ADRENAL GLAND

The adrenal glands, small organs near the kidney, produce glucocorticoids (approximately 25 mg cortisol/day), mineralocorticoids (approximately 100 micrograms aldosterone/day) and androgens (e.g. dehydroepiandrosterone = DHEA approximately 10 mg/day) in their cortex and catecholamines in their medulla. The production of cortisol by the adrenals is precisely regulated by the brain's hypothalamus and the pituitary gland, a bean-sized organ at the base of the brain. First, the hypothalamus sends releasing hormones to the pituitary gland. The pituitary responds by secreting hormones that regulate the various endocrine, hormone producing glands (e.g. thyroid, adrenals, ovaries, testes, breast) as well certain bodily function, as for example growth. One of the pituitary's main functions is to secrete adrenocorticotropic hormone (ACTH), a substance that stimulates the adrenal glands. When the adrenals receive the pituitary's signal, in the form of ACTH, they respond by producing cortisol as well as some of the other adrenal hormones. Completing the cycle, cortisol then signals the pituitary to lower secretion of ACTH. Glucocorticoids affect almost every organ and tissue in the body. Among its vital tasks cortisol helps to maintain blood pressure and cardiovascular functions, to balance the effects of insulin in breaking down sugar for energy, to slow the immune system's inflammatory response, and to help in general to regulate the metabolism of proteins (primarily catabolic effect), carbohydrates, and fats. One of cortisol's most important jobs is to help the body respond to stress. In fact, the adrenal glands naturally produce more cortisol during stress. Aldosterone belongs to a class of hormones called mineralocorticoids, which are 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. When aldosterone production falls too low, the kidneys are not able to regulate salt and water balance, causing blood volume and blood pressure to drop.

Conditions associated with hyperactivity of the adrenal cortex

CUSHING'S SYNDROME. Excessive cortisol production leads to Cushing's syndrome. It is a curable cause of several problems: upper body obesity, muscle weakness, severe fatigue, high blood pressure, premature thinning of bone, insulin resistant diabetes, easy bruising and bluish-red stretch marks on the skin, increased growth of facial and body hair, acne, menstrual dysfunction, sometimes amenorrhea and some forms of depression. Cushing's syndrome is more common in women than in men. It accounts for as many as one in every thousand hospital admissions. In approximately 2/3 of the cases it is due to ACTH oversecretion, most often from a pituitary adenoma, and can be cured by removal of the adenoma. Cushing's syndrome caused by an adrenal adenoma, carcinoma or bilateral nodular adrenal hyperplasia is treated by adrenal surgery. Nelson's syndrome consists of hyperpigmentation of the skin and is often associated with an aggressively growing pituitary adenoma which secretes excessive amounts of ACTH and Melanocyte-Stimulating Hormone (MSH). The treatment is surgical.

CONN'S SYNDROME (PRIMARY HYPERALDOSTERONISM) is due to aldosterone hypersecretion most often from an adrenal adenoma (therapy: unilateral adrenalectomy), more seldom from bilaterally hyperplastic adrenals (therapy: spironolactone). Excessive adrenal androgen secretion is found in the adrenogenital syndrome in which defective cortisol biosynthesis leads to ACTH oversecretion and ACTH-stimulated overproduction of cortisol precursors, some of which are androgens. Treatment consists of glucocorticoids which suppress the ACTH oversecretion. Pheochromocytomas produce excessive amounts of catecholamines and cause hypertension which can be persistent as well as episodic. Therapy consists of adrenalectomy.

MALIGNANT TUMORS OF THE ADRENALS have a poor prognosis. Incidentally found adrenal masses (incidentalomas) should be observed at regular intervals if they are small and should be surgically removed if they have a tendency to grow or are large (greater than or equal to 5 cm).

Conditions associated with decreased production of adrenocortical hormones

ADDISON’S DISEASE.
Addison's disease occurs when the adrenal glands do not produce enough cortisol and in some cases, aldosterone. For this reason, the disease is sometimes called chronic adrenal insufficiency, or hypocorticism. It is characterized by weight loss, muscle weakness, fatigue, low blood pressure, and sometimes darkening of the skin in both exposed and non exposed parts of the body. The decrease of corticoids, both cortisol and aldosterone, can be due to primary adrenal insufficiency (due to destruction of the adrenal glands by an infectious process, an autoimmune disorder, surgical extirpation or idiopathic) or to inadequate secretion of ACTH by the pituitary gland (secondary adrenal insufficiency).

PRIMARY ADRENAL INSUFFICIENCY.
In most instances the adrenal cortex is destroyed by an insidious and slow process related to an autoimmune disorder. The majority of adrenal tissue (90%) must be destroyed before clinical signs of hypocorticism occur. Thus, the disease may be present for years before it is discovered. The less common causes are infectious, primarily tuberculous or of fungal etiology.

SECONDARY ADRENAL INSUFFICIENCY.
This form of Addison's disease is due to a lack of ACTH secretion by the pituitary gland. The normal physiologic mechanism calls for the pituitary gland to secrete ACTH upon stimulation by a brain (hypothalamic) hormone, Corticotropin Releasing Hormone (CRH). If CRH production is suppressed, for example by the administration of high doses of a synthetic glucocorticoid ( e.g. dexamethasone), the production of ACTH drops. This causes a decrease in adrenal cortisol production by the adrenal gland. The adrenal, however, retains the ability to produce mineral corticoids, e.g. aldosterone. A temporary form of secondary adrenal insufficiency may occur after an abrupt discontinuation of treatment with massive doses of glucocorticoids usually used to treat non-endocrine problems, for example, to treat various inflammatory diseases. Another cause of secondary adrenal insufficiency is the surgical removal of noncancerous, ACTH-producing tumors of the pituitary gland (Cushing's Disease). The source of ACTH is suddenly removed, and replacement hormone must be taken indefinitely or until normal ACTH and cortisol production resumes. Adrenal insufficiency may also occur when ACTH production decreases due to growth of other types of pituitary tumors, occurrence of pituitary infections (hypophysitis), loss of blood flow to the pituitary, radiation for the treatment of pituitary tumors, or surgical removal of parts of the hypothalamus or the pituitary gland during neurosurgery of these areas.

Symptoms of Adrenal Hypoactivity

Since, except for postsurgical instances, the diminution of adrenal function is a very slow pathologic process, the onset of the symptoms is slow and the lack of specificity makes the diagnosis difficult. Progressive character of the symptoms helps to alert the physician when he is confronted with the symptoms of fatigue, weight loss, loss of appetite, nausea, diarrhea, vomiting, dizziness and fainting associated with low blood pressure and low sodium. Patient develops irritability, depression and craving for salt. One of the more characteristic symptoms which may call the physicians' attention to the diagnosis is marked darkening of the skin over both exposed and unexposed areas, particularly in skin creases and pressure points. Women develop menstrual irregularities, even amenorrhea. Some may suffer the symptoms for years and not be diagnosed until adrenal crises (addisonian crisis, acute adrenal insufficiency) occur. These are associated with suddenly occurring severe abdominal pains, diarrhea, vomiting followed by dehydration and hypotensive shock. If left untreated patient may die in adrenal crisis.

Treatment of Addison disease, once the diagnosis is established, is relatively simple. It requires appropriate replacement therapy with adrenal hormones.

CONGENITAL ADRENAL HYPERPLASIA (CAH) is a disease that can cause lifelong disorders and even death. It adversely influences the manufacture of the stress hormone, cortisol, produced by the adrenal gland, and, in the female, is associated with excessive production of androgens by the adrenal gland. CAH occurs in two forms: severe or "classical" and mild or "nonclassical". Girls with classical CAH are born, due to the excessive secretion of male hormone by the adrenal gland during the fetal life, with masculine appearing external genitals but with female internal sex organs. Boys with classical CAH look normal at birth, so the diagnosis of CAH is sometimes missed. People with CAH are likely to have trouble retaining salt, a condition that can be life-threatening. Everyone with CAH also has an unusually high level of the male sex hormone testosterone in his/her blood. Among the difficulties it causes are infertility, excessive hair growth, acne, and early growth of sexual hair. In addition, adrenal crises (acute hypercorticoidism) may occur and result in death. Congenital adrenal hyperplasia is an autosomal recessive genetic disease. To have a child with CAH, both parents must be carriers of the defective gene. Occurring in at least one in every 1,000 people, the nonclassical, mild form of the disease is the most common of all autosomal recessive diseases. Its incidence is higher in certain ethnic groups. Thus, it affects one in every 27 Ashkenazi Jewish people, one of every 53 Hispanics, one of every 63 Yugoslavs, and one in every 333 Italians. The classical severe form occurs in one in every 12,000 people. Carriers of CAH may have mild forms of the disease. Their symptoms are like those of the classical disease, but less severe. The symptoms may begin at any time in life and may come and go.

Treatment. Throughout life, and especially as newborns, people with CAH must be treated with steroid hormones. This treatment is effective in restoring normal hormone levels and preventing dangerous and potentially fatal adrenal crises (acute diminution of adrenal cortisol production). The symptoms experienced by people with the milder form of CAH also respond well to steroid glucocorticoid treatment . CAH can be diagnosed and treated before birth. The diagnosis can be accomplished through the use of amniocentesis or chorionic villi sampling early in pregnancy. This early treatment spares affected girls from the corrective surgery that they would otherwise need after birth. Some states have mandated newborn blood screening programs to identify CAH in infants during the first few days of life.

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