The adrenal gland synthesizes steroid hormones in the cortex and catecholamines in the medulla. Adrenal insufficiency is deficiency of adrenal gland hormone production in the cortex. Primary adrenal insufficiency, or Addison’s disease, is due to intrinsic adrenal gland dysfunction and results in decreased cortisol, aldosterone, and sex hormone production. The condition is rare, with prevalence ranging from 39 to 144 cases per million population.¹

Secondary adrenal insufficiency is due to hypothalamic-pituitary dysfunction with failure to secrete corticotropin-releasing hormone and/or adrenocorticotropic hormone. This disorder results in cortisol deficiency only.

Adrenal crisis is a life-threatening exacerbation of adrenal insufficiency when an increased demand fails to increase hormone production.

The adrenal gland is made up of the cortex and medulla producing steroid hormones and catecholamines, respectively. The adrenal cortex produces three categories of steroids: the glucocorticoids (cortisol), mineralocorticoids (aldosterone), and gonadocorticoids (sex hormones). Glucocorticoids are produced in the zona fasciculata, and mineralocorticoids and gonadocorticoids are produced in the zona glomerulosa and zona reticularis of the adrenal cortex. The adrenal medulla produces adrenaline, noradrenaline, and a small amount of dopamine in response to stimulation by sympathetic preganglionic neurons.

Cortisol is secreted in response to direct stimulation by adrenocorticotropic hormone. Adrenocorticotropic hormone secretion is stimulated by corticotropin-releasing factor released from the hypothalamus. Secretion occurs in a diurnal rhythm, with higher levels secreted in the morning and lower levels in the evening. In normal circumstances, the daily cortisol equivalent is about 20 milligrams/d of hydrocortisone. Plasma cortisol suppresses the release of adrenocorticotropic hormone through negative feedback inhibition. Cortisol facilitates the stress response by affecting the heart, vascular bed, water excretion, electrolyte balance, potentiation of catecholamine action, and control of water distribution. It affects fat, protein, and carbohydrate metabolism by stimulating glycogenolysis and neoglycogenesis. It is involved in immunologic and inflammatory responses and affects calcium metabolism. It promotes growth and development but, in excess, interferes with the GI tract mucosa maintenance, leading to peptic ulcer.

Aldosterone secretion is controlled primarily by the renin-angiotensin system and serum potassium concentration. The renin-angiotensin system controls aldosterone levels in response to changes in volume, posture, and sodium intake. Serum potassium (hyperkalemia) influences the adrenal cortex directly to increase aldosterone secretion. Aldosterone maintains sodium and potassium plasma concentrations. It regulates extracellular volume and controls sodium and water balance.

Gonadocorticoids include androgen hormones and estrogen. Androgens produced include testosterone, dehydroepiandrosterone, and dehydroepiandrosterone sulfate, which are present in both men and women. In women, androgens are produced in the adrenal glands as well as the ovaries and promote the development of sex characteristics such as axillary and pubic hair and libido. In men, most androgens (testosterone) are produced in the testes. Androgens made by the adrenal glands are less important for normal sexual function.

PRIMARY ADRENAL INSUFFICIENCY

Causes of primary adrenal insufficiency (Addison’s disease) are shown in Table 230-1. Approximately 90% of the gland must be destroyed for clinical adrenal insufficiency to develop.² In the United States, autoimmune disorders are responsible for most cases of primary adrenal insufficiency.^1,3 Autoimmune disorders may occur as an isolated process or as a component of polyglandular autoimmune syndrome types I and II. Polyglandular autoimmune syndrome type I is associated with candidiasis, hypoparathyroidism, and adrenal failure. Polyglandular autoimmune syndrome type II consists of Addison’s disease plus either an autoimmune thyroid disease or type 1 diabetes mellitus associated with hypogonadism, pernicious anemia, celiac disease, or primary biliary cirrhosis.

In terms of infection, worldwide, tuberculosis is the most common cause of primary adrenal insufficiency. Human immunodeficiency virus may cause adrenal insufficiency through opportunistic infections (principally cytomegalovirus) or use of medications, such as ketoconazole. Secondary adrenal insufficiency can develop through inhibition of the hypothalamus-pituitary-adrenal axis.^4,5,6,7

Infiltrative diseases such as amyloidosis, hemosiderosis, and bilateral metastasis from cancer may also cause primary adrenal insufficiency. Thrombosis and/or hemorrhage of the adrenals may occur as a complication of anticoagulation therapy, sepsis, disseminated intravascular coagulation, meningococcemia (Waterhouse-Friderichsen syndrome), or antiphospholipid syndrome.^8,9,10

SECONDARY ADRENAL INSUFFICIENCY

Causes of secondary adrenal insufficiency are shown in Table 230-2. Secondary adrenal failure is usually characterized by depressed adrenocorticotropic hormone secretion, which reduces cortisol production, but aldosterone levels remain normal because of preserved stimulation by both the renin-angiotensin axis and potassium. Adrenal sex hormone production is also preserved. Intracranial disorders such as brain tumor, pituitary disease, postpartum pituitary necrosis, or major head trauma may affect the hypothalamic-pituitary function, resulting in secondary adrenal insufficiency.¹¹