Post-Dexamethasone Free Cortisol - Pathophysiology, Diagnosis, and Interfering Factors

Introduction

The hypothalamic-pituitary-adrenal (HPA) axis is not suppressed by exogenous corticosteroids, which is checked as part of the Dexamethasone suppression test (DST), which is used to evaluate endogenous Cushing syndrome. Dexamethasone is a powerful synthetic corticosteroid with a long half-life and strong affinity for glucocorticoid receptors (biological half-life 36 to 54 hours; plasma half-life four to five hours). Unlike other glucocorticoids, it does not interfere with detecting cortisol in the plasma, urine, or saliva, and it has negligible mineralocorticoid activity. These qualities make dexamethasone the preferred steroid for assessing the hypothalamus-pituitary axis.

What Is the Pathophysiology Behind Regulating Serum Cortisol?

• A fundamental neuroendocrine system, the hypothalamus-pituitary axis, supports the body's homeostatic processes and stress response. Corticotropin-releasing hormone, which is produced by the neurons in the paraventricular nucleus of the hypothalamus, is carried to the anterior pituitary by the hypophysial portal blood and stimulates the synthesis of the adrenocorticotrophic hormone.

• The blood then carries adrenocorticotrophic hormone to the adrenal glands, activating the adrenal cortex's zona fasciculata to produce and secrete cortisol. In turn, serum cortisol, also known as the stress hormone, provides negative feedback on the anterior pituitary and hypothalamus, decreasing the release of corticotropin-releasing hormone and adrenocorticotrophic hormone.

• The body's stress response and blood cortisol levels are regulated by this positive or negative feedback process. When the hypothalamus-pituitary axis is healthy, exogenously administered corticosteroids suppress blood cortisol synthesis and release by binding to the hypothalamus and pituitary glucocorticoid receptors, respectively.

• This results in feedback inhibition on the production of serum corticotropin-releasing hormone and adrenocorticotrophic hormone. The hypothalamus-pituitary axis, however, becomes partially or completely resistant to exogenous steroid feedback inhibition in pathological hypercortisolism.

What Are the Diagnostics Used to Detect Post Dexamethasone Free Cortisol?

The patient will be given Dexamethasone throughout this test. This is a potent synthetic (man-made) glucocorticoid drug. Blood is then taken from the patient to determine the cortisol level in the patient's blood. Dexamethasone suppression tests are:

1. Dexamethasone Suppression Test At a Low Dose:

• 1 mg Test Overnight - One milligram (mg) of Dexamethasone will be administered to the patient at 11 P.M. The patient's blood will be drawn the following morning at 8 A.M for the cortisol measurement.

• 2 mg Test Over Two Days - Cortisol levels are measured using urine collected over the course of three days and kept in 24-hour collection containers. Dexamethasone will be administered orally in a low dose (0.5 mg) on day two for a 48-hour period.

2. Dexamethasone Suppression Test At a High Dose:

• 8 mg Overnight Test - On the morning of the test, the provider will measure the patient's cortisol. Dexamethasone 8 mg will then be administered to the patients at 11 P.M. The next morning at 8 A.M blood sample is taken to measure patients' cortisol levels.

• 8 mg Test Over Two Days - Urine is collected over three days and preserved in 24-hour collection containers for cortisol measurement. On day two, the patient will be given a high dose of Dexamethasone (2 mg) orally every six hours for 48 hours.

3. Intravenous Dexamethasone Suppression Test:

The initial diagnosis of Cushing syndrome is aided by this test, which lessens concerns about drug compliance and malabsorption. Separating Cushing's disease from adrenocorticotrophic hormone-dependent ectopic tumors and adrenocorticotrophic hormone-independent adrenal etiologies is also helpful. The administration of an intravenous Dexamethasone infusion at 1 mg/hour for four to seven hours follows the acquisition of a baseline morning blood cortisol level. Repeat serum cortisol measurements are taken on day one (the last day of the infusion) and 23 to 24 hours afterward (day two).

4. Test for Dexamethasone - Corticotropic Releasing Hormone:

This test aids in differentiating between Cushing disease and pseudo-Cushing syndrome (physiologic hypercortisolism), based on the theory that glucocorticoid suppression of the hypothalamus pituitary adrenal axis can be overridden by corticotropin-releasing hormone stimulation in the Cushing disease but not in the latter. For 48 hours, Dexamethasone 0.5 mg is taken orally at regular intervals (12 PM, 6 PM, 12 AM, and 6 AM). An intravenous corticotropin-releasing hormone dose of 1 mcg/kg is given two hours after the last dose of Dexamethasone (8 AM), and serum cortisol is taken 15 minutes later.

What Are the Interfering Factors Associated With Post Dexamethasone Free Cortisol?

1. Exogenous Cushing syndrome may be brought on by iatrogenic hypercortisolism. Because most exogenous steroids react negatively with cortisol immunoassays, biochemical testing reveals high serum cortisol levels and reduced adrenocorticotrophic hormone levels, typical of adrenocorticotrophic hormone-independent Cushing syndrome. Before conducting a work-up for pathological hypercortisolemia, it is essential to identify the people receiving exogenous corticosteroids (inhaled, topical, parenteral, or intraarticular).

2. Due to hypothalamus pituitary adrenal axis stimulation, pseudo-Cushing syndrome, also known as physiological or non-neoplastic hypercortisolism, is present in situations like alcoholism, obesity, insulin resistance, and neuropsychiatric disorders. A comprehensive history and physical examination can identify many people with pseudo-Cushing syndrome. In cases where the situation is unclear, tests for Desmopressin, Dexamethasone - corticotropic releasing hormone, late-night salivary cortisol, and midnight serum cortisol can help determine.

3. The evaluation for Cushing syndrome should be done after the resolution of acute stress because the hypothalamus pituitary adrenal axis might exhibit a stress response in any acute disease (emotional or physical), leading to high adrenocorticotrophic hormone and cortisol levels.

4. Dexamethasone bioavailability may vary, which can affect the results. This can happen due to malabsorption, a change in metabolism, or non-compliance with prescription administration. Utilizing CYP3A4, the liver breaks down Dexamethasone. Consequently, CYP3A4 inducers (Phenytoin, Carbamazepine, etc.) or inhibitors (Itraconazole, Fluoxetine, Ritonavir) may cause a decrease in or an increase in the clearance of the Dexamethasone, which may lead to false positive or negative results, respectively. To avoid this mistake, serum Dexamethasone levels should be measured simultaneously with serum cortisol levels.

Conclusion

The most frequent cause of Cushing syndrome is iatrogenic hypercortisolism, which should be identified before these patients undergo additional diagnostic testing. Instead, the emphasis should be on titrating down (or increasing, if possible) the recommended steroid dosages. The performance and interpretation of the Dexamethasone suppression test must consider the pre-test probability, which should be based on a comprehensive history and physical examination. Clinicians should also be aware of the limitations and confounding variables of each test's diagnostic accuracy. Repeat testing should be done in three to six months in people with a high clinical suspicion of having Cushing syndrome but with conflicting or negative test results because untreated hypercortisolemia has deleterious effects.