adrenal glands There are two adrenal glands, one sitting on top of each of the kidneys. They are pyramidal in shape and weigh about 4 g each. Their presence was recognized as early as the late sixteenth century, but it was not until 1805 that Cuvier reported that the adrenal was made up of two regions, the cortex on the outside and an inner medulla. Fifty years later, a Guy's Hospital physician, Thomas Addison, showed that the adrenal glands were necessary for life, by identifying them as the site of damage in a previously mysterious and ultimately fatal illness, which became known as Addison's disease.

The adrenal cortex

is known now to have three distinct regions: the zona glomerulosa, zone fasciculata, and zona reticularis. The first of these regions produces the steroid aldosterone, while another steroid hormone, cortisol, is produced by the other two regions. The cells which make up all of these regions are full of lipid droplets containing cholesterol, which can be converted into the steroid hormones.

Aldosterone,

by acting on the kidneys, controls the salt content of the body — by which means it also indirectly controls the blood pressure. The amount of aldosterone produced is controlled by other substances, including a protein from the kidney known as renin. Specialized cells in the kidney, which form the juxtaglomerular apparatus, are very sensitive to changes in blood pressure — well placed for this function by being wrapped around arterioles. If there is a fall in blood pressure, for example when getting out of bed in the morning, this is sensed by these cells and they respond by increasing the amount of renin put out into the bloodstream. Renin is an enzyme that converts the protein angiotensinogen to angiotensin I which is converted to angiotensin II. This in turn stimulates more aldosterone to be produced by the adrenal cortex; the aldosterone acts on the kidneys to retain more salt, and the salt is followed by water; both the salt and the water are reabsorbed into the blood and the resulting increase in the volume of the blood helps to restore the blood pressure to normal. Abnormally high production of aldosterone (hyperaldosteronism) causes excessive retention of salt and water in the body. This results in oedema and high blood pressure. If insufficient aldosterone is produced (hypoaldosteronism) there is a loss of water and salt which causes a fall in blood pressure, heart and kidney abnormalities, and general weakness.

Cortisol

acts on cells in many tissues in the body and influences general metabolism, blood pressure, and appetite. The amount of cortisol produced is controlled by another hormone, adrenocorticotrophic hormone (ACTH), secreted by the pituitary gland. This secretion in turn is controlled by corticotrophin-releasing hormone (CRH) from the hypothalamus. CRH secretion responds to signals from elsewhere in the brain, but both CRH and ACTH secretion are also influenced by the amount of cortisol in the blood. A major stimulus to this whole sequence of hormone secretions is stress. The biggest increase in the amount of cortisol produced by the adrenal glands is seen during surgery, although modern anaesthetics minimize the increase. Anxiety such as waiting for the beginning of a race or examinations also causes an increase in cortisol production. Cortisol is therefore a key component of the ‘fight or flight’ reaction of the individual in moments of crisis. The condition of cortisol excess is known as Cushing's syndrome after Harvey Cushing, the American neurosurgeon who, in 1932, described a condition associated with obesity and stretch marks (striae) around the abdomen, a round rosy face, hypertension, muscle weakness, diabetes, and increased hair growth on the face and body. These changes are attributable mainly to the action of cortisol on fat and protein in the body, although the growth of hair is due to an excess of the weak androgenic steroids also produced by the adrenal cortex. The features of this condition are associated with the presence of high levels of cortisol in the blood over a long period; it can be due either to overstimulation of the adrenal cortex by an excessive secretion of ACTH from a tumour of the anterior pituitary (the context in which Cushing encountered it), or to an abnormal growth of cortisol-secreting tissue in the adrenals themselves. Prolonged medication with corticosteroids can also mimic the syndrome.

Abnormally low levels of cortisol (hypocortisolism), result in a general feeling of being unwell, with tiredness, vomiting, nausea, and weight loss. A person in this condition is unable to cope with stress and liable to collapse with relatively minor injury or insult. Because there is insufficient cortisol in the blood to inhibit the secretion of ACTH, this hormone is produced in very high amounts and causes the skin to become dark or ‘bronzed’.

There can be loss of secretion of both cortisol and aldosterone if there is destruction of the adrenal glands by tumour or infection. This condition is known as Addison's disease, following its elegant description by Thomas Addison in 1855.

The adrenal medulla

makes up about 10% of the substance of the adrenal glands and is essentially and developmentally a part of the sympathetic division of the autonomic nervous system. It consists of ‘chromaffin cells’ (so named because of their affinity for chromium) and their main product is adrenaline (also known as epinephrine), which is involved in the fight or flight reaction along with cortisol. More adrenaline is produced in times of stress, by the stimulating action of sympathetic nerves directly upon the chromaffin cells. Adrenaline was the first hormone to be discovered, in 1894 — an event which encouraged the search for similar chemical mediators in the body, and led to the creation of the specialty of endocrinology. Unlike cortisol, which is produced exclusively in the adrenal cortex, adrenaline is produced in other parts of the body, including the brain, as well as in the adrenal medulla. Like cortisol, adrenaline has widespread actions at many sites in the body, including the heart, lungs, and blood vessels, facilitating an increase in the supply of nutrients and oxygen. It also redeploys necessary fuels very rapidly, in readiness for immediate action if required: acting for example in the liver to enhance the release of glucose into the blood. However, because adrenaline is produced in other areas of the body, removing the medulla does not seem to be a critical threat to life, though there does seem to be benefit in having adrenaline produced from the medulla at times of acute stress. Noradrenaline (norepinephrine), better known and most important as a neurotransmitter at sympathetic nerve endings, is also secreted by the medulla, along with adrenaline, but in much smaller amounts.

None of the adrenal hormones are released at a constant rate, but in amounts which change in response to various stimuli throughout the day. In addition, in the case of cortisol and to a certain extent aldosterone, there is a gradual change of background levels in the blood over each 24-hour period. This pattern of release is called a circadian rhythm, and is linked to the sleep–wake cycle of the individual — the ‘body clock’. In the normal individual the greatest amounts of cortisol are released at about 8 o'clock in the morning; the level in the blood gradually falls during the day so that the lowest levels are found at about midnight. ACTH also shows a circadian rhythm reaching maximum levels in the blood just before those of cortisol. The circadian rhythm of aldosterone is of much smaller amplitude than that of cortisol. Changing the times a person is asleep or awake will change the pattern of secretion; if shift workers sleep during the day and are awake at night then the circadian rhythm will be displaced by about 12 hours, with the highest blood levels of cortisol occurring in the early evening and the lowest levels about mid-day. Similar changes occur when travelling across time zones. The shift in the circadian rhythm occurs gradually over a period of several days

Corticosteroid therapy

Treatment of a variety of conditions by synthetic corticosteroids became common from the latter half of the twentieth century. They have been invaluable in suppressing adverse reactions to curative drugs, such as in the treatment of tuberculosis and other life-threatening illnesses; also in controlling inflammatory and allergic conditions, notably rheumatoid arthritis, asthma, and some skin diseases. It follows, however, from the normal control of cortisol secretion, that when the level of corticosteroids in the blood is deliberately raised by medication, the secretion of ACTH from the pituitary is suppressed. This becomes a problem if treatment is suddenly withdrawn, leaving the person liable to collapse under stress because there is no ACTH to stimulate the adrenal glands to produce their own cortisol.

M. Wheeler

Adrenal Glands

Definition

Adrenal glands produce and release several different hormones that maintain internal fluid levels, maintain sodium and potassium levels, and mediate the stress response.

Description

The human body contains two adrenal glands, one on top of each kidney. The gland is triangular in shape and yellowish in appearance. Subdivisions include the adrenal cortex and the medulla. The cortex is the outer layer and is responsible for the production of steroid hormones called glucocorticoids, mineralcorticoids, and androgens. The medulla forms the inner layer of the adrenal glands and releases norepinephrine and epinephrine (known commonly as noradrenaline and adrenaline) directly into the bloodstream. The adrenal cortex and medulla serve very different functions in the human body because of the different hormones that they produce and release.

Function

The adrenal cortex converts cholesterol into glucocorticoids, mineralcorticoids, and androgens. The glucocorticoids are so named due to their role in regulating body glucose levels. The major glucocorticoid produced by the adrenal is cortisol. Cortisol is also known as the stress hormone because the body releases cortisol in order to help cope with stressful situations. The immediate effects of cortisol are to increase levels of fatty acids, proteins, and glucose in the blood. Cortisol causes these increases by taking protein from muscles, fatty acids from fatty tissues, increasing gluconeogenesis (the process of making glucose), and decreasing the body's uses of glucose. Thus, in Cushing's syndrome (hypercortisolism), patients may experience muscle wasting (too much protein is taken from the muscles). Paradoxically, although cortisol increases the levels of free fatty acids, patients with too much cortisol over a long period of time experience an increase in fat on the upper body.

Cortisol and other glucocorticoids are also potent inhibitors of the immune system. Thus, it is not too surprising that synthetic glucocorticoids, like prednisone, are used to treat autoimmune diseases and allergies—diseases in which the immune system is too active. The release of cortisol is under the control of the anterior pituitary. The anterior pituitary accomplishes this by releasing the peptide hormone, adrenocorticotropin (ACTH) onto the adrenal gland.

The mineralcorticoids are so named due to their role in establishing mineral and water levels in the body. The major mineralcorticoid produced by the adrenal gland is aldosterone (although the glucocorticoid cortisol has some mineralcorticoid activity). The primary role of aldosterone is to regulate the balance of potassium, sodium, and water by affecting the absorption of all three in the kidney. Briefly, aldosterone causes the kidney to reabsorb more water and sodium, while causing potassium to be excreted in exchange for the sodium. When too much aldosterone is produced by the adrenal glands, as in primary aldosteronism, the level of potassium in the blood is low (hypokalemia) and the retention of sodium and water is high. Patients can experience hypertension and muscle weakness.

When there is too little aldosterone, potassium levels are high and there are extreme water and sodium losses. The loss of water and increased potassium levels can lead to extremely low blood pressure and death. A disease that might result in a loss of mineralcorticoid function is Addison's disease. In Addison's disease, the adrenals are usually at least 90% decimated before symptoms arise. The peptide, angiotensin II, and potassium levels are the main control for the release of aldosterone from the adrenals.

The adrenal glands also secrete small amounts of androgens such as testosterone. However, in the adult, that amount of androgens produced from a normally functioning adrenal gland is so small that it is unlikely to have a major effect. Nevertheless, pathology of the adrenals may result in abnormally high levels of androgens being secreted. The androgens may cause masculinization in males or females.

The adrenal medulla is really an extension of the sympathetic division of the autonomic nervous system. The sympathetic nervous system mediates "fight or flight" responses to environmental stimuli. Sympathetic nerves that originate in the spinal cord release the neurotransmitter, acetylcholine, onto the adrenal glands. The adrenal glands respond by releasing dopamine, norepinephrine, and epinephrine directly into the bloodstream. Norepinephrine and epinephrine are commonly referred to as noradrenaline and adrenaline, respectively. Epinephrine makes up the majority of the substance secreted by the adrenal medulla. Circulating norepinephrine and epinephrine can increase heart rate, constrict blood vessels, dilate eye pupils, inhibit motility and digestion in the stomach and intestines, increase sweating, increase metabolism, and increase breathing. The adrenal medulla is stimulated to release norepinephrine and epinephrine under stressful situations such as exercise or emotional distress.

Role in human health

Thus, the adrenal glands play a significant role in mental and physical health. Not only are the adrenal glands vital for maintaining a proper balance of sodium and potassium, they mediate the body's response to stress, both short-term and long-term. In response to immediate stress, the adrenal glands produce epinephrine, norepinephrine, and the hormone cortisol. The body is prepared for flight or fight, and energy is made available for instant use. In the long term, the adrenal glands may have a negative impact on human health. Prolonged stress can produce undesirable changes in the body that range from immune system depression to fertility complications.

Diseases and disorders

Addison's disease

Addison's disease arises from a hypoactive adrenal cortex. The adrenal cortex fails to produce adequate amounts of the glucocorticoid cortisol, and sometimes the mineralcorticoid aldosterone. A lack of aldosterone causes the kidneys to excrete excess sodium and water while retaining potassium. This can lead to hyperkalemia (high levels of potassium), hypovolemia (low blood volume), and hypotension (low blood pressure). Hyperkalemia may cause fatal heart arrhythmias, and (severe) hypovolemia can lead to shock and kidney failure. Common symptoms include frequent urination, dehydration, fatigue, dizziness, skin discoloration, nausea, vomiting, weakness, and cold intolerance. Treatment includes oral or intravenous glucocorticoids such as prednisone, and, if necessary, administration of the oral mineralcorticoid fludrocortisone acetate to replace aldosterone. The cause of Addison's disease is not known, but in 80% of the cases there is a wasting or atrophy of the adrenal cortex.

Primary aldosteronism

Conn's syndrome is also known as primary aldosteronism. In this disease, too much of the mineralcorticoid, aldosterone, is made by the adrenal glands. The increased levels of aldosterone cause excessive potassium excretion while promoting excessive sodium and water retention. This leads to hypertension (high blood pressure) and hypokalemia (low serum potassium). Hypokalemia is an important diagnostic clue in the process of differentiating primary aldosteronism from other similar disorders. In some cases, Conn's syndrome is due to an adrenal tumor, in which case it may be surgically removed. In other cases, the diuretic drugs, spironalactone or amiloride, are given to block the effects of aldosterone.

Cushing's syndrome

The adrenal cortex is overactive in Cushing's syndrome. The adrenal cortex overproduces glucocorticoids, which can lead to high blood sugar levels and high blood pressure. Symptoms include obesity, muscle wasting, fatigue, irritability, excessive hair growth in women, irregular menstrual cycles, and decreased male fertility. A tumor of the adrenal gland, or an overproduction of ACTH by the pituitary, may cause Cushing's syndrome. Treatment may include chemotherapy or hormone-inhibiting medications.

Pheochromocytoma

Pheochromocytomas are tumors of the adrenal glands that secrete large quantities of norepinephrine and epinephrine. The most common symptom is extremely high blood pressure. Treatment is usually surgical removal of the tumor.

KEY TERMS

Adrenal cortex— Outer layer of the adrenal gland that produces steroid hormones.

Adrenal medulla— Inner layer of the adrenal gland that releases adrenaline.

Androgens— Male sex hormones.

Hyperkalemia— An abnormally high level of potassium in the blood.

Hypokalemia— An abnormally low level of potassium in the blood.

Hypovolemia— An abnormally low volume of blood.

Glucocorticoid— A steroid hormone, like cortisol, that affects fat, carbohydrate, and protein levels in the blood as well as regulating the immune response.

Mineralcorticoid— A steroid hormone, like aldosterone, that regulates the excretion of salt, potassium, and water.

Resources

BOOKS

Guyton A.C. and J.E. Hall. Medical Physiology, 10th edition, Philadelphia, PA: W.B. Saunders Company, 2000.

Guyton A.C. Medical Physiology. 8th edition. Philadelphia, PA: W.B. Saunders Company, 1991.

PERIODICALS

Hostetter T.H., Rosenber M.E., Ibrahim H.N., and Juknevicius I. "Aldosterone in renal disease." Current Opinion in Nephrology Hypertension (10 January 2001): 105-110.

ORGANIZATIONS

National Adrenal Diseases Foundation. 505 Northern Blvd, Great Neck, NY 11021. (516) 487-4992. 〈http://medhlp.netusa.net/nadf/〉.

Adrenal Gland

The adrenal glands are located on the upper pole of each kidney. In fact, their name designates their location: the prefix ad means "adjacent," and renal refers to the kidney. In the human body, they are small yellowish glands that weigh about five grams (0.175 ounces) each.

The adrenal gland is actually two organs in one. The outer portion, called the adrenal cortex (cortex means "bark," as in the bark of a tree), is about nine-tenths of the gland's total weight. The inner part, called the adrenal medulla (medulla means "marrow," as found in the inside of a bone), is about one-tenth. They are both endocrine glands, meaning that they secrete chemical messengers called hormones into the bloodstream. However, the adrenal cortex and medulla are different in their embryological development, their tissue structure, the types of hormones they secrete, and the way they are regulated. So why is one located inside the other?

Adrenal Cortex

The adrenal cortex develops from the mesoderm (middle layer) of the embryo. The tissue destined to become the adrenal cortex aggregates near the developing kidney and becomes organized into three zones. The outer zone is called the zona glomerulosa (meaning that the cells are arranged in little balls called glomeruli), the middle zone is the zona fasiculata (the cells are in parallel fascicles or bundles), and the zona reticularis (reticular means network) is innermost.

The hormones secreted from each zone all resemble the molecule cholesterol and are called steroids , but each zone secretes slightly different hormones. The zona glomerulosa secretes hormones that influence the kidneys to excrete or retain sodium and potassium, depending on the needs of the body. These hormones are called mineralocorticoids (sodium and potassium are minerals ). The zona fasiculata secretes hormones called glucocorticoids that influence the metabolism of carbohydrates , including glucose . The glucocorticoids include hydrocortisone, corticosterone, and cortisone.

In addition to regulating metabolism, these steroids provide resistance to stress and suppress the inflammatory response and some allergic reactions. Steroids such as these are often rubbed onto inflamed and itchy skin to make it feel better. The zona reticularis secretes steroids that resemble the sex hormones secreted by the ovary in the female and testes in the male.

The adrenal cortex is regulated by the pituitary gland in the head. The pituitary gland secretes a hormone called adrenocorticotropic hormone (ACTH). Tropic (pronounced with a long o) is from a Greek word meaning "nourishment," so ACTH simply refers to this hormone's ability to produce a change in the adrenal cortex. ACTH is necessary for cell growth and maintenance and stimulates glucocorticoid synthesis.

Adrenal Medulla

The adrenal medulla forms from ectoderm (outer layer) very near the embryonic spinal cord. From its beginnings, the adrenal medulla is part of the nervous system. These cells migrate into the middle of the developing adrenal cortex and form into a solid ball. The cells of the adrenal medulla secrete a class of hormones called catecholamines, adrenaline (or epinephrine) being the best known. Norepinephrine is also secreted.

In times of acute stress, the brain and spinal cord send a signal to the adrenal medulla, and it secretes adrenaline into the bloodstream. This causes the heart to beat faster, opens up the airways, and gets the body ready for physical activity. This "fight or flight" reaction is a survival mechanism, allowing people (and other animals) to escape from a dangerous situation. A person experiences the effects of the adrenal medulla when he or she gets scared or excited.

Why is the adrenal medulla inside the cortex? Steroids in the adrenal cortex activate the enzyme that puts the final atoms onto adrenaline. Therefore, the adrenal cortex helps the adrenal medulla to synthesize adrenaline, allowing the medulla to do its job.

see also Anabolic Steroids; Endocrine System; Homeostasis; Hormones; Pituitary Gland; Stress Response

Stephen W. Carmichael

Bibliography

Carmichael, Stephen W., and Hans Winkler. "The Adrenal Chromaffin Cell." Scientific American 253 (August 1985): 40–49.

Ross, Michael H., Lynn J. Rommerell, and Gordon I. Kaye. Histology: A Text and Atlas, 3rd ed. Baltimore: Williams & Wilkins, 1995.

adrenal gland In vertebrates, an organ that secretes certain hormones. Many vertebrates possess multiple adrenal glands, but in mammals there is one gland close to each kidney. In tetrapods, each gland consists of a central medulla and an outer cortex. The medulla secretes adrenalin and noradrenalin, hormones needed when the animal is in an excited state and must engage in strenuous activity (e.g. fighting or fleeing). The cortex secretes sex hormones and other hormones concerned with regulating the water and salt balances of the body.

adrenal glands A pair of endocrine glands situated immediately above the kidneys (hence they are also known as the suprarenal glands). The inner portion of the adrenals, the medulla, contains chromaffin tissue and secretes the hormones adrenaline and noradrenaline; the outer cortex secretes small amounts of sex hormones (androgens and oestrogens) and various corticosteroids, which have a wide range of effects on the body. See also ACTH.