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. See the images below.

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.

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 independent, 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.

Table 1. Glucocorticoid Equivalencies^[1] (Open Table in a new window)

Cushing syndrome can be divided into ACTH-dependent and ACTH-independent forms. The proportion of adrenal and pituitary disease varies in different regions; however, in Western countries, 90-95% of cases of Cushing syndrome in children older than 5 years are ACTH-dependent, and 90-95% of those cases are due to Cushing disease caused by an ACTH-secreting pituitary adenoma. Tumors that ectopically secrete ACTH are rare, and tumors that secrete corticotropin-releasing hormone (CRH) are extremely rare, together accounting for fewer than 5% of cases of Cushing syndrome.

In children younger than 5 years, the proportion of ACTH-independent cases of Cushing syndrome approaches 50%. Such cases are due to a combination of congenital disorders of the adrenal cortex and adrenocortical neoplasms that result in autonomous overproduction of cortisol and other adrenal cortical hormones (summarized below). All children in this age group who have been proven to have ACTH-independent Cushing syndrome require adrenalectomy because of the significant incidence of malignancy in this age group.

Pathophysiology of ACTH-dependent Cushing syndrome

Relative frequency is as follows:

• Age younger than 5 years - 50% of Cushing syndrome cases
• Age older than 5 years - 80-90% of Cushing syndrome cases

ACTH-producing pituitary adenoma (corticotropinoma) represents 80-90% of ACTH-dependent Cushing syndrome cases in people of all ages. It is usually a microadenoma and may invade the cavernous sinus. It is associated with a risk of Nelson syndrome after bilateral adrenalectomy

Ectopic ACTH production is very rare in children. Ectopic ACTH production is from carcinoid tumors (bronchial tumors most frequent, although may also be in GI tract), ACTH-producing pancreatic islet cell tumors (especially multiple endocrine neoplasia type 1 [MEN1]), pheochromocytoma, ganglioneuroma or other neuroendocrine tumor.

Ectopic CRH production is extremely rare.

Pathophysiology of ACTH-independent Cushing syndrome

Frequency is as follows:

• Age younger than 5 years - 50% of Cushing syndrome cases
• Age older than 5 years - 10-20% of Cushing syndrome cases

Adrenocortical neoplasms have a risk of malignancy significant in young children.

Macronodular disease is very rare in children.

Ectopic expression of receptors on cortisol-producing cells, resulting in hypercortisolemia shown in some cases^[2]

Micronodular disease may include the following:

• Primary pigmented nodular adrenal disease (PPNAD)
• Carney complex (See Table 3.)

McCune-Albright syndrome may be present. See the discussion of McCune-Albright syndrome in Table 3.

Frequency

United States

Cushing syndrome is a rare disorder, with 90% of cases occurring during adulthood. Overall incidence is estimated to be 2 new cases per million population per year. Incidence in children is estimated at approximately 0.2 cases per million population per year.

The National Cancer Institute (NCI) estimates the incidence of adrenal cortical carcinoma as 2 cases per million population per year. Pituitary causes of Cushing disease are 5-6 times more common than adrenal causes.

Prevalence of exogenous Cushing syndrome depends on the frequency and spectrum of medical conditions requiring glucocorticoid treatment in a given population. Considerable variation in this frequency is observed in populations of different cultural and ethnic backgrounds.

International

In certain regions of the world (eg, Japan, Brazil), adrenal tumors are more frequently observed. Whether this and other aberrations are due to a genetically determined founder effect in a small subset of the population or whether environmental factors may be acting to increase patient risk is unknown.

Mortality/Morbidity

As a result of the multiple adverse effects of chronic glucocorticoid excess, both endogenous and exogenous Cushing syndrome are associated with significant morbidity. Untreated, they are also associated with an increased risk of premature death. Specific information about the effects of glucocorticoids on different systems is summarized in Table 2.

Sex

Endogenous Cushing syndrome of pituitary etiology is more prevalent in women than in men, with a female-to-male ratio of 9:1. Females are 8 times more likely than males to develop an ACTH-secreting pituitary adenoma and 3 times more likely to develop a cortisol-secreting adrenal tumor.

Age

Onset of endogenous Cushing syndrome of pituitary etiology occurs primarily in the third and fourth decades of life.