Free Full Text]
