Adrenal Gland

Disorders

Rahmi Yosmar, S. Farm, M. Farm, Apt

Anatomi

Fisiologi Kelenjar Adrenal

Potongan melintang: Cortex ( luar)

Berfungsi untuk mensekresikan hormon kortikosteroid dan androgen

Tersusun atas 3 zona (lapisan) :Z. glomerulosa ( luar) minerakortikoid

(aldosteron)Z. faciculata (tengah) glukokortikoid

(cortison,cortisol,corticosteron) bersama Z. reticularis

Z. reticularis (dalam) androgenMedula (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 HydrocortisoneCorticosteroids 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 steroidsAndrogenic 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 norepinephrineCommonly 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.

HYPERFUNCTION OF THE ADRENAL GLAND

• 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 rounding.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.

SYMPTOMS• About 65% and 58% of patients complain of

myopathies (sakit pada otot) and muscular weakness, respectively.

LABORATORY TESTS• Amidnight plasma cortisol, 24-hour urine free

cortisol, and/or low-dose Dexamethasone Suppresion Test (DST) will establish the presence of hypercorticalism.

OTHER DIAGNOSTIC TESTS• The high-dose DST, plasma ACTH test,

metyrapone stimulation test, and CRH stimulation test will help determine the etiology.

TREATMENT: Cushing’s Syndrome

• The etiology of the disease is identified, the treatment of choice for both ACTH-dependent and ACTH-independent

• Cushing’s syndrome is surgical resection of any offending tumors.

• However, several pharmacologic secondary treatment plans are available, depending on the etiology of the disease

• Pharmacologic agents that may be used to manage the patient with Cushing’s syndrome include:

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 : mifepristone

• 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 rashes.

• 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 hyperprolactinemia

• 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 monitored.

• 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 relapses.

• 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 syndrome.

• 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.

HYPOFUNCTION OF THE ADRENAL GLAND

• 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 pressureHyperpigmentation

• 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 occur.

• 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.

LABORATORY TESTS• The short cosyntropin stimulation test can

be used to assess patients suspected of hypercortisolism.

OTHER DIAGNOSTIC TESTS• 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 production

• 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 daily.

• 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.

PRINCIPLES OF GLUCOCORTICOIDADMINISTRATION

• In general, most steroids given by the oral route are well absorbed. Water-soluble agents are more rapidly absorbed following intramuscular injection than are lipid-soluble 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 DISORDERS

• 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 prolactin•Lobes Intermedia : Somatotropin (GH), MSH,•Lobes posterior : oxytocin, vasopresin (ADH)

GROWTH HORMONE EXCESS

• 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 growthCoarse facial markingsEnlargement of the feet and handsSome problems in visionAbnormal growth develops at pubertyCan grow to a height of 8 feet or more

Therapy :

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 IGF-I concentrations in up to 97% of patients

GROWTH HORMONE DEFICIENCY

• 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

Terapi :• 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• 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.

Therapy :• Treatment options for the management of

prolactinomas include clin-ical observation, medical therapy with dopamine agonists, radiation therapy, and transsphenoidal surgical removal of the tumor.

• Medical therapy with dopamine agonists is usually more ef-fective than transsphenoidal surgery for both types of pituitary prolactinomas

• 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