Chapter 27: Androgen Hormones Flashcards
CORTICOSTEROIDS
Betamethasone CELESTONE, DIPROLENE,
LUXIQ
Cortisone CORTISONE ACETATE
Dexamethasone DECADRON
Fludrocortisone FLORINEF
Hydrocortisone
Methylprednisolone MEDROL
Prednisolone ORAPRED, PEDIAPRED
Prednisone
Triamcinolone KENALOG, NASACORT,
ARISTOSPAN
INHIBITORS OF ADRENOCORTICOID
BIOSYNTHESIS OR FUNCTION
Eplerenone INSPRA
Ketoconazole NIZORAL
Spironolactone ALDACTONE
Glucocorticoids
Glucocorticoids
Cortisol is the principal human glucocorticoid. Normally, its production
is diurnal, with a peak early in the morning followed by a decline and then a secondary, smaller peak in the late afternoon. Factors such
as stress and levels of the circulating steroid influence secretion. The
effects of cortisol are many and diverse. In general, all glucocorticoids:
1. Promote normal intermediary metabolism: Glucocorticoids
favor gluconeogenesis through increasing amino acid uptake
by the liver and kidney and elevating activities of gluconeogenic
enzymes. They stimulate protein catabolism (except in the liver)
and lipolysis, thereby providing the building blocks and energy
that are needed for glucose synthesis. [Note: Glucocorticoid insufficiency
may result in hypoglycemia (for example, during stressful
periods or fasting).]
2. Increase resistance to stress: By raising plasma glucose levels,
glucocorticoids provide the body with energy to combat stress
caused by trauma, fright, infection, bleeding, or debilitating disease.
3. Alter blood cell levels in plasma: Glucocorticoids cause a
decrease in eosinophils, basophils, monocytes, and lymphocytes
by redistributing them from the circulation to lymphoid tissue.
Glucocorticoids also increase hemoglobin, erythrocytes, platelets,
and polymorphonuclear leukocytes.
4. Have anti-inflammatory action: The most important therapeutic
properties of the glucocorticoids are their potent anti-inflammatory
and immunosuppressive activities. These therapeutic effects of
glucocorticoids are the result of a number of actions. The lowering
of circulating lymphocytes is known to play a role. In addition,
these agents inhibit the ability of leukocytes and macrophages to
respond to mitogens and antigens. Glucocorticoids also decrease
the production and release of proinflammatory cytokines. They
inhibit phospholipase A2, which blocks the release of arachidonic
acid (the precursor of the prostaglandins and leukotrienes) from
membrane-bound phospholipid. The decreased production of
prostaglandins and leukotrienes is believed to be central to the
anti-inflammatory action. Lastly, these agents influence the inflammatory
response by stabilizing mast cell and basophil membranes,
resulting in decreased histamine release.
5. Affect other systems: High levels of glucocorticoids serve as
feedback inhibitors of ACTH production and affect the endocrine
system by suppressing further synthesis of glucocorticoids and
thyroid-stimulating hormone. In addition, adequate cortisol levels
are essential for normal glomerular filtration. The effects of corticosteroids
on other systems are mostly associated with adverse
effects of the hormones (see Adverse Effects below).
B. Mineralocorticoids
Mineralocorticoids help to control fluid status and concentration of
electrolytes, especially sodium and potassium. Aldosterone acts on
distal tubules and collecting ducts in the kidney, causing reabsorption
of sodium, bicarbonate, and water. Conversely, aldosterone
decreases reabsorption of potassium, which, with H+, is then lost in
the urine. Enhancement of sodium reabsorption by aldosterone also
occurs in gastrointestinal mucosa and in sweat and salivary glands [Note: Elevated aldosterone levels may cause alkalosis and hypokalemia,
retention of sodium and water, and increased blood volume and
blood pressure. Hyperaldosteronism is treated with spironolactone.]
Target cells for aldosterone contain mineralocorticoid receptors that
interact with the hormone in a manner analogous to that of glucocorticoid
receptors.
Therapeutic use of glucocorticoids
. Therapeutic uses of the corticosteroids
Several semisynthetic derivatives of corticosteroids are available.
These agents vary in anti-inflammatory potency, mineralocorticoid
activity, and duration of action (Figure 27.4). Corticosteroids are used
in replacement therapy and in the treatment of severe allergic reactions,
asthma, rheumatoid arthritis, other inflammatory disorders, and
some cancers.
1. Replacement therapy for primary adrenocortical insufficiency
(Addison disease): Addison disease is caused by adrenal
cortex dysfunction (as diagnosed by the lack of response to
ACTH administration). Hydrocortisone [hye-droe-KOR-tih-sone],
which is identical to natural cortisol, is given to correct the deficiency.
Failure to do so results in death. The dosage of hydrocortisone
is divided so that two-thirds of the daily dose is given in the
morning and one-third is given in the afternoon. [Note: The goal
of this regimen is to mimic the normal diurnal variation in cortisol
levels.]
Administration of fludrocortisone [floo-droe-KOR-tih-sone],
a potent synthetic mineralocorticoid with some glucocorticoid
activity, may also be necessary to supplement mineralocorticoid
deficiency.
2. Replacement therapy for secondary or tertiary adrenocortical
insufficiency: These disorders are caused by a defect in
CRH production by the hypothalamus or in ACTH production by
the pituitary. [Note: Under these conditions, the synthesis of mineralocorticoids
in the adrenal cortex is less impaired than that of
glucocorticoids.] Hydrocortisone is used for treatment of these
deficiencies.
3. Diagnosis of Cushing syndrome: Cushing syndrome is caused
by hypersecretion of glucocorticoids (hypercortisolism) that results
from excessive release of ACTH by the anterior pituitary or an
adrenal tumor. [Note: Chronic treatment with high doses of glucocorticoids
is a frequent cause of iatrogenic Cushing syndrome.]
Cortisol levels (urine, plasma, and saliva) and the dexamethasone
[dex-a-METH-a-sone] suppression test are used to diagnose
Cushing syndrome. The synthetic glucocorticoid dexamethasone
suppresses cortisol release in normal individuals, but not those
with Cushing syndrome.
4. Replacement therapy for congenital adrenal hyperplasia
(CAH): CAH is a group of diseases resulting from an enzyme
defect in the synthesis of one or more of the adrenal steroid hormones.
CAH may lead to virilization in females due to overproduction of adrenal androgens. Treatment of the condition requires
administration of sufficient corticosteroids to normalize hormone levels by suppressing release of CRH and ACTH. This decreases
production of adrenal androgens. The choice of replacement
hormone
depends on the specific enzyme defect.
5. Relief of inflammatory symptoms: Corticosteroids significantly
reduce the manifestations of inflammation associated with rheumatoid
arthritis and inflammatory skin conditions, including redness,
swelling, heat, and tenderness that may be present at the site of
inflammation. These agents are also important for maintenance
of symptom control in persistent asthma, as well as management
of asthma exacerbations and active inflammatory bowel disease.
In noninflammatory disorders such as osteoarthritis, intra-articular
corticosteroids may be used for treatment of a disease flare.
Corticosteroids are not curative in these disorders.
6. Treatment of allergies: Corticosteroids are beneficial in the treatment
of allergic rhinitis, as well as drug, serum, and transfusion
allergic reactions. [Note: In the treatment of allergic rhinitis and
asthma, fluticasone [floo-TIK-a-sone] and others (see Figure 27.5)
are applied topically to the respiratory tract through inhalation
from a metered dose dispenser. This minimizes systemic effects
and allows the patient to reduce or eliminate the use of oral
corticosteroids.]
7. Acceleration of lung maturation: Respiratory distress syndrome
is a problem in premature infants. Fetal cortisol is a regulator of lung maturation. Consequently, a regimen of betamethasone or
dexamethasone administered intramuscularly to the mother within
the 48 hours proceeding premature delivery can accelerate lung
maturation in the fetus.
D. Pharmacokinetics
1. Absorption and fate: Orally administered corticosteroid preparations
are readily absorbed. Selected compounds can also be
administered intravenously, intramuscularly, intra-articularly (for
example, into arthritic joints), topically, or via inhalation or intranasal
delivery (Figure 27.5). All topical and inhaled glucocorticoids
are absorbed to some extent and, therefore, have the potential
to cause hypothalamic–pituitary–adrenal (HPA) axis suppression.
Greater than 90% of absorbed glucocorticoids are bound to
plasma proteins, mostly corticosteroid-binding globulin or albumin.
Corticosteroids are metabolized by the liver microsomal oxidizing
enzymes. The metabolites are conjugated to glucuronic acid or
sulfate, and the products are excreted by the kidney. [Note: The
half-life of corticosteroids may increase substantially in hepatic
dysfunction.] Prednisone [PRED-nih-sone] is preferred in pregnancy
because it minimizes steroid effects on the fetus. It is a prodrug
that is not converted to the active compound, prednisolone
[pred-NIH-so-lone], in the fetal liver. Any prednisolone formed in
the mother is biotransformed to prednisone by placental enzymes.
2. Dosage: Many factors should be considered in determining the
dosage of corticosteroids, including glucocorticoid versus mineralocorticoid
activity, duration of action, type of preparation, and
time of day when the drug is administered. When large doses of
the hormone are required for more than 2 weeks, suppression of
the HPA axis occurs. Alternate-day administration of the corticosteroid
may prevent this adverse effect by allowing the HPA axis to
recover/function on days the hormone is not taken.
E. Adverse effects
Common side effects of long-term corticosteroid therapy are summarized
in Figure 27.6. Adverse effects are often dose related. For
example, in patients with rheumatoid arthritis, the daily dose of prednisone
was the strongest predictor of occurrence of adverse effects
(Figure 27.7). Osteoporosis is the most common adverse effect due
to the ability of glucocorticoids to suppress intestinal Ca2+ absorption,
inhibit bone formation, and decrease sex hormone synthesis.
Patients are advised to take calcium and vitamin D supplements.
Bisphosphonates may also be useful in the treatment of glucocorticoid-
induced osteoporosis. [Note: Increased appetite is not necessarily
an adverse effect. In fact, it is one of the reasons for the use of
prednisone in cancer chemotherapy.] The classic Cushing-like syndrome
(redistribution of body fat, puffy face, hirsutism, and increased
appetite) is observed in excess corticosteroid replacement. Cataracts
may also occur with long-term corticosteroid therapy. Hyperglycemia
may develop and lead to diabetes mellitus. Diabetic patients should
monitor blood glucose and adjust medications accordingly if taking
corticosteroids. Coadministration of medications that induce or inhibit
the hepatic mixed-function oxidases may require adjustment of the glucocorticoid dose. Topical therapy can also cause skin atrophy,
ecchymosis, and purple striae.
Discontinuation
Sudden discontinuation of these drugs can be a serious problem
if the patient has suppression of the HPA axis. In this case, abrupt
removal of corticosteroids causes acute adrenal insufficiency that can
be fatal. This risk, coupled with the possibility that withdrawal might
cause an exacerbation of the disease, means that the dose must be
tapered slowly according to individual tolerance. The patient must be
monitored carefully.
Inhibitors of adrenocorticoid biosynthesis or function
Several substances have proven to be useful as inhibitors of the synthesis
or function of adrenal steroids: ketoconazole, spironolactone,
and eplerenone
- Ketoconazole: Ketoconazole [kee-toe-KON-ah-zole] is an antifungal
agent that strongly inhibits all gonadal and adrenal steroid
hormone synthesis. It is used in the treatment of patients with
Cushing syndrome. - Spironolactone: This antihypertensive drug competes for the
mineralocorticoid receptor and, thus, inhibits sodium reabsorption
in the kidney. It can also antagonize aldosterone and testosterone
synthesis. It is effective for hyperaldosteronism and is used along
with other standard therapies for the treatment of heart failure with
reduced ejection fraction. Spironolactone [speer-oh-no-LAK-tone]
is also useful in the treatment of hirsutism in women, probably due
to interference at the androgen receptor of the hair follicle. Adverse
effects include hyperkalemia, gynecomastia, menstrual irregularities,
and skin rashes. - Eplerenone: Eplerenone [e-PLER-ih-none] specifically binds to
the mineralocorticoid receptor, where it acts as an aldosterone
antagonist. This specificity avoids the side effect of gynecomastia
that is associated with the use of spironolactone. It is approved
for the treatment of hypertension and also for heart failure with
reduced ejection fraction
