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0005 Oxytocin and vasopressin are synthesized as pre-

cursors in the cell bodies of (different) neurons in the

hypothalamus. They are packaged into granules,

which pass down the axons of these neurons, through

the pituitary stalk, to the swollen axonal endings in

the neurohypophysis, where they are stored. Conver-

sion of precursors to active peptides occurs during

formation and transport of secretory vesicles, cata-

lyzed by prohormone-converting enzymes included

within the vesicles. Also formed by processing of

these precursors are neurophysins, which act as bind-

ing proteins for oxytocin and vasopressin prior to

release. Secretion of the hormones from the nerve

endings occurs by exocytosis in response to nerve

signals coming down the axons of the same cells.

For oxytocin a neural loop links sensory receptors in

the mammary gland (detecting suckling) via a number

of synapses, to the cell bodies of the neurons that

synthesize the hormone. This in turn triggers firing

of these neurons, so that an electrical signal passes

down their axons and causes depolarization of the

plasma membrane of the swollen nerve endings in

the neurohypophysis. The entry of Ca

2þ

which

follows this provides the signal for exocytosis. The

released oxytocin passes via the blood stream to the

mammary gland, where it induces milk ejection

within a few seconds of the initial suckling stimulus.

Similar neural loops regulate secretion of vasopressin,

initiated at receptors in the brain that detect changes

in osmotic pressure, or in the atrium and carotid sinus

that detect changes in blood volume or pressure.

Adenohypophysial Hormones

0006The hormones of the adenohypophysis are all peptide

or protein in nature, and fall into three main families:

(1) corticotropin (ACTH), melanocyte-stimulating

hormone (MSH) and related peptides (the melanocor-

tin family); (2) growth hormone (GH) and prolactin;

(3) thyrotropin or thyroid-stimulating hormone

(TSH), follicle-stimulating hormone (FSH) and lu-

teinizing hormone (LH) – the glycoprotein hormone

family.

The Melanocortin Family

0007ACTH is a peptide of 39 residues concerned mainly

with regulation of the adrenal cortex, including pro-

duction and secretion of corticosteroids. It binds to a

G-protein-linked receptor in the membrane of target

cells in the adrenal cortex, and acts at various points

on the pathway leading to steroid synthesis partly via

action of cyclic AMP as a second messenger. MSHs

tbl0001 Table 1 The hormones of the mammalian pituitary gland

Hormone Abbreviation Chemical nature Main actions

Posterior lobe

Oxytocin Peptide (9 residues) Stimulates milk ejection, uterus contraction

Vasopressin (antidiuretic hormone) VP (ADH) Peptide (9 residues) Antidiuretic, raises blood pressure

Intermediate lobe

a-Melanotropin (a-melanocyte-stimulating

hormone)

a-MSH Peptide (13 residues) Causes skin darkening, especially in

amphibia; functions as neuropeptide in the

brain

Anterior lobe

b-Melanotropin (b-melanocyte-stimulating

hormone)

b-MSH Peptide (18–22 residues) Causes skin darkening, especially in

amphibia

Corticotropin (adrenocorticotropic

hormone)

ACTH Peptide (39 residues) Stimulates corticosteroidogenesis and growth

of adrenal cortex

Lipotropin LPH Peptide/protein

(*91 residues)

Weakly lipotropic (may be primarily a

precursor of b-MSH and b-endorphin)

b-Endorphin Peptide (31 residues) Analgesia?

Growth hormone (somatotropin) GH Protein (*190 residues) Promotes growth, many anabolic actions,

stimulates insulin-like growth factor

1 production

Prolactin PRL Protein (*200 residues) Lactogenic activity (many other actions,

particularly in lower vertebrates)

Thyrotropin (thyroid-stimulating hormone) TSH Glycoprotein (2 subunits) Stimulates thyroid hormone production

Follicle-stimulating hormone FSH Glycoprotein (2 subunits) Stimulates maturation of the Graafian follicle

in female, spermatogenesis in male

Luteinizing hormone (interstitial

cell-stimulating hormone)

LH Glycoprotein (2 subunits) Stimulates maturation and release of ovum

and early development of corpus luteum in

female, steroid production by gonads in

male

Note that some doubt remains as to whether b-MSH, LPH, and b-endorphin are physiologically significant hormones.

HORMONES/Pituitary Hormones 3159

are peptides of 13–22 amino acids, produced charac-

teristically in the intermediate lobe of the pituitary,

which regulate skin color in some species by stimulat-

ing synthesis and altering distribution of pigment in

cells called melanocytes. The actions of MSHs are

particularly marked in amphibia. Although they

occur in the pituitary gland of many mammals their

physiological role there is not clear, although in at

least some species they probably do have a role in

controlling skin pigmentation. MSHs have been de-

scribed in the human pituitary, but there is some

evidence that in the adult at least they are artifacts

of extraction procedures and of little physiological

importance. ACTH and MSHs show similarity in

amino acid sequences, and it is now known that

they are formed from a common biosynthetic precur-

sor, proopiomelanocortin (POMC), together with a

larger peptide b-lipotropin and the opioid peptide

b-endorphin. Despite this, ACTH and a-MSH are

secreted from different cell types (corticotrophs and

melanotrophs), reflecting different processing path-

ways in different cells.

0008 Although MSHs and the other POMC-derived pep-

tides were originally characterized in the pituitary, it

is now clear that they are also expressed in the brain,

and that as neuropeptides they may play an important

role in energy homeostasis and the regulation of

obesity. Recent studies indicate that the peptide hor-

mone leptin, produced by adipose cells, acts at least

partly by stimulating production of a-MSH in hypo-

thalamic neurons. Binding of a-MSH to specific re-

ceptors (MC4 receptors) in hypothalamus and cortex

leads to reduced feed intake and increased energy

expenditure. Animals with defective MC4 receptors

become obese, but the importance of this mechanism

for human obesity has not yet been established.

The Growth Hormone/Prolactin Family

0009 GH and prolactin are both medium-sized proteins

comprising a single polypeptide chain of 190–200

amino acids. They are structurally similar, and are

related to the placental lactogens found in humans,

ruminants, and rodents. GH plays a major role in

regulating somatic growth and is discussed further

below. Prolactin has a number of different actions in

mammals, the most important being concerned with

regulation of lactation and mammary growth. Prolac-

tin acts with other hormones, including insulin, insu-

lin-like growth factors, corticosteroids, thyroid

hormone, and GH (depending on the species) to

stimulate growth of the mammary gland and synthe-

sis and secretion of milk components including pro-

teins (caseins, a-lactalbumin, etc.), sugar, and fat. It

acts partly at the gene level to stimulate production of

specific proteins via a membrane-bound receptor,

Jak kinase and STAT proteins, a mechanism similar

to that of GH (see below). In ruminants milk produc-

tion appears to be stimulated more effectively by GH

than prolactin, and the use of GH to enhance agricul-

tural milk production is being actively pursued.

Whether GH and/or prolactin can influence the nu-

tritional content of milk, as well as total production,

is not clear.

The Glycoprotein Hormone Family

0010The third family of pituitary hormones includes the

glycoprotein hormones: the two gonadotropins, FSH

and LH, and TSH. These are structurally related to

the chorionic gonadotropin (hCG) produced in the

human placenta. They are complex proteins, includ-

ing in each case two subunits (a and b), each of which

is about 100 amino acids long and carries one or more

carbohydrate moieties. The a-subunit is common to

FSH, LH, and TSH (and also hCG), while the b-

subunits are different, and provide the hormonal spe-

cificities. A three-dimensional (3D) structure has been

reported for hCG which shows a number of interest-

ing features, including a ‘disulfide knot’ in each sub-

unit and a very close association between a- and

b-subunits, ‘sealed’ by a peptide strand and disulfide

bridge which act as a kind of ‘seat belt.’ In the female,

FSH and LH control the estrus cycle (menstrual cycle

in primates): FSH stimulates growth of the Graafian

follicle and production of estrogen by granulosa cells,

while LH stimulates maturation of the ovum, ovula-

tion, and development of the corpus luteum. In the

male, LH stimulates the steroid-producing interstitial

cells to produce androgens, while FSH stimulates

spermatogenesis. The actions of both LH and FSH

involve binding to G-protein-linked receptors and are

mediated in part by cyclic AMP. The actions of TSH

are concerned almost exclusively with regulation of

the thyroid gland, including stimulation of growth

of the gland and production of thyroxine and

triiodothyronine.

Regulation of Secretion of Adenohypophysial

Hormones

0011The secretion and synthesis of the hormones of the

pituitary gland are largely under the control of

the hypothalamus. For the neurohypophysis, as dis-

cussed above, such regulation involves nerve signals

operating via the axons of the hypothalamic neurons

within which vasopressin and oxytocin are synthe-

sized and transported to the neurohypophysis.

0012Hypothalamic regulation of synthesis and secre-

tion of adenohypophysial hormones in mammals in-

volves primarily blood-borne neuroendocrine factors

rather than nerve signals. A capillary plexus in the

3160 HORMONES/Pituitary Hormones

hypothalamus allows the blood to pick up neuroen-

docrine secretions; the capillaries then combine to

form the hypothalamic–hypophysial portal vessels

which pass down the pituitary stalk and form a

second capillary network in the adenohypophysis.

This system allows efficient transfer of neuroendo-

crine factors from the hypothalamus to the adenohy-

pophysis (Figure 1). These factors are mostly

peptides, though the catecholamine dopamine is also

an important regulator. Most stimulate secretion of

one or more adenohypophysial hormones, but some

are inhibitors. They are listed in Table 2.

0013 ACTH secretion is stimulated by the hypothalamic

peptide corticotropin-releasing hormone (CRH),

which synergizes with vasopressin and possibly

other factors. a-MSH secretion from the intermediate

lobe may be partly under neural control, but is also

regulated by hypothalamic peptides and inhibited by

dopamine. Secretion of TSH is stimulated by the tri-

peptide TSH-releasing hormone (TRH). Secretion of

FSH and LH is stimulated by the decapeptide LH-

releasing hormone (LHRH: gonadotropin-releasing

hormone (GnRH)); FSH and LH are synthesized in

and secreted from the same cell type (gonadotroph).

Prolactin secretion is largely under inhibitory control,

by hypothalamic dopamine and possibly other

factors. TRH and a number of other peptides can

stimulate prolactin secretion, but their physiological

significance is not clear. GH secretion is stimulated

by the 44-residue peptide GH-releasing hormone

(GHRH), and inhibited by the 14-residue peptide

somatostatin. Both appear to be physiologically im-

portant, though stimulatory control predominates.

Recently another peptide (ghrelin) that stimulates

GH secretion has been characterized (see below).

0014 Many other factors can influence anterior pituitary

secretion, by modulating the actions of the hypothal-

amic regulators and/or in some cases by direct action

at the pituitary. Thus, the secretion of FSH and LH

may be modified by hormones produced by the

gonads, including gonadal steroids and peptide hor-

mones such as inhibin. Such modulation probably

underlies differential release of LH and FSH from a

single cell type. Hormones produced from other

endocrine organs can also affect secretion of the pitu-

itary hormones regulating those organs. Thus thyroid

hormones modulate TSH secretion, and corticoster-

oids affect ACTH secretion. Secretion of GH is modu-

lated by insulin-like growth factors (IGFs).

0015At the physiological level, factors controlling the

release of hypothalamic peptides are obviously im-

portant in the overall control of pituitary hormone

secretion. These factors include neural signals (in-

cluding sensory inputs and signals deriving from en-

dogenous rhythms) and hormonal/metabolic factors,

such as glucose or amino acid levels, steroid hormone

levels, etc. The hypothalamus provides a mechanism

by which the neural and hormonal regulatory systems

can be integrated, providing a combined input to the

pituitary gland which in turn controls many of the

endocrine glands of the body.

Growth Hormone

0016Each of the pituitary hormones has direct or indirect

effects on nutrition. Thus, ACTH and TSH stimulate

production of hormones involved in metabolic regu-

lation. Prolactin, by stimulating lactation, affects

both the nutrition of the offspring and the nutritional

balance of the mother in whom much of the meta-

bolic effort may be diverted towards milk production.

However, the pituitary hormone that is most directly

involved in regulating the nutritional balance of the

organism is GH.

Structure

0017GH is a protein hormone of about 22 kDa molecular

weight. Amino acid sequences of GHs from many

tbl0002 Table 2 The hypothalamic hormones that regulate the adenohypophysis

Hormone Abbreviation Chemical nature Main actions

TSH-releasing hormone TRH Peptide (3 residues) Stimulates release of TSH and possibly prolactin

LH-releasing hormone LHRH Peptide (10 residues) Stimulates release of LH and FSH

Somatostatin

(GH release-inhibiting hormone)

SRIF Peptide (14 residues) Inhibits release of GH (and many other secreted peptides)

Dopamine DA Catecholamine Inhibits release of prolactin and MSH

GH-releasing hormone GHRH Peptide (44 residues) Stimulates release of GH

Corticotropin-releasing hormone CRH Peptide (41 residues) Stimulates release of corticotropin

TSH, Thyroid-stimulating hormone; LH, luteinizing hormone; FSH, follicle-stimulating hormone; GH, growth hormone; MSH, melanocyte-stimulating

hormone.

Note that these are the hypothalamic factors that have now been well characterized. Other factors have been proposed, but either they have not been fully

characterized or their physiological significance is in doubt. These include oxytocin-related peptides that may be involved in regulating MSH secretion, a

factor that may specifically stimulate FSH secretion, an inhibitor of adenocorticotropic hormone secretion, and factors involved in stimulation of prolactin

release.

HORMONES/Pituitary Hormones 3161

species are available, and the three-dimensional struc-

tures of pig and human GHs have been determined,

using X-ray diffraction. The structure comprises a

four-helix bundle with an unusual (‘up-up-down-

down’) topology. A similar topology has now been

seen in a variety of cytokines and growth factors,

indicating that GH is a member of a large protein

superfamily (the cytokine family). The receptors for

members of this family are also related. There is

considerable sequence variation between GHs from

different mammals. Most notably, human GH is very

different from GHs of nonprimate mammals. Vari-

ation in biological properties is also seen – in particu-

lar, nonprimate GHs are not active in humans, and

human GH, unlike most nonprimate GHs, possesses

lactogenic (prolactin-like) activity. The species speci-

ficity has meant that it has been necessary for thera-

peutic purposes to prepare human GH on a large

scale in order to treat human hypopituitary dwarfism

(see below).

Biological Actions

0018 GH stimulates somatic growth in most vertebrates.

Removal of the pituitary gland leads to marked

slowing of growth in young animals, and the effect

can be reversed by GH treatment. Humans with defi-

cient GH production suffer from retarded growth,

leading to dwarfism, which can often be treated by

exogenous GH. On the other hand, excess GH, due

usually to an adenohypophysial tumor, leads to giant-

ism (if the tumor develops early in life, before the

epiphyses of the long bones fuse) or acromegaly (if

the tumor develops later, when only certain bones,

characteristically those of the face, hands and feet,

can still grow). GH is not the only factor affecting

growth, of course. All animals have a genetic program

that determines their normal adult size range, pre-

sumably optimized by evolutionary pressure to fit a

particular niche. The role of GH is presumably to

regulate growth of the organism within this optimum

range, relative to environmental factors, particularly

nutrition. Thus, if food is in short supply, normal

growth is slowed, and if the short supply is followed

by surplus, growth may be increased to above normal

levels (catch-up growth). The final size that an adult

mammal achieves will be a compromise between the

optimal size that the genetic program determines, and

what can be achieved given the environmental cir-

cumstances, particularly with regard to nutrition.

For an animal to grow in an unregulated fashion

towards a predetermined size (defined mainly in

terms of bone length) could lead to decreased fitness,

due to decreased muscle mass or bone strength. The

link between the effects of nutrition and GH on

growth is emphasized by the observation that

responses to GH in experimental animals may be

influenced markedly by the plane of nutrition.

0019The biological actions of GH are complex, and not

well understood. The overall effect of the hormone is

to promote growth, and it has direct or indirect

effects on many aspects of protein, carbohydrate,

and lipid metabolism, as well as effects on division

and differentiation of some cell types. Whether all of

these effects should be seen as directly related to

stimulation of growth, or whether some of the actions

of the hormone should be considered quite separately

from the growth-promoting effects, is not clear. Some

of the actions of GH are mediated by somatomedins/

IGFs (Figure 2). These are single-chain polypeptides

that show structural similarity to insulin. Two main

IGFs have been characterized – IGF-1 and IGF-2.

IGF-1 is most markedly GH-dependent. IGFs occur

in the circulation largely in association with specific

binding proteins, of which there are at least six types.

These binding proteins extend the half-life and modu-

late the activity of IGFs; at least one of them is itself

GH-dependent.

0020Circulating levels of IGF-1 are low in hypophysec-

tomized rats or GH-deficient animals or people, and

are increased following administration of GH. Unlike

GH, IGF-1 stimulates cartilage growth directly,

which is a prerequisite for growth of bone. For some

time it was considered that circulating IGF-1 (pro-

duced mainly in the liver) was the main mediator of

the actions of GH on cartilage and bone growth, but

it is now clear that GH stimulates IGF-1 production

in many tissues, including cartilage, and that the

growth factor probably acts locally to stimulate tissue

growth, possible synergizing with GH itself.

0021In addition to its actions on cartilage and bone

growth, mediated largely by IGFs, GH also has ana-

bolic effects on various other tissues. For example it

stimulates protein synthesis in muscle and liver, in-

cluding both a general enhancement of the protein

synthetic machinery, and induction of gene expres-

sion for specific proteins, including IGFs and their

binding proteins. GH also has effects on carbohydrate

and lipid metabolism. The effects on carbohydrate

metabolism include short-term insulin-like effects

and longer-term antiinsulin (diabetogenic) effects.

Actions on lipid metabolism include stimulation of

lipid mobilization and uptake, and decrease in lipid

synthesis. Overall the metabolic effect of the hormone

is to promote lipid utilization and decrease carbohy-

drate utilization. The extent to which these metabolic

actions are mediated by IGFs is not clear.

Mechanism of Action of Growth Hormone

0022Understanding of the mechanism by which GH acts

has increased substantially over the past decade. As

3162 HORMONES/Pituitary Hormones

with other polypeptide hormones the interaction

with the target cell is via a membrane-bound receptor.

When the GH receptor was first cloned and charac-

terized in 1987 it proved to be of a type not previously

observed. Since then, receptors of a similar type have

been identified for a number of other polypeptide

signaling molecules (members of the cytokine recep-

tor family), including prolactin, erythropoietin,

and various growth factors and lymphokines. All of

these receptors comprise a single membrane-spanning

domain, with substantial extracellular (ligand-

binding) and intracellular domains. For GH there is

evidence that the hormone binds to two receptor

molecules, effectively dimerizing or cross-linking the

receptor. The most striking demonstration of this

has come from X-ray crystallographic studies,

which revealed the detailed 3D structure of GH

bound to two molecules of the extracellular domain

of the receptor. Cross-linking of two extracellular

domains brings together the corresponding intr-

acellular domains, and it is thought that interaction

between these allows the signal to be transmitted

to the interior of the target cell. Thus far there is

evidence for only one GH receptor gene in any

one mammalian species, but there is generation of

receptor heterogeneity by allelic variation, alternative

splicing during pre-mRNA processing and/or

posttranslational modification. The significance of

such receptor heterogeneity is not yet clear, but a

notable feature of it is the presence of a soluble

form of the extracellular domain in the normal circu-

lation – this acts as a GH-binding protein and may

modulate the activity of the hormone and/or prolong

its half-life.

Hypothalamus

Somatostatin

GHRH

Pituitary

Adipose

tissue

Muscle

Skeleton

IGF-1

Other

tissues

GH-BP

Growth

hormone

−+

Liver

IGF-BP

fig0002 Figure 2 The hypothalamic–pituitary–somatic axis. Circulating insulin-like growth factor 1 (IGF-1) derives both from the liver and

other tissues; at least some of the actions of IGF-1 involve local rather than humoral effects. The half-life and actions of growth

hormone (GH) and IGH-1 are modulated by corresponding binding proteins (BP). GHRH, growth hormone-releasing hormone.

Modified from Wallis M (1988) The molecular basis of growth hormone deficiency. MolecularAspects of Medicine 10: 429–509.

HORMONES/Pituitary Hormones 3163

0023 The GH receptor is neither a G-protein-linked re-

ceptor, nor does it include a protein kinase. However,

a major aspect of its mechanism of action is that on

activation, following hormone binding and dimeriza-

tion, it binds and activates a soluble cytosolic protein

kinase Jak2. This leads to phosphorylation of the

receptor itself and of a number of intracellular ef-

fector proteins, including members of the Stat (signal

transduction and activation of transcription) protein

family, particularly Stat5. Phosphorylated Stat5

moves to the nucleus where it acts as a transcription

factor, stimulating the transcription of key GH-de-

pendent genes, including the gene for IGF-1. Acti-

vation of Jak2 also leads to stimulation of various

other intracellular signal transduction mechanisms,

including the MAP kinase pathway.

Regulation of GH Secretion and Synthesis

0024 The secretion of GH is regulated by stimulatory and

inhibitory peptides produced in the hypothalamus,

including GHRH and somatostatin. Stimulatory con-

trol generally predominates. Recently another pep-

tide that stimulates GH release, ghrelin, has been

identified in the stomach. Its physiological role is

not yet clear, but it also stimulates appetite and may

provide a link between GH secretion and food intake.

The actions of these peptides are modulated by

factors acting directly at the pituitary level, including

IGFs, thyroid hormones, and glucocorticoids. Secre-

tion of the hypothalamic peptides is in turn regulated

by neural and metabolic factors. GHRH, and hence

GH secretion, is stimulated by hypoglycemia, high

levels of amino acids such as arginine or leucine

(which may result from a high protein meal), and

lowered free fatty acid levels. GH levels are lowered

in obese subjects, and recent studies suggest that the

‘fat hormone’ leptin may play some role in modulat-

ing GH secretion. GH secretion is normally pulsatile

in animals and humans, which complicates the deter-

mination of ‘normal’ levels.

Growth Hormone Deficiency

0025 In humans GH deficiency gives rise to stunted

growth/dwarfism and can have a number of causes,

some of which are hereditary. Hereditary GH defi-

ciency can be due to: (1) deletion of the gene that

codes for GH; (2) mutations that prevent normal

development of GH-producing cells (somatotrophs)

and GH synthesis; (3) defective GH receptors (so that

although normal levels of the hormone are produced

they fail to produce normal responses in the target

cells); and (4) other reasons, not fully understood.

Most cases of GH deficiency in humans are not her-

editary in origin, however; they often appear to be

due to damage to the link between hypothalamus and

pituitary, so that the normal control of GH secretion

by GHRH is disrupted. Such disruption can be due to

birth trauma, blows to the head in infancy, or other

causes. In such cases the pituitary can often respond

to GHRH administered exogenously, and this is being

explored as a therapeutic approach to treat human

hypopituitary dwarfism.

0026Children suffering from stunted growth due to

clearly established GH-deficiency can be treated

using human GH, and this has become a standard

therapy. Provided GH treatment is started sufficiently

early, growth can be restored to near normal, and

heights within the normal range can be achieved.

For about 20 years the GH used for such therapy

was extracted from human pituitary glands obtained

postmortem, and in many countries extensive

schemes were established for collection of such

material. In the mid-1980s, however, concern arose

about the contamination of some human GH prepar-

ations with infective agents, particularly the

prions causing Creutzfeldt–Jakob disease (CJD),

and use of GH derived from human pituitaries was

largely stopped. Fortunately at that time the possibil-

ity arose of using human GH prepared by genetic

engineering techniques, and this is now widely

employed.

0027The possibility of using GH to treat forms of short

stature other than those due to clear-cut GH defi-

ciency has been considered for some time. The avail-

ability of GH produced by recombinant DNA

methods in potentially unlimited quantities makes

wider usage more feasible, and this is being explored

actively. As well as extending treatment to children

whose short stature is due to primary causes other

than GH deficiency, the use of recombinant DNA-

derived GH to treat adults with GH deficiency is

being considered, as is its use for promoting anabol-

ism in muscle-wasting conditions such as acquired

immunodeficiency syndrome (AIDS), cachexia, and

even old age.

Growth Hormone Excess

0028Oversecretion of GH, usually due to a pituitary

tumor, leads to excessive growth. Where this occurs

before puberty it can lead to giantism, though this is

rare. Where it occurs after puberty (when further

growth of the long bones is not possible) it can lead

to acromegaly, in which those bones which can still

grow in response to GH do so, leading to enlarged

hands and feet and distorted facial features. The

very high circulating levels of GH and IGF-1 seen in

acromegalic patients also lead to thickening of the

skin, enlargement of some soft tissues, and often

3164 HORMONES/Pituitary Hormones

disorders of the cardiovascular, muscular, and endo-

crine systems. Diabetes mellitus is relatively common

in acromegaly, and shows clinical features rather dif-

ferent from normal, presumably because GH itself

has diabetogenic properties.

0029 Acromegaly can be treated by surgical removal

of the pituitary tumor, radiation therapy, administra-

tion of a drug (e.g., bromocriptine or a somatostatin

analog) that inhibits GH secretion and tumor growth

and/or use of a GH receptor antagonist (pegviso-

mant). Very rarely acromegaly is caused by a

GHRH-secreting tumor elsewhere in the body, such

as the pancreas.

Growth Hormone and Malnutrition; Catch-up

Growth

0030 The role of GH in malnutrition and starvation is

complex and poorly understood. In humans, GH

levels increase on fasting, in both normal and obese

subjects, and fall again on refeeding. Paradoxically,

IGF-1 levels fall in response to starvation, despite the

high GH levels. Such a dissociation of GH and IGF-

1 levels is particularly marked in protein-calorie mal-

nutrition (kwashiorkor), where IGF levels may be in

the hypopituitary level despite elevated GH levels, but

it is also seen in conditions such as anorexia. The

mechanism by which the dissociation of GH and

IGF-1 levels arises is poorly understood, as is its

significance for the control of nutritional balance

during malnutrition, but it may effectively allow a

dissociation of the actions of the hormone on growth

promotion (much reduced during periods of malnu-

trition) from those on metabolism (still required since

the hormone promotes utilization of fat). GH re-

sponses to starvation in the rat differ from those

seen in humans – both GH and IGF-1 levels fall;

responses in ruminants and pig are similar to those

in humans.

0031 In children, if nutrition improves after a period of

malnutrition, the phenomenon of catch-up growth

can occur, in which growth increases to an above

normal rate, allowing some or all of the lost ground

to be restored. Involvement of the GH/IGF axis in this

phenomenon is likely, but the mechanism is unclear.

Nutritional Control of IGF Levels

0032 Although GH clearly plays an essential part in the

control of circulating and local IGF-1 levels, it is by

no means the only factor. Insulin and thyroxine are

important, and nutritional level also regulates both

the level and activity of IGF-1. Indeed, IGF-1 levels in

the circulation are remarkably sensitive to nutrients,

and can provide a marker for nutritional status and

effectiveness of treatment. Nutritional influence on

IGF-1 levels may be mediated to some extent by

insulin or thyroid hormones (but not GH, given the

divorce between GH and IGF-1 levels in malnutri-

tion, referred to above), but it is clear that to some

extent they are direct. Actions on GH receptor levels,

which are lowered on fasting, may be involved in

severe dietary restriction, but in less severe protein

restriction postreceptor mechanisms appear to

predominate. Nutritional level also affects the activ-

ity of circulating IGF-1: (1) by altering the balance of

the IGF-binding proteins that modulate the half-life,

tissue availability, and receptor-binding of IGF-1; (2)

by regulating formation of inhibitors of IGF-1; and

(3) by altering type 1 IGF receptor levels. The involve-

ment of so many factors in regulating IGF levels and

activity probably plays an important part in integrat-

ing their various influences on growth.

Growth Hormone and Animal Biotechnology

0033GH can stimulate growth, meat production, and lac-

tation in farm animals and the availability of large

quantities of the hormone produced by recombinant

DNA methodology has stimulated work designed to

assess and apply the hormone in animal agriculture.

Recombinant DNA-derived bovine GH (frequently

referred to as bovine somatotropin, BST) has been

subjected to extensive trials as an agent for promoting

milk production, and is now being used commercially

for this purpose in some countries. The ability of GH

to promote meat production in various farm animals

has been studied extensively. Not only is muscle

growth stimulated, but fat content is much reduced,

so that a potentially healthier product results. Pos-

sible applications of GH in fish farming have also

been studied.

0034The potential for the use of recombinant DNA-

derived GH in agriculture is great, but such usage

remains controversial because of concerns about

food safety, animal welfare, and economic impact.

Indirect ways of modulating GH levels and actions

in farm animals may prove more acceptable than

direct administration of the hormone. Such indirect

approaches include immunological modulation,

modification of endogeneous hypothalamic activity,

and use of the transgenic approach to introduce ad-

ditional genes for GH into animals. The transgenic

approach, coupled with cloning, is particularly

powerful, though again welfare and other consider-

ations may limit its usefulness.

See also: Biotechnology in Food Production; Famine,

Starvation, and Fasting; Growth and Development;

Malnutrition: The Problem of Malnutrition; Renal

Function and Disorders: Kidney: Structure and Function

HORMONES/Pituitary Hormones 3165

Further Reading

Boersma B and Wit JM (1997) Catch-up growth. Endocrine

Reviews 18: 646–661.

Bole-Feysot C, Goffin V, Edery M, Binart N and Kelly PA

(1998) Prolactin (PRL) and its receptor: actions, signal

transduction pathways and phenotypes observed in PRL

receptor knockout mice. Endocrine Reviews 19: 225–

268.

Cone RD (1999) The central melanocortin system and

energy homeostasis. Trends in Endocrinology and Me-

tabolism 10: 211–216.

Drake WM, Parkinson C, Besser GM and Trainer PJ (2001)

Clinical use of a growth hormone receptor antagonist in

the treatment of acromegaly. Trends in Endocrinology

and Metabolism 12: 408–413.

Grossmann M, Weintraub BD and Szkudlinski MW (1997)

Novel insights into the molecular mechanisms of human

thyrotropin action: structural, physiological, and thera-

peutic implications for the glycoprotein hormone family.

Endocrine Reviews 18: 476–501.

Herrington J and Carter-Su C (2001) Signaling pathways

activated by the growth hormone receptor. Trends in

Endocrinology and Metabolism 12: 252–257.

Hwa V, Oh Y and Rosenfeld RG (1999) The insulin-like

growth factor-binding protein (IGFBP) superfamily.

Endocrine Reviews 20: 761–787.

Jordan SA and Jackson IJ (1998) Melanocortin receptors

and antagonists regulate pigmentation and body weight.

Bioessays 20: 603–606.

Kajima M, Hosoda H, Matsuo H and Kangawa K (2001)

Ghrelin: discovery of the natural endogenous ligand for

the growth hormone secretagogue receptor. Trends in

Endocrinology and Metabolism 12: 118–122.

Lapthorn AJ, Harris DC, Littlejohn A et al. (1994) Crystal

structure of human chorionic gonadotropin. Nature

369: 455–461.

Mohr E, Meyerhof W and Richter D (1995) Vasopressin

and oxytocin: molecular biology and evolution of the

peptide hormones and their receptors. Vitamins and

Hormones 51: 235–266.

Norman AW and Litwack GD (1997) Hormones. New

York: Academic Press.

Ohlsson C, Bengtsson BA, Isaksson OGP, Andreassen TT

and Slootweg MC (1998) Growth hormone and bone.

Endocrine Reviews 19: 55–79.

Pell JM and Bates PC (1990) The nutritional regulation of

growth hormone action. Nutrition Research Reviews 3:

163–192.

Thissen J-P, Ketelslegers J-M and Underwood LE (1994)

Nutritional regulation of the insulin-like growth factors.

Endocrine Reviews 15: 80–101.

Wallis M (1988) The molecular basis of growth hormone

deficiency. Molecular Aspects of Medicine 10: 429–509.

Wallis M, Howell SL and Taylor KW (1985) Biochemistry

of the Polypeptide Hormones. Chichester: John Wiley.

Wilson JD, Foster DW, Kronenberg HM and Larsen PR

(eds) (1998) Williams Textbook of Endocrinology, 9th

edn. Philadelphia: Saunders.

Steroid Hormones

A W Norman, University of California-Riverside,

Riverside, CA, USA

Introduction

0001Steroid hormones are well known both physiologic-

ally and clinically as regulators of diverse biological

responses, including profound effects on cellular me-

tabolism, development, and physiology. The steroid

hormones are the estrogens (female sex steroids),

androgens (male sex steroids), progestins, mineralo-

corticoids, glucocorticoids, and vitamin D with its

daughter metabolites.

0002All these different steroid hormones are synthe-

sized from the common precursor, cholesterol, and

structurally differ only in the pattern of chemical

bonds within the rings and modifications on the

side chain. The exquisite specificity of physiological

effects that these steroid hormones evoke is mediated

by high-affinity intracellular receptor proteins that

are exclusively localized in the specific target tissues

for each steroid hormone. Specific interaction of the

hormone–receptor complex with DNA sequences of

the hormone-responsive gene(s) results in the tissue-

specific expression of proteins which either directly or

indirectly generate the biological responses attribut-

able to the steroid hormones. The application of

cellular and molecular biological techniques has

allowed greater understanding of the way in which

such small molecules exert diverse biological effects

with exquisite specificity.

Historical Perspective

0003The first steroid hormone that was discovered,

estrone, was isolated in 1929, before the character-

ization of the ring structure of the steroid

nucleus. Studies by Professor A. Windaus in Go

ttin-

gen, Germany, in the 1930s led to the chemical

characterization and structural determination of

cholesterol, using classical organic chemistry

manipulations. Methodological advances such as

radioisotopes, chromatography, mass spectropho-

tometry, and nuclear magnetic resonance spectros-

copy have all facilitated the elucidation of structures

of the other steroid hormones.

Chemistry

0004In mammalian systems, there are six families of ster-

oid hormones that can be classified on both a struc-

tural and a biological (hormonal) basis. These are

3166 HORMONES/Steroid Hormones

the: (1) mineralocorticoids, which instruct the renal

tubule to retain sodium; (2) glucocorticoids, which

exert manifold effects on carbohydrate metabolism;

(3) progestins, which are essential for reproduction;

(4) estrogens, which induce female secondary sexual

characteristics; (5) androgens, which induce male

secondary sexual characteristics; and (6) the vita-

min-D hormone, 1,25-dihydroxyvitamin D

(1,25-

(OH)

), which is important for regulation of

calcium and phosphorus homeostasis, bone growth,

and development. Also, the bile acids are structurally

related to cholesterol and thus constitute a seventh

member of the steroid family. All of these steroids are

biologically derived from cholesterol.

0005 All steroids are derived from a cyclopentano-

perhydrophenanthrene backbone that comprises

three C

cyclohexane rings designated as A, B, and

C, fused to a fourth C

cyclopentane ring, notated as

the D ring. Within the family of steroid hormones,

each member is distinguished by chemical alterations

such as isomerization, aromatization, dehydrogen-

ation, and fission in the ring structure, and modifica-

tions such as hydroxylations in the side chains of the

cholesterol backbone that are catalyzed by specific

enzymes present in the endocrine glands. The

chemical formulae of these steroid hormones are

depicted in Figure 1.

Biosynthesis of Steroids

0006 Figure 2 summarizes in general terms the metabolic

pathways leading from cholesterol to the six major

steroid hormones (Table 1). The principal tissues

of synthesis of the five classical steroid hormones

(estrogens, androgens, progestins, glucocorticoids,

and mineralocorticoids) are the adrenal cortex, ovar-

ies, and testes. Also, during pregnancy, the fetal–pla-

cental unit can serve as a source of estrogen and some

other hormones. The sites of synthesis of the sixth

class of steroid hormones, the prohormone vitamin

and its metabolites, are the skin, liver, and kidney.

The bile acids, which are the seventh important struc-

tural class of mammalian steroids, have no known

hormonal activity; they are principally synthesized

in the liver and are secreted from the gallbladder to

participate in digestion and absorption where they

function as a detergent to solubilize fats.

0007 Figure 3 describes the relationship between the

stimulatory peptide hormone and the six classes of

steroid hormones. The biosynthesis of each steroid

hormone by its endocrine gland is stimulated by a

specific cognate peptide hormone. Thus, for example,

the biosynthesis of cortisol in the adrenal cortex is

only stimulated by its tropic (stimulatory) peptide

hormone adrenocorticotropic hormone (ACTH).

ACTH is only secreted by the anterior pituitary gland.

Biosynthesis of Progestins

0008As evident from Figure 2, the common pathway

leading to the production of six classes of steroid

hormones primarily involves conversion of choles-

terol (which possesses 27 carbon atoms) into pregne-

nolone and then progesterone (which possesses 21

carbon atoms). Progesterone is synthesized by the

corpus luteum of the ovary and placenta and consti-

tutes the chief progestational steroid in humans.

Biosynthesis of Glucocorticoids and

Mineralocorticoids

0009The glucocorticoids and mineralocorticoids are

21-carbon corticosteroids produced by the adrenal

cortex (Figure 1). The principal glucocorticoid in

males is cortisol, while aldosterone is the main

mineralocorticoid.

Biosynthesis of Androgens and Estrogens

0010The androgens, which possess 19 carbon atoms, are

produced in the testes in males, and in the ovaries and

placenta in females. Under some circumstances the

adrenal cortex can also produce physiologically sig-

nificant androgens such as androsterone, 4-andro-

stene-3,17-dione, and dehydroepiandrosterone. The

major naturally occurring steroids with androgenic

activity (in decreasing order of relative potency) are

5a-dihydrotestosterone (5a-DHT; 150–200%), tes-

tosterone (100%), androstanediol (65%), androst-

4-ene-3,17-dione (25%), androsterone (10%), and

dehydroepiandrosterone (10%). The hormonally

active form of testosterone in males is 5a-DHT,

which is chiefly produced in the prostate gland,

although skin, testis, and submaxillary glands also

can produce small quantities.

0011The estrogens, which possess 18 carbon atoms, are

produced in the ovarian follicle, corpus luteum,

and fetal–placental unit. In both males and females,

the adrenal cortex can generate small quantities

of estrone from androst-4-ene-3,17-dione. The

major naturally occurring steroids with estrogenic

activity are estra-3,17b-diol, estra-3,16a,17b-triol,

and estrone.

Biosynthesis of Vitamin D Metabolites

0012Chemically, the vitamin D steroids are secosteroids

because of the breakage of the B-ring, leaving the A-,

C-, and D-rings intact (Figure 1). The parent vitamin

D is produced in the skin from 7-dehydrocholesterol

as a consequence of ultraviolet or sunlight action,

which breaks the 9,10 carbon–carbon bond. The

sites of synthesis of the vitamin D metabolites are the

liver and kidney. The hormonally active forms of vita-

min D are 1,25(OH)

and 24,25-dihydroxyvitamin

HORMONES/Steroid Hormones 3167

Progesterone Cortisol Aldosterone Testosterone Estradiol 1,25-Dihydroxyvitamin D

Cholic acid

Progestins Glucocorticoids

5α-Pregnane (C21)

Mineralocorticoids Androgens Estrogens Vitamin D

Cholesterol (C27)

Cholestane (C27)

5α-Estrane (C18)5α-Androstane (C19) Cholane (C24)

Bile acids

Figure 1 Family tree of the seven principal classes of steroids (bottom row); all of the steroids except cholic acids are steroid hormones. All of the steroids are structurally derived from

cholestane (top row), which is closely related to cholesterol.

fig0001