Adrenocortical Hormones

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% of the cholesterol used for steroid synthesis is provided by low-density lipoproteins (LDLs) 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 ( Figure 78-2 ). 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 conversion of cholesterol to pregnenolone.

Synthetic Pathways for Adrenal Steroids

Figure 78-2 gives the principal steps in the formation of the important steroid products of the adrenal cortex: aldosterone, cortisol, and the androgens. Essentially all these steps occur in two of the organelles of the cell, the mitochondria and the endoplasmic reticulum, with 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 major mineralocorticoid and glucocorticoid hormones, respectively, are shown in Figure 78-2 . 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. Furthermore, several additional potent steroid hormones not normally formed in the adrenal glands have been synthesized and are used in various forms of therapy. Some of the more important of the corticosteroid hormones, including the synthetic ones, are the following, as summarized in Table 78-1 .

Mineralocorticoids

• Aldosterone (very potent; accounts for ≈90% of all mineralocorticoid activity)

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

• Corticosterone (slight mineralocorticoid activity)

• 9α-Fluorocortisol (synthetic; slightly more potent than aldosterone)

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

• Cortisone (slight mineralocorticoid activity)

Glucocorticoids

• Cortisol (very potent; accounts for ≈95% of all glucocorticoid activity)

• Corticosterone (provides ≈4% of total glucocorticoid activity, but is much less potent than cortisol)

• Cortisone (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 and synthetic steroids have both glucocorticoid and mineralocorticoid activities. It is especially significant that cortisol normally has some 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 it an especially important drug for stimulating specific glucocorticoid activity.

Adrenocortical Hormones Are Bound to Plasma Proteins

Approximately 90% to 95% of the cortisol in 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 half-life of 60 to 90 minutes. Only about 60% of circulating aldosterone combines with the plasma proteins, and about 40% is in the free form; as a result, aldosterone has a relatively short half-life of about 20 minutes. These hormones are transported throughout the extracellular fluid compartment in both the combined and free forms.

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 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 are conjugated especially to glucuronic acid and, to a lesser extent, to sulfates. These substances are inactive and do not have mineralocorticoid or glucocorticoid activity. About 25% 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 milliliters, and the average secretory rate is approximately 150 μg/day (0.15 mg/day). The blood concentration of aldosterone, however, depends greatly on several factors, including dietary intake of sodium and potassium.

The concentration of cortisol in the blood averages 12 μg/100 ml, and the secretory rate averages 15 to 20 mg/day. However, blood concentration and secretion rate of cortisol fluctuate throughout the day, rising in the early morning and declining in the evening, as discussed later.

Mineralocorticoid Deficiency Causes Severe Renal Sodium Chloride Wasting and Hyperkalemia

Total loss of adrenocortical secretion may cause death within 3 to 14 days unless the person receives extensive salt therapy or injection of mineralocorticoids.

Without mineralocorticoids, 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. Diminished cardiac output soon develops, which progresses to a shock-like state, followed by death. This entire sequence can be prevented by 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, because they allow the person to resist the destructive effects of life’s intermittent physical and mental “stresses,” as discussed later in the chapter.

Aldosterone Is the Major Mineralocorticoid Secreted by the Adrenals

In humans, 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. The mineralocorticoid activity of aldosterone is about 3000 times greater than that of cortisol, but the plasma concentration of cortisol is nearly 2000 times that of aldosterone.

Cortisol can also bind to mineralocorticoid receptors with high affinity. However, the renal epithelial cells express the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which has actions that prevent cortisol from activating mineralocorticoid receptors. One action of 11β-HSD2 is to convert cortisol to cortisone, which does not avidly bind mineralocorticoid receptors. There is also evidence that 11β-HSD2 may have effects on the intracellular redox (reduction and oxidation) state that prevent cortisol from activating the mineralocorticoid receptors. In patients with genetic deficiency of 11β-HSD2 activity, cortisol may have substantial mineralocorticoid effects. This condition is called apparent mineralocorticoid excess syndrome (AME) because the patient has essentially the same pathophysiological changes as a patient with excess aldosterone secretion, except that plasma aldosterone levels are very low in the patient with AME. Ingestion of large amounts of licorice, which contains glycyrrhetinic acid, may also cause AME because of its ability to block 11β-HSD2 enzyme activity.

Aldosterone Increases Renal Tubular Reabsorption of Sodium and Secretion of Potassium

As discussed in Chapter 28 , aldosterone increases reabsorption of sodium and simultaneously increases secretion of potassium by the renal tubular epithelial cells, especially 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 per day. At the same time, potassium loss into the urine transiently 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; Aldosterone Deficiency Causes Hyponatremia

Although aldosterone has a potent effect to decrease the rate of sodium excretion by the kidneys, the concentration of sodium in the extracellular fluid often rises only a few milliequivalents. The reason for this is that when sodium is reabsorbed by the tubules, simultaneous osmotic absorption of almost equivalent amounts of water occurs. Also, small increases in extracellular fluid sodium concentration stimulate thirst and increased water intake, if water is available, and increase secretion of antidiuretic hormone, which enhances water reabsorption by the distal and collecting tubules of the kidneys. Therefore, the 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, as explained in Chapter 19 . The rise in arterial pressure then increases kidney excretion of both sodium and water, called pressure natriuresis and pressure diuresis, respectively. Thus, after the extracellular fluid volume increases 5% to 15% above normal, arterial pressure also increases 15 to 25 mm Hg, and this elevated blood pressure returns the renal output of sodium and water to normal despite excess aldosterone ( Figure 78-3 ).

This return to normal sodium and water excretion by the kidneys as a result of pressure natriuresis and diuresis is called aldosterone escape. Thereafter, the rate of gain of sodium and water by the body is zero, and balance is maintained between sodium and water intake and output by the kidneys, despite continued excess aldosterone. In the meantime, however, hypertension has developed, which lasts as long as the person remains exposed to high levels of aldosterone.

In contrast, severe aldosterone deficiency may cause substantial reductions in plasma sodium concentration (hyponatremia) due to reduced renal sodium reabsorption and increased sodium excretion. The renal sodium wasting causes reductions in extracellular fluid volume, arterial pressure, and cardiac output, which stimulate secretion of antidiuretic hormone (ADH). Increased levels of ADH attenuate renal water excretion and contribute to hyponatremia, along with increases in thirst and water intake that are also stimulated by hypovolemia and hypotension.

When aldosterone secretion becomes zero, large amounts of sodium are lost in the urine, not only diminishing the amount of sodium chloride in the extracellular fluid but also decreasing the extracellular fluid volume. The result is severe extracellular fluid dehydration and low blood volume, leading to circulatory shock. Without therapy, this usually causes death within a few days after the adrenal glands suddenly stop secreting aldosterone.

Excess Aldosterone Causes Hypokalemia and Muscle Weakness; Aldosterone Deficiency Causes Hyperkalemia and Cardiac Toxicity

Excess aldosterone not only causes loss of potassium ions from the extracellular fluid into the urine but also stimulates transport of potassium from the extracellular fluid into most cells of the body. Therefore, excessive secretion of aldosterone, as occurs with some types of adrenal tumors, may cause a serious decrease in the plasma potassium concentration (hypokalemia), sometimes from the normal value of 4.5 mEq/L to as low as 2 mEq/L. When plasma potassium ion concentration falls below about one-half normal, severe muscle weakness often develops. This muscle weakness is caused by alteration of the electrical excitability of the nerve and muscle fiber membranes (see Chapter 5 ), which prevents transmission of normal action potentials.

Conversely, when aldosterone is deficient, the extracellular fluid potassium ion concentration can rise far above normal. When it rises to 60% to 100% above normal, serious cardiac toxicity, including weakness of heart contraction and development of arrhythmia, becomes evident, and progressively higher concentrations of potassium lead inevitably to heart failure.

Excess Aldosterone Increases Tubular Hydrogen Ion Secretion and Causes Alkalosis

Aldosterone not only causes potassium to be secreted into the tubules in exchange for sodium reabsorption in the principal cells of the renal collecting tubules but also causes secretion of hydrogen ions in exchange for potassium in the intercalated cells of the cortical collecting tubules, as discussed in Chapter 28, Chapter 31 . This decreases the hydrogen ion concentration in the extracellular fluid, causing metabolic alkalosis.