Caballero B. (ed.) Encyclopaedia of Food Science, Food Technology and Nutrition. Ten-Volume Set

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for about 0.5% of the solids. The acids account for

the low average pH (3.99) value, which is in part

responsible for the excellent stability of honey.

Several acids have been found in honey, gluconic

acid being present in considerable excess over the

others. It arises from glucose through the action of

the enzyme glucose oxidase, added by the honeybee.

The combined effect of its acidity and the hydrogen

peroxide concurrently produced assist in preserving

nectar and honey from spoilage. Less prominent acids

reported to be in honey are formic, acetic, butyric,

lactic, oxalic, succinic, tartaric, maleic, pyruvic, pyr-

oglutamic, a-ketoglutaric, glycollic, citric, malic, 2-

or 3-phosphoglyceric acids, and glucose 6-phosphate.

(See Acids: Properties and Determination.)

Proteins and Amino Acids

0021 Protein and amino acid levels in honey are reflected in

nitrogen content, which is low, 0.04% on the average,

but variable, ranging up to 0.1%. About 40–80% of

the total nitrogen in honey is in protein, and most

of the remainder resides in the free amino acids.

About 20 different nonenzymatic proteins have been

identified in honey, many of which are common to all

honeys. Some appear to originate in the honeybee,

and others in the plant source of nectar. Except for

the honey enzymes, little is known about many of the

proteins in honey. Their presence results in honeys

having a lower surface tension than they would have

otherwise, and this encourages the formation of fine

air bubbles and a marked tendency to foam. (See

Protein: Food Sources.)

0022 The quantity of free amino acids in honey is small and

of no nutritional significance. Honeys have been found

tocontainbetween11and21freeaminoacids.Proline

accounts for about half of the total, most of which

originates from the honeybee, rather than from nectar

or pollen. Aside from proline, the amino acids glutamic

acid, alanine, phenylalanine, tyrosine, leucine, and iso-

leucine are present in the highest levels. Amino acids

react with some of the honey sugars to produce yellow

or brown materials, and age-related darkening of honey

is probably a result of these reactions.

Flavor, Aroma, and Color

0023 The dominant flavor of honey is sweetness, arising

from the blend of the major sugars fructose and glu-

cose, and the wide array of other sugars. Sweetness is

common to all honeys, regardless of the floral source

of the nectar. Other components common to all

honeys, such as gluconic acid and proline, also make

contributions to the general flavor of honey. The

uniqueness of a given honey is due to contributions

of compounds from the wide variety of floral nectar

sources. Honey assumes many of the subtle flavor and

aroma characteristics of these sources, and there are

perhaps as many variations in flavor and aroma as

there are nectar sources. Flavors are sufficiently dis-

tinctive that experienced honey tasters can identify

dozens of different floral sources. Typical flavors

range from the most delicate and desirable to those

that are harsh and objectionable. (See Flavor (Fla-

vour) Compounds: Structures and Characteristics.)

0024As many as 129 components have been separated

from extracts of honey, and many of these are

volatile organic compounds. Each of these is

present in very low levels. About two-thirds have

been identified, and many of these probably contrib-

ute to honey flavor and aroma, and perhaps color.

Low-molecular-weight aldehydes, ketones, alcohols,

and esters, make up the bulk of the compounds. One

compound present in all honeys is hydroxymethylfur-

fural. This is produced from decomposition of sugars,

especially fructose, in the presence of acid. The high

fructose level and low pH of honey combine to favor

its formation, which is accelerated when honey is

heated. Synthetic honey flavors contain a large pro-

portion of phenylacetic esters, as most of these com-

pounds have a honey taste and aroma. A closely

related compound, phenylethyl alcohol, is present in

several natural honeys. The flavor and delicate bou-

quet of honey are vulnerable to heat and improper

storage, which can level the subtle distinctions among

unique floral sources. Honey is heated during com-

mercial processing in order to delay granulation and

avoid fermentation, but careful attention must be

given to the time and amount of heat, or valuable

flavor and aroma compounds can be lost.

0025Generally, lighter colors are associated with the

milder, more pleasantly flavored honeys. Honey

cannot be judged solely on the basis of color, as

some of the most distinctively and strongly flavored

honeys, such as basswood, are very light, whereas

very mild and pleasant honeys such as tulip poplar

can be quite dark. Color limits are often specified in

trading of honey, however, because flavor is so sub-

jective. Several systems are used for the objective

measurement of honey color, and some are designated

as official in various countries. Seven classifications

are used for international trade; water white, extra

white, white, extra light amber, light amber, amber,

and dark amber.

Quality Assurance

0026Much of what has been learned about the compos-

ition and properties of honey has resulted from re-

search aimed at verifying its authenticity. Being of

HONEY 3129

limited supply and relatively expensive, for many

years, honey has been a target for adulteration with

inexpensive, highly refined sweeteners. High profits

are realized when mixtures of these sweeteners

and honey are illegally labeled and marketed as pure

honeys. Sweeteners that have been mixed with honey

over the years have included corn syrup, which con-

tains mostly glucose, and hydrolyzed cane and beet

sugars, which contain both fructose and glucose.

High fructose corn syrup was the most recent

sweetener used to adulterate honey, and it also con-

tains fructose and glucose. Corn syrup is easy to

detect, because glucose levels in adulterated mixtures

are higher than those normally found in honey.

The other three sweeteners are difficult to detect,

because adulterated mixtures contain fructose and

glucose within the range normally found in honeys.

0027 Methods to detect adulteration of honey have been

required to guarantee the integrity of honey markets,

therefore assuring an adequate supply of honeybee

colonies for crop pollination. In 1977, shortly after

the advent of high fructose corn syrup, a method was

developed to detect its presence or the presence of

sugar cane-derived sweeteners in honey. The test

was based on differences in the ratios

C be-

tween honey plants and corn and sugar cane plants.

The tropical grasses sugar cane and corn employ a

different photosynthesis process to fix carbon diox-

ide, and this results in higher ratios of

C than

are found in honeys. These ratios can be precisely

measured using isotope ratio mass spectrometry.

The application of these tests by government agencies

largely discouraged widespread adulteration of honey

with sweeteners from corn and sugar cane. Adulter-

ation strategies have shifted to the addition of hydro-

lyzed beet sugar syrups, which have

C values in

the same range as honey. Some progress is being

made in its detection, as some oligosaccharides are

present in the adulterants that are not present in

honey, and these can be detected using sophisticated

chromatographic approaches.

Uses of Honey

0028 Most of the honey produced is used directly as a table

sweetener or spread. The most significant indirect

uses are in baking, cereal, confectionary, and meads.

Honey is primarily a high-energy carbohydrate food,

possessing distinct flavors that cannot be found

elsewhere. The honey sugars are largely the easily

digestible simple sugars, similar to those in many

fruits. The protein and enzymes of honey, though

used as indicators of heating history and hence table

quality in some countries, are not present in sufficient

quantities to be considered nutritionally significant.

Several of the essential vitamins are present in honey,

but in insignificant levels. The mineral content of

honey is variable, but in the darker honeys, the level

can be quite high. Honey is also included in many

over-the-counter pharmaceutical preparations, pro-

viding flavor and textural properties valued by

consumers.

See also: Acids: Natural Acids and Acidulants; Amino

Acids: Properties and Occurrence; Enzymes: Functions

and Characteristics; Fructose; Glucose: Properties and

Analysis; Protein: Chemistry; Quality Assurance and

Quality Control; Sensory Evaluation: Descriptive

Analysis; Aroma; Taste

Further Reading

Aureli P, Franciosa G and Fenicia L (2002) Infant botulism

and honey in Europe: a commentary. Pediatric Infec-

tious Diseases Journal 21(9): 866–868.

Crane E (ed.) (1979) Honey: A Comprehensive Survey.

London: Heinemann.

Doner LW (1977) The sugars of honey – A review. Journal

of the Science of Food and Agriculture 28: 443–456.

Doner LW (1991) The enzymes of honey. In: Fox PF (ed.)

Food Enzymology, pp. 143–161. London: Elsevier

Applied Science.

Gheldof N, Wang XH and Engeseth NJ (2002) Identifica-

tion and quantification of antioxidant components of

honeys from various floral sources. Journal of Agricul-

tural Food Chemistry 9; 50(21): 5870–5877.

Graham JM (ed.) (1992) The Hive and the Honey Bee.

Hamilton, IL: Dadant & Sons.

Low NH, Va Vong K and Sporns P (1986) A new enzyme,

b-glucosidase in honey. Journal of Apicultural Research

25: 178–181.

White JW, Jr. (1962) Composition of American Honeys.

Technical Bulletin No. 1261. US Department of Agricul-

ture.

White JW, Jr. (1978) Honey. In: Chichester CO, Mrak

EM and Stewart GF (eds) Advances in Food Research,

pp. 288–374. New York: Academic Press.

White JW, Jr. (1992) Honey. In: Graham JM (ed.) The Hive

and the Honey Bee, pp. 869–925. Hamilton, IL: Dadant

& Sons.

3130 HONEY

HORMONES

Contents

Adrenal Hormones

Thyroid Hormones

Gut Hormones

Pancreatic Hormones

Pituitary Hormones

Steroid Hormones

Adrenal Hormones

L N Parker, University of California, Long Beach, CA,

USA

Background and History

0001 Hormones secreted by both parts of the adrenal

gland, the cortex and medulla, affect metabolism of

proteins, carbohydrates, fat, minerals, and water. The

human adrenal glands are paired structures located at

the superior pole of each kidney. They are compound

glands, composed of an outer cortex and an inner

medulla. The cortex secretes three classes of steroid

hormones. In humans, the main examples of these

hormones are cortisol, a glucocorticoid; dehydroepi-

androsterone (DHEA), an androgen; and aldoster-

one, a mineralocorticoid.

0002 The adrenal medulla secretes nonsteroidal hor-

mones with a catechol nucleus, among them epineph-

rine (adrenaline), norepinephrine (noradrenaline),

and dopamine. Norepinephrine and epinephrine are

primarily involved in the biological alarm mechanism

of the sympathoadrenal system. The embryological

development of the adrenal cortex and medulla are

different, as are their control mechanisms and func-

tions, and in some nonhuman vertebrates, including

fish, are located apart from each other.

0003 The adrenal glands were described in the sixteenth

century by Eustachius, although their functions

remained unknown for approximately three centur-

ies. In the nineteenth century, histological studies

revealed three zones in the adrenal cortex, and an

inner medullary zone which stained differently from

the cortex in the fetal and adult adrenal gland. The

functions of the adrenal glands were then gradually

elucidated. In 1855, Thomas Addison described a

group of patients with anemia, pigmented skin, gas-

trointestinal symptoms, and marked weakness, who

were found at autopsy to have atrophied adrenal

glands. Their condition of adrenal failure still bears

his name, Addison’s disease. At approximately the

same time, the physiologists Claude Bernard and

Charles Brown-Se

quard popularized the concept of

internal secretions by glands, and showed by

adrenalectomies in animals that the adrenal glands

are essential for life.

0004The next clues about the role of the adrenal glands

were discovered beginning at the turn of the twentieth

century, when a substance with vasopressor activity

was isolated from the adrenal medulla, purified and

named adrenaline, or epinephrine. In retrospect, epi-

nephrine thereby became the first hormone with a

known chemical structure. Shortly thereafter, it was

hypothesized that the adrenal glands controlled salt

balance as well as blood pressure when it was found

that sodium salts could prolong the life of adrenalec-

tomized animals. A generation later, by the use of

lipid, rather than aqueous extracts, steroid hormones

were sequentially discovered and purified after it was

observed that crude lipid extracts of adrenal glands

could keep adrenalectomized animals alive indefin-

itely. The first adrenal steroid hormone synthesized

was deoxycorticosterone (DOC), a weak mineralo-

corticoid, in 1937. The first glucocorticoid synthe-

sized was cortisone in 1949, and by 1955 the main

mineralocorticoid in humans, aldosterone, had been

characterized and synthesized. Experiments soon

demonstrated adrenocortical control by the pituitary

gland, and in turn hypothalamic control of adreno-

corticotropin (ACTH) was demonstrated conclu-

sively by the characterization and synthesis of

corticotropin-releasing hormone (CRH) in 1981.

More recent research has focused on many aspects

of adrenal gland function, such as hormone synthesis,

hormone receptors, and mechanisms of intracellular

action. Clinical research has shown the clinical use-

fulness of epinephrine and related substances in the

treatment of asthma, glucocorticoids in the treatment

of inflammatory and other conditions, and mineralo-

corticoids and related substances in the management

of autonomic insufficiency.

HORMONES/Adrenal Hormones 3131

Structure of the Adrenal Glands and

Hormones Secreted

Adrenal Cortex

0005 The location of the human adrenal glands and the

structures surrounding them are shown in Figure 1.

The weight range of each adrenal gland is approxi-

mately 3.5–5 g, and the cortex comprises about 90%

of the gland volume. Chronically increased ACTH

secretion causes adrenal weight to increase. The

adrenal glands, normally adjacent to the kidneys,

are surrounded by fat, and can be separated from

the kidney in obesity. Occasionally, accessory adrenal

tissue is found in the connective tissue near the main

glands, most commonly in locations such as in

the retroperitoneal celiac plexus, in the hilum of the

spleen, near the ovaries or broad ligament, in the

scrotum or in the liver. Embryologically, the adrenal

cortex is derived from mesenchymal cells adjacent to

the urogenital ridge. The fetal adrenal can be recog-

nized by 2 months of gestation, at which time it is

invaded by neuroectodermal cells which will form the

medulla. By the second trimester, there is a thin outer

definitive zone, which will later form the adult ad-

renal cortex, but the inner fetal zone comprises most

of the adrenal mass. After birth, the fetal zone, which

secretes mostly DHEA sulfate (DHEAS), rapidly in-

volutes by 2 months of age, and disappears by 1 year.

0006By 1 year of age, three zones can be identified by

light microscopy in the definitive adrenal cortex, as

shown in Figure 2. The outer zone, the zona glomer-

ulosa, is relatively thin, and consists of cells which

secrete aldosterone. The middle zone, the zona fasci-

culata, is usually the thickest layer of the adrenal

cortex, and has a columnar structure. Its cells are

relatively clear, since they are large and have a high

lipid content. The inner zone, the zona reticularis,

surrounds the medulla. Its cells are relatively dark-

staining and compact in appearance, and often

contain lipofuscin pigment granules. Both the zona

fasciculata and the zona reticularis produce cortisol

and androgens, but in the human, the zona reticularis

has sulfotransferase activity, and produces DHEAS.

Chronically increased ACTH concentrations result

in lipid depletion from the zona fasciculata and an

increase in the width of the zona reticularis.

Adrenal Medulla

0007The adrenal medulla is part of the sympathetic ner-

vous system, which arises from cells of the neural

crest during embryonic development. Storage gran-

ules which stain brown with chromic acid due to

oxidation of catecholamines to melanin give the cells

which contain them the name chromaffin or pheo-

chrome cells. These cells are also found on both sides

of the aorta, and comprise the paraganglia. The larg-

est collection of these cells is found near the inferior

mesenteric artery, where the cells fuse to form a fetal

structure called the organ of Zuckerkandl, which

undergoes involution within the first year of life.

The remainder of the chromaffin cells in the paragan-

glia and adrenal medulla persist during adult life and

secrete norepinephrine, epinephrine, and dopamine.

In the adrenal medulla, the cells are arranged in an

irregular network with a rich blood supply, and are in

contact with sympathetic ganglia. The cells of the

adrenal medulla are innervated by preganglionic

Adrenal glands

Esophagus

(cut)

Kidney

Aorta

Inferior vena cava

fig0001 Figure 1 Location and surrounding structures of the human

adrenal glands. Reproduced from Gaudin A and Jones K (1989)

Human Anatomy and Physiology. San Diego: Harcourt Brace

Jovanovich, with permission.

Connective tissue

capsule

Zona

glomerulosa

Zona

fasciculata

Zona

reticularis

Cortex

Medulla

fig0002Figure 2 Histology of the human adrenal gland. Reproduced

from Gaudin A and Jones K (1989) Human Anatomy and Physiology,

San Diega: Harcourt Brace Jovanovich, with permission.

3132 HORMONES/Adrenal Hormones

fibers of the sympathetic nervous system. Most of the

blood supply of the adrenal glands enters through the

cortex and drains into the medulla, except for some

vessels which supply the medulla directly.

Physiological Effects of Adrenal Gland

Hormones

Adrenal Cortex

0008 As in the case of other steroid hormones, glucocorti-

coids exert their effects on target cells by interacting

with soluble cytosolic receptor proteins, after mostly

passive diffusion into cells. The glucocorticoid recep-

tor is a single-chain polypeptide with a molecular

weight of 94 kDa which binds glucocorticoids with

a high affinity. After binding glucocorticoids at the

COOH-terminus, the DNA-binding region in mid-

molecule binds to the nucleus. The glucocorticoid

receptor is a member of a family of DNA-binding

proteins which act as regulators of gene transcription,

including receptors for all types of steroid hormones,

the thyroid hormone receptor, and the retinoic acid

receptor. The hormone-binding domain of these

receptors is well conserved, but the most distinctive

feature is the highly conserved central DNA-binding

domain. This is the zinc-finger domain, a series of

finger-like loop structures of amino acids anchored

at the base by a zinc ion chelated between two pairs of

cysteine and histidine residues (Figure 3), which

interact with coils of the DNA double helix. Gluco-

corticoid receptor complexes interact with specific

glucocorticoid response elements, usually located

near the promoter region of target genes.

0009 Glucocorticoids are named for their effect of

increasing hepatic glucose production by several

mechanisms. They increase activity of hepatic gluco-

neogenic enzymes such as glucose-6-phosphatase and

phosphoenolpyruvate carboxykinase, in the latter

case by gene transcription. Glucocorticoids also acti-

vate glycogen synthase and inactivate the glycogen-

mobilizing enzyme glycogen phosphorylase, with a

net increase in hepatic glycogen synthesis. Finally,

glucocorticoids decrease peripheral glucose utiliza-

tion in part by decreasing adipocyte glucose trans-

porter mRNA levels.

0010 With respect to protein and fat metabolism, gluco-

corticoids stimulate catabolism of nonhepatic pro-

teins with a resultant release of glucogenic amino

acids, largely from skeletal muscle, and an increased

uptake into liver for gluconeogenesis. In adipose

tissue, glucocorticoids stimulate lipolysis and subse-

quent release of glycerol and free fatty acids, while

enhancing the rate of fat oxidation. Pharmacological

amounts of glucocorticoids cause osteopenia on

a chronic basis, by inhibiting osteoblast function,

thereby decreasing new bone formation, and by

decreasing intestinal calcium absorption.

0011Cortisol is a major stress hormone and is secreted in

so many different forms of stress that an increase in

cortisol secretion is often considered to be part of the

definition of a stressful stimulus. It has been specu-

lated that cortisol functions to aid survival in stress

by improving the metabolic milieu by means of the

energy-producing and biosynthetic pathways de-

scribed above. The inflammatory process is common

in stress caused by illness or injury, and cortisol may

also help to minimize damage to the body resulting

from excessive inflammation by stimulating mechan-

isms such as lysosomal membrane stabilization, which

prevents release of proteolytic enzymes, and reduction

in capillary permeability to avoid leakage of plasma

and blood cells into an inflamed area. Among the

mechanisms by which cortisol performs these func-

tions is the inhibition of the action of histamine, and

the synthesis of prostaglandins. Cortisol inhibits the

accumulation of neutrophils at sites of inflammation.

Cortisol also has numerous other effects, such as

maintenance of normal cardiac output and renal

blood flow, and modification of immunological

responses. One mechanism for the modification

of immunological responses is the promotion of

lymphocyte apoptosis.

0012Adrenal androgens such as DHEAS circulate at

high concentrations in young adults, and in the case

of DHEAS, the concentration is much greater than

that of cortisol. However, their functions are not as

clearly elucidated. There is evidence that these

steroids have a hepatic receptor, and that they may

prevent osteoporosis, facilitate the birth process by

Cys

His

(b)(a)

fig0003Figure 3 Two postulated models (a, b) of zinc-finger structures

in the DNA-binding region of the glucocorticoid receptor. Repro-

duced from Evans R and Hollenberg S (1988) Zinc Fingers. Cell

52: 1. Cambridge, MA: Cell Press, with permission.

HORMONES/Adrenal Hormones 3133

causing cervical softening, modify immunological

processes, mediate female libido, and serve as precur-

sors for the more potent sex steroids. In animal stud-

ies these steroids have been shown to protect against

obesity, diabetes, and certain types of infections and

tumors. There is DHEAS in the human brain, and it

has been shown to be synthesized in rat brain, but

its function in the nervous system of either species is

not known.

0013 Aldosterone and other mineralocorticoids main-

tain normal sodium and potassium concentrations

and intravascular volume by regulating electrolyte

transport across epithelial surfaces. The specific

renal type I mineralocorticoid receptor is unrelated

to the glucocorticoid receptor at the amino-terminus,

but partially homologous at the steroid-binding

COOH-terminus, and highly homologous at the

DNA-binding zinc-finger domain. Cortisol displaces

aldosterone from this receptor, but in vivo is con-

verted locally to cortisone by the microsomal 11-b

hydroxysteroid dehydrogenase enzyme, and

cortisone has relatively little affinity for the mineralo-

corticoid receptor. After binding to the mineralocor-

ticoid receptor, mineralocorticoids induce protein

synthesis and subsequent activation of a sodium

pump, which transports sodium across cell mem-

branes. In the kidney, sodium is absorbed, and potas-

sium and hydrogen ions are secreted. Under the

influence of aldosterone, sodium is therefore con-

served, and potassium and hydrogen ions are excreted

into the urine. Aldosterone has similar effects in sweat

glands, salivary glands, and in the intestinal lumen.

Adrenal Medulla

0014 Catecholamines exert their effects via two classes of

receptors, a and b. Adrenergic receptors interact with

catecholamines on the extracellular side of the plasma

membrane, and with G proteins within the cell mem-

brane. Adrenergic receptors are part of a large family

of membrane-associated proteins which includes

muscarinic acetylcholine receptors. Regions of these

proteins show considerable homology with each

other, especially the membrane-spanning domains.

As with other receptors which are coupled to G

proteins, there are seven hydrophobic membrane-

spanning domains connected by three extracellular

and cytoplasmic loops. Stimulation of the a class of

receptors by norepinephrine results in a variety of

actions, such as vasoconstriction and blood pressure

elevation, pupillary dilatation, and bladder sphincter

contraction. Epinephrine also stimulates a receptors.

However, in addition, epinephrine also stimulates

the b types of receptors, which result in actions

such as vasodilatation, acceleration of the heart rate,

bronchodilatation, glycogenolysis, and lipolysis.

These actions are part of the physiological response

to stressful stimuli, and complement those of cortisol.

Dopamine is a weak agonist of both the a and b

classes of receptors, but in addition, there are several

classes of dopaminergic receptors in the central ner-

vous system and peripheral tissues.

0015In liver, catecholamines promote glucose output by

activating glycogenolysis, accelerating gluconeogen-

esis, and inhibiting glycogen synthesis. Stimulation of

adrenergic receptors by catecholamines increases ac-

tivity of adrenyl cyclase and conversion of glycogen

phosphorylase from the inactive to the active form,

while there is a simultaneous increase of amino acid

uptake by the liver, which increases substrate avail-

ability for gluconeogenesis. In adipose tissue, cat-

echolamines also stimulate lipolysis by increasing

activity of hormone-sensitive lipase, and the cleavage

of triglycerides into fatty acids and glycerol for

increased gluconeogenesis and energy availability.

Synthesis and Control of Adrenal Gland

Hormones

Adrenal Cortex

0016The adrenal cortex produces cortisol in response to

ACTH secreted by the pituitary gland. The secretion

of ACTH occurs in response to decreased circulating

concentrations of cortisol, as part of a negative-

feedback system, and in response to stressors of

many types, including surgery, hemorrhage, thermal

injury, and hypoglycemia. In addition, there is a cir-

cadian rhythm of pulsatile ACTH and cortisol secre-

tion which in humans results in increased secretion

towards the end of the sleep period, and therefore

higher levels of circulating cortisol in the morning.

ACTH is a 39-amino-acid peptide derived from a

larger molecule, 241-amino-acid proopiomelanocor-

tin (POMC). The first 24 amino acids of ACTH are

constant and bioactive in many species. POMC secre-

tion is under the control of neurotransmitters and

hypothalamic CRH, as shown in Figure 4. POMC

undergoes extensive posttranslational processing,

producing many peptides, including ACTH, as

shown in Figure 5. There is evidence from animal

experiments that non-ACTH POMC peptides may

synergize with ACTH in control of corticosteroid

secretion. Concentrations of CRH, a 41-amino-acid

peptide, are high in the hypophysical portal system.

0017The mechanism of action of ACTH involves many

steps, including initial binding to an adrenal cell

surface receptor, which ACTH upregulates, thereby

increasing the steroidogenic response to ACTH

stimulation. ACTH binding activates adenyl cyclase

3134 HORMONES/Adrenal Hormones

which increases cyclic 3

-monophosphate (cAMP)

concentrations, which in turn activate cAMP-

dependent protein kinase and phosphorylation of a

number of proteins in the presence of extracellular

calcium. There is an increase in activity of cholesterol

ester hydrolase, which produces free cholesterol for

the rate-limiting conversion of cholesterol to pregne-

nolone. Intracellular delivery of cholesterol to the

inner mitochondrial membrane is facilitated by the

30-kDa steroidogenic acute regulatory protein,

induced by cAMP. The conversion of cholesterol to

pregnenolone then proceeds via the mitochondrial

side-chain cleavage enzyme. Plasma lipoproteins

also provide cholesterol for steroidogenesis.

0018 As shown in Figure 6, pregnenolone can be con-

verted to mineralocorticoids, glucocorticoids, or

androgens. Many of the microsomal enzymatic steps

are controlled by ACTH by regulation of the rate of

steroidogenic enzyme synthesis. In contrast to the

situation in the human, there is little activity of the

enzyme 17b-hydroxylase (Figure 6) in rodents, and

therefore the main glucocorticoid is corticosterone in

this species.

0019Cortisol and ACTH secretion are closely related,

and linked by a negative-feedback loop, as described

above. Adrenal androgens, such as DHEA, are also

secreted in response to acute ACTH stimulation, but

their control is more complex since in some situations

they are not secreted in parallel with cortisol. These

situations include adrenarche, puberty, aging,

polycystic ovarian syndrome, stress, serious illness,

anorexia nervosa, and starvation. Adrenarche is the

process of adrenal gland maturation which occurs

before puberty at approximately age 7, and which

involves increased secretion of DHEA and DHEAS

along with unchanged secretion of cortisol. In con-

trast, during aging, while basal levels of cortisol are

unchanged, levels of DHEAS peak in young adult-

hood in both sexes, and then decline markedly, as

shown in Figure 7. The decrease in concentrations

of adrenal androgens in stress, serious illness, anor-

exia nervosa, and starvation is somewhat similar to

the situation in aging, except that it is reversible with

recovery. The reason for the dissociation between

cortisol and adrenal androgen secretion is not clear,

but may involve regulation by a non-ACTH POMC-

related peptide.

0020Aldosterone is produced only by the zona glomer-

ulosa, because it is the only zone with aldosterone

synthase activity. The zona glomerulosa does not

have 17b-hydroxylase activity, and does not produce

cortisol. Although ACTH causes acute stimulation

of aldosterone secretion, there are other more im-

portant control mechanisms in addition to ACTH.

Angiotensin II is the major regulator of aldosterone

secretion. Secretion of angiotensin II is controlled by

renin, as shown in Figure 8. Renin release is regu-

lated primarily by the sodium concentration of fluid

in contact with the renal juxtaglomerular cells, and

renal perfusion, as sensed by renal baroreceptors.

Increased renin release is stimulated by decreased

sodium concentration or renal arteriolar blood pres-

sure. Renin mediates the conversion of hepatic renin

substrate (angiotensinogen) to the 10-amino-acid

peptide, angiotensin I, which in turn is converted

to the 8-amino-acid peptide angiotensin II, a potent

vasopressor, by the converting enzyme in lung and

other tissues. The 7-amino-acid peptide angiotensin

III is also bioactive in stimulation of aldosterone

secretion.

0021Angiotensins II and III bind to high-affinity zona

glomerulosa cell surface receptors and stimulate al-

dosterone production from cholesterol by a calcium-

dependent mechanism involving activation of protein

ACTH

Cortisol

Adrenal cortex

pit.

CRH

(+)

(−)

fig0004 Figure 4 Cortisol feedback loop in the hypothalamic–pituitary–

adrenal system. CRH, corticotropin-releasing hormone; pit,

pituitary gland; ACTH, adrenocorticotropic hormone. Cortisol

negative feedback shown by dashed lines. Reproduced from

Darlington D and Dallman M (1990) Feedback Control in Endocrine

Systems. Principles and Practice of Endocrinology and Metabolism.

Philadelphia: JB Lippincott, with permission.

HORMONES/Adrenal Hormones 3135

kinase C, rather than adenylate cyclase. In addition,

aldosterone synthesis may be modified by lipoxygen-

ase pathway metabolites of arachidonic acid. Potas-

sium ion also influences aldosterone secretion by a

direct effect on zona glomerulosa cells, and forms the

basis for a feedback mechanism to regulate the con-

centration of extracellular potassium ions. Concen-

trations of potassium ion have the opposite effect on

renin concentrations, but the direct effect on aldoster-

one secretion is predominant. In addition, as in the

case of cortisol and adrenal androgen secretion, there

is evidence that an influence on aldosterone secretion

may be exerted by non-ACTH POMC-related

peptides.

Adrenal Medulla

0022 Control of the adrenal medulla is exerted by the

sympathetic nervous system. Whereas preganglionic

fibers of the parasympathetic branch of the auto-

nomic nervous system emerge from cranial and

sacral spinal nerves, those of the sympathetic ner-

vous system emerge from the thoracic and lumbar

spinal nerves and innervate many organs, including

the adrenal medulla. Preganglionic nerve impulses

are transmitted to postganglionic fibers by liberation

of acetylcholine at nerve terminals. This results in

secretion of catecholamines by the peripheral sym-

pathetic nervous system and by the adrenal medulla.

Norepinephrine is the major secretory product of

the peripheral nervous system, and is primarily a

neurotransmitter, not a circulating hormone. In the

human adrenal medulla, the ratio of epinephrine

to norepinephrine secretion is approximately 4:1,

and concentrations of epinephrine, a circulating

hormone, are sufficient to stimulate adrenergic

receptors.

0023Catecholamine biosynthetic pathways are shown

in Figure 9. The rate-limiting step in catecholamine

biosynthesis is the initial conversion of tyrosine to

dihydroxyphenylalanine (DOPA) by tyrosine hydro-

xylase (TH), an enzyme which is inhibited by DOPA,

dopamine, and norepinephrine. Tyrosine itself is de-

rived from the diet, or converted in the liver from

phenylalanine by phenylalanine hydroxylase. The

decarboxylation of DOPA to dopamine is catalyzed

by aromatic-l-amino acid decarboxylase (AADC).

Unlike the other enzymes of catecholamine biosyn-

thesis, AADC is not only found in sympathetic nerve

16 K fragment

β-LPH

β-endoγ-LPH

ACTH

β-LPH

16 K

JP JP

N-POC(1−76)

ACTH

β-endo

γ-LPH

N-POC(1−76)

K = kilodaltons;

Know maturation products;

lys−arg dibasic residues;

MSH (melanocyte-stimulating hormone) structural units;

O-glycosylation;

N-glycosylation.

fig0005 Figure 5 Structure and processing of proopiomelanocortin (POMC; POC). ACTH, adrenocorticotropic hormone; LPH, lipotropin;

endo, endorphin; JP, joining peptide. Reproduced from Seidah N et al. (1981) The missing fragment of the pro-sequence of human

POMC: sequence and evidence for C-terminal amidation. Biochemistry Biophys Research Commun 102: 710, with permission.

3136 HORMONES/Adrenal Hormones

−

CHO

Pregnenolone

17α-OH pregnenolone

Dehydroepiandrosterone Dehydroepiandrosterone

sulfate

Progesterone

11-Deoxycorticosterone

Corticosterone

Aldosterone

Cortisol

11-Deoxycortisol

17α-OH progesterone

Androstenedione

fig0006 Figure 6 Human adrenocortical steroidogenic pathways. Enzyme activities: A, 17a-hydroxylase (CYP 17); B, 3b-hydroxysteroid

dehydrogenase-isomerase (3b-HSD II); C, C17–20 desmolase (CYP 17); D, steroid sulfotransferase; E, steroid sulfatase; F,

21-hydroxylase (CYP21A2); G, 11b-hydroxylase (CYP11B1); H, aldosterone synthase (CYP11B2). Reproduced from Parker (1989) Ad-

renal Androgens in Clinical Medicine. San Diego: Academic Press, with permission.

HORMONES/Adrenal Hormones 3137

endings and the adrenal medulla, but also in nonneur-

onal tissues, including the kidney, and catalyzes the

decarboxylation of other aromatic amino acids in

addition to DOPA, including 5-hydroxytryptophan,

which is converted to serotonin.

0024 Dopamine b-hydroxylase (DBH) catalyzes the

hydroxylation of dopamine to form norepinephrine.

The enzyme is found in sympathetic nerve endings,

and also in adrenal medullary chromaffin granules,

which release DBH along with norepinephrine when

stimulated. The major difference between the cate-

cholaminergic pathways of the adrenal medulla and

the peripheral nervous system is the presence of the

enzyme phenylethanolamine-N-methyl transferase

(PNMT) in the medulla. This enzyme, also found in

small amounts in the brain, catalyzes the conversion

of norepinephrine to epinephrine, using S-adenosyl-

methionine as a methyl donor. PNMT is inducible by

high concentrations of cortisol which are present in

the capillary sinusoidal circulation from the adrenal

cortex to the medulla.

0025A large percentage of synaptically released cat-

echolamines are inactivated by reuptake into storage

granules. Metabolism of circulating catecholamines

occurs via two main pathways, mediated by the

enzymes catechol-O-methyltransferase (COMT)

and by monoamine oxidase (MAO), as shown

in Figure 10. The end product of norepinephrine

and epinephrine metabolism, after transformation

by both enzymes, is 3-methoxy-4-hydroxymandelic

acid (vanillylmandelic acid). Catecholamines in the

liver and gut are also inactivated by sulfate or glucur-

onide conjugation of the phenolic hydroxyl group.

ECF depletion

Decrease in renal

arterial pressure

Sympathetic nerves

[Na

] at macula densa

Hypokalemia

Prostaglandins

Stimulate

JUXTAGLOMERULAR

APPARATUS

Potassium

Increase in

renal arterial

pressure or

volume

Inhibit

'Long-loop

feedback'

'Short-loop

feedback'

ECF

expansion

Renal sodium

retention

Blood

angiotensinogen

Angiotensin I

Converting

enzyme

Angiotensin II

Renin

Inhibit

Arteriolar

constriction

Angiotensinases

Inactive

Aldosterone

ADRENAL

GLAND

Angiotensin

III

fig0008 Figure 8 Control of aldosterone secretion by the renin–

angiotensin system. ECF, extracellular fluid. Reproduced from

Bondy P and Rosenberg L (1980) Metabolic Control and Disease.

Philadelphia: WB Saunders, with permission.

CHCOOH

CHCH

NHCH

Tyrosine

hydroxylase

Tyrosine

Aromatic

L-amino

acid decarboxylase

Dihydroxyphenyl-

alanine (DOPA)

Dopamine

Norepinephrine

Epinephrine

Phenylethanolamine

N-methyl transferase

Dopamine

β-hydroxylase

fig0009Figure 9 Catecholamine biosynthetic pathway of the sympa-

thetic nervous system. Reproduced from Cryer P (1987) Diseases

of the sympathochromaffin system. In: Felig P (ed.) Endocrinology

and Metabolism. New York: McGraw-Hill, with permission.

10 20 30 40

Age (years)

DHAS (µg per 100 ml)

Males

Females

50 60 70 80

100

200

300

400

500

600

fig0007 Figure 7 Serum concentrations of dehydroepiandrosterone

sulfate (DHAS) in normal subjects 1–73 years of age. Reproduced

from Smith M, et al. (1975) A radioimmunoassay for the estima-

tion of serum DHAS in normal and pathological sera. Clinica Chi-

mica Acta 65: 5, with permission.

3138 HORMONES/Adrenal Hormones