Endocrine Metabolism III: Adrenal Glands
Regulation of renin release. Numbers 1-7 indicate the steps involved in
the secretion of renin by the juxtaglomerular apparatus and its action.
© , Stimulatory, © inhibitory; f increased production.
uptake of low-density lipoprotein (LDL) by increasing the
number of LDL receptor sites. The adrenal cortex, al-
though capable of
de novo
cholesterol synthesis, normally
depends on LDL for its cholesterol needs. By increasing
the size of the pregnenolone pool, ACTH promotes
the flow of steroids through the major pathways of the
zona fasciculata. It also stimulates DHEA and DHEAS
secretion by the zona reticularis and aldosterone secretion
from the zona glomerulosa. ACTH is not an important
regulator of aldosterone secretion because there is no
feedback communication between ACTH release and the
zona glomerulosa.
Metabolism of Corticosteroids
states and have different fractional distributions (see
Table 30-3). Because of the relatively large fraction of
unbound (40%) and loosely bound (50%) forms, aldo-
sterone is cleared from blood much faster than is corti-
sol (half-lives in blood: aldosterone, ~30 minutes; corti-
sol, ~10 hours). Both steroids are metabolized mainly in
the liver. The major metabolite of aldosterone is tetrahy-
droaldosterone glucuronide and that of cortisol is tetrahy-
drocortisol glucuronide. These water-soluble conjugates
are excreted by the kidney. Another metabolite of cor-
tisol is cortisone (4-pregnen-17a,21-diol-3,l 1-20-trione),
which has no intrinsic activity but can be reconverted to
cortisol in certain peripheral tissues (e.g., lung, liver).
Synthetic Corticosteroids
Because of inactivation in the liver, the corticosteroids
are ineffective when taken by mouth. Synthetic corti-
costeroids have been developed that are relatively resis-
tant to hepatic inactivation and are active when taken
orally (Table 32-2). Certain structural modifications en-
hance glucocorticoid activity while suppressing miner-
alocorticoid activity; other modifications enhance both
activities. For example, the double bond at position
1 (A1) of prednisolone increases glucocorticoid activ-
ity fourfold while decreasing mineralocorticoid activity
by a one-third. If a 16-a-methyl group also is added
to form methylprednisolone, glucocorticoid activity is
further enhanced and mineralocorticoid activity is fur-
ther reduced. Addition of a 9-a-fluoro group to produce
dexamethasone gives one of the most potent glucocor-
ticoids available, with negligible mineralocorticoid ac-
tivity. If, however, the 9-a-fluoro group is introduced
into cortisol to produce fludrocortisone, the result is a
very potent mineralocorticoid with enhanced glucocorti-
coid activity. Thus, the 1
-hydroxyl group of corticos-
teroids, which is protected from oxidation by a 9-a-fluoro
group, is essential for glucocorticoid and mineralocorti-
coid activities. It also appears that steric hindrance of the
A ring and the 20,21-a-ketol side chain enhances glu-
cocorticoid activity while diminishing mineralocorticoid
Biological Actions of Aldosterone
Mechanism o f Action
Aldosterone exerts its effect by binding to type I corti-
costeroid receptors in the cytoplasm, translocating to the
nucleus, and binding to an acceptor site in the chromatin,
which results in gene activation and synthesis of a spe-
cific protein (see Chapter 30). Aldosterone induces the
synthesis of aldosterone-induced protein (AIP), which is
involved in transcellular Na+,K+-ATPase.
The type I corticosteroid receptor (mineralocorticoid
receptor) binds cortisol and aldosterone with equal affin-
ity. Because the circulating level of cortisol normally ex-
ceeds that of aldosterone by about 1000-fold (Table 32-1),
activation of the receptor by aldosterone would proba-
bly not occur, were it not for the presence of a cortisol-
inactivating enzyme in cells responsive to aldosterone.
This enzyme, 11 /1HSD (Chapter 30), catalyzes the con-
version of cortisol to cortisone, a metabolite that is not
recognized by the receptor. Inhibition or absence of this
enzyme leads to excessive aldosterone-like effects due to
receptor activation by cortisol, a condition referred to as
“apparent mineralocorticoid excess” (AME). AME can
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