Question: Does a 24-hour urinary cortisol measurement give any information on whether a patient without any adrenal glands is taking the correct amount of replacement hydrocortisone? Are there other tests that can be used to determine the correct replacement dose?

Answer: For the most part, adequacy of the hydrocortisone (glucocorticoid) dose is judged by clinical features. For example, weight gain and the development of Cushingoid features suggests that the dose is too high, while weight loss and adrenal insufficiency symptoms (joint aches, nausea), suggests that the dose is too low.

The 24-hour urine free cortisol concentration (UFC) may provide a very gross and imprecise sense of the adequacy of replacement hydrocortisone. In healthy individuals, UFC reflects the integrated blood cortisol levels during the day, and the two values correlate well. However, in the setting of hydrocortisone therapy, the relationship between blood and urine values do not always correlate well. This is explained by the way in which cortisol is carried in the blood. Only a small amount is “free” while nearly all is bound to a carrier protein. Usually the amount of cortisol in the blood can be accommodated by the carrier proteins and the appropriate amount is free. This free fraction is the part that is excreted in urine and that is available to the cells to exert hormonal effects. When a person takes a large dose of hydrocortisone, the resulting blood concentrations of cortisol may exceed the ability of the binding proteins to carry it, and the large “free” fraction is excreted in the urine. If this occurs the amount of cortisol in the urine will reflect more the “free” fraction that was excreted, rather than the “free” fraction that was available to the cells in the body. As a result, the UFC may overestimate the amount of cortisol actually available, and falsely suggest that the hydrocortisone dose is too high. This occurs most often when hydrocortisone is given as a single daily dose. On the other hand, a low UFC does not necessarily mean that the hydrocortisone dose is too low, as normal individuals may have UFC values in the lower normal range.

The question mentions a patient without adrenal glands. In general, all such patients also require a mineralocorticoid supplement, given as fludrocortisone (Florinef®). The clinical indicators of under-replacement are dizziness, salt craving and a low blood pressure, and the clinical indicators of over-replacement are high blood pressure and fluid retention. In addition to these clinical indicators of an appropriate dose, it is also very useful to measure the plasma renin activity (PRA) or renin concentration, and the serum potassium concentration. If the fludrocortisone dose is too high, potassium and renin levels will be low, while if the dose is too low, these levels, especially renin, will be high. When fine-tuning the doses of these medications, the hydrocortisone dose should not be changed without also checking the potassium and renin levels and adjusting the fludrocortisone dose as needed.

Patients without adrenal glands have elevated ACTH values-often 100 – 400 pg/mL. If ACTH values are consistently in the normal range or low, one might suspect over-treatment with hydrocortisone, and conversely, if they are always greater than 500 pg/mL, one might suspect under-treatment. However, the value may vary depending on how the specimen is handled, and the time at which it is collected in relation to the previous hydrocortisone dose, so that in general ACTH, like UFC, tends to provide an imprecise measure of the adequacy of replacement.

By Dr. Lynette K. Nieman MD (Winter, 2003)