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Subject: Corticotropin-Releasing Hormone (CRH) Stimulation Test
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CRH is a 41-amino-acid peptide, secreted by the paraventricular nucleus of the hypothalamus in response to stress. It acts on the anterior lobes of the pituitary to release ACTH. There is considerable sequence homology of CRH among species; as a result, both ovine and human CRH can be used in testing. Also known as: CRH after low-dose dexamethasone test.
CRH stimulation test:
Most patients with Cushing disease respond with ACTH and cortisol increases within 45 minutes after CRH. However, the criteria for interpretation have varied at different centers.
Basal plasma ACTH concentrations increase 35–9,005 (mean 400%) in normal subjects and reach a peak of 10–120 pg/mL, 10–30 minutes after CRH injection; serum cortisol concentrations increase 20–600% (mean 250%) to 13–36 μg/dL (mean 25 μg/dL), reaching a peak 30–60 minutes after CRH injection.
CRH after low-dose dexamethasone test:
Cortisol 1.4 μg/L is virtually 100% specific and 100% diagnostic for Cushing syndrome.
To evaluate the cause of ACTH-dependent Cushing syndrome (with or without vasopressin analogs)
To discriminate between pseudo-Cushing and Cushing syndrome
To discriminate between primary and central adrenal insufficiency
CRH stimulation test: The patient fasts for 4 hours or more, after which an intravenous access line is established and synthetic ovine CRH (1 μg/kg body weight or 100 μg total dose) is injected as an intravenous bolus. Blood samples for ACTH and cortisol are drawn 15 (or 5) and 0 minutes before and as often as 5, 10, 15, 30, 45, 60, 90, and 120 minutes after CRH injection. However, in Cushing syndrome, if one measures only the plasma ACTH response, the samples at −5, −0, 15, and 30 minutes are sufficient, and if one measures only the serum cortisol response, the samples at −15, 0, 45, and 60 minutes are sufficient. Normally both hormones should be measured, since the criteria for a positive response may include increases in either plasma ACTH or serum cortisol concentrations.
CRH test after low-dose dexamethasone procedure: The patient takes 0.5 mg of dexamethasone every 6 hours for 2 days (a total of eight doses); 2 hours after the last dexamethasone dose is taken, 1 μg/kg of CRH is administered intravenously. Blood for a plasma cortisol measurement is drawn 15 minutes after the CRH injection.
Normal or exaggerated response: pituitary Cushing disease
No response: ectopic ACTH-secreting tumor
Responses to CRH are variable among subjects and from one time to another in the same subject.
The increment in plasma ACTH is the same in the morning and evening; however, the peak value is greater in the morning in normal subjects when the basal plasma ACTH concentration is higher. In contrast, the peak serum cortisol value is similar at both times of day, but the increment is smaller in the morning when the basal value is higher. In patients with Cushing syndrome, in whom the normal circadian rhythm in ACTH secretion is absent, the CRH test can be performed at any time of day with similar results.
The response to CRH depends on the cause of the hypoadrenalism.
Patients with primary pituitary ACTH deficiency (secondary adrenal insufficiency) have decreased plasma ACTH and serum cortisol responses to CRH.
Patients with hypothalamic disease (i.e., CRH deficiency) usually have exaggerated and prolonged plasma ACTH responses; the plasma cortisol responses are subnormal.
The CRH stimulation test is more reliable than the ACTH stimulation test in detecting pituitary–adrenal suppression in preterm infants whose mothers received a short course of dexamethasone before delivery to hasten fetal lung development.