A physician is treating a female patient (age and ethnicity unstated) with cystic fibrosis who also has adrenal insufficiency, and wants to determine if the patient is absorbing the oral hydrocortisone. Is a 24-hour urinary free cortisol (UFC) measurement helpful?

Response: 

Most laboratories do not report a lower limit of the reference interval for UFC. Below is from the reference range provided by a prominent reference laboratory:

Cortisol (µg/day)

Females                                      Males
3-8 years: <18 µg/day                 3-8 years: <18 µg/day
9-12 years: <37 µg/day               9-12 years: <37 µg/day
13-17 years: <56 µg/day             13-17 years: <56 µg/day
18 years and older: <45 µg/day   18 years and older: <60 µg/day

This does not reflect a limitation in the analytical method used by the reference laboratory; however, UFC is not generally helpful in the diagnosis of cortisol deficiency.

A PubMed search for studies on "ufc" AND "addison disease" yielded 3 references. The most recent study, in 2004, measured UFC to evaluate "two cortisol replacement regimens in primary adrenal insufficiency patients" [1]. This study did not validate UFC as a measure of cortisol deficiency.

The authors of a 1999 study state: " . . .there is no compelling need for using determinations of either UFC excretion or of the serum cortisol profile in the routine management of patients on replacement therapy." [2].

The oldest reference (from 1982) is interesting: The author reports UFC concentrations in 523 healthy controls [3], but does not describe the analytical method. Approximately 8% of the healthy subjects included in this study had UFC measurements between 5 and 10 ug/24 hours. None of the subjects had a UFC of less than 5 ug/24 hours. This study provides a reference interval for UFC, representing a 14-fold interval from the lowest (5 ug/24 hours) to the highest (70 ug/24 hours) UFC. With such a wide reference interval, many would conclude that UFC is a poor discriminator between low versus adequate cortisol levels in the plasma. After  review of UFC measurements in 9 patients with primary adrenal insufficiency, the author concluded: "The UFC is a useful biochemical marker that correlated clinically with glucocorticoid deficiency or excess in patients with hypoadrenalism receiving maintenance steroid replacement." However, the literature does not support the conclusion that UFC is helpful in monitoring steroid replacement. UFC is useful, however, for measuring cortisol excess (e.g., Cushing syndrome).

Using either "sufficiency of hydrocortisone replacement" or "sufficiency of cortisol replacement" in the PubMed search box yielded two  references that concern assessment of post-operative adrenal sufficiency following pituitary surgery. These studies were not relevant to the physician's question and UFC was not assessed in either study. 

Clinical evaluation appears to be the the best tool to assess the sufficiency of exogenous hydrocortisone replacement. What are your thoughts? Did we miss something in the literature?

[1]  Alonso N, Granada ML, Lucas A, Salinas I, Reverter J, Oriol A, Sanmarti A. Evaluation of two replacement regimens in primary adrenal insufficiency patients. effect on clinical symptoms, health-related quality of life and biochemical parameters. J Endocrinol Invest. 2004 May;27(5):449-54.

[2]  Jeffcoate W. Assessment of corticosteroid replacement therapy in adults with adrenal insufficiency. Ann Clin Biochem. 1999 Mar;36 ( Pt 2):151-7.

[3] Burch WM. Urine free-cortisol determination. A useful tool in the management of chronic hypoadrenal states. JAMA. 1982 Apr 9;247(14):2002-4.