Adrenocortical Hormones pdf - Endocrinology and Reproduction

the middle and widest layer, constitutes about 75 per

zona fasciculata,

2. The

which is necessary for synthesis of aldosterone. The secretion of these cells

aldosterone synthase,

capsule, constitutes about 15 per cent of the adrenal cortex. These cells are

zona glomerulosa,

1. The

Figure 77–1 shows that the adrenal

Adrenocortical Hormones

Synthesis and Secretion of

which is the principal mineralocorticoid, and

aldosterone,

More than 30 steroids have been isolated from the adrenal cortex, but two

exhibit important effects that increase blood glucose concentration. They have

sium, in particular. The

the electrolytes (the “minerals”) of the extracellular fluids-sodium and potas-

The

chapter) and can result in masculinizing effects.

cortices, extreme quantities can be secreted (which is discussed later in the

mally of only slight importance, although in certain abnormalities of the adrenal

same effects in the body as the male sex hormone testosterone. They are nor-

androgenic hormones,

mones are secreted, especially

secreted by the adrenal cortex. In addition to these, small amounts of sex hor-

glucocorticoids,

adrenocortical hormones, the

Two major types of

molecular structures give them several different but very important functions.

and they all have similar chemical formulas. However, slight differences in their

These hormones are all synthesized from the steroid cholesterol,

corticosteroids.

The adrenal cortex secretes an entirely different group of hormones, called

These hormones and their effects are discussed in detail in Chapter 60 in rela-

effects as direct stimulation of the sympathetic nerves in all parts of the body.

to sympathetic stimulation. In turn, these hormones cause almost the same

sympathetic nervous system; it secretes the hor-

per cent of the gland, is functionally related to the

The adrenal medulla, the central 20

two distinct parts, the

As shown in Figure 77–1, each gland is composed of

4 grams, lie at the superior poles of the two kidneys.

adrenal glands,

The two

944

Adrenocortical Hormones

each of which weighs about

adrenal medulla and the

adrenal cortex.

mones epinephrine and norepinephrine in response

tion to the sympathetic nervous system.

Corticosteroids Mineralocorticoids, Glucocorticoids, and Androgens.

mineralocorticoids and the

are

which exhibit about the

mineralocorticoids have gained this name because they especially affect

glucocorticoids have gained their name because they

additional effects on both protein and fat metabolism that are equally as impor-
tant to body function as their effects on carbohydrate metabolism.

are of exceptional importance to the normal endocrine function of the human
body:

cortisol, which

is the principal glucocorticoid.

The Adrenal Cortex Has Three Distinct Layers.

cortex is composed of three relatively distinct layers:

a thin layer of cells that lies just underneath the

the only ones in the adrenal gland capable of secreting significant amounts
of aldosterone because they contain the enzyme

is controlled mainly by the extracellular fluid concentrations of angiotensin
II and potassium, both of which stimulate aldosterone secretion.

cent of the adrenal cortex and secretes the glucocorticoids cortisol and

-Fluorocortisol (synthetic, slightly more potent

• Corticosterone (slight mineralocorticoid activity)

aldosterone, but very small quantities secreted)

• Desoxycorticosterone (1/30 as potent as

• Aldosterone (very potent, accounts for about 90 per

following as summarized in Table 77–1:

teroid hormones, including the synthetic ones, are the

therapy. Some of the more important of the corticos-

adrenal cortex. And several additional potent steroid

both, are normally secreted in small amounts by the

having glucocorticoid or mineralocorticoid activities, or

In addition to aldosterone and cortisol, other steroids

21. The mineralocorticoid aldosterone has an oxygen

Figure 77–2. Cortisol has a keto-oxygen on carbon

glucocorticoid hormones, respectively, are shown in

The chemical formulas of aldosterone and cortisol,

activity of only one of the enzymes in this pathway.

formed. For example, very large quantities of masculin-

catalyzed by a specific enzyme system. A change in even

of these organelles and some in the other. Each step is

mitochondria

in two of the organelles of the cell, the

tisol, and the androgens. Essentially all these steps occur

steroid products of the adrenal cortex: aldosterone, cor-

Figure 77–2 gives

pregnenolone.

secretion, increase the conversion of cholesterol to

tion, and angiotensin II, which stimulates aldosterone

example, both ACTH, which stimulates cortisol secre-

major hormone products aldosterone and cortisol. For

cortex, this initial step in steroid synthesis is stimulated

steroids (Figure 77–2). In all three zones of the adrenal

cholesterol desmolase

the mitochondria, where it is cleaved by the enzyme

Once the cholesterol enters the cell, it is delivered to

for LDL, as well as the activity of enzymes that liberate

ACTH, which stimulates adrenal steroid synthesis,

the amount available for steroid synthesis. For example,

Transport of cholesterol into the adrenal cells is reg-

hormones.

endocytosis,

the adrenocortical cell membranes. The coated pits are

high concentrations of cholesterol, diffuse from the

(LDL) in the circulating plasma. The LDLs, which have

de novo small amounts of cholesterol from acetate,

by the adrenal cortex, are synthesized from cholesterol.

All human steroid hormones, including those produced

as ACTH that increase secretion of cortisol and

no effect on the other two zones. Similarly, factors such

independent mechanisms. Factors such as angiotensin

mineralocorticoids.

androgen production, however, are not nearly as

involved. The mechanisms for controlling adrenal

released from the pituitary, may also be

hormone,

regulates secretion of these cells, although other

estrogens and some glucocorticoids. ACTH also

androstenedione,

cortex, secretes the adrenal androgens

zona reticularis,

3. The

adrenocorticotropic hormone (ACTH).

The secretion

estrogens.

corticosterone,

Chapter 77

Adrenocortical Hormones

945

as well as small amounts of

adrenal androgens and
of these cells is controlled in large part by
the hypothalamic-pituitary axis via

the deep layer of the

dehydroepiandrosterone (DHEA) and

as well as small amounts of

factors such as cortical androgen-stimulating

well understood as those for glucocorticoids and

Aldosterone and cortisol secretion are regulated by

II that specifically increase the output of aldosterone
and cause hypertrophy of the zona glomerulosa have

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.

Although the cells of the adrenal cortex can synthesize

approximately 80 per cent of the cholesterol used for
steroid synthesis is provided by low-density lipoproteins

plasma into the interstitial fluid and attach to specific
receptors contained in structures called coated pits on

then internalized by

forming vesicles that

eventually fuse with cell lysosomes and release choles-
terol that can be used to synthesize adrenal steroid

ulated by feedback mechanisms that can markedly alter

increases the number of adrenocortical cell receptors

cholesterol from LDL.

to form pregnenolone; this is the

rate-limiting step in the eventual formation of adrenal

by the different factors that control secretion of the

Synthetic Pathways for Adrenal Steroids.

the principal steps in the formation of the important

and

the endoplasmic reticulum, some steps occurring in one

a single enzyme in the schema can cause vastly differ-
ent types and relative proportions of hormones to be

izing sex hormones or other steroid compounds not
normally present in the blood can occur with altered

which are the most important mineralocorticoid and

number 3 and is hydroxylated at carbon numbers 11 and

atom bound at the number 18 carbon.

hormones not normally formed in the adrenal glands
have been synthesized and are used in various forms of

Mineralocorticoids

cent of all mineralocorticoid activity)

• 9

than aldosterone)

Cortisol
and
androgens

Magnified section

Zona glomerulosa
aldosterone

Zona fasciculata

Zona reticularis

Cortex

Medulla

(catecholamines)

adrenal cortex and secretion of catecholamines by the adrenal

Secretion of adrenocortical hormones by the different zones of the

Figure 77–1

medulla.

946

Unit XIV

Endocrinology and Reproduction

20 Lyase

(P450 c11AS)

(P450 c11)

Cholesterol

desmolase
(P450 scc)

-Hydroxylase

(P450 c17)

-Hydroxysteroid

dehydrogenase

21 20

23
24

-Hydroxylase

(P450 c17)

-Hydroxylase

(P450 c21)

-Hydroxylase

Aldosterone

synthase

(P450 c17)

Pregnenolone

Progesterone

11-Deoxycorticosterone

Corticosterone

17-Hydroxypregnenolone

17-Hydroxyprogesterone

Dehydroepl-
androsterone

Androstenedione

11-Deoxycortisol

Cortisol

Aldosterone

Cholesterol

Pathways for synthesis of steroid hormones by the adrenal cortex. The enzymes are shown in italics.

Figure 77–2

tration of the extracellular fluid rises markedly, sodium

Without mineralocorticoids, potassium ion concen-

therapy or injection of mineralocorticoids.

Total loss of adreno-

Chloride Wasting and Hyperkalemia.

Aldosterone

Mineralocorticoids-

20 mg/day.

12 µg/100 ml, and the secretory rate averages 15 to

The concentration of cortisol in the blood averages

150 µg/day (0.15 mg/day).

100 ml, and the average secretory rate is approximately

The normal concentration of aldosterone in blood

inactive conjugates.

mones, and kidney diseases reduce the excretion of the

and excreted in the urine. Diseases of the liver markedly

plasma, and are therefore filtered readily by the kidneys

bound to plasma proteins, are highly soluble in the

the bile and then in the feces. The remaining conjugates

not have mineralocorticoid or glucocorticoid activity.

extent, sulfates. These substances are inactive and do

and, to a lesser

The

Adrenocortical Hormones Are Metabolized in the Liver.

tion of the adrenal hormones to the tissues.

episodic secretion of ACTH. This reservoir function

example, with cortisol during brief periods of stress and

in free hormone concentrations, as would occur, for

minutes. In both the combined and free forms, the hor-

so that about 40 per cent is in the free form; as a result,

culating aldosterone combines with the plasma proteins,

life of 60 to 90 minutes. Only about 60 per cent of cir-

the plasma; therefore, cortisol has a relatively long half-

lesser extent, to albumin. This high degree of binding to

and, to a

plasma binds to plasma proteins, especially a globulin

tant drug for stimulating specific glucocorticoid activity.

eralocorticoid activity, makes this an especially impor-

hormone dexamethasone, which has almost zero min-

The intense glucocorticoid activity of the synthetic

potent glucocorticoid effects.

mineralocorticoid effects, along with its much more

amount of mineralocorticoid activity, because some syn-

ties.

• Dexamethasone (synthetic, 30 times as potent as

• Methylprednisone (synthetic, five times as potent as

• Prednisone (synthetic, four times as potent as

• Cortisone (synthetic, almost as potent as cortisol)

glucocorticoid activity, but much less potent than

• Corticosterone (provides about 4 per cent of total

• Cortisol (very potent, accounts for about 95 per

• Cortisone (synthetic, slight mineralocorticoid

• Cortisol (very slight mineralocorticoid activity, but

Chapter 77

Adrenocortical Hormones

947

large quantity secreted)

activity)

Glucocorticoids

cent of all glucocorticoid activity)

cortisol)

cortisol)
It is clear from this list that some of these hormones

have both glucocorticoid and mineralocorticoid activi-

It is especially significant that cortisol has a small

dromes of excess cortisol secretion can cause significant

Adrenocortical Hormones Are Bound to Plasma Proteins.

Approximately 90 to 95 per cent of the cortisol in the

called cortisol-binding globulin or transcortin

plasma proteins slows the elimination of cortisol from

aldosterone has a relatively short half-life of about 20

mones are transported throughout the extracellular
fluid compartment.

Binding of adrenal steroids to the plasma proteins

may serve as a reservoir to lessen rapid fluctuations

may also help to ensure a relatively uniform distribu-

adrenal steroids are degraded mainly in the liver and
conjugated especially to glucuronic acid

About 25 per cent of these conjugates are excreted in

formed by the liver enter the circulation but are not

depress the rate of inactivation of adrenocortical hor-

is about 6 nanograms (6 billionths of a gram) per

Functions of the

Mineralocorticoid Deficiency Causes Severe Renal Sodium

cortical secretion usually causes death within 3 days to
2 weeks unless the person receives extensive salt

Table 77–1

-fluorocortisol

—

125

Dexamethasone

—

Methylprednisone

—

Prednisolone

—

0.8

Cortisone

—

1.0

Dehydroepiandrosterone

175

—

Deoxycorticosterone

0.006

0.2

100

Aldosterone

0.006

0.15

0.3

3000

Corticosterone

0.4

0.3

15.0

Cortisol

g/100 ml)

Secreted (mg/24 hr)

Activity

(free and bound,

Average Amount

Glucocorticoid

Mineralocorticoid

Average Plasma

Adrenal Steroid Hormones in Adults; Synthetic Steroids and Their Relative Glucocorticoid and Mineralocorticoid Activities

Concentration

Steroids

Adrenal Steroids

Synthetic Steroids

Glucocorticoid and mineralocorticoid activities of the steroids are relative to cortisol, with cortisol being 1.0.

This return to normal of salt and water excretion by

water to normal despite the excess aldosterone (Figure

sure also increases 15 to 25 mm Hg, and this elevated

increases 5 to 15 per cent above normal, arterial pres-

respectively. Thus, after the extracellular fluid volume

pressure diuresis,

water, called

explained in Chapter 19. The rise in arterial pressure

also leads to an increase in arterial pressure, as

secreted. An aldosterone-mediated increase in extra-

powerful sodium-retaining hormones, only transient

Even though aldosterone is one of the body’s most

retained sodium, but without much change in sodium

intake, if water is available. Therefore, the extracellu-

Also, small increases in extracellular fluid sodium

absorption of almost equivalent amounts of water.

sorbed by the tubules, there is simultaneous osmotic

lents. The reason for this is that when sodium is reab-

by the kidneys, the concentration of sodium in the

Excess Aldosterone Increases Extracellular Fluid Volume and

of all the sodium in the body. At the same time, potas-

urine a day, an amount equal to one tenth to one fifth

Conversely, total lack of aldosterone secretion can

fold. Therefore, the net effect of excess aldosterone

time, potassium loss into the urine increases several-

to as little as a few milliequivalents a day. At the same

potassium excretion in the urine.

lecting ducts. Therefore, aldosterone causes sodium to

and, to a lesser extent, in the distal tubules and col-

Aldosterone Increases Renal Tubular Reabsorption of Sodium

nearly 2000 times that of aldosterone.

of cortisol, but the plasma concentration of cortisol is

of mineralocorticoid activity. Aldosterone’s mineralo-

the adrenal cortex, also provides a significant amount

tions, but cortisol, the major glucocorticoid secreted by

discussed later in the chapter.

life’s intermittent physical and mental “stresses,” as

The glucocorticoids are equally necessary, however,

“lifesaving” portion of the adrenocortical hormones.

fore, the mineralocorticoids are said to be the acute

aldosterone or some other mineralocorticoid. There-

shocklike state, followed by death. This entire

diminished cardiac output, which progresses to a

become greatly reduced. The person soon develops

and chloride are rapidly lost from the body, and the

948

Unit XIV

Endocrinology and Reproduction

total extracellular fluid volume and blood volume

sequence can be prevented by the administration of

allowing the person to resist the destructive effects of

Aldosterone Is the Major Mineralocorticoid Secreted by the
Adrenals.

Aldosterone exerts nearly 90 per cent of the

mineralocorticoid activity of the adrenocortical secre-

corticoid activity is about 3000 times greater than that

Renal and Circulatory Effects
of Aldosterone

and Secretion of Potassium.

It will be recalled from

Chapter 27 that aldosterone increases absorption
of sodium and simultaneously increases secretion
of potassium by the renal tubular epithelial cells-
especially in the principal cells of the collecting tubules

be conserved in the extracellular fluid while increasing

A high concentration of aldosterone in the plasma

can transiently decrease the sodium loss into the urine

in the plasma is to increase the total quantity of
sodium in the extracellular fluid while decreasing the
potassium.

cause transient loss of 10 to 20 grams of sodium in the

sium is conserved tenaciously in the extracellular fluid.

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

extracellular fluid often rises only a few milliequiva-

concentration stimulate thirst and increased water

lar fluid volume increases almost as much as the

concentration.

sodium retention occurs when excess amounts are

cellular fluid volume lasting more than 1 to 2 days

then increases kidney excretion of both salt and

pressure natriuresis and

blood pressure returns the renal output of salt and

77–3).

the kidneys as a result of pressure natriuresis and

110

10 12

100

400

300

200

Urinary sodium

excretion (mEq/day)

100

120

Extracellular fluid

volume (% Normal)

100

120

Mean arterial

pressure (mm Hg)

Time (days)

Aldosterone

arterial pressure in aldosterone “escape.” Hypertension 6 (suppl

Granger JP, Smith MJ Jr, Premen N: Role of hemodynamics and

sodium excretion returned to normal. (Drawn from data in Hall JE,

second day of infusion as arterial pressure increased and urinary

20 times normal, note the “escape” from sodium retention on the

fluid volume, and sodium excretion in dogs. Although aldosterone

Effect of aldosterone infusion on arterial pressure, extracellular

Figure 77–3

was infused at a rate that raised plasma concentrations to about

I):I-183–I-192, 1984.)

from the tubular lumen into the cell; then the sodium

equally important, are epithelial sodium channel pro-

renal tubular cells. Additional proteins, perhaps

potassium adenosine triphosphatase,

and hydrogen transport through the cell membrane.

acting together, are required for sodium, potassium,

and (2) membrane transport proteins that, all

ribosomes, it causes protein formation. The proteins

cytoplasm, where, operating in conjunction with the

Fourth, the messenger RNA diffuses back into the

one or more types of messenger RNA related to the

ing one or more specific portions of the DNA to form

where it may undergo further alterations, finally induc-

product of this complex diffuses into the nucleus,

Third, the aldosterone-receptor complex or a

terone combines with a highly specific cytoplasmic

Second, in the cytoplasm of the tubular cells, aldos-

of the tubular epithelial cells.

membranes, aldosterone diffuses readily to the interior

First, because of its lipid solubility in the cellular

following.

However, the cellular sequence of events that leads

effects of mineralocorticoids on the body, the basic

Aldosterone Action

loss of salt from the body.

chloride and water then lead to diarrhea, with further

anions and water as well. The unabsorbed sodium

poor, leading to failure to absorb chloride and other

absence of aldosterone, sodium absorption can be

prevents loss of sodium in the stools. Conversely, in the

tion by the intestines, especially in the colon, which

environments, and the effect on the salivary glands is

secretion of potassium by the ducts. The effect on the

bicarbonate ions are secreted. Aldosterone greatly

excretory ducts, is reabsorbed, whereas potassium and

much of the sodium chloride, on passing through the

that contains large quantities of sodium chloride, but

tubules. Both these glands form a primary secretion

Potassium Transport in Sweat Glands,

Aldosterone Stimulates Sodium and

cellular fluid, causing a mild degree of alkalosis.

of the cortical collecting tubules. This

Excess Aldosterone Increases Tubular Hydrogen Ion Secretion,

of potassium lead inevitably to heart failure.

becomes evident; progressively higher concentrations

normal, serious cardiac toxicity, including weakness of

above normal.When it rises to 60 to 100 per cent above

Conversely, when aldosterone is deficient, the extra-

vents transmission of normal action potentials.

muscle fiber membranes (see Chapter 5), which pre-

muscle weakness often develops. This is caused by

tration falls below about one-half normal, severe

When the potassium ion concen-

4.5 mEq/L to as low as 2 mEq/L. This condition is

concentration, sometimes from the normal value of

as occurs with some types of adrenal tumors, may

body. Therefore, excessive secretion of aldosterone,

Toxicity.

ness; Too Little Aldosterone Causes Hyperkalemia and Cardiac

Excess Aldosterone Causes Hypokalemia and Muscle Weak-

stop secreting aldosterone.

Without therapy, this usually causes death

tory shock.

dehydration and low blood volume, leading to

fluid volume. The result is severe extracellular fluid

zero, large amounts of salt are lost in the urine, not

Conversely, when aldosterone secretion becomes

person remains exposed to high levels of aldosterone.

developed hypertension, which lasts as long as the

aldosterone. In the meantime, however, the person has

rate of gain of salt and water by the body is zero, and

Thereafter, the

aldosterone escape.

Chapter 77

Adrenocortical Hormones

949

diuresis is called

balance is maintained between salt and water intake
and output by the kidneys despite continued excess

only diminishing the amount of sodium chloride in the
extracellular fluid but also decreasing the extracellular

circula-

within a few days after the adrenal glands suddenly

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

cause a serious decrease in the plasma potassium

called hypokalemia.

alteration of the electrical excitability of the nerve and

cellular fluid potassium ion concentration can rise far

heart contraction and development of arrhythmia,

and Causes Mild 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 sodium in the interca-
lated cells
decreases the hydrogen ion concentration in the extra-

Salivary Glands, and Intestinal
Epithelial Cells

Aldosterone has almost the same effects on sweat
glands and salivary glands as it has on the renal

increases the reabsorption of sodium chloride and the

sweat glands is important to conserve body salt in hot

necessary to conserve salt when excessive quantities of
saliva are lost.

Aldosterone also greatly enhances sodium absorp-

Cellular Mechanism of

Although for many years we have known the overall

action of aldosterone on the tubular cells to increase
transport of sodium is still not fully understood.

to increased sodium reabsorption seems to be the

receptor protein, a protein that has a stereomolecular
configuration that allows only aldosterone or very
similar compounds to combine with it.

process of sodium and potassium transport.

formed are a mixture of (1) one or more enzymes

One of the enzymes especially increased is sodium-

which serves as

the principal part of the pump for sodium and potas-
sium exchange at the basolateral membranes of the

teins inserted into the luminal membrane of the same
tubular cells that allows rapid diffusion of sodium ions

remain considerably deranged. Furthermore, the

for utilization of proteins, carbohydrates, and fats

is far from normal. Instead, its metabolic systems

an acutely adrenalectomized animal, the animal still

Glucocorticoids

aldosterone is required, but total absence of ACTH

anterior pituitary gland, it is usually enough to permit

there is even a small amount of ACTH secreted by the

double aldosterone secretion. In the case of ACTH, if

tion, which occurs on rare occasions, can perhaps

tion are usually minor. Nevertheless, a 10 to 20 per cent

per se and of ACTH in controlling aldosterone secre-

By contrast, the effects of sodium ion concentration

fold. Note that blocking angiotensin II formation

Figure 77–4 shows the effects on plasma aldosterone

functions.

maintaining life, and the reader is referred again to

These feedback control mechanisms are essential for

angiotensin system toward its normal level of activity.

volume and arterial pressure, thus returning the renin-

increase in aldosterone secretion. In turn, the aldos-

kidneys or to sodium loss, can cause a severalfold

Likewise, activation of the renin-angiotensin system,

potent in regulating aldosterone secretion. A small

Of these factors,

4. ACTH from the anterior pituitary gland is

3. Increased sodium ion concentration in the

2. Increased activity of the renin-angiotensin system

1. Increased potassium ion concentration in the

their importance, they are as follows:

regulation of aldosterone. In the probable order of

Four factors are known to play essential roles in the

ciculata and zona reticularis.

The regulation of aldosterone secretion by the zona

referred. However, it is important to list here some of

detail in Chapters 28 and 29, to which the reader is

of all these other factors. This subject is presented in

blood volume, arterial pressure, and many special

electrolyte concentrations, extracellular fluid volume,

The regulation of aldosterone secretion is so deeply

Regulation of Aldosterone Secretion

terone has not been determined, nor is the physiolog-

messenger system. However, the precise structure of

teins. In other cell types, aldosterone has been shown

less than two minutes, a time period that is far too

For example, aldosterone has been shown to increase

that are coupled to second messenger systems, similar

These nongenomic actions are believed to be medi-

in a few seconds or minutes.

teins, but also rapid

effects that have a latency of 60 to 90 minutes and

aldosterone, elicit not only slowly developing

Recent studies suggest that many steroids, including

of Aldosterone and Other

Possible Nongenomic Actions

several hours.

increase; the effect reaches maximum only after

RNA appears in the cells, and about 45 minutes is

transport. About 30 minutes is required before new

on sodium transport; rather, this effect must await the

Thus, aldosterone does not have an immediate effect

950

Unit XIV

Endocrinology and Reproduction

is pumped the rest of the way by the sodium-potassium
pump located in the basolateral membranes of the cell.

sequence of events that leads to the formation of the
specific intracellular substances required for sodium

required before the rate of sodium transport begins to

Steroid Hormones

genomic

require gene transcription and synthesis of new pro-

nongenomic effects that take place

ated by binding of steroids to cell membrane receptors

to those used for peptide hormone signal transduction.

formation of cAMP in vascular smooth muscle cells
and in epithelial cells of the renal collecting tubules in

short for gene transcription and synthesis of new pro-

to rapidly stimulate the phosphatidylinositol second

receptors responsible for the rapid effects of aldos-

ical significance of these nongenomic actions of
steroids well understood.

intertwined with the regulation of extracellular fluid

aspects of renal function that it is difficult to discuss
the regulation of aldosterone secretion independently

the more important points of aldosterone secretion
control.

glomerulosa cells is almost entirely independent of the
regulation of cortisol and androgens by the zona fas-

extracellular fluid greatly increases aldosterone
secretion.

(increased levels of angiotensin II) also greatly
increases aldosterone secretion.

extracellular fluid very slightly decreases
aldosterone secretion.

necessary for aldosterone secretion but has little
effect in controlling the rate of secretion.

potassium ion concentration

and the renin-angiotensin system are by far the most

percentage increase in potassium concentration can
cause a severalfold increase in aldosterone secretion.

usually in response to diminished blood flow to the

terone acts on the kidneys (1) to help them excrete the
excess potassium ions and (2) to increase the blood

Chapters 27 and 29 for a full understanding of their

concentration caused by blocking the formation of
angiotensin II with an angiotensin-converting enzyme
inhibitor after several weeks of a low-sodium diet that
increases plasma aldosterone concentration several-

markedly decreases plasma aldosterone concentration
without significantly changing cortisol concentration;
this indicates the important role of angiotensin II in
stimulating aldosterone secretion when sodium intake
and extracellular fluid volume are reduced.

decrease in extracellular fluid sodium ion concentra-

the adrenal glands to secrete whatever amount of

can significantly reduce aldosterone secretion.

Functions of the

Even though mineralocorticoids can save the life of

adrenal diabetes.

The increase in blood glucose concentration is occa-

hormone.

insulin’s actions on the tissues. In this way, excess

ticoids to mobilize lipids from fat depots, may impair

levels of fatty acids, caused by the effect of glucocor-

and utilization. One possible explanation is that high

tissues, especially skeletal muscle and adipose tissue,

For reasons that are not entirely clear, high levels

plasma glucose as they are under normal conditions.

insulin, however, are not as effective in maintaining

secretion of insulin. The increased plasma levels of

rise. The rise in blood glucose in turn stimulates

by the cells.

NADH must be oxidized to allow glycolysis, this effect

. Because

dinucleotide (NADH) to form NAD

delays the rate of glucose utilization. A suggested

into the cells and its final degradation, cortisol directly

decrease is unknown, most physiologists believe that

by most cells in the body. Although the cause of this

glucose in times of need, such as between meals.

mones, such as epinephrine and glucagon, to mobilize

This effect of cortisol allows other glycolytic hor-

marked increase in glycogen storage in the liver cells.

of glucose.

result, more amino acids become available in the

As a

the extrahepatic tissues mainly from muscle.

required for gluconeogenesis.

RNAs that in turn lead to the array of enzymes

renal tubular cells, with formation of messenger

activate DNA transcription in the liver cell nuclei

This

amino acids into glucose in the liver cells.

This results mainly from two effects of cortisol.

some other substances) by the liver, often increasing

Effects of Cortisol on

corticosterone.

addition to this, a small but significant amount of glu-

hydrocortisone.

sections.

eralocorticoids. They are explained in the following

tract infections can lead to death. Therefore, the glu-

mental stress, and minor illnesses such as respiratory

Chapter 77

Adrenocortical Hormones

951

animal cannot resist different types of physical or even

cocorticoids have functions just as important to the
long-continued life of the animal as those of the min-

At least 95 per cent of the glucocorticoid activity of

the adrenocortical secretions results from the secre-
tion of cortisol, known also as

cocorticoid activity is provided by

Carbohydrate Metabolism

Stimulation of Gluconeogenesis.

By far the best-known

metabolic effect of cortisol and other glucocorticoids
on metabolism is their ability to stimulate gluconeo-
genesis (formation of carbohydrate from proteins and

the rate of gluconeogenesis as much as 6- to 10-fold.

1. Cortisol increases the enzymes required to convert

results from the effect of the glucocorticoids to

in the same way that aldosterone functions in the

2. Cortisol causes mobilization of amino acids from

plasma to enter into the gluconeogenesis process
of the liver and thereby to promote the formation

One of the effects of increased gluconeogenesis is a

Decreased Glucose Utilization by Cells.

Cortisol also causes

a moderate decrease in the rate of glucose utilization

somewhere between the point of entry of glucose

mechanism is based on the observation that glucocor-
ticoids depress the oxidation of nicotinamide-adenine

could account for the diminished utilization of glucose

Elevated Blood Glucose Concentration and “Adrenal Diabetes.”

Both the increased rate of gluconeogenesis and the
moderate reduction in the rate of glucose utilization
by the cells cause the blood glucose concentrations to

of glucocorticoid reduce the sensitivity of many

to the stimulatory effects of insulin on glucose uptake

secretion of glucocorticoids may produce disturbances
of carbohydrate metabolism very similar to those
found in patients with excess levels of growth

sionally great enough (50 per cent or more above
normal) that the condition is called
Administration of insulin lowers the blood glucose
concentration only a moderate amount in adrenal
diabetes-not nearly as much as it does in pancreatic

Control

ACE inhibitor

0.0

3.0

2.0

1.0

Ang II infusion

ACE

inhibitor

Plasma cortisol

(

g/100 ml)

Plasma aldosterone

g/100 ml)

Coleman TG: Chronic blockade of angiotensin II formation during

tion. (Drawn from data in Hall JE, Guyton AC, Smith MJ Jr,

Ang II in stimulating aldosterone secretion during sodium deple-

with little effect on cortisol, demonstrating the important role of

ing Ang II formation reduced plasma aldosterone concentration

restore plasma Ang II levels after ACE inhibition. Note that block-

converting enzyme (ACE) inhibitor for 7 days to block formation

Effects of treating sodium-depleted dogs with an angiotensin-

Figure 77–4

of angiotensin II (Ang II) and of infusing exogenous Ang II to

sodium deprivation. Am J Physiol 237:F424, 1979.)

cortical secretion of cortisol. This is demonstrated

in ACTH secretion by the anterior pituitary gland,

genic, causes an immediate and marked increase

Almost any type of stress, whether physical or neuro-

Cortisol is Important in Resisting

results from excess stimulation of food intake, with fat

unknown, it has been suggested that this obesity

and a rounded “moon face.” Although the cause is

head regions of the body, giving a buffalo-like torso

obesity, with excess deposition of fat in the chest and

mobilization from adipose tissue, many people with

in insulin, as we discuss in Chapter 78. Nevertheless,

tisol mechanism, however, requires several hours to

acids in times of starvation or other stresses. This cor-

cells, helps shift the metabolic systems of the cells from

The increased mobilization of fats by cortisol, com-

the fat cells begin to release fatty acids.

nance of triglycerides in these cells, and in its absence

glucose, is required for both deposition and mainte-

-glycerophosphate, which is derived from

diminished transport of glucose into the fat cells.

However, part of the effect probably results from

The mechanism by which cortisol promotes fatty

cells.

lization for energy. Cortisol also seems to have a direct

fatty acids in the plasma, which also increases their uti-

adipose tissue. This increases the concentration of free

muscle, it promotes mobilization of fatty acids from

Effects of Cortisol on Fat Metabolism

the hepatic effects.

gluconeogenesis. Thus, it is possible that many of the

version of amino acids to glucose-that is, enhanced

plasma proteins by the liver, and (4) increased con-

synthesis in the liver, (3) increased formation of

of amino acids by the liver, (2) increased protein

The increased plasma concentration of amino acids

cortisol mobilizes amino acids from the nonhep-

fore,

increase the plasma amino acid concentration. There-

existing proteins, and these diffuse out of the cells to

thesis of protein.Yet, catabolism of proteins in the cells

The decreased transport of amino acids into extra-

cells.

Acids into Extrahepatic Cells, and Enhanced Transport into

Increased Blood Amino Acids, Diminished Transport of Amino

liver enzymes required for protein synthesis.

occurs elsewhere in the body. It is believed that this

then released into the blood) are also increased. These

the liver proteins become enhanced. Furthermore, the

tally with the reduced proteins elsewhere in the body,

rise from the squatting position. And the immunity

In the presence of great excesses of cortisol, the

lymphoid tissue.

in many extrahepatic tissues, especially in muscle and

formation of RNA and subsequent protein synthesis

the major cause, because cortisol also depresses the

hepatic tissues, as discussed later; this probably is not

of protein already in the cells. Both these effects may

cells except those of the liver. This is caused by both

Effects of Cortisol on

952

Unit XIV

Endocrinology and Reproduction

diabetes-because the tissues are resistant to the effects
of insulin.

Protein Metabolism

Reduction in Cellular Protein.

One of the principal effects

of cortisol on the metabolic systems of the body is
reduction of the protein stores in essentially all body

decreased protein synthesis and increased catabolism

result from decreased amino acid transport into extra-

muscles can become so weak that the person cannot

functions of the lymphoid tissue can be decreased to a
small fraction of normal.

Cortisol Increases Liver and Plasma Proteins.

Coinciden-

plasma proteins (which are produced by the liver and

increases are exceptions to the protein depletion that

difference results from a possible effect of cortisol to
enhance amino acid transport into liver cells (but
not into most other cells) and to enhance the

Hepatic Cells.

Studies in isolated tissues have demon-

strated that cortisol depresses amino acid transport
into muscle cells and perhaps into other extrahepatic

hepatic cells decreases their intracellular amino acid
concentrations and consequently decreases the syn-

continues to release amino acids from the already

atic tissues and in doing so diminishes the tissue stores
of protein.

and enhanced transport of amino acids into the
hepatic cells by cortisol could also account for
enhanced utilization of amino acids by the liver to
cause such effects as (1) increased rate of deamination

effects of cortisol on the metabolic systems of the body
result mainly from this ability of cortisol to mobilize
amino acids from the peripheral tissues while at the
same time increasing the liver enzymes required for

Mobilization of Fatty Acids.

In much the same manner

that cortisol promotes amino acid mobilization from

effect to enhance the oxidation of fatty acids in the

acid mobilization is not completely understood.

Recall that

bined with increased oxidation of fatty acids in the

utilization of glucose for energy to utilization of fatty

become fully developed-not nearly so rapid or so pow-
erful an effect as a similar shift elicited by a decrease

the increased use of fatty acids for metabolic energy is
an important factor for long-term conservation of
body glucose and glycogen.

Obesity Caused by Excess Cortisol.

Despite the fact that

cortisol can cause a moderate degree of fatty acid

excess cortisol secretion develop a peculiar type of

being generated in some tissues of the body more
rapidly than it is mobilized and oxidized.

Stress and Inflammation

followed within minutes by greatly increased adreno-

decreased quantity.

stored in the lysosomes, are released in greatly

cells to cause inflammation, which are mainly

lysosomes to rupture. Therefore, most of the

effects, because it is much more difficult than

This

Cortisol stabilizes the lysosomal membranes.

ing Lysosomes and by Other Effects.

Cortisol Prevents the Development of Inflammation by Stabiliz-

explained further as follows.

increased rapidity of healing. These effects are

even begins, or (2) if inflammation has already begun,

injected into a person, the cortisol has two basic

When large amounts of cortisol are secreted or

healing process.

the area by leukocytes; and (5) after days or weeks,

ability, followed by clotting of the tissue fluid, thus

some of the released products from the tissues, an

enzymes, prostaglandins, and leukotrienes; (2) an

chemicals such as histamine, bradykinin, proteolytic

There are five main stages of inflammation: (1)

process, discussed in more detail in Chapter 33.

once it has begun. Before attempting to explain the

aging than the trauma or disease itself. The adminis-

rheumatoid arthritis, the inflammation is more dam-

become “inflamed.” In some conditions, such as in

with bacteria, or in other ways, they almost always

When tissues are damaged by trauma, by infection

of Cortisol

Anti-inflammatory Effects of High Levels

tial to life.

released. This preferential effect of cortisol in

neurons, until almost all other proteins have been

the basic functional proteins of the cells, such as

But all this is mainly supposition. It is supported

of new cells.

pyrimidines, and creatine phosphate, which are neces-

other essential intracellular substances such as purines,

Also, the amino acids are perhaps used to synthesize

new proteins that are essential to the lives of the cells.

Indeed, it has been shown in a few instances that

ing glucose, needed by the different tissues of the body.

energy and for synthesis of other compounds, includ-

stores, making them immediately available both for

why this is of significant benefit to the animal. One

increases greatly in stressful situations, we are not sure

8. Almost any debilitating disease

7. Restraining an animal so that it cannot move

6. Injection of necrotizing substances beneath the

5. Surgery

4. Injection of norepinephrine and other

3. Intense heat or cold

2. Infection

1. Trauma of almost any type

fracture of two leg bones.

dramatically by the experiment shown in Figure 77–5,

Chapter 77

Adrenocortical Hormones

953

in which corticosteroid formation and secretion
increased sixfold in a rat within 4 to 20 minutes after

Some of the different types of stress that increase

cortisol release are the following:

sympathomimetic drugs

skin

Even though we know that cortisol secretion often

possibility is that the glucocorticoids cause rapid mobi-
lization of amino acids and fats from their cellular

damaged tissues that are momentarily depleted of pro-
teins can use the newly available amino acids to form

sary for maintenance of cellular life and reproduction

only by the fact that cortisol usually does not mobilize

the muscle contractile proteins and the proteins of

mobilizing labile proteins could make amino acids
available to needy cells to synthesize substances essen-

tration of large amounts of cortisol can usually block
this inflammation or even reverse many of its effects

way in which cortisol functions to block inflammation,
let us review the basic steps in the inflammation

release from the damaged tissue cells of chemical
substances that activate the inflammation process-

increase in blood flow in the inflamed area caused by

effect called erythema; (3) leakage of large quantities
of almost pure plasma out of the capillaries into the
damaged areas because of increased capillary perme-

causing a nonpitting type of edema; (4) infiltration of

ingrowth of fibrous tissue that often helps in the

anti-

inflammatory effects: (1) it can block the early stages
of the inflammation process before inflammation

it causes rapid resolution of the inflammation and

Cortisol has the fol-

lowing effects in preventing inflammation:
1.

is one of its most important anti-inflammatory

normal for the membranes of the intracellular

proteolytic enzymes that are released by damaged

45 60 90 2

3 4 5 6 8 101215 20 25 30

Seconds

Minutes

45
40
35
30
25
20
15
10

55
50
45
40
35
30
25
20
15
10

Plasma corticosterone

concentration

(mg/100 ml)

Adrenal cortisone

concentration

(mg/g)

Dear, and Lipscomb.)

terone is secreted in place of cortisol.) (Courtesy Drs. Guillemin,

fracture of the tibia and fibula at time zero. (In the rat, corticos-

Rapid reaction of the adrenal cortex of a rat to stress caused by

Figure 77–5

that mediate their multiple physiologic effects. Thus,

many genes to alter synthesis of mRNA for the proteins

coid response elements.

factors,

scription. Other proteins in the cell, called

coid response elements,

specific regulatory DNA sequences, called

cortisol binds with its protein receptor in the cytoplasm,

diffuse through the cell membrane. Once inside the cell,

cells. Because cortisol is lipid soluble, it can easily

Cortisol, like other steroid hormones, exerts its effects

Cortisol Action

Cellular Mechanism of

no cortisol, anemia often results.

results, and conversely, when the adrenal glands secrete

secreted by the adrenal glands, polycythemia often

by mechanisms that are unclear. When excess cortisol is

transplanted hearts, kidneys, and other tissues.

been arrested. Conversely, this ability of cortisol and

that would otherwise not be lethal, such as fulminating

invaders of the body is decreased. This occasionally can

As a result, the level of immunity for almost all foreign

of both T cells and antibodies from the lymphoid tissue.

throughout the body, which in turn decreases the output

Likewise, the administration of large doses of cortisol

phocytopenia or eosinopenia is an important diagnostic

marked within a few hours. Indeed, a finding of lym-

phocytes in the blood; this effect begins within a few

anaphylaxis, which otherwise kills many people, as

instance, cortisol effectively prevents shock or death in

release of inflammatory products, can be lifesaving. For

effects of allergic reactions, administration of cortisol,

However, because the inflammatory response is respon-

secondary effects of the allergic reaction still occur.

body is not affected by cortisol, and even some of the

The basic allergic reaction between antigen and anti-

Cortisol Blocks the Inflammatory Response to Allergic Reactions.

Other Effects of Cortisol

often be a lifesaving measure.

ing effects of the inflammatory response, this alone can

basic disease condition, merely preventing the damag-

the inflammation begins to subside within 24 hours.

tered to patients with these diseases, almost invariably

When cortisol or other glucocorticoids are adminis-

disease.

characterized by severe local inflammation, and the

and acute glomerulonephritis. All these diseases are

eases, such as rheumatoid arthritis, rheumatic fever,

anti-inflammatory effect occurs, this effect of cortisol

products.

lular energy; or perhaps it depends on some effect of

able in critical metabolic systems; perhaps it results

the damaged tissues; perhaps it results from the

cortisol are secreted. Perhaps this results from the

undefined, factors that allow the body to resist many

enhanced. This probably results from the same, mainly

inflammation. But in addition, the rate of healing is

within hours to a few days. The immediate effect is to

inflammation has become well established, the admin-

membranes and other effects of cortisol is unclear.

ing all aspects of the inflammatory process. How much

Thus, cortisol has an almost global effect in reduc-

hypothalamic temperature control system. The

cells,

process.

turn, reduced amounts of T cells and antibodies

The T lymphocytes are especially suppressed. In

lymphocyte reproduction to decrease markedly.

Cortisol suppresses the immune system, causing

permeability, and mobility of white blood cells.

otherwise would increase vasodilation, capillary

These effects probably result from

damaged cells.

prevents loss of plasma into the tissues.

reduced release of proteolytic enzymes. This

capillaries,

954

Unit XIV

Endocrinology and Reproduction

2. Cortisol decreases the permeability of the

probably as a secondary effect of the

3. Cortisol decreases both migration of white blood

cells into the inflamed area and phagocytosis of the

the fact that cortisol diminishes the formation
of prostaglandins and leukotrienes that

in the inflamed area lessen the tissue reactions
that would otherwise promote the inflammation

5. Cortisol attenuates fever mainly because it reduces

the release of interleukin-1 from the white blood

which is one of the principal excitants to the

decreased temperature in turn reduces the degree
of vasodilation.

of this results from the simple effect of cortisol in
stabilizing lysosomal and cell membranes versus its
effect to reduce the formation of prostaglandins and
leukotrienes from arachidonic acid in damaged cell

Cortisol Causes Resolution of Inflammation.

Even after

istration of cortisol can often reduce inflammation

block most of the factors that are promoting the

other types of physical stress when large quantities of

mobilization of amino acids and use of these to repair

increased glucogenesis that makes extra glucose avail-

from increased amounts of fatty acids available for cel-

cortisol for inactivating or removing inflammatory

Regardless of the precise mechanisms by which the

plays a major role in combating certain types of dis-

harmful effects on the body are caused mainly by
the inflammation itself and not by other aspects of the

And even though the cortisol does not correct the

sible for many of the serious and sometimes lethal

followed by its effect in reducing inflammation and the

explained in Chapter 34.

Effect on Blood Cells and on Immunity in Infectious Diseases.

Cortisol decreases the number of eosinophils and lym-

minutes after the injection of cortisol and becomes

criterion for overproduction of cortisol by the adrenal
gland.

causes significant atrophy of all the lymphoid tissue

lead to fulminating infection and death from diseases

tuberculosis in a person whose disease had previously

other glucocorticoids to suppress immunity makes them
useful drugs in preventing immunological rejection of

Cortisol increases the production of red blood cells

by first interacting with intracellular receptors in target

and the hormone-receptor complex then interacts with

glucocorti-

to induce or repress gene tran-

transcription

are also necessary for the hormone-receptor

complex to interact appropriately with the glucocorti-

Glucocorticoids increase or decrease transcription of

most of the metabolic effects of cortisol are not

at times when the body is not experiencing stress.

There is also direct feedback of the cortisol to both

the damaging nature of the stressful state.

release of cortisol, and the cortisol in turn initiates a

tation of the hypothalamus by different types of stress.

cortisol secretion. The key to this control is the exci-

Figure 77–6 shows the overall system for control of

Summary of the Cortisol Control System

feedbacks automatically reduce the ACTH toward

the cortisol concentration becomes too great, the

the plasma concentration of cortisol. That is, whenever

of ACTH. Both of these feedbacks help regulate

Anterior Pituitary to Decrease ACTH Secretion.

Inhibitory Effect of Cortisol on the Hypothalamus and on the

hypothalamus.

region of the amygdala and hippocampus, both of

increased activity in the limbic system, especially in the

ACTH secretion. This is believed to result from

secreted into the hypophysial portal system. Within

hypothalamus, as shown in Figure 77–6. Here CRF is

responses after trauma shown in Figure 77–5.

tion as much as 20-fold. This effect was demonstrated

quently cortisol as well, often increasing cortisol secre-

to greatly enhanced secretion of ACTH and conse-

As pointed out earlier in the chapter, almost any type

Adrenocortical Secretion

Physiologic Stress Increases ACTH and

and zona reticularis, where cortisol and the androgens

adrenocortical cells, especially in the zona fasciculata

cortex by ACTH not only increases secretory activity

to be formed. Long-term stimulation of the adrenal

adrenocortical hormones, which explains why ACTH

initial conversion is the “rate-limiting” step for all the

This

initial conversion of cholesterol to pregnenolone.

protein kinase A,

The most important of all the ACTH-stimulated

This is another example of cAMP as a

that cause formation of the adrenocortical hormones.

The cAMP in turn activates the intracellular enzymes

plasm, reaching its maximal effect in about 3 minutes.

in the cell cyto-

in the cell membrane. This

principal effect of ACTH on the adrenocortical cells is

The

regions of the brain, including the hypothalamus, and

most conditions that cause high ACTH secretory rates

quantities of ACTH in the absence of CRF. Instead,

The anterior pituitary gland can secrete only minute

tricular nucleus of the hypothalamus. This nucleus in

posed of 41 amino acids. The cell bodies of the neurons

it induces ACTH secretion. CRF is a peptide com-

and then carried to the anterior pituitary gland, where

(CRF). It is secreted into the

also controls ACTH secretion. This is called

from the hypothalamus, an important releasing factor

total molecule.

chain length of 24 amino acids, has all the effects of the

polypeptide, a digested product of ACTH having a

tide, having a chain length of 39 amino acids. A smaller

form from the anterior pituitary. It is a large polypep-

ACTH has been isolated in pure

Chemistry of ACTH.

of adrenal androgens.

pituitary gland. This hormone, also called

almost entirely by ACTH secreted by the anterior

cortisol. Instead, secretion of cortisol is controlled

on the adrenocortical cells, almost no stimuli have

secretion by the zona glomerulosa, which is controlled

from the Pituitary Gland

by Adrenocorticotropic Hormone

Regulation of Cortisol Secretion

port that may contribute to their therapeutic benefits.

especially at high concentrations, may also have some

develop. Recent evidence suggests that glucocorticoids,

be synthesized, and up to several hours or days to fully

Chapter 77

Adrenocortical Hormones

955

immediate but require 45 to 60 minutes for proteins to

rapid nongenomic effects on cell membrane ion trans-

ACTH Stimulates Cortisol Secretion.

Unlike aldosterone

mainly by potassium and angiotensin acting directly

direct control effects on the adrenal cells that secrete

corticotropin

or adrenocorticotropin, also enhances the production

ACTH Secretion Is Controlled by Corticotropin-Releasing Factor
from the Hypothalamus.

In the same way that other pitu-

itary hormones are controlled by releasing factors

corti-

cotropin-releasing factor
primary capillary plexus of the hypophysial portal
system in the median eminence of the hypothalamus

that secrete CRF are located mainly in the paraven-

turn receives many nervous connections from the
limbic system and lower brain stem.

initiate this secretion by signals that begin in the basal

are then transmitted by CRF to the anterior pituitary
gland.

ACTH Activates Adrenocortical Cells to Produce Steroids by
Increasing Cyclic Adenosine Monophosphate (cAMP).

to activate adenylyl cyclase
then induces the formation of cAMP

second messen-

ger signal system.

steps for controlling adrenocortical secretion is acti-
vation of the enzyme

which causes

normally is necessary for any adrenocortical hormones

but also causes hypertrophy and proliferation of the

are secreted.

of physical or mental stress can lead within minutes

by the rapid and strong adrenocortical secretory

Pain stimuli caused by physical stress or tissue

damage are transmitted first upward through the brain
stem and eventually to the median eminence of the

minutes the entire control sequence leads to large
quantities of cortisol in the blood.

Mental stress can cause an equally rapid increase in

which then transmit signals to the posterior medial

Cortisol has

direct negative feedback effects on (1) the hypothala-
mus to decrease the formation of CRF and (2) the
anterior pituitary gland to decrease the formation

a normal control level.

Stress stimuli activate the entire system to cause rapid

series of metabolic effects directed toward relieving

the hypothalamus and the anterior pituitary gland to
decrease the concentration of cortisol in the plasma

pituitary lobes. This lobe secretes an especially large

developed, lying between the anterior and posterior

the pituitary gland, called the

In some lower animals, an intermediate “lobe” of

genetically dark skins than in light-skinned people.

skin. The effect is much greater in people who have

it to the epidermis. Injection of MSH into a person

dermis and epidermis of the skin, MSH stimulates

-MSH, but not ACTH. As

-, and

hypothalamus, the expression of PC2 leads to the

-lipotropin. In the

-endorphin, and

peptide, ACTH,

ing in the production of N-terminal peptide, joining

(PC1), but not PC2, result-

the tissue. Thus, pituitary corticotroph cells express

form a series of smaller peptides. The precise type

tissue. In all of these cell types, POMC is processed to

the hypothalamus, cells of the dermis, and lymphoid

pituitary, POMC neurons in the arcuate nucleus of

tissues, including the corticotroph cells of the anterior

The POMC gene is actively transcribed in several

disease, formation of some of the other POMC-

tion of ACTH is high, as may occur in Addison’s

effect on the human body, but when the rate of secre-

conditions, none of these hormones is secreted in

, and a few others (Figure 77–8)

as several other peptides, including

which is the precursor of ACTH as well

RNA molecule that causes ACTH synthesis initially

ical structures are secreted simultaneously. The reason

gland, several other hormones that have similar chem-

When ACTH is secreted by the anterior pituitary

Hormone, Lipotropin, and Endorphin

Synthesis and Secretion of ACTH in

measurements are made.

expressed in terms of the time in the cycle at which the

changes correspondingly. Therefore, measurements of

When a person changes daily sleeping habits, the cycle

results from a 24-hour cyclical alteration in the signals

g/dl around midnight. This effect

77–7; the plasma cortisol level ranges between a high of

morning but low in the late evening, as shown in Figure

rates of CRF, ACTH, and cortisol are high in the early

The secretory

times of chronic stress.

day (Figure 77–7) or prolonged cortisol secretion in

feedback of cortisol, causing either periodic exacerba-

However, the stress stimuli are the prepotent ones;

956

Unit XIV

Endocrinology and Reproduction

they can always break through this direct inhibitory

tions of cortisol secretion at multiple times during the

Circadian Rhythm of Glucocorticoid Secretion.

about 20

mg/dl an hour before arising in the morning

and a low of about 5

from the hypothalamus that cause cortisol secretion.

blood cortisol levels are meaningful only when

Association with Melanocyte-Stimulating

for this is that the gene that is transcribed to form the

causes the formation of a considerably larger protein,
a preprohormone called proopiomelanocortin
(POMC),

melanocyte-

stimulating hormone (MSH),

b-lipotropin, b-endor-

phin

. Under normal

enough quantity by the pituitary to have a significant

derived hormones may also be increased.

of POMC-derived products from a particular tissue
depends on the type of processing enzymes present in

prohormone convertase 1

production of

a-, b

discussed in Chapter 71,

a-MSH formed by neurons of

the hypothalamus plays a major role in appetite
regulation.

In melanocytes located in abundance between the

formation of the black pigment melanin and disperses

over 8 to 10 days can greatly increase darkening of the

pars intermedia, is highly

Portal
vessel
(CRF)

1 Gluconeogenesis
2 Protein mobilization
3 Fat mobilization
4 Stabilizes lysosomes

Inhibits

Cortisol

ACTH

Adrenal

cortex

Relieves

Stress

Excites

Hypothalamus

Median

eminence

adrenocorticotropic hormone; CRF, corticotropin-releasing factor.

Mechanism for regulation of glucocorticoid secretion. ACTH,

Figure 77–6

12:00 4:00

8:00 12:00 4:00

8:00 12:00

Cortisol concentration

(

g/dl)

Noon

or so after awaking in the morning.

oscillations in secretion as well as a daily secretory surge an hour

Typical pattern of cortisol concentration during the day. Note the

Figure 77–7

many other metabolic functions of the body. This

proteins and fats from the tissues, thereby depressing

quantities of glucose by gluconeogenesis. Furthermore,

it impossible for a person with Addison’s disease to

Glucocorticoid Deficiency.

in shock, death usually occurring in the untreated

markedly, cardiac output decreases, and the patient dies

volume falls, red blood cell concentration rises

As the extracellular fluid becomes depleted, plasma

volume. Furthermore, hyponatremia, hyperkalemia, and

and water to be lost into urine in great profusion. The

tion and consequently allows sodium ions, chloride ions,

Mineralocorticoid Deficiency.

turbances in Addison’s disease are as follows.

or invasion of the adrenal cortices by cancer. The dis-

tices. Adrenal gland hypofunction is also frequently

the adrenal cortices. In about 80 per cent of the cases,

cortices to produce adrenocortical hormones, and this

Addison’s disease results from failure of the adrenal

Adrenocortical Secretion

Abnormalities of

androgenic activity. The physiologic effects of andro-

hormone, which probably accounts for much of their

gens are converted to testosterone, the primary male sex

In extra-adrenal tissues, some of the adrenal andro-

results from the action of these hormones.

before puberty but also throughout life. Much of the

androgens also exert mild effects in the female, not only

hood secretion of adrenal androgens. The adrenal

effects in humans. It is possible that part of the early

Normally, the adrenal androgens have only weak

in minute quantities.

estrogens, which are female sex hormones, are secreted

cussed more fully in Chapter 83. Also, progesterone and

the adrenal cortex, especially during fetal life, as dis-

Adrenal Androgens

ACTH normally is more important than MSH in

small, whereas those of ACTH are large, it is likely that

MSH. Furthermore, because the quantities of pure

about 1/30 as much melanocyte-stimulating effect as

ACTH, because it contains an MSH sequence, has

winter.

instance, some arctic animals develop darkened fur in

or in response to other environmental factors. For

amount of MSH. Furthermore, this secretion is inde-

Chapter 77

Adrenocortical Hormones

957

pendently controlled by the hypothalamus in response
to the amount of light to which the animal is exposed

the summer and yet have entirely white fur in the

MSH secreted in the human being are extremely

determining the amount of melanin in the skin.

Several moderately active male sex hormones called
adrenal androgens (the most important of which is
dehydroepiandrosterone) are continually secreted by

development of the male sex organs results from child-

growth of the pubic and axillary hair in the female

gens are discussed in Chapter 80 in relation to male
sexual function.

Hypoadrenalism-Addison’s Disease

in turn is most frequently caused by primary atrophy of

the atrophy is caused by autoimmunity against the cor-

caused by tuberculous destruction of the adrenal glands

Lack of aldosterone secre-

tion greatly decreases renal tubular sodium reabsorp-

net result is a greatly decreased extracellular fluid

mild acidosis develop because of failure of potassium
and hydrogen ions to be secreted in exchange for
sodium reabsorption.

patient 4 days to 2 weeks after cessation of mineralo-
corticoid secretion.

Loss of cortisol secretion makes

maintain normal blood glucose concentration between
meals because he or she cannot synthesize significant

lack of cortisol reduces the mobilization of both

N-Terminal protein

Proopiomelanocortin

COOH

ACTH

Joining

protein

-MSH

-Lipotropin

CLIP

PCI

PC2

-Lipotropin

-Endorphin

CLIP, corticotropin-like intermedi-

hormone (MSH), but not ACTH.

mus leads to the production of

-lipotropin. Expres-

terminal peptide, joining peptide,

PC1, resulting in formation of N-

The anterior pituitary expresses

tides produced in various tissues.

enzymes results in different pep-

cific expression of these two

PC 2 (blue arrows). Tissue spe-

vertase 1 (PC1, red arrows) and

processing by prohormone con-

Proopiomelanocortin (POMC)

Figure 77–8

ACTH, and

sion of PC2 within the hypothala-

a-,

b-, and g-melanocyte stimulating

ate peptide.

patients die of infections. Even the protein collagen

a suppressed immune system, so that many of these

the muscles in particular causes severe weakness. The

teins also remain unaffected. The loss of protein from

the body with the exception of the liver; the plasma pro-

are often profound in Cushing’s syndrome, causing

The effects of glucocorticoids on protein catabolism

tissues.

as twice normal. This results mainly from enhanced glu-

times to values as high as 200 mg/dl after meals-as much

cause increased blood glucose concentration, some-

dance of cortisol secreted in Cushing’s syndrome can

The abun-

About 80 per cent of patients have hypertension, pre-

with Cushing’s syndrome to the left in Figure 77–8.

“moon face,” as demonstrated in the untreated patient

acne and hirsutism (excess growth of facial hair). The

potency of some of the hormones sometimes causes

matous appearance of the face, and the androgenic

The excess secretion of steroids also leads to an ede-

upper abdominal regions, giving rise to a buffalo torso.

mobilization of fat from the lower part of the body, with

A special characteristic of Cushing’s syndrome is

symptoms of Cushing’s syndrome.

longed periods for therapeutic purposes. For example,

Cushing’s syndrome can also occur when large

the differential diagnosis of Cushing’s syndrome.

Therefore, it is usually considered to be a first step in

dexamethasone with suppressed ACTH secretion.

some ACTH-secreting pituitary tumors respond to

can sometimes give an incorrect diagnosis, because

ACTH. The dexamethasone test, although widely used,

primary adrenal overproduction of cortisol (ACTH-

suppress ACTH secretion. In contrast, patients with

tion of ACTH due to an ACTH-secreting pituitary

Cushing’s syndrome. In patients who have overproduc-

ACTH-independent

ACTH-dependent

a synthetic glucocorticoid, can be used to distinguish

Administration of large doses of dexamethasone,

levels due to cortisol feedback inhibition of ACTH

drome and is usually associated with reduced ACTH

about 20 to 25 per cent of clinical cases of Cushing’s syn-

levels of ACTH as well as cortisol. Primary overpro-

Cushing’s syndrome and is characterized by high plasma

Excess ACTH secretion is the most common cause of

Cushing’s disease.

pituitary, this is referred to as

ondary to excess secretion of ACTH by the anterior

the adrenal cortex. When Cushing’s syndrome is sec-

such as an abdominal carcinoma; and (4) adenomas of

secretion” of ACTH by a tumor elsewhere in the body,

which stimulates excess ACTH release; (3) “ectopic

adrenal hyperplasia and excess cortisol secretion; (2)

that secrete large amounts of ACTH, which then causes

causes, including (1) adenomas of the anterior pituitary

effects. Hypercortisolism can occur from multiple

ascribable to abnormal amounts of cortisol, but excess

Most of the abnormalities of Cushing’s syndrome are

Cushing’s syndrome.

addisonian crisis.

This critical need for extra glucocorticoids and the

stresses, such as surgical operations, supervene, a person

whenever different types of trauma, disease, or other

glucocorticoids does not increase during stress. Yet

stress. In a person with Addison’s disease, the output of

As noted earlier in the chapter, great

coids are administered daily.

circulatory shock. Yet such a person can live for years if

Treatment of People with Addison’s Disease.

the same way that MSH does.

stimulate formation of melanin by the melanocytes in

MSH. Probably the tremendous amounts of ACTH

allowing tremendous rates of ACTH secretion as well

anterior pituitary gland is also depressed, therefore

the following: When cortisol secretion is depressed, the

The cause of the melanin deposition is believed to be

thin skin of the nipples.

areas, such as the mucous membranes of the lips and the

blotches, and it is deposited especially in the thin skin

of the mucous membranes and skin. This melanin is not

people with Addison’s disease is melanin pigmentation

the deteriorating effects of different types of stress, and

a person with Addison’s disease highly susceptible to

are weak, indicating that glucocorticoids are needed to

and other nutrients are available, the person’s muscles

cocorticoid lack. Even when excess quantities of glucose

958

Unit XIV

Endocrinology and Reproduction

sluggishness of energy mobilization when cortisol is not
available is one of the major detrimental effects of glu-

maintain other metabolic functions of the tissues in
addition to energy metabolism.

Lack of adequate glucocorticoid secretion also makes

even a mild respiratory infection can cause death.

Melanin Pigmentation.

Another characteristic of most

always deposited evenly but occasionally is deposited in

normal negative feedback to the hypothalamus and

as simultaneous secretion of increased amounts of

cause most of the pigmenting effect because they can

An untreated

person with total adrenal destruction dies within a few
days to a few weeks because of weakness and usually

small quantities of mineralocorticoids and glucocorti-

Addisonian Crisis.

quantities of glucocorticoids are occasionally secreted
in response to different types of physical or mental

is likely to have an acute need for excessive amounts of
glucocorticoids and often must be given 10 or more
times the normal quantities of glucocorticoids to
prevent death.

associated severe debility in times of stress is called an

Hyperadrenalism-Cushing’s
Syndrome

Hypersecretion by the adrenal cortex causes a complex
cascade of hormone effects called

secretion of androgens may also cause important

abnormal function of the hypothalamus that causes high
levels of corticotropin-releasing hormone (CRH),

duction of cortisol by the adrenal glands accounts for

secretion by the anterior pituitary gland.

between

and

adenoma or to hypothalamic-pituitary dysfunction,
even large doses of dexamethasone usually do not

independent) usually have low or undetectable levels of

amounts of glucocorticoids are administered over pro-

patients with chronic inflammation associated with dis-
eases such as rheumatoid arthritis are often treated with
glucocorticoids and may develop some of the clinical

concomitant extra deposition of fat in the thoracic and

appearance of the face is frequently described as a

sumably because of the slight mineralocorticoid effects
of cortisol.

Effects on Carbohydrate and Protein Metabolism.

coneogenesis and decreased glucose utilization by the

greatly decreased tissue proteins almost everywhere in

loss of protein synthesis in the lymphoid tissues leads to

fibers in the subcutaneous tissue are diminished so that

finding can be used in diagnosing the disease.

gens) in the urine may be 10 to 15 times normal. This

the adult male. In adrenogenital syndrome, the excre-

of the testosterone secreted by the testes. It is often dif-

adrenogenital syndrome. In the adult male, the viriliz-

in Figure 77–9, which depicts a 4-year-old boy with

rapid development of the male sexual organs, as shown

In the prepubertal male, a virilizing adrenal tumor

to give typical masculine characteristics.

growth of the clitoris to resemble a penis, and deposi-

masculine distribution of hair on the body and the pubis,

baldness if she also has the genetic trait for baldness,

growth of a beard, a much deeper voice, occasionally

female, she develops virile characteristics, including

ing effects throughout the body. If this occurs in a

most of the adrenal tissue when hyperplasia is the cause.

from the aldosteronism. Treatment of primary aldos-

nism is a decreased plasma renin concentration. This

the nerve fibers, as explained in Chapter 5.

paralysis caused by the hypokalemia. The paralysis is

almost always, hypertension. Especially interesting in

not more than a 4 to 6 mEq/L increase), and,

in extracellular fluid volume and blood volume, very

important effects are hypokalemia, slight increase

discussed in detail earlier in the chapter. The most

than cortisol. The effects of the excess aldosterone are

nism” or “Conn’s syndrome.” Also, in a few instances,

the resulting condition is called “primary aldostero-

to make up for any insufficiency that develops.

lectomy, followed by administration of adrenal steroids

cannot easily be decreased, the only satisfactory treat-

used when surgery is not feasible. If ACTH secretion

GABA-transaminase inhibitors,

that inhibit ACTH secretion, such as

aminoglutethimide,

metyrapone, ketoconazole,

by radiation. Drugs that block steroidogenesis, such as

small tumors in the pituitary that oversecrete ACTH

this is possible. Hypertrophied pituitary glands or even

is the cause or decreasing the secretion of ACTH, if

Treatment of Cushing’s

Treatment of Cushing’s Syndrome.

consequent weakness of the bones.

apart. In addition, severely diminished protein deposi-

the subcutaneous tissues tear easily, resulting in devel-

Chapter 77

Adrenocortical Hormones

959

opment of large purplish striae where they have torn

tion in the bones often causes severe osteoporosis with

syndrome consists of removing an adrenal tumor if this

can sometimes be surgically removed or destroyed

and

serotonin antago-

nists and

can also be

ment is usually bilateral partial (or even total) adrena-

Primary Aldosteronism
(Conn’s Syndrome)

Occasionally a small tumor of the zona glomerulosa
cells occurs and secretes large amounts of aldosterone;

hyperplastic adrenal cortices secrete aldosterone rather

slight increase in plasma sodium concentration (usually

primary aldosteronism are occasional periods of muscle

caused by a depressant effect of low extracellular potas-
sium concentration on action potential transmission by

One of the diagnostic criteria of primary aldostero-

results from feedback suppression of renin secretion
caused by the excess aldosterone or by the excess extra-
cellular fluid volume and arterial pressure resulting

teronism is usually surgical removal of the tumor or of

Adrenogenital Syndrome

An occasional adrenocortical tumor secretes excessive
quantities of androgens that cause intense masculiniz-

tion of proteins in the skin and especially in the muscles

causes the same characteristics as in the female plus

ing characteristics of adrenogenital syndrome are
usually obscured by the normal virilizing characteristics

ficult to make a diagnosis of adrenogenital syndrome in

tion of 17-ketosteroids (which are derived from andro-

(Courtesy Dr. Leonard Posey.)

) subtotal adrenalectomy.

drome before (

A person with Cushing’s syn-

Figure 77–9

left) and after

(right

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960

Unit XIV

Endocrinology and Reproduction

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Figure 77–10