Tests of Pituitary Function: Adrenal Insufficiency.

From Lewis Blevins, MD – The pituitary gland secretes ACTH that in turn drives cortisol production by the adrenal glands. ACTH secretion is determined by ambient cortisol levels, which inhibit ACTH production and secretion, and CRH and vasopressin from the hypothalamus that simulate ACTH.

Disease processes that impair ACTH production and release can lead to cortisol deficiency. We usually refer to this as central adrenal insufficiency. It can be divided in the secondary adrenal insufficiency due to pituitary disease and tertiary adrenal insufficiency due to hypothalamic disease.

The most common cause of low cortisol levels is prior treatment with excessive doses of glucocorticoid medications such as dexamethasone, prednisone, methylprednisolone, injectable steroids, etc. Generally, it can take months for pituitary-adrenal function to recover after long-term exposure to supraphysiological doses of glucocorticoids.

Another common cause of low cortisol levels in a pattern that mimics central adrenal insufficiency is that of chronic narcotic use and abuse. Fentanyl patches and intrathecal administration of opioids via pumps are notorious for causing low cortisol levels.

There is a term called isolated ACTH deficiency that has been used to explain central adrenal insufficiency in people with otherwise normal pituitary function and no anatomic abnormalities of the hypothalamus or the pituitary gland. I am not certain this disorder exists. In my experience, most patients have been exposed to injectable, inhaled, topical, or oral steroids or narcotics.

ACTH is a hormone that must be processed in a special way to be biologically active in stimulating adrenal function. In patients with hypothalamic and pituitary disorders, the absolute value or measurement of a ACTH is of little use because the ACTH that is not often a functional molecule. I find the levels to be all over the place in patients with bonafide pituitary disorders and central adrenal insufficiency.

Morning or random serum cortisol determinations can be of some utility in evaluating the adequacy of pituitary – adrenal function in patients with documented hypothalamic a pituitary disease. Morning serum cortisol levels less than 5 mcg/dL almost always indicate adrenal insufficiency in patients with disease of the hypothalamic – pituitary unit. Levels greater than 12 mcg/dL are generally reflective of normal pituitary adrenal function and highly correlated with the results of insulin-induced hypoglycemia tests. Levels between 5 and 12 mcg/dL require further investigation.

The insulin – induced hypoglycemia test has long been considered the gold standard in evaluating the adequacy of the hypothalamic-pituitary-adrenal unit. Unfortunately, however, hypoglycemia can precipitate seizures and myocardial infarction as well as adrenal crisis so this test is not routinely used in most practices.

The low – dose ACTH stimulation test is a reliable and accurate test of the adequacy of pituitary-adrenal function. Results strongly correlate with those of the insulin – induced hypoglycemia test. The positive predictive value of the test is excellent. In this test, 1 µg of ACTH is administered intravenously. A serum cortisol is obtained 30 minutes later. Serum cortisol levels greater than 18 mcg/dL are considered normal. The traditional ACTH stimulation test falsely classifies a considerable number of patients who have mild adrenal insufficiency. The low-dose test is definitely the ACTH stimulation test of choice in patients with hypothalamic and pituitary disorders.

The metyrapone test is an old-fashioned test to assess the adequacy of the response of the hypothalamic– pituitary – adrenal axis in the setting of low cortisol levels. I actually like this test but it is difficult to obtain metyrapone so I have largely abandoned it in my practice.

Finally, a decision to treat patients with glucocorticoid replacement hormones is not to be taken lightly. While some patients are treated empirically, and in anticipation of developing central adrenal insufficiency, it is usually best to test before committing patients to a lifetime of therapy with this class of drugs given the potential for complications of therapy.

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