From the Guidelines
The workup for HPA axis disorders should begin with a thorough clinical assessment, followed by laboratory testing, including AM cortisol and ACTH levels, as well as evaluation of TSH, free T4, and electrolytes. This initial evaluation is crucial in determining the underlying cause of the disorder, whether it be primary, secondary, or tertiary 1.
Initial Evaluation
- Evaluate ACTH (AM) and cortisol (AM) levels to determine the abnormality
- Assess TSH, free T4, and electrolytes to evaluate thyroid function and potential electrolyte imbalances
- Consider standard-dose ACTH stimulation testing for indeterminate results (AM cortisol < 3 mg/dL and < 15 mg/dL) 1
Additional Testing
- Consider evaluating LH and testosterone in males, FSH, and estrogen in premenopausal females with fatigue, loss of libido, and mood changes, or oligomenorrhea
- Consider MRI brain w/wo contrast with pituitary or sellar cuts in all patients with new hormonal deficiencies and particularly those with multiple endocrine abnormalities, new severe headaches, or complaints of vision changes 1
- Perform MRI brain w/wo contrast with pituitary or sellar cuts for all patients presenting with diabetes insipidus (DI is most commonly from metastatic disease) 1
Imaging Studies
- Pituitary MRI for central disorders
- Adrenal CT for primary disorders It is essential to prioritize a systematic approach to identify the specific disorder affecting the HPA axis and guide appropriate treatment decisions 1.
From the FDA Drug Label
2.1 Important Information Before Conducting Metopirone Testing Stop drugs affecting pituitary or adrenocortical function before administration of Metopirone in accordance with half-life of the drugs (consider at least 5 half-lives to avoid any interference with Metopirone testing). Assess ability of patient's adrenals to respond to exogenous ACTH before Metopirone is employed as a test 2. 2 Single-Dose Short Test- Recommended Dose and Interpretation This test, usually given on an outpatient basis, determines plasma 11-desoxycortisol and/or ACTH levels after a single dose of Metopirone.
The workup for HPA axis disorders involves assessing the ability of the patient's adrenals to respond to exogenous ACTH before employing Metyrapone as a test.
- The Metyrapone test is used to diagnose adrenal insufficiency in adult and pediatric patients.
- The test involves administering a single dose of Metyrapone (30 mg/kg, maximum 3 grams) at midnight, followed by a blood sample for assay the next morning.
- An intact HPA axis function is generally indicated by an increase in 11-desoxycortisol to over 70 mcg/L.
- Patients with suspected adrenocortical insufficiency should be hospitalized overnight as a precautionary measure 2, 2.
From the Research
HPA Axis Disorders Workup
The workup for HPA axis disorders involves a comprehensive evaluation of the hypothalamic-pituitary-adrenal (HPA) axis, a highly dynamic endocrine system 3. The initial step should be the correct diagnosis of adrenal insufficiency (AI), which requires careful evaluation of the HPA axis.
Diagnosis of Adrenal Insufficiency
The diagnosis of AI in patients with frank manifestations is not challenging, and basal cortisol is usually enough to give a correct diagnosis 3. However, most cases of secondary adrenal insufficiency (SAI) take place in a gray zone when clinical manifestations are mild, and more complicated methods are required to simulate the response of the HPA axis to a major stress.
Tests Used in Diagnosis
Numerous studies have been published on the assessment of HPA axis, and various tests are used in the diagnosis of secondary AI or in the investigation of suspected HPA axis insufficiency 3. These tests include:
- Basal cortisol measurement
- Dynamic tests to simulate the response of the HPA axis to a major stress
- Evaluation of the cortisol/ACTH circadian rhythm
- Cortisol suppression to dexamethasone
- Response to CRH and desmopressin
Treatment and Management
Treatment of HPA axis disorders depends on the underlying cause and may involve glucocorticoid replacement therapy, surgery, or medication 4, 5. In some cases, complete restoration of the physiological characteristics of the HPA axis is possible with medication, as seen in a rare case of Cushing's disease treated with cabergoline 4.
Associated Conditions
HPA axis disorders can be associated with other conditions, such as Cushing's syndrome, congenital adrenal hyperplasia, and chronic central serous chorioretinopathy 5, 6. Understanding the dynamics of the HPA axis is necessary to master the diagnosis and differential diagnosis of pituitary-adrenal diseases.
Future Directions
Mathematical models of the HPA axis can be used to identify effective interventions for lowering long-term cortisol in mood disorders and chronic stress 7. Targets such as corticotropin-releasing hormone (CRH) may be effective in reducing long-term cortisol, while other targets may fail due to gland mass compensation or harm other aspects of the HPA axis.