Clinical Uses of Corticotropin-Releasing Hormone in the
Evaluation of Patients with Cushing's Syndrome
Beverly M. K. Biller, M.D.

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• Testing Protocol
• CRH Testing - Differential Diagnosis of Cushing's Syndrome
• CRH Testing - Bilateral Inferior Petrosal Sinus Sampling
• CRH Test - Cushing Syndrome versus Pseudo-Cushing's
• Table 1 : Bilateral inferior petrosal sinus sampling with CRH at the Massachusetts General Hospital
• References

Corticotropin-releasing hormone (CRH), the hypothalamic peptide which stimulates ACTH release from the pituitary gland, has been available for investigational use for nearly a decade. The formulation of greatest clinical utility, ovine CRH, is currently under evaluation by the United States Food and Drug Administration for approval as a new drug. Because approval is anticipated in the near future, it is important to define the clinical indications for this peptide. A key utilization of CRH will be in patients with Cushing's syndrome. Three settings in which oCRH testing has been useful in the evaluation of patients with Cushing's syndrome are: 1) the differential diagnosis of ACTH dependent versus ACTH independent Cushing's syndrome, 2) to enhance the diagnostic accuracy of bilateral inferior petrosal sinus sampling, and 3) distinguishing between Cushing's syndrome and pseudo-Cushing's syndrome.

Testing Protocol

To perform a CRH test, blood is drawn for baseline ACTH and cortisol levels at -15 and 0 minutes followed by a 1 mg/kg dose of oCRH administered as an IV bolus. Samples for ACTH and cortisol are then drawn at 15, 30, 60, 90 and 120 minutes. The test is well tolerated, with the most common side effects being transient facial flushing occurring in 20% of subjects, and rare dyspnea and hypotension. Normal subjects experience a rapid rise in ACTH and cortisol, with a gradual decline over the subsequent two hours.

CRH Testing - Differential Diagnosis of Cushing's Syndrome

The first use of oCRH is in the differential diagnosis of Cushing's syndrome to establish the site of hormone excess in patients with documented cortisol excess (Fig. 1). The use of CRH in this setting is based on the principle that pituitary tumors are responsive to exogenous CRH, whereas ectopic and adrenal tumors are not. In Cushing's disease, at least a 50% rise in ACTH and a 20% rise in cortisol compared to baseline have been described as criteria providing a 91% sensitivity and 95% specificity for pituitary Cushing's. It has also been shown that using both the CRH test and the high dose dexamethasone suppression test enhances diagnostic accuracy. In adrenal Cushing's, the low ACTH and high cortisol levels at baseline are not affected by CRH injection. In ectopic Cushing's, typically due to carcinoid or oat cell tumors of the lung but reported for a wide variety of tumor types, the high ACTH and high cortisol levels at baseline are usually not altered by the CRH administration. However, a few cases of ectopic Cushing's in which some response was seen to CRH have been reported. Interestingly, in nearly all of those cases, ACTH rises without a concomitant increase in cortisol, suggesting that the cortisol response to CRH may be the most specific biochemical test differentiating between pituitary and ectopic Cushing's syndrome. It has been theorized that this discrepancy between ACTH and cortisol release may be due to the secretion of "big ACTH" by ectopic tumors, with these abnormal forms of ACTH being less bioactive, resulting in a smaller adrenal response to a given amount of ACTH.

Figure 1

Reprinted by permission of the New England Journal of Medicine Vol. 310, page 622, 1984

CRH Testing - Bilateral Inferior Petrosal Sinus Sampling

The second use of CRH is to enhance the diagnostic accuracy of bilateral inferior petrosal sinus sampling (BIPSS) for ACTH. BIPSS is performed via femoral catheterization to sample blood from the inferior petrosal sinuses draining from the pituitary. This provides for comparison between central and peripheral ACTH values, allowing definitive confirmation of the site of hormone excess. It is also possible, by comparing right versus left side ACTH values to predict the tumor location and provide this information to the pituitary neurosurgeon. (See Vol. 1 of newsletter). The rationale for using CRH during BIPSS is that false negative test results may occur in up to 18% of patients subsequently proven to have pituitary Cushing's. This is due to the fact that secretion of ACTH from corticotroph adenomas can be episodic, and a low value may be measured from the petrosal sinuses if the blood is collected between ACTH pulses. Use of CRH stimulates ACTH release from the corticotroph adenoma, producing a higher pituitary-to- peripheral ratio, and thereby allowing better discrimination between pituitary and ectopic Cushing's. If the pituitary to peripheral ratio is >3 with CRH, the patient has Cushing's disease. In contrast, if it is <3, the patient has ectopic Cushing's. The sensitivity and specificity of BIPSS each reach 100% if CRH is used. Approximately 100 BIPSS's have been performed at the Massachusetts General Hospital with results very similar to those reported by the NIH and with no neurologic complications. An example of data from a BIPSS with CRH performed at the Massachusetts General Hospital is shown in Table 1.

CRH Test - Cushing Syndrome versus Pseudo-Cushing's

The most recently described use of CRH in the evaluation of patients with Cushing's has been a new test designed to distinguish Cushing's syndrome from pseudo-Cushing's states. Differentiating between hypercortisolemia associated with endogenous depression (pseudo-Cushing's) versus depression associated with true Cushing's syndrome can be extremely difficult. Insulin tolerance tests, in which patients with primary depression have a normal cortisol response and patients with Cushing's syndrome have a blunted response, and CRH tests, in which patients with primary depression have a blunted response and patients with Cushing's syndrome have a normal to exaggerated response, have been advocated to make the distinction between these diagnoses. However, the data show substantial overlap between groups. Therefore, although these tests have been useful in studying the physiology of these disorders, they have not been as useful diagnostically as initially hoped. It has often been necessary to follow patients with depression versus Cushing's for many years with improvement in primary endogenous depression (either spontaneously or with pharmacotherapy) indicating absence of Cushing's syndrome. A recent study has suggested that it is possible to distinguish patients with pseudo-Cushing's from those with Cushing's syndrome by performing a CRH test immediately following a standard low dose dexamethasone suppression test. The last dose of the eight 0.5 dexamethasone pills is given at 6 a.m., followed by an 8 a.m. injection of CRH. A plasma cortisol greater than 1.4 mg/dl measured 15 minutes after the CRH injection differentiated all patients with Cushing's syndrome from those with pseudo-Cushing's. The values for plasma cortisol in the 39 patients with Cushing's syndrome and the 19 patients with pseudo-Cushing's who had elevated urine free cortisol are shown in the Figure 2. This test had 100 % specificity, sensitivity and diagnostic accuracy and is extremely promising for the diagnosis of Cushing's syndrome in this difficultsituation.

In summary, the CRH test is a safe, well-tolerated diagnostic tool which will have a beneficial impact on our ability to diagnose accurately patients with Cushing's syndrome.

Figure 2

References

1. Yanovski JA, et al. Corticotropin-releasing hormone stimulation following low-dose dexamethasone administration. JAMA. 1993; 269: 2232.
2. Chrousos GP, et al. The corticotropin-releasing factor stimulation test: An aid in the evaluation of patients with Cushing's syndrome. N Engl J Med. 1984; 310:622.
3. Oldfield EH, et al. Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing's syndrome. N Engl J Med. 1991; 325:897.
4. Nieman LK, et al. The ovine corticotropin-releasing hormone stimulation test and the dexamethasone suppression test in the differential diagnosis of Cushing's syndrome. Ann Int Med. 1986; 105:862.
   

Table 1

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