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mones. Glucocorticoids are administered concomitantly
tantly administered drugs that are also metabolized by
to suppress enhanced corticotrophin release. Cortisol is
this pathway.
preferable to dexamethasone in this situation because
aminoglutethimide markedly enhances the hepatic
microsomal metabolism of dexamethasone. Hepatic en-
zyme induction may be responsible for the develop-
Ketoconazole
ment of tolerance to the side effects of aminoglu-
Ketoconazole (Nizoral), an orally effective broad-
tethimide, such as ataxia, lethargy, dizziness, and rashes.
spectrum antifungal agent (see Chapter 52), blocks hy-
Aminoglutethimide is suitable for use in Cushing s
droxylating enzyme systems by interacting with cy-
syndrome that results from adrenal carcinoma and in
tochrome P450 at the heme iron site to inhibit steroid
congenital adrenal hyperplasia, in which it protects the
and/or androgen synthesis in adrenals, gonads, liver, and
patient from excessive secretion of endogenous andro-
kidney. The most sensitive site of action appears to be
gens. The drug is not curative, and relapse occurs when
the C17-20 lyase reaction involved in the formation of
treatment is terminated. Since aminoglutethimide ther-
sex steroids. This explains the greater suppressibility of
apy is frequently associated with mineralocorticoid de-
testosterone production than with cortisol. Cholesterol
ficiency, mineralocorticoid supplements may be needed.
side-chain cleavage and 11 /18-hydroxylase are second-
Aminoglutethimide and metyrapone are frequently
ary sites of inhibition.
used in combination at lower doses of both drugs as an
Ketoconazole can be used as palliative treatment for
adjunct to radiation or surgical therapy.
Cushing s syndrome in patients undergoing surgery or
receiving pituitary radiation and in those for whom
Mitotane
more definitive treatment is still contemplated. Because
Mitotane (Lysodren) produces selective atrophy of the surgical treatment is not always well tolerated by eld-
zona fasciculata and zona reticularis, which results in a erly patients, ketoconazole 200 to 1,000 mg/day can be a
decrease in the secretion of 17-hydroxycorticosteroids. valuable alternative for the control of hypercortisolism.
Direct inhibition of cholesterol side-chain cleavage and Common side effects include pruritus, liver dysfunction,
11 /18-hydroxylase activities has also been demon- and gastrointestinal symptoms.
strated. Mitotane is capable of inducing remission of Because of its effectiveness in blocking C17-20 lyase
Cushing s disease, but only after several weeks of ther- activities, ketoconazole does not enhance existing hir-
apy and at the price of severe gastrointestinal distress. sutism associated with metyrapone. On the other hand,
Moreover, more than half of patients relapse following the antiandrogenic effects of ketoconazole may prove
cessation of therapy. Other side effects include lethargy, disconcerting to male patients.
60 Adrenocortical Hormones and Drugs Affecting the Adrenal Cortex 701
cated with mifepristone. Hypoadrenalism, nausea, and
Mifepristone (RU 486)
drowsiness have been reported during prolonged ad-
Mifepristone is a progesterone receptor antagonist that
ministration of mifepristone.
has a high affinity for glucocorticoid receptors and little
agonist effect. This drug has recently been approved for
Dexamethasone
use in the United States for the treatment of hypercor-
tisolism. At high doses, mifepristone blocks negative Cushing s disease is defined as hypercortisolism due to
feedback of the hypothalamic pituitary axis, thereby in- chronic overproduction of corticotrophin by a corti-
creasing endogenous corticotrophin and cortisol levels. cotroph adenoma. Cortisol s lack of suppressibility dur-
Because mifepristone exerts its effects at the receptor ing the administration of low doses of dexamethasone
level and not by altering glucocorticoid production, ele- but suppressibility during high-dose dexamethasone is
vated serum cortisol and corticotrophin levels may not the key diagnostic finding in 99% of the patients with
accurately reflect the effectiveness of the therapeutic Cushing s disease. This contrasts with the lack of gluco-
regimen. Mifepristone does not inhibit cortisol binding corticoid suppressibility typically found in patients with
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