The endogenous corticosteroids are produced by the adrenal cortex
and are essential for life. As with the gonadal steroid hormones
discussed in Chapter 22, corticosteroids are synthesized from cholesterol.
They comprise two major physiologic and pharmacologic groups, glucocorticoids and
mineralocorticoids (Figure 23–1). Glucocorticoids have
important effects on intermediary metabolism, catabolism, immune
responses, and inflammation. Mineralocorticoids regulate sodium
and potassium transport in the collecting tubules of the kidney.
A third group, the adrenal androgens (dehydroepiandrosterone [DHEA] and
androstenedione) constitute the major endogenous precursors of estrogen
in females in whom ovarian function is deficient or absent (e.g.,
postmenopausal) and in preadolescent males. Drugs that modulate
the physiologic effects of endogenous corticosteroids either mimic
the corticosteroids or inhibit corticosteroid synthesis or receptor
Classification of drugs that mimic or block the effects
of endogenous corticosteroids.
Like other hormones under the control of the hypothalamic and
pituitary endocrine system, glucocorticoids provide feedback inhibition
of their own production by acting in the hypothalamus and pituitary.
Glucocorticoids inhibit the production of corticotropin-releasing
factor (CRF) within the hypothalamus and adrenocorticotropic
hormone (ACTH) within the pituitary. CRF controls the release
of ACTH, which in turn regulates corticosteroid production within
the adrenal cortex. A key action of exogenous glucocorticoids
is activation of this feedback inhibition system with subsequent
suppression of endogenous adrenal steroid production. After chronic
treatment with exogenous glucocorticoids, recovery of the endogenous
system takes weeks to months.
A large number of synthetic glucocorticoids are available. They
can be delivered by a variety of routes, including oral, intravenous,
intra-articular, and topical.
Steroid hormones enter the cell and bind to cytosolic receptors.
The complex of the receptor and its bound steroid translocates to
the nucleus where it alters gene expression by binding to glucocorticoid response elements (GREs)
(Figure 23–2). Tissue-specific responses to steroids are
made possible by the presence of different protein regulators in
each tissue that control the interaction between the hormone-receptor
complex, other transcription factors, and particular response elements.
Mechanism of glucocorticoid action. This figure models
the interaction of a steroid (S), with its receptor (R) and the
subsequent events in a target cell. The steroid is present in the
blood—bound to the corticosteroid-binding globulin (CBG)—but
it enters the cell as the free form. The intracellular receptor
(R) is bound to stabilizing proteins, including heat shock protein
90 (Hsp90) and several others. When the complex binds a molecule
of steroid, the Hsp90 and associated molecules are released. The
steroid-receptor complex enters the nucleus as a dimer, binds to
the glucocorticoid response element (GRE), and thereby regulates
gene transcription by RNA polymerase II and associated transcription
factors. The resulting mRNA is edited and exported to the cytoplasm ...