Adrenal Disorders

Rahmi Yosmar, S. Farm, M. Farm, Apt
Potongan melintang:
 Cortex ( luar)
 Berfungsi untuk mensekresikan hormon kortikosteroid dan
Tersusun atas 3 zona (lapisan) :
Z. glomerulosa ( luar)
Z. faciculata (tengah)
(cortison,cortisol,corticosteron) bersama Z.
Z. reticularis (dalam)
Medula (dalam)
 Menghasilkan katekolamin
 Mensekresikan hormon epinefrin dan norepinefrin
Fungsi hormon-hormon yang dihasilkan oleh
kelenjar adrenal :
1. Aldosteron
Its main function is to regulate the amount of
potassium, and sodium passed into the urine. Its
production is controlled by the renin angiotensin system
(RAS) or renin angiotensin aldosterone system (RAAS).
This is a hormone system that regulates blood pressure
and fluid balance in the body. Generally renin is
produced by the kidneys in the conditions of excess loss
of salt and water from the body.
2 . Corticosterone and Hydrocortisone
Corticosteroids are released from the cortex
region of the adrenal glands. Corticosteroid hormones
secreted by the adrenal glands include hydrocortisone
hormone and corticosterone. Hydrocortisone or cortisol
regulates carbohydrate, protein and fat metabolism.
Both hydrocortisone and corticosterone play important
roles in regulating the inflammatory response of the
body. Corticosterone can also affect the immune system,
and hence can be used as an immune suppressing agent.
Its secretion is controlled by the adrenocorticotropic
hormone (ACTH), secreted by the pituitary gland.
3. Androgenic steroids
Androgenic steroids or androgens are secreted by the
reticularis zone (innermost layer) of the adrenal cortex. They are the
male sex hormones and are responsible for the development of male
characteristics. They play a crucial role in the development of male sex
organs during embryonic development.
4. Epinephrine and norepinephrine
Commonly known as adrenaline. They are called
catecholamines, as they are released by the adrenal glands in
response to physical or mental stress. Epinephrine, also known as
adrenaline plays an important role in the conversion of glycogen into
glucose. It is also required by the body for the smooth flow of blood to
the brain and the muscles. Besides, it also increases the heart rate and
relaxes the smooth muscles of the lungs and digestive system
decreases blood sugar level. It also causes dilation of the small
arteries of the heart, lung, kidneys and muscles.
• Cushing's disease is a condition of hypercortisolemi caused due to
excessive production of ACTH from a pituitary adenoma.
• Cushing's syndroma hypercortisolemia is a condition resulting from a
variety of sources other than the pituitary
Clinical manifestations:
The most common findings in patients with Cushing’s syndrome,
which are present in 90% of patients, are central obesity and facial
Hypertension is seen in 75% to 85% of patients, with diastolic blood
pressures greater than 119 mm Hg noted in over 20% of patients.
About 50% to 60% of patients will develop Cushing’s-induced
osteoporosis. Of these, 40% will present with back pain and
20% will progress to compression fractures of the spine.
Gonadal dysfunction is common, with amenorrhea seen in up to
75% of females.
Excess androgen secretion is responsible for 80% of females
presenting with hirsutism.
• About 65% and 58% of patients complain of myopathies
(sakit pada otot) and muscular weakness, respectively.
• Amidnight plasma cortisol, 24-hour urine free cortisol, and/or
low-dose Dexamethasone Suppresion Test (DST) will establish
the presence of hypercorticalism.
• The high-dose DST, plasma ACTH test, metyrapone stimulation
test, and CRH stimulation test will help determine the etiology.
• The etiology of the disease is identified, the treatment
of choice for both ACTH-dependent and ACTHindependent
• Cushing’s syndrome is surgical resection of any
offending tumors.
• However, several pharmacologic secondary treatment
plans are available, depending on the etiology of the
• Pharmacologic agents that may be used to
manage the patient with Cushing’s syndrome
 Steroidogenic in-hibitors : metyrapone,
aminoglutethimide, and ketoconazole
 Adrenolytic agents : mitotane
 Neuromodulators of ACTH release :
cyproheptadine, bromocriptine, valproic acid,
ritanserin, and octreotide
 Glucocorticoid-receptor blocking agents :
• Metyrapone inhibits 11-hydroxylase activity, resulting
in inhibition of cortisol synthesis.
• Nausea, vomiting, vertigo, headache, dizziness,
abdominal discomfort, and allergic rash have been
reported following administration.
• Aminoglutethimide inhibits the conversion of cholesterol
to pregnenolone early in the cortisol pathway.
• Plasma cortisol con-centrations are reduced by up to
50% following aminoglutethimide therapy. Side effects
include severe sedation, nausea, ataxia, and skin
• The imidazole derivative antifungal ketoconazole is highly
effective in lowering cortisol in Cushing’s disease, resulting in
normal corticosteroid values in 84% of patients, with an
additional 11% of patients reporting improvement. Patients
can be maintained successfully for months to years on
ketoconazole therapy.
• In addition to lowering serum cortisol levels, ketoconazole can
cause gynecomastia and lower plasma testosterone values.
** Gynecomastia : Excessive development of the male
mammary glands, even to produce milk. This is caused
by a metabolic disorder that causes accumulation of
estrogen, testosterone deficiency, and
• Mitotane is a cytotoxic drug
• Mitotane inhibits the 11-hydroxylation of 11-desoxycortisol and
11-desoxycorticosterone in the cortex.
• The net result is a reduced synthesis of cortisol and
corticosterone. It decreases the cortisol secretion rate, plasma
cortisol concentrations, urinary free cortisol, and plasma
concentrations of the 17-substituted steroids.
• Cyproheptadine can decrease ACTH secretion in the Cushing’s
disease patient. Morning plasma cortisol concentrations, as well
as 24-hour urinary cortisol (free) concentrations should be
• Side effects are minor and include sedation and hyperphagia.
Cypro-heptadine should be reserved for nonsurgical candidates
who fail more conventional therapy. Because the response rate
is no more than 30%, patients should be followed closely for
• Spironolactone, a competitive inhibitor of aldosterone, is the
drug of choice in bilateral adrenal hyperplasia (BAH)dependent hyperaldosteronism.
• Spironolactone can provide symptomatic relief of the
hypertension and hypokalemia often seen in Cushing’s
• Secondary adrenal insufficiency usually results from exogenous
steroid use, leading to hypothalamic-pituitary-adrenal (HPA)axis suppression followed by a decrease in ACTH re-lease, and
low levels of androgens and cortisol.
• Virilism results from the excessive secretion of androgens from
the adrenal gland and is usually seen as hirsutism in females.
• ** Excessive growth of facial or body hair in women caused
excess of androgen is called hirsutism.
• Addison’s disease (primary adrenal insufficiency) is a
deficiency in cortisol, aldosterone, and various
androgens resulting from the loss of function of all
regions of the adrenal cortex.
Sympotoms :
The most common symptoms are fatigue, muscle
weakness, fever, weight loss, difficulty in standing
up, anxiety, nausea, vomiting, diarrhea,
headache, sweating, changes in mood and
personality, and joint and muscle pains.
Clinical Sign :
Low blood pressure
• Most people with primary Addison's have darkening
(hyperpigmentation) of the skin, including areas not exposed to the
sun; characteristic sites are skin creases (e.g. of the hands), nipple,
and the inside of the cheek (buccal mucosa); also, old scars may
darken. This occurs because melanocyte-stimulating hormone (MSH)
and adrenocorticotropic hormone (ACTH) share the same precursor
molecule, pro-opiomelanocortin (POMC). After production in anterior
pituitary gland, POMC gets cleaved into gamma-MSH, ACTH and
beta-lipotropin. The subunit ACTH undergoes further cleavage to
produce alpha-MSH, the most important MSH for skin pigmentation.
In secondary and tertiary forms of Addison's, skin darkening does not
• Medical conditions, such as type I diabetes, thyroid disease
(Hashimoto's thyroiditis and goiter), and vitiligo often occur together
with Addison's (often in the setting of autoimmune polyendocrine
syndrome). Hence, symptoms and signs of any of the former
conditions may also be present in the individual with Addison's. The
occurrence of Addison's disease in someone who also has Hashimoto's
thyroiditis is called Schmidt syndrome.
• The short cosyntropin stimulation test can be used to
assess patients suspected of hypercortisolism.
• Other tests include the insulin hypoglycemia test, the
metyrapone test, and the corticotropin releasing
hormone stimulation test.
• Treatment of Addison’s disease must include
adequate patient education, so that the patient
is aware of treatment complications, expected
outcome, missed doses, and drug side effects.
• The agents of choice are prednisone,
hydrocortisone, and cortisone, administered
twice daily with the treatment objective being
the establishment of the lowest effective dose
while mimicking the normal diurnal adrenal
rhythm. Usually a twice-daily dosing schedule is
adequate with the dose depending on the
agent used.
• Recent studies indicate that the daily cortisol
• varies between 5 and 10 mg/m2 Hence, the 12- to
15-mg/m2 per day rule for cortisol supplementation,
which is roughly equivalent to 15 to 25 mg of
hydrocortisone or 25 to 37.5 mg of cortisone acetate
• A morning dose of cortisone (20 mg), hydrocortisone
(15 mg), or prednisone (2.5 mg) followed by an
evening dose of the same agent at 33% to 50% of
the morning dose is usually sufficient to duplicate the
normal circadian rhythm of cortisol production.
• To replace the mineralocorticoid loss, fludrocortisone
acetate can be used. A dose of 0.05 to 0.2 mg by
mouth once a day is adequate.
• If parenteral therapy is needed, 2 to 5 mg of
deoxycorticosterone trimethylacetate in oil
intramuscularly every 3 to 4 weeks can be used. The
main reason for adding the mineralocorticoid is to
minimize the development of hyperkalemia.
• In general, most steroids given by the oral route are well
absorbed. Water-soluble agents are more rapidly
absorbed following intramuscular injection than are lipidsoluble agents. Intravenous administration is recommended
when a quick onset of action is needed.
• In addition to systemic steroids causing iatrogenic Cushing’s
syndrome, they also can lead to increased susceptibility to
infection, osteoporosis, sodium retention with resultant
edema, hypokalemia, hypomagnesemia, cataracts, peptic
ulcer disease, seizures, and generalized suppression of the
HPA-axis. Long-term complications tend to be insidious and
less likely to respond to steroid withdrawal.
Therefore, long-term steroid use, should not be
abruptly discontinued. It should tapering dose, it’s
means the lower the dose slowly.
• Pituitary Gland
The largest endocrine glands, called the master
gland, because it affects the activity of other glands.
• The pituitary gland is composed of 3 lobes :
• Lobes anterior : TSH, ACTH, FSH, LH, ICSH dan
• Lobes Intermedia : Somatotropin (GH), MSH,
• Lobes posterior : oxytocin, vasopresin (ADH)
• Acromegaly is a pathologic condition characterized by
excessive production of growth hormone.
• Growth only occurs in the pipeline such as the finger
bone, chin.
• Gigantisme : condition of growth hormone excess
person, with a big high and exceed the normal limits.
Differences acromegaly with gigantism:
If acromegaly growing slowly, otherwise gigantism
develops suddenly and very quickly.
• Clinical manifestations gigantism:
Rapid linear growth
Coarse facial markings
Enlargement of the feet and hands
Some problems in vision
Abnormal growth develops at puberty
Can grow to a height of 8 feet or more
1. Surgery: depending on the size of the tumor
2. Radiation beneficial for tumor shrinkage, lowering
levels of GH
3. Pharmacologic treatment : options include dopamine
agonists, somatostatin analogs, and the GH receptor
antagonist, pegvisomant. Dopamine agonists such as
bromocriptine, pergolide, or cabergoline are effective in a
small sub-set of patients and provide the advantages of
oral dosing and reduced cost. Somatostatin analogs are
more effective than dopamine agonists, reducing GH
concentrations and normalizing IGF-I in approximately 50%
to 60% of patients. Pegvisomant is a newly approved GH
receptor antagonist that is highly effective, normalizing IGFI concentrations in up to 97% of patients
• Short stature is a very broad term describing a condition
that may be the result of many different causes. A true
lack of GH is among the least common causes and is known
as growth-hormone-deficient (GHD) short stature.
• Absolute GH deficiency is a congenital disorder that can
result from various genetic abnormalities such as GHRH
deficiency, GH gene deletion, or developmental disorders
including pituitary aplasia or hypoplasia.
• GH insufficiency is an acquired condition that can result
secondary to hypothalamic or pituitary tumors, cranial
irradiation, head trauma, pituitary infarction, and various
types of CNS infections.
• Pharmacologic agents such as glucocorticoids,
methylphenidate, and dextroamphetamine may induce
transient GH insufficiency.
• Short stature also occurs with several conditions that
are not associated with a true GH deficiency or
insufficiency. These conditions include constitutional
growth delay; malnutrition; malabsorption of nutrients
associated with inflammatory bowel disease, and
cystic fibrosis; chronic renal failure; skeletal and
cartilage dysplasia; and genetic syndromes.
• Children with GHD short stature are usually born with
an average birth weight. Decreases in growth velocity
generally become evident between the age of 6
months and 3 years
• Somatrem (Protropin) was the first recombinant GH product
developed and used for the treatment of GH deficiency. This
formulation contains the same 191-amino-acid sequence as
human pituitary growth hormone.
• The remaining GH formulations (Genotropin, Norditropin,
Nutropin, Nutropin AQ, Nutropin Depot, Humatrope, Serostim,
and Saizen) contain somatropin. Somatropin is composed of
the same amino acid sequence as human pituitary GH.
Recombinant GH formulations must be administered by
intramuscular or subcutaneous injection. Nutropin AQ is the
only GH product that is available as a liquid formulation. The
remaining products are formulated as lyophilized powders
for injection, and patients must be instructed regarding
proper reconstitution, storage, and administration.
• Asynthetic growth hormone-releasing hormone (GHRH)
product known as sermorelin (Geref ) is currently FDA
approved for the treatment of idiopathic growth
hormone deficiency in children.
• Hyperprolactinemia has several etiologies. The most common
• causes are benign prolactin-secreting pituitary tumors, known as
prolactinomas, and various medications.
• Hyperprolactin can stop the menstrual cycle, making the breasts
produce milk and become flabby and lead to infertility.
• Treatment options for the management of prolactinomas include
clin-ical observation, medical therapy with dopamine agonists,
radiation therapy, and transsphenoidal surgical removal of the
• Medical therapy with dopamine agonists is usually more ef-fective
than transsphenoidal surgery for both types of pituitary
• In most cases, medical therapy with dopamine agonists is
considered the most effective treatment. Cabergoline has
replaced bromocriptine as the mainstay of medical therapy, as it
appears to be better tolerated and more effective.
• However, due to limited data regarding the safety of cabergoline
during pregnancy, bromocriptine remains the preferred agent
when fertility is the primary purpose for treatment.
Thank You