What is the treatment for secondary adrenal insufficiency (Adrenal Insufficiency due to pituitary or hypothalamic disease)?

From the Guidelines

Treatment of secondary adrenal insufficiency should prioritize hormone replacement therapy with oral hydrocortisone at a total daily dose of 15-20 mg in divided doses, as recommended by the most recent guidelines 1. The primary goal of treatment is to compensate for the body's inability to produce adequate cortisol due to pituitary dysfunction.

• Hydrocortisone is the preferred glucocorticoid replacement therapy, as it allows for recreation of the diurnal rhythm of cortisol, with 2/3 of the dose given in the morning and 1/3 in the early afternoon 1.
• The initial dose of hydrocortisone can be titrated to a maximum of 30 mg daily total dose for residual symptoms of adrenal insufficiency, and reduced for symptoms of iatrogenic Cushing's syndrome 1.
• Mineralocorticoid replacement with fludrocortisone is not typically needed, as aldosterone production remains intact in secondary adrenal insufficiency.
• Patient education on stress dosing, emergency injectables, and medical alert identification is crucial for successful management of this chronic condition, and early endocrinology consultation is recommended 1.
• During illness, surgery, or significant stress, glucocorticoid doses should be increased to 2-3 times the maintenance dose, and patients should be monitored closely for signs of under or over-replacement 1.

From the FDA Drug Label

Fludrocortisone acetate tablets, 0.1 mg are indicated as partial replacement therapy for primary and secondary adrenocortical insufficiency in Addison’s disease and for the treatment of salt-losing adrenogenital syndrome. Prednisolone sodium phosphate oral solution is indicated in the following conditions: ... Endocrine Disorders: Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the first choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy mineralocorticoid supplementation is of particular importance);

The treatment of secondary adrenal insufficiency may involve the use of fludrocortisone or prednisolone.

• Fludrocortisone is indicated for partial replacement therapy in secondary adrenocortical insufficiency.
• Prednisolone is indicated for primary or secondary adrenocortical insufficiency, with hydrocortisone or cortisone as the first choice, and synthetic analogs may be used in conjunction with mineralocorticoids where applicable 2 3.

From the Research

Treatment of Secondary Adrenal Insufficiency

• The current standard treatment regimen for secondary adrenal insufficiency involves twice- or thrice-daily dosing with a glucocorticoid, most commonly oral hydrocortisone 4.
• Glucocorticoid replacement therapy has been established for some 50 years, but data from the past 10-15 years have shown that morbidity remains high and life expectancy is reduced 4.
• The increased morbidity and decreased life expectancy appear to be due to both increased exposure to cortisol and insufficient cortisol coverage during infections and other stress-related events 4.
• Multiple glucocorticoid formulations are available, including short-acting, intermediate, long-acting, and novel modified-release hydrocortisone, as well as subcutaneous formulations 5.
• The benefit of hormone replacement therapy is evident, but long-term adverse effects may arise due to non-physiological glucocorticoid doses and treatment regimens used 5.
• Recent updates and new directions for diagnosis and management of secondary adrenal insufficiency focus on the etiology, epidemiology, and clinical presentation, as well as diagnostic and management challenges 6.
• Susceptibility to adrenal crisis is associated with differences in cortisol excretion in patients with secondary adrenal insufficiency, suggesting a biological predisposition in certain patients for the development of an adrenal crisis 7.
• A contemporary approach to the diagnosis and management of adrenal insufficiency includes recent advancements in diagnostic strategy and approaches to optimal treatment, particularly in the domains of timely diagnosis, patient education, and determination of optimal replacement therapies 8.

Management Challenges

• Management of secondary adrenal insufficiency poses several challenges, including the need for individualized cortisol exposure and management of patients during stress-related events 4.
• The resulting over- or under-treatment may result in Cushing-like symptoms or adrenal crisis, respectively 4.
• European Reference Networks on rare endocrine conditions aim to harmonize treatment and ensure access to specialized patient care for individual case-by-case treatment decisions 5.
• Patient education is crucial for averting adrenal crises, and the determination of optimal replacement therapies is an ongoing challenge 8.

Future Directions

• Further research is needed to improve the treatment of secondary adrenal insufficiency, including the development of more physiological glucocorticoid replacement regimens and the identification of biomarkers for susceptibility to adrenal crisis 4, 7.
• The use of novel modified-release hydrocortisone and subcutaneous formulations may offer improved treatment options for patients with secondary adrenal insufficiency 5.
• A multidisciplinary approach to the management of secondary adrenal insufficiency, including endocrinologists, primary care physicians, and other healthcare professionals, is essential for optimal patient care 6, 8.