What are the drug-induced adrenal diseases and syndromes, specifically those related to adrenal insufficiency (Addison's disease) or Cushing's syndrome?

From the Guidelines

Drug-activated adrenal diseases and syndromes, such as secondary adrenal insufficiency, can be managed with hydrocortisone replacement therapy, with a typical dose of 15-20 mg in divided doses, and fludrocortisone, starting at 0.05-0.1 mg/d, as recommended by the most recent guidelines 1.

Management of Drug-Activated Adrenal Diseases

The management of drug-activated adrenal diseases and syndromes involves a comprehensive approach to prevent morbidity, mortality, and improve quality of life.

• The most common drug-induced adrenal condition is secondary adrenal insufficiency, typically caused by glucocorticoids like prednisone, dexamethasone, or hydrocortisone when taken at doses above 5-7.5mg of prednisone (or equivalent) daily for more than 2-3 weeks.
• Other medications that can affect adrenal function include ketoconazole, etomidate, and metyrapone, which directly inhibit cortisol synthesis, and mitotane, which is toxic to adrenal cells.
• Opioids, phenytoin, and rifampin can also disrupt adrenal function through various mechanisms.
• Drug-induced Cushing's syndrome can result from excessive glucocorticoid use, presenting with weight gain, moon face, buffalo hump, and skin changes.

Treatment Approach

The treatment approach for drug-activated adrenal diseases and syndromes involves:

• Gradual tapering of steroids over weeks to months, allowing the adrenal glands to resume normal function.
• Stress-dose steroids during illness or surgery to prevent adrenal crisis, characterized by severe hypotension, nausea, vomiting, and confusion.
• Hydrocortisone replacement therapy, with a typical dose of 15-20 mg in divided doses, and fludrocortisone, starting at 0.05-0.1 mg/d, as recommended by the most recent guidelines 1.
• Education on steroid stress dosing, emergency injections, and a medical alert bracelet or necklace, accessory, or system.

Key Considerations

Key considerations in the management of drug-activated adrenal diseases and syndromes include:

• Early endocrinology consultation to plan for surgery or high-stress treatments.
• Monitoring for the development of new autoimmune disorders, particularly hypothyroidism.
• Assessment for the complications of glucocorticoid therapy, including monitoring of bone mineral density every 3-5 years.
• The use of adrenostatic agents, such as ketoconazole and mitotane, to reduce cortisol levels in patients with Cushing's syndrome.

From the FDA Drug Label

The following adverse reactions have been reported with prednisone or other corticosteroids: ... secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery or illness) Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage This type of relative insufficiency may persist for up to 12 months after discontinuation of therapy following large doses for prolonged periods; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. ... development of the cushingoid state; suppression of growth in children; secondary adrenocortical and pituitary unresponsiveness, particularly in times of stress (e.g., trauma, surgery, or illness);

Drug-activated adrenal diseases and syndromes include:

• Cushing's syndrome: characterized by the development of a cushingoid state, which can occur with prolonged use of corticosteroids 2
• Adrenal insufficiency: secondary adrenocortical insufficiency may occur, particularly in times of stress, and can persist for up to 12 months after discontinuation of therapy 2
• Adrenocortical suppression: suppression of growth in children and secondary adrenocortical and pituitary unresponsiveness can occur with corticosteroid use 2 3

From the Research

Drug Activated Adrenal Diseases and Syndromes

• Adrenal diseases and syndromes can be caused or exacerbated by certain medications, including steroidogenesis inhibitors and glucocorticoids 4, 5, 6.
• Cushing's syndrome, a condition characterized by excess cortisol production, can be caused by exogenous glucocorticoid therapy (iatrogenic Cushing's syndrome) or endogenous cortisol overproduction (spontaneous Cushing's syndrome) 4, 6.
• Secondary adrenal insufficiency, a condition characterized by a lack of normal cortisol secretion, can result from a rapid discontinuation of long-term, pharmacological glucocorticoid therapy, leading to HPA axis suppression and adrenal atrophy 6, 7.
• Certain medications, such as protease inhibitors and inhaled steroids, can interact to cause Cushing's syndrome and adrenal suppression, as seen in a case report of a 14-year-old female with HIV 5.
• Adrenal incidentalomas, primary aldosteronism, and adrenal insufficiency are common adrenal disorders that can be encountered in general practice, and require a practical approach to diagnosis and management 8.

Specific Medications and Adrenal Diseases

• Osilodrostat, a steroidogenesis inhibitor, has been shown to be highly effective in maintaining normal urinary free cortisol in patients with Cushing's disease, but requires close patient monitoring due to the risk of adverse effects, including adrenal insufficiency 4.
• Fluticasone, an inhaled steroid, can cause Cushing's syndrome and adrenal suppression when combined with protease inhibitors, such as atazanavir and ritonavir, in HIV-infected patients 5.
• Metyrapone, ketoconazole, and etomidate are other steroidogenesis inhibitors that can be used to treat Cushing's syndrome, but lack prospective evaluation and have a wide efficacy range in treating patients with the condition 4.