ADRENAL GLANDS Two adrenal glands Each weighs 4 grams Lie at the superior poles of the two kidneys Two distinct parts, adrenal medulla and adrenal cortex Adrenal medulla, central 20 % of the gland, is functionallyrelated to the SNS It secretes epinephrine and norepinephrine in response tosympathetic stimulation Adrenal cortex secretes corticosteroids.
CORTICOSTEROIDS Adrenocortical hormones: Mineralocorticoids Glucocorticoids Androgens (small amounts) Mineralocorticoids: affect electrolytes (“minerals”) ofextracellular ﬂuids -sodium and potassium, in particular Glucocorticoids : important effects that increase bloodglucose concentration + additional effects on protein and fatmetabolism More than 30 steroids have been isolated from the adrenalcortex Aldosterone principal mineralocorticoid Cortisol principal glucocorticoid.
ADRENAL CORTEX Three Distinct Layers1. Zona glomerulosa, 15% of the adrenal cortex A thin layer of cells that lies just underneath the capsule Secrete aldosterone Secretion is controlled by ECF concentrations ofangiotensin II and potassium, which stimulate aldosteronesecretion.2. Zona fasciculata, 75% of the adrenal cortex Middle and widest layer Secretes glucocorticoids cortisol, corticosterone, andsmall amounts of adrenal androgens and estrogens. Secretion is controlled by the hypothalamic-pituitary axisvia adrenocorticotropic hormone (ACTH).
Zona reticularis, deep layer of cortex Secretes adrenal androgens, dehydroepiandrosterone(DHEA) and androstenedione, small amounts of estrogensand glucocorticoids. ACTH regulates secretion of these cells Cortical androgen-stimulating hormone, released from thepituitary, may also be involved.
ADRENOCORTICAL HORMONES ARE STEROIDS Derived from Cholesterol Cholesterol is provided by LDL in the circulating plasma. Transport of cholesterol is regulated by feedback mechanisms For example, ACTH increases the number of adrenocorticalcell receptors for LDL, as well as the activity of enzymes thatliberate cholesterol from LDL. Cholesterol enters cell, delivered to mitochondria, cleaved byenzyme cholesterol desmolase to form pregnenolone This initial step in steroid synthesis is stimulated by thedifferent factors that control secretion of the major hormone
SYNTHESIS OF ADRENAL STEROIDS Synthesis occur in two of the organelles ofthe cell, mitochondria and endoplasmicreticulum Each step is catalyzed by a speciﬁc enzymesystem.
MINERALOCORTICOIDS1. Aldosterone (very potent, accounts for about 90 percent of all mineralocorticoid activity)2. Desoxycorticosterone3. Corticosterone4. 9a-Fluorocortisol (synthetic)5. Cortisol (very slight mineralocorticoid activity)6. Cortisone (synthetic)
GLUCOCORTICOIDS1. Cortisol (very potent, accounts for about 95percent of all glucocorticoid activity)2. Corticosterone3. Cortisone (synthetic)4. Prednisone (synthetic)5. Methylprednisone (synthetic)6. Dexamethasone (synthetic)
FUNCTIONS OF THEMINERALOCORTICOIDS-ALDOSTERONE
MINERALOCORTICOID DEFICIENCY Causes Severe Renal Sodium Chloride Wasting andHyperkalemia. Total loss of adrenocortical secretion death within 3days to 2 weeks unless the person receives extensive salttherapy or injection of mineralocorticoids. Without mineralocorticoids: Potassium ion concentration of ECF rises Sodium and chloride are rapidly lost from the body Total ECF volume and blood volume greatly reduced Develops diminished cardiac output Progresses to a shock like state Followed by death Mineralocorticoids are said to be the acute “lifesaving” portionof the adrenocortical hormones.
RENAL AND CIRCULATORY EFFECTS Increases Renal Tubular Reabsorption of Sodium andSecretion of Potassium From renal tubular epithelial cells especially in the principalcells of the collecting tubules and, to a lesser extent, in thedistal tubules and collecting ducts. Aldosterone causes sodium to be conserved in the ECF whileincreasing potassium excretion in the urine.
Excess Aldosterone Increases ECF Volume andArterial Pressure but Has Only a Small Effect onPlasma Sodium Concentration Concentration of sodium in the ECF rises only a fewmilliequivalents, when sodium is reabsorbed by thetubules, there is simultaneous osmotic absorption of almostequivalent amounts of water. ECF volume increases almost as much as the retainedsodium, but without much change in sodium concentration. Aldosterone-mediated increase in ECF volume lastingmore than 1 to 2 days also leads to an increase in arterialpressure The rise in arterial pressure then increases kidneyexcretion of both salt and water, called pressure natriuresisand pressure diuresis This return to normal of salt and water excretion by thekidneys is called aldosterone escape
When aldosterone secretion becomes zero, large amountsof salt are lost in the urine, not only diminishing the amountof sodium chloride in the extracellular ﬂuid but alsodecreasing the ECF volume. The result is severe ECF dehydration and low bloodvolume, leading to circulatory shock. Without therapy, this usually causes death within a few daysafter the adrenal glands suddenly stop secretingaldosterone.
EXCESS ALDOSTERONE CAUSES HYPOKALEMIA ANDMUSCLE WEAKNESS Excess aldosterone causes loss of potassium ions from theECF into the urine and also stimulates transport of potassiumfrom ECF into most cells of the body. Excessive secretion of aldosterone, may cause a seriousdecrease in the plasma potassium concentration, Thiscondition is called hypokalemia. When the potassium ion concentration falls below about one-half normal, severe muscle weakness often develops.
TOO LITTLE ALDOSTERONE CAUSES HYPERKALEMIAAND CARDIAC TOXICITY When aldosterone is deﬁcient, ECF potassium ionconcentration can rise far above normal. When it rises to 60 to 100 per cent above normal,serious cardiac toxicity, including weakness of heartcontraction and development of arrhythmia becomesevident Progressively higher concentrations of potassium leadinevitably to heart failure.
EXCESS ALDOSTERONE INCREASES TUBULAR HYDROGENION SECRETION, CAUSES MILD ALKALOSIS Also causes secretion of hydrogen ions in exchange forsodium in the intercalated cells of the cortical collectingtubules. This decreases the hydrogen ion concentration in theextracellular ﬂuid, causing a mild degree of alkalosis.
SWEAT GLANDS, SALIVARY GLANDS, ANDINTESTINAL EPITHELIAL CELLS Aldosterone Stimulates Sodium and Potassium Transport These glands form a primary secretion that contains largequantities of sodium chloride, but most of it is reabsorbed,whereas potassium and bicarbonate ions are secreted. Aldosterone greatly increases the reabsorption of sodiumchloride and the secretion of potassium by the ducts. This effect is used to conserve body salt in hot environments The effect on the salivary glands is necessary to conservesalt when excessive quantities of saliva are lost. Aldosterone also greatly enhances sodium absorption by theintestines, especially in the colon, which prevents loss ofsodium in the stools.
REGULATION OF ALDOSTERONE SECRETION1. Increased potassium ion concentration in theextracellular ﬂuid greatly increases aldosteronesecretion.2. Increased activity of the renin-angiotensin system(increased levels of angiotensin II) also greatlyincreases aldosterone secretion.3. Increased sodium ion concentration in the extracellularﬂuid very slightly decreases aldosterone secretion.4. ACTH from the anterior pituitary gland is necessary foraldosterone secretion but has little effect in controllingthe rate of secretion.
Cortisol Is the Primary Glucocorticoid Secreted by theAdrenal Cortex More than 95% of glucocorticoid activity exerted by theadrenocortical hormones can be attributed to cortisolknown also as hydrocortisone Most of the remaining glucocorticoid activity is due tocorticosterone. Cortisol mediates most of its effects by binding withintracellular receptors in target tissues and inducing orrepressing gene transcription This results in alterations in the synthesis of enzymesthat alter cell function.
EFFECTS OF CORTISOL ON CARBOHYDRATE METABOLISM Stimulation of Gluconeogenesis. Formation of carbohydrate from proteins and some othersubstances by the liver Decreased Glucose Utilization by Cells Elevated Blood Glucose Concentration and “AdrenalDiabetes.” The rise in blood glucose in turn stimulates secretion ofinsulin. High levels of glucocorticoid reduce the sensitivity of manytissues to the stimulatory effects of insulin on glucoseuptake and utilization.
EFFECTS ON PROTEIN METABOLISM Reduction in Cellular Protein. Reduction of the protein stores in essentially all body cellsexcept those of the liver. protein synthesis catabolism of protein in the cells. amino acid transport into extra hepatic tissues Enhance amino acid in plasma and increased transportinto liver cells Cortisol Increases Liver and Plasma Proteins. Increased conversion of amino acids to glucose-that is,enhanced gluconeogenesis
EFFECTS ON FAT METABOLISM Mobilization of Fatty Acids from adipose tissue Increases concentration of free fatty acids in the plasma,increases their utilization for energy. Cortisol also enhance the oxidation of fatty acids in cells. Obesity Caused by Excess Cortisol A peculiar type of obesity, with excess deposition of fat inthe chest and head regions of the body, giving a buffalo-like torso and a rounded “moon face.” Results from excess stimulation of food intake, with fatbeing generated in some tissues of the body more rapidlythan it is mobilized and oxidized.
Any type of physical or mental stress causes an immediateand marked increase in ACTH secretion by the pituitarygland, followed by greatly increased adrenocorticalsecretion of cortisolCORTISOL IN RESISTING STRESS AND INﬂAMMATION
ANTI-INﬂAMMATORY EFFECTS OF CORTISOL Large amounts of cortisol have two basic antiinﬂammatoryeffects:1. It can block early stages of inﬂammation process before iteven begins2. If inﬂammation has already begun, it causes rapidresolution of the inﬂammation and increased rapidity ofhealing
OTHER EFFECTS OF CORTISOL Blocks Inﬂammatory Response to Allergic Reactions Cortisol effectively prevents shock or death in anaphylaxis,which otherwise kills many people Effect on Blood Cells and on Immunity in InfectiousDiseases Large amount of Cortisol decreases the number ofeosinophils and lymphocytes in the blood Large doses also causes atrophy of lymphoid tissue, whichdecreases the output of T cells and antibodies The level of immunity for foreign invaders is decreased Leads to increased infection and death from diseases Useful drugs in preventing immunological rejection oftransplanted hearts, kidneys, and other tissues. Cortisol increases the production of red blood cells
ADRENAL ANDROGENS The adrenal androgens DHEA and androstenedione aresecreted in appreciable amounts, but they have only weakandrogenic effects. Consequently, the normal plasma concentrations of thesehormones exert little effect on secondary sexcharacteristics In females, adrenal androgens are responsible for pubicand axillary hair. In males Most of the androgenic activity of adrenalhormones may be due to the conversion of adrenalandrogens to testosterone in peripheral tissues The secretion of adrenal androgens is stimulated by ACTH.
HYPOADRENALISM-ADDISON’S DISEASE Failure of the adrenal cortices to produce adrenocorticalhormones Most frequently caused by primary atrophy of the adrenalcortices, caused by autoimmunity against the cortices. Also caused by tuberculous destruction of the adrenalglands or invasion of the adrenal cortices by cancer. These processes usually are gradual, leading to aprogressive reduction in glucocorticoid andmineralocorticoid function. As a result of the decreased cortisol secretion, there is acompensatory increase in ACTH secretion, which produceshyperpigmentation.
Mineralocorticoid Deficiency Excessive loss of sodium, hypovolemia, hypotension, andincreased plasma renin activity Excessive potassium retention and hyperkalemia Mild acidosis Glucocorticoid Deficiency Abnormal carbohydrate, fat, and protein metabolismresulting in muscle weakness, fasting hypoglycemia, andimpaired utilization of fats for energy Loss of appetite and weight loss Poor tolerance to stress. The inability to secrete increased amounts of cortisolduring stress leads to an Addisonian crisis that mayculminate in death if supplemental doses of adrenocorticalhormones are not administered.
Treatment An untreated person with total adrenal destruction dieswithin a few days to a few weeks because of weaknessand usually circulatory shock. Such a person can live for years if small quantities ofmineralocorticoids and glucocorticoids are administereddaily.
HYPERADRENALISM-CUSHING’S SYNDROME Hypersecretion by the adrenal cortex causes a complexcascade of hormone effects called Cushing’s syndrome. Hypercortisolism can occur from multiple causes:1) adenomas of the anterior pituitary ACTHadrenal hyperplasia cortisol secretion2) abnormal function of the hypothalamus CRHACTH release3) “ectopic secretion” of ACTH by a tumor in the body4) adenomas of the adrenal cortex5) by administration of large amounts of exogenousglucocorticoids. When Cushing’s syndrome is secondary to excesssecretion of ACTH by the anterior pituitary, this is referredto as Cushing’s disease.
Symptoms: Mobilization of fat from the extremities to the abdomen, face,and supraclavicular areas Protein depletion resulting in muscle weakness, loss ofconnective tissue and thinning of the skin (leading to purplestriae), and impaired growth in children Osteoporosis and vertebral fractures Impaired response to infections resulting from a suppressedimmune system Impaired carbohydrate metabolism, hyperglycemia, andeven insulin-resistant diabetes mellitus Masculinizing effects when adrenal androgens are secretedin excess
Treatment Remove an adrenal tumor Hypertrophied pituitary glands can be surgically removed ordestroyed by radiation. Drugs that block steroidogenesis, such as metyrapone,ketoconazole, and aminoglutethimide, or that inhibit ACTHsecretion can also be used. If ACTH secretion cannot easily be decreased, the onlysatisfactory treatment is usually bilateral partial (or eventotal) adrenalectomy, followed by administration of adrenalsteroids to make up for any insufﬁciency that develops.
FUNCTION OF THE ADRENAL MEDULLAE Stimulation of the sympathetic nerves to the adrenalmedulla causes large quantities of epinephrine andnorepinephrine to be released into the circulating blood. About 80% of the secretion from the adrenal medulla isepinephrine, and about 20% is norepinephrine. The effect of the epinephrine and norepinephrine releasedfrom the adrenal medulla lasts 5 to 10 times longer thanwhen they are released by sympathetic neurons becausethese hormones are slowly removed from the blood.
ADRENERGIC RECEPTORS Alpha and Beta Receptors Norepinephrine excites mainly alpha receptors butexcites the beta receptors to a lesser extent as well. Conversely, epinephrine excites both types ofreceptors approximately equally. Therefore, the relative effects of norepinephrineand epinephrine on different effector organs aredetermined by the types of receptors in the organs.
ALPHA AND BETA RECEPTORS The stimulation of α-receptors results in vasoconstriction,dilation of the iris, contraction of the intestinal and bladdersphincters, and contraction of the pilomotor muscles. The β-receptor is subdivided into β1-, β2-, and β3receptor subtypes. Stimulation of β1-receptors causes an increase in heartrate and strength of contraction. Stimulation of β2-receptors causes skeletal musclevasodilation, bronchodilation, uterine relaxation,calorigenesis, and glycogenolysis. Stimulation of β3-receptors induces lipolysis in adiposetissue and the conversion of energy in lipids into heat(thermogenesis).
NOREPINEPHRINE The circulating Norepinephrine causes: Vasoconstriction Increased heart rate and contractility Inhibition of the gastrointestinal tract Dilated pupils.
EPINEPHRINE Epinephrine causes almost the same effects as thosecaused by norepinephrine, except The circulating epinephrine has a greater effect oncardiac performance Epinephrine causes only weak constriction of the bloodvessels in muscles Slight increase in arterial pressure A dramatic increase in cardiac output. The metabolic rate of every cell of the body is increasedby these hormones, especially by epinephrine, as muchas 100 per cent above normal
Epinephrine and norepinephrine are almost alwaysreleased by the adrenal medullae at the same time thatthe different organs are stimulated directly bygeneralized sympathetic activation. Therefore, the organs are actually stimulated in twoways: directly by the sympathetic nerves and indirectlyby the adrenal medullary hormones. The two means of stimulation support each other, andeither can, in most instances, substitute for the other.