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GLUCOCORTICOID ACTION

The receptors for steroids, vitamin D, thyroxine, and many other molecules are zinc-finger transcription factors, which, in the liganded state, bind to specific DNA sequences to modulate gene expression. The half-lives of the encoded RNAs and proteins vary, so that the biological half-life of a steroid hormone varies with the target being considered. There is 1 glucocorticoid receptor gene whose mRNAs are alternatively spliced into numerous forms; these vary in tissue-specific posttranslational modifications and steroid-binding affinity, explaining tissue-specific and interindividual differences in glucocorticoid sensitivity. The nucleotide polymorphism A3669G (rs6198), present in approximately 35% of people, reduces glucocorticoid sensitivity and increases risk for autoimmune disease. ER22/23EK (rs6189/rs6190) (~7% of people) is associated with mild glucocorticoid resistance and a healthier metabolic profile. N363S (rs1695) (~8%) and Bcl1 (rs41423247) (~45%) are associated with mildly increased sensitivity, yielding more body fat, less lean mass, increased insulin resistance, and so on.

Glucocorticoids are used for adrenal replacement therapy and as pharmacologic agents. Following withdrawal of long-term glucocorticoid therapy, adrenal insufficiency can persist for months, especially during stress. Differences among various glucocorticoids relate to their ratio of glucocorticoid to mineralocorticoid activity, their capacity to bind to plasma proteins, their molar potency, and their biologic half-life. Dexamethasone is commonly used for reducing increased intracranial pressure and brain edema. Neurosurgical experience indicates that optimal doses are 10 to 100 times those that would thoroughly saturate available glucocorticoid receptors, suggesting that this action of dexamethasone may be mediated by another mechanism.

REPLACEMENT THERAPY

Glucocorticoid replacement therapy is complicated by undesirable side effects of overtreatment or undertreatment. Even minimal overtreatment can impair growth; long-standing undertreatment may resemble adrenal insufficiency. Pediatric glucocorticoid replacement is based on the endogenous secretory rate of cortisol, which is approximately 6 mg/m2, but there is considerable variation in this rate. Several factors must be considered in tailoring a child’s glucocorticoid replacement regimen:

Cause of Adrenal Insufficiency

When treating Addison disease (Chapter 527), it is prudent to err slightly on the side of undertreatment. This will eliminate glucocorticoid-induced iatrogenic growth retardation and will permit continued production of normal or slightly increased amounts of corticotropin (ACTH). ACTH will continue to stimulate the remaining functional steroidogenic machinery and also provide a convenient means of monitoring therapy. By contrast, when treating virilizing congenital adrenal hyperplasia (CAH), the adrenal should be suppressed more completely to suppress the production of unwanted androgens, which cause virilization and advanced bone age. However, overtreatment will also compromise growth.

Associated Mineralocorticoid Deficiency

Children with mild degrees of mineralocorticoid insufficiency (eg, simple virilizing CAH) may have mildly elevated ACTH (suggesting insufficient glucocorticoid replacement) in association with elevated plasma renin activity (PRA). The ACTH may be elevated in response to chronic, compromised hypovolemia, attempting to stimulate the adrenal to produce more mineralocorticoid. Even without overt signs of mineralocorticoid insufficiency, treatment with ...

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