The two adrenal glands, each of which weighs about 4 grams, lie at the superior poles of the two kidneys. Each gland is composed of two distinct parts, the adrenal medulla and the adrenal cortex. Adrenal medulla, the central 20% of the gland, is functionally related to the sympathetic nervous system; it secretes the hormones epinephrine and norepinephrine in response to sympathetic stimulation. In turn, these hormones cause almost the same effects as direct stimulation of the sympathetic nerves in all parts of the body. The adrenal cortex secretes an entirely different group of hormones, called corticosteroids. These hormones are all synthesized from the steroid cholesterol, and they all have similar chemical formulas. However, slight differences in their molecular structures give them several different but very important functions.

Corticosteroids Mineralocorticoids, Glucocorticoids and Androgens. Two major types of
adrenocortical hormones, the mineralocorticoids and the glucocorticoids, are secreted by the adrenal cortex. In addition to these, small amounts of sex hormones are secreted, especially androgenic hormones, which exhibit about the same effects in the body as the male sex hormone testosterone. They are normally of only slight importance, although in certain abnormalities of the adrenal cortices, extreme quantities can be secreted (which is discussed later in the chapter) and can result in masculinizing effects.

The mineralocorticoids have gained this name because they especially affect the electrolytes (the “minerals”) of the extracellular fluids-sodium and potassium, in particular. The glucocorticoids have gained their name because they exhibit important effects that increase blood glucose concentration. They have additional effects on both protein and fat metabolism that are equally as important to body function as their effects on carbohydrate metabolism. More than 30 steroids have been isolated from the adrenal cortex, but two are of exceptional importance to the normal endocrine function of the human body: aldosterone, which is the principal mineralocorticoid, and cortisol, which is the principal glucocorticoid.

Synthesis and Secretion of Adrenocortical Hormones

The Adrenal Cortex Has Three Distinct Layers. Adrenal cortex is composed of three relatively distinct layers:

1. The zona glomerulosa, a thin layer of cells that lies just underneath the capsule, constitutes about 15% of the adrenal cortex. These cells are the only ones in the adrenal gland capable of secreting significant amounts of aldosterone because they contain the enzyme aldosterone synthase, which is necessary for synthesis of aldosterone. The secretion of these cells is controlled mainly by the extracellular fluid concentrations of angiotensin-II and potassium, both of which stimulate aldosterone secretion.

2. The zona fasciculata, the middle and widest layer, constitutes about 75 per cent of the adrenal cortex and secretes the glucocorticoids cortisol and corticosterone, as well as small amounts of adrenal androgens and estrogens. The secretion of these cells is controlled in large part by
the hypothalamic-pituitary axis via adrenocorticotropic hormone (ACTH).

3. The zona reticularis, the deep layer of the cortex, secretes the adrenal androgens dehydroepiandrosterone (DHEA) and androstenedione, as well as small amounts of estrogens and some glucocorticoids. ACTH also regulates secretion of these cells, although other factors such as cortical androgen-stimulating hormone, released from the pituitary, may also be involved. The mechanisms for controlling adrenal androgen production, however, are not nearly as well understood as those for glucocorticoids and mineralocorticoids.

Aldosterone and cortisol secretion are regulated by independent mechanisms. Factors such as angiotensin II that specifically increase the output of aldosterone and cause hypertrophy of the zona glomerulosa have no effect on the other two zones. Similarly, factors such as ACTH that increase secretion of cortisol and adrenal androgens and cause hypertrophy of the zona fasciculata and zona reticularis have little or no effect on the zona glomerulosa.

Adrenocortical Hormones are Steroids Derived from Cholesterol.

All human steroid hormones, including those produced by the adrenal cortex, are synthesized from cholesterol. Although the cells of the adrenal cortex can synthesize de novo small amounts of cholesterol from acetate, approximately 80 per cent of the cholesterol used for steroid synthesis is provided by low-density lipoproteins (LDL) in the circulating plasma. The LDLs, which have high concentrations of cholesterol, diffuse from the plasma into the interstitial fluid and attach to specific receptors contained in structures called coated pits on the adrenocortical cell membranes. The coated pits are then internalized by endocytosis, forming vesicles that eventually fuse with cell lysosomes and release cholesterol that can be used to synthesize adrenal steroid hormones.

Transport of cholesterol into the adrenal cells is regulated by feedback mechanisms that can markedly alter the amount available for steroid synthesis. For example, ACTH, which stimulates adrenal steroid synthesis, increases the number of adrenocortical cell receptors for LDL, as well as the activity of enzymes that liberate cholesterol from LDL.

Once the cholesterol enters the cell, it is delivered to the mitochondria, where it is cleaved by the enzyme cholesterol desmolase to form pregnenolone; this is the rate-limiting step in the eventual formation of adrenal steroids. In all three zones of the adrenal cortex, this initial step in steroid synthesis is stimulated by the different factors that control secretion of the major hormone products aldosterone and cortisol. For example, both ACTH, which stimulates cortisol secretion, and angiotensin II, which stimulates aldosterone secretion, increase the conversion of cholesterol to pregnenolone.

Synthetic Pathways for Adrenal Steroids. Important steroid products of the adrenal cortex include aldosterone, cortisol, and the androgens. Essentially all the synthetic steps occur in two of the organelles of the cell, the mitochondria and the endoplasmic reticulum, some steps occurring in one of these organelles and some in the other. Each step is catalyzed by a specific enzyme system. A change in even a single enzyme in the schema can cause vastly different types and relative proportions of hormones to be formed. For example, very large quantities of masculinizing sex hormones or other steroid compounds not normally present in the blood can occur with altered activity of only one of the enzymes in this pathway. The chemical formulas of aldosterone and cortisol, which are the most important mineralocorticoid and glucocorticoid hormones, respectively. Cortisol has a keto-oxygen on carbon number 3 and is hydroxylated at carbon numbers 11 and 21. The mineralocorticoid aldosterone has an oxygen atom bound at the number 18 carbon. In addition to aldosterone and cortisol, other steroids having glucocorticoid or mineralocorticoid activities, or both, are normally secreted in small amounts by the adrenal cortex. And several additional potent steroid hormones not normally formed in the adrenal glands have been synthesized and are used in various forms of . Some of the more important of the corticosteroid hormones.

Mineralocorticoids
• Aldosterone (very potent, accounts for about 90 per cent of all mineralocorticoid activity)

• Desoxycorticosterone (1/30 as potent as aldosterone, but very small quantities secreted)          

• Corticosterone (slight mineralocorticoid activity)

• 9a-Fluorocortisol (synthetic, slightly more potent than aldosterone)

• Cortisol (very slight mineralocorticoid activity, but large quantity secreted)

• Cortisone (synthetic, slight mineralocorticoid activity)

Glucocorticoids
• Cortisol (very potent, accounts for about 95 per cent of all glucocorticoid activity)
• Corticosterone (provides about 4% of total glucocorticoid activity, but much less potent than cortisol)

• Cortisone (synthetic, almost as potent as cortisol)

• Prednisone (synthetic, four times as potent as cortisol)

• Methylprednisone (synthetic, five times as potent as cortisol)

• Dexamethasone (synthetic, 30 times as potent as cortisol)

It is clear from this list that some of these hormones have both glucocorticoid and mineralocorticoid activities. It is especially significant that cortisol has a small amount of mineralocorticoid activity, because some syndromes of excess cortisol secretion can cause significant mineralocorticoid effects, along with its much more potent glucocorticoid effects.
The intense glucocorticoid activity of the synthetic hormone dexamethasone, which has almost zero mineralocorticoid activity, makes this an especially important drug for stimulating specific glucocorticoid activity.

Adrenocortical Hormones are Bound to Plasma Proteins.

Approximately 90-95% of the cortisol in the plasma binds to plasma proteins, especially a globulin called cortisol-binding globulin or transcortin and, to a lesser extent, to albumin. This high degree of binding to plasma proteins slows the elimination of cortisol from the plasma; therefore, cortisol has a relatively long halflife of 60-90 minutes. Only about 60% of circulating aldosterone combines with the plasma proteins, so that about 40 per cent is in the free form; as a result, aldosterone has a relatively short half-life of about 20 minutes. In both the combined and free forms, the hormones are transported throughout the extracellular fluid compartment.
Binding of adrenal steroids to the plasma proteins may serve as a reservoir to lessen rapid fluctuations in free hormone concentrations, as would occur, for example, with cortisol during brief periods of stress and episodic secretion of ACTH. This reservoir function may also help to ensure a relatively uniform distribution of the adrenal hormones to the tissues.

Adrenocortical Hormones Are Metabolized in the Liver. The adrenal steroids are degraded mainly in the liver and conjugated especially to glucuronic acid and, to a lesser extent, sulfates. These substances are inactive and do not have mineralocorticoid or glucocorticoid activity.
About 25 per cent of these conjugates are excreted in the bile and then in the feces. The remaining conjugates formed by the liver enter the circulation but are not bound to plasma proteins, are highly soluble in the plasma, and are therefore filtered readily by the kidneys and excreted in the urine. Diseases of the liver markedly depress the rate of inactivation of adrenocortical hormones, and kidney diseases reduce the excretion of the inactive conjugates.
The normal concentration of aldosterone in blood is about 6 nanograms (6 billionths of a gram) per 100 ml, and the average secretory rate is approximately 150 µg/day (0.15 mg/day). The concentration of cortisol in the blood averages 12 µg/100 ml, and the secretory rate averages 15 to 20 mg/day.

Functions of the Mineralocorticoids Aldosterone Mineralocorticoid Deficiency Causes Severe Renal Sodium Chloride Wasting and Hyperkalemia. Total loss of adrenocortical secretion usually causes death within 3 days to 2 weeks unless the person receives extensive salt
therapy or injection of mineralocorticoids. Without these, potassium ion concentration of the extracellular fluid rises markedly, sodium and chloride are rapidly lost from the body, and the total extracellular fluid volume and blood volume become greatly reduced. The person soon develops diminished cardiac output, which progresses to a shocklike state, followed by death. This entire sequence can be prevented by the administration of aldosterone or some other mineralocorticoid. Therefore, the mineralocorticoids are said to be the acute “lifesaving” portion of the adrenocortical hormones. The glucocorticoids are equally necessary, however, allowing the person to resist the destructive effects of life’s intermittent physical and mental “stresses”.

Aldosterone Is the Major Mineralocorticoid Secreted by the Adrenals. Aldosterone exerts nearly 90% of the mineralocorticoid activity of the adrenocortical secretions, but cortisol, the major glucocorticoid secreted by the adrenal cortex, also provides a significant amount of mineralocorticoid activity. Aldosterone’s mineralocorticoid activity is about 3000 times greater than that of cortisol, but the plasma concentration of cortisol is nearly 2000 times that of aldosterone.
Renal and Circulatory Effects of Aldosterone

Aldosterone Increases Renal Tubular Reabsorption of Sodium and Secretion of Potassium. Aldosterone increases absorption of sodium and simultaneously increases secretion of potassium by the renal tubular epithelial cellsespecially in the principal cells of the collecting tubules and, to a lesser extent, in the distal tubules and collecting ducts. Therefore, aldosterone causes sodium to be conserved in the extracellular fluid while increasing potassium excretion in the urine. A high concentration of aldosterone in the plasma can transiently decrease the sodium loss into the urine to as little as a few milliequivalents a day. At the same time, potassium loss into the urine increases severalfold. Therefore, the net effect of excess aldosterone in the plasma is to increase the total quantity of sodium in the extracellular fluid while decreasing the potassium. Conversely, total lack of aldosterone secretion can cause transient loss of 10 to 20 grams of sodium in the urine a day, an amount equal to one tenth to one fifth of all the sodium in the body. At the same time, potassium is conserved tenaciously in the extracellular fluid.

Excess Aldosterone Increases Extracellular Fluid Volume and Arterial Pressure but Has Only a Small Effect on Plasma Sodium Concentration. Although aldosterone has a potent
effect in decreasing the rate of sodium ion excretion by the kidneys, the concentration of sodium in the extracellular fluid often rises only a few milliequivalents. The reason is that when sodium is reabsorbed by the tubules, there is simultaneous osmotic absorption of almost equivalent amounts of water. Also, small increases in extracellular fluid sodium concentration stimulate thirst and increased water intake, if water is available. So, extracellular fluid volume increases almost as much as the retained sodium, but without much change in sodium concentration.
Even though aldosterone is one of the body’s most powerful sodium-retaining hormones, only transient sodium retention occurs when excess amounts are secreted. An aldosterone-mediated increase in extracellular fluid volume lasting more than 1 to 2 days also leads to an increase in arterial pressure. The rise in arterial pressure increases kidney excretion of both salt and water, called pressure natriuresis and pressure diuresis, respectively. Thus, after the extracellular fluid volume increases 5 to 15 per cent above normal, arterial pressure also increases 15 to 25 mm Hg, and this elevated blood pressure returns the renal output of salt and water to normal despite the excess aldosterone. This return to normal of salt and water excretion by the kidneys as a result of pressure natriuresis.