Glycoprotein Hormones

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Glycoprotein Hormones
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_________________ (Thyrotropin) Found in
pituitaries of all _____________ Most important
role is control of thyroid gland to liberate
thyroid hormones Also induces ___________ in
amphibians Important role in
____________________ in mammals
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________ ____, or thyrotropin, is secreted from
thyrotrophs in the anterior pituitary finds its
receptors on _____ cells in the thyroid gland,
and stimulates that gland to synthesize and
release ___________. ____ is a glycoprotein
hormone composed of 2 subunits which are
non-covalently bound to one another.

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The most important controller of TSH secretion is
__________ ___ is secreted by hypothalamic
neurons into hypothalamic-hypophyseal portal
blood, finds its receptors on ___________ in the
anterior pituitary and stimulates secretion of
TSH. One interesting aspect of TRH is that it
is only __ amino acids long. Its basic sequence
is glutamic acid-histidine-proline, although both
ends of the peptide are _________

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Gonadotropins Luteinizing and Follicle
Stimulating Hormones LH and FSH are called
gonadotropins because stimulate the ______ in
males-the testes in females-the ovaries. Not
necessary for ______ Essential for
__________ Both hormones are secreted from
gonadotrophs in the anterior pituitary. Most
gonadotrophs secrete only LH or FSH, but some
appear to secrete ____ hormones.

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Physiologic Effects of Gonadotropins Physiologic
effects of the gonadotrophins are known only in
the ______________________ Together, then
regulate many aspects of gonadal function in both
males and females.

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Luteinizing Hormone In both sexes, LH stimulates
secretion of _____steroids from the gonads. In
the _______, LH binds to receptors on Leydig
cells, stimulating synthesis and secretion of
testosterone. Theca cells in the _______
respond to LH stimulation by secretion of
testosterone, which is converted into estrogen by
adjacent granulosa cells.

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Control of Gonadotropin Secretion principle
regulator of LH and FSH secretion is
_________________ ____________ is a 10 aa
peptide that is synthesized and secreted from
hypothalamic neurons and binds to receptors on
________________

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Control of Gonadotropin Secretion In a classical
______ feedback loop, sex steroids inhibit
secretion of GnRH and also have direct negative
effects on _________. This regulatory loop leads
to pulsatile secretion of LH and, to a much
lesser extent, FSH. The number of pulses of GnRH
and LH varies from a ____per day to one or more
per hour. In females, pulse frequency is clearly
related to stage of the _____.

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Disease States Diminished secretion of LH or FSH
can result in failure of gonadal function
(_________onadism). This condition is typically
manifest in males as failure in production of
normal numbers of sperm. In females, cessation
of reproductive cycles is commonly observed.
Elevated blood levels of gonadotropins usually
reflect lack of steroid negative feedback.

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Disease States Removal of the gonads from
either males or females, as is commonly done to
animals, leads to _______________ in LH and FSH.
In humans, excessive secretion of FSH and/or LH
are most commonly the result of gonadal failure
or ____________. In general, elevated levels of
gonadotropins per se have ____________________.

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Pharmacologic Manipulation of Gonadotropin
Secretion Normal patterns of gonadotropin
secretion are absolutely required for
reproduction, and interfering particularly with
_____ secretion is a widely-used strategy for
contraception. Oral contraceptive pills contain
a progestin (progesterone-mimicking compound),
usually combined with an estrogen. As discussed
in feedback inhibition slide, progesterone and
estrogen inhibit LH secretion, and oral
contraceptives are effective because they inhibit
the _____ surge that induces ovulation.

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caused by prolonged exposure of the body's
tissues to high levels of the ______l.
Sometimes called "hypercortisolism,"
relatively rare and most commonly affects adults
aged _____. An estimated 10-15 of every ______
people are affected each year.
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What Are the Symptoms? Symptoms vary most
people have upper body _______, rounded face,
increased ___ around the neck, and thinning
arms and legs. Children tend to be obese with
slowed growth rates.
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What Are the Symptoms? Other symptoms appear in
the ____, which becomes fragile and thin. It
bruises easily and heals poorly. Purplish pink
stretch marks may appear on the abdomen, thighs,
buttocks, arms and breasts. bones are weakened,
and routine activities such as bending, lifting
or rising from a chair may lead to backaches, rib
and spinal column fractures.
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Most people have severe fatigue, weak muscles,
high blood pressure and high blood ______.
Irritability, anxiety and depression are
common. Women usually have excess _____ growth on
their faces, necks, chests, abdomens, and thighs.
Their menstrual periods may become irregular or
stop. Men have decreased ______ with diminished
or absent desire for sex.
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What Causes Cushing's Syndrome? Cushing's
syndrome occurs when the body's tissues are
exposed to excessive levels of ________ for long
periods of time. Many people suffer the symptoms
of Cushing's syndrome because they take
_______hormones such as prednisone for asthma,
rheumatoid arthritis, lupus and other
inflammatory diseases, or for immunosuppression
after transplantation.
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What Causes Cushing's Syndrome? Others develop
Cushing's syndrome because of overproduction of
cortisol by ______________. Normally, the
production of cortisol follows a precise chain of
events. CRH-_____-cortisol
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Cortisol performs vital tasks in the body. helps
maintain blood ______e and __________function,
reduces the immune system's inflammatory
response, balances the effects of insulin in
breaking down sugar for energy, regulates the
metabolism of proteins, __________, and fats.
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One of cortisol's most important jobs is to help
the body respond to _____ For this reason, women
in their last 3 months of pregnancy and highly
trained athletes normally have high levels of the
hormone. People suffering from depression,
alcoholism, malnutrition and panic disorders also
have increased cortisol levels.
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What Causes Cushing's Syndrome? _________ cause
most cases of Cushing's syndrome. secrete
increased amounts of ACTH. Most patients have a
single adenoma. This form of the syndrome, known
as "Cushing's ______," affects women ___ more
frequently than men.
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What Causes Cushing's Syndrome? Ectopic
_____________Some benign or malignant
(cancerous) tumors that arise outside the
pituitary can produce _____. Lung tumors cause
over 50 of these cases. Men are affected ___
more frequently than women. The most common forms
of ACTH-producing tumors are oat cell, or small
cell lung cancer, which accounts for about 25
of all lung cancer cases Other less common types
of tumors that can produce ACTH are thymomas,
pancreatic islet cell tumors, and medullary
carcinomas of the thyroid.
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What Causes Cushing's Syndrome? _______
TumorsSometimes, an abnormality of the adrenal
glands, most often an adrenal tumor, causes
Cushing's syndrome. average age of onset is
about 40 years. Most cases involve
non-cancerous tumors of adrenal tissue which
release excess cortisol into the
blood. Adrenocortical carcinomas, or adrenal
cancers, are the least common cause of Cushing's
syndrome. Cancer cells secrete excess levels of
several adrenal cortical hormones, including
cortisol and adrenal androgens. Adrenocortical
carcinomas usually cause very high hormone levels
and rapid development of symptoms.
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What Causes Cushing's Syndrome? _________
Cushing's SyndromeMost cases of Cushing's
syndrome are not inherited. Rarely, however,
some individuals have special causes of Cushing's
syndrome due to an inherited tendency to develop
________of one or more endocrine glands. In
Primary Pigmented Micronodular Adrenal Disease,
children or young adults develop small
cortisol-producing tumors of the adrenal glands.
In Multiple Endocrine Neoplasia Type I (MEN I),
hormone secreting tumors of the parathyroid
glands, pancreas and pituitary occur. Cushing's
syndrome in MEN I may be due to pituitary,
ectopic or adrenal tumors.
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How Is Cushing's Syndrome Diagnosed? Often X-ray
exams of the adrenal or pituitary glands are
useful for locating tumors. 24-Hour Urinary
Free Cortisol LevelsThis is the most specific
diagnostic test. The patient's urine is
collected over a 24-hour period and tested for
the amount of cortisol. Levels higher than 50100
micrograms a day for an adult suggest Cushing's
syndrome. The normal upper limit varies in
different laboratories, depending on which
measurement technique is used.
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How Is Cushing's Syndrome Diagnosed? Once
Cushing's syndrome has been diagnosed, other
tests are used to find the exact ________of the
abnormality that leads to excess cortisol
production. The choice of test depends, in part,
on the preference of the endocrinologist or the
center where the test is performed.
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How Is Cushing's Syndrome Diagnosed? ____________
____ Suppression Test This test helps to
distinguish patients with excess production of
ACTH due to pituitary adenomas from those with
________ ACTH-producing tumors. Patients are
given dexamethasone, a synthetic glucocorticoid,
by mouth every 6 hours for 4 days. For the first
2 days, low doses of dexamethasone are given, and
for the last 2 days, higher doses are given.
Twenty-four hour urine collections are made
before dexamethasone is administered and on each
day of the test.
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Dexamethasone Suppression Test Since cortisol
and other glucocorticoids signal the pituitary to
lower secretion of ACTH, the normal response
after taking dexamethasone is a drop in blood and
urine cortisol levels. Different responses of
cortisol to dexamethasone are obtained depending
on whether the cause of Cushing's syndrome is a
pituitary adenoma or an ectopic ACTH-producing
tumor.
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How Is Cushing's Syndrome Diagnosed? ____Stimulat
ion TestThis test helps to distinguish between
patients with pituitary adenomas and those with
ectopic ACTH syndrome or cortisol-secreting
adrenal tumors. Patients are given an injection
of CRH, which causes the pituitary to secrete
ACTH. Patients with pituitary adenomas usually
experience a rise in blood levels of ACTH and
cortisol. This response is rarely seen in
patients with ectopic ACTH syndrome and
practically never in patients with
cortisol-secreting adrenal tumors.
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How Is Cushing's Syndrome Diagnosed? Direct
Visualization of the Endocrine Glands
(Radiologic Imaging)Imaging tests reveal the
size and shape of the pituitary and adrenal
glands and help determine if a tumor is present.
most common are the CT (computerized
tomography) scan and MRI (magnetic resonance
imaging). A CT scan produces a series of x-ray
pictures giving a cross-sectional image of a body
part. MRI also produces images of the internal
organs of the body but without exposing the
patient to ionizing radiation.
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How Is Cushing's Syndrome Diagnosed? ________
Sinus SamplingThis test is not always required,
but in many cases, it is the best way to separate
pituitary from ectopic causes of Cushing's
syndrome. Samples of blood are drawn from the
petrosal sinuses, veins which drain the
pituitary, by introducing catheters through a
vein in the upper thigh/groin region, with local
anesthesia and mild sedation. X-rays are used to
confirm the correct position of the catheters.
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How Is Cushing's Syndrome Diagnosed? Petrosal
Sinus Sampling Often ____, the hormone which
causes the pituitary to secrete ____, is given
during this test to improve diagnostic accuracy.
Levels of ACTH in the petrosal sinuses are
measured and compared with ACTH levels in a
forearm vein. ACTH levels higher in the petrosal
sinuses than in the forearm vein indicate the
presence of a pituitary adenoma similar levels
suggest ectopic _____syndrome.
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How Is Cushing's Syndrome Diagnosed? Imaging
procedures are used to find a tumor after a
diagnosis has been established. Imaging is not
used to make the diagnosis of Cushing's syndrome
because benign tumors, sometimes called
"incidentalomas," are commonly found in the
pituitary and adrenal glands. These tumors do
not produce hormones detrimental to health and
are not removed unless blood tests show they are
a cause of symptoms or they are unusually large.
Conversely, pituitary tumors are not detected by
imaging in almost 50 of patients who ultimately
require pituitary surgery for Cushing's syndrome.
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How Is Cushing's Syndrome Treated? Pituitary
Adenomas Several therapies are available to
treat the ACTH-secreting pituitary adenomas of
Cushing's disease. The most widely used treatment
is _________________________________
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How Is Cushing's Syndrome Treated? Pituitary
Adenomas If surgery has failed or person not
suitable candidates for surgery, radiotherapy is
another possible treatment. ___________ to the
pituitary gland is given over a 6-week period,
with improvement occurring in 40-50 of adults
and up to 80 of children. It may take several
months or years before patients feel better from
radiation treatment alone. However, the
combination of radiation and the drug mitotane
(Lysodren) can help speed recovery.
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How Is Cushing's Syndrome Treated? Pituitary
Adenomas ________ suppresses cortisol production
and lowers plasma and ______ hormone levels.
Treatment with mitotane alone can be successful
in 30- 40 of patients. Other drugs used alone
or in combination to control the production of
excess cortisol Aminoglutethimide
metyrapone trilostane and ketoconazole ,
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How Is Cushing's Syndrome Treated? Ectopic
______Syndrome To cure the overproduction of
cortisol caused by ectopic ACTH syndrome, it is
necessary to eliminate all of the cancerous
tissue that is secreting ACTH. The choice of
cancer treatmentsurgery, radiotherapy,
chemotherapy, immunotherapy, or a combination of
these treatmentsdepends on the type of cancer
and how far it has spread. Since ACTH-secreting
tumors (for example, small cell lung cancer) may
be very small or widespread at the time of
diagnosis, cortisol-inhibiting drugs, like
mitotane, are an important part of treatment.
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How Is Cushing's Syndrome Treated? Ectopic ACTH
Syndrome In some cases, if pituitary surgery is
not successful, surgical removal of the adrenal
glands (bilateral adrenalectomy) may take the
place of drug therapy.
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How Is Cushing's Syndrome Treated? Adrenal
Tumors _____ is the mainstay of treatment for
benign as well as cancerous tumors of the adrenal
glands.
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Addison's disease occurs when the adrenal glands
do not produce enough of the hormone cortisol
and, in some cases, the hormone aldosterone. The
disease is also called adrenal insufficiency, or
_______cortisolism.
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Multiple functions of cortisol
Aldosterone Aldosterone belongs to a class of
hormones called mineralocorticoids, also produced
by the adrenal glands. It helps maintain blood
pressure and water and salt balance in the body
by helping the kidney retain sodium and excrete
potassium.
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Symptoms The symptoms of adrenal insufficiency
usually begin gradually. Characteristics of the
disease are chronic, worsening fatigue muscle
weakness loss of appetite weight loss About
50 percent of the time, one will notice nausea
vomiting diarrhea
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Other Symptoms low blood pressure that falls
further when standing, causing dizziness or
fainting skin changes in Addison's disease,
with areas of hyperpigmentation, or dark
tanning, covering exposed and nonexposed parts of
the body this darkening of the skin is most
visible on scars skin folds pressure points
such as the elbows, knees, knuckles, and toes
lips and mucous membranes Addison's disease
can cause irritability and depression. Because of
salt loss, a craving for salty foods also is
common. Hypoglycemia, or low blood glucose, is
more severe in children than in adults. In women,
menstrual periods may become irregular or stop.
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Because the symptoms progress slowly, they are
usually ignored until a stressful event like an
illness or an accident causes them to become
worse. This is called an ________________, or
acute adrenal insufficiency. In most cases,
symptoms are severe enough that patients seek
medical treatment before a crisis occurs.
However, in about 25 of patients, symptoms
first appear during an addisonian
crisis. Symptoms of an addisonian crisis
include sudden penetrating pain in the lower
back, abdomen, or legs severe vomiting and
diarrhea dehydration low blood pressure loss
of consciousness
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Diagnosis In its early stages, adrenal
insufficiency can be difficult to diagnose. A
review of a patient's medical history based on
the symptoms, especially the dark tanning of the
skin, will lead a doctor to suspect Addison's
disease. A diagnosis of Addison's disease is made
by laboratory tests. The aim of these tests is
first to determine whether levels of cortisol are
insufficient and then to establish the cause.
X-ray exams of the adrenal and pituitary glands
also are useful in helping to establish the cause.
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Diagnosis ACTH Stimulation Test This is the
most specific test for diagnosing Addison's
disease. In this test, blood cortisol, urine
cortisol, or both are measured before and after a
synthetic form of ACTH is given by injection. In
the so-called short, or rapid, ACTH test,
measurement of cortisol in blood is repeated 30
to 60 minutes after an intravenous ACTH
injection. The normal response after an
injection of ACTH is a rise in blood and urine
cortisol levels. Patients with either form of
adrenal insufficiency respond poorly or do not
respond at all.
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Diagnosis CRH Stimulation Test When the
response to the short ACTH test is abnormal, a
"long" CRH stimulation test is required to
determine the cause of adrenal insufficiency. In
this test, synthetic CRH is injected
intravenously and blood cortisol is measured
before and 30, 60, 90, and 120 minutes after the
injection. Patients with primary adrenal
insufficiency have high ACTHs but do not produce
cortisol. Patients with secondary adrenal
insufficiency have deficient cortisol responses
but absent or delayed ACTH responses. Absent ACTH
response points to the pituitary as the cause a
delayed ACTH response points to the hypothalamus
as the cause.
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Diagnosis CRH Stimulation Test . In patients
suspected of having an addisonian crisis, the
doctor must begin treatment with injections of
salt, fluids, and glucocorticoid hormones
immediately. Although a reliable diagnosis is not
possible while the patient is being treated for
the crisis, measurement of blood ACTH and
cortisol during the crisis and before
glucocorticoids are given is enough to make the
diagnosis. Once the crisis is controlled and
medication has been stopped, the doctor will
delay further testing for up to 1 month to obtain
an accurate diagnosis.
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Causes Failure to produce adequate levels of
cortisol can occur for different reasons. The
problem may be due to a disorder of the adrenal
glands themselves (primary adrenal insufficiency)
or to inadequate secretion of ACTH by the
pituitary gland (secondary adrenal insufficiency).
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Primary Adrenal Insufficiency- Addison's disease
cause affects about 1 in 100,000 people. Most
cases are caused by the gradual destruction of
the adrenal cortex by the body's own immune
system. About 70 of reported cases of Addison's
disease are caused by autoimmune disorders, in
which the immune system makes antibodies that
attack the body's own tissues or organs and
slowly destroy them.
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Primary Adrenal Insufficiency- Addison's disease
cause Adrenal insufficiency occurs when at least
90 of the adrenal cortex has been destroyed.
As a result, often both glucocorticoid
(cortisol) and mineralocorticoid (aldostertone)
hormones are lacking. Sometimes only the
adrenal gland is affected, as in idiopathic
adrenal insufficiency sometimes other glands
also are affected, as in the polyendocrine
deficiency syndrome.
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Causes Tuberculosis TB an infection which can
destroy the adrenal glands, accounts for about
20 of cases of primary adrenal insufficiency in
developed countries. When adrenal insufficiency
was first identified by Dr. Thomas Addison in
1849, TB was found at autopsy in 70 -90 of
cases. As the treatment for TB improved,
however, the incidence of adrenal insufficiency
due to TB of the adrenal glands has greatly
decreased.
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Other Causes Less common causes of primary
adrenal insufficiency are chronic infection,
mainly fungal infections cancer cells spreading
from other parts of the body to the adrenal
glands surgical removal of the adrenal glands
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Secondary Adrenal Insufficiency This form of
adrenal insufficiency is much more common than
primary adrenal insufficiency and can be traced
to a lack of ACTH. Without ACTH to stimulate the
adrenals, the adrenal glands' production of
cortisol drops, but not aldosterone. A
temporary form of secondary adrenal insufficiency
may occur when a person who has been receiving a
glucocorticoid hormone such as prednisone for a
long time abruptly stops or interrupts taking the
medication. Glucocorticoid hormones block the
release of both CRH and ACTH.
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Treatment Treatment of Addison's disease
involves replacing, or substituting, the hormones
that the adrenal glands are not making. Cortisol
is replaced orally with hydrocortisone tablets, a
synthetic glucocorticoid, taken once or twice a
day. If aldosterone is also deficient, it is
replaced with oral doses of a mineralocorticoid
called fludrocortisone acetate (Florinef), which
is taken once a day. Patients receiving
aldosterone replacement therapy are usually
advised by a doctor to increase their salt
intake. Because patients with secondary adrenal
insufficiency normally maintain aldosterone
production, they do not require aldosterone
replacement therapy.
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Treatment During an addisonian crisis, low blood
pressure, low blood glucose, and high levels of
potassium can be life threatening. Standard
therapy involves intravenous injections of
hydrocortisone, saline (salt water), and dextrose
(sugar). This treatment usually brings rapid
improvement.
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