The main methods of investigation in endocrinology
Adrenals are a pair of triangular structures located
on top of the kidney and weighting approximately
Vascularization: a. renalis superior (from a. phrenica inferior), a. suprarenalis media (from aorta abdominalis), a suprarenalis inferior (from a. renalis). Innervation: n. splanchnicus major (through plexus celiacus and plexus renalis), fibrae n. vagus and n. phrenicus).
Anatomy of adrenal glands
The adrenals are divided into an outer area, the cortex, which accounts for about four fifth of the gland, and inner area or medulla. The cortex originates from mesodermal tissue and the medulla from the ectodermal tissue.
Adrenal cortex include three zones:
Pict. Structure of adrenals.
- Glomerular (glomerulosa) (produces mineralocorticoids (e.g., aldosterone));
- fascicular (fasciculata) (produces glucocorticoids (e.g., cortisol (hydrocortisone)));
- reticular (reticularis) (produces cortisol and androgens (dehydroisoandrosterone (dehydroepiandrosterone)), which exert their chief physiologic activity after conversion to testosterone and dihydrotestosterone).
- A fetal zone, unique to primates, produces dehydroepiandrosterone, a precursor of both androgens and estrogens. This zone involutes within the first few months of postnatal life
Action of mineralocorticoids:
- regulation of electrolyte balance in the organism (increasing the level of sodium (by sodium retention in distal nephron, colon, salivary gland) and decreasing the level of potassium (by excretion)).
Action of glucocorticoids:
- increasing of glycogen synthesis in liver and decreasing of glucose utilization by peripheral tissues, increasing gluconeogenesis;
- increasing of protein synthesis in liver and decreasing of its synthesis in muscles and increasing of protein destruction in muscles;
- increasing of lipolisis;
- anti-inflammatory function and immunomodulation;
- cardiovascular regulation (increasing of blood pressure).
Pict. Regulation of secretion of glucocorticoids
Cortisol secretion is regulated by ACTH, which, in turn, is regulated by CRH from the hypothalamus. Serum cortisol inhibits secretion of CRH and ACTH, thus preventing excessive secretion of cortisol from the adrenal glands. Adrenal androgen secretion is regulated partially by ACTH but also by other unknown factors. ACTH not only stimulates cortisol secretion, it also promotes growth of the adrenal cortex in conjunction with growth factors such as insulinlike growth factor (IGF)-1 and IGF-2.
The cortisol levels in the blood show a circadian rhythm.
Regulation of aldosterone synthesis in the human body.
Humans possess two mitochondrial 11 β-hydroxylase isoenzymes that are responsible for cortisol and aldosterone synthesis (designated CYP11B1 and CYP11B2). Both are encoded on chromosome 8. CYP11B1, which is responsible for conversion of 11-deoxycortisol to cortisol, is expressed only in the zona reticularis. CYP11B2, which is responsible for the conversion of corticosterone to aldosterone, is expressed only in the zona glomerulosa. CYP11B1 activity is stimulated by ACTH, whereas CYP11B2 is stimulated by angiotensin II or hypokalemia.
Adrenal medulla produces catecholamines. (Catecholamines are produced from the tyrosine (organism takes it from the meal or from the phenilalanine in the liver) → dioxyphenilalanine (DOPHA) → dopamine (it goes into blood only from some neurons of the central nervous system) → norepinephrine (noradrenaline) (it goes into blood only from sympathetic teleneurons) → epinephrine (adrenaline) (it goes into blood only from adrenal medulla). The principle urinary metabolic products of epinephrine and norepinephrine are the metanephrines and vanillylmandalic acid (VMA).
Action of catecholamines:
- modulate vascular tone;
- increase heart rate;
- antagonize insulin action.
Regulation of secretion of catecholamines:
- mineralocorticoids’ secretion is regulated by the renin – angiotensin system, the level of Na+, K+ in blood, and to a lesser extent of ACTH.
Chronic adrenocortical insufficiency
It is an insidious and usually progressive disease resulting from adrenocortical hypofunction.
The calculated incidence is approximately 5-6 cases per million persons per year.
Adrenal insufficiency is a potentially fatal disease if unrecognized and untreated. Death usually results from hypotension or cardiac arrhythmia secondary to hyperkalemia.
Race: Adrenal insufficiency exhibits no racial predilection.
· Autoimmune adrenal insufficiency is more common in females than males.
· Adrenal insufficiency due to adrenoleukodystrophy is limited to males because it is X-linked, as is a form of congenital adrenal hypoplasia, termed adrenal hypoplasia congenita (AHC). Both conditions are relatively rare.
· Secondary adrenal insufficiency due to a deficiency of ACTH or CRH, or to a lack of ACTH receptors, is equally common among males and females.
Age: Autoimmune adrenal insufficiency is more common in adults than in children. Congenital causes, such as congenital adrenal hyperplasia (CAH), congenital adrenal hypoplasia, and defects in the ACTH receptor, are more commonly recognized in childhood.
1. Primary adrenocortical insufficiency (Addison’s disease).
2. Secondary adrenocortical insufficiency .
Primary adrenal insufficiency occurs when the adrenal gland itself is dysfunctional. Secondary adrenal insufficiency, also termed central adrenal insufficiency, occurs when lack of corticotropin-releasing hormone (CRH) secretion from the hypothalamus or adrenocorticotropic hormone (ACTH) secretion from the pituitary is responsible for hypofunction of the adrenal cortex. Adrenal insufficiency can be classified further as congenital or acquired.
primary adrenocortical insufficiency:
1. In developed countries, the most common cause is autoimmune destruction (50 – 65 %) of the adrenal cortex. This disorder may exist in isolation or may be part of a polyglandular autoimmune disorder
- Type 1 autoimmune polyglandular disease presents in the first decade of life and is transmitted as an autosomal recessive disorder with all or some of the following:
o Adrenal failure
o Gonadal failure
o Diabetes mellitus type 1
o Pernicious anemia
o Chronic mucocutaneous candidiasis
- Type 2 autoimmune polyglandular disease consists of type 1 diabetes mellitus, autoimmune thyroid disease, and adrenal failure. This condition presents in the second and third decades of life and is transmitted as an autosomal disorder with variable penetrance.
2. Less common causes of adrenal failure include the following:
Pic. Normal adrenal glands pic. Pic. Tuberculosis destruction of adrenal glands
(Photograph © 1993 Joseph R. Siebert/Custom Medical Stock Photo.)
2) neoplasm, metastatic carcinoma;
3) inflammatory necrosis;
5) bilateral adrenal hemorrhage or infarction, intra – adrenal hemorrhage (Waterhouse – Friedrichsen syndrome following meningococcal septicemia);
6) heamochromatosis (may cause either primary or secondary adrenal insufficiency. Iron deposition in the pituitary and/or adrenal glands in multiply transfused patients with thalassemia patients also may cause adrenal insufficiency);
7) bilateral adrenalectomy;
3. Congenital primary adrenal insufficiency
o Congenital disease may occur from adrenal hypoplasia or hyperplasia.
o Adrenal hypoplasia congenita (AHC), inherited as an X-linked disorder, is caused by deletion of the DAX1 gene on chromosome X and often is part of a contiguous gene deletion that involves glycerol kinase deficiency, Duchenne muscular dystrophy, and hypogonadotropic hypogonadism. An alternate form, also X-linked, has been described characterized by intrauterine growth retardation and skeletal and genital anomalies. A third form of AHC is autosomal recessive.
o CAH results from a deficiency of 1 of several enzymes required for adrenal synthesis of cortisol. Adrenal insufficiency most often develops with combined deficiencies of cortisol and aldosterone. The most prevalent form of CAH is caused by a steroid 21-hydroxylase deficiency.
o Lipoid adrenal hyperplasia is another rare form of adrenal insufficiency caused either by a mutation in the steroid acute regulatory protein or a mutation in the cholesterol side chain cleavage gen. This disease causes a defective synthesis of all adrenocortical hormones and, in its complete form, is lethal.
o Mutations or deletions of P450 oxidoreductase, a flavoprotein that provides electrons to various enzyme systems, results in combined deficiencies of 17 hydroxylase, 21 hydroxylase, and 17-20 lyase activities resulting in adrenal insufficiency often accompanied by primary hypogonadism.
secondary adrenocortical insufficiency:
1) Most cases are iatrogenic, caused by long-term administration of glucocorticoids. A mere 2 weeks' exposure to pharmacological doses of glucocorticoids can cause CRH-ACTH-adrenal axis suppression. Suppression can be so great that acute withdrawal or stress may prevent the axis from responding with sufficient cortisol production to prevent an acute adrenal crisis. Recently, treatment with megesterol acetate, an orixegenic agent, has resulted in iatrogenic adrenal suppression, presumably through glucocorticoid properties of megesterol acetate.
2) hypothalamic or pituitary disease (primary injury of these organs leads to insufficiency of ACTH secretion that cause the two – side atrophy of adrenal glands).
Cortisol deficiency contributes to the hypotension and produces in carbohydrate, fat, and protein metabolism, and severe insulin sensitivity. In the absence of cortisol, insufficient carbohydrate is formed from protein; hypoglycemia and diminished liver glycogen result. Weakness, due in part to deficient neuromuscular function follows. Resistance to infection, trauma, and other stress is diminished because of reduced adrenal output. Cardiac output is reduced and circulatory failure can occur. Reduced cortisol blood levels result in increased pituitary ACTH production and an increase in beta – lipotropin, which has melanocyte – stimulating activity and produces the hyperpigmentation of skin and mucous membranes characteristic of Addison’s disease.
There is increased excretion of Na and decreased excretion of K chiefly in the urine, but also in the sweat, saliva, and gastrointestinal tract. Low blood concentrations of Na and Cl and high serum K result. These changes in electrolyte balance produce increased water excretion with severe dehydration, increased plasma concentration, decreased circulatory volume, hypotension, and circulatory collapse.
Symptoms and signs.
Presentation may be acute and chronic. Frequently clinical signs of the primary chronic adrenocortical insufficiency are manifested in that time when adrenocortical tissue is destroyed on 70-90 %.
The most common complaints are: weakness, malaise, weight loss, anorexia, depression.
1. Increased pigmentation (in patients with primary adrenal insufficiency) is characterized by diffuse tanning of both exposed and nonexposed portions of the body, especially on pressure points (bony prominences), skin folds, scars, and extensor surfaces, black freckles over the forehead, face, neck, and shoulders; bluish – black discoloration of the areolas and the mucous membranes of the lips, mouth, rectum and vagina are common. After compensation hyperpigmentation will decrease. Patients in 15 – 20 % of cases may have areas of vitiligo (depigmentation) as the sign of autoimmune process.
2. Hypotension or postural hypotension (88 – 90 %) with syncopal attacks can occur.
4. Weight loss (due to dyspeptic syndrome, true muscle tissue catabolism, dehydration).
5. Anorexia, nausea, vomiting, abdominal pain, diarrhea are often. Gastritis, ulcer disease can occur.
6. Decreased cold tolerance, with hypometabolism may be noted.
7. Sexual disorders.
8. Neurologic and psychiatric disorders: decreasing of the memory, mental activity, concentration of attention, depressions, hallucinations can occur due to chronic hypoglycemia which leads to changes of metabolism in brain tissue.
There are three stages of severity: mild, moderate and severe.
· Clinical suspicion is important because presentation of the disorder may be insidious and subtle. When adrenal insufficiency is suspected, the following laboratory studies help establish the diagnosis:
o Fasting blood sugar
o Serum ACTH
o Plasma renin activity
o Serum cortisol
o Serum aldosterone
1. A low serum Na level and a high serum K level together with a characteristic clinical picture suggest the possibility of Addison’s disease.
2. Adrenal insufficiency can be specifically diagnosed by:
- low levels of plasma glucocorticoids and mineralocorticoids, or urinary 17 – hydroxycorticosteroid (17 – OHCS) or 17 – ketogenic steroid (17 – KGS);
- demonstrating failure to increase plasma cortisol levels, or urinary 17 – OHCS or 17 – KGS excretion, upon administration of ACTH (in patients with primary adrenal insufficiency).
3. To distinguish between primary and secondary adrenal insufficiency, me have to find the level of plasma ACTH: primary shows increased, and secondary shows decreased level: when plasma ACTH determination is not available, 0.25 mg of cosyntropin or depo-senacten(a synthetic ACTH that has fewer side effects than the natural preparations) may be infused IV (after dilution with dextrose or sodium chloride solution) over a period of 8 h daily for 2 days. Patients with primary adrenocortical insufficiency will show a little or no increase in plasma cortisol or 24 - h urinary corticosteroid levels. Those with secondary adrenocortical insufficiency will have a significant increase in plasma cortisol or 24 - h urinary corticosteroid levels.
· So, when hyponatremia or hyperkalemia is found, conduct a spot urine or 24-hour urine test for sodium, potassium, and creatinine, along with a simultaneous serum creatinine test to determine whether inappropriate natriuresis is occurring.
o Interpret random serum cortisol concentrations within the context from which they were obtained. (For example, adrenal insufficiency is unlikely in an otherwise healthy individual with an 8:00 am serum cortisol concentration more than 10 mcg/dL. Yet a serum cortisol concentration less than 18 mcg/dL in a sick and stressed patient highly suggests adrenal insufficiency.)
o A diagnosis of adrenal insufficiency is confirmed by a serum cortisol concentration less than 18 mcg/dL in the presence of an elevated serum ACTH concentration and plasma renin activity, or a concentration lower than that level obtained 60 minutes following cosyntropin administration.
o Diagnosis also is confirmed when serum cortisol concentrations fail to increase to more than 18-20 mcg/dL by 60 minutes following cosyntropin administration.
o Note that these guidelines do not apply to premature and low birth weight infants, who have much lower cortisol secretion.
· If serum cortisol is low with elevated ACTH, measure antiadrenal antibodies. Antibodies to 1 or more steroidogenic enzymes, particularly 21-hydroxylase, often are found in autoimmune adrenal disease.
· Cosyntropin administration is controversial because whether the best dose is the standard 250 mcg, the 1 mcg, or the low 0.5 mcg/m2 is unresolved, particularly in the pediatric age group. The standard dose, therefore, is suggested. The common preparation of cosyntropin makes it cumbersome to deliver 1 mcg or less, and both doses seem supraphysiological.
· When serum cortisol response to cosyntropin is subnormal, but serum ACTH is not elevated, confirm the possibility of central adrenal insufficiency. In this context, a 6-hour or 3-day treatment with ACTH can produce a normal cortisol response, confirming that initial low cortisol response to cosyntropin was related to chronic ACTH deficiency. The dose of ACTH for the 6-hour test is 25 IU administered IV over the 6 hours. If the 3-day test is chosen, administer 25 mg/m2 of ACTH gel IM every 12 hours for the 3 days. Plasma cortisol should increase to more than 40 mcg/dL in response to either of these tests. Alternatively, 24-hour urinary 17-hydroxysteroid concentrations should increase 5-10 fold in response to the 3-day ACTH stimulation test.
· If the patient has recent onset (ie, <10 d) of central adrenal insufficiency (as in a recent surgery in the hypothalamus or pituitary regions), resorting to a more cumbersome and risk-bearing insulin tolerance test or metyrapone stimulation test may be preferable. These conditions are the only real indication for performing these tests in a patient with adrenal insufficiency
· An insulin tolerance test requires IV administration of insulin (usually 0.05-0.15 units regular insulin/kg) to induce a 50% drop in blood sugar. Measure cortisol and glucose concentrations every 15 minutes for 60 minutes. The test is considered adequate if the blood sugar drops by at least 50%. In response to this hypoglycemic stimulus, serum or plasma cortisol concentrations should rise to more than 20 mcg/dL. This test involves some risk of hypoglycemic seizure; therefore, closely monitor the patient and reverse the hypoglycemia if the patient becomes overly symptomatic.
· Standard metyrapone stimulation tests involve administering 300 mg/m2 metyrapone in 6 divided doses over 24 hours. Because metyrapone inhibits 11-hydroxylase, the last enzyme step in cortisol synthesis, the cortisol precursor 11-deoxycortisol increases in the plasma. A normal response is a rise in 11-deoxycortisol concentrations to more than 10.5 mcg/dL 4 hours following the last dose of metyrapone or a 2- to 3-fold increase in 24-hour urinary 17-hydroxycorticosteroid concentrations (which include tetrahydro compound S [urinary metabolite of 11-deoxycortisol]), on the day or day following metyrapone administration. This test is cumbersome and carries some risk of inducing an adrenal crisis.
· When primary adrenal insufficiency is confirmed, antiadrenal antibodies can confirm an autoimmune cause for the disorder. If the test results for antiadrenal antibodies are negative, search for another etiology such as TB, adrenal hemorrhage, or adrenoleukodystrophy.
· The standard ovine or human CRH stimulation test is reliable in the diagnosis and differential diagnosis of adrenal insufficiency.
o Patients with glucocorticoid deficiency of any etiology have subnormal cortisol responses.
o Patients with primary glucocorticoid deficiency have elevated ACTH concentrations basally and after CRH administration.
o Patients with secondary glucocorticoid deficiency have low ACTH levels throughout the test if they suffer from a primary pituitary deficiency, or these patients have exaggerated responses if their problem is tertiary.
1. ECG: K > 6.5 mEq/L causes further slowing of conduction with widening of the QRS interval, disappearance of the P wave, and nodal and escape ventricular arrhythmias. Finally, the QRS complex degenerates into a sine wave pattern, and ventricular fibrillation or asystole ensues.
2. The EEG shows alized slowing of the α – rhythm.
3. CT is the imaging study of choice and helps identify adrenal hemorrhage, calcifications, or infiltrative disease. MRI is not as useful as CT.
4. Abdominal radiographs may reveal bilateral adrenal calcifications, which suggest a history of bilateral adrenal hemorrhage, TB, or Wolman disease.
5. Ultrasonography is a poor imaging modality for investigation of the adrenal glands.
6. Iodocholesterol scanning is not particularly useful.
· CT-guided fine-needle aspiration sometimes helps diagnose the etiology of infiltrative adrenal diseases.
Findings depend on the underlying cause. In cases of autoimmune adrenal failure, the adrenal gland is destroyed by lymphocytic infiltration. Granulomatous changes within the adrenal glands indicate tuberculous adrenal insufficiency. Neoplastic infiltrations are caused by metastatic tumors. Hemorrhagic adrenal insufficiency shows hemorrhagic destruction of adrenals. Fungal disease produces typical pictures.
- primary and secondary adrenocortical insufficiency (patients with secondary adrenal insufficiency are not hyperpigmented, they have relatively normal electrolyte values; those with panhypopituitarism have depressed thyroid and gonadal function; tests to differentiate primary and secondary adrenal insufficiency were discussed earlier);
Primary and secondary
- hyperpigmetation due to bronchogenic carcinoma, ingestion of heavy metals such as iron or silver, chronic skin conditions or hemochromatosis; Peutz – Jeghers syndrome (pigmentation of the buccal and rectal mucosa);
- neuropsychiatric weakness;
- anorexia nervosa:
- diseases of the gastrointestinal tract.
I. Etiologic: appropriate treatment of complicating infections (e.g., tuberculosis).
1. Diet (enough quantity of proteins, vitamins, salt and water).
2. Glucocorticoids (normally, glucocorticoids are secreted maximally in the early morning hours, little being secreted at night).
Average dosage is:
- cortisol: 20 – 25 mg daily;
- prednisolone 5 – 7.5 mg daily;
- hydrocortisone 30 – 40 mg orally daily.
Louzada P, Sarti W. Corticosteróides. In Campos CAH, Costa HOO, editores. Tratado de Otorrinolaringologia. São Paulo: Roca; 2002. p.243-9.
2/3 of the dose can be given in the morning and 1/3 in the afternoon. Night doses should be avoided, as they may produce insomnia.
DOCSA 5 mg orally daily should be used in patients with severe and moderate duration or fludrocortisone 0.1 – 0.2 mg orally once a day is recommended (this mineralocorticoid replaces aldosterone, some times it is necessary to reduce the dose to 0.05 mg every 2nd day on initial institution of therapy because of ankle edema, but the patient usually adjusts and can then take the larger doses)
4. Intercurrent illnesses (e.g., infections) should be regarded as potentially serious and the patient should double his dosage until he is well.
5. If nausea or vomiting preclude oral therapy, medical attention should be sought immediately and parental therapy started.
ACUTE adrenocortical insufficiency
is a medical emergency caused by sudden marked insufficiency of adrenocortical hormones.
1) stress (infection (especially with septicemia, trauma, surgery, prolonged fasting, salt loss due to excessive sweating during hot weather);
2) sudden withdrawal of adrenocortical hormone therapy in patients with chronic insufficiency.
An adrenal crisis is characterized by:
- profound asthenia,
- severe pains in the abdomen, lower back or legs;
- nausea, vomiting diarrhea;
- peripheral vascular collapse;
- renal shutdown with azotemia.
- Body temperature may be subnormal, through severe hyperthermia due to infection is often seen.
Therapy should be instituted immediately once a provisional diagnosis of adrenocortical failure has been made.
1) hydrocortisone 100 – 150 mg as a water – soluble
ester (usually the succinate or phosphate) is injected IV over 30 seconds,
followed by infusion of
2) Treatment of complications (hyperpyrexia, psychotic reactions).
With a substitution therapy, the prognosis is excellent and a patient with Addison’s disease should be able to lead a full life.
Types of cancer which occur in the adrenal glands
Carcinomas may arise in the adrenal cortex (adrenocortical carcinomas) or the adrenal medulla (malignant pheochromocytomas). They also may metastasize to the adrenals from other primary sites.
Approximately 50-70% adrenocortical carcinomas secrete steroid hormones, whereas 30-50% are nonfunctioning.
Functioning adrenocortical carcinomas secrete aldosterone, cortisol, or androgens-alone or in combination. Excessive aldosterone (Conn's syndrome) causes hypertension and hypokalemia. Cortisol overproduction results in Cushing's syndrome. Excessive androgen secretion causes hirsutism and virilization in women and precocious puberty in children but is often asymptomatic in men.
Nonfunctioning adrenocortical carcinomas present clinically as abdominal or flank pain or as an adrenal mass discovered incidentally during an imaging procedure.
strongly suggested by tumor size >
Treatment for an adrenocortical carcinoma
The treatment of choice is surgery.
Mitotane, an adrenal cytotoxic agent, has produced partial or complete tumor regression, reduced production of adrenal hormones, and improved survival in nonrandomized, noncontrolled trials.
The combination of mitotane with etoposide, cisplatin, and doxorubicin has shown some promise, but responses to chemotherapy have, in general, been disappointing.
Radiation therapy has not been shown to be effective with these tumors.
What tumors metastasize to the adrenal glands?
The vascular adrenal glands are a frequent site of bilateral metastatic spread from cancers of the lung, breast, stomach, pancreas, colon, and kidney, and from melanomas and lymphomas.
Incidental adrenal masses should be
assessed for evidence of malignancy and excess hormone secretion. Size is the
best predictor of cancer; 25% of masses >
Nonfunctioning masses >
Hormonal active tumors of adrenal glands.
It is a tumor of chromaffin cells that secrete catecholamines.
Pheochromocytoma is a rare catecholamine-secreting tumor derived from chromaffin cells. Tumors that arise outside the adrenal gland are termed extra-adrenal pheochromocytomas or paragangliomas. Because of excessive catecholamine secretion, pheochromocytomas may precipitate life-threatening hypertension or cardiac arrhythmias. If the diagnosis of a pheochromocytoma is overlooked, the consequences could be disastrous, even fatal; however, if a pheochromocytoma is found, it is potentially curable.
The term pheochromocytoma (phios means dusky, chroma means color, and cytoma means tumor) refers to the color the tumor cells acquire when stained with chromium salts.
Etiology is unknown.
In about 80 – 90 % of cases, pheochromocytomas are found in the adrenal medulla, but may also be found in other tissues derived from neural crest cells (e.g., tumors may be found in the paraganglia of the sympathetic chain, retroperitoneally along the course of the aorta, in the carotid body, in the organ of Zuckerkandl (at the aortic bifurcation) in the GU system, in the brain, and in the dermoid cysts.
Pict. Localization of pheochromocytomas.
· Pheochromocytomas are known to occur in certain familial syndromes. These include MEN 2A and 2B, neurofibromatosis (von Recklinghausen disease), and VHL disease. The MEN 2A and 2B syndromes, which are autosomally inherited, have been found to have germline mutations in the ret proto-oncogene. The ret proto-oncogene, located on chromosome 10, encodes a tyrosine kinase receptor involved in the regulation of cell growth and differentiation. Pheochromocytomas occur bilaterally in the MEN syndromes in as many as 70% of cases. Pheochromocytomas occur in 1% of neurofibromatosis cases. VHL syndrome is associated with pheochromocytomas, cerebellar hemangioblastomas, and renal cell carcinoma.
o MEN 2A (Sipple syndrome) is characterized by medullary thyroid carcinoma, hyperparathyroidism, pheochromocytomas, and Hirschsprung disease. Over 95% of cases of MEN 2A are associated with mutations in the ret proto-oncogene affecting 1 of 5 codons in exon 10 (codons 609, 611, 618, 620) or exon 11 (codon 634).
o Medullary thyroid carcinoma, pheochromocytoma, mucosal neurofibromatosis, intestinal ganglioneuromatosis, Hirschsprung disease, and a marfanoid body habitus characterize MEN 2B. A germline missense mutation in the tyrosine kinase domain of the ret proto-oncogene (exon 16, codon 918) has been reported to be present in 95% of patients with MEN 2B.
o Pheochromocytoma, cerebellar hemangioblastoma, renal cell carcinoma, renal and pancreatic cysts, and epididymal cystadenomas are associated with VHL disease. One study found that this syndrome was present in nearly 19% of patients with pheochromocytomas (Neumann, 1993). More than 75 germline mutations have been identified in a VHL suppressor gene located on chromosome 3.
o Congenital anomalies (often benign tumors) of the skin, nervous system, bones, and endocrine glands characterize neurofibromatosis, or von Recklinghausen disease. Only 1% of patients with neurofibromatosis have been found to have pheochromocytomas, but as many as 5% of patients with pheochromocytomas have been found to have neurofibromatosis.
o Other neuroectodermal disorders associated with pheochromocytomas include tuberous sclerosis (Bourneville disease, epiloia) and Sturge-Weber syndrome.
o Pheochromocytomas may produce calcitonin, opioid peptides, somatostatin, corticotropin, and vasoactive intestinal peptide. Corticotropin hypersecretion has caused Cushing syndrome, and vasoactive intestinal peptide overproduction causes watery diarrhea.
1. Paroxysmal form (45 %).
2. Permanent form (50 %):
- with crisis;
- without crises.
3. Latent or silent form (nonsymptomatic).
is due to secretion of one or more of the catecholamine hormones or precursors: norepinephrine (noradrenaline), epinephrine (adrenaline), dopamine.
· Clinical signs
o The most prominent feature is hypertension (paroxysmal in 50% of cases)
o Postural hypotension: This results from volume contraction.
o Hypertensive retinopathy
o Hypertrophy of left ventricle
o Weight loss
Café au lait spots: These are
patches of cutaneous pigmentation, which vary from 1-
o Pulmonary edema
o cold and clammy skin, severe headache, angina, palpitation,
o visual disturbances,
o dyspnea, parasthesias,
o nausea, vomiting, epigastric pain, constipation or diarrhea and a sense of impending doom are common; some or all of these symptoms and signs may occur in any patient.
Duration of hypertensive crisis is variable, lasting from a seconds or few minutes to a days., but 50 % of the paroxysms last less than 15 min. Permanent form of the disease’s duration looks like malignant hypertension. Nonsymptomatic form of the disease is rare.
The severity of the retinopathy and cardiomegaly is often less extensive than might be expected for the degree of hypertension present.
Laboratory features and investigations.
4. An increased 3-h (24-h) urinary excretion of epinephrine, norepinephrine and their metabolic products (VMA or metanephrines).
5. Increased plasma epinephrine, norepinephrine.
CT scanning or MRI of the abdomen for the localization of the adrenal and extra – adrenal tumors is useful.
· Over 90 % of pheochromocytomas are located within the adrenal glands, and 98 % are within the abdomen. Extra-adrenal pheochromocytomas develop in the paraganglion chromaffin tissue of the sympathetic nervous system. They may occur anywhere from the base of the brain to the urinary bladder. Common locations for extra-adrenal pheochromocytomas include the organ of Zuckerkandl (close to origin of the inferior mesenteric artery), bladder wall, heart, mediastinum, and carotid and glomus jugulare bodies.
· Only perform imaging studies after biochemical studies have confirmed the diagnosis of a pheochromocytoma. MRI is preferred over CT scanning. MRI has a reported sensitivity of up to 100% in detecting adrenal pheochromocytomas , does not require contrast, and does not expose the patient to ionizing radiation. MRI is also superior to CT scanning for detecting extra-adrenal pheochromocytomas. Typically, (approximately 70% of cases), pheochromocytomas appear hyperintense on T2-weighted images because of their high water content.
Pict. Abdominal MRI showing right-sided pheochromocytoma
CT scanning of the abdomen has an
accuracy of 85-95% for detecting adrenal masses with a spatial resolution of
· A scan with iodine I 131–labeled metaiodobenzylguanidine (MIBG) is reserved for cases in which a pheochromocytoma is confirmed biochemically but CT scanning or MRI do not show a tumor. The molecular structure of iodine I 123 MIBG resembles norepinephrine and concentrates within adrenal or extra-adrenal pheochromocytomas. This isotope has a short half-life and is expensive. It frequently is used in cases of familial pheochromocytoma syndromes, recurrent pheochromocytoma, or malignant pheochromocytoma. In the United States, only 131I-labeled MIBG is available, whereas 123I MIBG is used in Europe and Japan.
Pict. MIBGscan of left adrenal pheochromocytoma
· A somatostatin receptor analog indium In 111 pentetreotide is less sensitive than MIBG and may be used to visualize pheochromocytomas that do not concentrate MIBG.
· Positron emission tomography (PET) scanning has been used as an imaging modality and has shown promising results. PET of 18F-fluorodeoxyglucose, which is selectively concentrated as part of the abnormal metabolism of many neoplasms, has been demonstrated to detect occult pheochromocytomas. Pheochromocytomas usually show increased uptake on PET scanning, as do adrenal metastases. The most impressive results to date have been with 6-[18F] fluorodopamine PET scanning and carbon 11 hydroxyephedrine PET scanning. Results of these studies suggest that PET scanning performed with both of these radioisotopes is extremely useful in the detection and localization of pheochromocytomas. Further study results with these agents are eagerly awaited.
can help in differentiation of benign and malignant tumors.
Pict This higher power field emphasizes the variety of sizes and
shapes and nuclear pleomorphism of the cluster of cells that make up even a benign pheochromocytoma.
hypertensive disease, symptomatic hypertension.
Surgical resection of the tumor is the treatment of choice and usually results in cure of the hypertension. Careful treatment with alpha- and beta-blockers is required preoperatively to control blood pressure and prevent intraoperative hypertensive crises.
· Start alpha blockade with phenoxybenzamine 7-10 days preoperatively to allow for expansion of blood volume.
· The patient should undergo volume expansion with isotonic sodium chloride solution. Encourage liberal salt intake.
· Initiate a beta-blocker only after adequate alpha blockade. If beta blockade is started prematurely, unopposed alpha stimulation could precipitate a hypertensive crisis.
· Administer the last doses of oral alpha- and beta-blockers on the morning of surgery.
Both an experienced anesthesiologist and an experienced surgeon are crucial to the success of the operation. Surgical mortality rates are less than 2-3% with an experienced anesthesiologist and surgeon.
· Administer stress-dose steroids if bilateral resection is planned.
An anterior midline abdominal
approach was used in the past; however, in current practice, laparoscopic
adrenalectomy is the preferred procedure for lesions smaller than
Pict. Laparoscopic adrenalectomy
If the pheochromocytoma is intra-adrenal, remove the entire adrenal gland. In the case of a malignant pheochromocytoma, resect as much of the tumor as possible.
Medical therapy is used for preoperative preparation prior to surgical resection, acute hypertensive crises, and primary therapy for patients with metastatic pheochromocytomas. Preoperative preparation requires combined alpha and beta blockade to control blood pressure and to prevent an intraoperative hypertensive crisis. Alpha-adrenergic blockade, in particular, is required to control blood pressure and prevent a hypertensive crisis. High circulating catecholamine levels stimulate alpha-receptors on blood vessels and cause vasoconstriction.
Phenoxybenzamine (Dibenzyline) is the preferred alpha-blocker in preparation for surgery. After effective alpha blockade, administer a beta-blocker. Beta-blockers are needed to control the tachycardia associated with high circulating catecholamine levels and alpha blockade. Beta-adrenergic blockers are used if significant tachycardia occurs after alpha blockade. Only administer beta-adrenergic blockers after adequate alpha blockade because unopposed alpha-adrenergic receptor stimulation can precipitate a hypertensive crisis. Noncardioselective beta-blockers, such as propranolol (Inderal) or nadolol (Corgard), are often used; however, cardioselective agents, such as atenolol (Tenormin) and metoprolol (Lopressor), also may be used.
Labetalol (Trandate, Normodyne) is a noncardioselective beta-adrenergic blocker and selective alpha-adrenergic blocker that has been shown to be effective in controlling hypertension associated with pheochromocytoma. It has also been associated with paradoxic episodes of hypertension thought to be secondary to incomplete alpha blockade. Thus, its use in the preoperative treatment of patients with pheochromocytoma is controversial.
During surgery, intravenous phentolamine, a rapid-acting alpha-adrenergic antagonist, is used to control blood pressure. Rapid-acting intravenous beta-blockers, such as esmolol, are also used to normalize blood pressure. Selective alpha1-blocking agents, such as prazosin (Minipress), terazosin (Hytrin), and doxazosin (Cardura), have more favorable adverse effect profiles and are used when long-term therapy is required (metastatic pheochromocytoma). These medications are not used to prepare patients for surgery because of their incomplete alpha blockade.
During crisis a combination of α- and β- adrenergic blocking agents (phentolamine (tropaphen) 2 - 4 mg every 5 - 10 min till stopping of the crisis, phenoxybenzamine 10 – 20 mg 3 – 4 times daily, propranolol 30 – 60 mg/day) and infusion of sodium nitroprusside.
is a generic term for a group of disorders, in which excessive production of aldosterone by the zona glomerulosa of the adrenal cortex occurs independently of normal renin-angiotensin stimulation.
These primary disorders of the adrenal system are distinct from forms of secondary hyperaldosteronism due to excessive renin, such as renal artery stenosis.
The five clinical entities comprising primary aldosteronism includ:
- solitary aldosterone-producing adenoma (APA),
- bilateral hyperplasia of the zona glomerulosa (also known as idiopathic hyperaldosteronism [IHA]),
- primary adrenal hyperplasia (PAH),
- adrenal carcinoma, and
- glucocorticoid-remediable aldosteronism.
The most common manifestation of hyperaldosteronism is hypertension. It is estimated that 0.05-12% of the hypertensive population may have primary aldosteronism. Primary aldosteronism affects more women than men and occurs most commonly in the third through fifth decades of life.
Aldosterone normally acts at the renal distal convoluted tubule to stimulate reabsorption of sodium ions (Na+), as well as secretion of potassium (K+) and hydrogen ions (H+), and at the cortical and medullary collecting ducts to cause direct secretion of H+.
Excess secretion of aldosterone in primary aldosteronism results in hypertension, hypokalemia, and metabolic alkalosis; hypomagnesemia may occur.
Spontaneous hypokalemia (K < 3.5 mEq/L) occurs in 80% of cases of primary aldosteronism; the remaining patients develop hypokalemia within 3-5 days of initiation of liberal sodium intake (150 mEq/day).
Most symptoms are manifestations of hypokalemia: weakness, muscle cramping, paresthesias, headaches, palpitations, polyuria, and polydipsia. Hyperglycemia due to insulinopenia occurs in approximately 25% of patients.
Unfortunately, there is no single specific and sensitive screening test. One method of screening the hypertensive, hypokalemic patient is to obtain concomitant PA and PRA values. A PA/PRA ratio (PA in ng/dL; PRA in ng/mL/h) that exceeds 20 raises the possibility of primary aldosteronism. Most antihypertensive agents do not affect the PA/PRA ratio; spironolactone, however, must be discontinued for 6 weeks before screening. A 24-hour urine collection for aldosterone should also be collected. Because 12% of patients may have PA/PRA ratios lower than 20, review of the urinary aldosterone value is helpful. Urinary excretion of aldosterone (18-monogluconide) that exceeds 12 mg/day is also suggestive of primary aldosteronism.
It is important to differentiate APA from IHAAPA is amenable to surgical resection of the involved adrenal gland, whereas IHA is usually treated medicallyAPAs produce greater amounts of aldosterone and can be stimulated by ACTH.
Patients with APA, therefore, have greater PA levels at 8:00 AM, and these levels decrease over the ensuing 4 hours as normal secretion of ACTH diminishes. Patients with IHA, on the other hand, have somewhat lower levels of PA at 8:00 AM, and they experience an increase with upright ambulation. Finally, APAs produce large amounts of 18-OHB; levels > 100 ng/dL occur only in APA and PAH.
Computed tomography (CT) or magnetic resonance imaging (MRI). To a limited
extent, both localizing procedures may aid in identifying the cause of primary
aldosteronism. A large APA may be discernible on high-resolution CT, which at
some institutions can identify adenomas as small as
After the APA is localized, unilateral adrenalectomy is performed. Laparoscopic resection is now widely available and is preferable to the "standard" posterior approach. One year postoperatively, 70% of patients are normotensive. By the fifth postoperative year, only 53% remain normotensive. Normal potassium balance tends to be permanent.
Pharmacologic therapy of IHAis quite effective.
1) The agent of choice is spironolactone (50-200 mg b.i.d.), a competitive inhibitor of aldosterone. Hypokalemia corrects dramatically, whereas hypertension responds after 4-8 weeks. Unfortunately, spironolactone also inhibits synthesis of testosterone and peripheral action of androgens, causing decreased libido, impotence, and gynecomastia in men. Eplerenone (50 mg b.i.d.) is a recently developed aldosterone antagonist without many of the side effects of spironolactone.
2) In patients intolerant of spironolactone, amiloride (5-15 mg b.i.d.) corrects hypokalemia within several days. A concomitant antihypertensive agent is usually necessary to reduce blood pressure. Success also has been reported in cases of IHA treated with calcium channel blockers (calcium is involved in the final common pathway for production of aldosterone) and angiotensin-converting enzyme (ACE) inhibitors (IHA appears to be sensitive to low concentrations of angiotensin II).
Management of a patient with PAH. During evaluation, these rare cases appear to be APA. Screening and confirmatory tests, seemingly indicate an APA. Levels of 18-OHB exceed 100 mg/dL. Localizing tests are consistent with APA, and patients usually undergo surgical resection of a nodular hyperplastic gland. The diagnosis is made retrospectively, but surgery is curative.
A patient with glucocorticoid-remediable aldosteronism have to be managed with low doses of dexamethasone (0.75 mg/day) or any of the agents used for therapy of IHA (see above) may be effective.
Congenital adrenal hyperplasia (CAH)
is a family of inherited disorders that result from a decrease in the activity of one of the various enzymes required for the biosynthesis of cortisol. These defects are inherited as autosomal recessive traits and are manifested during both prenatal and postnatal life.
Defects in any of the enzymes required for the synthesis of cortisol from cholesterol can lead to CAH, including steroidogenic acute regulatory (StAR) protein, which is essential in transporting cholesterol to the mitochondria; 3 β-hydroxysteroid dehydrogenase, which is responsible for cholesterol side-chain cleavage; and three hydroxylases, CYP 17 (17 α-hydroxylase), CYP21A2 (21-hydroxylase), and CYP11B1 (11 β-hydroxylase).
All of the enzyme defects leading to CAH are autosomal recessive disorders, that is, both copies of the involved gene must be abnormal for the condition to occur.
The process of adrenal hyperplasia begins in utero. Reduced production of cortisol in the fetus, due to decreased activity of one of the enzymes needed for cortisol synthesis, results in lowered levels of serum cortisol. Cortisol normally acts through a negative feedback loop to inhibit the secretion of ACTH by the pituitary gland and corticotropin-releasing hormone (CRH) by the hypothalamus. Thus, the low serum cortisol levels that occur in a person with CAH increase the secretion of ACTH and CRH in an attempt to stimulate the adrenal glands to overcome the enzyme block and to return the serum cortisol level to normal. As this process continues over time, the elevated levels of serum ACTH stimulate growth of the adrenal glands, leading to hyperplasia.
Adrenal crisis in the newborn period is the most serious consequence of CAH. It usually occurs with genetic defects that result in severe reductions in enzyme activity. It is especially insidious in genetic males who do not have ambiguous genitalia as a clue to the diagnosis. Overall, about two-thirds of patients with 21-hydroxylase deficiency have the salt-wasting form. These patients have decreased production of DOC and aldosterone, which results in hypotension, volume depletion, hyponatremia, hyperkalemia, and increased renin activity. The degree of residual activity of the defective enzyme varies greatly from one affected family to another, depending on the specific genetic alteration
Clinical consequences of CAH in females
Many of the precursors and metabolites that build up behind the blocked enzymes 21-hydroxylase, 11 β-hydroxylase, or 3β-hydroxysteroid dehydrogenase are androgens. They may cause the following:
· Masculinization of the external genitalia of a genetic female fetus, leading to ambiguous genitalia at birth (female pseudohermaphroditism).
· Behaviors more typical of boys during childhood in terms of toy preference, rough play, and aggressiveness. (However, most females are heterosexual and their sexual identity is invariably female.)
· Rapid growth during early childhood with ultimate short stature as an adult due to early closure of epiphyses.
Children with nonclassic CAH (also called late-onset CAH) usually are asymptomatic and have normal external genitalia but later present with the following:
· Premature puberty
· Severe cystic acne
Newborn males with CAH due to deficiency of 21-hydroxylase or 11 β-hydroxylase do not have ambiguous genitalia. Due to typical normal physical appearance, it is often difficult to detect an affected male, especially when symptoms of salt-wasting occur after the first week of life. Later in childhood or early adulthood, males can present with the following:
· Premature puberty
· Advanced height in early childhood with ultimate short stature
· Testicular enlargement due to adrenal rests
· Infertility (rare)
How is the diagnosis of CAH confirmed?
Because one does not know which enzyme is deficient in a newborn with suspected CAH (unless the family has a documented history of a particular enzyme defect), serum levels of all steroids that may be in the affected biosynthetic pathway can be measured before and after the administration of 250 μg of ACTH. Urinary measurement of these steroids by gas chromatography/mass spectroscopy has recently become economically feasible. Plasma renin activity and aldosterone levels should also be measured to assess the adequacy of aldosterone synthesis. Determination of which steroid levels are supranormal and which are low facilitates localization of the exact enzyme block.
1. CAH, the most common inherited disease, is a group of autosomal recessive disorders, the most frequent of which is 21-hydroxylase deficiency.
2. The most serious consequences of CAH are ambiguous genitalia at birth, neonatal salt-wasting, short stature, and premature puberty.
3. CAH is diagnosed through measurement of cortisol precursors before and 1 hour after the intravenous administration of 250 μg of synthetic ACTH.
4. Predicted adult height can be achieved through early diagnosis, lower doses of corticosteroids in the first year of life, and the use of fludrocortisone even in those who are salt-wasters genetically but not clinically.
5. CAH is a rare cause of ambiguous genitalia in a genetic male.
The most important goal of treatment is to prevent salt loss and adrenal crisis in the newborn period. This goal requires the prompt administration of glucocorticoids and, in many cases, mineralocorticoids, as well as careful monitoring of salt intake. This treatment not only replaces the deficient hormones but also suppresses elevated serum ACTH levels, thereby reducing adrenal production of androgenic precursors and metabolites. Such treatment may be given presumptively while awaiting the results of definitive laboratory tests and then discontinued if the tests are not confirmatory.
Surgical correction of ambiguous genitalia, such as repair of labioscrotal fusion, usually is carried out at a later time. Single-stage surgery is now implemented between 2 and 6 months of life.
The preferred glucocorticoid for chronic replacement is hydrocortisone because of its short half-life, which minimizes growth suppression in children. It is sometimes extremely difficult or impossible to find a dosage of glucocorticoid that normalizes production of androgen without impairing growth. In such situations, mineralocorticoids (fludrocortisone) and/or spironolactone/flutamide (androgen receptor blockers that prevent virilization) in combination with the aromatase inhibitor testolactone (which prevents estrogen-induced epiphyseal fusion) may be useful adjunctive therapy in combination with nonsuppressive replacement doses of glucocorticoids. Rarely, adrenalectomy has been used for difficult-to-control patients since treatment of adrenal insufficiency is relatively much simpler.
In adolescents and adults: prednisone or dexamethasone may be used once growth has been completed.
THE HYPOTHALAMIC – PITUITARY RELATIONSHIPS
The hypothalamus modulates the activity of the pituitary gland (hypophysis) via 2 distinct routes, one to the posterior and other to the anterior pituitary. The hypothalamus is connected with the posterior pituitary (neurohypophysis) by the supraopticohypophyseal nerve tract (peptidergic neurons). No nervous connection with the anterior pituitary (adenohypophysis) exists, but blood coursing through the hypothalamus gathers into a portal venous system which traverses the anterior pituitary and thus serves as a channel for direct transmission of the hypothalamic neurohormones. By these 2 routs, the hypothalamus is able to stimulate or release pituitary hormones.
The supraoptic and paraventricular nuclei of the hypothalamus secrete 2 octapeptide hormones – vasopressin and oxytocin. Both hormones are transported down axons bound as granules to carrier proteins, and are stored in the nerve endings of the posterior pituitary. They are released from these endings into the general circulation, where the granules dissociate, releasing free hormone and proteins.
Vasopressin (antidiuretic hormone, ADH) regulates water balance by stimulating resorption in the distal renal tubule. Secretion of ADH is controlled by increased osmotic pressure and decreased effective plasma volume.
Oxytocin stimulates uterine contractions (more so as pregnancy progresses), causes the myoepithelial cells of the breast to contract, expressing milk into the ducts. Secretion of oxytocin is controlled by suckling.
The hypothalamus plays an important role in hormone regulation by secreting a series of small peptides which stimulate or inhibit the synthesis and release of hormones by the anterior pituitary. Traditionally, these hypothalamic peptides have been known as releasing factors or as hypophysiotropic hormones (because they affect not only hormone release but also secretion). The neurons that secrete the hypothalamic peptides are located in the ventromedial nucleus nearby the median eminence. Secretion of these peptides is intimately related to the release of neurotransmitters by neurosecretory cells which are located in the same anatomical area (the best known neurotransmitters are the catecholamines dopamine and norepinephrine and the indoleamine serotonin).
The corticotropin-releasing hormone (CRH) stimulates the synthesis and release of corticotropin (ACTH) by the anterior pituitary.
The thyrotropin-releasing hormone (TRH) controls the secretion of thyrotropin (TSH) and also causes release of prolactin.
The gonadotropin-releasing hormone (GnRH), or luteinizing hormone-releasing hormone (LHRH) stimulates pituitary secretion of luteinizing hormone (LH) and to lesser extent that of follicle-stimulating hormone (FSH).
The growth-hormone-releasing hormone (GRH) stimulates and growth-hormone-inhibiting hormone (GIH, or somatotropin release-inhibiting factor (SRIF), or somatostatin) inhibits growth hormone (somatotropin) secretion from the anterior pituitary. GIH also inhibits insulin and glucagon secretion, gastrointestinal secretion of water, bicarbonate, pancreatic enzymes, gastric acid gastrin; glucose absorption and calcium transport.
The prolactin-inhibiting factor (PIF) controls prolactin secretion.
The pituitary gland lies in a bony structure, the sella turcica, located at the base of the skull. The gland is a small organ about I cm long; it weighs 500 mg and is divided into two parts, anterior (adenohypophysis) and posterior (neurohypophysis). Both parts derive from the ectoderm, but their origins differ. The anterior pituit