What are the consequences of adrenal insufficiency due to glucocorticoid (cortisol) deficiency?

From the Guidelines

Adrenal insufficiency due to glucocorticoid (cortisol) deficiency can lead to life-threatening consequences, including adrenal crisis, which has an incidence of 8.3 per 100 replacement years and a mortality rate, as reported in a prospective study of 423 patients with primary and secondary adrenal insufficiency 1. The primary manifestations of glucocorticoid insufficiency include profound fatigue, weakness, weight loss, anorexia, and hypotension, which can progress to life-threatening adrenal crisis if untreated.

• Metabolically, patients experience hypoglycemia due to impaired gluconeogenesis and increased insulin sensitivity, alongside sodium loss and potassium retention causing hyponatremia and hyperkalemia.
• Gastrointestinal symptoms like nausea, vomiting, and abdominal pain are common.
• Patients typically present with hyperpigmentation (in primary adrenal insufficiency) due to elevated ACTH levels.
• Cardiovascular effects include hypotension and decreased cardiac output, while the immune system becomes dysregulated with paradoxical inflammation despite cortisol's normal anti-inflammatory role.
• Neuropsychiatric manifestations range from irritability and depression to confusion and psychosis in severe cases. The consequences of adrenal insufficiency can be managed with prompt glucocorticoid replacement, typically with hydrocortisone, and the recommended dose is 100 mg intravenously at the start of surgery, followed by an infusion of 200 mg/24 h, and doubling the regular oral replacement dose for 48 h, and for up to a week following major surgery before the maintenance dose is resumed, as suggested by the guidelines for the management of glucocorticoids during the peri-operative period for patients with adrenal insufficiency 1. It is vital that physiological replacement therapy is not interrupted, and that the daily dose is increased at times of physiological stress, and patients with comorbidities, such as asthma and diabetes, are more vulnerable to adrenal crisis, and require close monitoring and management 1.

From the FDA Drug Label

Corticosteroids can produce reversible hypothalamic-pituitary adrenal (HPA) axis suppression with the potential for corticosteroid insufficiency after withdrawal of treatment. Adrenocortical insufficiency may result from too rapid withdrawal of corticosteroids and may be minimized by gradual reduction of dosage This type of relative insufficiency may persist for up to 12 months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted.

The consequences of adrenal insufficiency due to glucocorticoid (cortisol) deficiency include:

• Adrenocortical insufficiency
• Corticosteroid insufficiency after withdrawal of treatment
• Potential for increased risk of infection and other complications during periods of stress
• Need for hormone therapy reinstitution in situations of stress occurring up to 12 months after discontinuation of therapy 2

From the Research

Consequences of Adrenal Insufficiency

The consequences of adrenal insufficiency due to glucocorticoid (cortisol) deficiency can be severe and impact the quality of life of patients. Some of the key consequences include:

• Increased morbidity and reduced life expectancy, as seen in patients receiving conventional glucocorticoid replacement therapy 3
• Risk of life-threatening adrenal crisis, particularly during infections and other stress-related events 3, 4
• Cushing-like symptoms due to over-treatment with glucocorticoids 3
• Adrenal crisis due to under-treatment or insufficient cortisol coverage during stress-related events 3, 4
• Impaired cognitive functioning associated with prolonged phases of hypo- or hypercortisolism 5

Management and Treatment

The management of adrenal insufficiency primarily involves physiological replacement of glucocorticoid secretion. However, there are several controversies surrounding standard glucocorticoid therapy, including:

• Difficulty in replicating the natural circadian rhythm of cortisol release 3, 6
• Uncertainties in dose adjustment and treatment monitoring due to the absence of reliable biomarkers 6
• Side effects of inadequate replacement, which can significantly hinder the quality of life of patients 6
• Need for improved awareness and education of clinicians and patients to manage glucocorticoid-induced adrenal insufficiency effectively 4

Research and Developments

Recent studies have explored new approaches to glucocorticoid replacement therapy, including:

• Transition to circadian hydrocortisone therapy 6
• Use of oral hydrocortisone modified-release compounds or continuous subcutaneous hydrocortisone infusion 6
• Measurement of salivary cortisol levels to assess daily cortisol exposure and adjust glucocorticoid doses accordingly 7