What is the diagnosis and treatment for Hypothalamic-Pituitary-Adrenal (HPA) axis dysfunction?

From the Guidelines

HPA axis dysfunction should be managed by addressing the underlying cause and supporting adrenal function, with hydrocortisone replacement therapy prescribed for adrenal insufficiency at a typical dose of 15-25mg daily in divided doses, as recommended by the most recent and highest quality study 1.

Diagnosis and Treatment

The diagnosis of primary adrenal insufficiency (PAI) should be considered in patients presenting with unexplained collapse, hypotension, vomiting, or diarrhea, and hyperpigmentation, hyponatremia, hyperkalemia, acidosis, and hypoglycemia increase clinical suspicion of PAI 1.

• The diagnostic test for primary PAI should be paired measurement of serum cortisol and plasma ACTH, and in equivocal cases, a synacthen (tetracosactide) stimulated peak serum cortisol <500 nmol L-1 is diagnostic of PAI 1.
• Treatment of suspected acute adrenal insufficiency should never be delayed by diagnostic procedures, and all patients with adrenal insufficiency should wear Medic Alert identification jewelry and carry a steroid/alert card 1.

Therapy and Follow-up

• Most patients with primary adrenal insufficiency should take 15–25 mg of hydrocortisone (HC) daily in split doses, and the lowest dose compatible with health and a sense of well-being should be used 1.
• Patients with PAI should be reviewed at least annually, with assessment of health and well-being, measurement of weight, blood pressure, and serum electrolytes, and occasional monitoring for the development of new autoimmune disorders, particularly hypothyroidism, is worthwhile 1.

Adrenal Crisis

• Adrenal crisis should be treated immediately with iv or im HC, 100 mg followed by 100 mg 6–8 hourly until recovered, and isotonic (0.9%) sodium chloride solution should usually be administered, at an initial rate of 1 L h-1 until haemodynamic improvement 1. The management of HPA axis dysfunction prioritizes the patient's morbidity, mortality, and quality of life, and the treatment approach should be individualized based on the underlying cause and severity of the condition.

From the FDA Drug Label

An intact HPA axis function is generally indicated by an increase in 11‑desoxycortisol to over 70 mcg/L. The HPA axis dysfunction can be assessed using metyrapone testing, which evaluates the response of the hypothalamic-pituitary-adrenal (HPA) axis to the drug.

• Key points:
  • Metyrapone testing is used to diagnose adrenal insufficiency.
  • The test measures the increase in 11-desoxycortisol levels after metyrapone administration.
  • An increase in 11-desoxycortisol to over 70 mcg/L indicates an intact HPA axis function.
  • The test should be performed with caution in patients with suspected adrenal insufficiency, and a prophylactic dose of glucocorticoid may be considered for patients with high risk for acute adrenal insufficiency 2.

From the Research

HPA Axis Dysfunction

• The hypothalamic-pituitary-adrenal (HPA) axis is a crucial component of the stress system, and its dysfunction can lead to various health issues 3, 4, 5, 6, 7.
• HPA axis dysfunction can result in adrenal insufficiency, which can be life-threatening if left untreated 3.
• The diagnosis of adrenal insufficiency requires careful evaluation of the HPA axis, and various tests can be used to assess its function 3.
• Elevated cortisol levels can cause morbidity, including metabolic and cardiovascular diseases, and developing drugs that target the HPA axis to lower cortisol levels is an area of interest 4.
• However, several promising HPA-modulating drugs have failed to reduce long-term cortisol in mood disorders, despite being effective in other hypercortisolism conditions 4.
• Mathematical models of the HPA axis have identified potential targets for reducing long-term cortisol, including corticotropin-releasing hormone (CRH) 4.
• HPA axis dysfunction has been linked to various mental and physical disorders, including chronic fatigue syndrome, major depression, and posttraumatic stress disorder (PTSD) 5, 6.
• Sex differences in the regulation of the HPA axis in response to stress have been observed, which may partially explain the female predominance in stress-related mental disorders 6.
• Critical illness can also lead to HPA axis dysfunction, characterized by inappropriate cellular activity of corticosteroids for the severity of the disease 7.

Causes and Consequences of HPA Axis Dysfunction

• HPA axis dysfunction can be caused by various factors, including chronic stress, early-life stress, and low activity levels 5, 6.
• The consequences of HPA axis dysfunction can be severe, including increased risk of metabolic and cardiovascular diseases, and poorer outcomes in patients with chronic fatigue syndrome 3, 5.
• Addressing the underlying causes of HPA axis dysfunction, such as with cognitive behavioral therapy, can help correct the dysfunction and improve patient outcomes 5.

Diagnosis and Treatment of HPA Axis Dysfunction

• The diagnosis of HPA axis dysfunction requires careful evaluation of the HPA axis, using various tests such as basal cortisol and dynamic tests 3.
• Treatment of HPA axis dysfunction depends on the underlying cause and severity of the dysfunction, and may include glucocorticoid replacement therapy or other medications 3, 7.
• However, there is no consensus on the diagnostic criteria and treatment indications for critical illness-related corticosteroid insufficiency, and further research is needed to improve our understanding of HPA axis dysfunction in critical illness 7.