Introduction to Endocrinology pdf - Endocrinology and Reproduction

hormone systems and their most important actions.

source of the sex hormones. Table 74–1 provides an overview of the different

endocrine tissues of the body, except for the placenta, which is an additional

Figure 74–1 shows the anatomical loci of the major endocrine glands and

characteristics of the female body.

ovarian hormones

cortex, causing it to secrete adrenocortical hormones, and the

(ACTH)

have receptors for the hormone. For example,

target tissues,

tions in almost all the body’s cells.

thyroxine

(from the anterior pituitary gland) causes growth in most parts of the body, and

growth hormone

affect many different types of cells of the body; for example,

bind with receptors and initiate many reactions. Some endocrine hormones

throughout the body, including the nervous system in some cases, where they

The

of anterior pituitary hormones.

hypophysiotropic hormones,

(ADH), oxytocin,

eminence and secrete several neurohormones, including

thalamus, have axons that terminate in the posterior pituitary gland and median

in response to neural stimuli. The neuroendocrine cells, located in the hypo-

ger systems interact with one another to maintain homeostasis. For example,

hormone systems, keeping in mind that many of the body’s chemical messen-

In the next few chapters, we discuss mainly the endocrine and neuroendocrine

) produced by adipocytes are

34). Cytokine hormones (e.g.,

cytokines include the

function as autocrines, paracrines, or endocrine hormones. Examples of

receptors.

Autocrines

neighboring cells of a different type.

Paracrines

blood and influence the function of cells at another location in the body.

the body.

synaptic junctions and act locally to control nerve cell functions.

are released by axon terminals of neurons into the

The multiple activities of the cells, tissues, and

Coordination of Body

905

Introduction to Endocrinology

Functions by Chemical
Messengers

organs of the body are coordinated by the interplay
of several types of chemical messenger systems:

1. Neurotransmitters

2. Endocrine hormones are released by glands or specialized cells into the

circulating blood and influence the function of cells at another location in

3. Neuroendocrine hormones are secreted by neurons into the circulating

are secreted by cells into the extracellular fluid and affect

are secreted by cells into the extracellular fluid and affect the

function of the same cells that produced them by binding to cell surface

6. Cytokines are peptides secreted by cells into the extracellular fluid and can

interleukins and other lymphokines that are secreted

by helper cells and act on other cells of the immune system (see Chapter

leptin

sometimes called adipokines.

the adrenal medullae and the pituitary gland secrete their hormones primarily

antidiuretic hormone

and

which control the secretion

endocrine hormones are carried by the circulatory system to cells

(from the thyroid gland) increases the rate of many chemical reac-

Other hormones affect only specific

because only these tissues

adrenocorticotropic hormone

from the anterior pituitary gland specifically stimulates the adrenal

have specific effects on the female sex organs as well as on the secondary sexual

instances they are synthesized from cholesterol itself.

mones is similar to that of cholesterol, and in most

The chemical structure of steroid hor-

carried to their target tissues.

enter the circulatory system easily, where they are

peptide hormones are water soluble, allowing them to

kinases that initiate secretion of the hormone. The

receptor causes increased cyclic adenosine monophos-

instances, stimulation of an endocrine cell surface

depolarization of the plasma membrane. In other

increase in cytosolic calcium concentration caused by

In many cases, the stimulus for exocytosis is an

exocytosis.

until their secretion is needed. Secretion of the hor-

cytoplasm, and many are bound to the cell membrane

inactive fragments. The vesicles are stored within the

produce smaller, biologically active hormones and

packaging into secretory vesicles. In this process,

These are then transferred to the Golgi apparatus for

other proteins (Figure 74–2). They are usually synthe-

ferent endocrine cells, in the same fashion as most

than 100 amino acids are referred to as peptides.

amino acids are called proteins, and those with fewer

prolactin). In general, polypeptides with 100 or more

are polypeptides and proteins. These hormones range

Polypeptide and Protein Hormones Are Stored in Secretory Vesi-

polysaccharides or nucleic acid hormones.

norepinephrine). There are no known

Derivatives of the amino acid tyrosine,

progesterone), the testes (testosterone), and the

and aldosterone), the ovaries (estrogen and

many others (see Table 74–1).

parathyroid gland (parathyroid hormone), and

gland, the pancreas (insulin and glucagon), the

Proteins and polypeptides,

There are three general classes of hormones:

Synthesis of Hormones

Chemical Structure and

bohydrates for energy. And without the sex hormones,

creas, the body’s cells could use little of the food car-

become sluggish as well. Without insulin from the pan-

body would become sluggish, and the person would

thyroid gland, almost all the chemical reactions of the

Without thyroxine and triiodothyronine from the

without growth hormone, a person would be a dwarf.

balance, reproduction, and behavior. For instance,

olism, growth and development, water and electrolyte

regulating almost all body functions, including metab-

The multiple hormone systems play a key role in

906

Unit XIV

Endocrinology and Reproduction

sexual development and sexual functions would be
absent.

including hormones

secreted by the anterior and posterior pituitary

2. Steroids secreted by the adrenal cortex (cortisol

placenta (estrogen and progesterone).

secreted

by the thyroid (thyroxine and triiodothyronine)
and the adrenal medullae (epinephrine and

cles Until Needed.

Most of the hormones in the body

in size from small peptides with as few as 3 amino
acids (thyrotropin-releasing hormone) to proteins
with almost 200 amino acids (growth hormone and

Protein and peptide hormones are synthesized on

the rough end of the endoplasmic reticulum of the dif-

sized first as larger proteins that are not biologically
active (preprohormones) and are cleaved to form
smaller prohormones in the endoplasmic reticulum.

enzymes in the vesicles cleave the prohormones to

mones (as well as the inactive fragments) occurs when
the secretory vesicles fuse with the cell membrane and
the granular contents are extruded into the interstitial
fluid or directly into the blood stream by

phate (cAMP) and subsequently activation of protein

Steroid Hormones Are Usually Synthesized from Cholesterol and
Are Not Stored.

Pituitary gland

Adrenal
glands

Adipose
tissue

Thymus gland

Pineal gland

Hypothalamus

Parathyroid glands
(behind thyroid gland)

Stomach

Thyroid gland

Kidney

Pancreas

Ovaries

(female)

Small
intestine

Testes (male)

the body.

Figure 74–1

Anatomical loci of the principal endocrine glands and tissues of

Chapter 74

Introduction to Endocrinology

907

Table 74–1

Adipocytes

Leptin

Inhibits appetite, stimulates thermogenesis

Peptide

Cholecystokinin (CCK)

Stimulates gallbladder contraction and release of

Peptide

(Chapter 64)

bicarbonate and water

Small intestine

Secretin

Stimulates pancreatic acinar cells to release

Peptide

Stomach

Gastrin

Stimulates HCl secretion by parietal cells

Peptide

(Chapter 22)

blood pressure

Heart

Atrial natriuretic peptide (ANP)

Increases sodium excretion by kidneys, reduces

Peptide

Erythropoietin

Increases erythrocyte production

Peptide

1,25-Dihydroxycholecalciferol

Increases intestinal absorption of calcium and bone

Steroid

(Chapter 26)

angiotensin I (acts as an enzyme)

Kidney

Renin

Catalyzes conversion of angiotensinogen to

Peptide

Progesterone

See actions of progesterone from ovaries

Steroid

Estrogens

See actions of estrogens from ovaries

Steroid

fetal tissues as well as the mother’s breasts

Human somatomammotropin

Probably helps promote development of some

Peptide

(Chapter 82)

estrogens and progesterone by corpus luteum

Placenta

Human chorionic gonadotropin (HCG)

Promotes growth of corpus luteum and secretion of

Peptide

Progesterone

Stimulates secretion of “uterine milk” by the uterine

Steroid

(Chapter 81)

reproductive system, female breasts, and female

Ovaries

Estrogens

Promotes growth and development of female

Steroid

(Chapter 80)

system and male secondary sexual characteristics

Testes

Testosterone

Promotes development of male reproductive

Steroid

(Chapter 79)

increasing calcium absorption by the gut and

Parathyroid

Parathyroid hormone (PTH)

Controls serum calcium ion concentration by

Peptide

cells)

Increases synthesis and release of glucose from

Peptide

(Chapter 78)

this way controls carbohydrate metabolism

cells)

Promotes glucose entry in many cells, and in

Peptide

Pancreas

Insulin (

Adrenal medulla

Norepinephrine, epinephrine

Same effects as sympathetic stimulation

Amine

secretion, and hydrogen ion secretion

Aldosterone

Increases renal sodium reabsorption, potassium

Steroid

(Chapter 77)

metabolism of proteins, carbohydrates, and fats;

Adrenal cortex

Cortisol

Has multiple metabolic functions for controlling

Steroid

Calcitonin

Promotes deposition of calcium in the bones and

Peptide

(Chapter 76)

cells, thus increasing body metabolic rate

)

Increases the rates of chemical reactions in most

Amine

Thyroid

Thyroxine (T

Oxytocin

Stimulates milk ejection from breasts and uterine

Peptide

(Chapter 75)

vasopressin)

causes vasoconstriction and increased blood

Posterior pituitary

Antidiuretic hormone (ADH) (also called

Increases water reabsorption by the kidneys and

Peptide

luteum, and estrogen and progesterone synthesis

testes; stimulates ovulation, formation of corpus

Luteinizing hormone (LH)

Stimulates testosterone synthesis in Leydig cells of

Peptide

Follicle-stimulating hormone (FSH)

Causes growth of follicles in the ovaries and sperm

Peptide

Prolactin

Promotes development of the female breasts and

Peptide

hormones (cortisol, androgens, and aldosterone)

Adrenocorticotropic hormone (ACTH)

Stimulates synthesis and secretion of adrenocortical

Peptide

Thyroid-stimulating hormone (TSH)

Stimulates synthesis and secretion of thyroid

Peptide

(Chapter 75)

of most cells and tissues

Anterior pituitary

Growth hormone

Stimulates protein synthesis and overall growth

Peptide

Dopamine or prolactin-inhibiting factor (PIF)

Inhibits release of prolactin

Amine

Gonadotropin-releasing hormone (GnRH)

Causes release of LH and FSH

Growth hormone inhibitory hormone (GHIH)

Inhibits release of growth hormone

Peptide

Growth hormone–releasing hormone (GHRH)

Causes release of growth hormone

Peptide

(Chapter 75)

Corticotropin-releasing hormone (CRH)

Causes release of ACTH

Peptide

Hypothalamus

Thyrotropin-releasing hormone (TRH)

Stimulates secretion of TSH and prolactin

Peptide

Gland/Tissue

Hormones

Major Functions

Structure

Endocrine Glands, Hormones, and Their Functions and Structure

Chemical

(somatostatin)

hormones (thyroxine and triiodothyronine)

secretion of milk

maturation in Sertoli cells of testes

in ovaries

pressure

contractions

) and triiodothyronine (T

decreases extracellular fluid calcium ion
concentration

also has anti-inflammatory effects

(Chapter 60)

Glucagon (

the liver into the body fluids

kidneys and releasing calcium from bones

secondary sexual characteristics

endometrial glands and promotes development of
secretory apparatus of breasts

mineralization

(Chapter 64)

pancreatic enzymes

(Chapter 71)

functions are incredibly small. Their concentrations in

The concentrations of hormones

monal Secretion Rates.

full effect. Thus, each of the different hormones has its

roxine or growth hormone, may require months for

minutes; the actions of other hormones, such as thy-

seconds after the gland is stimulated, and they may

norepinephrine and epinephrine, are secreted within

Some hormones, such as

and Clearance from the Blood

Hormone Secretion, Transport,

with other substances.

Once the catecholamines enter the circulation, they

released from adrenal medullary cells by exocytosis.

stored in secretory granules, catecholamines are also

stored until secreted. Similar to the protein hormones

times more epinephrine than norepinephrine. Cate-

adrenal medulla, which normally secretes about four

hormones to the target tissues.

roxine-binding globulin,

mones combine with plasma proteins, especially

After entering the blood, most of the thyroid hor-

the amines are split from thyroglobulin, and the free

the thyroid gland. Hormone secretion occurs when

of the glandular cells. The thyroid hormones are

actions of enzymes in the cytoplasmic compartments

the adrenal medullary hormones, are formed by the

of hormones derived from tyrosine, the thyroid and

The two groups

Amine Hormones Are Derived from Tyrosine.

are synthesized, they simply diffuse across the cell

Because the steroids are highly lipid soluble, once they

synthesis of cholesterol in steroid-producing cells.

comes from the plasma, but there is also de novo

ulus. Much of the cholesterol in steroid-producing cells

stores of cholesterol esters in cytoplasm vacuoles can

storage in steroid-producing endocrine cells, large

structure (Figure 74–3).

rings and one cyclopentyl ring combined into a single

They are lipid soluble and consist of three cyclohexyl

908

Unit XIV

Endocrinology and Reproduction

Although there is usually very little hormone

be rapidly mobilized for steroid synthesis after a stim-

membrane and enter the interstitial fluid and then the
blood.

synthesized and stored in the thyroid gland and incor-
porated into macromolecules of the protein thy-
roglobulin, which is stored in large follicles within

hormones are then released into the blood stream.

thy-

which slowly releases the

Epinephrine and norepinephrine are formed in the

cholamines are taken up into preformed vesicles and

can exist in the plasma in free form or in conjugation

Onset of Hormone Secretion After a Stimulus, and Duration of
Action of Different Hormones.

develop full action within another few seconds to

own characteristic onset and duration of action—each
tailored to perform its specific control function.

Concentrations of Hormones in the Circulating Blood, and Hor-

required to control most metabolic and endocrine

the blood range from as little as 1 picogram (which is
one millionth of one millionth of a gram) in each mil-
liliter of blood up to at most a few micrograms (a few

Nucleus

DNA

Transcription

Golgi

apparatus

Storage

Secretion

Stimulus

Extracellular

fluid

cAMP

Secretory

vesicles

Endoplasmic
reticulum

Packaging

Synthesis

Translation

mRNA

hormone secretion often involves changes in intracellular calcium

Synthesis and secretion of peptide hormones. The stimulus for

Figure 74–2

or changes in cyclic adenosine monophosphate (cAMP) in the
cell.

Testosterone

Estradiol

Cortisol

Aldosterone

HC C

Chemical structures of several steroid hormones.

Figure 74–3

counting procedure. Then, using the formula just cited,

time, the plasma concentration of the radioactive

which gives one the rate of disappearance. At the same

centration in the plasma becomes steady. At this time,

Then the radioactive hormone is infused at a constant

be measured is tagged with a radioactive substance.

is the following: A purified solution of the hormone to

The usual procedure for making this measurement

hormone in each milliliter of plasma. Then, the meta-

To calculate this clearance rate, one measures (1)

liters of plasma cleared of the hormone per minute.

This

metabolic clearance rate.

hormone secretion into the blood. The second is

of a hormone in the blood. One of these is the rate of

Two factors can increase or decrease the concentration

target receptors or lost from the circulation. Binding

proteins serve as reservoirs, replenishing the concen-

The relatively large amounts of hormones bound to

proteins.

to plasma proteins. However, protein-bound hor-

the plasma exist free in solution. For example, more

in the blood mainly bound to plasma proteins. Usually

in contrast, circulate

Steroid and thyroid hormones,

stitial fluid, and ultimately to target cells.

where they diffuse out of the capillaries, into the inter-

ported from their sites of synthesis to target tissues,

Water-soluble hormones

Transport of Hormones in the Blood

release.

stages of sleep. In many cases, these cyclical variations

diurnal (daily) cycle, and sleep. For example, the secre-

changes, various stages of development and aging, the

Cyclical Variations Occur in Hormone Release.

tually, LH reaches an appropriate concentration, and

gen, which in turn causes more secretion of LH. Even-

itary before ovulation. The secreted LH then acts on

tion of the hormone. One example of this is the surge

positive feedback

few instances,

In a

hormones.

levels, including gene transcription and translation

Feedback regulation of hormones can occur at all

enough to slow further secretion of the hormone.

the target tissue. Therefore, only when the target tissue

The controlled variable is often not the secretory

target tissue.

release. In other words, the hormone (or one of its

the hormone, conditions or products resulting from the

at the target tissue. After a stimulus causes release of

negative feedback mech-

far appear to be closely controlled. In most instances,

occur throughout the day, all hormones studied thus

iological systems.

milligrams per day. We shall see later in this chapter

extremely small, usually measured in micrograms or

millionths of a gram) per milliliter of blood. Similarly,

Chapter 74

Introduction to Endocrinology

909

the rates of secretion of the various hormones are

that highly specialized mechanisms are available in the
target tissues that allow even these minute quantities
of hormones to exert powerful control over the phys-

Feedback Control of
Hormone Secretion

Negative Feedback Prevents Overactivity of Hormone Systems.

Although the plasma concentrations of many hor-
mones fluctuate in response to various stimuli that

this control is exerted through
anisms that ensure a proper level of hormone activity

action of the hormone tend to suppress its further

products) has a negative feedback effect to prevent
oversecretion of the hormone or overactivity at the

rate of the hormone itself but the degree of activity of

activity rises to an appropriate level will feedback
signals to the endocrine gland become powerful

steps involved in the synthesis of hormones and steps
involved in processing hormones or releasing stored

Surges of Hormones Can Occur with Positive Feedback.

occurs when the bio-

logical action of the hormone causes additional secre-

of luteinizing hormone (LH) that occurs as a result of
the stimulatory effect of estrogen on the anterior pitu-

the ovaries to stimulate additional secretion of estro-

typical negative feedback control of hormone secre-
tion is then exerted.

Superim-

posed on the negative and positive feedback control
of hormone secretion are periodic variations in
hormone release that are influenced by seasonal

tion of growth hormone is markedly increased during
the early period of sleep but is reduced during the later

in hormone secretion are due to changes in activity

of neural pathways involved in controlling hormone

(peptides and cate-

cholamines) are dissolved in the plasma and trans-

less than 10 per cent of steroid or thyroid hormones in

than 99 per cent of the thyroxine in the blood is bound

mones cannot easily diffuse across the capillaries and
gain access to their target cells and are therefore bio-
logically inactive until they dissociate from plasma

tration of free hormones when they are bound to

of hormones to plasma proteins greatly slows their
clearance from the plasma.

“Clearance” of Hormones
from the Blood

the rate of removal of the hormone from the blood,
which is called the
is usually expressed in terms of the number of milli-

the rate of disappearance of the hormone from the
plasma per minute and (2) the concentration of the

bolic clearance rate is calculated by the following
formula:

Metabolic clearance rate

= Rate of disappearance

of hormone from the plasma/Concentration of
hormone in each milliliter of plasma

rate into the blood stream until the radioactive con-

the rate of disappearance of the radioactive hormone
from the plasma equals the rate at which it is infused,

hormone is measured using a standard radioactive

the metabolic clearance rate is calculated.

effects on the postsynaptic cells. Although a few

calcium ions, and so forth. The altered movement of

for sodium ions, others for potassium ions, others for

ion channel–linked receptors

closing a channel for one or more ions. Some of these

in the structure of the receptor, usually opening or

naptic membrane. This almost always causes a change

norepinephrine, combine with receptors in the postsy-

transmitter substances, such as acetylcholine and

Virtually all the neuro-

types of interactions.

explain this, let us give a few examples of the different

activated receptor initiates the hormonal effects. To

This alters the function of the receptor itself, and the

Almost without exception, a hormone affects its target

Intracellular Signaling After Hormone

ing effects of the hormone.

the hormone. When this occurs, the target tissue

protein-manufacturing machinery of the target cell, or

and intracellular signaling proteins; that is, the stimu-

target tissue’s responsiveness to the hormone.

each case, receptor down-regulation decreases the

ized, or (5) decreased production of the receptors. In

interact with cell membrane receptors, (4) destruction

cell, away from the site of action of hormones that

intracellular protein signaling molecules, (3) tempo-

receptor molecules, (2) inactivation of some of the

down-regulation

decrease. This

For instance, increased hormone concentration and

course of their function, and at other times they

from minute to minute. The receptor proteins them-

does not remain constant from day to day, or even

The number of receptors in a target cell usually

one or more of the chromosomes.

The receptors for the thyroid

In the cell nucleus.

in the cytoplasm.

The primary receptors for

protein, peptide, and catecholamine hormones.

The

In or on the surface of the cell membrane.

The locations for the different types of hormone

that contain its specific receptors.

of hormone that will act on a particular tissue. The

specific for a single hormone; this determines the type

100,000 receptors. Also, each receptor is usually highly

Hormonal receptors are large proteins, and each cell

ates a cascade of reactions in the cell, with each stage

hormone combines with its receptor, this usually initi-

located in the cytoplasm or the nucleus. When the

membrane, whereas other hormone receptors are

tors for the hormones do not respond. Receptors

at the target cell. Cells that lack recep-

The first step of a hormone’s action is to bind to spe-

of Hormones

mones may be as long as 1 to 6 days.

for example, ranges between 20 and 100 minutes,

days. The half-life of adrenal steroids in the circulation,

in the blood is less than a minute.

For example, the half-life of angiotensin II circulating

liver, thus remaining in the blood for only a short time.

They are usually degraded by enzymes in the blood

tors are usually recycled back to the cell membrane.

hormone is then metabolized in the cell, and the recep-

the cell membrane hormone-receptor complex; the

cells by enzymatic processes that cause endocytosis of

“cleared” into the bile.

mones when the liver is diseased, because these hor-

For instance, this occurs for several of the steroid hor-

tration of the hormone in the circulating body fluids.

the urine. For certain hormones, a decreased metabolic

liver into the bile, and (4) excretion by the kidneys into

tissues, (2) binding with the tissues, (3) excretion by the

ways, including (1) metabolic destruction by the

Hormones are “cleared” from the plasma in several

910

Unit XIV

Endocrinology and Reproduction

clearance rate may cause an excessively high concen-

mones are conjugated mainly in the liver and then

Hormones are sometimes degraded at their target

Most of the peptide hormones and catecholamines

are water soluble and circulate freely in the blood.

and tissues and rapidly excreted by the kidneys and

Hormones that are bound to plasma proteins are

cleared from the blood at much slower rates and may
remain in the circulation for several hours or even

whereas the half-life of the protein-bound thyroid hor-

Mechanisms of Action

Hormone Receptors and Their
Activation

cific receptors

for some hormones are located on the target cell

becoming more powerfully activated so that even
small concentrations of the hormone can have a large
effect.

that is to be stimulated usually has some 2000 to

target tissues that are affected by a hormone are those

receptors are generally the following:
1.

membrane receptors are specific mostly for the

2. In the cell cytoplasm.

the different steroid hormones are found mainly

hormones are found in the nucleus and are
believed to be located in direct association with

The Number and Sensitivity of Hormone Receptors Are Regu-
lated.

selves are often inactivated or destroyed during the

are reactivated or new ones are manufactured by
the protein-manufacturing mechanism of the cell.

increased binding with its target cell receptors some-
times cause the number of active receptors to

of the receptors can

occur as a result of (1) inactivation of some of the

rary sequestration of the receptor to the inside of the

of the receptors by lysosomes after they are internal-

Some hormones cause up-regulation of receptors

lating hormone induces greater than normal formation
of receptor or intracellular signaling molecules by the

greater availability of the receptor for interaction with

becomes progressively more sensitive to the stimulat-

Receptor Activation

tissues by first forming a hormone-receptor complex.

Ion Channel–Linked Receptors.

open (or close) channels

these ions through the channels causes the subsequent

(Figure 74–5). Leptin is a hormone

activity, others rely on enzymes that are closely asso-

is activated (or occasionally inactivated). Although

tor, an enzyme immediately inside the cell membrane

alytic or enzyme-binding site on the inside. When the

seven-transmembrane G protein–coupled receptors.

through the membrane only once, in contrast to the

These

closely associated with enzymes that they activate.

when activated, function directly as enzymes or are

Some receptors,

target tissues of the body.

of intracellular enzymes. This complex system of cell

receptor to an inhibitory or stimulatory G protein, a

teins). Thus, depending on the coupling of a hormone

proteins), whereas others are

units to form an inactive, membrane-bound trimeric G

itself by converting its bound GTP to GDP; then the

The signaling event is rapidly terminated when the

phospholipase C,

lular signaling proteins; these proteins, in turn, alter

trimeric G protein to associate with the cytoplasmic

subunit. When the receptor is activated, it undergoes

, and

In their inactive state,

guanosine nucleotides.

The trimeric G proteins are named for their ability

activity of an enzyme in the cytoplasm of the cell.

cellular part of the receptor, a conformational change

units. When the ligand (hormone) binds to the extra-

, and

include three (i.e., trimeric) parts—the

trude into the cell cytoplasm (especially the cytoplas-

cell membrane. Some parts of the receptor that pro-

protein–coupled receptors, all of which have seven

(Figure 74–4). There are more than 1000 known G

of target proteins (e.g., enzymes or ion channels) by

receptors, as discussed next.

activation of ion channel receptors, most hormones

Chapter 74

Introduction to Endocrinology

911

hormones may exert some of their actions through

that open or close ions channels do this indirectly by
coupling with G protein–linked or enzyme-linked

G Protein–Linked Hormone Receptors.

Many hormones

activate receptors that indirectly regulate the activity

coupling with groups of cell membrane proteins called
heterotrimeric GTP-binding proteins (G proteins)

transmembrane segments that loop in and out of the

mic tail of the receptor) are coupled to G proteins that

a, b

g sub-

occurs in the receptor that activates the G proteins and
induces intracellular signals that either (1) open or
close cell membrane ion channels or (2) change the

to bind
the

a, b

g subunits of G proteins form a complex

that binds guanosine diphosphate (GDP) on the

a conformational change that causes the GDP-bound

part of the receptor and to exchange GDP for guano-
sine triphosphate (GTP). Displacement of GDP by
GTP causes the

a subunit to dissociate from the

trimeric complex and to associate with other intracel-

the activity of ion channels or intracellular enzymes

such as adenylyl cyclase or

which

alters cell function.

hormone is removed and the

a subunit inactivates

a subunit once again combines with the b and g sub-

protein.

Some hormones are coupled to inhibitory G pro-

teins (denoted G

coupled to stimulatory G proteins (denoted G

pro-

hormone can either increase or decrease the activity

membrane G proteins provides a vast array of poten-
tial cell responses to different hormones in the various

Enzyme-Linked Hormone Receptors.

enzyme-linked receptors are proteins that pass

Enzyme-linked receptors have their hormone-binding
site on the outside of the cell membrane and their cat-

hormone binds to the extracellular part of the recep-

many enzyme-linked receptors have intrinsic enzyme

ciated with the receptor to produce changes in cell
function.

One example of an enzyme-linked receptor is the

leptin receptor

GTP activated

Receptor

Hormone

Cytoplasm

Extracellular

fluid

target protein

(enzyme)

GTP

G-protein

(active)

GDP

G-protein

(inactive)

membrane-bound target proteins (enzymes) that initiate intracellular signals.

subunits of the G protein and to interact with

subunit (to which the GTP is bound) to dissociate from the

complex associates with the receptor and is activated, with an exchange of guanosine triphosphate (GTP) for guanosine diphospha

G protein

Mechanism of activation of a G protein–coupled receptor. When the hormone activates the receptor, the inactive

Figure 74–4

a, b, and g

(GDP). This causes the

b and g

single type of membrane receptor. The second mes-

cellular effects of the hormone. Thus, the only direct

membrane. The cAMP then causes subsequent intra-

We noted earlier that one of the means by which hor-

the receptor regulates.

are tissue specific. Thus, the responses of different

teins is present, and many of these regulatory proteins

regulate are different in the various tissues. An intra-

hormone receptors, but the genes that the receptors

or altered cellular functions.

hormone has entered the cell, newly formed proteins

Therefore, minutes, hours, or even days after the

mation of messenger RNA (mRNA) (Figure 74–6).

(promoter) sequence of the DNA called the

the cytoplasm or nucleus. The activated hormone-

Because these hormones are lipid soluble, they readily

inside the cell rather than in the cell membrane.

mones, and vitamin D, bind with protein receptors

steroid hormones, thyroid hormones, retinoid hor-

Several hormones, including adrenal and gonadal

messenger.

cAMP, serves in a similar manner as a second

For a few peptide hormones, such as atrial natri-

cause these effects.

instead, the cAMP serves as a second messenger to

ity, as discussed in greater detail later. cAMP is called

cyclase catalyzes the formation of cAMP, which has a

end that protrudes to the interior of the cell. This

with a special transmembrane receptor, which then

control of cell function, is for the hormone to bind

Another example, one widely used in hormonal

synthesis of new proteins.

a result of activation of these intracellular enzymes,

JAK2 also leads to activation of other intracellular

genes to initiate protein synthesis. Phosphorylation of

teins, which activates transcription by leptin target

transducer and activator of transcription (STAT)

JAK2 complex to mediate intracellular signaling. The

The activated JAK2 molecules then phosphorylate

tion of the intracellular associated JAK2 molecules.

conformation, enabling phosphorylation and activa-

tor exists as a dimer (i.e., in two parts), and binding of

The leptin recep-

JAK2.

family,

janus kinase (JAK)

enzymes. In the case of the leptin receptor, one of the

71. The leptin receptor is a member of a large family

appetite and energy balance, as discussed in Chapter

effects, but it is especially important in regulating

912

Unit XIV

Endocrinology and Reproduction

secreted by fat cells and has many physiological

of cytokine receptors that do not themselves contain
enzymatic activity but signal through associated

signaling pathways occurs through a tyrosine kinase of
the

leptin to the extracellular part of the receptor alters its

other tyrosine residues within the leptin receptor–

intracellular signals include phosphorylation of signal

pro-

enzyme pathways such as mitogen-activated protein
kinases (MAPK) and phosphatidylinositol 3-kinase
(PI3K). Some of the effects of leptin occur rapidly as

whereas other actions occur more slowly and require

becomes the activated enzyme adenylyl cyclase at the

multitude of effects inside the cell to control cell activ-

a second messenger because it is not the hormone itself
that directly institutes the intracellular changes;

uretic peptide (ANP), cyclic guanosine monophos-
phate (cGMP), which is only slightly different from

Intracellular Hormone Receptors and Activation of Genes.

cross the cell membrane and interact with receptors in

receptor complex then binds with a specific regulatory

hormone

response element, and in this manner either activates
or represses transcription of specific genes and for-

appear in the cell and become the controllers of new

Many different tissues have identical intracellular

cellular receptor can activate a gene response only if
the appropriate combination of gene regulatory pro-

tissues to a hormone are determined not only by the
specificity of the receptors but also by the genes that

Second Messenger Mechanisms
for Mediating Intracellular
Hormonal Functions

mones exert intracellular actions is to stimulate for-
mation of the second messenger cAMP inside the cell

effect that the hormone has on the cell is to activate a

senger does the rest.

Target gene

mRNA

Translation

Activation

of enzymes

Leptin receptor

Physiological

effects

Stat3

Jak2

Leptin

Jak2

Stat3

mediate some of the more rapid effects of leptin.

phorylation also activates several other enzyme systems that

tion of target genes and the synthesis of proteins. JAK2 phos-

transcription (STAT) proteins, which then activates the transcrip-

This causes phosphorylation of signal transducer and activator of

the extracellular part of the receptor, causing phosphorylation and

exists as a homodimer (two identical parts), and leptin binds to

An enzyme-linked receptor—the leptin receptor. The receptor

Figure 74–5

activation of the intracellular associated janus kinase 2 (JAK2).

lead to the cell’s response to the hormone.

cell, triggering biochemical reactions that ultimately

kinase,

cell. This then activates

(ATP) into cAMP inside the

the conversion of a small amount of cytoplasmic

brane-bound enzyme, by the G

G protein. Stimulation of adenylyl cyclase, a mem-

system, it is called a

G protein stimulates the adenylyl cyclase–cAMP

itself. Binding of the hormones with the receptor

lyl cyclase–cAMP second messenger system

their target tissues, and Figure 74–7 shows the adeny-

the adenylyl cyclase–cAMP mechanism to stimulate

Table 74–2 shows a few of the many hormones that use

different hormones. Two other especially important

Chapter 74

Introduction to Endocrinology

913

cAMP is not the only second messenger used by the

ones are (1) calcium ions and associated calmodulin
and (2) products of membrane phospholipid
breakdown.

Adenylyl Cyclase–cAMP Second
Messenger System

allows coupling of the receptor to a G protein. If the

protein, denoting a stimulatory

protein then catalyzes

adenosine triphosphate

cAMP-dependent protein

which phosphorylates specific proteins in the

Table 74–2

Some Hormones That Use the Adenylyl Cyclase–cAMP

Thyroid-stimulating hormone (TSH)

Follicle-stimulating hormone (FSH)

Adrenocorticotropic hormone (ACTH)

Second Messenger System

Angiotensin II (epithelial cells)
Calcitonin
Catecholamines (

b receptors)

Corticotropin-releasing hormone (CRH)

Glucagon
Human chorionic gonadotropin (HCG)
Luteinizing hormone (LH)
Parathyroid hormone (PTH)
Secretin
Somatostatin

receptor, epithelial cells)

Vasopressin (V

Target cell

Diffusion

Lipophilic hormone

Extracellular fluid

Proteins

Ribosome

Nuclear envelope

Nuclear pore

mRNA

Hormone
response
element

Hormone

receptor
complex

Hormone

receptor
complex

Cytoplasmic

receptor

Cytoplasmic

receptor

Nucleus

Nuclear
receptor

DNA

mRNA

protein synthesis.

gene transcription, formation of

element (promoter) on the DNA.

binds to the hormone response

the hormone-receptor complex

hormone binds to the receptor in

tors in target cells. After the

steroids, with intracellular recep-

lipophilic hormones, such as

Figure 74–6

Mechanisms of interaction of

the cytoplasm or in the nucleus,

This either activates or inhibits

messenger RNA (mRNA), and

ATP

ADP Protein

Active

cAMP-

dependent

protein

kinase

Inactive

cAMP-

dependent

protein

kinase

cAMP

Adenylyl
cyclase

Protein – PO4

Cell’s response

Cytoplasm

Extracellular

fluid

Hormone

GTP

sine diphosphate; ATP, adenosine triphosphate.

many hormones exert their control of cell function. ADP, adeno-

Figure 74–7

Cyclic adenosine monophosphate (cAMP) mechanism by which

or inhibition of protein kinases. Activation of

multiple effects inside the cell, including activation

calcium, the calmodulin changes its shape and initiates

This protein has four calcium sites,

On entering a cell, calcium ions bind with the

calcium channels.

response to the entry of calcium into the cells. Calcium

throughout the body.

arachidonic acid,

effects, the lipid portion of DAG is

cell’s response (Figure 74–8). In addition to these

phorylates a large number of proteins, leading to the

DAG, the other lipid second messenger, activates

second messenger effects, such as smooth muscle con-

reticulum, and the calcium ions then have their own

The IP

diacylglycerol (DAG).

pholipids in the cell membrane, especially

This enzyme catalyzes the breakdown of some phos-

the inside projections of the receptors (Table 74–3).

increases their permeability to water.

mones. In epithelial cells of the renal tubules, cAMP

metabolic hormones thyroxine and triiodothyronine,

Thus, a thyroid cell stimulated by cAMP forms the

secretion by the cells, and altering cell permeability.

causing muscle contraction or relaxation, initiating

ating synthesis of specific intracellular chemicals,

tions are elicited in different target cells, such as initi-

cells have other enzymes. Therefore, different func-

ery—some cells have one set of enzymes, and other

The specific action that occurs in response to

G protein, a hormone can either increase or decrease

action in the cell. Thus, depending on the coupling of

adenylyl cyclase will be inhibited, reducing the forma-

so forth. In this way, even the slightest amount of

molecules of the third enzyme to be activated, and

enzyme to be activated, which can cause still more

adenylyl cyclase immediately inside the cell mem-

vates a third, and so forth. The importance of this

activated, which activates a second enzyme, which acti-

That is, first one enzyme is

cascade of enzymes.

Once cAMP is formed inside the cell, it usually acti-

914

Unit XIV

Endocrinology and Reproduction

vates a

mechanism is that only a few molecules of activated

brane can cause many more molecules of the next

hormone acting on the cell surface can initiate a pow-
erful cascading activating force for the entire cell.

If binding of the hormone to its receptors is coupled

to an inhibitory G protein (denoted G

protein),

tion of cAMP and ultimately leading to an inhibitory

the hormone receptor to an inhibitory or a stimulatory

the concentration of cAMP and phosphorylation of
key proteins inside the cell.

increases or decreases of cAMP in each type of target
cell depends on the nature of the intracellular machin-

whereas the same cAMP in an adrenocortical cell
causes secretion of the adrenocortical steroid hor-

The Cell Membrane Phospholipid Second
Messenger System

Some hormones activate transmembrane receptors
that activate the enzyme phospholipase C attached to

phos-

phatidylinositol biphosphate (PIP

), into two different

second messenger products: inositol triphosphate
(IP

) and

mobilizes

calcium ions from mitochondria and the endoplasmic

traction and changes in cell secretion.

the enzyme protein kinase C (PKC), which then phos-

which is the precursor for the prostaglandins and other
local hormones that cause multiple effects in tissues

Calcium-Calmodulin Second
Messenger System

Another second messenger system operates in

entry may be initiated by (1) changes in membrane
potential that open calcium channels or (2) a hormone
interacting with membrane receptors that open

protein calmodulin.
and when three or four of these sites have bound with

Some Hormones That Use the Phospholipase C Second

Table 74–3

Thyroid-releasing hormone (TRH)

Messenger System

Angiotensin II (vascular smooth muscle)
Catecholamines (

a receptors)

Gonadotropin-releasing hormone (GnRH)
Growth hormone–releasing hormone (GHRH)
Oxytocin

receptor, vascular smooth muscle)

Vasopressin (V

s response

Cell

Protein

Active

protein

kinase C

Inactive

protein

kinase C

Protein – PO

Endoplasmic reticulum

Cytoplasm

Receptor

Peptide

hormone

Cell membrane

Extracellular fluid

G protein

Phospholipase C

DAG

PIP

Cell’

’s response

diacylglycerol; IP

which some hormones exert their control of cell function. DAG,

Figure 74–8

The cell membrane phospholipid second messenger system by

, inositol triphosphate; PIP

, phosphatidylinosi-

tol biphosphate.

hormone in the assayed fluid was small. Conversely, if

hormone to compete with the radioactive hormone,

radioactive hormone has bound with the antibody, it is

radioactive counting techniques. If a large amount of

remainder of the solution, and the quantity of radio-

Third, after binding has reached equilibrium, the

radioactive, that binds is proportional to its concen-

tity of each of the two hormones, the natural and the

of the antibody. In the process of competing, the quan-

and the hormone in the fluid to be assayed. Therefore,

must be met: There must be too little antibody to bind

radioactive isotope. However, one specific condition

Second, a small quantity of this antibody is (1)

follows. First, an antibody that is highly specific for the

The method of performing radioimmunoassay is as

radioimmunoassay.

ucts. This method is called

mones, their precursors, and their metabolic end prod-

sensitive method, however, was developed about 40

centrations by the usual chemical means.An extremely

Therefore, it was very difficult to measure these con-

one billionth of a milligram (1 picogram) per milliliter.

minute quantities; some concentrations are as low as

Measurement of Hormone

control functions for days or even weeks.

2. Once bound to the intranuclear receptors, the

metabolic activity in virtually all cells of the body.

proteins—probably 100 or more. Many of these

1. They activate the genetic mechanisms for the

Two important features of thyroid hormone func-

operators, as explained in Chapter 3.

located within the chromosomal complex, and they

nucleus. To accomplish this, these hormones first bind

thyroxine

The thyroid hormones

Transcription in the Cell Nucleus

Thyroid Hormones Increase Gene

vasopressin and norepinephrine.

peptide and amino acid–derived hormones, such as

several hours or even days. This is in marked contrast

Thus, the full action of the steroid hormone is charac-

the tubules and potassium secretion into the tubules.

about 45 minutes, proteins begin to appear in the renal

the sequence of events cited earlier ensues. After

aldosterone receptor protein. Therefore, in these cells,

plasm of renal tubular cells, which contain a specific

mones secreted by the adrenal cortex, enters the cyto-

aldosterone,

To give an example,

to form new proteins.

4. The mRNA diffuses into the cytoplasm, where it

mRNA.

DNA strands in the chromosomes, which activates

3. The combination binds at specific points on the

diffuses into or is transported into the nucleus.

2. The combined receptor protein–hormone then

membrane and enters the cytoplasm of the cell,

1. The steroid hormone diffuses across the cell

The sequence of events in steroid function is essen-

which in turn provide other functions of the cells.

enzymes, transport proteins, or structural proteins,

the target cells. These proteins then function as

ovaries, and testes—is to cause synthesis of proteins in

Another means by which hormones act—specifically,

Steroid Hormones Increase Protein Synthesis

Genetic Machinery of the Cell

Hormones That Act Mainly on the

both function and protein structure.

tal muscle contraction, as explained in Chapter 7. It is

tal muscle to activate troponin C, which causes skele-

actions of calmodulin. This is almost exactly the same

to activate the calmodulin system. But when the

mol/L, which is not enough

The normal calcium ion concentration in most cells

myosin kinase,

example, one specific function of calmodulin is to acti-

involved in the cell’s response to the hormone. For

phosphorylation, activation or inhibition of proteins

calmodulin-dependent protein kinases causes, via

Chapter 74

Introduction to Endocrinology

915

vate

which acts directly on the myosin

of smooth muscle to cause smooth muscle contraction.

of the body is 10

-8

to 10

-7

calcium ion concentration rises to 10

-6

to 10

-5

mol/L,

enough binding occurs to cause all the intracellular

amount of calcium ion change that is required in skele-

interesting that troponin C is similar to calmodulin in

the steroid hormones secreted by the adrenal cortex,

tially the following:

where it binds with a specific receptor protein.

the transcription process of specific genes to form

promotes the translation process at the ribosomes

one of the hor-

tubular cells and promote sodium reabsorption from

teristically delayed for at least 45 minutes—up to

to the almost instantaneous action of some of the

and triiodothyronine

cause increased transcription by specific genes in the

directly with receptor proteins in the nucleus itself;
these receptors are probably protein molecules

likely control the function of the genetic promoters or

tion in the nucleus are the following:

formation of many types of intracellular

are enzymes that promote enhanced intracellular

thyroid hormones can continue to express their

Concentrations in the Blood

Most hormones are present in the blood in extremely

years ago that revolutionized the measurement of hor-

Radioimmunoassay

hormone to be measured is produced.

mixed with a quantity of fluid from the animal con-
taining the hormone to be measured and (2) mixed
simultaneously with an appropriate amount of purified
standard hormone that has been tagged with a

completely both the radioactively tagged hormone

the natural hormone in the assay fluid and the radio-
active standard hormone compete for the binding sites

tration in the assay fluid.

antibody-hormone complex is separated from the

active hormone bound in this complex is measured by

clear that there was only a small amount of natural

and therefore the concentration of the natural

in the central nervous system. Ann N Y Acad Sci 1007:6,

Kelly MJ, Qiu J, Ronnekleiv OK: Estrogen modulation of G-

Biol 3:893, 2002.

tion and multivesicular-body sorting. Nat Rev Mol Cell

Katzmann DJ, Odorizzi G, Emr SD: Receptor downregula-

Ann N Y Acad Sci 994:111, 2003.

tion, and internalization of the ACTH receptor (MC2R).

Clark AJ, Baig AH, Noon L, et al: Expression, desensitiza-

expression. Physiol Rev 81:1269, 2001.

Aranda A, Pascual A: Nuclear hormone receptors and gene

the Cell. New York: Garland Science, 2002.

Alberts B, Johnson A, Lewis J, et al: Molecular Biology of

hormone levels.

mated using 96-well plates, and (3) it has proved to be

radioactive isotopes, (2) much of the assay can be auto-

The ELISA method has become widely used in clin-

antibody-hormone complexes. Therefore, the amount

assay methods, ELISA methods use excess antib-

detected. In contrast to competitive radioimmuno-

formation of many thousands of product molecules,

methods.

molecule. A third antibody (AB

or standards are added to each of the wells, followed

that is specific for the hormone being assayed. Samples

small wells. Each well is coated with an antibody (AB

74–10 shows the basic elements of this method, which

with the sensitivity of simple enzyme assays. Figure

mones. This test combines the specificity of antibodies

be used to measure almost any protein, including hor-

of hormone can often be assayed in this way.

fluid. As little as billionths or even trillionths of a gram

centration of the hormone in the “unknown” assayed

assay procedures with the standard curve, one can

radioactive counts recorded from the “unknown”

plotted, as shown in Figure 74–9. By comparing the

concentration levels. Then a “standard curve” is

“standard” solutions of untagged hormone at several

Fourth, to make the assay highly quantitative, the

natural hormone to compete for the binding sites.

bound, it is clear that there was a large amount of

916

Unit XIV

Endocrinology and Reproduction

only a small amount of radioactive hormone has

radioimmunoassay procedure is also performed for

determine within an error of 10 to 15 per cent the con-

Enzyme-Linked Immunosorbent
Assay (ELISA)

Enzyme-linked immunosorbent assays (ELISAs) can

is often performed on plastic plates that each have 96

)

by a second antibody (AB

) that is also specific for the

hormone but binds to a different site of the hormone

) is added that recog-

nizes AB

and is coupled to an enzyme that converts

a suitable substrate to a product that can be easily

detected by colorimetric or fluorescent optical

Because each molecule of enzyme catalyzes the

even very small amounts of hormone molecules can be

odies so that all hormone molecules are captured in

of hormone present in the sample or in the standard
is proportional to the amount of product formed.

ical laboratories because (1) it does not employ

a cost-effective and accurate method for assessing

References

protein-coupled receptor activation of potassium channels

2003.

100

128

Percent of antibody bound with

radioactive aldosterone

Aldosterone concentration in

test sample (ng/d)

Dr. Manis Smith.)

“Standard curve” for radioimmunoassay of aldosterone. (Courtesy

Figure 74–9

the amount of hormone in the well if there are excess antibodies

product is measured using optical methods and is proportional to

fluorescent product (P) from a substrate (S). The amount of the

that catalyzes the formation of a colored

is an antibody that recognizes AB

are antibodies that recognize the hormone at different

(ELISA) for measuring the concentration of a hormone (H). AB

Figure 74–10

Basic principles of the enzyme-linked immunosorbent assay

and AB

binding sites, and AB

. E is an

enzyme linked to AB

in the well.

hormone action. Physiol Rev 81:1097, 2001.

Yen PM: Physiological and molecular basis of thyroid

molecular specificity. Physiol Rev 82:923, 2002.

hormone receptor interactions: physiological flexibility by

Vasudevan N, Ogawa S, Pfaff D: Estrogen and thyroid

84:137, 2004.

ated by distinct routes of protein kinase A. Physiol Rev

Tasken K, Aandahl EM: Localized effects of cAMP medi-

55:27, 2004.

proteins and G protein-coupled receptors. Annu Rev Med

Spiegel AM, Weinstein LS: Inherited diseases involving G

Physiol Rev 84:489, 2004.

model for convergence in cellular signaling pathways.

Spat A, Hunyady L: Control of aldosterone secretion: a

Physiol 66:315, 2004.

regulation by nuclear hormone receptors. Annu Rev

Privalsky ML: The role of corepressors in transcriptional

pathways in animal development. Nat Rev Genet 4:39,

Pires-daSilva A, Sommer RJ: The evolution of signaling

pathway. Nat Rev Drug Discov 3:555, 2004.

ity for immunosuppression: targeting the JAK/STAT

O’Shea JJ, Pesu M, Borie DC, Changelian PS: A new modal-

Physiol 283:R7, 2002.

leukocyte trafficking. Am J Physiol Regul Integr Comp

Olson TS, Ley K: Chemokines and chemokine receptors in

N Y Acad Sci 1024:213, 2004.

trafficking and gene targeting by steroid receptors. Ann

Nagaich AK, Rayasam GV, Martinez ED, et al: Subnuclear

16:251, 2001.

brane, cytosolic, and nuclear effects. News Physiol Sci

Nadal A, Diaz M, Valverde MA: The estrogen trinity: mem-

protein-linked signaling. Physiol Rev 79:1373, 1999.

Morris AJ, Malbon CC: Physiological regulation of G

Physiol Rev 83:965, 2003.

steroid action: controversies, questions, and answers.

Lösel RM, Falkenstein E, Feuring M, et al: Nongenomic

WB Saunders, 2003.

Williams Textbook of Endocrinolog, 10th ed. Philadelphia:

Larsen PR, Kronenberg HM, Melmed S, Polonsky KS:

guanylyl cyclase-A. Circ Res 93:700, 2003.

membrane guanylyl cyclase receptors, with a focus on

Kuhn M: Structure, regulation, and function of mammalian

Chapter 74

Introduction to Endocrinology

917

2003.