INDICATIONS AND USAGE
ACTHREL is indicated for use in differentiating pituitary and ectopic production of ACTH in patients with ACTH-dependent Cushing's syndrome.
Differential Diagnosis
There are two forms of Cushing's syndrome:
ACTH-dependent (83%), in which hypercortisolism is due either to pituitary hypersecretion of ACTH (Cushing's disease) resulting from an adenoma (40%, usually microadenomas) or nonadenomatous hyperplasia, possibly of hypothalamic origin (28%), or to hypercortisolism that is secondary to ectopic secretion of ACTH (15%) and,
ACTH- independent (17%), in which hypercortisolism is due to autonomous cortisol secretion by an adrenal tumor (9% adenomas, 8% carcinomas).
After the establishment of hypercortisolism consistent with the presence of Cushing's syndrome, and following the elimination of autonomous adrenal hyperfunction as its cause, the corticorelin test is used to aid in establishing the source of excessive ACTH secretion.
The corticorelin stimulation test helps to differentiate between the etiologies of ACTH-dependent hypercortisolism as follows:
High basal plasma ACTH plus high basal plasma cortisol (20 - 40 mcg/dL). ACTHREL injection (1 mcg/kg) results in:
Increased plasma ACTH levels
Increased plasma cortisol levels
Diagnosis: Cushing's disease (ACTH of pituitary origin)
High basal plasma ACTH (may be very high) plus high basal plasma cortisol (20 - 40 mcg/dL). ACTHREL injection (1 mcg/kg) results in:
Little or no response of plasma ACTH levels
Little or no response of plasma cortisol levels
Diagnosis: Ectopic ACTH syndrome
Test Methodology
To evaluate the status of the pituitary-adrenal axis in the differentiation of a pituitary source from an ectopic source of excessive ACTH secretion, a corticorelin test procedure requires a minimum of five blood samples.
Procedure
Venous blood samples should be drawn 15 minutes before and immediately prior to ACTHREL administration. The ACTH baseline is obtained by averaging the values of the two samples.
Administer ACTHREL as an intravenous infusion over a 30 to 60- second interval at a dose of 1 mcg/kg body weight. Higher doses are not recommended (see
PRECAUTIONS
and
ADVERSE REACTIONS
).
Draw venous blood samples at 15, 30, and 60 minutes after administration.
Blood samples should be handled as recommended by the laboratory that will determine their ACTH content. Itis extremely important to recognize that the reliability of the ACTHREL test is directly related to the inter-assay and intra-assay variability of the laboratory performing the assay.
Cortisol determinations may be performed on the same blood samples for the same time points as outlined above. The blood sample handling precautions noted for ACTH should be followed for cortisol.
Interpretation of Test Results
The interpretation of the ACTH and cortisol responses following ACTHREL administration requires a knowledge of the clinical status of the individual patient, understanding of hypothalamic-pituitary-adrenal physiology, and familiarity with the normal hormonal ranges and the standards used by the laboratory that performs the ACTH and cortisol assays.
Cushing's Disease
The results of challenge with corticorelin injection have been reported in approximately 300 patients with Cushing's disease. Although the ACTH and cortisol responses were variable, a hyper-response to corticorelin was seen in a majority of patients, despite high basal cortisol levels. This response pattern indicates an impairment of the negative feedback of cortisol on the pituitary. Patients with pituitary-dependent Cushing's disease tested with corticorelin do not show the negative correlation between basal and stimulated levels of ACTH and cortisol that is found in normal subjects. A positive correlation between basal ACTH levels and maximum ACTH increments after corticorelin administration has been found in Cushing's disease patients.
Ectopic ACTH Secretion
Patients with Cushing's syndrome due to ectopic ACTH secretion (N=32) were found to have very high basal levels of ACTH and cortisol, which were not further stimulated by corticorelin. However, there have been rare instances of patients with ectopic sources of ACTH that have responded to the corticorelin test.
SUMMARY OF ACTH RESPONSES IN PATIENTS WITH HIGH BASAL CORTISOL
High ACTH Response
Low ACTH Response
High Basal ACTH
Cushing's Disease
Ectopic ACTH Secretion
CUSHING'S DISEASE ACTH RESPONSES
(mean of 181 patients)Basal ACTH 63
72 pg/mL (mean
SD)Peak ACTH 189
262 pg/mL (mean
SD)Mean of individual change from baseline + 227%
ECTOPIC ACTH SECRETION RESPONSES
(mean for 31 patients)Basal ACTH 266
464 pg/mL (mean
SD)Peak ACTH 276
466 pg/mL (mean
SD)Mean of individual change from baseline + 15%
False negative responses to the corticorelin test in Cushing's disease patients occur approximately 5 to 10% of the time, which may lead the clinician to an incorrect diagnosis of ectopic production of ACTH at that frequency (see
INDICATIONS AND USAGE, Differential Diagnosis
).