Corticotropin, also known as adrenocorticotropic hormone (ACTH), is secreted by specialized cells in the anterior pituitary gland known as the corticotrophs. They constitute about 20% of the anterior pituitary cells. Besides ACTH, corticotrophs also release melanocyte-stimulating hormone (MSH) and lipotropin. While synthetic derivatives of ACTH are used commonly in the diagnostic assessment of adrenal cortex function, synthetic corticosteroids, rather than ACTH, are used therapeutically.
The adrenal cortex synthesizes and secretes steroid hormones essential for adaptive responses to stress (glucocorticoid) and mineral balance (mineralocorticoid) and for some direct and indirect androgenic functions, particularly in women (adrenal androgens). Glucocorticoids and mineralocorticoids are collectively referred as corticosteroids, with cortisol and aldosterone being the main physiologic forms. Corticosteroids and their biologically active synthetic derivatives may differ individually in their glucocorticoid (metabolic/anti-inflammatory) and mineralocorticoid (electrolyte-regulating) actions. These agents are used as physiological replacement therapy when endogenous production is impaired, as in adrenal insufficiency.
The broad anti-inflammatory and immunosuppressive properties of glucocorticoids are of great therapeutic value in numerous conditions where suppression of inflammation is needed (such as autoimmune diseases and allergic reactions), making them among the most frequently prescribed classes of drugs. Shortly after synthetic cortisone became available, Hench and colleagues demonstrated its dramatic effect in the treatment of rheumatoid arthritis, setting the stage for the clinical use of corticosteroids in a wide variety of diseases, as discussed in this chapter. Because glucocorticoids exert effects on almost every organ system, their administration and withdrawal may be complicated by severe side effects. Therefore, the decision to institute therapy with systemic glucocorticoids always requires careful consideration of the relative risks and benefits in each patient.
Addison described fatal outcomes in patients with adrenal destruction in 1849. A few years later, Brown-Séquard demonstrated that bilateral adrenalectomy was fatal in laboratory animals. It became clear that the adrenal cortex, rather than the medulla, was essential for survival in these ablation experiments and that the cortex regulated carbohydrate metabolism and fluid and electrolyte balance. The isolation and identification of the adrenal steroids by Reichstein and Kendall and the effects of these compounds on carbohydrate metabolism (hence the term glucocorticoids) culminated with the synthesis of cortisone, the readily available, pharmacologically effective glucocorticoid. Subsequently, Tait and colleagues isolated and characterized aldosterone, which potently affected fluid and electrolyte balance and was termed a mineralocorticoid. That distinct corticosteroids regulated carbohydrate metabolism and fluid/electrolyte balance led to the concept that the adrenal cortex comprises two largely independent units: an outer zone that produces mineralocorticoids and an inner region that synthesizes glucocorticoids and androgen precursors. Kendall, Reichstein, and Hench shared the 1950 Nobel Prize in Physiology/Medicine “for their discoveries relating to the hormones of the adrenal cortex, their structure and biological effects.”
Studies of adrenocortical steroids also were key in delineating the role of the anterior pituitary. As early as 1912, Cushing described patients with hypercorticism; he later recognized that pituitary basophilism caused the ...