Glucocorticoid Therapy and Cushing Syndrome

Cushing syndrome (CS) takes its name from Harvey Cushing, who, in 1912, was one of the first physicians to report a patient affected with excessive glucocorticoid. More than 99% of cases of Cushing syndrome are due to administration of excessive amounts of glucocorticoid. This article discusses issues relating to both endogenous and exogenous glucocorticoid excess, with emphasis on the safest possible therapeutic use of glucocorticoids.

Although distinguishing endogenous from exogenous Cushing syndrome is usually straightforward, the investigation and differentiation of Cushing syndrome from other causes of hypercortisolism require a sound understanding of the physiology of the hypothalamic-pituitary-adrenal (HPA) axis.

Diagnosis of Cushing syndrome.
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Diagnosis of Cushing syndrome.

Etiology of Cushing syndrome.
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Etiology of Cushing syndrome.

Pathophysiology
Glucocorticoid synthesis and release is strictly regulated by the pituitary and hypothalamus by negative feedback and, to a lesser extent, by catecholamines from the adrenal medulla and neural inputs from the autonomic system. In addition to the glucocorticoid effects that cortisol has because of binding to the glucocorticoid receptor (GR), cortisol can also bind to and activate the mineralocorticoid receptor (MR). When cortisol binds to the kidney, MR is physiologically inhibited by conversion of cortisol to its inactive metabolite cortisone by the enzyme 11beta-hydroxy-steroid dehydrogenase (11beta-OHSD2), which co-localizes with the MR.

The basal daily rate of cortisol secretion is approximately 6-8 mg/m2 body surface area, although this can increase as much as 10-fold in response to acute severe stress. Physiological replacement of cortisol requires higher doses of 10-15 mg/m2 because the oral bioavailability is 50-60%. Other natural and synthetic glucocorticoids are noted, all of which have different relative potencies as glucocorticoids and mineralocorticoids because of their differing structures and affinities for the GR and MR, as well as for 11beta-OHSD2. Table 1 summarizes the relative potencies and half-lives of main steroid hormones (for a printable version of Table 1, see Media file 1).

The glucocorticoid receptor is an intracellular protein that, in its ligand-bound form, acts as a nuclear transcription factor to regulate the expression of a diverse array of genes in many areas of the body. Factors that influence the spectrum of adverse effects observed in hypercortisolemic individuals include duration of treatment, potency of the steroid, dose and route of administration, and the site and rate of metabolism and clearance.

Since the late 1940s, when glucocorticoids first came into use for their anti-inflammatory and immunomodulatory effects, much work has been conducted by science and industry to maximize their beneficial effects while minimizing their adverse effects. Thus, many synthetic compounds with glucocorticoid activity have been manufactured and tested.

Alterations of the basic steroid nucleus and its side groups give rise to the pharmacologic differences between these chemicals. Such changes may affect the bioavailability of these steroid compounds, including their GI absorption; parenteral distribution; plasma half-life; their metabolism in the liver, fat, or target tissues; and their ability to interact with the GR and MR and modulate the transcription of glucocorticoid-responsive genes. In addition, structural modifications can diminish the natural cross-reactivity of glucocorticoids with the MR, eliminating their undesirable salt-retaining activity. Other modifications enhance their water solubility for parenteral administration or reduce their water solubility to enhance topical potency.

Most synthetic glucocorticoids (eg, methyl-prednisolone, dexamethasone) are minimally bound to cortisol-binding globulin and circulate freely, or they are weakly bound to albumin. A relatively constant percentage of synthetic glucocorticoids is bound to plasma proteins, and, because this percentage is concentration indeperinent, the rate of metabolic clearance remains constant for synthetic glucocorticoids, regardless of dose. Table 1 shows the relative glucocorticoid and mineralocorticoid potencies of different, commonly used systemic glucocorticoids and their approximate plasma and biologic effect half-lives.

Glucocorticoid activity has been defined mostly in rat bioassays, which may not always reflect human responses, particularly the growth-suppressing properties of synthetic glucocorticoids, which have been markedly underestimated. Glucocorticoids can be categorized as short, intermediate, or long acting, based on their biologic effective half-life, which is defined as the duration of corticotropin (ACTH) suppression after a single dose of the compound.