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Ganong’s Review of
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A LANGE medical book
T W E N T Y F O U R T H E D I T I O N
Kim E. Barrett, PhD
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Dean of Graduate Studies
University of California, San Diego
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Professor, Department of Pharmacology/
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Michigan State University
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Associate Professor, Physiology
Arizona Respiratory Center
Bio5 Collaborative Research Institute
University of Arizona
Tucson, Arizona
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Associate Professor, Physiology
College of Medicine
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University of Arizona
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CHAPTER 15 Learning, Memory, Language, & Speech 289
of transmission at relevant synaptic junctions so that all the
components are brought to consciousness when the memory
is recalled.
Once long-term memories have been established, they can
be recalled or accessed by a large number of diff erent associations.
For example, the memory of a vivid scene can be evoked
not only by a similar scene but also by a sound or smell associated
with the scene and by words such as “scene,” “vivid,” and
“view.” Th us, each stored memory must have multiple routes
or keys. Furthermore, many memories have an emotional
component or “color,” that is, in simplest terms, memories can
be pleasant or unpleasant.
STRANGENESS & FAMILIARITY
It is interesting that stimulation of some parts of the temporal
lobes in humans causes a change in interpretation of one’s surroundings.
For example, when the stimulus is applied, the subject
may feel strange in a familiar place or may feel that what is
happening now has happened before. Th e occurrence of a sense
of familiarity or a sense of strangeness in appropriate situations
probably helps the normal individual adjust to the environment.
In strange surroundings, one is alert and on guard,
whereas in familiar surroundings, vigilance is relaxed. An
inappropriate feeling of familiarity with new events or in new
surroundings is known clinically as the déjà vu phenomenon,
from the French words meaning “already seen.” Th e phenomenon
occurs from time to time in normal individuals, but it
also may occur as an aura (a sensation immediately preceding
a seizure) in patients with temporal lobe epilepsy.
ALZHEIMER DISEASE
& SENILE DEMENTIA
Alzheimer disease is the most common age-related neurodegenerative
disorder. Memory decline initially manifests as a
loss of episodic memory, which impedes recollection of recent
events. Loss of short-term memory is followed by general loss
of cognitive and other brain functions, agitation, depression,
the need for constant care, and, eventually, death. Clinical
Box 15–3 describes the etiology and therapeutic strategies for
the treatment of Alzheimer disease.
Figure 15–5 summarizes some of the risk factors,
pathogenic processes, and clinical signs linked to cellular
CLINICAL BOX 15–3
Alzheimer Disease
Alzheimer disease was originally characterized in middle-aged
people, and similar deterioration in elderly individuals is technically
senile dementia of the alzheimer type, though it is
frequently just called Alzheimer disease. Both genetic and environmental
factors are thought to contribute to the etiology
of the disease. Most cases are sporadic, but a familial form of
the disease (accounting for about 5% of the cases) is seen in
an early-onset form of the disease. In these cases, the disease is
caused by mutations in genes for the amyloid precursor protein
on chromosome 21, presenilin I on chromosome 14, or presenilin
II on chromosome 1. It is transmitted in an autosomal dominant
mode, so off spring in the same generation have a 50/50
chance of developing familial Alzheimer disease if one of their
parents is aff ected. Each mutation leads to an overproduction
of the β-amyloid protein found in neuritic plaques. Senile dementia
can be caused by vascular disease and other disorders,
but Alzheimer disease is the most common cause, accounting
for 50–60% of the cases. Alzheimer disease is present in
8–17% of the population over the age of 65, with the incidence
increasing steadily with age (nearly doubling every 5 years after
reaching the age of 60). In those who are 95 years of age
and older, the incidence is 40–50%. It is estimated that by the
year 2050, up to 16 million people age 65 and older in the US
alone will have Alzheimer disease. Although the prevalence of
the disease appears to be higher in women, this may be due to
their longer life span as the incidence rates are similar for men
and women. Alzheimer disease plus the other forms of senile
dementia are a major medical problem.
THERAPEUTIC HIGHLIGHTS
Research is aimed at identifying strategies to prevent
the occurrence, delay the onset, slow the progression,
or alleviate the symptoms of Alzheimer disease. The use
of acetylcholinesterase inhibitors (eg, rivastigmine ,
donepezil , or galantamine ) in early stages of the disease
increases the availability of acetylcholine in the
synaptic cleft. It has shown some promise in ameliorating
global cognitive dysfunction, but not learning and
memory impairments in these patients. These drugs also
delay the worsening of symptoms for up to 12 months
in about 50% of the cases studied. Antidepressants (eg,
paroxetine , imipramine ) have been useful for treating
depression in Alzheimer patients. Memantine (an NMDA
receptor antagonist) prevents glutamate-induced excitotoxicity
in the brain and is used to treat moderate to
severe Alzheimer disease. It has been shown to delay the
worsening of symptoms in some patients. Drugs used to
block the production of β-amyloid proteins are under development.
An example is R-fl urbiprofen . Also attempts
are underway to develop vaccines that would allow the
body’s immune system to produce antibodies to attack
these proteins.
290 SECTION II Central and Peripheral Neurophysiology
abnormalities that occur in Alzheimer disease. Th e cytopathologic
hallmarks of Alzheimer disease are intracellular
neurofi brillary tangles, made up in part of hyperphosphorylated
forms of the tau protein that normally binds to microtubules,
and extracellular senile plaques, which have a core of
β-amyloid peptides surrounded by altered nerve fi bers and
reactive glial cells. Figure 15–6 compares a normal nerve cell to
one showing abnormalities associated with Alzheimer disease.
Th e β-amyloid peptides are products of a normal protein,
amyloid precursor protein (APP) , a transmembrane protein
that projects into the extracellular fl uid (ECF) from all nerve
cells. Th is protein is hydrolyzed at three diff erent sites by
α-secretase, β-secretase, and γ-secretase, respectively. When
APP is hydrolyzed by α-secretase, nontoxic peptide products
are produced. However, when it is hydrolyzed by β-secretase
and γ-secretase, polypeptides with 40–42 amino acids are
produced; the actual length varies because of variation in the
site at which γ-secretase cuts the protein chain. Th ese polypeptides
are toxic, the most toxic being Aβσ 1–42 . Th e polypeptides
form extracellular aggregates, which can stick to AMPA receptors
and Ca 2+ ion channels, increasing Ca 2+ infl ux. Th e polypeptides
also initiate an infl ammatory response, with production
of intracellular tangles. Th e damaged cells eventually die.
An interesting fi nding that may well have broad physiologic
implications is the observation—now confi rmed in a rigorous
prospective study—that frequent eff ortful mental activities,
such as doing diffi cult crossword puzzles and playing board
games, slow the onset of cognitive dementia due to Alzheimer
disease and vascular disease. Th e explanation for this “use it or
lose it” phenomenon is as yet unknown, but it certainly suggests
that the hippocampus and its connections have plasticity like
other parts of the brain and skeletal and cardiac muscles.
Risk factors*
- Age
- Presenilin 1 mutations (chromosome 14)
- Presenilin 2 mutations (chromosome 1)
- Amyloid precursor protein gene
mutations (chromosome 21)
- apoE alleles (chromosome 19)
- Trisomy 21
* Recently a mutation in the α-2 macroglobulin gene
has been implicated in the late-onset disease
Vulnerable neurons
Monoaminergic systems,
basal forebrain cholinergic
system, hippocampus,
entorhinal cortex, and
neocortex
Cytopathology
Neurofibrillary tangles,
neurites, Aβ peptide
deposition, other cellular
abnormalities
End-stage disease
Senile plaques,
death of neurons,
gliosis
Pathogenic mechanisms
Clinical signs
Memory loss,
cognitive deficits
FIGURE 155 Relationships of risk
factors, pathogenic processes, and clinical
signs to cellular abnormalities in the brain
during Alzheimer disease. (From Kandel ER,
Schwartz JH, Jessell TM [editors]: Principles of Neural
Science , 4th ed. McGraw-Hill, 2000.)
A Normal
Neuropil
threads
Neurofibrillary
tangles
B Alzheimer disease
Neurites
Senile plaque
Abnormal
membranous
organelles
Aβ
(fibrillar)
Paired helical
filaments
Nerve
terminals
FIGURE 156 Comparison of a normal
neuron and one with abnormalities
associated with Alzheimer disease. The
cytopathologic hallmarks are intracellular
neurofi brillary tangles and extracellular
senile plaques that have a core of β-amyloid
peptides surrounded by altered nerve fi bers
and reactive glial cells. (From Kandel ER, Schwartz
JH, Jessell TM [editors]: Principles of Neural Science , 4th
ed. McGraw-Hill, 2000.)
CHAPTER 15 Learning, Memory, Language, & Speech 291
LANGUAGE & SPEECH
Memory and learning are functions of large parts of the brain,
but the centers controlling some of the other “higher functions
of the nervous system,” particularly the mechanisms related to
language, are more or less localized to the neocortex. Speech
and other intellectual functions are especially well developed
in humans—the animal species in which the neocortical mantle
is most highly developed.
COMPLEMENTARY
SPECIALIZATION OF THE
HEMISPHERES VERSUS
“CEREBRAL DOMINANCE”
One group of functions localized to the neocortex in humans
consists of those related to language; that is, the understanding
of the spoken and printed word and expressing ideas in speech
and writing. It is a well-established fact that human language
functions depend more on one cerebral hemisphere than on
the other. Th is hemisphere is concerned with categorization
and symbolization and has oft en been called the dominant
hemisphere. However, the other hemisphere is not simply
less developed or “nondominant;” instead, it is specialized in
the area of spatiotemporal relations. It is this hemisphere that
is concerned, for example, with the identifi cation of objects
by their form and the recognition of musical themes. It also
plays a primary role in the recognition of faces. Consequently,
the concept of “cerebral dominance” and a dominant and
nondominant hemisphere has been replaced by a concept of
complementary specialization of the hemispheres, one for
sequential-analytic processes (the categorical hemisphere )
and one for visuospatial relations (the representational hemisphere
). Th e categorical hemisphere is concerned with language
functions, but hemispheric specialization is also present
in monkeys, so it predates the evolution of language. Clinical
Box 15–4 describes defi cits that occur in subjects with representational
or categorical hemisphere lesions.
Hemispheric specialization is related to handedness.
Handedness appears to be genetically determined. In 96% of
CLINICAL BOX 15–4
Lesions of Representational
& Categorical Hemispheres
Lesions in the categorical hemisphere produce language
disorders, whereas extensive lesions in the representational
hemisphere do not. Instead, lesions in the representational
hemisphere produce astereognosis— the inability to identify
objects by feeling them—and other agnosias. Agnosia is the
general term used for the inability to recognize objects by a
particular sensory modality even though the sensory modality
itself is intact. Lesions producing these defects are generally in
the parietal lobe. Especially when they are in the representational
hemisphere, lesions of the inferior parietal lobule, a region
in the posterior part of the parietal lobe that is close to
the occipital lobe, cause unilateral inattention and neglect .
Individuals with such lesions do not have any apparent primary
visual, auditory, or somatesthetic defects, but they ignore stimuli
from the contralateral portion of their bodies or the space
around these portions. This leads to failure to care for half their
bodies and, in extreme cases, to situations in which individuals
shave half their faces, dress half their bodies, or read half
of each page. This inability to put together a picture of visual
space on one side is due to a shift in visual attention to the side
of the brain lesion and can be improved, if not totally corrected,
by wearing eyeglasses that contain prisms. Hemispheric
specialization extends to other parts of the cortex as well. Patients
with lesions in the categorical hemisphere are disturbed
about their disability and often depressed, whereas patients
with lesions in the representational hemisphere are sometimes
unconcerned and even euphoric. Lesions of diff erent parts of
the categorical hemisphere produce fl uent , nonfl uent , and
anomic aphasias . Although aphasias are produced by lesions
of the categorical hemisphere, lesions in the representational
hemisphere also have eff ects. For example, they may impair
the ability to tell a story or make a joke. They may also impair
a subject’s ability to get the point of a joke and, more broadly,
to comprehend the meaning of diff erences in infl ection and
the “color” of speech. This is one more example of the way the
hemispheres are specialized rather than simply being dominant
and nondominant.
THERAPEUTIC HIGHLIGHTS
Treatments for agnosia and aphasia are symptomatic and
supportive. Individuals with agnosia can be taught exercises
to help them identify objects that are a necessity
for independence. Therapy for individuals with aphasia
helps them to use remaining language abilities, compensate
for language problems, and learn other methods of
communicating. Some individuals with aphasia experience
recovery but often some disabilities remain. Factors
that infl uence the degree of improvement include
the cause and extent of the brain damage, the area of
the brain that was damaged, and the age and health
of the individual. Computer assisted therapies have been
shown to improve retrieval of certain parts of speech as
well as allowing an alternative way to communicate.
292 SECTION II Central and Peripheral Neurophysiology
right-handed individuals, who constitute 91% of the human
population, the left hemisphere is the dominant or categorical
hemisphere, and in the remaining 4%, the right hemisphere
is dominant. In approximately 15% of left -handed individuals,
the right hemisphere is the categorical hemisphere and in
15%, there is no clear lateralization. However, in the remaining
70% of left -handers, the left hemisphere is the categorical
hemisphere. It is interesting that learning disabilities such as
dyslexia (see Clinical Box 15–5 ), an impaired ability to learn
to read, are 12 times as common in left -handers as they are in
right-handers, possibly because some fundamental abnormality
in the left hemisphere led to a switch in handedness early
in development. However, the spatial talents of left -handers
may be well above average; a disproportionately large number
of artists, musicians, and mathematicians are left -handed. For
unknown reasons, left -handers have slightly but signifi cantly
shorter life spans than right-handers.
Some anatomic diff erences between the two hemispheres
may correlate with the functional diff erences. Th e planum
temporale, an area of the superior temporal gyrus that is
involved in language-related auditory processing, is regularly
larger on the left side than the right (see Figure 10-13). It is
also larger on the left in the brain of chimpanzees, even though
language is almost exclusively a human trait. Imaging studies
show that other portions of the upper surface of the left
temporal lobe are larger in right-handed individuals, the right
frontal lobe is normally thicker than the left , and the left occipital
lobe is wider and protrudes across the midline. Chemical
diff erences also exist between the two sides of the brain.
For example, the concentration of dopamine is higher in the
nigrostriatal pathway on the left side in right-handed humans
but higher on the right in left -handers. Th e physiologic signifi -
cance of these diff erences is unknown.
In patients with schizophrenia, MRI studies have demonstrated
reduced volumes of gray matter on the left side in
the anterior hippocampus, amygdala, parahippocampal gyrus,
and posterior superior temporal gyrus. Th e degree of reduction
in the left superior temporal gyrus correlates with the
degree of disordered thinking in the disease. Th ere are also
apparent abnormalities of dopaminergic systems and cerebral
blood fl ow in this disease.
PHYSIOLOGY OF LANGUAGE
Language is one of the fundamental bases of human intelligence
and a key part of human culture. Th e primary brain
areas concerned with language are arrayed along and near the
sylvian fi ssure (lateral cerebral sulcus) of the categorical hemisphere.
A region at the posterior end of the superior temporal
gyrus called Wernicke’s area ( Figure 15–7 ) is concerned with
comprehension of auditory and visual information. It projects
via the arcuate fasciculus to Broca’s area in the frontal lobe
immediately in front of the inferior end of the motor cortex.
Broca’s area processes the information received from Wernicke’s
area into a detailed and coordinated pattern for vocalization
and then projects the pattern via a speech articulation area in
the insula to the motor cortex, which initiates the appropriate
movements of the lips, tongue, and larynx to produce speech.
Th e probable sequence of events that occurs when a subject
names a visual object is shown in Figure 15–8 . Th e angular
CLINICAL BOX 15–5
Dyslexia
Dyslexia , which is a broad term applied to impaired ability to
read, is characterized by diffi culties with learning how to decode
at the word level, to spell, and to read accurately and fl uently
despite having a normal or even higher than normal level
of intelligence. It is frequently due to an inherited abnormality
that aff ects 5% of the population with a similar incidence
in boys and girls. Dyslexia is the most common and prevalent
of all known learning disabilities. It often coexists with attention
defi cit disorder. Many individuals with dyslexic symptoms
also have problems with short-term memory skills and problems
processing spoken language. Although its precise cause
is unknown, dyslexia is of neurological origin. Acquired dyslexias
often occur due to brain damage in the left hemisphere’s
key language areas. Also, in many cases, there is a decreased
blood fl ow in the angular gyrus in the categorical hemisphere.
There are numerous theories to explain the causes of dyslexia.
The phonological hypothesis is that dyslexics have a specifi c
impairment in the representation, storage, and/or retrieval of
speech sounds. The rapid auditory processing theory proposes
that the primary defi cit is the perception of short or
rapidly varying sounds. The visual theory is that a defect in
the magnocellular portion of the visual system slows processing
and also leads to phonemic defi cit. More selective speech
defects have also been described. For example, lesions limited
to the left temporal pole cause inability to retrieve names of
places and persons but preserves the ability to retrieve common
nouns, that is, the names of nonunique objects. The ability
to retrieve verbs and adjectives is also intact.
THERAPEUTIC HIGHLIGHTS
Treatments for children with dyslexia frequently rely on
modifi ed teaching strategies that include the involvement
of various senses (hearing, vision, and touch) to
improve reading skills. The sooner the diagnosis is made
and interventions are applied, the better the prognosis.
CHAPTER 15 Learning, Memory, Language, & Speech 293
gyrus behind Wernicke’s area appears to process information
from words that are read in such a way that they can be converted
into the auditory forms of the words in Wernicke’s area.
It is interesting that in individuals who learn a second language
in adulthood, fMRI reveals that the portion of Broca’s
area concerned with it is adjacent to but separate from the area
concerned with the native language. However, in children who
learn two languages early in life, only a single area is involved
with both. It is well known, of course, that children acquire
fl uency in a second language more easily than adults.
LANGUAGE DISORDERS
Aphasias are abnormalities of language functions that are
not due to defects of vision or hearing or to motor paralysis.
Th ey are caused by lesions in the categorical hemisphere (see
Clinical Box 15–4 ). Th e most common cause is embolism or
thrombosis of a cerebral blood vessel. Many diff erent classifi
cations of the aphasias have been published, but a convenient
classifi cation divides them into nonfl uent , fl uent , and
anomic aphasias . In nonfl uent aphasia, the lesion is in Broca’s
area. Speech is slow, and words are hard to come by. Patients
with severe damage to this area are limited to two or three
words with which to express the whole range of meaning and
emotion. Sometimes the words retained are those that were
being spoken at the time of the injury or vascular accident that
caused the aphasia.
In one form of fl uent aphasia, the lesion is in Wernicke’s
area. In this condition, speech itself is normal and sometimes
the patients talk excessively. However, what they say is full of
jargon and neologisms that make little sense. Th e patient also
fails to comprehend the meaning of spoken or written words,
so other aspects of the use of language are compromised.
Arcuate
fasciculus
Angular gyrus
Wernicke’s area
Broca’s
area
FIGURE 157 Location of some of the areas in the
categorical hemisphere that are concerned with language
functions. Wernicke’s area is in the posterior end of the superior
temporal gyrus and is concerned with comprehension of auditory
and visual information. It projects via the arcuate fasciculus to
Broca’s area in the frontal lobe. Broca’s area processes information
received from Wernicke’s area into a detailed and coordinated
pattern for vocalization and then projects the pattern via a speech
articulation area in the insula to the motor cortex, which initiates
the appropriate movements of the lips, tongue, and larynx to
produce speech.
Wernicke’s
area
(area 22)
Angular gyrus
(area 39)
Higher order visual
cortical areas
(area 18) Primary visual cortex
(area 17)
From lateral
geniculate nucleus
Arcuate
fasciculus
Facial area of
motor cortex
(area 4)
Broca’s area
Left Right
6
5
4
3
2
1
FIGURE 158 Path taken by impulses when a subject
identifi es a visual object, projected on a horizontal section of
the human brain. Information travels from the lateral geniculate
nucleus in the thalamus to the primary visual cortex, to higher
order visual critical areas, and to the angular gyrus. Information
then travels from Wernicke’s area to Brocas’s area via the arcuate
fasciculus. Broca’s area processes the information into a detailed and
coordinated pattern for vocalization and then projects the pattern
via a speech articulation area in the insula to the motor cortex, which
initiates the appropriate movements of the lips, tongue, and larynx
to produce speech.
Another form of fl uent aphasia is a condition in which
patients can speak relatively well and have good auditory comprehension
but cannot put parts of words together or conjure
up words. Th is is called conduction aphasia because it was
thought to be due to lesions of the arcuate fasciculus connecting
Wernicke’s and Broca’s areas. However, it now appears that
it is due to lesions near the auditory cortex in the posterior
perisylvian gyrus.
When a lesion damages the angular gyrus in the categorical
hemisphere without aff ecting Wernicke’s or Broca’s areas,
there is no diffi culty with speech or the understanding of
auditory information; instead there is trouble understanding
written language or pictures, because visual information is not
processed and transmitted to Wernicke’s area. Th e result is a
condition called anomic aphasia.
Th e isolated lesions that cause the selective defects
described above occur in some patients, but brain destruction
is oft en more general. Consequently, more than one form
of aphasia is oft en present. Frequently, the aphasia is general
(global) , involving both receptive and expressive functions. In
this situation, speech is scant as well as nonfl uent. Writing is
abnormal in all aphasias in which speech is abnormal, but the
neural circuits involved are unknown. In addition, deaf subjects
who develop a lesion in the categorical hemisphere lose
their ability to communicate in sign language.
294 SECTION II Central and Peripheral Neurophysiology
Stuttering has been found to be associated with right
cerebral dominance and widespread overactivity in the cerebral
cortex and cerebellum. Th is includes increased activity of
the supplementary motor area. Stimulation of part of this area
has been reported to produce laughter , with the duration and
intensity of the laughter proportional to the intensity of the
stimulus.
RECOGNITION OF FACES
An important part of the visual input goes to the inferior temporal
lobe, where representations of objects, particularly faces,
are stored ( Figure 15–9 ). Faces are particularly important
in distinguishing friends from foes and the emotional state
of those seen. In humans, storage and recognition of faces is
more strongly represented in the right inferior temporal lobe
in right-handed individuals, though the left lobe is also active.
Damage to this area can cause prosopagnosia , the inability to
recognize faces. Patients with this abnormality can recognize
forms and reproduce them. Th ey can recognize people by their
voices, and many of them show autonomic responses when
they see familiar as opposed to unfamiliar faces. However,
they cannot identify the familiar faces they see. Th e left hemisphere
is also involved, but the role of the right hemisphere is
primary. Th e presence of an autonomic response to a familiar
face in the absence of recognition has been explained by postulating
the existence of a separate dorsal pathway for processing
information about faces that leads to recognition at only a
subconscious level.
LOCALIZATION OF
OTHER FUNCTIONS
Use of fMRI and PET scanning combined with study of
patients with strokes and head injuries has provided further
insight into the ways serial processing of sensory information
Stores
biographical
information
Extracts
facial
features
Connects facial features
to biographical information
FIGURE 159 Areas in the right cerebral hemisphere, in
right-handed individuals, that are concerned with recognition
of faces. An important part of the visual input goes to the inferior
temporal lobe, where representations of objects, particularly faces,
are stored. In humans, storage and recognition of faces is more
strongly represented in the right inferior temporal lobe in righthanded
individuals, though the left lobe is also active. (Modifi ed from
Szpir M: Accustomed to your face. Am Sci 1992;80:539.)
produce cognition, reasoning, comprehension, and language.
Analysis of the brain regions involved in arithmetic calculations
has highlighted two areas. In the inferior portion of the
left frontal lobe is an area concerned with number facts and
exact calculations. Frontal lobe lesions can cause acalculia , a
selective impairment of mathematical ability. Th ere are areas
around the intraparietal sulci of both parietal lobes that are
concerned with visuospatial representations of numbers and,
presumably, fi nger counting.
Two right-sided subcortical structures play a role in
accurate navigation in humans. One is the right hippocampus,
which is concerned with learning where places are
located, and the other is the right caudate nucleus, which
facilitates movement to the places. Men have larger brains
than women and are said to have superior spatial skills and
ability to navigate.
Other defects seen in patients with localized cortical
lesions include, for example, the inability to name animals,
though the ability to name other living things and objects is
intact. One patient with a left parietal lesion had diffi culty
with the second half but not the fi rst half of words. Some
patients with parietooccipital lesions write only with consonants
and omit vowels. Th e pattern that emerges from studies
of this type is one of precise sequential processing of information
in localized brain areas. Additional research of this type
should greatly expand our understanding of the functions of
the neocortex.
CHAPTER SUMMARY
Memory ■ is divided into explicit (declarative) and implicit
(nondeclarative). Explicit is further subdivided into semantic
and episodic. Implicit is further subdivided into priming,
procedural, associative learning, and nonassociative
learning.
■ Declarative memory involves the hippocampus and the
medial temporal lobe for retention. Priming is dependent
on the neocortex. Procedural memory is processed in the
striatum. Associative learning is dependent on the amygdala
for its emotional responses and the cerebellum for the motor
responses. Nonassociative learning is dependent on various
refl ex pathways.
■ Synaptic plasticity is the ability of neural tissue to change
as refl ected by LTP (an increased eff ectiveness of synaptic
activity) or LTD (a reduced eff ectiveness of synaptic activity)
aft er continued use. Habituation is a simple form of learning in
which a neutral stimulus is repeated many times. Sensitization
is the prolonged occurrence of augmented postsynaptic
responses aft er a stimulus to which one has become habituated
is paired once or several times with a noxious stimulus.
■ Alzheimer disease is characterized by progressive loss of shortterm
memory followed by general loss of cognitive function. Th e
cytopathologic hallmarks of Alzheimer disease are intracellular
neurofi brillary tangles and extracellular senile plaques.
■ Categorical and representational hemispheres are for
sequential-analytic processes and visuospatial relations,
respectively. Lesions in the categorical hemisphere produce
CHAPTER 15 Learning, Memory, Language, & Speech 295
language disorders, whereas lesions in the representational
hemisphere produce astereognosis.
Aphasias are abnormalities o ■ f language functions and are
caused by lesions in the categorical hemisphere. Th ey are
classifi ed as fl uent (Wernicke’s area), nonfl uent (Broca’s area),
and anomic (angular gyrus) based on the location of brain
lesions.
MULTIPLECHOICE QUESTIONS
For all questions, select the single best answer unless otherwise
directed.
1. A 17-year-old male suff ered a traumatic brain injury as a result
of a motor cycle accident. He was unconscious and was rushed
to the emergency room of the local hospital. A CT scan was
performed and appropriate interventions were taken. About
6 months later he still had memory defi cits. Which of the
following is correctly paired to show the relationship between a
brain area and a type of memory?
A. Hippocampus and implicit memory
B. Neocortex and associative learning
C. Medial temporal lobe and declarative memory
D. Angular gyrus and procedural memory
E. Striatum and priming
2. Th e optic chiasm and corpus callosum are sectioned in a dog,
and with the right eye covered, the animal is trained to bark
when it sees a red square. Th e right eye is then uncovered and
the left eye covered. Th e animal will now
A. fail to respond to the red square because the square does not
produce impulses that reach the right occipital cortex.
B. fail to respond to the red square because the animal has
bitemporal hemianopia.
C. fail to respond to the red square if the posterior commissure
is also sectioned.
D. respond to the red square only aft er retraining.
E. respond promptly to the red square in spite of the lack of
input to the left occipital cortex.
3. A 32-year-old male had medial temporal lobe epilepsy for over
10 years. Th is caused bilateral loss of hippocampal function. As
a result, this individual might be expected to experience a
A. disappearance of remote memories.
B. loss of working memory.
C. loss of the ability to encode events of the recent past into
long-term memory.
D. loss of the ability to recall faces and forms but not the ability
to recall printed or spoken words.
E. production of inappropriate emotional responses when
recalling events of the recent past.
4. A 70-year-old woman fell down a fl ight of stairs, hitting her
head on the concrete sidewalk. Th e trauma caused a severe
intracranial hemorrhage. Th e symptoms she might experience
are dependent on the area of the brain most aff ected. Which of
the following is incorrectly paired?
A. Damage to the parietal lobe of the representational
hemisphere : Unilateral inattention and neglect
B. Loss of cholinergic neurons in the nucleus basalis of
Meynert and related areas of the forebrain : Loss of recent
memory
C. Damage to the mammillary bodies : Loss of recent
memory
D. Damage to the angular gyrus in the categorical hemisphere :
Nonfl uent aphasia
E. Damage to Broca’s area in the categorical hemisphere : Slow
speech
5. Th e representational hemisphere is better than the categorical
hemisphere at
A. language functions.
B. recognition of objects by their form.
C. understanding printed words.
D. understanding spoken words.
E. mathematical calculations.
6. A 67-year-old female suff ered a stroke that damaged the
posterior end of the superior temporal gyrus . A lesion of
Wernicke’s area in the categorical hemisphere causes her to
A. lose her short-term memory.
B. experience nonfl uent aphasia in which she speaks in a slow,
halting voice.
C. experience déjà vu.
D. talk rapidly but make little sense, which is characteristic of
fl uent aphasia.
E. lose the ability to recognize faces, which is called
prosopagnosia.
7. Which of the following is most likely not involved in
production of LTP?
A. NO
B. Ca 2+
C. NMDA receptors
D. Membrane hyperpolarization
E. Membrane depolarization
8. An 79-year-old woman has been experiencing diffi culty fi nding
her way back home aft er her morning walks. Her husband has
also noted that she takes much longer to do routine chores
around the home and oft en appears to be confused. He is
hoping that this is just due to “old age” but fears it may be a sign
of Alzheimer disease. Which of the following is the defi nitive
sign of this disease?
A. Loss of short-term memory.
B. Th e presence of intracellular neurofi brillary tangles and
extracellular neuritic plaques with a core of β-amyloid
peptides.
C. A mutation in genes for amyloid precursor protein (APP) on
chromosome 21.
D. Rapid reversal of symptoms with the use of
acetylcholinesterase inhibitors.
E. A loss of cholinergic neurons in the nucleus basalis of
Meynert.
CHAPTER RESOURCES
Aimone JB, Wiles J, Gage FH: Computational infl uence of adult
neurogenesis on memory encoding. Neuron 2009;61:187.
Andersen P, Morris R, Amaral D, Bliss T, O’Keefe J: Th e
Hippocampus Book. Oxford University Press, 2007.
Bird CM, Burgess N: Th e hippocampus and memory: Insights from
spatial processing. Nature Rev Neurosci 2008;9:182.
Eichenbaum H: A cortical-hippocampal system for declarative
memory. Nat Neurosci Rev 2000;1:41.
296 SECTION II Central and Peripheral Neurophysiology
Goodglass H: Understanding Aphasia. Academic Press, 1993.
Ingram VM: Alzheimer’s disease. Am Scientist 2003;91:312.
Kandel ER: Th e molecular biology of memory: A dialogue between
genes and synapses. Science 2001;294:1028.
LaFerla FM, Green KN, Oddo S: Intracellular amyloid-β in
Alzheimer’s disease. Nature Rev Neurosci 2007;8:499.
Ramus F: Developmental dyslexia: Specifi c phonological defect
or general sensorimotor dysfunction. Curr Opin Neurobiol
2003;13:212.
Russ MD: Memories are made of this. Science 1998;281:1151.
Selkoe DJ: Translating cell biology into therapeutic advances in
Alzheimer’s disease. Nature 1999;399 (Suppl): A23.
Shaywitz S: Dyslexia. N Engl J Med 1998;338:307.
Squire LR, Stark CE, Clark RE: Th e medial temporal lobe. Annu Rev
Neurosci 2004;27:279.
Squire LR, Zola SM: Structure and function of declarative
and nondeclarative memory systems. Proc Natl Acad Sci
1996;93:13515.
S E C T ION I I I Endocrine and
Reproductive Physiology
The role of the endocrine system is to maintain whole body
homeostasis. This is accomplished via the coordination of
hormonal signaling pathways that regulate cellular activity in
target organs throughout the body. Endocrine mechanisms
are also concerned with the ability of humans to reproduce,
and the sexual maturation required for this function. Classic
endocrine glands are scattered throughout the body and
secrete hormones into the circulatory system, usually via
ductless secretion into the interstitial fl uid. Target organs
express receptors that bind the specifi c hormone to initiate
a cellular response. The endocrine system can be contrasted
with the neural regulation of physiological function that
was the focus of the previous section. Endocrine eff ectors
typically provide “broadcast” regulation of multiple tissues
and organs simultaneously, with specifi city provided for by
the expression of relevant receptors. A change in environmental
conditions, for example, often calls for an integrated
response across many organ systems. Neural regulation, on
the other hand, is often exquisitely spatially delimited, such
as the ability to contract just a single muscle. Nevertheless,
both systems must work collaboratively to allow for minuteto-
minute as well as longer term stability of the body’s interior
milieu.
Hormones are the soluble messengers of the endocrine system
and are classifi ed into steroids, peptides, and amines
(see Chapters 1 and 2 ). Steroid hormones can cross the lipidcontaining
plasma membrane of cells and usually bind to
intracellular receptors. Peptide and amine hormones bind
to cell surface receptors. Steroid hormones are produced
by the adrenal cortex ( chapter 20 ), the gonads, testes
( chapter 23 ), and ovaries ( chapter 22 ) in addition to steroid
hormones that are made by the placenta during pregnancy
( chapter 22 ). Amine hormones are derivatives of the amino
acid tyrosine and are made by the thyroid ( chapter 19 ) and
the adrenal medulla ( chapter 20 ). Interestingly, the tyrosinederived
thyroid hormone behaves more like a steroid than
a peptide hormone by binding to an intracellular receptor.
The majority of hormones, however, are peptides and they
are usually synthesized as preprohormones before being
cleaved fi rst to prohormones in the endoplasmic reticulum
and then to the active hormone in secretory vesicles.
Diseases of the endocrine system are numerous. Indeed, endocrine
and metabolic disorders are among the most common
affl ictions in developed countries, particularly when
nutrition and access to health care provisions are generous
and high risk individuals are identifi ed by regular screening.
At least 11 endocrine and metabolic disorders are present
in 5% or more of the adult US population, including diabetes
mellitus, osteopenia, dyslipidemia, metabolic syndrome,
and thyroiditis. For example, type 2 diabetes mellitus is
one of the most prevalent endocrine disorders of the 21st
century and involves an inability of the body to respond to
insulin. The resulting high blood glucose damages many tissues
leading to secondary complications (see Chapter 24 ).
In large part, the high and increasing prevalence of diabetes
and other metabolic disorders rests on the substantial
prevalence of obesity in developed countries, with as many
as a third of the US adult population now considered to be
obese, and two thirds overweight. Indeed, based on a 2009
report, obesity also aff ects 28% of US children aged 12–17,
and while the current prevalence of type 2 diabetes in children
is quite low, this prevalence is accordingly expected
to rise. Further, a number of endocrine disorders are more
prevalent in specifi c ethnic groups, or in a particular gender.
Overall, the burden of endocrine and metabolic disorders,
with their protean manifestations and complications, is a
serious public health crisis and even highlights an apparent
national shortage of trained endocrinologists. Many endocrine
disorders must be managed by primary care physicians
as a result.
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299
O B J E C T I V E S
After studying this chapter,
you should be able to:
■ Describe hormones and their contribution to whole body homeostatic
mechanisms.
■ Understand the chemical nature of diff erent classes of hormones and how this
determines their mechanism of action on target cells.
■ D efi ne how hormones are synthesized and secreted by cells of endocrine
glands, including how peptide hormones are cleaved from longer precursors.
■ Explain the relevance of protein carriers in the blood for hydrophobic
hormones, and the mechanisms that determine the level of free circulating
hormones.
■ Understand the principles of feedback control for hormone release and its
relevance for homeostasis.
■ Understand the principles governing disease states that result from over- or
under-production of key hormones.
Basic Concepts of
Endocrine Regulation
C H A P T E R 16
INTRODUCTION
Th is section of the text deals with the various endocrine
glands that control the function of multiple organ systems
of the body. In general, endocrine physiology is concerned
with the maintenance of various aspects of homeostasis.
Th e mediators of such control mechanisms are soluble
factors known as hormones. Th e word hormone was
derived from the Greek horman, meaning to set in motion.
In preparation for specifi c discussions of the various
endocrine systems and their hormones, this chapter will
address some concepts of endocrine regulation that are
common among all systems.
Another feature of endocrine physiology to keep in
mind is that, unlike other physiological systems that are
considered in this text, the endocrine system cannot be
cleanly defi ned along anatomic lines. Rather, the endocrine
system is a distributed system of glands and circulating
messengers that is oft en stimulated by the central nervous
system and/or autonomic nervous system.
EVOLUTION OF HORMONES AND
THEIR ACTIONS ON TARGET CELLS
As noted in the introduction to this section, hormones comprise
steroids, amines, and peptides. Peptide hormones are by far the
most numerous. Many hormones can be grouped into families
refl ecting their structural similarities as well as the similarities
of the receptors they activate. However, the number of hormones
and their diversity increases as one moves from simple
to higher life forms, refl ecting the added challenges in providing
for homeostasis in more complex organisms. For example,
among the peptide hormones, several are heterodimers that
share a common α chain, with specifi city being conferred by
the β-chain. In the specifi c case of thyroid-stimulating hormone
(TSH), follicle-stimulating hormone (FSH), and luteinizing hormone
(LH), there is evidence that the distinctive β-chains arose
from a series of duplications of a common ancestral gene. For
these and other hormones, moreover, this molecular evolution
implies that hormone receptors also needed to evolve to allow for
spreading of hormone actions/specifi city. Th is was accomplished
Ganong_Ch16_297-306.indd 299 1/4/12 1:01:52 PM
300 SECTION III Endocrine and Reproductive Physiology
levels of circulating glucose stimulate the translation of insulin
mRNA. Th ese eff ects are mediated by the ability of glucose
to increase the interaction of the insulin mRNA with specifi c
RNA binding proteins, which increase its stability and enhance
its translation. Th e net eff ect is a more precise and timely regulation
of insulin levels, and thus energy metabolism, than could
be accomplished with transcriptional regulation alone.
Th e precursors for peptide hormones are processed
through the cellular machinery that handles proteins destined
for export, including traffi cking through specifi c vesicles
where the propeptide form can be cleaved to the fi nal active
hormones. Mature hormones are also subjected to a variety of
posttranslational processing steps, such as glycosylation, which
can infl uence their ultimate biological activity and/or stability
in the circulation. Ultimately, all hormones enter either the
constitutive or regulated secretory pathway (see Chapter 2 ).
SECRETION
Th e secretion of many hormones is via a process of exocytosis
of stored granules, as discussed in Chapter 2 . Th e exocytotic
machinery is activated when the cell type that synthesizes
and stores the hormone in question is activated by a specifi c
signal, such as a neurotransmitter or peptide releasing factor.
One should, however, contrast the secretion of stored
hormones with that of those that are continually released by
diff usion (eg, steroids). Control of the secretion of the latter
molecules occurs via kinetic infl uences on the synthetic
enzymes or carrier proteins involved in hormone production.
For example, the steroidogenic acute regulatory protein
(StAR) is a labile protein whose expression, activation, and
deactivation are regulated by intracellular signaling cascades
and their eff ectors, including a variety of protein kinases and
phosphatases. StAR traffi cs cholesterol from the outer to the
inner membrane leafl et of the mitochondrion. Because this
is a rate-limiting fi rst step in the synthesis of the steroid precursor,
pregnenolone, this arrangement permits changes in
the rate of steroid synthesis, and thus secretion, in response
to homeostatic cues such as trophic hormones, cytokines and
stress ( Figure 16–1 ).
An additional complexity related to hormone secretion
relates to the fact that some hormones are secreted in a
pulsatile fashion. Secretion rates may peak and ebb relative
to circadian rhythms, in response to the timing of meals,
or as regulated by other pattern generators whose periodicity
may range from milliseconds to years. Pulsatile secretion
is oft en related to the activity of oscillators in the hypothalamus
that regulate the membrane potential of neurons, in turn
secreting bursts of hormone releasing factors into the hypophysial
blood fl ow that then cause the release of pituitary and
other downstream hormones in a similar pulsatile fashion (see
Chapters 17 and 18 ). Th ere is evidence that these hormone
pulses convey diff erent information to the target tissues that
they act upon than steady exposure to a single concentration
of the hormone. Th erapeutically, pulsatile secretion may pose
challenges if, due to defi ciency, it proves necessary to replace a
particular hormone that is normally secreted in this way.
by co-evolution of the basic G-protein coupled receptors (GPCR)
and receptor tyrosine kinases that mediate the eff ects of peptide
and amine hormones that act at the cell surface (see Chapter 2 ).
Th e underlying ancestral relationships sometimes re-emerge,
however, in the cross-reactivity that may be seen when hormones
rise to unusually high levels (eg, endocrine tumors).
Steroids and thyroid hormones are distinguished by their
predominantly intracellular sites of action, since they can diffuse
freely through the cell membrane. Th ey bind to a family of
largely cytoplasmic proteins known as nuclear receptors. Upon
ligand binding, the receptor–ligand complex translocates to
the nucleus where it either homodimerizes, or associates with
a distinct liganded nuclear receptor to form a heterodimer.
In either case, the dimer binds to DNA to either increase or
decrease gene transcription in the target tissue. Individual
members of the nuclear receptor family have a considerable
degree of homology, perhaps implying a common ancestral
gene, and share many functional domains, such as the zinc
fi ngers that permit DNA binding. However, sequence variations
allow for ligand specifi city as well as binding to specifi c
DNA motifs. In this way, the transcription of distinct genes is
regulated by individual hormones.
HORMONE SECRETION
SYNTHESIS AND PROCESSING
Th e regulation of hormone synthesis, of course, depends on
their chemical nature. For peptide hormones as well as hormone
receptors, synthesis is controlled predominantly at the
level of transcription. For amine and steroid hormones, synthesis
is controlled indirectly by regulating the production of
key synthetic enzymes, as well as by substrate availability.
Interestingly, the majority of peptide hormones are synthesized
initially as much larger polypeptide chains, and then
processed intracellularly by specifi c proteases to yield the fi nal
hormone molecule. In some cases, multiple hormones may be
derived from the same initial precursor, depending on the specifi
c processing steps present in a given cell type. Presumably this
provides for a level of genetic “economy.” It is also notable that
the hormone precursors themselves are typically inactive. Th is
may be a mechanism that provides for an additional measure
of regulatory control, or, in the case of thyroid hormones, may
dictate the site of highest hormone availability.
Th e synthesis of all of the proteins/peptides discussed
above is subject to the normal mechanisms of transcriptional
control in the cell (see Chapter 2 ). In addition, there is provision
for exquisitely specifi c regulation by other hormones, since
the regulatory regions of many peptide hormone genes contain
binding motifs for the nuclear receptors discussed above. For
example, thyroid hormone directly suppresses TSH expression
via the thyroid hormone receptor. Th ese specifi c mechanisms
to regulate hormone transcription are essential to the function
of feedback loops, as will be addressed in greater detail below.
In some cases, the abundance of selected hormones may also
be regulated via eff ects on translation. For example, elevated
CHAPTER 16 Basic Concepts of Endocrine Regulation 301
HORMONE TRANSPORT
IN THE BLOOD
In addition to the rate of secretion and its nature (steady vs.
pulsatile), a number of factors infl uence the circulating levels
of hormones. Th ese include the rates of hormone degradation
and/or uptake, receptor binding and availability of receptors,
and the affi nity of a given hormone for plasma carriers
( Figure 16–2 ). Stability infl uences the circulating half-life of a
given hormone and has therapeutic implications for hormone
replacement therapy, in addition to those posed by pulsatile
secretion as discussed above.
Plasma carriers for specifi c hormones have a number of
important physiological functions. First, they serve as a reservoir
of inactive hormone and thus provide a hormonal reserve.
Bound hormones are typically prevented from degradation or
uptake. Th us, the bound hormone reservoir can allow fl uctuations
in hormonal levels to be smoothed over time. Plasma
carriers also restrict the access of the hormone to some sites.
Ultimately, plasma carriers may be vital in modulating levels
of the free hormone in question. Typically, it is only the free
hormone that is biologically active in target tissues or can
mediate feedback regulation (see below) since it is the only
form able to access the extravascular compartment.
Catecholamine and most peptide hormones are soluble
in plasma and are transported as such. In contrast steroid
Bound (inactive)
hormone
Plasma
carrier
Receptor
Free (active)
hormone
Synthesis
Secretion
Degradation
Uptake
FIGURE 162 Summary of factors that determine the level
of free hormones circulating in the bloodstream. Factors that
increase (green upward arrow) or decrease (red downward arrow)
hormone levels are shown. Free hormones also equilibrate with the
forms bound to either receptors or plasma carrier proteins.
Hormones, growth
factors, cytokines
Cholesterol
Pregnenolone
Steroids
Kinases Transcription factors
StAR
Cell membrane
Mitochondria Nucleus
P
FIGURE 161 Regulation of steroid biosynthesis by the
steroidogenic acute regulatory protein (StAR). Extracellular signals
activate intracellular kinases that, in turn, phosphorylate transcription
factors that upregulate StAR expression. StAR is activated by
phosphorylation, and facilitates transfer of cholesterol from the outer
to inner mitochondrial membrane leafl et. This then allows entry of
cholesterol into the steroid biosynthetic pathway, beginning with
pregnenolone.
302 SECTION III Endocrine and Reproductive Physiology
through the pulmonary circulation or the liver. Th is may
markedly curtail the temporal window within which a given
hormone can act.
HORMONE ACTION
As we will see in later chapters, hormones exert a wide range
of distinctive actions on a huge number of target cells to eff ect
changes in metabolism, release of other hormones and regulatory
substances, changes in ion channel activity, and cell
growth, among others ( Clinical Box 16–1 ). Ultimately, the
concerted action of the hormones of the body ensures the
maintenance of homeostasis. Indeed, all hormones aff ect
homeostasis to some degree. However, a subset of the hormones,
as detailed in Table 16–1 , are the key contributors to
homeostasis. Th ese include thyroid hormone, cortisol, parathyroid
hormone, vasopressin, the mineralocorticoids, and
insulin. Detailed information on the precise biological eff ects
of these molecules can be found in subsequent chapters.
Hydrophilic hormones, including peptides and catecholamines,
exert their acute eff ects by binding to cell surface
receptors. Most of these are from the GPCR family. Hydrophobic
hormones, in the other hand, predominantly exert their
actions via nuclear receptors. Th ere are two classes of nuclear
receptors that are important in endocrine physiology. Th e fi rst
of these provide for direct stimulation of transcription via
induction of the binding of a transcriptional co-activator when
the hormonal ligand is bound. In the second class, hormone
binding triggers simultaneous dislodging of a transcriptional
co-repressor and recruitment of a co-activator. Th e latter class
of receptor allows for a wider dynamic range of regulation of
the genes targeted by the hormone in question.
hormones are hydrophobic and are mostly bound to large proteins
called steroid binding proteins (SBP), which are synthesized
in the liver. As a result, only small amounts of the
free hormone are dissolved in the plasma. Specifi cally, sex
hormone-binding globulin (SHBG) is a glycoprotein that
binds to the sex hormones, testosterone and 17β-estradiol.
Progesterone, cortisol, and other corticosteroids are bound by
transcortin.
Th e SBP-hormone complex and the free hormone are in
equilibrium in the plasma, and only the free hormone is able
to diff use across cell membranes. SBP have three main functions:
they increase the solubility of lipid based hormones in
the blood, they reduce the rate of hormone loss in the urine
by preventing the hormones from being fi ltered in the kidney,
and as mentioned above, they provide a source of hormone
in the bloodstream that can release free hormone as the equilibrium
changes. It follows that an additional way to regulate
the availability of hormones that bind to carrier proteins, such
as steroids, is to regulate the expression and secretion of the
carrier proteins themselves. Th is is a critical mechanism that
regulates the bioavailability of thyroid hormones, for example
(see Chapter 19 ).
In a pathophysiological setting, some medications can
alter levels of binding proteins or displace hormones that are
bound to them. In addition, some binding proteins are promiscuous
and bind multiple hormones (eg, SHBG). Th ese
observations may have clinical implications for endocrine
homeostasis, since free hormones are needed to feedback and
control their rates of synthesis and secretion (see below).
Finally, the anatomic relationship of sites of release and
action of hormones may play a key role in their regulation.
For example, a number of hormones are destroyed by passage
CLINICAL BOX 16–1
Breast Cancer
Breast cancer is the most common malignancy of women, with
about 1 million new cases diagnosed each year worldwide.
The proliferation of more than two-thirds of breast tumors
are driven by the ovarian hormone, estrogen, by virtue of the
fact that the tumor cells express high levels of posttranslationally
modifi ed estrogen receptors (ER). The clinical signifi -
cance of these molecular fi ndings has been known for more
than 100 years, since the Scottish surgeon, Sir Thomas Beatson,
reported delayed disease progression in patients with
advanced breast cancer following removal of their ovaries. In
modern times, determination of whether a given breast cancer
is, or is not, ER-positive is a critical diagnostic test that
guides treatment decisions, as well as an important prognosticator.
ER-positive tumors are typically of lower grade, and
patients with such tumors have improved survival (although
the latter is likely due, at least in part, to the availability of
excellent treatment options for ER-positive tumors compared
with those that are ER-negative—see below).
THERAPEUTIC HIGHLIGHTS
Estrogen-responsive breast tumors are dependent on the
presence of the hormone for growth. In modern times, cells
can be deprived of the eff ects of estrogen pharmacologically,
rather than resorting to oophorectomy. Tamoxifen
and related agents specifi cally inhibit the receptor and
may also hasten its degradation. In postmenopausal
women, where estrogen is derived from the metabolism
of testosterone in extragonadal tissues rather than from
the ovaries, aromatase inhibitors inhibit the conversion
of androgens to estrogen, and thereby deprive tumor cells
of their critical signal for continued proliferation.
CHAPTER 16 Basic Concepts of Endocrine Regulation 303
In recent years, it has become apparent that a number
of receptors for steroid and other hydrophobic hormones are
extranuclear, and some may even be present on the cell surface.
Th e characterization of such receptors at a molecular
level, their associated signaling pathways, and indeed proof of
their existence has been complicated by the ability of hydrophobic
hormones to diff use relatively freely into all cellular
compartments. Th ese extranuclear receptors, some of which
may be structurally related or even identical to the more classical
nuclear receptors, are proposed to mediate rapid responses
to steroids and other hormones that do not require alterations
in gene transcription. Th e physiological eff ects at these receptors
may therefore be distinct from those classically associated
with a given hormone. Evidence is accumulating, for example,
that plasma membrane receptors for estrogen can mediate
acute arterial vasodilation as well as reducing cardiac hypertrophy
in pathophysiological settings. Functions such as these
may account for diff erences in the prevalence of cardiovascular
disease in pre and postmenopausal women. In any event, this
active area of biomedical investigation is likely to broaden our
horizons of the full spectrum of action of steroid hormones.
PRINCIPLES OF
FEEDBACK CONTROL
A fi nal general principle that is critical for endocrine physiology
is that of feedback regulation. Th is holds that the responsiveness
of target cells to hormonal action subsequently “feeds
back” to control the inciting endocrine organ. Feedback can
regulate the further release of the hormone in either a negative
feedback or (more rarely) a positive feedback loop. Positive
feedback relates to the enhancement or continued stimulation
TABLE 161 Major hormonal contributors
to homeostasis.
Hormone Source Action
Thyroid
hormone
Thyroid Controls basal
metabolism in most
tissues
Cortisol Adrenal
cortex
Energy metabolism;
permissive action for
other hormones
Mineralocorticoids Adrenal
cortex
Regulate plasma volume
via eff ects on serum
electrolytes
Vasopressin Posterior
pituitary
Regulates plasma
osmolality via eff ects on
water excretion
Parathyroid
hormone
Parathyroids Regulates calcium and
phosphorus levels
Insulin Pancreas Regulates plasma glucose
concentration
+
+
Adrenal Gonads
Thyroid
Hypothalamus
CNS
Releasing
factors
Pituitary
Trophic
hormones
Target hormone
feedback
inhibition
FIGURE 163 Summary of feedback loops regulating
endocrine axes. CNS, central nervous system. (Reproduced
with permission from Jameson JL (editor): Harrison’s Endocrinology
2nd ed. McGraw Hill, 2010. )
of the original release mechanism/stimulus. Such mechanisms
are really only seen in settings that need to gather momentum
to an eventual outcome, such as parturition. Negative feedback
is a far more common control mechanism and involves
the inhibition or dampening of the initial hormone release
mechanism/stimulus. A general scheme for feedback inhibition
of endocrine axes is depicted in Figure 16–3 .
In general, the endocrine system uses a network of feedback
responses to maintain a steady state. Steady state can be
explained using blood osmolality as an example ( Figure 16–4 ).
Blood osmolality in humans must be maintained within a physiological
range of 275–299 mOsm, and to maintain homeostasis
this variable should not exceed that range. To ensure that
osmolality does not change in the context of an open system,
processes are in place that will add or remove water from the
system to ensure a constant osmolality. Th e osmolality of blood
will increase with dehydration and decrease with overhydration.
If blood osmolality increases outside the ideal range (by
10 mOsm or more), osmoreceptors are activated. Th ese signal
release of the peptide hormone, vasopressin, into the circulation
(from the pituitary). Vasopressin acts on the renal collecting
duct, and increases the permeability of the plasma membrane
to water via the insertion of a protein called an aquaporin.
Water is then moved from the urine into the circulation via
transcellular transport. Th e reabsorption of water from the
304 SECTION III Endocrine and Reproductive Physiology
water reabsorption from the urine is reduced. Further details
of this collaboration between the kidneys, hypothalamus and
pituitary are found in Chapter 38 .
Negative feedback control systems such as those described
are the most common feedback/homeostatic systems in the
body. Other examples include temperature regulation (see
Chapter 17 ) and the regulation of blood glucose concentrations
(see Chapter 24 ). Feedback control loops also provide
for diagnostic strategies in evaluating patients with suspected
endocrine disorders. For example, in a patient being evaluated
for hypothyroidism, normal levels of TSH (see Chapter 19 )
tend to rule out a primary defect at the level of the thyroid
gland itself, and rather suggest that a defect at the level of the
anterior pituitary should be sought. Conversely, if TSH is elevated,
it suggests that the normal ability of circulating thyroid
hormone to suppress TSH synthesis has been lost, likely due to
a reduction in the ability of the thyroid gland to synthesize the
hormone ( Clinical Box 16–2 ).
TYPES OF ENDOCRINE
DISORDERS
It is pertinent also to discuss briefl y the types of disease states
where endocrine physiology can become deranged. Additional
details of these disease states can be found in ensuing
chapters.
HORMONE DEFICIENCY
Defi ciencies of particular hormones are most commonly
seen in the setting where there is destruction of the glandular
structure responsible for their production, oft en as a result of
urine to the blood resets the osmolality of the blood to within
the physiological range. Th e decrease in blood osmolality then
exerts a negative feedback on the cells of the hypothalamus and
the pituitary and vasopressin release is inhibited, meaning that
CLINICAL BOX 16–2
Approach to the Patient
with Suspected Endocrine Disease
Unlike many of the disorders of individual organ systems considered
elsewhere in this volume, the symptoms of endocrine
disease may be protean because of the number of body systems
that are impacted by hormonal action. Further, many endocrine
glands are relatively inaccessible to direct physical examination.
Endocrine disorders must therefore be diagnosed on the basis
of the symptoms they produce in concert with appropriate biochemical
testing. Radioimmunoassays for specifi c hormones
remain the mainstay of diagnostic endocrinolology and can be
used to establish steady state concentrations as well as dynamic
changes of the hormone in question (the latter requiring repeated
blood sampling over time). In addition, the principles of
feedback regulation of hormone synthesis and release may allow
the physician to pinpoint the likely locus of any defect by comparing
the levels of hormones in the same axis. For example, if
testosterone levels are low but those of luteinizing hormone (LH)
are high, this suggests that the testes are unable to respond to
LH. Conversely, if both testosterone and LH are low, the problem
is more likely to be at the level of the pituitary. Synthetic hormones
can also be administered exogenously to test whether
increased basal levels of a given hormone can be suppressed, or
abnormally low levels can be stimulated by a relevant upstream
agent. An example of applying this type of reasoning to the evaluation
of suspected hypothyroidism is provided in Figure 16–5 .
THERAPEUTIC HIGHLIGHTS
The appropriate treatment of endocrine disorders depends
on their underlying basis. For example, if a particular
hormone or its releasing factor is defi cient, hormone
replacement therapy is often indicated to ameliorate
symptoms as well as long-term negative outcomes
( Figure 16–5).
Increase in blood
osmolality
Stimulates
osmoreceptors in
hypothalamus
Activates thirst
center
in hypothalmus
Increases thirst
Increases H2O
intake
Increase in
circulating
vasopressin
Increases
permeability of
collecting duct
H2O reabsorption
increases from
urine
Decrease in
blood
osmolality
FIGURE 164 Feedback loop that ensures homeostasis of
blood osmolality. An increase in blood osmolality triggers the thirst
mechanism as well as renal conservation of water via the release of
vasopressin from the hypothalamus. Both outcomes decrease blood
osmolality back towards the normal range, which feeds back to
terminate hypothalamic signaling.
CHAPTER 16 Basic Concepts of Endocrine Regulation 305
Measure unbound T4
Mild Measure unbound T4
hypothyroidism
Measure TSH
Elevated
Normal
Normal
Primary
hypothyroidism
Low
Autoimmune
hypothyroidism
Rule out other
causes of
hypothyroidism
T4 treatment
TPOAb or
symptomatic
TPOAb, no
symptoms
Annual follow-up T4 treatment
TPOAb TPOAb
Pituitary disease suspected?
No further
tests
Normal
Yes
Rule out drug effects, sick
euthyroid syndrome,
then evaluate anterior
pituitary function
No further
tests
No
Low
Evaluation of Hypothyroidism
inappropriate autoimmune attack. For example, in type 1 diabetes
mellitus, pancreatic β cells are destroyed leading to an
inability to synthesize insulin, oft en from a very young age.
Similarly, hormonal defi ciencies arise when there are inherited
mutations in the factors responsible for their release or
in the receptors for these releasing factors. Defects in the
enzymatic machinery needed for hormone production, or a
lack of appropriate precursors (eg, iodine defi ciency leads to
hypothyroidism) will also reduce the amount of the relevant
hormone available for bodily requirements.
HORMONE RESISTANCE
Many of the consequences of hormone defi ciency can by
reproduced in disease states where adequate levels of a given
hormone are synthesized and released, but the target tissues
become resistant to the hormone’s eff ects. Indeed, there is
oft en overproduction of the implicated hormone in these
conditions because the feedback loops that normally serve
to shut off hormone synthesis and/or secretion are similarly
desensitized. Mutations in hormone receptors (especially
nuclear receptors) may result in heritable syndromes
of hormone resistance. Th ese syndromes, while relatively
rare, usually exhibit severe outcomes, and have provided
insights into the basic cell biology of hormone signaling.
Functional hormone resistance that develops over time is
also seen. Resistance arises from a relative failure of receptor
signaling to couple effi ciently to downstream intracellular
eff ector pathways that normally mediate the eff ects of
the hormone. Th e most common example of this is seen in
type 2 diabetes mellitus. Target tissues for insulin gradually
become more and more resistant to its actions, secondary
to reduced activation of phosphatidylinositol 3-kinase and
other intracellular signaling pathways. A key factor precipitating
this outcome is obesity. In addition, because of excessive
insulin secretion, pancreatic β cells become “exhausted”
and may eventually fail, necessitating treatment with exogenous
insulin. An important therapeutic goal, therefore, is
to minimize progression to β cell exhaustion before irreversible
insulin resistance sets in, with diet, exercise, and treatment
with so-called insulin sensitizers (such as metformin
and rosiglitazone).
HORMONE EXCESS
Th e converse of disorders of hormone defi ciency or resistance
is seen in diseases associated with hormone excess and/
or over-stimulation of hormone receptors. A wide variety of
endocrine tumors may produce hormones in an excessive
and uncontrolled fashion. Note that the secretion of hormones
from tumor cells may not be subject to the same types
of feedback regulation that are seen for the normal source of
that hormone. In the setting of an endocrine tumor, exaggerated
eff ects of the hormone are seen. For example, acromegaly,
or gigantism, occurs in patients affl icted with an adenoma
derived from pituitary somatotropes that secretes excessive
quantities of growth hormone (see Chapter 18 ). In addition,
other endocrine tumors may secrete hormones other than
those characteristic of the cell type or tissue from which they
are originally derived. When hormone production is increased
FIGURE 165 Summary of a strategy for the laboratory evaluation of hypothyroidism. TSH, thyroid stimulating hormone; T 4 , thyroid
hormone; TPOAb + , positive for autoantibodies to thyroid peroxidase; TPOAb – , antiperoxidase antibodies not present. (Reproduced with permission
from Jameson JL (editor): Harrison’s Endocrinology 2nd ed. McGraw Hill, 2010. )
306 SECTION III Endocrine and Reproductive Physiology
uptake. Free hydrophobic hormones are also in equilibrium
with a form bound to plasma protein carriers, the latter
representing a hormone reservoir as well as an additional
mechanism to regulate hormone availability.
Th e synthesis and r ■ elease of many hormones is subject to
regulation by negative feedback loops.
■ Disease states can arise in the setting of both hormone
defi ciency and excess. Hormone defi ciencies may be mimicked
by inherited defects in their receptors or downstream signaling
pathways; hormone excess may be mimicked by autoantibodies
that bind to and activate hormone receptors, or by activating
mutations of these receptors.
CHAPTER RESOURCES
Jameson JL (editor): Harrison’s Endocrinology, 2nd ed. McGraw Hill,
2010.
Lee EK, Gorospe M: Minireview: Posttranslational regulation of
the insulin and insulin-like growth factor systems. Endocrinol
2010;151:1403.
Levin ER: Minireview: Extranuclear steroid receptors: Roles in
modulation of cell functions. Mol Endocrinol 2011;25:377.
Manna PR, Stocco DM: Th e role of specifi c mitogen-activated
protein kinase signaling cascades in the regulation of
steroidogenesis. J Signal Transduct 2011. Article ID 821615;
13 pp.
Musso C, Cochran E, Moran SA, Skarulis MC, Oral EA, Taylor
S, Gorden P: Clinical course of genetic diseases of the insulin
receptor (Type A and Rabson-Mendenhall syndromes).
A 30-year perspective. Medicine 2004;83:209.
Walker JJ, Terry JR, Tsaneva-Atanasova K, Armstrong SP, McArdle
CA, Lightman SL: Encoding and decoding mechanisms of
pulsatile hormone secretion. J Neuroendocrinol 2010;22:1226.
in all of these cases, there usually will also be downregulation
of upstream releasing factors due to the triggering of negative
feedback loops.
Disorders of hormone excess can also be mimicked by antibodies
that bind to, and activate, the receptor for the hormone.
A classic example of such a condition is Graves’ disease,
where susceptible individuals generate thyroid-stimulating
immunoglobulins (TSIs) that bind to the receptor for TSH.
Th is causes a conformational change that elicits receptor activation,
and thus secretion of thyroid hormone in the absence
of a physiological trigger for this event. Diseases associated
with hormone excess can also occur in a heritable fashion
secondary to activating mutations of hormone releasing factor
receptors or their downstream targets. As seen for endocrine
tumors, these pathophysiological triggers of excessive
hormone release are of course not subject to dampening by
negative feedback loops.
CHAPTER SUMMARY
■ Th e endocrine system consists of a distributed set of glands
and the chemical messengers that they produce, referred to
as hormones. Hormones play a critical role in ensuring the
relative stability of body systems, that is homeostasis.
■ Hormones can be grouped into peptide/protein, amine, and
steroid categories. Water-soluble hormones (peptides and
catecholamines) bind to cell surface receptors; hydrophobic
hormones diff use into the cell and activate nuclear receptors
to regulate gene transcription. Th e receptors and hormones
appear to have evolved in parallel.
■ Hormone availability is dictated by the rate of synthesis, the
presence of releasing factors, and rates of degradation or
307
O B J E C T I V E S
After reading this chapter
you should be able to:
■ Describe the anatomic connections between the hypothalamus and the
pituitary gland and the functional signifi cance of each connection.
■ List the factors that control water intake, and outline the way in which they
exert their eff ects.
■ Describe the synthesis, processing, storage, and secretion of the hormones of
the posterior pituitary.
■ Discuss the eff ects of vasopressin, the receptors on which it acts, and how its
secretion is regulated.
■ Discuss the eff ects of oxytocin, the receptors on which it acts, and how its
secretion is regulated.
■ Name the hypophysiotropic hormones, and outline the eff ects that each has an
anterior pituitary function.
■ List the mechanisms by which heat is produced in and lost from the body, and
comment on the diff erences in temperature in the hypothalamus, rectum, oral
cavity, and skin.
■ List the temperature-regulating mechanisms, and describe the way in which
they are integrated under hypothalamic control to maintain normal body
temperature.
■ Discuss the pathophysiology of fever.
hypothalamus also functions with the limbic system as a unit
that regulates emotional and instinctual behavior.
C H A P T E R
Hypothalamic Regulation
of Hormonal Functions 17
INTRODUCTION
Many of the complex autonomic mechanisms that maintain
the chemical constancy and temperature of the internal
environment are integrated in the hypothalamus. Th e
HYPOTHALAMUS: ANATOMIC
CONSIDERATIONS
Th e hypothalamus ( Figure 17–1 ) is the portion of the anterior
end of the diencephalon that lies below the hypothalamic
sulcus and in front of the interpeduncular nuclei. It is divided
into a variety of nuclei and nuclear areas.
AFFERENT & EFFERENT
CONNECTIONS OF THE
HYPOTHALAMUS
Th e principal aff erent and eff erent neural pathways to and from
the hypothalamus are mostly unmyelinated. Many connect the
hypothalamus to the limbic system. Important connections
Ganong_Ch17_307-322.indd 307 1/4/12 1:03:00 PM
308 SECTION III Endocrine and Reproductive Physiology
also exist between the hypothalamus and nuclei in the midbrain
tegmentum, pons, and hindbrain.
Norepinephrine-secreting neurons with their cell bodies in
the hindbrain end in many diff erent parts of the hypothalamus
(see Figure 7–2). Paraventricular neurons that secrete oxytocin
and vasopressin project in turn to the hindbrain and the spinal
cord. Neurons that secrete epinephrine have their cell bodies in
the hindbrain and end in the ventral hypothalamus.
An intrahypothalamic system is comprised of dopaminesecreting
neurons that have their cell bodies in the arcuate
nucleus and end on or near the capillaries that form the portal
vessels in the median eminence. Serotonin-secreting neurons
project to the hypothalamus from the raphe nuclei.
RELATION TO THE
PITUITARY GLAND
Th ere are neural connections between the hypothalamus and
the posterior lobe of the pituitary gland and vascular connections
between the hypothalamus and the anterior lobe. Embryologically,
the posterior pituitary arises as an evagination of the
fl oor of the third ventricle. It is made up in large part of the
endings of axons that arise from cell bodies in the supraoptic
and paraventricular nuclei and pass to the posterior pituitary
( Figure 17–2 ) via the hypothalamohypophysial tract. Most of
the supraoptic fi bers end in the posterior lobe itself, whereas
some of the paraventricular fi bers end in the median eminence.
Th e anterior and intermediate lobes of the pituitary arise in
the embryo from the Rathke pouch, an evagination from the
roof of the pharynx (see Figure 18–1). Sympathetic nerve fi bers
Dorsal hypothalamic area
Paraventricular nucleus
Anterior hypothalamic area
Preoptic area
Supraoptic nucleus
Suprachiasmatic nucleus
Arcuate nucleus
Optic chiasm
Median eminence
Superior hypophysial artery
Portal hypophysial vessel
Anterior lobe Pituitary
gland
Posterior lobe
Primary
plexus
Posterior hypothalamic nucleus
Dorsomedial nucleus
Ventromedial nucleus
Premamillary nucleus
Medial mamillary nucleus
Lateral mamillary nucleus
Mamillary body
FIGURE 171 Human hypothalamus, with a superimposed diagrammatic representation of the portal hypophysial vessels.
MB
OC
PL
Supraoptic and
paraventricular
nuclei
Arcuate
and other
nuclei
AL
Anterior
pituitary hormones
Posterior pituitary
hormones
FIGURE 172 Secretion of hypothalamic hormones. The
hormones of the posterior lobe (PL) are released into the general
circulation from the endings of supraoptic and paraventricular
neurons, whereas hypophysiotropic hormones are secreted into the
portal hypophysial circulation from the endings of arcuate and other
hypothalamic neurons. AL, anterior lobe; MB, mamillary bodies; OC,
optic chiasm.
CHAPTER 17 Hypothalamic Regulation of Hormonal Functions 309
reach the anterior lobe from its capsule, and parasympathetic
fi bers reach it from the petrosal nerves, but few if any nerve
fi bers pass to it from the hypothalamus. However, the portal
hypophysial vessels form a direct vascular link between the
hypothalamus and the anterior pituitary. Arterial twigs from
the carotid arteries and circle of Willis form a network of fenestrated
capillaries called the primary plexus on the ventral surface
of the hypothalamus ( Figure 17–1 ). Capillary loops also
penetrate the median eminence. Th e capillaries drain into the
sinusoidal portal hypophysial vessels that carry blood down the
pituitary stalk to the capillaries of the anterior pituitary. Th is
system begins and ends in capillaries without going through the
heart and is therefore a true portal system. In birds and some
mammals, including humans, there is no other anterior hypophysial
arterial supply other than capsular vessels and anastomotic
connections from the capillaries of the posterior pituitary.
Th e median eminence is generally defi ned as the portion of the
ventral hypothalamus from which the portal vessels arise. Th is
region is outside the blood–brain barrier (see Chapter 33 ).
HYPOTHALAMIC FUNCTION
Th e major functions of the hypothalamus are summarized
in Table 17–1 . Some are fairly clear-cut visceral refl exes, and
others include complex behavioral and emotional reactions;
however, all involve a particular response to a particular
stimulus. It is important to keep this in mind in considering
hypothalamic function.
RELATION TO
AUTONOMIC FUNCTION
Many years ago, Sherrington called the hypothalamus “the
head ganglion of the autonomic system.” Stimulation of the
hypothalamus produces autonomic responses, but the hypothalamus
does not seem to be concerned with the regulation
of visceral function per se. Rather, the autonomic responses
triggered in the hypothalamus are part of more complex
TABLE 171 Summary of principal hypothalamic regulatory mechanisms.
Function Afferents from Integrating Areas
Temperature regulation Temperature receptors in the skin, deep tissues, spinal cord,
hypothalamus, and other parts of the brain
Anterior hypothalamus, response to heat;
posterior hypothalamus, response to cold
Neuroendocrine control of:
Catecholamines
Vasopressin
Oxytocin
Thyroid-stimulating hormone
(thyrotropin, TSH) via TRH
Adrenocorticotropic hormone
(ACTH) and β-lipotropin (β-LPH)
via CRH
Follicle-stimulating hormone
(FSH) and luteinizing hormone
(LH) via GnRH
Prolactin via PIH and PRH
Growth hormone via
somatostatin and GRH
Limbic areas concerned with emotion
Osmoreceptors, “volume receptors,” others
Touch receptors in breast, uterus, genitalia
Temperature receptors in infants, perhaps others
Limbic system (emotional stimuli); reticular formation
(“systemic” stimuli); hypothalamic and anterior pituitary
cells sensitive to circulating blood cortisol level;
suprachiasmatic nuclei (diurnal rhythm)
Hypothalamic cells sensitive to estrogens, eyes, touch
receptors in skin and genitalia of refl ex ovulating species
Touch receptors in breasts, other unknown receptors
Unknown receptors
Dorsal and posterior hypothalamus
Supraoptic and paraventricular nuclei
Supraoptic and paraventricular nuclei
Paraventricular nuclei and neighboring areas
Paraventricular nuclei
Preoptic area; other areas
Arcuate nucleus; other areas (hypothalamus
inhibits secretion)
Periventricular nucleus, arcuate nucleus
“ Appetitive” behavior:
Thirst
Hunger
Sexual behavior
Osmoreceptors, probably located in the organum
vasculosum of the lamina terminalis; angiotensin II uptake
in the subfornical organ
Glucostat cells sensitive to rate of glucose utilization; leptin
receptors; receptors for other polypeptides
Cells sensitive to circulating estrogen and androgen, others
Lateral superior hypothalamus
Ventromedial, arcuate, and paraventricular
nuclei; lateral hypothalamus
Anterior ventral hypothalamus plus, in the
male, piriform cortex
Defensive reactions
(fear, rage)
Sense organs and neocortex, paths unknown Diff use, in limbic system and hypothalamus
Control of body rhythms Retina via retinohypothalamic fi bers Suprachiasmatic nuclei
310 SECTION III Endocrine and Reproductive Physiology
phenomena such as eating, and emotions such as rage. For
example, stimulation of various parts of the hypothalamus,
especially the lateral areas, produces diff use sympathetic discharge
and increased adrenal medullary secretion—the mass
sympathetic discharge seen in animals exposed to stress (the
fl ight or fi ght reaction; see Chapter 13 ).
It has been claimed that separate hypothalamic areas control
epinephrine and norepinephrine secretion. Diff erential
secretion of one or the other of these adrenal medullary catecholamines
does occur in certain situations (see Chapter 20 ),
but the selective increases are small.
Body weight depends on the balance between caloric
intake and utilization of calories. Obesity results when the former
exceeds the latter. Th e hypothalamus and related parts of
the brain play a key role in the regulation of food intake. Obesity
is considered in detail in Chapter 26 , and the relation of
obesity to diabetes mellitus is discussed in Chapter 24 .
Hypothalamic regulation of sleep and circadian rhythms
are discussed in Chapter 14 .
THIRST
Another appetitive mechanism under hypothalamic control
is thirst. Drinking is regulated by plasma osmolality
and extracellular fl uid (ECF) volume in much the same
fashion as vasopressin secretion (see Chapter 38 ). Water
intake is increased by increased eff ective osmotic pressure
of the plasma ( Figure 17–3 ), by decreases in ECF volume,
and by psychologic and other factors. Osmolality acts via
osmoreceptors, receptors that sense the osmolality of the
body fl uids. Th ese osmoreceptors are located in the anterior
hypothalamus.
Hypertonicity
Osmoreceptors
Hypovolemia
Hypothalamus
Thirst
Baroreceptors
Angiotensin II
FIGURE 174 Diagrammatic representation of the way in
which changes in plasma osmolality and changes in ECF volume
aff ect thirst by separate pathways.
10
8
6
4
2
0
280 300 320
Plasma osmolality (mosm/kg)
Intensity of thirst
FIGURE 173 Relation of plasma osmolality to thirst in
healthy adult humans during infusion of hypertonic saline. The
intensity of thirst is measured on a special analog scale. (Reproduced
with permission from Thompson CJ et al: The osmotic thresholds for thirst and
vasopressin release are similar in healthy humans. Clin Sci Lond 1986;71:651.)
Decreases in ECF volume also stimulate thirst by a
pathway independent of that mediating thirst in response to
increased plasma osmolality ( Figure 17–4 ). Th us, hemorrhage
causes increased drinking even if there is no change in
the osmolality of the plasma. Th e eff ect of ECF volume depletion
on thirst is mediated in part via the renin–angiotensin
system (see Chapter 38 ). Renin secretion is increased by hypovolemia
and results in an increase in circulating angiotensin II.
Th e angiotensin II acts on the subfornical organ , a specialized
receptor area in the diencephalon (see Figure 33–7), to stimulate
the neural areas concerned with thirst. Some evidence suggests
that it acts on the organum vasculosum of the lamina
terminalis (OVLT) as well. Th ese areas are highly permeable
and are two of the circumventricular organs located outside
the blood–brain barrier (see Chapter 33 ). However, drugs that
block the action of angiotensin II do not completely block the
thirst response to hypovolemia, and it appears that the baroreceptors
in the heart and blood vessels are also involved.
Th e intake of liquids is increased during eating (prandial
drinking) . Th e increase has been called a learned or habit
response, but it has not been investigated in detail. One factor
is an increase in plasma osmolality that occurs as food is
absorbed. Another may be an action of one or more gastrointestinal
hormones on the hypothalamus.
When the sensation of thirst is obtunded, either by direct
damage to the diencephalon or by depressed or altered states
of consciousness, patients stop drinking adequate amounts
of fl uid. Dehydration results if appropriate measures are not
instituted to maintain water balance. If the protein intake is
high, the products of protein metabolism cause an osmotic
diuresis (see Chapter 38 ), and the amounts of water required to
maintain hydration are large. Most cases of hypernatremia are
actually due to simple dehydration in patients with psychoses
or hypothalamic disease who do not or cannot increase their
water intake when their thirst mechanism is stimulated.
Lesions of the anterior communicating artery can also obtund
thirst because branches of this artery supply the hypothalamic
areas concerned with thirst.
CHAPTER 17 Hypothalamic Regulation of Hormonal Functions 311
OTHER FACTORS REGULATING
WATER INTAKE
A number of other well-established factors contribute to the
regulation of water intake. Psychologic and social factors
are important. Dryness of the pharyngeal mucous membrane
causes a sensation of thirst. Patients in whom fl uid intake must
be restricted sometimes get appreciable relief of thirst by sucking
ice chips or a wet cloth.
Dehydrated dogs, cats, camels, and some other animals
rapidly drink just enough water to make up their water defi cit.
Th ey stop drinking before the water is absorbed (while their
plasma is still hypertonic), so some kind of pharyngeal gastrointestinal
“metering” must be involved. Some evidence suggests
that humans have a similar metering ability, though it is
not well developed.
CONTROL OF POSTERIOR
PITUITARY SECRETION
VASOPRESSIN & OXYTOCIN
In most mammals, the hormones secreted by the posterior
pituitary gland are arginine vasopressin (AVP) and oxytocin.
In hippopotami and most pigs, arginine in the vasopressin
molecule is replaced by lysine to form lysine vasopressin . Th e
posterior pituitaries of some species of pigs and marsupials
contain a mixture of arginine and lysine vasopressin. Th e posterior
lobe hormones are nanopeptides with a disulfi de ring at
one end ( Figure 17–5 ).
BIOSYNTHESIS, INTRANEURONAL
TRANSPORT, & SECRETION
Th e hormones of the posterior pituitary gland are synthesized
in the cell bodies of the magnocellular neurons in the
supraoptic and paraventricular nuclei and transported down
Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2
1 2 3 4 5 6 7 8 9
S S
Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH2
1 2 3 4 5 6 7 8 9
S S
Arginine vasopressin
Oxytocin
FIGURE 175 Arginine vasopressin and oxytocin.
the axons of these neurons to their endings in the posterior
lobe, where they are secreted in response to electrical activity
in the endings. Some of the neurons make oxytocin and others
make vasopressin, and oxytocin-containing and vasopressincontaining
cells are found in both nuclei.
Oxytocin and vasopressin are typical neural hormones ,
that is, hormones secreted into the circulation by nerve cells.
Th is type of neural regulation is compared with other types in
Figure 17–6 . Th e term neurosecretion was originally coined
to describe the secretion of hormones by neurons, but the
term is somewhat misleading because it appears that all neurons
secrete chemical messengers (see Chapter 7 ).
Like other peptide hormones, the posterior lobe hormones
are synthesized as part of larger precursor molecules. Vasopressin
and oxytocin each have a characteristic neurophysin associated
with them in the granules in the neurons that secrete them—
neurophysin I in the case of oxytocin and neurophysin II in the
case of vasopressin. Th e neurophysins were originally thought
to be binding polypeptides, but it now appears that they are
simply parts of the precursor molecules. Th e precursor for AVP,
prepropressophysin , contains a 19-amino-acid residue leader
sequence followed by AVP, neurophysin II, and a glycopeptide
( Figure 17–7 ). Prepro-oxyphysin, the precursor for oxytocin, is
a similar but smaller molecule that lacks the glycopeptide.
Acetylcholine
Acetylcholine Acetylcholine Acetylcholine
Vasopressin
General
circulation
Norepinephrine
Epinephrine,
norepinephrine
ACTH, TSH,
GH, FSH, LH,
prolactin
Norepinephrine
or
acetylcholine
Releasing
and
inhibiting
hormones
Portal
vessels
Motor nerves
to skeletal
muscle
Motor nerves
to smooth and
cardiac muscle
Juxtaglomerular
cells
Adrenal
medulla
Anterior
pituitary
Posterior
pituitary
Renin
FIGURE 176 Neural control mechanisms. In the two situations on the left, neurotransmitters act at nerve endings on muscle; in the
two in the middle, neurotransmitters regulate the secretion of endocrine glands; and in the two on the right, neurons secrete hormones
into the hypophysial portal or general circulation.
312 SECTION III Endocrine and Reproductive Physiology
Th e precursor molecules are synthesized in the ribosomes
of the cell bodies of the neurons. Th ey have their leader
sequences removed in the endoplasmic reticulum, are packaged
into secretory granules in the Golgi apparatus, and are
transported down the axons by axoplasmic fl ow to the endings
in the posterior pituitary. Th e secretory granules, called
Herring bodies, are easy to stain in tissue sections, and they
have been extensively studied. Cleavage of the precursor molecules
occurs as they are being transported, and the storage
granules in the endings contain free vasopressin or oxytocin
and the corresponding neurophysin. In the case of vasopressin,
the glycopeptide is also present. All these products are
secreted, but the functions of the components other than the
established posterior pituitary hormones are unknown. Physiological
control of vasopressin secretion is described in detail
in Chapter 38 .
ELECTRICAL ACTIVITY OF
MAGNOCELLULAR NEURONS
Th e oxytocin-secreting and vasopressin-secreting neurons
also generate and conduct action potentials, and action potentials
reaching their endings trigger the release of hormones
by Ca 2+ -dependent exocytosis. At least in anesthetized rats,
these neurons are silent at rest or discharge at low, irregular
rates (0.1–3 spikes/s). However, their response to stimulation
varies ( Figure 17–8 ). Stimulation of the nipples causes a synchronous,
high-frequency discharge of the oxytocin neurons
aft er an appreciable latency. Th is discharge causes release of
a pulse of oxytocin and consequent milk ejection in postpartum
females. On the other hand, stimulation of vasopressinsecreting
neurons by a stimulus such as an increase in blood
osmolality during dehydration, or loss of blood volume due
to hemorrhage, causes an initial steady increase in fi ring rate
followed by a prolonged pattern of phasic discharge in which
periods of high-frequency discharge alternate with periods
of electrical quiescence (phasic bursting) . Th ese phasic
Unit
Rate
Control
5 mL blood removed
5 mL blood removed (+ 20 min)
1 min 10/s
ME
ME
50/s
A HFD
B
Intramammary pressure
FIGURE 178 Responses of magnocellular neurons to
stimulation . The tracings show individual extracellularly recorded
action potentials, discharge rates, and intramammary duct pressure.
A) Response of an oxytocin-secreting neuron. HFD, high-frequency
discharge; ME, milk ejection. Stimulation of nipples started before
the onset of recording. B) Responses of a vasopressin-secreting
neuron, showing no change in the slow fi ring rate in response to
stimulation of nipples and a prompt increase in the fi ring rate when
5 mL of blood was drawn, followed by typical phasic discharge.
(Modifi ed from Wakerly JB: Hypothalamic neurosecretory function: Insights from
electrophysiological studies of the magno-cellular nuclei. IBRO News 1985;4:15.)
bursts are generally not synchronous in diff erent vasopressinsecreting
neurons. Th ey are well suited to maintain a prolonged
increase in the output of vasopressin, as opposed to
the synchronous, relatively short, high-frequency discharge
of oxytocin-secreting neurons in response to stimulation of
the nipples.
1
1
2
3
4
2 3 4
Signal peptide
Vasopressin
Neurophysin II
Glycopeptide
19 aa
9 aa
95 aa
39 aa
-Gly-Lys-Arg- -Arg-
1
1
2
3
2 3
Signal peptide
Oxytocin
Neurophysin I
19 aa
9 aa
93 aa
-Gly-Lys-Arg- -Arg/His
FIGURE 177 Structure of bovine prepropressophysin (left) and prepro-oxyphysin (right). Gly in the 10 position of both peptides is
necessary for amidation of the Gly residue in position 9. aa, amino acid residues. (Reproduced with permission from Richter D: Molecular events in expression
of vasopressin and oxytocin and their cognate receptors. Am J Physiol 1988;255:F207.)
CHAPTER 17 Hypothalamic Regulation of Hormonal Functions 313
VASOPRESSIN & OXYTOCIN
IN OTHER LOCATIONS
Vasopressin-secreting neurons are found in the suprachiasmatic
nuclei, and vasopressin and oxytocin are also found in
the endings of neurons that project from the paraventricular
nuclei to the brain stem and spinal cord. Th ese neurons appear
to be involved in cardiovascular control. In addition, vasopressin
and oxytocin are synthesized in the gonads and the adrenal
cortex, and oxytocin is present in the thymus. Th e functions of
the peptides in these organs are unsettled.
Vasopressin Receptors
Th ere are at least three kinds of vasopressin receptors: V 1A , V 1B ,
and V 2 . All are G protein-coupled. Th e V 1A and V 1B receptors
act through phosphatidylinositol hydrolysis to increase intracellular
Ca 2+ concentrations. Th e V 2 receptors act through G s to
increase cAMP levels.
Eff ects of Vasopressin
Because one of its principal physiologic eff ects is the retention
of water by the kidney, vasopressin is oft en called the
antidiuretic hormone (ADH) . It increases the permeability
of the collecting ducts of the kidney so that water enters the
hypertonic interstitium of the renal pyramids (see Chapter 37 ).
Th e urine becomes concentrated and its volume decreases. Th e
overall eff ect is therefore retention of water in excess of solute;
consequently, the eff ective osmotic pressure of the body fl uids is
decreased. In the absence of vasopressin, the urine is hypotonic
to plasma, urine volume is increased, and there is a net water
loss. Consequently, the osmolality of the body fl uid rises.
Eff ects of Oxytocin
In humans, oxytocin acts primarily on the breasts and uterus,
though it appears to be involved in luteolysis as well (see
Chapter 22 ). A G protein-coupled oxytocin receptor has been
identifi ed in human myometrium, and a similar or identical
receptor is found in mammary tissue and the ovary. It triggers
increases in intracellular Ca 2+ levels.
The Milk Ejection Refl ex
Oxytocin causes contraction of the myoepithelial cells that
line the ducts of the breast. Th is squeezes the milk out of the
alveoli of the lactating breast into the large ducts (sinuses) and
thence out of the nipple (milk ejection) . Many hormones acting
in concert are responsible for breast growth and the secretion
of milk into the ducts (see Chapter 22 ), but milk ejection
in most species requires oxytocin.
Milk ejection is normally initiated by a neuroendocrine
refl ex. Th e receptors involved are touch receptors, which are
plentiful in the breast—especially around the nipple. Impulses
generated in these receptors are relayed from the somatic
touch pathways to the supraoptic and paraventricular nuclei.
Discharge of the oxytocin-containing neurons causes secretion
of oxytocin from the posterior pituitary ( Figure 17–8 ). Th e
suckling of an infant at the breast stimulates the touch receptors,
the nuclei are stimulated, oxytocin is released, and the
milk is expressed into the sinuses, ready to fl ow into the mouth
of the waiting infant. In lactating women, genital stimulation
and emotional stimuli also produce oxytocin secretion, sometimes
causing milk to spurt from the breasts.
Other Actions of Oxytocin
Oxytocin causes contraction of the smooth muscle of the
uterus. Th e sensitivity of the uterine musculature to oxytocin
is enhanced by estrogen and inhibited by progesterone. Th e
inhibitory eff ect of progesterone is due to a direct action of
the steroid on uterine oxytocin receptors. In late pregnancy,
the uterus becomes very sensitive to oxytocin coincident with
a marked increase in the number of oxytocin receptors and
oxytocin receptor mRNA (see Chapter 22 ). Oxytocin secretion
is then increased during labor. Aft er dilation of the cervix,
descent of the fetus down the birth canal initiates impulses
in the aff erent nerves that are relayed to the supraoptic and
paraventricular nuclei, causing secretion of suffi cient oxytocin
to enhance labor (Figure 22–24). Th e amount of oxytocin
in plasma is normal at the onset of labor. It is possible that
the marked increase in oxytocin receptors at this time allows
normal oxytocin levels to initiate contractions, setting up a
positive feedback. However, the amount of oxytocin in the
uterus is also increased, and locally produced oxytocin may
also play a role.
Oxytocin may also act on the nonpregnant uterus to facilitate
sperm transport. Th e passage of sperm up the female genital
tract to the uterine tubes, where fertilization normally takes
place, depends not only on the motile powers of the sperm
but also, at least in some species, on uterine contractions.
Th e genital stimulation involved in coitus releases oxytocin,
but whether oxytocin initiates the rather specialized uterine
contractions that transport the sperm is as yet unproven. Th e
secretion of oxytocin is also increased by stressful stimuli and,
like that of vasopressin, is inhibited by alcohol.
Circulating oxytocin increases at the time of ejaculation in
males, and it is possible that this causes increased contraction
of the smooth muscle of the vas deferens, propelling sperm
toward the urethra.
CONTROL OF ANTERIOR
PITUITARY SECRETION
ANTERIOR PITUITARY
HORMONES
Th e anterior pituitary secretes six hormones: adrenocorticotropic
hormone (corticotropin, ACTH) , thyroid- stimulating
hormone (thyrotropin, TSH) , growth hormone , folliclestimulating
hormone (FSH) , luteinizing hormone (LH) ,
314 SECTION III Endocrine and Reproductive Physiology
and prolactin (PRL) . An additional polypeptide, β-lipotropin
(β-LPH), is secreted with ACTH, but its physiologic role is
unknown. Th e actions of the anterior pituitary hormones are
summarized in Figure 17–9 . Th e hormones are discussed
in detail in subsequent chapters. Th e hypothalamus plays
an important stimulatory role in regulating the secretion of
ACTH, β-LPH, TSH, growth hormone, FSH, and LH. It also
regulates prolactin secretion, but its eff ect is predominantly
inhibitory rather than stimulatory.
NATURE OF HYPOTHALAMIC
CONTROL
Anterior pituitary secretion is controlled by chemical agents
carried in the portal hypophysial vessels from the hypothalamus
to the pituitary. Th ese substances used to be called releasing
and inhibiting factors, but now they are commonly called
hypophysiotropic hormones. Th e latter term seems appropriate
since they are secreted into the bloodstream and act at a
distance from their site of origin. Small amounts escape into
the general circulation, but they are at their highest concentration
in portal hypophysial blood.
HYPOPHYSIOTROPIC HORMONES
Th ere are six established hypothalamic releasing and inhibiting
hormones ( Figure 17–10 ): corticotropin-releasing hormone
(CRH) ; thyrotropin-releasing hormone (TRH) ; growth
hormone-releasing hormone (GRH) ; growth hormoneinhibiting
hormone (GIH , now generally called somatostatin);
luteinizing hormone-releasing hormone (LHRH ,
now generally known as gonadotropin-releasing hormone
(GnRH)) ; and prolactin-inhibiting hormone (PIH) . In
addition, hypothalamic extracts contain prolactin-releasing
activity, and a prolactin-releasing hormone (PRH) has been
postulated to exist. TRH, VIP, and several other polypeptides
found in the hypothalamus stimulate prolactin secretion, but
it is uncertain whether one or more of these peptides is the
physiologic PRH. Recently, an orphan receptor was isolated
from the anterior pituitary, and the search for its ligand led to
the isolation of a 31-amino-acid polypeptide from the human
Anterior pituitary
ACTH TSH FSH LH Prolactin
Growth
β-LPH hormone
? Breast
17-Hydroxycorticoids
Aldosterone,
sex hormones
Somatomedins
Thyroxine Estrogen Progesterone
FIGURE 179 Anterior pituitary hormones . In women, FSH and LH act in sequence on the ovary to produce growth of the ovarian
follicle, ovulation, and formation and maintenance of the corpus luteum. Prolactin stimulates lactation. In men, FSH and LH control the
functions of the testes.
Hypothalamus
CRH TRH
Anterior
pituitary
GnRH
GRH
GIH
PRH
PIH
β-LPH ACTH TSH LH FSH Growth Prolactin
hormone
FIGURE 1710 Eff ects of hypophysiotropic hormones on the secretion of anterior pituitary hormones.
CHAPTER 17 Hypothalamic Regulation of Hormonal Functions 315
hypothalamus. Th is polypeptide stimulated prolactin secretion
by an action on the anterior pituitary receptor, but additional
research is needed to determine if it is the physiologic
PRH. GnRH stimulates the secretion of FSH as well as that of
LH, and it seems unlikely that a separate FSH-releasing hormone
exists.
Th e structures of the six established hypophysiotropic
hormones are shown in Figure 17–11 . Th e structures of the
genes and preprohormones for TRH, GnRH, somatostatin,
CRH, and GRH are known. PreproTRH contains six copies of
TRH. Several other preprohormones may contain other hormonally
active peptides in addition to the hypophysiotropic
hormones.
Th e area from which the hypothalamic releasing and
inhibiting hormones are secreted is the median eminence of
the hypothalamus. Th is region contains few nerve cell bodies,
but many nerve endings are in close proximity to the capillary
loops from which the portal vessels originate.
Th e locations of the cell bodies of the neurons that project
to the external layer of the median eminence and secrete
the hypophysiotropic hormones are shown in Figure 17–12 ,
which also shows the location of the neurons secreting oxytocin
and vasopressin. Th e GnRH-secreting neurons are primarily
in the medial preoptic area, the somatostatin-secreting
neurons are in the periventricular nuclei, the TRH-secreting
and CRH-secreting neurons are in the medial parts of the paraventricular
nuclei, and the GRH-secreting (and dopaminesecreting)
neurons are in the arcuate nuclei.
Most, if not all, of the hypophysiotropic hormones aff ect
the secretion of more than one anterior pituitary hormone
( Figure 17–10 ). Th e FSH-stimulating activity of GnRH has
been mentioned previously. TRH stimulates the secretion
of prolactin as well as TSH. Somatostatin inhibits the secretion
of TSH as well as growth hormone. It does not normally
inhibit the secretion of the other anterior pituitary hormones,
but it inhibits the abnormally elevated secretion of ACTH in
patients with Nelson’s syndrome. CRH stimulates the secretion
of ACTH and β-LPH.
Hypophysiotropic hormones function as neurotransmitters
in other parts of the brain, the retina, and the autonomic
nervous system (see Chapter 7 ). In addition, somatostatin is
TRH (pyro)Glu-His-Pro-NH2
GnRH (pyro)Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2
Somatostatin Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys
Ser-Glu-Glu-Pro-Pro-Ile-Ser-Leu-Asp-Leu-Thr-Phe-His-Leu-Leu-Arg-Glu-Val-Leu-Glu-Met-Ala-Arg-Ala-Glu-Gln-Leu-
Ala-Gln-Gln-Ala-His-Ser-Asn-Arg-Lys-Leu-Met-Glu-Ile-Ile-NH2
CRH
GRH Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-
Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-Ala-Arg-Ala-Arg-Leu-NH2
PIH Dopamine
S S
FIGURE 1711 Structure of hypophysiotropic hormones in humans . Preprosomatostatin is processed to a tetradecapeptide
(somatostatin 14, [SS14], shown above) and also to a polypeptide containing 28 amino acid residues (SS28).
0.5 mm
Oxytocin
Vasopressin
SS
DA
CRH
GnRH
TRH
GRH
Peri
SO
PV
ME
ARC
IC
PL
IL
AL
BA
PC
MC
TRH
GRH
DA
FIGURE 1712 Location of cell bodies of hypophysiotropic
hormone-secreting neurons projected on a ventral view of the
hypothalamus and pituitary of the rat. AL, anterior lobe; ARC,
arcuate nucleus; BA, basilar artery; DA, dopamine; IC, internal carotid
artery; IL, intermediate lobe; MC, middle cerebral artery; ME, median
eminence; PC, posterior cerebral artery; Peri, periventricular nucleus;
PL, posterior lobe; PV, paraventricular nucleus; SO, supraoptic
nucleus. The names of the hormones are enclosed in boxes. (Courtesy
of LW Swanson and ET Cunningham Jr)
found in the pancreatic islets (see Chapter 24 ), GRH is secreted
by pancreatic tumors, and somatostatin and TRH are found in
the gastrointestinal tract (see Chapter 25 ).
316 SECTION III Endocrine and Reproductive Physiology
Receptors for most of the hypophysiotropic hormones are
coupled to G proteins. Th ere are two human CRH receptors:
hCRH-RI and hCRH-RII. Th e physiologic role of hCRH-RII
is unsettled, though it is found in many parts of the brain.
In addition, a CRH-binding protein in the peripheral circulation
inactivates CRH. It is also found in the cytoplasm
of corticotropes in the anterior pituitary, and in this location
it might play a role in receptor internalization. However,
the exact physiologic role of this protein is unknown. Other
hypophysiotropic hormones do not have known binding
proteins.
SIGNIFICANCE & CLINICAL
IMPLICATIONS
Research delineating the multiple neuroendocrine regulatory
functions of the hypothalamus is important because it helps
explain how endocrine secretion is matched to the demands of
a changing environment. Th e nervous system receives information
about changes in the internal and external environment
from the sense organs. It brings about adjustments to
these changes through eff ector mechanisms that include not
only somatic movement but also changes in the rate at which
hormones are secreted.
Th e manifestations of hypothalamic disease are neurologic
defects, endocrine changes, and metabolic abnormalities
such as hyperphagia and hyperthermia. Th e relative frequencies
of the signs and symptoms of hypothalamic disease in one
large series of cases are shown in Table 17–2 . Th e possibility of
hypothalamic pathology should be kept in mind in evaluating
all patients with pituitary dysfunction, especially those with
isolated defi ciencies of single pituitary tropic hormones.
A condition of considerable interest in this context is
Kallmann syndrome , the combination of hypogonadism due
to low levels of circulating gonadotropins (hypogonadotropic
hypogonadism) with partial or complete loss of the sense of
smell ( hyposmia or anosmia ). Embryologically, GnRH neurons
develop in the nose and migrate up the olfactory nerves
and then through the brain to the hypothalamus. If this migration
is prevented by congenital abnormalities in the olfactory
pathways, the GnRH neurons do not reach the hypothalamus
and pubertal maturation of the gonads does not occur. Th e
syndrome is most common in men, and the cause in many
cases is mutation of the KALIG1 gene, a gene on the X chromosome
that codes for an adhesion molecule necessary for the
normal development of the olfactory nerve. However, the condition
also occurs in women and can be due to other genetic
abnormalities.
TEMPERATURE REGULATION
In the body, heat is produced by muscular exercise, assimilation
of food, and all the vital processes that contribute to the
basal metabolic rate. It is lost from the body by radiation, conduction,
and vaporization of water in the respiratory passages
TABLE 172 Symptoms and signs in 60 patients
with hypothalamic disease.
Symptoms and Signs Percentage of Cases
Endocrine and metabolic fi ndings
Precocious puberty 40
Hypogonadism 32
Diabetes insipidus 35
Obesity 25
Abnormalities of temperature regulation 22
Emaciation 18
Bulimia 8
Anorexia 7
Neurologic fi ndings
Eye signs 78
Pyramidal and sensory defi cits 75
Headache 65
Extrapyramidal signs 62
Vomiting 40
Psychic disturbances, rage attacks, etc 35
Somnolence 30
Convulsions 15
Data from Bauer HG: Endocrine and other clinical manifestations of hypothalamic
disease. J Clin Endocrinol 1954;14:13. See also Kahana L, et al: Endocrine
manifestations of intracranial extrasellar lesions. J Clin Endocrinol 1962;22:304.
and on the skin. Small amounts of heat are also removed in
the urine and feces. Th e balance between heat production and
heat loss determines the body temperature. Because the speed
of chemical reactions varies with temperature and because the
enzyme systems of the body have narrow temperature ranges
in which their function is optimal, normal body function
depends on a relatively constant body temperature.
Invertebrates generally cannot adjust their body temperatures
and so are at the mercy of the environment. In
vertebrates, mechanisms for maintaining body temperature
by adjusting heat production and heat loss have evolved. In
reptiles, amphibians, and fi sh, the adjusting mechanisms are
relatively rudimentary, and these species are called “coldblooded”
(poikilothermic) because their body temperature
fl uctuates over a considerable range. In birds and mammals,
the “warm-blooded” (homeothermic) animals, a group of
refl ex responses that are primarily integrated in the hypothalamus
operate to maintain body temperature within a narrow
range in spite of wide fl uctuations in environmental temperature.
Th e hibernating mammals are a partial exception. While
awake they are homeothermic, but during hibernation their
body temperature falls.
CHAPTER 17 Hypothalamic Regulation of Hormonal Functions 317
NORMAL BODY TEMPERATURE
In homeothermic animals, the actual temperature at which
the body is maintained varies from species to species and,
to a lesser degree, from individual to individual. In humans,
the traditional normal value for the oral temperature is 37°C
(98.6°F), but in one large series of normal young adults, the
morning oral temperature averaged 36.7°C, with a standard
deviation of 0.2°C. Th erefore, 95% of all young adults would be
expected to have a morning oral temperature of 36.3–37.1°C
(97.3–98.8°F; mean ± 1.96 standard deviations). Various parts
of the body are at diff erent temperatures, and the magnitude
of the temperature diff erence between the parts varies with the
environmental temperature ( Figure 17–13 ). Th e extremities
are generally cooler than the rest of the body. Th e temperature
of the scrotum is carefully regulated at 32°C. Th e rectal temperature
is representative of the temperature at the core of the
body and varies least with changes in environmental temperature.
Th e oral temperature is normally 0.5°C lower than the
rectal temperature, but it is aff ected by many factors, including
ingestion of hot or cold fl uids, gum chewing, smoking, and
mouth breathing.
Th e normal human core temperature undergoes a regular
circadian fl uctuation of 0.5–0.7°C. In individuals who sleep at
night and are awake during the day (even when hospitalized
at bed rest), it is lowest at about 6:00 am and highest in the
evenings ( Figure 17–14 ). It is lowest during sleep, is slightly
higher in the awake but relaxed state, and rises with activity.
In women, an additional monthly cycle of temperature
variation is characterized by a rise in basal temperature at the
time of ovulation (Figure 22–15). Temperature regulation is
less precise in young children and they may normally have
37
36
35
34
33
32
31
30
29
28
27
26
25
24
23
22 23 24 25 26
Feet
Hands
27 28 29 30 31 32 33 34
Calorimetric temperature (°C)
Temperature (°C) of subject
Average
skin
Trunk
Head
Rectum
FIGURE 1713 Temperatures of various parts of the
body of a naked subject at various ambient temperatures in
a calorimeter. (Redrawn and reproduced, with permission, from Hardy JD,
DuBois EF: Basal heat production and elimination of thirteen normal women at
temperatures from 22 degrees C. to 35 degrees C. J Nutr 1938 Oct; 48(2):257–293.)
38
37
36
1 2 3 4 5
Admitted to hospital
Days
Oral temp (°C)
Hyperthyroidism
Hypothyroidism
Normal
FIGURE 1714 Typical temperature chart of a hospitalized
patient who does not have a febrile disease. Note the slight rise
in temperature, due to excitement and apprehension, at the time of
admission to the hospital, and the regular circadian temperature cycle.
a temperature that is 0.5°C or so above the established norm
for adults.
During exercise, the heat produced by muscular contraction
accumulates in the body and the rectal temperature normally
rises as high as 40°C (104 °F). Th is rise is due in part
to the inability of the heat-dissipating mechanisms to handle
the greatly increased amount of heat produced, but evidence
suggests that during exercise in addition there is an elevation
of the body temperature at which the heat-dissipating mechanisms
are activated. Body temperature also rises slightly during
emotional excitement, probably owing to unconscious tensing
of the muscles. It is chronically elevated by as much as 0.5°C
when the metabolic rate is high, as in hyperthyroidism, and
lowered when the metabolic rate is low, as in hypothyroidism
( Figure 17–14 ). Some apparently normal adults chronically
have a temperature above the normal range (constitutional
hyperthermia).
HEAT PRODUCTION
A variety of basic chemical reactions contribute to body heat
production at all times. Ingestion of food increases heat production,
but the major source of heat is the contraction of skeletal
muscle ( Table 17–3 ). Heat production can be varied by
endocrine mechanisms in the absence of food intake or muscular
exertion. Epinephrine and norepinephrine produce a
rapid but short-lived increase in heat production; thyroid hormones
produce a slowly developing but prolonged increase.
TABLE 173 Body heat production and heat loss.
Body heat is produced by:
Basic metabolic processes
Food intake (specifi c dynamic action)
Muscular activity
Body heat is lost by:
Radiation and conduction
Vaporization of sweat
Respiration
Urination and defecation
Percentage of heat lost at 21°C
70
27
2
1
318 SECTION III Endocrine and Reproductive Physiology
Furthermore, sympathetic discharge decreases during fasting
and is increased by feeding.
A source of considerable heat, particularly in infants,
is brown fat . Th is fat has a high rate of metabolism and its
thermogenic function has been likened to that of an electric
blanket.
HEAT LOSS
Th e processes by which heat is lost from the body when the
environmental temperature is below body temperature are
listed in Table 17–3 . Conduction is heat exchange between
objects or substances at diff erent temperatures that are in
contact with one another. A basic characteristic of matter is
that its molecules are in motion, with the amount of motion
proportional to the temperature. Th ese molecules collide
with the molecules in cooler objects, transferring thermal
energy to them. Th e amount of heat transferred is proportional
to the temperature diff erence between the objects in
contact (thermal gradient). Conduction is aided by convection
, the movement of molecules away from the area of
contact. Th us, for example, an object in contact with air at a
diff erent temperature changes the specifi c gravity of the air,
and because warm air rises and cool air falls, a new supply of
air is brought into contact with the object. Of course, convection
is greatly aided if the object moves about in the medium
or the medium moves past the object, for example, if a subject
swims through water or a fan blows air through a room.
Radiation is the transfer of heat by infrared electromagnetic
radiation from one object to another at a diff erent temperature
with which it is not in contact. When an individual is
in a cold environment, heat is lost by conduction to the surrounding
air and by radiation to cool objects in the vicinity.
Conversely, of course, heat is transferred to an individual and
the heat load is increased by these processes when the environmental
temperature is above body temperature. Note that
because of radiation, an individual can feel chilly in a room
with cold walls even though the room is relatively warm. On
a cold but sunny day, the heat of the sun refl ected off bright
objects exerts an appreciable warming eff ect. It is the heat
refl ected from the snow, for example, that in part makes it
possible to ski in fairly light clothes even though the air temperature
is below freezing.
Because conduction occurs from the surface of one object
to the surface of another, the temperature of the skin determines
to a large extent the degree to which body heat is lost or
gained. Th e amount of heat reaching the skin from the deep
tissues can be varied by changing the blood fl ow to the skin.
When the cutaneous vessels are dilated, warm blood wells into
the skin, whereas in the maximally vasoconstricted state, heat
is held centrally in the body. Th e rate at which heat is transferred
from the deep tissues to the skin is called the tissue conductance
. Further, birds have a layer of feathers next to the
skin, and most mammals have a signifi cant layer of hair or fur.
Heat is conducted from the skin to the air trapped in this layer
and from the trapped air to the exterior. When the thickness of
the trapped layer is increased by fl uffi ng the feathers or erection
of the hairs (horripilation), heat transfer across the layer
is reduced and heat losses (or, in a hot environment, heat gains)
are decreased. “Goose pimples” are the result of horripilation
in humans; they are the visible manifestation of cold-induced
contraction of the piloerector muscles attached to the rather
meager hair supply. Humans usually supplement this layer
of hair with one or more layers of clothes. Heat is conducted
from the skin to the layer of air trapped by the clothes, from
the inside of the clothes to the outside, and from the outside of
the clothes to the exterior. Th e magnitude of the heat transfer
across the clothing, a function of its texture and thickness, is the
most important determinant of how warm or cool the clothes
feel, but other factors, especially the size of the trapped layer of
warm air, are also important. Dark clothes absorb radiated heat
and light-colored clothes refl ect it back to the exterior.
Th e other major process transferring heat from the body
in humans and other animals that sweat is vaporization of
water on the skin and mucous membranes of the mouth and
respiratory passages. Vaporization of 1 g of water removes
about 0.6 kcal of heat. A certain amount of water is vaporized
at all times. Th is insensible water loss amounts to 50 mL/h
in humans. When sweat secretion is increased, the degree to
which the sweat vaporizes depends on the humidity of the
environment. It is common knowledge that one feels hotter on
a humid day. Th is is due in part to the decreased vaporization
of sweat, but even under conditions in which vaporization of
sweat is complete, an individual in a humid environment feels
warmer than an individual in a dry environment. Th e reason
for this diff erence is unknown, but it seems related to the fact
that in the humid environment sweat spreads over a greater
area of skin before it evaporates. During muscular exertion
in a hot environment, sweat secretion reaches values as high
as 1600 mL/h, and in a dry atmosphere, most of this sweat is
vaporized. Heat loss by vaporization of water therefore varies
from 30 to over 900 kcal/h.
Some mammals lose heat by panting . Th is rapid, shallow
breathing greatly increases the amount of water vaporization
in the mouth and respiratory passages and therefore the
amount of heat lost. Because the breathing is shallow, it produces
relatively little change in the composition of alveolar air
(see Chapter 34 ).
Th e relative contribution of each of the processes that
transfer heat away from the body ( Table 17–3 ) varies with the
environmental temperature. At 21°C, vaporization is a minor
component in humans at rest. As the environmental temperature
approaches body temperature, radiation losses decline
and vaporization losses increase.
TEMPERATUREREGULATING
MECHANISMS
Th e refl ex and semirefl ex thermoregulatory responses in
humans are listed in Table 17–4 . Th ey include autonomic,
somatic, endocrine, and behavioral changes. One group of
CHAPTER 17 Hypothalamic Regulation of Hormonal Functions 319
responses increases heat loss and decreases heat production;
the other decreases heat loss and increases heat production.
In general, exposure to heat stimulates the former group of
responses and inhibits the latter, whereas exposure to cold
does the opposite.
Curling up “in a ball” is a common reaction to cold in
animals and has a counterpart in the position some people
assume on climbing into a cold bed. Curling up decreases
the body surface exposed to the environment. Shivering is
an involuntary response of the skeletal muscles, but cold also
causes a semiconscious general increase in motor activity.
Examples include foot stamping and dancing up and down on
a cold day. Increased catecholamine secretion is an important
endocrine response to cold. Mice unable to make norepinephrine
and epinephrine because their dopamine β-hydroxylase
gene is knocked out do not tolerate cold; they have defi cient
vasoconstriction and are unable to increase thermogenesis
in brown adipose tissue through UCP 1. TSH secretion is
increased by cold and decreased by heat in laboratory animals,
but the change in TSH secretion produced by cold in adult
humans is small and of questionable signifi cance. It is common
knowledge that activity is decreased in hot weather—the
“it’s too hot to move” reaction.
Th ermoregulatory adjustments involve local responses
as well as more general refl ex responses. When cutaneous
blood vessels are cooled they become more sensitive to catecholamines
and the arterioles and venules constrict. Th is
local eff ect of cold directs blood away from the skin. Another
heat-conserving mechanism that is important in animals
living in cold water is heat transfer from arterial to venous
blood in the limbs. Th e deep veins (venae comitantes) run
alongside the arteries supplying the limbs and heat is transferred
from the warm arterial blood going to the limbs to
the cold venous blood coming from the extremities ( countercurrent
exchange ; see Chapter 37 ). Th is limits the ability
to maintain heat in the tips of the extremities but conserves
body heat.
Th e refl ex responses activated by cold are controlled
from the posterior hypothalamus. Th ose activated by warmth
are controlled primarily from the anterior hypothalamus,
although some thermoregulation against heat still occurs aft er
decerebration at the level of the rostral midbrain. Stimulation
of the anterior hypothalamus causes cutaneous vasodilation
and sweating, and lesions in this region cause hyperthermia,
with rectal temperatures sometimes reaching 43°C (109.4°F).
Posterior hypothalamic stimulation causes shivering, and the
body temperature of animals with posterior hypothalamic
lesions falls toward that of the environment.
AFFERENTS
Th e hypothalamus is said to integrate body temperature
information from sensory receptors (primarily cold receptors)
in the skin, deep tissues, spinal cord, extrahypothalamic
portions of the brain, and the hypothalamus itself. Each of
these fi ve inputs contributes about 20% of the information
that is integrated. Th ere are threshold core temperatures for
each of the main temperature-regulating responses and when
the threshold is reached the response begins. Th e threshold is
37°C for sweating and vasodilation, 36.8°C for vasoconstriction,
36°C for nonshivering thermogenesis, and 35.5°C for
shivering.
FEVER
Fever is perhaps the oldest and most universally known hallmark
of disease. It occurs not only in mammals but also in
birds, reptiles, amphibia, and fi sh. When it occurs in homeothermic
animals, the thermoregulatory mechanisms behave
as if they were adjusted to maintain body temperature at a
higher than normal level, that is, “as if the thermostat had
been reset” to a new point above 37°C. Th e temperature
receptors then signal that the actual temperature is below
the new set point, and the temperature-raising mechanisms
are activated. Th is usually produces chilly sensations due to
cutaneous vasoconstriction and occasionally enough shivering
to produce a shaking chill. However, the nature of the
response depends on the ambient temperature. Th e temperature
rise in experimental animals injected with a pyrogen is
due mostly to increased heat production if they are in a cold
environment and mostly to decreased heat loss if they are in
a warm environment.
Th e pathogenesis of fever is summarized in Figure 17–15 .
Toxins from bacteria, such as endotoxin, act on monocytes,
macrophages, and Kupff er cells to produce cytokines that act
as endogenous pyrogens (EPs) . Th ere is good evidence that
TABLE 174 Temperature-regulating mechanisms.
Mechanisms activated by cold
Shivering
Hunger
Increased voluntary activity
Increased secretion of norepinephrine and epinephrine
Decreased heat loss
Cutaneous vasoconstriction
Curling up
Horripilation
Mechanisms activated by heat
Increased heat loss
Cutaneous vasodilation
Sweating
Increased respiration
Decreased heat production
Anorexia
Apathy and inertia
320 SECTION III Endocrine and Reproductive Physiology
IL-1β, IL-6, IFN-β, IFN-γ, and TNF-α (see Chapter 3 ) can
act independently to produce fever. Th ese circulating cytokines
are polypeptides and it is unlikely that they penetrate the
brain. Instead, evidence suggests that they act on the OVLT,
one of the circumventricular organs (see Chapter 33 ). Th is in
turn activates the preoptic area of the hypothalamus. Cytokines
are also produced by cells in the central nervous system
(CNS) when these are stimulated by infection, and these may
act directly on the thermoregulatory centers.
Th e fever produced by cytokines is probably due to local
release of prostaglandins in the hypothalamus. Intrahypothalamic
injection of prostaglandins produces fever. In addition, the
antipyretic eff ect of aspirin is exerted directly on the hypothalamus,
and aspirin inhibits prostaglandin synthesis. PGE 2 is one of
the prostaglandins that causes fever. It acts on four sub-types of
prostaglandin receptors—EP 1 , EP 2 , EP 3 , and EP 4 —and knockout
of the EP 3 receptor impairs the febrile response to PGE 2 , IL-1β,
and endotoxin, or bacterial lipopolysaccharide (LPS).
Th e benefi t of fever to the organism is uncertain. A benefi -
cial eff ect is assumed because fever has evolved and persisted as
a response to infections and other diseases. Many microorganisms
grow best within a relatively narrow temperature range and
a rise in temperature inhibits their growth. In addition, antibody
production is increased when body temperature is elevated.
Before the advent of antibiotics, fevers were artifi cially induced
for the treatment of neurosyphilis and proved to be benefi cial.
Hyperthermia also benefi ts individuals infected with anthrax,
pneumococcal pneumonia, leprosy, and various fungal, rickettsial,
and viral diseases. Hyperthermia also slows the growth
of some tumors. However, very high temperatures are harmful.
A rectal temperature over 41°C (106°F) for prolonged periods
results in some permanent brain damage. When the temperature
is over 43°C, heat stroke develops and death is common.
Endotoxin
Inflammation
Other pyrogenic stimuli
Monocytes
Macrophages
Kupffer cells
Cytokines
Preoptic area
of hypothalamus
Prostaglandins
Raise temperature
set point
Fever
FIGURE 1715 Pathogenesis of fever.
In malignant hyperthermia, various mutations of the
gene coding for the ryanodine receptor (see Chapter 5 ) lead
to excess Ca 2+ release during muscle contraction triggered
by stress. Th is in turn leads to contractures of the muscles,
increased muscle metabolism, and a great increase in heat
production in muscle. Th e increased heat production causes a
marked rise in body temperature that is fatal if not treated.
Periodic fevers also occur in humans with mutations in
the gene for pyrin, a protein found in neutrophils; the gene for
mevalonate kinase, an enzyme involved in cholesterol synthesis;
and the gene for the type 1 TNF receptor, which is involved
in infl ammatory responses. However, how any of these three
mutant gene products cause fever is unknown.
HYPOTHERMIA
In hibernating mammals, body temperature drops to low
levels without causing any demonstrable ill eff ects on subsequent
arousal. Th is observation led to experiments on induced
hypothermia. When the skin or the blood is cooled enough to
lower the body temperature in nonhibernating animals or in
humans, metabolic and physiologic processes slow down. Respiration
and heart rate are very slow, blood pressure is low, and
consciousness is lost. At rectal temperatures of about 28°C, the
ability to spontaneously return the temperature to normal is
lost, but the individual continues to survive and, if rewarmed
with external heat, returns to a normal state. If care is taken to
prevent the formation of ice crystals in the tissues, the body
temperature of experimental animals can be lowered to subfreezing
levels without producing any detectable damage aft er
subsequent rewarming.
Humans tolerate body temperatures of 21–24°C (70–
75°F) without permanent ill eff ects, and induced hypothermia
has been used in surgery. On the other hand, accidental hypothermia
due to prolonged exposure to cold air or cold water
is a serious condition and requires careful monitoring and
prompt rewarming.
CHAPTER SUMMARY
Neural connections ■ run between the hypothalamus and the
posterior lobe of the pituitary gland, and vascular connections
between the hypothalamus and the anterior lobe of the
pituitary.
■ In most mammals, the hormones secreted by the posterior
pituitary gland are vasopressin and oxytocin. Vasopressin
increases the permeability of the collecting ducts of the kidney
to water, thus concentrating the urine. Oxytocin acts on the
breasts (lactation) and the uterus (contraction).
■ Th e anterior pituitary secretes six hormones:
adrenocorticotropic hormone (corticotropin, ACTH), thyroidstimulating
hormone (thyrotropin, TSH), growth hormone,
follicle-stimulating hormone (FSH), luteinizing hormone (LH),
and prolactin (PRL).
■ Other complex autonomic mechanisms that maintain
the chemical constancy and temperature of the internal
environment are integrated in the hypothalamus.
CHAPTER 17 Hypothalamic Regulation of Hormonal Functions 321
MULTIPLECHOICE QUESTIONS
For all questions, select the single best answer unless otherwise
directed.
1. Th irst is stimulated by
increases in p A. lasma osmolality and volume.
B. an increase in plasma osmolality and a decrease in plasma
volume.
C. a decrease in plasma osmolality and an increase in plasma
volume.
D. decreases in plasma osmolality and volume.
E. injection of vasopressin into the hypothalamus.
2. When an individual is naked in a room in which the air
temperature is 21°C (69.8°F) and the humidity 80%, the greatest
amount of heat is lost from the body by
A. elevated metabolism.
B. respiration.
C. urination.
D. vaporization of sweat.
E. radiation and conduction.
In questions 3–8, select A if the item is associated with (a) below,
B if the item is associated with (b) below, C if the item is associated
with both (a) and (b), and D if the item is associated with neither (a)
nor (b).
(a) V 1A vasopressin receptors
(b) V 2 vasopressin receptors
3. Activation of G s
4. Vasoconstriction
5. Increase in intracellular inositol triphosphate
6. Movement of aquaporin
7. Proteinuria
8. Milk ejection
CHAPTER RESOURCES
Brunton PJ, Russell JA, Douglas AJ: Adaptive responses
of the maternal hypothalamic-pituitary-adrenal axis
during pregnancy and lactation. J Neuroendocrinol 2008;
20:764.
Lamberts SWJ, Hofl and LJ, Nobels FRE: Neuroendocrine tumor
markers. Front Neuroendocrinol 2001;22:309.
Loh JA, Verbalis JG: Disorders of water and salt metabolism
associated with pituitary disease. Endocrinol Metab Clin
2008;37:213.
McKinley MS, Johnson AK: Th e physiologic regulation of thirst and
fl uid intake. News Physiol Sci 2004;19:1.
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323
O B J E C T I V E S
After studying this chapter,
you should be able to :
■ Describe the structure of the pituitary gland and how it relates to its function.
■ D efi ne the cell types present in the anterior pituitary and understand how their
numbers are controlled in response to physiologic demands.
■ Understand the function of hormones derived from proopiomelanocortin in
humans, and how they are involved in regulating pigmentation in humans,
other mammals, and lower vertebrates.
■ D efi ne the eff ects of the growth hormone in growth and metabolic function,
and how insulin-like growth factor I (IGF-I) may mediate some of its actions in
the periphery.
■ List the stimuli that regulate growth hormone secretion and defi ne their
underlying mechanisms.
■ Understand the relevance of pituitary secretion of gonadotropins and
prolactin, and how these are regulated.
■ Understand the basis of conditions where pituitary function and growth
hormone secretion and function are abnormal, and how they can be treated.
C H A P T E R
The Pituitary Gland 18
INTRODUCTION
Th e pituitary gland, or hypophysis, lies in a pocket of the
sphenoid bone at the base of the brain. It is a coordinating
center for control of many downstream endocrine glands,
some of which are discussed in subsequent chapters. In
many ways, it can be considered to consist of at least two
(and in some species, three) separate endocrine organs
that contain a plethora of hormonally active substances.
Th e anterior pituitary secretes thyroid-stimulating
hormone (TSH, thyrotropin), adrenocorticotropic
hormone (ACTH), luteinizing hormone (LH), folliclestimulating
hormone (FSH), prolactin , and growth
hormone (see Figure 17–9 ), and receives almost all of
its blood supply from the portal hypophysial vessels that
pass initially through the median eminence, a structure
immediately below the hypothalamus. Th is vascular
arrangement positions the cells of the anterior pituitary to
respond effi ciently to regulatory factors released from the
hypothalamus. Of the listed hormones, prolactin acts on
the breast. Th e remaining fi ve are, at least in part, tropic
hormones ; that is, they stimulate secretion of hormonally
active substances by other endocrine glands or, in the case of
growth hormone, the liver and other tissues (see below). Th e
tropic hormones for some endocrine glands are discussed in
the chapter on that gland: TSH in Chapter 19 ; and ACTH in
Chapter 20 . However, the gonadotropins FSH and LH, along
with prolactin, are covered here.
Th e posterior pituitary in mammals consists
predominantly of nerves that have their cell bodies in the
hypothalamus, and stores oxytocin and vasopressin in the
termini of these neurons, to be released into the bloodstream.
Th e secretion of these hormones, as well as a discussion of
the overall role of the hypothalamus and median eminence
in regulating both the anterior and posterior pituitary,
was covered in Chapter 17 . In some species, there is also a
well-developed intermediate lobe of the pituitary, whereas
in humans it is rudimentary. Nevertheless, the intermediate
Ganong_Ch18_323-338.indd 323 1/4/12 1:03:56 PM
324 SECTION III Endocrine and Reproductive Physiology
MORPHOLOGY
GROSS ANATOMY
Th e anatomy of the pituitary gland is summarized in
Figure 18–1 and discussed in detail in Chapter 17 . Th e posterior
pituitary is made up largely of the endings of axons
from the supraoptic and paraventricular nuclei of the hypothalamus
and arises initially as an extension of this structure.
Th e anterior pituitary, on the other hand, contains endocrine
cells that store its characteristic hormones and arises embryologically
as an invagination of the pharynx ( Rathke’s pouch ).
In species where it is well developed, the intermediate lobe is
formed in the embryo from the dorsal half of Rathke’s pouch,
but is closely adherent to the posterior lobe in the adult. It is
separated from the anterior lobe by the remains of the cavity
in Rathke’s pouch, the residual cleft .
HISTOLOGY
In the posterior lobe, the endings of the supraoptic and paraventricular
axons can be observed in close relation to blood
vessels. Pituicytes , stellate cells that are modifi ed astrocytes,
are also present.
As noted above, the intermediate lobe is rudimentary in
humans and a few other mammalian species. In these species,
most of its cells are incorporated in the anterior lobe. Along
the residual cleft are small thyroid-like follicles, some containing
a little colloid (see Chapter 19 ). Th e function of the colloid,
if any, is unknown.
Th e anterior pituitary is made up of interlacing cell
cords and an extensive network of sinusoidal capillaries. Th e
endothelium of the capillaries is fenestrated, like that in other
endocrine organs. Th e cells contain granules of stored hormone
that are extruded from the cells by exocytosis. Th eir
constituents then enter the capillaries to be conveyed to target
tissues.
CELL TYPES IN THE
ANTERIOR PITUITARY
Five types of secretory cells have been identifi ed in the anterior
pituitary by immunocytochemistry and electron microscopy.
Th e cell types are the somatotropes, which secrete growth
hormone; the lactotropes (also called mammotropes), which
secrete prolactin; the corticotropes, which secrete ACTH; the
thyrotropes, which secrete TSH; and the gonadotropes, which
secrete FSH and LH. Th e characteristics of these cells are summarized
in Table 18–1 . Some cells may contain two or more
hormones. It is also notable that the three pituitary glycoprotein
hormones, FSH, LH, and TSH, while being made up of
two subunits, all share a common α subunit that is the product
of a single gene and has the same amino acid composition in
each hormone, although their carbohydrate residues vary. Th e
α subunit must be combined with a β subunit characteristic of
each hormone for maximal physiologic activity. Th e β subunits,
which are produced by separate genes and diff er in structure,
confer hormonal specifi city (see Chapter 16 ). Th e α subunits
are remarkably interchangeable and hybrid molecules can be
created. In addition, the placental glycoprotein gonadotropin
human chorionic gonadotropin (hCG) has α and β subunits
(see Chapter 22 ).
Th e anterior pituitary also contains folliculostellate
cells that send processes between the granulated secretory
Pars
tuberalis
Anterior
lobe
Posterior
lobe
Rathke’s pouch Intermediate lobe
Third ventricle Third ventricle
FIGURE 181 Diagrammatic outline of the formation of the
pituitary (left) and the various parts of the organ in the adult
(right).
TABLE 181 Hormone-secreting cells of the
human anterior pituitary gland.
Cell Type
Hormones
Secreted
Percentage of Total
Secretory Cells
Somatotrope Growth hormone 50
Lactotrope Prolactin 10–30
Corticotrope ACTH 10
Thyrotrope TSH 5
Gonadotrope FSH, LH 20
lobe, as well as the anterior pituitary, contains hormonally
active derivatives of the proopiomelanocortin (POMC)
molecule that regulate skin pigmentation, among other
functions (see below). To avoid redundancy, this chapter
will focus predominantly on growth hormone and its role in
growth and facilitating the activity of other hormones, along
with a number of general considerations about the pituitary.
Th e melanocyte-stimulating hormones (MSHs) of the
intermediate lobe of the pituitary, α-MSH and β-MSH, will
also be touched upon.
CHAPTER 18 The Pituitary Gland 325
cells. Th ese cells produce paracrine factors that regulate the
growth and function of the secretory cells discussed above.
Indeed, the anterior pituitary can adjust the relative proportion
of secretory cell types to meet varying requirements for
diff erent hormones at diff erent life stages. Th is plasticity has
recently been ascribed to the presence of a small number of
pluripotent stem cells that persist in the adult gland.
PROOPIOMELANOCORTIN
& DERIVATIVES
BIOSYNTHESIS
Intermediate-lobe cells, if present, and corticotropes of the
anterior lobe both synthesize a large precursor protein that is
cleaved to form a family of hormones. Aft er removal of the
signal peptide, this prohormone is known as proopiomelanocortin
(POMC) . Th is molecule is also synthesized in the
hypothalamus, the lungs, the gastrointestinal tract, and the
placenta. Th e structure of POMC, as well as its derivatives,
is shown in Figure 18–2 . In corticotropes, it is hydrolyzed
to ACTH and β-lipotropin (LPH), plus a small amount of
β-endorphin, and these substances are secreted. In the intermediate
lobe cells, POMC is hydrolyzed to corticotropin-like
intermediate-lobe peptide (CLIP), γ-LPH, and appreciable
quantities of β-endorphin. Th e functions, if any, of CLIP and
γ-LPH are unknown, whereas β-endorphin is an opioid peptide
(see Chapter 7 ) that has the fi ve amino acid residues of
met-enkephalin at its amino terminal end. Th e melanotropins
α- and β-MSH are also formed. However, the intermediate lobe
in humans is rudimentary, and it appears that neither α-MSH
nor β-MSH is secreted in adults. In some species, however, the
melanotropins have important physiological functions, as discussed
below.
CONTROL OF SKIN COLORATION
& PIGMENT ABNORMALITIES
Fish, reptiles, and amphibia change the color of their skin for
thermoregulation, camoufl age, and behavioral displays. Th ey
do this in part by moving black or brown granules into or out
of the periphery of pigment cells called melanophores. Th e
granules are made up of melanins, which are synthesized
from dopamine (see Chapter 7 ) and dopaquinone. Th e movement
of these granules is controlled by a variety of hormones
and neurotransmitters, including α- and β-MSH, melaninconcentrating
hormone, melatonin, and catecholamines.
Mammals have no melanophores containing pigment granules
that disperse and aggregate, but they do have melanocytes,
which have multiple processes containing melanin granules.
Melanocytes express melanotropin-1 receptors. Treatment with
MSHs accelerates melanin synthesis, causing readily detectable
darkening of the skin in humans in 24 h. As noted above, α- and
β-MSH do not circulate in adult humans, and their function
is unknown. However, ACTH binds to melanotropin-1 receptors.
Indeed, the pigmentary changes in several human endocrine
diseases are due to changes in circulating ACTH. For
example, abnormal pallor is a hallmark of hypopituitarism.
Hyperpigmentation occurs in patients with adrenal insuffi
ciency due to primary adrenal disease. Indeed, the presence
of hyperpigmentation in association with adrenal insuffi ciency
rules out the possibility that the insuffi ciency is secondary to
pituitary or hypothalamic disease because in these conditions,
plasma ACTH is not increased (see Chapter 20 ). Other disorders
of pigmentation result from peripheral mechanisms.
Th us, albinos have a congenital inability to synthesize melanin.
Th is can result from a variety of diff erent genetic defects in the
pathways for melanin synthesis. Piebaldism is characterized
by patches of skin that lack melanin as a result of congenital
defects in the migration of pigment cell precursors from the
Signal
peptide
(–131)
γ−MSH
(–55 to –44)
β-LPH (42–134)
β-LPH
ACTH (1–39)
AL and IL
γ−MSH α-MSH
(1–13)
β-MSH
(84–101)
Met-enkephalin
(104–108)
γ-LPH
(42–101)
β-Endorphin
(104–134)
CLIP
(18–39)
Arg-Lys
Arg-Arg
Lys-Arg
Lys-Arg
Lys-Arg
Lys-Arg
Lys-Lys
Lys-Lys
Lys-Lys
Arg-Arg
Fast in IL
Slow in AL
ACTH
AL and IL IL only
Amino terminal fragment
FIGURE 182 Schematic representation of
the preproopiomelanocortin molecule formed
in pituitary cells, neurons, and other tissues . The
numbers in parentheses identify the amino acid
sequences in each of the polypeptide fragments.
For convenience, the amino acid sequences are
numbered from the amino terminal of ACTH and
read toward the carboxyl terminal portion of the
parent molecule, whereas the amino acid sequences
in the other portion of the molecule read to the left
to – 131, the amino terminal of the parent molecule.
The locations of Lys–Arg and other pairs of basic
amino acids residues are also indicated; these are
the sites of proteolytic cleavage in the formation of
the smaller fragments of the parent molecule. AL,
anterior lobe; IL, intermediate lobe.
326 SECTION III Endocrine and Reproductive Physiology
neural crest during embryonic development. Not only the condition
but also the precise pattern of the loss is passed from one
generation to the next. Vitiligo involves a similar patchy loss of
melanin, but the loss develops progressively aft er birth secondary
to an autoimmune process that targets melanocytes.
GROWTH HORMONE
BIOSYNTHESIS & CHEMISTRY
Th e long arm of human chromosome 17 contains the growth
hormone-hCS cluster that contains fi ve genes: one, hGH-N ,
codes for the most abundant (“normal”) form of growth hormone;
a second, hGH-V , codes for the variant form of growth
hormone (see below); two code for human chorionic somatomammotropin
(hCS) (see Chapter 22 ); and the fi ft h is probably
an hCS pseudogene.
Growth hormone that is secreted into the circulation by
the pituitary gland consists of a complex mixture of hGH-N,
peptides derived from this molecule with varying degrees of
posttranslational modifi cations, such as glycosylation, and a
splice variant of hGH-N that lacks amino acids 32–46. Th e
physiologic signifi cance of this complex array of hormones has
yet to be fully understood, particularly since their structural
similarities make it diffi cult to assay for each species separately.
Nevertheless, there is emerging evidence that, while the various
peptides share a broad range of functions, they may occasionally
exert actions in opposition to one another. hGH-V and
hCS, on the other hand, are primarily products of the placenta,
and as a consequence are only found in appreciable quantities
in the circulation during pregnancy (see Chapter 22 ).
SPECIES SPECIFICITY
Th e structure of growth hormone varies considerably from
one species to another. Porcine and simian growth hormones
have only a transient eff ect in the guinea pig. In monkeys
and humans, bovine and porcine growth hormones do not
even have a transient eff ect on growth, although monkey and
human growth hormones are fully active in both monkeys and
humans. Th ese facts are relevant to public health discussions
surrounding the presence of bovine growth hormones (used
to increase milk production) in dairy products, as well as the
popularity of growth hormone supplements, marketed via the
Internet, with body builders. Controversially, recombinant
human growth hormone has also been given to children who
are short in stature, but otherwise healthy (ie, without growth
hormone defi ciency), with apparently limited results.
PLASMA LEVELS, BINDING,
& METABOLISM
A portion of circulating growth hormone is bound to a
plasma protein that is a large fragment of the extracellular
domain of the growth hormone receptor (see below). It
appears to be produced by cleavage of receptors in humans,
and its concentration is an index of the number of growth
hormone receptors in the tissues. Approximately 50% of
the circulating pool of growth hormone activity is in the
bound form, providing a reservoir of the hormone to compensate
for the wide fl uctuations that occur in secretion (see
below).
Th e basal plasma growth hormone level measured by
radioimmunoassay in adult humans is normally less than
3 ng/mL. Th is represents both the protein-bound and free
forms. Growth hormone is metabolized rapidly, at least in
part in the liver. Th e half-life of circulating growth hormone
in humans is 6–20 min, and the daily growth hormone output
has been calculated to be 0.2–1.0 mg/d in adults.
GROWTH HORMONE RECEPTORS
Th e growth hormone receptor is a 620-amino-acid protein
with a large extracellular portion, a transmembrane domain,
and a large cytoplasmic portion. It is a member of the cytokine
receptor superfamily, which is discussed in Chapter 3 . Growth
hormone has two domains that can bind to its receptor, and
when it binds to one receptor, the second binding site attracts
another, producing a homodimer ( Figure 18–3 ). Dimerization
is essential for receptor activation.
Growth hormone has widespread eff ects in the body (see
below), so even though it is not yet possible precisely to correlate
intracellular and whole body eff ects, it is not surprising
that, like insulin, growth hormone activates many diff erent
intracellular signaling cascades ( Figure 18–3 ). Of particular
note is its activation of the JAK2–STAT pathway. JAK2 is a
member of the Janus family of cytoplasmic tyrosine kinases.
STATs (for signal transducers and activators of transcription)
are a family of cytoplasmic transcription factors that, upon
phosphorylation by JAK kinases, migrate to the nucleus where
they activate various genes. JAK–STAT pathways are known
also to mediate the eff ects of prolactin and various other
growth factors.
EFFECTS ON GROWTH
In young animals in which the epiphyses have not yet fused
to the long bones (see Chapter 21 ), growth is inhibited by
hypophysectomy and stimulated by growth hormone. Chondrogenesis
is accelerated, and as the cartilaginous epiphysial
plates widen, they lay down more bone matrix at the ends of
long bones. In this way, stature is increased. Prolonged treatment
of animals with growth hormone leads to gigantism.
When the epiphyses are closed, linear growth is no
longer possible. In this case, an overabundance of growth
hormone produces the pattern of bone and soft tissue deformities
known in humans as acromegaly . Th e sizes of most
of the viscera are increased. Th e protein content of the body
is increased, and the fat content is decreased (see Clinical
Box 18–1 ).
CHAPTER 18 The Pituitary Gland 327
EFFECTS ON PROTEIN &
ELECTROLYTE HOMEOSTASIS
Growth hormone is a protein anabolic hormone and produces
a positive nitrogen and phosphorus balance, a rise in plasma
phosphorus, and a fall in blood urea nitrogen and amino acid
levels. In adults with growth hormone defi ciency, recombinant
human growth hormone produces an increase in lean body
mass and a decrease in body fat, along with an increase in
metabolic rate and a fall in plasma cholesterol. Gastrointestinal
absorption of Ca 2+ is increased. Na + and K + excretion is
reduced by an action independent of the adrenal glands, probably
because these electrolytes are diverted from the kidneys to
the growing tissues. On the other hand, excretion of the amino
acid 4-hydroxyproline is increased during this growth, refl ective
of the ability of growth hormone to stimulate the synthesis
of soluble collagen.
EFFECTS ON CARBOHYDRATE
& FAT METABOLISM
Th e actions of growth hormone on carbohydrate metabolism
are discussed in Chapter 24 . At least some forms of growth
hormone are diabetogenic because they increase hepatic glucose
output and exert an anti-insulin eff ect in muscle. Growth
hormone is also ketogenic and increases circulating free fatty
acid (FFA) levels. Th e increase in plasma FFA, which takes
several hours to develop, provides a ready source of energy for
the tissues during hypoglycemia, fasting, and stressful stimuli.
Growth hormone does not stimulate β cells of the pancreas
directly, but it increases the ability of the pancreas to respond
to insulinogenic stimuli such as arginine and glucose. Th is is
an additional way growth hormone promotes growth, since
insulin has a protein anabolic eff ect (see Chapter 24 ).
SOMATOMEDINS
Th e eff ects of growth hormone on growth, cartilage, and protein
metabolism depend on an interaction between growth
hormone and somatomedins , which are polypeptide growth
factors secreted by the liver and other tissues. Th e fi rst of these
factors isolated was called sulfation factor because it stimulated
the incorporation of sulfate into cartilage. However, it
also stimulated collagen formation, and its name was changed
to somatomedin. It then became clear that there are a variety
of diff erent somatomedins and that they are members of an
increasingly large family of growth factors that aff ect many
diff erent tissues and organs.
Th e principal (and in humans probably the only) circulating
somatomedins are insulin-like growth factor I
(IGF-I, somatomedin C) and IGF-II . Th ese factors are
closely related to insulin, except that their C chains are not
P P
P
P
P
P
P
P
GH
GHR
JAK2
IRS
P
P
SHC
DAG
PKC
P
MAP K
Grb2
STATs
STAT5
STAT1
STAT3
SRF
SRF
TCF
PLC
p90RSK PLA2
GLE-2 P450-3A10
GLE-1 Spi 2.1
SIE SRE c-fos
STAT5
Ca2+
FIGURE 183 Some of the principal signaling pathways
activated by the dimerized growth hormone receptor (GHR) .
Solid arrows indicate established pathways; dashed arrows indicate
probable pathways. The details of the PLC pathway and the pathway
from Grb2 to MAP K are discussed in Chapter 2 . The small uppercase
letter P’s in yellow hexagons represent phosphorylation of the
factor indicated. GLE-1 and GLE-2, interferon γ-activated response
elements; IRS, insulin receptor substrate; p90 RSK , an S6 kinase; PLA 2 ,
phospholipase A 2 ; SIE, Sis-induced element; SRE, serum response
element; SRF, serum response factor; TCF, ternary complex factor.
328 SECTION III Endocrine and Reproductive Physiology
separated ( Figure 18–4 ) and they have an extension of the
A chain called the D domain. Th e hormone relaxin (see
Chapter 22 ) is also a member of this family. Humans have
two related relaxin isoforms, and both resemble IGF-II. In
humans a variant form of IGF-I lacking three amino terminal
amino acid residues has been found in the brain, and there
are several variant forms of human IGF-II ( Figure 18–4 ).
Th e mRNAs for IGF-I and IGF-II are found in the liver, in
GPETLCGAELVDALQFVCGDRGFYFNKPTGYGSSSRRAPQTGIVDECCFRSCDLRRLEMYCAPLKPAKSA
AYRPSETLCGGELVDTLQFVCGDRGFYFSRPA--SRVSRRSR--GIVEECCFRSCDLALLETYCAT--PAKSE
FVNQHLCGSHLVEALYLVCGERGFFYTPKT GIVEQCCTSICSLYQLENYCN
hlGF-I
hlGF-II
h ins
I II II II I
B C A D
C
C
C
G
C
D
C
E
E
E
L
L
P
P P
P
L
A
A
A
A
A
K
S
E
21 1
T T
V
I
T
Y
Y
C
Q
C
G
G
G
G
G
G
E
E
S
S S
S
R
R R
R
R
R
R
R
S
Y
L
L
V L
V
V
D
D
D
T
L
F
F
F
F
R
S
FIGURE 184 Structure of human IGF-I, IGF-II, and insulin (ins) (top) . The lower panel shows the structure of human IGF-II with its
disulfi de bonds, as well as three variant structures shown: a 21-aa extension of the C-terminus, a tetrapeptide substitution at Ser-29, and a
tripeptide substitution of Ser-33.
CLINICAL BOX 18–1
Gigantism & Acromegaly
Tumors of the somatotropes of the anterior pituitary (pituitary
adenoma) secrete large amounts of growth hormone, leading
to gigantism in children and to acromegaly in adults. If the
tumor arises before puberty, the individual may grow to an extraordinary
height. After linear growth is no longer possible, on
the other hand, the characteristic features of acromegaly arise,
including greatly enlarged hands and feet, vertebral changes
attributable to osteoarthritis, soft tissue swelling, hirsutism,
and protrusion of the brow and jaw. Abnormal growth of internal
organs may eventually impair their function such that the
condition, which has an insidious onset, can prove fatal if left
untreated. Hypersecretion of growth hormone is accompanied
by hypersecretion of prolactin in 20–40% of patients with acromegaly.
About 25% of patients have abnormal glucose tolerance
tests, and 4% develop lactation in the absence of pregnancy.
Acromegaly can be caused by extra-pituitary as well as
intrapituitary growth hormone-secreting tumors and by hypothalamic
tumors that secrete GHRH, but the latter are rare.
THERAPEUTIC HIGHLIGHTS
The mainstay of therapy for acromegaly remains the use of
somatostatin analogues that inhibit the secretion of growth
hormone. A growth hormone receptor antagonist has
recently become available and has been found to reduce
plasma IGF-I and produce clinical improvement in cases of
acromegaly that fail to respond to other treatments. Surgical
removal of the pituitary tumor is also helpful in both
acromegaly and gigantism, but sometimes challenging to
perform due to the tumor’s often invasive nature. In any
case, adjuvant pharmacological therapy must often be
continued after surgery to control ongoing symptoms.
CHAPTER 18 The Pituitary Gland 329
cartilage, and in many other tissues, indicating that they are
likely synthesized in these tissues.
Th e properties of IGF-I, IGF-II, and insulin are compared
in Table 18–2 . Both IGF-I and IGF-II are tightly bound to proteins
in the plasma, and, at least for IGF-I, this prolongs their
half-life in the circulation. Six diff erent IGF-binding proteins,
with diff erent patterns of distribution in various tissues, have
been identifi ed. All are present in plasma, with IGF-binding
protein-3 (IGFBP-3) accounting for 95% of the binding in
the circulation. Th e contribution of the IGFs to the insulinlike
activity in blood is discussed in Chapter 24 . Th e IGF-I
receptor is very similar to the insulin receptor and probably
uses similar or identical intracellular signaling pathways. Th e
IGF-II receptor has a distinct structure (see Figure 24–5 ) and
TABLE 182 Comparison of insulin and the
insulin-like growth factors.
Insulin IGF-I IGF-II
Other
names
… Somatomedin C Multiplicationstimulating
activity (MSA)
Number
of amino
acids
51 70 67
Source Pancreatic B
cells
Liver and other
tissues
Diverse tissues
Level
regulated
by
Glucose Growth
hormone after
birth, nutritional
status
Unknown
Plasma
levels
0.3–2 ng/mL 10–700 ng/
mL; peaks at
puberty
300–800 ng/mL
Plasmabinding
proteins
No Yes Yes
Major
physiologic
role
Control of
metabolism
Skeletal and
cartilage growth
Growth
during fetal
development
is involved in the intracellular targeting of acid hydrolases and
other proteins to intracellular organelles. Secretion of IGF-I
is independent of growth hormone before birth but is stimulated
by growth hormone aft er birth, and it has pronounced
growth-stimulating activity. Its concentration in plasma rises
during childhood and peaks at the time of puberty, then
declines to low levels in old age. IGF-II is largely independent
of growth hormone and plays a role in the growth of the fetus
before birth. In human fetuses in which it is overexpressed,
several organs, especially the tongue, other muscles, kidneys,
heart, and liver, develop out of proportion to the rest of the
body. In adults, the gene for IGF-II is expressed only in the
choroid plexus and meninges.
DIRECT & INDIRECT ACTIONS
OF GROWTH HORMONE
Our understanding of the mechanism of action of growth hormone
has evolved. It was originally thought to produce growth
by a direct action on tissues, and then later was believed to act
solely through its ability to induce somatomedins. However, if
growth hormone is injected into one proximal tibial epiphysis,
a unilateral increase in cartilage width is produced, and cartilage,
like other tissues, makes IGF-I. A current hypothesis to
explain these results holds that growth hormone acts on cartilage
to convert stem cells into cells that respond to IGF-I.
Locally produced as well as circulating IGF-I then makes the
cartilage grow. However, the independent role of circulating
IGF-I remains important, since infusion of IGF-I in hypophysectomized
rats restores bone and body growth. Overall, it
seems that growth hormone and somatomedins can act both
in cooperation and independently to stimulate pathways that
lead to growth. Th e situation is almost certainly complicated
further by the existence of multiple forms of growth hormone
in the circulation that can, in some situations, have opposing
actions.
Figure 18–5 is a summary of current views of the other
actions of growth hormone and IGF-I. However, growth hormone
probably combines with circulating and locally produced
IGF-I in various proportions to produce at least some
of the latter eff ects.
GH
Na+
retention
Decreased
insulin
sensitivity
Lipolysis Protein
synthesis
Epiphysial
growth
IGF-I
Insulin-like
activity
Antilipolytic
activity
Protein
synthesis
Epiphysial
growth
FIGURE 185 Direct and indirect actions of growth
hormone (GH). The latter are mediated by the ability of
growth hormone to induce production of IGF-I. (Courtesy
of R Clark and N Gesundheit.)
330 SECTION III Endocrine and Reproductive Physiology
HYPOTHALAMIC & PERIPHERAL
CONTROL OF GROWTH
HORMONE SECRETION
Th e secretion of growth hormone is not stable over time.
Adolescents have the highest circulating levels of growth hormone,
followed by children and fi nally adults. Levels decline
in old age, and there has been considerable interest in injecting
growth hormone to counterbalance the eff ects of aging.
Th e hormone increases lean body mass and decreases body
fat, but it does not produce statistically signifi cant increases
in muscle strength or mental status. Th ere are also diurnal
variations in growth hormone secretion superimposed on
these developmental stages. Growth hormone is found at
relatively low levels during the day, unless specifi c triggers
for its release are present (see below). During sleep, on the
other hand, large pulsatile bursts of growth hormone secretion
occur. Th erefore, it is not surprising that the secretion of
growth hormone is under hypothalamic control. Th e hypothalamus
controls growth hormone production by secreting
growth hormone-releasing hormone (GHRH) as well
as somatostatin, which inhibits growth hormone release
(see Chapter 17 ). Th us, the balance between the eff ects of
these hypothalamic factors on the pituitary will determine
the level of growth hormone release. Th e stimuli of growth
hormone secretion can therefore act by increasing hypothalamic
secretion of GHRH, decreasing secretion of somatostatin,
or both. A third regulator of growth hormone secretion
is ghrelin . Th e main site of ghrelin synthesis and secretion is
the stomach, but it is also produced in the hypothalamus and
has marked growth hormone-stimulating activity. In addition,
it appears to be involved in the regulation of food intake
(see Chapter 26 ).
Growth hormone secretion is under feedback control
(see Chapter 16 ), like the secretion of other anterior pituitary
hormones. It acts on the hypothalamus to antagonize GHRH
release. Growth hormone also increases circulating IGF-I,
and IGF-I in turn exerts a direct inhibitory action on growth
hormone secretion from the pituitary. It also stimulates somatostatin
secretion ( Figure 18–6 ).
Stimuli Aff ecting Growth
Hormone Secretion
Th e basal plasma growth hormone concentration ranges
from 0 to 3 ng/mL in normal adults. However, secretory
rates cannot be estimated from single values because of their
irregular nature. Th us, average values over 24 h (see below)
and peak values may be more meaningful, albeit diffi cult to
assess in the clinical setting. Th e stimuli that increase growth
hormone secretion are summarized in Table 18–3 . Most of
them fall into three general categories: (1) conditions such
as hypoglycemia and/or fasting in which there is an actual
or threatened decrease in the substrate for energy production
in cells, (2) conditions in which the amounts of certain
SS
Anterior
pituitary
Liver
(and other
organs)
GH
Tissues
IGF-I
GHRH Hypothalamus
Ghrelin
FIGURE 186 Feedback control of growth hormone
secretion . Solid arrows represent positive eff ects and dashed arrows
represent inhibition. GH, growth hormone; GHRH, growth hormone
releasing hormone; IGF-I, insulin-like growth factor-I; SS, somatostatin.
TABLE 183 Stimuli that affect growth hormone
secretion in humans.
Stimuli that increase secretion
Hypoglycemia
2-Deoxyglucose
Exercise
Fasting
Increase in circulating levels of certain amino acids
Protein meal
Infusion of arginine and some other amino acids
Glucagon
Stressful stimuli
Pyrogen
Lysine vasopressin
Various psychologic stresses
Going to sleep
L -Dopa and α-adrenergic agonists that penetrate the brain
Apomorphine and other dopamine receptor agonists
Estrogens and androgens
Stimuli that decrease secretion
REM sleep
Glucose
Cortisol
FFA
Medroxyprogesterone
Growth hormone and IGF-I
amino acids are increased in the plasma, and (3) stressful
stimuli. Th e response to glucagon has been used as a test
of growth hormone reserve. Growth hormone secretion is
also increased in subjects deprived of rapid eye movement
CHAPTER 18 The Pituitary Gland 331
(REM) sleep (see Chapter 14 ) and inhibited during normal
REM sleep.
Glucose infusions lower plasma growth hormone levels
and inhibit the response to exercise. Th e increase produced
by 2-deoxyglucose is presumably due to intracellular glucose
defi ciency, since this compound blocks the catabolism of glucose
6-phosphate. Sex hormones induce growth hormone
secretion, increase growth hormone responses to provocative
stimuli such as arginine and insulin, and also serve as permissive
factors for the action of growth hormone in the periphery.
Th is likely contributes to the relatively high levels of circulating
growth hormone and associated growth spurt in puberty.
Growth hormone secretion is also induced by thyroid hormones.
Growth hormone secretion is inhibited, on the other
hand, by cortisol, FFA, and medroxyprogesterone.
Growth hormone secretion is increased by l -dopa, which
increases the release of dopamine and norepinephrine in the
brain, and by the dopamine receptor agonist apomorphine.
PHYSIOLOGY OF GROWTH
Growth hormone, while being essentially unimportant for
fetal development, is the most important hormone for postnatal
growth. However, growth overall is a complex phenomenon
that is aff ected not only by growth hormone and
somatomedins, but also, as would be predicted by the previous
discussion, by thyroid hormones, androgens, estrogens,
glucocorticoids, and insulin. It is also aff ected, of course, by
genetic factors, and it depends on adequate nutrition. It is normally
accompanied by an orderly sequence of maturational
changes, and it involves accretion of protein and an increase
in length and size, not just an increase in weight (which could
refl ect the formation of fat or retention of salt and water rather
than growth per se).
ROLE OF NUTRITION
Th e food supply is the most important extrinsic factor aff ecting
growth. Th e diet must be adequate not only in protein content
but also in essential vitamins and minerals (see Chapter 26 )
and in calories, so that ingested protein is not burned for
energy. However, the age at which a dietary defi ciency occurs
appears to be an important consideration. For example, once
the pubertal growth spurt has commenced, considerable linear
growth continues even if caloric intake is reduced. Injury and
disease, on the other hand, stunt growth because they increase
protein catabolism.
GROWTH PERIODS
Patterns of growth vary somewhat from species to species. Rats
continue to grow, although at a declining rate, throughout life.
In humans, two periods of rapid growth occur ( Figure 18–7 ):
the fi rst in infancy and the second in late puberty just before
10 12 14 16 18 20
Girls
Height gain (cm/yr)
Boys
Age in years
2 4 6 8
0
5.1
10.2
15.2
20.3
25.4
FIGURE 187 Rate of growth in boys and girls from birth to
age 20.
10 12 14 16 18 20
Brain
and
head
Percent of size at age 20
Body and
most visceral
organs
Age in years
0 2 4 6 8
20
40
60
80
100
120
140
160
180
200
Lymphoid
tissue
Reproductive
organs
FIGURE 188 Growth of diff erent tissues at various ages as a
percentage of size at age 20 . The curves are composites that include
data for both boys and girls.
growth stops. Th e fi rst period of accelerated growth is partly
a continuation of the fetal growth period. Th e second growth
spurt, at the time of puberty, is due to growth hormone,
androgens, and estrogens, and the subsequent cessation of
growth is due in large part to closure of the epiphyses in the
long bones by estrogens (see Chapter 21 ). Aft er this time, further
increases in height are not possible. Because girls mature
earlier than boys, this growth spurt appears earlier in girls. Of
course, in both sexes the rate of growth of individual tissues
varies ( Figure 18–8 ).
332 SECTION III Endocrine and Reproductive Physiology
It is interesting that at least during infancy, growth is not
a continuous process but is episodic or saltatory. Increases
in length of human infants of 0.5–2.5 cm in a few days are
separated by periods of 2–63 days during which no measurable
growth can be detected. Th e cause of the episodic growth
is unknown.
HORMONAL EFFECTS
Th e contributions of hormones to growth aft er birth are
shown diagrammatically in Figure 18–9 . Plasma growth
hormone is elevated in newborns. Subsequently, average
resting levels fall but the spikes of growth hormone secretion
are larger, especially during puberty, so the mean plasma
level over 24 h is increased; it is 2–4 ng/mL in normal adults,
but 5–8 ng/mL in children. One of the factors stimulating
IGF-I secretion is growth hormone, and plasma IGF-I levels
rise during childhood, reaching a peak at 13–17 years of age.
In contrast, IGF-II levels are constant throughout postnatal
growth.
Th e growth spurt that occurs at the time of puberty
( Figure 18–7 ) is due in part to the protein anabolic eff ect of
androgens, and the secretion of adrenal androgens increases
at this time in both sexes; however, it is also due to an interaction
among sex steroids, growth hormone, and IGF-I. Treatment
with estrogens and androgens increases the secretion of
growth hormone in response to various stimuli and increases
plasma IGF-I secondary to this increase in circulating growth
hormone. Th is, in turn, causes growth.
Although androgens and estrogens initially stimulate
growth, estrogens ultimately terminate growth by causing
the epiphyses to fuse to the long bones (epiphysial closure).
Once the epiphyses have closed, linear growth ceases (see
Chapter 21 ). Th is is why patients with sexual precocity are
apt to be dwarfed. On the other hand, men who were castrated
before puberty tend to be tall because their estrogen
production is decreased and their epiphyses remain open,
allowing some growth to continue past the normal age of
puberty.
Birth 2 4 6 8 10 12 14 16 18 20
Thyroid
hormones
Growth
hormone
Androgens
and
estrogens
Age (years)
FIGURE 189 Relative importance of hormones in human
growth at various ages . (Courtesy of Fisher DA.)
In hypophysectomized animals, growth hormone
increases growth but this eff ect is potentiated by thyroid
hormones, which by themselves have no eff ect on growth.
Th e action of thyroid hormones in this situation is therefore
permissive to that of growth hormone, possibly via potentiation
of the actions of somatomedins. Th yroid hormones also
oft en appear to be necessary for the normal rate of growth
hormone secretion; basal growth hormone levels are normal
in hypothyroidism, but the response to hypoglycemia is frequently
blunted. Th yroid hormones have widespread eff ects
on the ossifi cation of cartilage, the growth of teeth, the contours
of the face, and the proportions of the body. Hypothyroid
dwarfs (also known as cretins ) therefore have infantile
features ( Figure 18–10 ). Patients who are dwarfed because
of panhypopituitarism have features consistent with their
chronologic age until puberty, but since they do not mature
sexually, they have juvenile features in adulthood ( Clinical
Box 18–2 ).
Th e eff ect of insulin on growth is discussed in Chapter 24 .
Diabetic animals fail to grow, and insulin causes growth in
hypophysectomized animals. However, the growth is appreciable
only when large amounts of carbohydrate and protein
are supplied with the insulin.
Adrenocortical hormones other than androgens exert a
permissive action on growth in the sense that adrenalectomized
animals fail to grow unless their blood pressures and circulations
are maintained by replacement therapy. On the other
hand, glucocorticoids are potent inhibitors of growth because
of their direct action on cells, and treatment of children with
pharmacologic doses of steroids slows or stops growth for as
long as the treatment is continued.
CATCHUP GROWTH
Following illness or starvation in children, a period of catchup
growth ( Figure 18–11 ) takes place during which the
growth rate is greater than normal. Th e accelerated growth
usually continues until the previous growth curve is reached,
then slows to normal. Th e mechanisms that bring about and
control catch-up growth are unknown.
PITUITARY GONADOTROPINS
& PROLACTIN
CHEMISTRY
FSH and LH are each made up of an α and a β subunit.
Th ey are glycoproteins that contain the hexoses mannose
and galactose, the hexosamines N-acetylgalactosamine and
N-acetylglycosamine, and the methylpentose fucose. Th ey
also contain sialic acid. Th e carbohydrate in the gonadotropin
molecules increases their potency by markedly slowing
their metabolism. Th e half-life of human FSH is about
170 min; the half-life of LH is about 60 min. Loss-of-function
CHAPTER 18 The Pituitary Gland 333
mutations in the FSH receptor cause hypogonadism. Gainof-
function mutations cause a spontaneous form of ovarian
hyperstimulation syndrome , a condition in which many follicles
are stimulated and cytokines are released from the ovary,
causing increased vascular permeability and shock.
Human pituitary prolactin contains 199 amino acid
residues and three disulfi de bridges and has considerable
structural similarity to human growth hormone and human
chorionic somatomammotropin (hCS). Th e half-life of prolactin,
like that of growth hormone, is about 20 min. Structurally
similar prolactins are secreted by the endometrium and by the
placenta.
RECEPTORS
Th e receptors for FSH and LH are G-protein coupled receptors
coupled to adenylyl cyclase through a stimulatory G protein
(G s ; see Chapter 2 ). In addition, each has an extended, glycosylated
extracellular domain.
Th e human prolactin receptor resembles the growth
hormone receptor and is one of the superfamily of receptors
that includes the growth hormone receptor and receptors
for many cytokines and hematopoietic growth factors (see
Chapters 2 and 3 ). It dimerizes and activates the Janus
kinase/signal transducers and activators of transcription
(JAK–STAT) pathway and other intracellular enzyme cascades
( Figure 18–3 ).
ACTIONS
Th e testes and ovaries become atrophic when the pituitary
is removed or destroyed. Th e actions of prolactin and the
gonadotropins FSH and LH, as well as those of the gonadotropin
secreted by the placenta, are described in detail in
Chapters 22 and 23 . In brief, FSH helps maintain the spermatogenic
epithelium by stimulating Sertoli cells in the male
and is responsible for the early growth of ovarian follicles in
the female. LH is tropic for the Leydig cells and, in females,
is responsible for the fi nal maturation of the ovarian follicles
and estrogen secretion from them. It is also responsible for
ovulation, the initial formation of the corpus luteum, and
secretion of progesterone.
Prolactin causes milk secretion from the breast aft er
estrogen and progesterone priming. Its eff ect on the breast
involves increasing mRNA levels and subsequent production
of casein and lactalbumin. However, the action of the hormone
is not exerted on the cell nucleus and is prevented by
inhibitors of microtubules. Prolactin also inhibits the eff ects of
Level of symphysis
Normal
2 years
Normal
8 years
Hypothyroid
8 years
Dwarf–not hypothyroid
8 years
Inches Centimeters
60
55
50
45
40
35
30
25
20
15
10
5
0 0
150
140
130
120
110
100
90
80
70
60
50
40
30
20
10
FIGURE 1810 Normal and abnormal growth . Hypothyroid
dwarfs (cretins) retain their infantile proportions, whereas dwarfs of
the constitutional type and, to a lesser extent, of the hypopituitary
type have proportions characteristic of their chronologic age. See
also Clinical Box 18–2 . (Reproduced, with permission, from Wilkins L: The
Diagnosis and Treatment of Endocrine Disorders in Childhood and Adolescence ,
3rd ed. Thomas, 1966.)
334 SECTION III Endocrine and Reproductive Physiology
gonadotropins, possibly by an action at the level of the ovary.
It also prevents ovulation in lactating women. Th e function
of prolactin in normal males is unsettled, but excess prolactin
secreted by tumors causes impotence.
REGULATION OF
PROLACTIN SECRETION
Th e regulatory factors for prolactin secretion by the pituitary
overlap, in part, with those causing secretion of growth hormone,
but there are important diff erences, and some stimuli
increase prolactin secretion while decreasing that of growth
hormone (and vice versa) ( Table 18–4 ). Th e normal plasma
prolactin concentration is approximately 5 ng/mL in men
and 8 ng/mL in women. Secretion is tonically inhibited by the
hypothalamus, and section of the pituitary stalk leads to an
increase in circulating prolactin. Th us, the eff ect of the hypothalamic
prolactin-inhibiting hormone, dopamine, must
normally be greater than the eff ects of the various hypothalamic
peptides with prolactin-releasing activity. In humans,
prolactin secretion is increased by exercise, surgical and psychologic
stresses, and stimulation of the nipple ( Table 18–4 ).
Th e plasma prolactin level rises during sleep, the rise starting
aft er the onset of sleep and persisting throughout the sleep
period. Secretion is increased during pregnancy, reaching
a peak at the time of parturition. Aft er delivery, the plasma
concentration falls to nonpregnant levels in about 8 days.
Suckling produces a prompt increase in secretion, but the
magnitude of this rise gradually declines aft er a woman has
been nursing for more than 3 months. With prolonged lactation,
milk secretion occurs with prolactin levels that are in
the normal range.
l -Dopa decreases prolactin secretion by increasing the
formation of dopamine; bromocriptine, and other dopamine
agonists inhibit secretion because they stimulate
dopamine receptors. Chlorpromazine and related drugs
that block dopamine receptors increase prolactin secretion.
Th yrotropin-releasing hormone (TRH) stimulates the
secretion of prolactin in addition to TSH, and additional
polypeptides with prolactin-releasing activity are present in
hypothalamic tissue. Estrogens produce a slowly developing
increase in prolactin secretion as a result of a direct action
on the lactotropes.
It has now been established that prolactin facilitates
the secretion of dopamine in the median eminence. Th us,
CLINICAL BOX 18–2
Dwarfi sm
The accompanying discussion of growth control should suggest
several possible etiologies of short stature. It can be due
to GHRH defi ciency, growth hormone defi ciency, or defi cient
secretion of IGF-I. Isolated growth hormone defi ciency is often
due to GHRH defi ciency, and in these instances, the growth
hormone response to GHRH is normal. However, some patients
with isolated growth hormone defi ciency have abnormalities
of their growth hormone secreting cells. In another group of
dwarfed children, the plasma growth hormone concentration is
normal or elevated but their growth hormone receptors are unresponsive
as a result of loss-of-function mutations. The resulting
condition is known as growth hormone insensitivity or
Laron dwarfi sm . Plasma IGF-I is markedly reduced, along with
IGFBP 3, which is also growth hormone-dependent. African pygmies
have normal plasma growth hormone levels and a modest
reduction in the plasma level of growth hormone-binding protein.
However, their plasma IGF-I concentration fails to increase
at the time of puberty and they experience less growth than
nonpygmy controls throughout the prepubertal period.
Short stature may also be caused by mechanisms independent
of specifi c defects in the growth hormone axis. It is
characteristic of childhood hypothyroidism (cretinism) and occurs
in patients with precocious puberty. It is also part of the
syndrome of gonadal dysgenesis seen in patients who have
an XO chromosomal pattern instead of an XX or XY pattern (see
Chapter 22 ). Various bone and metabolic diseases also cause
stunted growth, and in many cases there is no known cause
(“constitutional delayed growth”). Chronic abuse and neglect
can also cause dwarfi sm in children, independent of malnutrition.
This condition is known as psychosocial dwarfi sm or
the Kaspar Hauser syndrome , named for the patient with the
fi rst reported case. Finally, achondroplasia , the most common
form of dwarfi sm in humans, is characterized by short limbs
with a normal trunk. It is an autosomal dominant condition
caused by a mutation in the gene that codes for fi broblast
growth factor receptor 3 (FGFR3) . This member of the fi broblast
growth receptor family is normally expressed in cartilage
and the brain.
THERAPEUTIC HIGHLIGHTS
The treatment of dwarfi sm is dictated by its underlying
cause. If treatment to replace the relevant hormone is
commenced promptly in appropriate childhood cases,
almost normal stature can often be attained. Thus, the
availability of recombinant forms of growth hormone and
IGF-I has greatly improved treatment in cases where these
hormones are defi cient.
CHAPTER 18 The Pituitary Gland 335
INSULIN SENSITIVITY
Hypophysectomized animals have a tendency to become
hypoglycemic, especially when fasted. Hypophysectomy
ameliorates diabetes mellitus (see Chapter 24 ) and markedly
increases the hypoglycemic eff ect of insulin. Th is is due in part
to the defi ciency of adrenocortical hormones, but hypophysectomized
animals are more sensitive to insulin than adrenalectomized
animals because they also lack the anti-insulin
eff ect of growth hormone.
WATER METABOLISM
Although selective destruction of the supraoptic–posterior
pituitary causes diabetes insipidus (see Chapter 17 ), removal
of both the anterior and posterior pituitary usually causes no
more than a transient polyuria. In the past, there was speculation
that the anterior pituitary secreted a “diuretic hormone,”
but the amelioration of the diabetes insipidus is actually
TABLE 184 Comparison of factors affecting the
secretion of human prolactin and growth hormone.
Factor Prolactin
Growth
Hormone
Sleep I+ I+
Nursing I++ N
Breast stimulation in
nonlactating women
I N
Stress I+ I+
Hypoglycemia I I+
Strenuous exercise I I
Sexual intercourse in
women
I N
Pregnancy I++ N
Estrogens I I
Hypothyroidism I N
TRH I+ N
Phenothiazines,
butyrophenones
I+ N
Opioids I I
Glucose N D
Somatostatin N D+
L -Dopa D+ I+
Apomorphine D+ I+
Bromocriptine and
related ergot derivatives
D+ I
I, moderate increase; I+, marked increase; I++, very marked increase; N, no
change; D, moderate decrease; D+, marked decrease; TRH, thyrotropin-releasing
hormone.
prolactin acts in the hypothalamus in a negative feedback
fashion to inhibit its own secretion.
EFFECTS OF PITUITARY
INSUFFICIENCY
CHANGES IN OTHER
ENDOCRINE GLANDS
Th e widespread changes that develop when the pituitary is
removed surgically or destroyed by disease in humans or animals
are predictable in terms of the known hormonal functions
of the gland. In hypopituitarism, the adrenal cortex
atrophies, and the secretion of adrenal glucocorticoids and sex
hormones falls to low levels. Stress induced increases in aldosterone
secretion are absent, but basal aldosterone secretion
and increases induced by salt depletion are normal, at least for
some time. Since no mineralocorticoid defi ciency is present,
salt loss and hypovolemic shock do not develop, but the inability
to increase glucocorticoid secretion makes patients with
pituitary insuffi ciency sensitive to stress. Th e development
of salt loss in long-standing hypopituitarism is discussed in
Chapter 20 . Growth is inhibited (see above). Th yroid function
is depressed to low levels, and cold is tolerated poorly. Th e
gonads atrophy, sexual cycles stop, and some of the secondary
sex characteristics disappear.
60
70
80
90
100
110
120
130
140
150
160
170
180
190
200
1 2 3 4 5 6 7 8 9 10111213141516171819
Age (y)
Height (cm)
Illness
Catch-up
growth
FIGURE 1811 Growth curve for a normal boy who had
an illness beginning at age 5 and ending at age 7 . The shaded
area shows the range of normal heights for a given age. The red
line shows actual growth of the boy studied. Catch-up growth
eventually returned his height to his previous normal growth
curve. (Modifi ed from Boersma B, Wit JM: Catch-up growth. Endocr Rev
1997;18:646.)
336 SECTION III Endocrine and Reproductive Physiology
explained by a decrease in the osmotic load presented for
excretion. Osmotically active particles hold water in the renal
tubules (see Chapter 38 ). Because of the ACTH defi ciency,
the rate of protein catabolism is decreased in hypophysectomized
animals. Because of the TSH defi ciency, the metabolic
rate is low. Consequently, fewer osmotically active products of
catabolism are fi ltered and urine volume declines, even in the
absence of vasopressin. Growth hormone defi ciency contributes
to the depression of the glomerular fi ltration rate in hypophysectomized
animals, and growth hormone increases the
glomerular fi ltration rate and renal plasma fl ow in humans.
Finally, because of the glucocorticoid defi ciency, there is the
same defective excretion of a water load that is seen in adrenalectomized
animals. Th e “diuretic” activity of the anterior pituitary
can thus be explained in terms of the actions of ACTH,
TSH, and growth hormone.
OTHER DEFECTS
When growth hormone defi ciency develops in adulthood, it
is usually accompanied by defi ciencies in other anterior pituitary
hormones. Th e defi ciency of ACTH and other pituitary
hormones with MSH activity may be responsible for the pallor
of the skin in patients with hypopituitarism. Th ere may be
some loss of protein in adults, but wasting is not a feature of
hypopituitarism in humans, and most patients with pituitary
insuffi ciency are well nourished.
CAUSES OF PITUITARY
INSUFFICIENCY IN HUMANS
Tumors of the anterior pituitary cause pituitary insuffi ciency.
Suprasellar cysts, remnants of Rathke’s pouch that enlarge and
compress the pituitary, are another cause of hypopituitarism.
In women who have an episode of shock due to postpartum
hemorrhage, the pituitary may become infarcted, with the
subsequent development of postpartum necrosis (Sheehan
syndrome). Th e blood supply to the anterior lobe is vulnerable
because it descends on the pituitary stalk through the
rigid diaphragma sellae, and during pregnancy the pituitary is
enlarged. Pituitary infarction is usually extremely rare in men.
CHAPTER SUMMARY
Th e pituitary ■ gland plays a critical role in regulating the
function of downstream glands, and also exerts independent
endocrine actions on a wide variety of peripheral organs and
tissues. It consists of two functional sections in humans: the
anterior pituitary, which secretes mainly tropic hormones;
and the posterior pituitary, which contains nerve endings
that release oxytocin and vasopressin. Th e intermediate lobe
is prominent in lower vertebrates but not in humans or other
mammals.
■ Corticotropes of the anterior lobe synthesize
proopiomelanocortin, which is the precursor of ACTH,
endorphins, and melanotropins. Th e latter have a critical role in
the control of skin coloration in fi sh, amphibians, and reptiles,
whereas ACTH is a primary regulator of skin pigmentation in
mammals.
■ Growth hormone is synthesized by somatotropes. It is secreted
in an episodic fashion in response to hypothalamic factors, and
secretion is subject to feedback inhibition. A portion of the
circulating pool is protein-bound.
■ Growth hormone activates growth and infl uences protein,
carbohydrate, and fat metabolism to react to stressful
conditions. Many, but not all, of the peripheral actions of
growth hormone can be attributed to its ability to stimulate
production of IGF-I.
■ Growth reflects a complex interplay of growth hormone,
IGF-I, and many other hormones as well as extrinsic
influences and genetic factors. The consequences of
over- or underproduction of such influences depends on
whether this occurs before or after puberty. Deficiencies in
components of the growth hormone pathway in childhood
lead to dwarfism; overproduction results in gigantism,
acromegaly, or both.
■ Th e pituitary also supplies hormones that regulate reproductive
tissues and lactation—follicle-stimulating hormone, luteinizing
hormone, and prolactin. Prolactin, in particular, is regulated
by many of the factors that also regulate growth hormone
secretion, although specifi c regulators may have opposing
eff ects.
MULTIPLECHOICE QUESTIONS
For all questions, select the single best answer unless otherwise
directed .
1. A neuroscientist is studying communication between the
hypothalamus and pituitary in a rat model. She interrupts
blood fl ow through the median eminence and then measures
circulating levels of pituitary hormones following appropriate
physiological stimulation. Secretion of which of the following
hormones will be unaff ected by the experimental manipulation?
A. Growth hormone
B. Prolactin
C. Th yroid stimulating hormone
D. Follicle-stimulating hormone
E. Vasopressin
2. Which of the following pituitary hormones is an opioid
peptide?
A. α-melanocyte-stimulating hormone (α-MSH)
B. β-MSH
C. ACTH
D. Growth hormone
E. β-endorphin
3. During childbirth, a woman suff ers a serious hemorrhage and
goes into shock. Aft er she recovers, she displays symptoms of
hypopituitarism. Which of the following will not be expected in
this patient?
A. Cachexia
B. Infertility
C. Pallor
D. Low basal metabolic rate
E. Intolerance to stress
CHAPTER 18 The Pituitary Gland 337
4. A scientist fi nds that infusion of growth hormone into the
median eminence of the hypothalamus in experimental animals
inhibits the secretion of growth hormone and concludes that
this proves that growth hormone feeds back to inhibit GHRH
secretion. Do you accept this conclusion?
No, because growth A. hormone does not cross the blood–
brain barrier.
B. No, because the infused growth hormone could be
stimulating dopamine secretion.
C. No, because substances placed in the median eminence
could be transported to the anterior pituitary.
D. Yes, because systemically administered growth hormone
inhibits growth hormone secretion.
E. Yes, because growth hormone binds GHRH, inactivating it.
5. Th e growth hormone receptor
A. activates G s .
B. requires dimerization to exert its eff ects.
C. must be internalized to exert its eff ects.
D. resembles the IGF-I receptor.
E. resembles the ACTH receptor.
CHAPTER RESOURCES
Ayuk J, Sheppard MC: Growth hormone and its disorders. Postgrad
Med J 2006;82:24.
Boissy RE, Nordlund JJ: Molecular basis of congenital
hypopigmentary disorders in humans: A review. Pigment Cell
Res 1997;10:12.
Brooks AJ, Waters MJ: Th e growth hormone receptor: mechanism
of activation and clinical implications. Nat Rev Endocrinol
2010;6:515.
Buzi F, Mella P, Pilotta A, Prandi E, Lanfranchi F, Carapella T:
Growth hormone receptor polymorphisms. Endocr Dev
2007;11:28.
Fauquier T, Rizzoti K, Dattani M, Lovell-Badge R, Robinson ICAF:
SOX2-expressing progenitor cells generate all of the major cell
types in the adult mouse pituitary gland. Proc Natl Acad Sci USA
2008;105:2907.
Hindmarsh PC, Dattani MT: Use of growth hormone in children.
Nat Clin Pract Endocrinol Metab 2006;2:260.
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339
O B J E C T I V E S
After studying this chapter,
you should be able to:
The Thyroid Gland
C H A P T E R 19
INTRODUCTION
Th e thyroid gland is one of the larger endocrine glands of
the body. Th e gland has two primary functions. Th e fi rst is
to secrete the thyroid hormones, which maintain the level
of metabolism in the tissues that is optimal for their normal
function. Th yroid hormones stimulate O 2 consumption by most
of the cells in the body, help to regulate lipid and carbohydrate
metabolism, and thereby infl uence body mass and mentation.
Consequences of thyroid gland dysfunction depend on the life
stage at which they occur. Th e thyroid is not essential for life,
but its absence or hypofunction during fetal and neonatal life
results in severe mental retardation and dwarfi sm. In adults,
hypothyroidism is accompanied by mental and physical slowing
and poor resistance to cold. Conversely, excess thyroid secretion
leads to body wasting, nervousness, tachycardia, tremor, and
excess heat production. Th yroid function is controlled by the
thyroid-stimulating hormone (TSH, thyrotropin) of the anterior
pituitary. Th e secretion of this hormone is in turn increased by
thyrotropin-releasing hormone (TRH) from the hypothalamus
and is also subject to negative feedback control by high
circulating levels of thyroid hormones acting on the anterior
pituitary and the hypothalamus.
Th e second function of the thyroid gland is to secrete
calcitonin, a hormone that regulates circulating levels
of calcium. Th is function of the thyroid gland is discussed
in Chapter 21 in the broader context of whole body calcium
homeostasis.
ANATOMIC CONSIDERATIONS
Th e thyroid is a butterfl y-shaped gland that straddles the trachea
in the front of the neck. It develops from an evagination
of the fl oor of the pharynx, and a thyroglossal duct marking
the path of the thyroid from the tongue to the neck sometimes
persists in the adult. Th e two lobes of the human thyroid are
■ Describe the structure of the thyroid gland and how it relates to its function.
■ D efi ne the chemical nature of the thyroid hormones and how they are
synthesized.
■ Understand the critical role of iodine in the thyroid gland and how its transport
is controlled.
■ Describe the role of protein binding in the transport of thyroid hormones and
peripheral metabolism.
■ Identify the role of the hypothalamus and pituitary in regulating thyroid function.
■ D efi ne the eff ects of the thyroid hormones in homeostasis and development.
■ Understand the basis of conditions where thyroid function is abnormal and
how they can be treated.
connected by a bridge of tissue, the thyroid isthmus , and
there is sometimes a pyramidal lobe arising from the isthmus
in front of the larynx ( Figure 19–1 ). Th e gland is well vascularized,
and the thyroid has one of the highest rates of blood
fl ow per gram of tissue of any organ in the body.
Th e portion of the thyroid concerned with the production
of thyroid hormone consists of multiple acini
Ganong_Ch19_339-352.indd 339 1/5/12 7:25:10
340 SECTION III Endocrine and Reproductive Physiology
reticulum is prominent, a feature common to most glandular
cells, and secretory granules containing thyroglobulin are seen
( Figure 19–3 ). Th e individual thyroid cells rest on a basal
lamina that separates them from the adjacent capillaries. Th e
capillaries are fenestrated, like those of other endocrine glands
(see Chapter 31).
FORMATION & SECRETION
OF THYROID HORMONES
CHEMISTRY
Th e primary hormone secreted by the thyroid is thyroxine
(T 4 ), along with much lesser amounts of triiodothyronine
(T 3 ). T 3 has much greater biological activity than T 4 and is
specifi cally generated at its site of action in peripheral tissues
by deiodination of T 4 (see below). Both hormones are iodinecontaining
amino acids ( Figure 19–4 ). Small amounts of
reverse triiodothyronine (3,3′,5′-triiodothyronine, RT 3 ) and
other compounds are also found in thyroid venous blood.
RT 3 is not biologically active.
IODINE HOMEOSTASIS
Iodine is an essential raw material for thyroid hormone synthesis.
Dietary iodide is absorbed by the intestine and enters the
circulation; its subsequent fate is summarized in Figure 19–5 .
(follicles) . Each spherical follicle is surrounded by a single
layer of polarized epithelial cells and fi lled with pink-staining
proteinaceous material called colloid. Colloid consists
predominantly of the glycoprotein, thyroglobulin. When the
gland is inactive, the colloid is abundant, the follicles are
large, and the cells lining them are fl at. When the gland is
active, the follicles are small, the cells are cuboid or columnar,
and areas where the colloid is being actively reabsorbed
into the thyrocytes are visible as “reabsorption lacunae”
( Figure 19–2 ).
Microvilli project into the colloid from the apexes of the
thyroid cells and canaliculi extend into them. Th e endoplasmic
Left
lobe
Right
lobe
Larynx
Pyramidal
lobe
Hyoid bone
FIGURE 191 The human thyroid.
Inactive Active
Colloid Reabsorption
lacunae
Parafollicular
cells
FIGURE 192 Thyroid histology. The appearance of the gland
when it is inactive (left) and actively secreting (right) is shown. Note
the small, punched-out “reabsorption lacunae” in the colloid next to
the cells in the active gland.
Secretory
droplets
Lumen of
follicle
Uptake of
colloid by
endocytosis
Lysosome
coalescing
with endocytotic
vacuole
Golgi
apparatus
Capillary
endothelium
Normal TSH-stimulated
Capillary
basal lamina
Cell basal
lamina
FIGURE 193 Thyroid cell. Left: Normal pattern. Right: After TSH
stimulation. The arrows on the right show the secretion of thyroglobulin
into the colloid. On the right, endocytosis of the colloid and merging of
a colloid-containing vacuole with a lysosome are also shown. The cell
rests on a capillary with gaps (fenestrations) in the endothelial wall.
CHAPTER 19 The Thyroid Gland 341
IODIDE TRANSPORT
ACROSS THYROCYTES
Th e basolateral membranes of thyrocytes facing the capillaries
contain a symporter that transports two Na + ions and one
I – ion into the cell with each cycle, against the electrochemical
gradient for I – . Th is Na + /I – symporter (NIS) is capable of
producing intracellular I – concentrations that are 20–40 times
as great as the concentration in plasma. Th e process involved
is secondary active transport (see Chapter 2), with the energy
provided by active transport of Na + out of thyroid cells by Na,
K ATPase. NIS is regulated both by transcriptional means and
by active traffi cking into and out of the thyrocyte basolateral
membrane; in particular, thyroid stimulating hormone (TSH;
see below) induces both NIS expression and the retention of
NIS in the basolateral membrane, where it can mediate sustained
iodide uptake.
Iodide must also exit the thyrocyte across the apical membrane
to access the colloid, where the initial steps of thyroid
hormone synthesis occur. Th is transport step is believed to
be mediated, at least in part, by a Cl – /I – exchanger known as
pendrin. Th is protein was fi rst identifi ed as the product of the
gene responsible for the Pendred syndrome, whose patients suffer
from thyroid dysfunction and deafness. Pendrin (SLC26A4)
is one member of the larger family of SLC26 anion exchangers.
Th e relation of thyroid function to iodide is unique. As
discussed in more detail below, iodide is essential for normal
thyroid function, but iodide defi ciency and iodide excess both
inhibit thyroid function.
Th e salivary glands, the gastric mucosa, the placenta,
the ciliary body of the eye, the choroid plexus, the mammary
glands, and certain cancers derived from these tissues also
express NIS and can transport iodide against a concentration
gradient, but the transporter in these tissues is not aff ected by
TSH. Th e physiologic signifi cance of all these extrathyroidal
iodide-concentrating mechanisms is obscure, but they may
provide pathways for radioablation of NIS-expressing cancer
cells using iodide radioisotopes. Th is approach is also useful
for the ablation of thyroid cancers.
THYROID HORMONE
SYNTHESIS & SECRETION
At the interface between the thyrocyte and the colloid, iodide
undergoes a process referred to as organifi cation. First, it is
oxidized to iodine, and then incorporated into the carbon
3 position of tyrosine residues that are part of the thyroglobulin
molecule in the colloid ( Figure 19–6 ). Th yroglobulin is
a glycoprotein made up of two subunits and has a molecular
weight of 660 kDa. It contains 10% carbohydrate by weight. It
also contains 123 tyrosine residues, but only 4–8 of these are
normally incorporated into thyroid hormones. Th yroglobulin
is synthesized in the thyroid cells and secreted into the colloid
by exocytosis of granules. Th e oxidation and reaction of
iodide with the secreted thyroglobulin is mediated by thyroid
Th e minimum daily iodine intake that will maintain normal
thyroid function is 150 μg in adults. In most developed
countries, supplementation of table salt means that the average
dietary intake is approximately 500 μg/d. Th e principal organs
that take up circulating I – are the thyroid, which uses it to
make thyroid hormones, and the kidneys, which excrete it in
the urine. About 120 μg/d enter the thyroid at normal rates of
thyroid hormone synthesis and secretion. Th e thyroid secretes
80 μg/d in the form of T 3 and T 4 , while 40 μg/d diff uses back
into the extracellular fl uid (ECF). Circulating T 3 and T 4 are
metabolized in the liver and other tissues, with the release
of a further 60 μg of I – per day into the ECF. Some thyroid
hormone derivatives are excreted in the bile, and some of the
iodine in them is reabsorbed (enterohepatic circulation), but
there is a net loss of I – in the stool of approximately 20 μg/d.
Th e total amount of I – entering the ECF is thus 500 + 40 + 60,
or 600 μg/d; 20% of this I – enters the thyroid, whereas 80% is
excreted in the urine.
HO O CH2 CH
NH2
C OH
O
Ι
Ι
Ι
Ι
3'
5'
3
5
3,5,3',5',-Tetraiodothyronine (thyroxine, T4)
HO O CH2 CH
NH2
C OH
O
Ι
Ι
Ι
3,5,3',-Triiodothyronine (T3)
FIGURE 194 Thyroid hormones. The numbers in the rings in
the T 4 formula indicate the number of positions in the molecule. RT 3
is 3,3′,5′-triiodothyronine.
Liver
and other
tissues
Thyroid
120 μg I−
40 μg I−
60 μg I−
Extracellular
fluid
500 μg I−
in diet
480 μg I−
in urine
20 μg I−
in stool
80 μg in
T3, T4
Bile
FIGURE 195 Iodine metabolism. The fi gure shows the
movement of iodide amongst various body compartments on a
daily basis.
342 SECTION III Endocrine and Reproductive Physiology
One holds that the coupling occurs with both DIT molecules
attached to thyroglobulin (intramolecular coupling). Th e other
holds that the DIT that forms the outer ring is fi rst detached
from thyroglobulin (intermolecular coupling). In either case,
thyroid peroxidase is involved in coupling as well as iodination.
T 3 is formed by condensation of MIT with DIT. A small
amount of RT 3 is also formed, probably by condensation of DIT
with MIT. In the normal human thyroid, the average distribution
of iodinated compounds is 3% MIT, 33% DIT, 35% T 4 , and
7% T 3 . Only traces of RT 3 and other components are present.
Th e human thyroid secretes about 80 μg (103 nmol) of
T 4 , 4 μg (7 nmol) of T 3 , and 2 μg (3.5 nmol) of RT 3 per day
( Figure 19–7 ). MIT and DIT are not secreted. Th ese iodinated
tyrosines are deiodinated by a microsomal iodotyrosine deiodinase.
Th is represents a mechanism to recover iodine and
bound tyrosines and recycle them for additional rounds of
hormone synthesis. Th e iodine liberated by deiodination of
MIT and DIT is reutilized in the gland and normally provides
about twice as much iodide for hormone synthesis as NIS
does. In patients with congenital absence of the iodotyrosine
deiodinase, MIT and DIT appear in the urine and there are
symptoms of iodine defi ciency (see below). Iodinated thyronines
are resistant to the activity of iodotyrosine deiodinase,
thus allowing T 4 and T 3 to pass into the circulation.
peroxidase, a membrane-bound enzyme found in the thyrocyte
apical membrane. Th e thyroid hormones so produced
remain part of the thyroglobulin molecule until needed. As
such, colloid represents a reservoir of thyroid hormones, and
humans can ingest a diet completely devoid of iodide for up
to 2 months before a decline in circulating thyroid hormone
levels is seen. When there is a need for thyroid hormone secretion,
colloid is internalized by the thyrocytes by endocytosis,
and directed toward lysosomal degradation. Th us, the peptide
bonds of thyroglobulin are hydrolyzed, and free T 4 and T 3
are discharged into cytosol and thence to the capillaries (see
below). Th yrocytes thus have four functions: Th ey collect and
transport iodine, they synthesize thyroglobulin and secrete it
into the colloid, they fi x iodine to the thyroglobulin to generate
thyroid hormones, and they remove the thyroid hormones
from thyroglobulin and secrete them into the circulation.
Th yroid hormone synthesis is a multistep process. Th yroid
peroxidase generates reactive iodine species that can
attack thyroglobulin. Th e fi rst product is monoiodotyrosine
(MIT). MIT is next iodinated on the carbon 5 position to form
diiodotyrosine (DIT). Two DIT molecules then undergo an
oxidative condensation to form T 4 with the elimination of the
alanine side chain from the molecule that forms the outer ring.
Th ere are two theories of how this coupling reaction occurs.
HO CH2− CH
CH
CH
HO CH2−
Tyrosine
Ι Ι − Ι−
(Iodide)
Ι
(Iodine)
HO CH2−
Ι
Ι
O CH2− CH
Ι
Ι
DIT + DIT Alanine + HO
Ι
Ι
3-Monoiodotyrosine (MIT)
3,5-Diiodotyrosine (DIT)
Ι− Ι− Ι
MIT + DIT Alanine + 3,5,3'-Triiodothyronine (T3)
DIT + MIT Alanine + 3,3',5'-Triiodothyronine (reverse T3)
Thyroxine (T4)
THYROID
CELL
Active
transport
PLASMA COLLOID
THYROGLOBULIN
MOLECULE
FIGURE 196 Outline of thyroid hormone biosynthesis.
Iodide is transported from the plasma across the cells of the
thyroid gland by both secondary active and passive transport. The
iodide is converted to iodine, which reacts with tyrosine residues
exposed on the surface of thyroglobulin molecules resident in the
colloid. Iodination of tyrosine takes place at the apical border of the
thyroid cells while the molecules are bound in peptide linkage in
thyroglobulin.
CHAPTER 19 The Thyroid Gland 343
T 4 and T 3 can both be measured by radioimmunoassay. Th ere
are also direct assays that specifi cally measure only the free
forms of the hormones. Th e latter are the more clinically relevant
measures given that these are the active forms, and also
due to both acquired and congenital variations in the concentrations
of binding proteins between individuals.
Th e plasma proteins that bind thyroid hormones are
albumin , a prealbumin called transthyretin (formerly called
thyroxine-binding prealbumin) , and a globulin known as
thyroxine-binding globulin (TBG) . Of the three proteins,
albumin has the largest capacity to bind T 4 (ie, it can bind the
most T 4 before becoming saturated) and TBG has the smallest
capacity. However, the affi nities of the proteins for T 4 (ie,
the avidity with which they bind T 4 under physiologic conditions)
are such that most of the circulating T 4 is bound to
TBG ( Table 19–1 ), with over a third of the binding sites on the
protein occupied. Smaller amounts of T 4 are bound to transthyretin
and albumin. Th e half-life of transthyretin is 2 days,
that of TBG is 5 days, and that of albumin is 13 days.
Normally, 99.98% of the T 4 in plasma is bound; the free T 4
level is only about 2 ng/dL. Th ere is very little T 4 in the urine.
Its biologic half-life is long (about 6–7 days), and its volume
of distribution is less than that of ECF (10 L, or about 15%
of body weight). All of these properties are characteristic of a
substance that is strongly bound to protein.
T 3 is not bound to quite as great an extent; of the 0.15 μg/
dL normally found in plasma, 0.2% (0.3 ng/dL) is free. Th e
remaining 99.8% is protein-bound, 46% to TBG and most of
the remainder to albumin, with very little binding to transthyretin
( Table 19–1 ). Th e lesser binding of T 3 correlates with the
facts that T 3 has a shorter half-life than T 4 and that its action
on the tissues is much more rapid. RT 3 also binds to TBG.
FLUCTUATIONS IN BINDING
When a sudden, sustained increase in the concentration of
thyroid-binding proteins in the plasma takes place, the concentration
of free thyroid hormones falls. Th is change is temporary,
however, because the decrease in the concentration of
free thyroid hormones in the circulation stimulates TSH secretion,
which in turn causes an increase in the production of free
thyroid hormones. A new equilibrium is eventually reached at
TRANSPORT & METABOLISM
OF THYROID HORMONES
PROTEIN BINDING
Th e normal total plasma T 4 level in adults is approximately
8 μg/dL (103 nmol/L), and the plasma T 3 level is approximately
0.15 μg/dL (2.3 nmol/L). T 4 and T 3 are relatively lipophilic;
thus, their free forms in plasma are in equilibrium with a much
larger pool of protein-bound thyroid hormones in plasma and
in tissues. Free thyroid hormones are added to the circulating
pool by the thyroid. It is the free thyroid hormones in plasma
that are physiologically active and that feed back to inhibit pituitary
secretion of TSH ( Figure 19–8 ). Th e function of proteinbinding
appears to be maintenance of a large pool of hormone
that can readily be mobilized as needed. In addition, at least for
T 3 , hormone binding prevents excess uptake by the fi rst cells
encountered and promotes uniform tissue distribution. Total
Conjugates,
etc
Thyroid
Secretion
Interconversion
Metabolism
and Excretion
4 80
27 36
2
17
RT3
38 μg
T4
80 μg
T3
31 μg
FIGURE 197 Secretion and interconversion of thyroid
hormones in normal adult humans . Figures are in micrograms per
day. Note that most of the T 3 and RT 3 are formed from T 4 deiodination
in the tissues and only small amounts are secreted by the thyroid.
T 4 is also conjugated for subsequent excretion from the body.
Pituitary
TSH
Free T4
0.002 μg/dL
Plasma protein-bound T4
8 μg/dL
Tissue protein-bound T4
Thyroid
T4
FIGURE 198 Regulation of thyroid hormone synthesis.
T4 is secreted by the thyroid in response to TSH. Free T 4 secreted
by the thyroid into the circulation is in equilibrium with T 4 bound
to both plasma and tissue proteins. Free T 4 also feeds back to inhibit
TSH secretion by the pituitary.
TABLE 19–1 Binding of thyroid hormones to plasma
proteins in normal adult humans .
Protein
Plasma
Concentration
(mg/dL)
Amount of Circulating
Hormone Bound (%)
T 4 T 3
Thyroxine-binding
globulin (TBG)
2 67 46
Transthyretin
(thyroxine-binding
prealbumin, TBPA)
15 20 1
Albumin 3500 13 53
344 SECTION III Endocrine and Reproductive Physiology
is essential for their enzymatic activity. D 1 is present in high
concentrations in the liver, kidneys, thyroid, and pituitary. It
appears primarily to be responsible for maintaining the formation
of T 3 from T 4 in the periphery. D 2 is present in the brain,
pituitary, and brown fat. It also contributes to the formation
of T 3 . In the brain, it is located in astroglia and produces a
supply of T 3 to neurons. D 3 is also present in the brain and in
reproductive tissues. It acts only on the 5 position of T 4 and
T 3 and is probably the main source of RT 3 in the blood and
tissues. Overall, the deiodinases appear to be responsible for
maintaining diff erences in T 3 /T 4 ratios in the various tissues in
the body. In the brain, in particular, high levels of deiodinase
activity ensure an ample supply of active T 3 .
Some of the T 4 and T 3 is further converted to deiodotyrosines
by deiodinases. T 4 and T 3 are also conjugated in the
liver to form sulfates and glucuronides. Th ese conjugates enter
the bile and pass into the intestine. Th e thyroid conjugates are
hydrolyzed, and some are thereaft er reabsorbed (enterohepatic
circulation), but others are excreted in the stool. In addition,
some T 4 and T 3 passes directly from the circulation to the
intestinal lumen. Th e iodide lost by these routes amounts to
about 4% of the total daily iodide loss.
FLUCTUATIONS IN DEIODINATION
Much more RT 3 and much less T 3 are formed during fetal life,
and the ratio shift s to that of adults about 6 weeks aft er birth.
Various drugs inhibit deiodinases, producing a fall in plasma
T 3 levels and a reciprocal rise in RT 3 . Selenium defi ciency has
the same eff ect. A wide variety of nonthyroidal illnesses also
suppress deiodinases. Th ese include burns, trauma, advanced
cancer, cirrhosis, renal failure, myocardial infarction, and
febrile states. Th e low-T 3 state produced by these conditions
disappears with recovery. It is diffi cult to decide whether individuals
with the low-T 3 state produced by drugs and illness
have mild hypothyroidism.
Diet also has a clear-cut eff ect on conversion of T 4 to T 3 .
In fasted individuals, plasma T 3 is reduced by 10–20% within
24 h and by about 50% in 3–7 days, with a corresponding rise
in RT 3 ( Figure 19–9 ). Free and bound T 4 levels remain essentially
normal. During more prolonged starvation, RT 3 returns
which the total quantity of thyroid hormones in the blood is
elevated but the concentration of free hormones, the rate of
their metabolism, and the rate of TSH secretion are normal.
Corresponding changes in the opposite direction occur when
the concentration of thyroid-binding protein is reduced. Consequently,
patients with elevated or decreased concentrations
of binding proteins, particularly TBG, are typically neither
hyper- nor hypothyroid; that is, they are euthyroid .
TBG levels are elevated in estrogen-treated patients and
during pregnancy, as well as aft er treatment with various drugs
( Table 19–2 ). Th ey are depressed by glucocorticoids, androgens,
the weak androgen danazol, and the cancer chemotherapeutic
agent L-asparaginase. A number of other drugs,
including salicylates, the anti-convulsant phenytoin, and the
cancer chemotherapeutic agents mitotane (o, p′-DDD) and
5-fl uorouracil inhibit binding of T 4 and T 3 to TBG and consequently
produce changes similar to those produced by a
decrease in TBG concentration. Changes in total plasma T 4
and T 3 can also be produced by changes in plasma concentrations
of albumin and prealbumin.
METABOLISM OF
THYROID HORMONES
T 4 and T 3 are deiodinated in the liver, the kidneys, and many
other tissues. Th ese deiodination reactions serve not only to
catabolize the hormones, but also to provide a local supply specifi
cally of T 3 , which is believed to be the primary mediator of the
physiological eff ects of thyroid secretion. One third of the circulating
T 4 is normally converted to T 3 in adult humans, and 45%
is converted to RT 3 . As shown in Figure 19–7 , only about 13% of
the circulating T 3 is secreted by the thyroid while 87% is formed
by deiodination of T 4 ; similarly, only 5% of the circulating RT 3 is
secreted by the thyroid and 95% is formed by deiodination of T 4 .
It should be noted as well that marked diff erences in the ratio of
T 3 to T 4 occur in various tissues. Two tissues that have very high
T 3 /T 4 ratios are the pituitary and the cerebral cortex, due to the
expression of specifi c deiodinases, as discussed below.
Th ree diff erent deiodinases act on thyroid hormones: D 1 ,
D 2 , and D 3 . All are unique in that they contain the rare amino
acid selenocysteine, with selenium in place of sulfur, which
TABLE 192 Effect of variations in the concentrations of thyroid hormone-binding proteins in the plasma on
various parameters of thyroid function after equilibrium has been reached.
Condition
Concentrations of
Binding Proteins
Total Plasma
T 4 , T 3 , RT 3
Free Plasma
T 4 , T 3 , RT 3
Plasma
TSH Clinical State
Hyperthyroidism Normal High High Low Hyperthyroid
Hypothyroidism Normal Low Low High Hypothyroid
Estrogens, methadone, heroin, major
tranquilizers, clofi brate
High High Normal Normal Euthyroid
Glucocorticoids, androgens, danazol,
asparaginase
Low Low Normal Normal Euthyroid
CHAPTER 19 The Thyroid Gland 345
Th e functional specifi city of TSH is conferred by the β subunit.
Th e structure of TSH varies from species to species, but other
mammalian TSHs are biologically active in humans.
Th e biologic half-life of human TSH is about 60 min. TSH
is degraded for the most part in the kidneys and to a lesser
extent in the liver. Secretion is pulsatile, and mean output starts
to rise at about 9:00 PM, peaks at midnight, and then declines
during the day. Th e normal secretion rate is about 110 μg/d.
Th e average plasma level is about 2 μg/mL.
Because the α subunit in hCG is the same as that in TSH,
large amounts of hCG can activate thyroid receptors (TR)
nonspecifi cally. In some patients with benign or malignant
tumors of placental origin, plasma hCG levels can rise so high
that they produce mild hyperthyroidism.
EFFECTS OF TSH ON THE THYROID
When the pituitary is removed, thyroid function is depressed
and the gland atrophies; when TSH is administered, thyroid
function is stimulated. Within a few minutes aft er the injection
of TSH, there are increases in iodide binding; synthesis of T 3 , T 4 ,
and iodotyrosines; secretion of thyroglobulin into the colloid;
and endocytosis of colloid. Iodide trapping is increased in a few
hours; blood fl ow increases; and, with chronic TSH treatment,
the cells hypertrophy and the weight of the gland increases.
Whenever TSH stimulation is prolonged, the thyroid
becomes detectably enlarged. Enlargement of the thyroid is
called a goiter .
TSH RECEPTORS
Th e TSH receptor is a typical G protein-coupled, seven-transmembrane
receptor that activates adenylyl cyclase through G s .
It also activates phospholipase C (PLC). Like other glycoprotein
hormone receptors, it has an extended, glycosylated extracellular
domain.
OTHER FACTORS AFFECTING
THYROID GROWTH
In addition to TSH receptors, thyrocytes express receptors for
insulin-like growth factor I (IGF-I), EGF, and other growth
factors. IGF-I and EGF promote growth, whereas interferon
γ and tumor necrosis factor α inhibit growth. Th e exact
physiologic role of these factors in the thyroid has not been
established, but the eff ect of the cytokines implies that thyroid
function might be inhibited in the setting of chronic infl ammation,
which could contribute to cachexia, or weight loss.
CONTROL MECHANISMS
Th e mechanisms regulating thyroid secretion are summarized
in Figure 19–8 . Th e negative feedback eff ect of thyroid hormones
on TSH secretion is exerted in part at the hypothalamic
level, but it is also due in large part to an action on the pituitary,
since T 4 and T 3 block the increase in TSH secretion produced
to normal but T 3 remains depressed. At the same time, the
basal metabolic rate (BMR) falls and urinary nitrogen excretion,
an index of protein breakdown, is decreased. Th us, the
decline in T 3 conserves calories and protein. Conversely, overfeeding
increases T 3 and reduces RT 3 .
REGULATION OF
THYROID SECRETION
Th yroid function is regulated primarily by variations in the circulating
level of pituitary TSH ( Figure 19–8 ). TSH secretion is
increased by the hypothalamic hormone TRH (see Chapter 17)
and inhibited in a negative feedback fashion by circulating free
T 4 and T 3 . Th e eff ect of T 4 is enhanced by production of T 3 in
the cytoplasm of the pituitary cells by the 5′-D 2 they contain.
TSH secretion is also inhibited by stress, and in experimental
animals it is increased by cold and decreased by warmth.
CHEMISTRY &
METABOLISM OF TSH
Human TSH is a glycoprotein that contains 211 amino acid residues.
It is made up of two subunits, designated α and β. Th e α subunit
is encoded by a gene on chromosome 6 and the β subunit by
a gene on chromosome 1. Th e α and β subunits become noncovalently
linked in the pituitary thyrotropes. TSH-α is identical to
the α subunit of LH, FSH, and hCG-α (see Chapters 18 and 22).
Starvation
Days
240
200
160
120
80
40
0
−4 −2 0 2 4 6 8 10 +2 +4
12
10
8
6
4
2
0
T4
T3
RT3
ng/dL
μg/dL
FIGURE 199 Eff ect of starvation on plasma levels of T 4 , T 3 ,
and RT 3 in humans . The scale for T 3 and RT 3 is on the left and the scale
for T 4 is on the right. The most pronounced eff ect is a reduction in T 3
levels with a reciprocal rise in RT 3 . The changes, which conserve calories
by reducing tissue metabolism, are reversed promptly by re-feeding.
Similar changes occur in wasting diseases. (Reproduced with permission
from Burger AG: New aspects of the peripheral action of thyroid hormones. Triangle
1983;22:175. Copyright © 1983 Sandoz Ltd., Basel, Switzerland.)
346 SECTION III Endocrine and Reproductive Physiology
the increased secretion of thyroid hormones produced by cold
and, presumably, the decrease produced by heat. It is worth noting
that although cold produces clear-cut increases in circulating
TSH in experimental animals and human infants, the rise
produced by cold in adult humans is negligible. Consequently,
in adults, increased heat production due to increased thyroid
hormone secretion (thyroid hormone thermogenesis) plays
little if any role in the response to cold. Stress has an inhibitory
eff ect on TRH secretion. Dopamine and somatostatin act at
the pituitary level to inhibit TSH secretion, but it is not known
whether they play a physiologic role in the regulation of TSH
secretion. Glucocorticoids also inhibit TSH secretion.
Th e amount of thyroid hormone necessary to maintain
normal cellular function in thyroidectomized individuals used
to be defi ned as the amount necessary to normalize the BMR,
but it is now defi ned as the amount necessary to return plasma
TSH to normal. Indeed, with the accuracy and sensitivity of
modern assays for TSH and the marked inverse correlation
by TRH. Infusion of either T 4 or T 3 reduces the circulating
level of TSH, which declines measurably within 1 h. In experimental
animals, there is an initial rise in pituitary TSH content
before the decline, indicating that thyroid hormones inhibit
secretion before they inhibit synthesis. Th e day-to-day maintenance
of thyroid secretion depends on the feedback interplay
of thyroid hormones with TSH and TRH ( Figure 19–8 ).
Th e adjustments that appear to be mediated via TRH include
TABLE 193 Causes of congenital hypothyroidism.
Maternal iodine defi ciency
Fetal thyroid dysgenesis
Inborn errors of thyroid hormone synthesis
Maternal antithyroid antibodies that cross the placenta
Fetal hypopituitary hypothyroidism
CLINICAL BOX 19–1
Reduced Thyroid Function
The syndrome of adult hypothyroidism is generally called myxedema
, although this term is also used to refer specifi cally to the
skin changes in the syndrome. Hypothyroidism may be the end
result of a number of diseases of the thyroid gland, or it may be
secondary to pituitary or hypothalamic failure. In the latter two
conditions, the thyroid remains able to respond to TSH. Thyroid
function may be reduced by a number of conditions ( Table 19–3 ).
For example, when the dietary iodine intake falls below 50 μg/d,
thyroid hormone synthesis is inadequate and secretion declines.
As a result of increased TSH secretion, the thyroid hypertrophies,
producing an iodine defi ciency goiter that may become very
large. Such “endemic goiters” have been substantially reduced by
the practice of adding iodide to table salt. Drugs may also inhibit
thyroid function. Most do so either by interfering with the iodidetrapping
mechanism or by blocking the organic binding of iodine.
In either case, TSH secretion is stimulated by the decline in circulating
thyroid hormones, and a goiter is produced. Paradoxically,
another substance that inhibits thyroid function under certain
conditions is iodide itself. In normal individuals, large doses of
iodide act directly on the thyroid to produce a mild and transient
inhibition of organic binding of iodide and hence of hormone
synthesis. This inhibition is known as the Wolff –Chaikoff eff ect .
In completely athyreotic adults, the BMR falls to about
40%. The hair is coarse and sparse, the skin is dry and yellowish
(carotenemia), and cold is poorly tolerated. Mentation is slow,
memory is poor, and in some patients there are severe mental
symptoms (“myxedema madness”). Plasma cholesterol is elevated.
Children who are hypothyroid from birth or before are called
cretins . They are dwarfed and mentally retarded. Worldwide,
congenital hypothyroidism is one of the most common causes
of preventable mental retardation. The main causes are included
in Table 19–3 . They include not only maternal iodine defi ciency
and various congenital abnormalities of the fetal hypothalamo–
pituitary–thyroid axis, but also maternal antithyroid antibodies
that cross the placenta and damage the fetal thyroid. T 4 crosses
the placenta, and unless the mother is hypothyroid, growth and
development are normal until birth. If treatment is started at
birth, the prognosis for normal growth and development is good,
and mental retardation can generally be avoided; for this reason,
screening tests for congenital hypothyroidism are becoming
routine. When the mother is hypothyroid as well, as in the case of
iodine defi ciency, the mental defi ciency is more severe and less
responsive to treatment after birth. It has been estimated that
20 million people in the world now have various degrees of brain
damage caused by iodine defi ciency in utero.
Uptake of tracer doses of radioactive iodine can be used
to assess thyroid function (contrast this with the use of large
doses to ablate thyroid tissue in cases of hyperthyroidism
(Clinical Box 19–2).
THERAPEUTIC HIGHLIGHTS
The treatment of hypothyroidism depends on the underlying
mechanisms. Iodide defi ciency can be addressed by
adding it to the diet, as is done routinely in developed
countries with the use of iodized salt. In congenital hypothyroidism,
levothyroxine—a synthetic form of the thyroid
hormone T 4 —can be given. It is important that this
take place as soon as possible after birth, with levels regularly
monitored, to minimize long-term adverse eff ects.
CHAPTER 19 The Thyroid Gland 347
TABLE 194 Causes of hyperthyroidism.
Thyroid overactivity
Graves disease
Solitary toxic adenoma
Toxic multinodular goiter
Early stages of Hashimoto thyroiditis a
TSH-secreting pituitary tumor
Mutations causing constitutive activation of TSH receptor
Other rare causes
Extrathyroidal
Administration of T 3 or T 4 (factitious or iatrogenic hyperthyroidism)
Ectopic thyroid tissue
a Note that ultimately the thyroid will be destroyed in Hashimoto disease, resulting
in hypothyroidism. Many patients only present after they become hypothyroid, and
do not recall a transient phase of hyperthyroidism.
between plasma free thyroid hormone levels and plasma TSH,
measurement of TSH is now widely regarded as one of the
best tests of thyroid function. Th e amount of T 4 that normalizes
plasma TSH in athyreotic individuals averages 112 μg
of T 4 by mouth per day in adults. About 80% of this dose is
absorbed from the gastrointestinal tract. It produces a slightly
greater than normal FT 4 I but a normal FT 3 I, indicating that in
CLINICAL BOX 19–2
Hyperthyroidism
The symptoms of an overactive thyroid gland follow logically
from the actions of thyroid hormone discussed in this chapter.
Thus, hyperthyroidism is characterized by nervousness;
weight loss; hyperphagia; heat intolerance; increased pulse
pressure; a fi ne tremor of the outstretched fi ngers; warm, soft
skin; sweating; and a BMR from +10 to as high as +100. It has
various causes ( Table 19–4 ); however, the most common cause
is Graves disease (Graves hyperthyroidism), which accounts
for 60–80% of the cases. This is an autoimmune disease, more
common in women, in which antibodies to the TSH receptor
stimulate the receptor. This produces marked T 4 and T 3 secretion
and enlargement of the thyroid gland (goiter). However,
due to the feedback eff ects of T 4 and T 3 , plasma TSH is low, not
high. Another hallmark of Graves disease is the occurrence of
swelling of tissues in the orbits, producing protrusion of the
eyeballs (exophthalmos). This occurs in 50% of patients and
often precedes the development of obvious hyperthyroidism.
Other antithyroid antibodies are present in Graves disease, including
antibodies to thyroglobulin and thyroid peroxidase. In
Hashimoto thyroiditis, autoimmune antibodies and infi ltrating
cytotoxic T cells ultimately destroy the thyroid, but during the
early stage the infl ammation of the gland causes excess thyroid
hormone secretion and thyrotoxicosis similar to that seen in
Graves disease.
THERAPEUTIC HIGHLIGHTS
Some of the symptoms of hyperthyroidism can be controlled
by the thioureylenes . These are a group of compounds
related to thiourea, which inhibit the iodination of
monoiodotyrosine and block the coupling reaction. The
two used clinically are propylthiouracil and methimazole.
Iodination of tyrosine is inhibited because propylthiouracil
and methimazole compete with tyrosine residues for
iodine and become iodinated. In addition, propylthiouracil
but not methimazole inhibits D 2 deiodinase, reducing
the conversion of T 4 to T 3 in many extrathyroidal tissues.
In severe cases, hyperthyroidism can also be treated by
the infusion of radioactive iodine, which accumulates in
the gland and then partially destroys it. Surgery is also
considered if the thyroid becomes so large that it aff ects
swallowing and/or breathing.
humans, unlike some experimental animals, it is circulating T 3
rather than T 4 that is the principal feedback regulator of TSH
secretion (see Clinical Boxes 19–1 and 19–2).
EFFECTS OF THYROID HORMONES
Some of the widespread eff ects of thyroid hormones in the
body are secondary to stimulation of O 2 consumption (calorigenic
action) , although the hormones also aff ect growth and
development in mammals, help regulate lipid metabolism, and
increase the absorption of carbohydrates from the intestine
( Table 19–5 ). Th ey also increase the dissociation of oxygen
from hemoglobin by increasing red cell 2,3-diphosphoglycerate
(DPG) (see Chapter 35).
MECHANISM OF ACTION
Th yroid hormones enter cells and T 3 binds to TR in the nuclei.
T 4 can also bind, but not as avidly. Th e hormone–receptor
complex then binds to DNA via zinc fi ngers and increases
(or in some cases, decreases) the expression of a variety of
diff erent genes that code for proteins that regulate cell function
(see Chapters 1 and 16). Th us, the nuclear receptors for
thyroid hormones are members of the superfamily of hormone-
sensitive nuclear transcription factors.
Th ere are two human TR genes: an α receptor gene on
chromosome 17 and a β receptor gene on chromosome 3. By
348 SECTION III Endocrine and Reproductive Physiology
alternative splicing, each forms at least two diff erent mRNAs
and therefore two diff erent receptor proteins. TRβ2 is found
only in the brain, but TRα1, TRα2, and TRβ1 are widely distributed.
TRα2 diff ers from the other three in that it does not
bind T3 and its function is not yet fully established. TRs bind
to DNA as monomers, homodimers, and heterodimers with
other nuclear receptors, particularly the retinoid X receptor
(RXR) . Th e TR/RXR heterodimer does not bind to 9-cis retinoic
acid, the usual ligand for RXR, but TR binding to DNA
is greatly enhanced in response to thyroid hormones when
the receptor is in the form of this heterodimer. Th ere are also
coactivator and corepressor proteins that aff ect the actions of
TRs. Presumably, this complexity underlies the ability of thyroid
hormones to produce many diff erent eff ects in the body.
In most of its actions, T 3 acts more rapidly and is three to
fi ve times more potent than T 4 ( Figure 19–10 ). Th is is because
T 3 is less tightly bound to plasma proteins than is T 4 , but binds
TABLE 195 Physiologic effects of thyroid hormones.
Target Tissue Effect Mechanism
Heart Chronotropic and Inotropic Increased number of β-adrenergic receptors
Enhanced responses to circulating catecholamines
Increased proportion of α-myosin heavy chain (with higher ATPase activity)
Adipose tissue Catabolic Stimulated lipolysis
Muscle Catabolic Increased protein breakdown
Bone Developmental Promote normal growth and skeletal development
Nervous system Developmental Promote normal brain development
Gut Metabolic Increased rate of carbohydrate absorption
Lipoprotein Metabolic Formation of LDL receptors
Other Calorigenic Stimulated oxygen consumption by metabolically active tissues (exceptions: testes,
uterus, lymph nodes, spleen, anterior pituitary)
Increased metabolic rate
Modifi ed and reproduced with permission from McPhee SJ, Lingarra VR, Ganong WF (editors): Pathophysiology of Disease , 6th ed. McGraw-Hill, 2010.
80
60
40
20
20 40 60
Increased metabolism
(mL O2/100 g/h)
80 100
Dose (μg/kg/d)
T3
T4
FIGURE 1910 Calorigenic responses of thyroidectomized
rats to subcutaneous injections of T 4 and T 3 . Note the substantially
greater potency of T 3 . (Redrawn and reproduced with permission from Barker
SB: Peripheral actions of thyroid hormones. Fed Proc 1962;21:635.)
more avidly to thyroid hormone receptors. As previously
noted, RT 3 is inert (see Clinical Box 19–3).
CALORIGENIC ACTION
T 4 and T 3 increase the O 2 consumption of almost all metabolically
active tissues. Th e exceptions are the adult brain, testes,
uterus, lymph nodes, spleen, and anterior pituitary. T 4 actually
depresses the O 2 consumption of the anterior pituitary, presumably
because it inhibits TSH secretion. Th e increase in metabolic
rate produced by a single dose of T 4 becomes measurable
aft er a latent period of several hours and lasts 6 days or more.
Some of the calorigenic eff ect of thyroid hormones is due
to metabolism of the fatty acids they mobilize. In addition, thyroid
hormones increase the activity of the membrane-bound
Na, K ATPase in many tissues.
Eff ects Secondary to Calorigenesis
When the metabolic rate is increased by T 4 and T 3 in adults,
nitrogen excretion is increased; if food intake is not increased,
endogenous protein and fat stores are catabolized and weight
is lost. In hypothyroid children, small doses of thyroid hormones
cause a positive nitrogen balance because they stimulate
growth, but large doses cause protein catabolism similar
to that produced in the adult. Th e potassium liberated during
protein catabolism appears in the urine, and there is also an
increase in urinary hexosamine and uric acid excretion.
When the metabolic rate is increased, the need for all
vitamins is increased and vitamin defi ciency syndromes may
be precipitated. Th yroid hormones are necessary for hepatic
conversion of carotene to vitamin A, and the accumulation of
carotene in the bloodstream (carotenemia) in hypothyroidism
is responsible for the yellowish tint of the skin. Carotenemia
CHAPTER 19 The Thyroid Gland 349
EFFECTS ON THE
CARDIOVASCULAR SYSTEM
Large doses of thyroid hormones cause enough extra heat production
to lead to a slight rise in body temperatures (Chapter
17), which in turn activates heat-dissipating mechanisms.
Peripheral resistance decreases because of cutaneous vasodilation,
and this increases levels of renal Na + and water absorption,
expanding blood volume. Cardiac output is increased
by the direct action of thyroid hormones, as well as that of catecholamines,
on the heart, so that pulse pressure and cardiac
rate are increased and circulation time is shortened.
T 3 is not formed from T 4 in cardiac myocytes to any
degree, but circulatory T 3 enters the myocytes, combines with
its receptors, and enters the nucleus, where it promotes the
expression of some genes and inhibits the expression of others.
Th ose that are enhanced include the genes for α-myosin heavy
chain, sarcoplasmic reticulum Ca 2+ ATPase, β-adrenergic
receptors, G proteins, Na, K ATPase, and certain K + channels.
Th ose that are inhibited include the genes for β-myosin
heavy chain, phospholamban, two types of adenylyl cyclase,
T 3 nuclear receptors, and NCX, the Na + –Ca 2+ exchanger. Th e
net result is increased heart rate and force of contraction.
Th e two myosin heavy chain (MHC) isoforms, α-MHC and
β-MHC, produced by the heart are encoded by two highly
homologous genes located on the short arm of chromosome 17.
Each myosin molecule consists of two heavy chains and two
pairs of light chains (see Chapter 5). Th e myosin containing
β-MHC has less ATPase activity than the myosin containing
α-MHC. α-MHC predominates in the atria in adults, and its
level is increased by treatment with thyroid hormone. Th is
increases the speed of cardiac contraction. Conversely, expression
of the α-MHC gene is depressed and that of the β-MHC
gene is enhanced in hypothyroidism.
EFFECTS ON THE
NERVOUS SYSTEM
In hypothyroidism, mentation is slow and the cerebrospinal
fl uid (CSF) protein level is elevated. Th yroid hormones reverse
these changes, and large doses cause rapid mentation, irritability,
and restlessness. Overall, cerebral blood fl ow and glucose
and O 2 consumption by the brain are normal in adult hypoand
hyperthyroidism. However, thyroid hormones enter the
brain in adults and are found in gray matter in numerous different
locations. In addition, astrocytes in the brain convert
T 4 to T 3 , and there is a sharp increase in brain D 2 activity aft er
thyroidectomy that is reversed within 4 h by a single intravenous
dose of T 3 . Some of the eff ects of thyroid hormones
on the brain are probably secondary to increased responsiveness
to catecholamines, with consequent increased activation
of the reticular activating system (see Chapter 14). In addition,
thyroid hormones have marked eff ects on brain development.
Th e parts of the central nervous system (CNS) most aff ected
are the cerebral cortex and the basal ganglia. In addition, the
can be distinguished from jaundice because in the former condition
the sclera are not yellow.
Th e skin normally contains a variety of proteins combined
with polysaccharides, hyaluronic acid, and chondroitin sulfuric
acid. In hypothyroidism, these complexes accumulate, promoting
water retention and the characteristic puffi ness of the
skin (myxedema). When thyroid hormones are administered,
the proteins are metabolized, and diuresis continues until the
myxedema is cleared.
Milk secretion is decreased in hypothyroidism and stimulated
by thyroid hormones, a fact sometimes put to practical
use in the dairy industry. Th yroid hormones do not stimulate
the metabolism of the uterus but are essential for normal menstrual
cycles and fertility.
CLINICAL BOX 19–3
Thyroid Hormone Resistance
Some mutations in the gene that codes for TRβ are associated
with resistance to the eff ects of T 3 and T 4 . Most
commonly, there is resistance to thyroid hormones in the
peripheral tissues and the anterior pituitary gland. Patients
with this abnormality are usually not clinically hypothyroid,
because they maintain plasma levels of T 3 and T 4 that are
high enough to overcome the resistance, and hTRα is unaffected.
However, plasma TSH is inappropriately high relative
to the high circulating T 3 and T 4 levels and is diffi cult to suppress
with exogenous thyroid hormone. Some patients have
thyroid hormone resistance only in the pituitary. They have
hypermetabolism and elevated plasma T 3 and T 4 levels with
normal, nonsuppressible levels of TSH. A few patients apparently
have peripheral resistance with normal pituitary sensitivity.
They have hypometabolism despite normal plasma
levels of T 3 , T 4 , and TSH An interesting fi nding is that attention
defi cit hyperactivity disorder , a condition frequently
diagnosed in children who are overactive and impulsive, is
much more common in individuals with thyroid hormone
resistance than in the general population. This suggests that
hTRβ may play a special role in brain development.
THERAPEUTIC HIGHLIGHTS
Most patients remain euthyroid in this condition, even
in the face of a goiter. It is important to consider thyroid
hormone resistance in the diff erential diagnosis
of Graves disease to avoid the inappropriate use of
antithyroid medications or even thyroid ablation.
Isolated peripheral resistance to thyroid hormones
can be treated by supplying large doses of synthetic
T 4 exogenously. These are suffi cient to overcome the
resistance and increase the metabolic rate.
350 SECTION III Endocrine and Reproductive Physiology
EFFECTS ON CARBOHYDRATE
METABOLISM
Th yroid hormones increase the rate of absorption of carbohydrates
from the gastrointestinal tract, an action that is
probably independent of their calorigenic action. In hyperthyroidism,
therefore, the plasma glucose level rises rapidly aft er a
carbohydrate meal, sometimes exceeding the renal threshold.
However, it falls again at a rapid rate.
EFFECTS ON CHOLESTEROL
METABOLISM
Th yroid hormones lower circulating cholesterol levels. Th e
plasma cholesterol level drops before the metabolic rate rises,
which indicates that this action is independent of the stimulation
of O 2 consumption. Th e decrease in plasma cholesterol
concentration is due to increased formation of low-density
lipoprotein (LDL) receptors in the liver, resulting in increased
hepatic removal of cholesterol from the circulation. Despite
considerable eff ort, however, it has not been possible to produce
a clinically useful thyroid hormone analog that lowers
plasma cholesterol without increasing metabolism.
EFFECTS ON GROWTH
Th yroid hormones are essential for normal growth and skeletal
maturation (see Chapter 21). In hypothyroid children,
bone growth is slowed and epiphysial closure delayed. In the
absence of thyroid hormones, growth hormone secretion
is also depressed. Th is further impairs growth and development,
since thyroid hormones normally potentiate the eff ect
of growth hormone on tissues.
CHAPTER SUMMARY
Th e thyroid g ■ land transports and fi xes iodide to amino acids
present in thyroglobulin to generate the thyroid hormones
thyroxine (T 4 ) and triiodothyronine (T 3 ).
■ Synthesis and secretion of thyroid hormones is stimulated
by thyroid-stimulating hormone (TSH) from the pituitary,
which in turn is released in response to thyrotropin-releasing
hormone (TRH) from the hypothalamus. Th ese releasing
factors are controlled by changes in whole body status (eg,
exposure to cold or stress).
■ Th yroid hormones circulate in the plasma predominantly in
protein-bound forms. Only the free hormones are biologically
active, and both feed back to reduce secretion of TSH.
■ Th yroid hormones exert their eff ects by entering cells and
binding to thyroid receptors. Th e liganded forms of thyroid
receptors are nuclear transcription factors that alter gene
expression.
■ Th yroid hormones stimulate metabolic rate, calorigenesis,
cardiac function, and normal mentation, and interact
synergistically with catecholamines. Th yroid hormones
cochlea is also aff ected. Consequently, thyroid hormone defi -
ciency during development causes mental retardation, motor
rigidity, and deaf–mutism. Defi ciencies in thyroid hormone
synthesis secondary to a failure of thyrocytes to transport
iodide presumably also contribute to deafness in Pendred syndrome,
discussed above.
Th yroid hormones also exert eff ects on refl exes. Th e
reaction time of stretch refl exes (see Chapter 12) is shortened
in hyperthyroidism and prolonged in hypothyroidism.
Measurement of the reaction time of the ankle jerk (Achilles
refl ex) has attracted attention as a clinical test for evaluating
thyroid function, but this reaction time is also aff ected by
other diseases and thus is not a specifi c assessment of thyroid
activity.
RELATION TO CATECHOLAMINES
Th e actions of thyroid hormones and the catecholamines
norepinephrine and epinephrine are intimately interrelated.
Epinephrine increases the metabolic rate, stimulates the
nervous system, and produces cardiovascular eff ects similar
to those of thyroid hormones, although the duration of these
actions is brief. Norepinephrine has generally similar actions.
Th e toxicity of the catecholamines is markedly increased in
rats treated with T 4 . Although plasma catecholamine levels
are normal in hyperthyroidism, the cardiovascular eff ects,
tremulousness, and sweating that are seen in the setting of
excess thyroid hormones can be reduced or abolished by
sympathectomy. Th ey can also be reduced by drugs such
as propranolol that block β-adrenergic receptors. Indeed,
propranolol and other β blockers are used extensively in the
treatment of thyrotoxicosis and in the treatment of the severe
exacerbations of hyperthyroidism called thyroid storms .
However, even though β blockers are weak inhibitors of
extrathyroidal conversion of T 4 to T 3 , and consequently
may produce a small fall in plasma T 3 , they have little eff ect
on the other actions of thyroid hormones. Presumably, the
functional synergism observed between catecholamines
and thyroid hormones, particularly in pathological settings,
arises from their overlapping biological functions as well as
the ability of thyroid hormones to increase expression of catecholamine
receptors and the signaling eff ectors to which
they are linked.
EFFECTS ON SKELETAL MUSCLE
Muscle weakness occurs in most patients with hyperthyroidism
(thyrotoxic myopathy) , and when the hyperthyroidism is
severe and prolonged, the myopathy may be severe. Th e muscle
weakness may be due in part to increased protein catabolism.
Th yroid hormones aff ect the expression of the MHC genes in
skeletal as well as cardiac muscle (see Chapter 5). However, the
eff ects produced are complex and their relation to the myopathy
is not established. Hypothyroidism is also associated with
muscle weakness, cramps, and stiff ness.
CHAPTER 19 The Thyroid Gland 351
Hyperthyroidism due to D. diff use hyperplasia of thyrotropes
of the anterior pituitary
E. Iodine defi ciency
6. Hypothyroidism due to disease of the thyroid gland is
associated with increased plasma levels of
A. Cholesterol
B. Albumin
C. RT 3
D. Iodide
E. TBG
7. A young woman has puff y skin and a hoarse voice. Her plasma
TSH concentration is low but increases markedly when she is
given TRH. She probably has
A. hyperthyroidism due to a thyroid tumor.
B. hypothyroidism due to a primary abnormality in the thyroid
gland.
C. hypothyroidism due to a primary abnormality in the
pituitary gland.
D. hypothyroidism due to a primary abnormality in
the hypothalamus.
E. hyperthyroidism due to a primary abnormality
in the hypothalamus.
8. Th e enzyme primarily responsible for the conversion of T 4 to T 3
in the periphery is
A. D 1 thyroid deiodinase
B. D 2 thyroid deiodinase
C. D 3 thyroid deiodinase
D. Th yroid peroxidase
E. None of the above
9. Which of the following would be least aff ected by injections
of TSH?
A. Th yroidal uptake of iodine
B. Synthesis of thyroglobulin
C. Cyclic adenosine monophosphate (AMP) in thyroid cells
D. Cyclic guanosine monophosphate (GMP) in thyroid cells
E. Size of the thyroid
10. Th yroid hormone receptors bind to DNA in which of the
following forms?
A. A heterodimer with the prolactin receptor
B. A heterodimer with the growth hormone receptor
C. A heterodimer with the retinoid X receptor
D. A heterodimer with the insulin receptor
E. A heterodimer with the progesterone receptor
CHAPTER RESOURCES
Brent GA: Graves’ disease. N Engl J Med 2008;358:2594.
Dohan O, Carrasco N: Advances in Na + /I – symporter (NIS) research
in the thyroid and beyond. Mol Cell Endocrinol 2003;213:59.
Glaser B: Pendred syndrome. Pediatr Endocrinol Rev
2003;1(Suppl 2):199.
Peeters RP, van der Deure WM, Visser TJ: Genetic variation in
thyroid hormone pathway genes: Polymorphisms in the TSH
receptor and the iodothyronine deiodinases. Eur J Endocrinol
2006;155:655.
also play critical roles in development, particularly of the
nervous system, and growth.
■ Disease results with both under- and overactivity of the thyroid
gland. Hypothyroidism is accompanied by mental and physical
slowing in adults, and by mental retardation and dwarfi sm if
it occurs in neonatal life. Overactivity of the thyroid gland,
which most commonly is caused by autoantibodies that trigger
secretion (Graves disease) results in body wasting, nervousness,
and tachycardia.
MULTIPLECHOICE QUESTIONS
For all questions, select the single best answer unless otherwise
directed .
1. A 40-year-old woman comes to her primary care physician
complaining of nervousness and an unexplained weight loss of
20 pounds over the past 3 months despite her impression that
she is eating all the time. On physical examination, her eyes are
found to be protruding, her skin is moist and warm, and her
fi ngers have a slight tremor. Compared to a normal individual,
a biopsy of her thyroid gland would most likely reveal which of
the following:
A. Decreased numbers of reabsorption lacunae
B. Decreased evidence of endocytosis
C. A decrease in the cross-sectional area occupied by colloid
D. Increased levels of NIS in the basolateral membrane of
thyrocytes
E. Decreased evidence of lysosomal activity
2. Which of the following is not essential for normal biosynthesis
of thyroid hormones?
A. Iodine
B. Ferritin
C. Th yroglobulin
D. Protein synthesis
E. TSH
3. Increasing intracellular I – due to the action of NIS is an
example of
A. Endocytosis
B. Passive diff usion
C. Na + and K + cotransport
D. Primary active transport
E. Secondary active transport
4. Th e metabolic rate is least aff ected by an increase in the plasma
level of
A. TSH
B. TRH
C. TBG
D. Free T 4
E. Free T 3
5. In which of the following conditions is it most likely that the
TSH response to TRH will be reduced?
A. Hypothyroidism due to tissue resistance to thyroid hormone
B. Hypothyroidism due to disease destroying the thyroid gland
C. Hyperthyroidism due to circulating antithyroid antibodies
with TSH activity
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353
O B J E C T I V E S
After reading this chapter,
you should be able to:
■ Name the three catecholamines secreted by the adrenal medulla and
summarize their biosynthesis, metabolism, and function.
■ List the stimuli that increase adrenal medullary secretion.
■ Diff erentiate between C
18 , C 19 , and C 21 steroids and give examples of each.
■ Outline the steps involved in steroid biosynthesis in the adrenal cortex.
■ Name the plasma proteins that bind adrenocortical steroids and discuss their
physiologic role.
■ Name the major site of adrenocortical hormone metabolism and the
principal metabolites produced from glucocorticoids, adrenal androgens, and
aldosterone.
■ Describe the mechanisms by which glucocorticoids and aldosterone produce
changes in cellular function.
■ List and briefl y describe the physiologic and pharmacologic eff ects of
glucocorticoids.
■ Contrast the physiologic and pathologic eff ects of adrenal androgens.
■ Describe the mechanisms that regulate secretion of glucocorticoids and
adrenal sex hormones.
■ List the actions of aldosterone and describe the mechanisms that regulate
aldosterone secretion.
■ Describe the main features of the diseases caused by excess or defi ciency of
each of the hormones of the adrenal gland.
C H A P T E R
The Adrenal Medulla
& Adrenal Cortex 20
INTRODUCTION
Th ere are two endocrine organs in the adrenal gland, one
surrounding the other. Th e main secretions of the inner
adrenal medulla ( Figure 20–1 ) are the catecholamines
epinephrine, norepinephrine, and dopamine; the outer
adrenal cortex secretes steroid hormones.
Th e adrenal medulla is in eff ect a sympathetic ganglion
in which the postganglionic neurons have lost their axons
and become secretory cells. Th e cells secrete when stimulated
by the preganglionic nerve fi bers that reach the gland via the
splanchnic nerves. Adrenal medullary hormones work mostly
to prepare the body for emergencies, the so-called “fi ght-orfl
ight” responses.
Th e adrenal cortex secretes glucocorticoids, steroids
with widespread eff ects on the metabolism of carbohydrate
and protein; and a mineralocorticoid essential to the
maintenance of Na + balance and extracellular fl uid (ECF)
volume. It is also a secondary site of androgen synthesis,
secreting sex hormones such as testosterone, which can exert
eff ects on reproductive function. Mineralocorticoids and the
glucocorticoids are necessary for survival. Adrenocortical
Ganong_Ch20_353-376.indd 353 1/5/12 7:26:48
354 SECTION III Endocrine and Reproductive Physiology
ADRENAL MORPHOLOGY
Th e adrenal medulla, which constitutes 28% of the mass of the
adrenal gland, is made up of interlacing cords of densely innervated
granule-containing cells that abut on venous sinuses.
Two cell types can be distinguished morphologically: an epinephrine-
secreting type that has larger, less dense granules; and
a norepinephrine-secreting type in which smaller, very dense
granules fail to fi ll the vesicles in which they are contained. In
humans, 90% of the cells are the epinephrine-secreting type and
10% are the norepinephrine-secreting type. Th e type of cell that
secretes dopamine is unknown. Paraganglia, small groups of
cells resembling those in the adrenal medulla, are found near
the thoracic and abdominal sympathetic ganglia ( Figure 20–1 ).
In adult mammals, the adrenal cortex is divided into three
zones ( Figure 20–2 ). Th e outer zona glomerulosa is made up
of whorls of cells that are continuous with the columns of cells
that form the zona fasciculata. Th ese columns are separated by
venous sinuses. Th e inner portion of the zona fasciculata merges
into the zona reticularis, where the cell columns become interlaced
in a network. Th e zona glomerulosa makes up 15% of the
mass of the adrenal gland; the zona fasciculata, 50%; and the
FIGURE 201 Human adrenal glands. Adrenocortical tissue
is yellow; adrenal medullary tissue is orange. Note the location of
the adrenals at the superior pole of each kidney. Also shown are
extra-adrenal sites (gray) at which cortical and medullary tissue is
sometimes found. (Reproduced with permission from Williams RH: Textbook of
Endocrinology, 4th ed. Williams RH [editor]: Saunders, 1968.)
zona reticularis, 7%. Th e adrenocortical cells contain abundant
lipid, especially in the outer portion of the zona fasciculata.
All three cortical zones secrete corticosterone, but the active
enzymatic mechanism for aldosterone biosynthesis is limited to
the zona glomerulosa, whereas the enzymatic mechanisms for
forming cortisol and sex hormones are found in the two inner
zones. Furthermore, subspecialization occurs within the inner
two zones, with the zona fasciculata secreting mostly glucocorticoids
and the zona reticularis secreting mainly sex hormones.
Arterial blood reaches the adrenal from many small
branches of the phrenic and renal arteries and the aorta. From
a plexus in the capsule, blood fl ows through the cortex to the
sinusoids of the medulla. Th e medulla is also supplied by a
few arterioles that pass directly to it from the capsule. In most
species, including humans, blood from the medulla fl ows into
a central adrenal vein. Th e blood fl ow through the adrenal is
large, as it is in most endocrine glands.
During fetal life, the human adrenal is large and under
pituitary control, but the three zones of the permanent cortex
represent only 20% of the gland. Th e remaining 80% is the large
fetal adrenal cortex, which undergoes rapid degeneration at
the time of birth. A major function of this fetal adrenal is synthesis
and secretion of sulfate conjugates of androgens that are
converted in the placenta to estrogens (see Chapter 22 ). No
structure is comparable to the human fetal adrenal in laboratory
animals.
An important function of the zona glomerulosa, in addition
to aldosterone synthesis, is the formation of new cortical
cells. Th e adrenal medulla does not regenerate, but when
the inner two zones of the cortex are removed, a new zona
fasciculata and zona reticularis regenerate from glomerular
cells attached to the capsule. Small capsular remnants regrow
large pieces of adreno-cortical tissue. Immediately aft er hypophysectomy,
the zona fasciculata and zona reticularis begin to
atrophy, whereas the zona glomerulosa is unchanged because
of the action of angiotensin II on this zone. Th e ability to
secrete aldosterone and conserve Na + is normal for some time
aft er hypophysectomy, but in long-standing hypopituitarism,
aldosterone defi ciency may develop, apparently because of the
absence of a pituitary factor that maintains the responsiveness
of the zona glomerulosa. Injections of ACTH and stimuli that
cause endogenous ACTH secretion produce hypertrophy of
the zona fasciculata and zona reticularis but actually decrease,
rather than increase, the size of the zona glomerulosa.
Th e cells of the adrenal cortex contain large amounts
of smooth endoplasmic reticulum, which is involved in the
steroid-forming process. Other steps in steroid biosynthesis
occur in the mitochondria. Th e structure of steroid-secreting
cells is very similar throughout the body. Th e typical features
of such cells are shown in Figure 20–3 .
secretion is controlled primarily by adrenocorticotropic
hormone (ACTH) from the anterior pituitary, but
mineralocorticoid secretion is also subject to independent
control by circulating factors, of which the most important is
angiotensin II, a peptide formed in the bloodstream by the
action of renin.
CHAPTER 20 The Adrenal Medulla & Adrenal Cortex 355
ADRENAL MEDULLA:
STRUCTURE & FUNCTION
OF MEDULLARY HORMONES
CATECHOLAMINES
Norepinephrine, epinephrine, and small amounts of dopamine
are synthesized by the adrenal medulla. Cats and some
other species secrete mainly norepinephrine, but in dogs and
humans, most of the catecholamine output in the adrenal vein
is epinephrine. Norepinephrine also enters the circulation
from noradrenergic nerve endings.
Th e structures of norepinephrine, epinephrine, and dopamine
and the pathways for their biosynthesis and metabolism
are discussed in Chapter 7 . Norepinephrine is formed by
hydroxylation and decarboxylation of tyrosine, and epinephrine
by methylation of norepinephrine. Phenylethanolamine-Nmethyltransferase
(PNMT), the enzyme that catalyzes the formation
of epinephrine from norepinephrine, is found in appreciable
quantities only in the brain and the adrenal medulla. Adrenal
medullary PNMT is induced by glucocorticoids. Although relatively
large amounts are required, the glucocorticoid concentration
is high in the blood draining from the cortex to the medulla.
Aft er hypophysectomy, the glucocorticoid concentration of this
blood falls and epinephrine synthesis is decreased. In addition,
glucocorticoids are apparently necessary for the normal development
of the adrenal medulla; in 21β-hydroxylase defi ciency, glucocorticoid
secretion is reduced during fetal life and the adrenal
medulla is dysplastic. In untreated 21β-hydroxylase defi ciency,
circulating catecholamines are low aft er birth.
In plasma, about 95% of the dopamine and 70% of the
norepinephrine and epinephrine are conjugated to sulfate.
Sulfate conjugates are inactive and their function is unsettled.
In recumbent humans, the normal plasma level of free norepinephrine
is about 300 pg/mL (1.8 nmol/L). On standing, the
level increases 50–100% ( Figure 20–4 ). Th e plasma norepinephrine
level is generally unchanged aft er adrenalectomy, but
the free epinephrine level, which is normally about 30 pg/mL
(0.16 nmol/L), falls to essentially zero. Th e epinephrine found
in tissues other than the adrenal medulla and the brain is for
the most part absorbed from the bloodstream rather than synthesized
in situ. Interestingly, low levels of epinephrine reappear
in the blood some time aft er bilateral adrenalectomy, and
these levels are regulated like those secreted by the adrenal
medulla. Th ey may come from cells such as the intrinsic cardiac
adrenergic (ICA) cells (see Chapter 13 ), but their exact
source is unknown.
Zona
glomerulosa
Zona
fasciculata
Medulla Cortex
Zona
reticularis
Aldosterone
Cortisol
and
androgens
Epinephrine
and
norepinephrine
Cortex
Medulla
FIGURE 202 Section through an adrenal
gland showing both the medulla and the zones
of the cortex, as well as the hormones they
secrete. (Reproduced with permission from Widmaier EP,
Raff H, Strang KT: Vander’s Human Physiology: The Mechanisms
of Body Function, 11th ed. McGraw-Hill, 2008.)
356 SECTION III Endocrine and Reproductive Physiology
Plasma dopamine levels are normally very low, about
0.13 nmol/L. Most plasma dopamine is thought to be derived
from sympathetic noradrenergic ganglia.
Th e catecholamines have a half-life of about 2 min in the
circulation. For the most part, they are methoxylated and then
oxidized to 3-methoxy-4-hydroxymandelic acid (vanillylmandelic
acid [VMA]; see Chapter 7 ). About 50% of the secreted
catecholamines appear in the urine as free or conjugated metanephrine
and normetanephrine, and 35% as VMA. Only small
amounts of free norepinephrine and epinephrine are excreted.
In normal humans, about 30 μg of norepinephrine, 6 μg of epinephrine,
and 700 μg of VMA are excreted per day.
7
6
5
4
3
1
Receptor
2
Smooth
endoplasmic
reticulum
Mitochondrion
Shuttling of
intermediates
P450 enzymes
located on inner
membrane
Free
cholesterol
Lipid droplet
(from LDL)
Phosphoproteins
(cholesterol esterase)
Proteins
PKA
active
cAMP
PKA
inactive
G-protein Adenylyl cyclase
Nucleus
ATP
H
Diffusion of steroid hormone into blood
FIGURE 203 Schematic overview of the structures
of steroid-secreting cells and the intracellular pathway of
steroid synthesis. LDL, low-density lipoprotein; PKA, protein
kinase A. (Reproduced with permission from Widmaier EP, Raff H, Strang
KT: Vander’s Human Physiology: The Mechanisms of Body Function, 11th ed.
McGraw-Hill, 2008.)
Pheochromocytoma (16)
Cigarette smoking (10)
To < 40 mg/dL (6)
95 → 60 mg/dL (10)
Mild (8)
Moderate (8)
Heavy (8)
During (11)
After (11)
Ketoacidosis (10)
Myocardial infarction (11)
Quiet standing (40)
Resting supine (60)
Hypoglycemia
Exercise
Surgery
0 500 1000 1500 2000 2500
0 500 1000 1500 2000 2500
(5310)
Plasma norepinephrine (pg/mL)
0
0 100
Plasma epinephrine (pg/mL)
200 300 400 500 1000 5000
100 200 300 400 500 1000 5000
FIGURE 204 Norepinephrine and epinephrine levels in
human venous blood in various physiologic and pathologic states.
Note that the horizontal scales are diff erent. The numbers to the left
in parentheses are the numbers of subjects tested. In each case, the
vertical dashed line identifi es the threshold plasma concentration
at which detectable physiologic changes are observed. (Modifi ed and
reproduced with permission from Cryer PE: Physiology and pathophysiology of the
human sympathoadrenal neuroendocrine system. N Engl J Med 1980;303:436.)
CHAPTER 20 The Adrenal Medulla & Adrenal Cortex 357
OTHER SUBSTANCES SECRETED
BY THE ADRENAL MEDULLA
In the medulla, norepinephrine and epinephrine are stored in
granules with ATP. Th e granules also contain chromogranin A
(see Chapter 7 ). Secretion is initiated by acetylcholine released
from the preganglionic neurons that innervate the secretory
cells. Acetylcholine activates cation channels allowing Ca 2+ to
enter the cells from the ECF and trigger the exocytosis of the
granules. In this fashion, catecholamines, ATP, and proteins
from the granules are all released into the blood together.
Epinephrine-containing cells of the medulla also contain
and secrete opioid peptides (see Chapter 7 ). Th e precursor
molecule is preproenkephalin. Most of the circulating metenkephalin
comes from the adrenal medulla. Th e circulating opioid
peptides do not cross the blood–brain barrier.
Adrenomedullin, a vasodepressor polypeptide found in
the adrenal medulla, is discussed in Chapter 32 .
EFFECTS OF EPINEPHRINE
& NOREPINEPHRINE
In addition to mimicking the eff ects of noradrenergic nervous
discharge, norepinephrine and epinephrine exert metabolic
eff ects that include glycogenolysis in liver and skeletal muscle,
mobilization of free fatty acids (FFA), increased plasma
lactate, and stimulation of the metabolic rate. Th e eff ects of
norepinephrine and epinephrine are brought about by actions
on two classes of receptors: α- and β-adrenergic receptors.
α receptors are subdivided into two groups, α 1 and α 2 receptors,
and β receptors into β 1 , β 2 , and β 3 receptors, as outlined in
Chapter 7 . Th ere are three subtypes of α 1 receptors and three
subtypes of α 2 receptors (see Table 7–2 ).
Norepinephrine and epinephrine both increase the force
and rate of contraction of the isolated heart. Th ese responses
are mediated by β 1 receptors. Th e catecholamines also increase
myocardial excitability, causing extrasystoles and, occasionally,
more serious cardiac arrhythmias. Norepinephrine produces
vasoconstriction in most if not all organs via α 1 receptors, but
epinephrine dilates the blood vessels in skeletal muscle and
the liver via β 2 receptors. Th is usually overbalances the vasoconstriction
produced by epinephrine elsewhere, and the total
peripheral resistance drops. When norepinephrine is infused
slowly in normal animals or humans, the systolic and diastolic
blood pressures rise. Th e hypertension stimulates the carotid
and aortic baroreceptors, producing refl ex bradycardia that
overrides the direct cardioacceleratory eff ect of norepinephrine.
Consequently, cardiac output per minute falls. Epinephrine
causes a widening of the pulse pressure, but because baroreceptor
stimulation is insuffi cient to obscure the direct eff ect of
the hormone on the heart, cardiac rate, and output increase.
Th ese changes are summarized in Figure 20–5 .
Catecholamines increase alertness (see Chapter 14 ). Epinephrine
and norepinephrine are equally potent in this regard,
although in humans epinephrine usually evokes more anxiety
and fear.
150
100
50
30
20
10
15 20 35 40
Epi Nor
4
6
8
50
100
Time (min)
Epi = Epinephrine Nor = Norepinephrine
Cardiac output Heart rate
(L/min)
Total peripheral
resistance
Arterial BP
(mm Hg)
FIGURE 205 Circulatory changes produced in humans
by the slow intravenous infusion of epinephrine and
norepinephrine.
Th e catecholamines have several diff erent actions that
aff ect blood glucose. Epinephrine and norepinephrine both
cause glycogenolysis. Th ey produce this eff ect via β-adrenergic
receptors that increase cyclic adenosine monophosphate
(cAMP), with activation of phosphorylase, and via α-adrenergic
receptors that increase intracellular Ca 2+ (see Chapter 7 ). In
addition, the catecholamines increase the secretion of insulin
and glucagon via β-adrenergic mechanisms and inhibit the
secretion of these hormones via α-adrenergic mechanisms.
Norepinephrine and epinephrine also produce a prompt
rise in the metabolic rate that is independent of the liver and
a smaller, delayed rise that is abolished by hepatectomy and
coincides with the rise in blood lactate concentration. Th e initial
rise in metabolic rate may be due to cutaneous vasoconstriction,
which decreases heat loss and leads to a rise in body
temperature, or to increased muscular activity, or both. Th e
second rise is probably due to oxidation of lactate in the liver.
Mice unable to make norepinephrine or epinephrine because
their dopamine β-hydroxylase gene is knocked out are intolerant
of cold, but surprisingly, their basal metabolic rate is
elevated. Th e cause of this elevation is unknown.
When injected, epinephrine and norepinephrine cause
an initial rise in plasma K + because of release of K + from the
liver and then a prolonged fall in plasma K + because of an
increased entry of K + into skeletal muscle that is mediated by
β 2 -adrenergic receptors. Some evidence suggests that activation
of α receptors opposes this eff ect.
Th e increases in plasma norepinephrine and epinephrine
that are needed to produce the various eff ects listed above
have been determined by infusion of catecholamines in resting
humans. In general, the threshold for the cardiovascular and the
358 SECTION III Endocrine and Reproductive Physiology
metabolic eff ects of norepinephrine is about 1500 pg/mL, that
is, about fi ve times the resting value ( Figure 20–4 ). Epinephrine,
on the other hand, produces tachycardia when the plasma
level is about 50 pg/mL, that is, about twice the resting value.
Th e threshold for increased systolic blood pressure and lipolysis
is about 75 pg/mL; the threshold for hyperglycemia, increased
plasma lactate, and decreased diastolic blood pressure is about
150 pg/mL; and the threshold for the α-mediated decrease
in insulin secretion is about 400 pg/mL. Plasma epinephrine
oft en exceeds these thresholds. On the other hand, plasma norepinephrine
rarely exceeds the threshold for its cardiovascular
and metabolic eff ects, and most of its eff ects are due to its
local release from postganglionic sympathetic neurons. Most
adrenal medullary tumors (pheochromocytomas) secrete norepinephrine,
or epinephrine, or both, and produce sustained
hypertension. However, 15% of epinephrine-secreting tumors
secrete this catecholamine episodically, producing intermittent
bouts of palpitations, headache, glycosuria, and extreme
systolic hypertension. Th ese same symptoms are produced by
intravenous injection of a large dose of epinephrine.
EFFECTS OF DOPAMINE
Th e physiologic function of the dopamine in the circulation is
unknown. However, injected dopamine produces renal vasodilation,
probably by acting on a specifi c dopaminergic receptor. It
also produces vasodilation in the mesentery. Elsewhere, it produces
vasoconstriction, probably by releasing norepinephrine,
and it has a positive inotropic eff ect on the heart by an action on
β 1 -adrenergic receptors. Th e net eff ect of moderate doses of dopamine
is an increase in systolic pressure and no change in diastolic
pressure. Because of these actions, dopamine is useful in the
treatment of traumatic and cardiogenic shock (see Chapter 32 ).
Dopamine is made in the renal cortex. It causes natriuresis
and may exert this eff ect by inhibiting renal Na , K , ATPase.
REGULATION OF ADRENAL
MEDULLARY SECRETION
NEURAL CONTROL
Certain drugs act directly on the adrenal medulla, but physiologic
stimuli aff ect medullary secretion through the nervous
system. Catecholamine secretion is low in basal states, but the
secretion of epinephrine and, to a lesser extent, that of norepinephrine
is reduced even further during sleep.
Increased adrenal medullary secretion is part of the diffuse
sympathetic discharge provoked in emergency situations,
which Cannon called the “emergency function of the
sympathoadrenal system.” Th e ways in which this discharge
prepares the individual for fl ight or fi ght are described in
Chapter 13 , and the increases in plasma catecholamines under
various conditions are shown in Figure 20–4 .
Th e metabolic eff ects of circulating catecholamines are
probably important, especially in certain situations. Th e calorigenic
action of catecholamines in animals exposed to cold is
HO 3
4
5
6
1A
2
19
10
14 15
18
13
17
D
12 16
9
8
7
B
C
11
20
22
23
24
26
25
27
21
Cyclopentanoperhydrophenanthrene nucleus
CH3
C O
Progesterone
Corticoids
Androgens
Estrogens
Cholesterol
(27 carbons)
Pregnane
derivatives
(21 carbons)
Androstane
derivatives
(19 carbons)
Estrane
derivatives
(18 carbons)
FIGURE 206 Basic structure of adrenocortical and gonadal
steroids. The letters in the formula for cholesterol identify the four
basic rings, and the numbers identify the positions in the molecule.
As shown here, the angular methyl groups (positions 18 and 19) are
usually indicated simply by straight lines.
an example, and so is the glycogenolytic eff ect (see Chapter 24 )
in combating hypoglycemia.
SELECTIVE SECRETION
When adrenal medullary secretion is increased, the ratio of norepinephrine
to epinephrine in the adrenal effl uent is generally
unchanged. However, norepinephrine secretion tends to be selectively
increased by emotional stresses with which the individual
is familiar, whereas epinephrine secretion rises selectively in situations
in which the individual does not know what to expect.
ADRENAL CORTEX:
STRUCTURE & BIOSYNTHESIS OF
ADRENOCORTICAL HORMONES
CLASSIFICATION & STRUCTURE
Th e hormones of the adrenal cortex are derivatives of cholesterol.
Like cholesterol, bile acids, vitamin D, and ovarian and
testicular steroids, they contain the cyclopentanoperhydrophenanthrene
nucleus ( Figure 20–6 ). Gonadal and adrenocortical
steroids are of three types: C 21 steroids, which have
a two-carbon side chain at position 17; C 19 steroids, which
CHAPTER 20 The Adrenal Medulla & Adrenal Cortex 359
have a keto or hydroxyl group at position 17; and C 18 steroids,
which, in addition to a 17-keto or hydroxyl group, have no
angular methyl group attached to position 10. Th e adrenal
cortex secretes primarily C 21 and C 19 steroids. Most of the C 19
steroids have a keto group at position 17 and are therefore
called 17-ketosteroids. Th e C 21 steroids that have a hydroxyl
group at the 17 position in addition to the side chain are oft en
called 17-hydroxycorticoids or 17-hydroxycorticosteroids.
Th e C 19 steroids have androgenic activity. Th e C 21 steroids
are classifi ed, using Selye’s terminology, as mineralocorticoids
or glucocorticoids. All secreted C 21 steroids have both mineralocorticoid
and glucocorticoid activity; mineralocorticoids
are those in which eff ects on Na + and K + excretion predominate
and glucocorticoids are those in which eff ects on glucose
and protein metabolism predominate.
Th e details of steroid nomenclature and isomerism can
be found elsewhere. However, it is pertinent to mention
that the Greek letter Δ indicates a double bond and that the
groups that lie above the plane of each of the steroid rings
are indicated by the Greek letter β and a solid line (—OH),
whereas those that lie below the plane are indicated by α and
a dashed line (- - -OH). Th us, the C 21 steroids secreted by the
adrenal have a Δ 4 -3-keto confi guration in the A ring. In most
naturally occurring adrenal steroids, 17-hydroxy groups are in
the α confi guration, whereas 3-, 11-, and 21-hydroxy groups
are in the β confi guration. Th e 18-aldehyde confi guration of
naturally occurring aldosterone is the D form. l -aldosterone is
physiologically inactive.
C O
O
CH2OH
C O
HO
O
CH2OH
Corticosterone
11-Deoxycorticosterone
C O
O
CH3
Progesterone
C O
HO
CH3
Pregnenolone
ACTH
C O
O
CH2OH
C O
HO
O
CH2OH
C O
O
CH3
C O
OH
HO
CH3
17-Hydroxypregnenolone
17-Hydroxyprogesterone
11-Deoxycortisol
Cortisol
Cholesterol
Cholesterol
desmolase
3β-Hydroxysteroid
dehydrogenase
17α-Hydroxylase 17,20-Lyase
21β-Hydroxylase
11β-Hydroxylase
OH
O
O
HO
O
Dehydroepiandrosterone
Androstenedione
Testosterone
Estradiol
OH
OH
Sulfokinase
DHEA
sulfate
FIGURE 207 Outline of hormone biosynthesis in the zona fasciculata and zona reticularis of the adrenal cortex. The major secretory
products are underlined. The enzymes for the reactions are shown on the left and at the top of the chart. When a particular enzyme is defi cient,
hormone production is blocked at the points indicated by the shaded bars.
SECRETED STEROIDS
Innumerable steroids have been isolated from adrenal tissue,
but the only steroids normally secreted in physiologically
signifi cant amounts are the mineralocorticoid aldosterone,
the glucocorticoids cortisol and corticosterone, and
the androgens dehydroepiandrosterone (DHEA) and
androstenedione. Th e structures of these steroids are shown
in Figure 20–7 and Figure 20–8. Deoxycorticosterone is a
mineralocorticoid that is normally secreted in about the same
amount as aldosterone ( Table 20–1 ) but has only 3% of the
mineralocorticoid activity of aldosterone. Its eff ect on mineral
metabolism is usually negligible, but in diseases in which its
secretion is increased, its eff ect can be appreciable. Most of the
estrogens that are not formed in the ovaries are produced in
the circulation from adrenal androstenedione. Almost all the
dehydroepiandrosterone is secreted conjugated with sulfate,
although most if not all of the other steroids are secreted in the
free, unconjugated form (Clinical Box 20–1).
SPECIES DIFFERENCES
In all species from amphibia to humans, the major C 21 steroid
hormones secreted by adrenocortical tissue appear to
be aldosterone, cortisol, and corticosterone, although the
ratio of cortisol to corticosterone varies. Birds, mice, and rats
secrete corticosterone almost exclusively; dogs secrete approximately
equal amounts of the two glucocorticoids; and cats,
360 SECTION III Endocrine and Reproductive Physiology
tion. LDL receptors are especially abundant in adrenocortical
cells. Th e cholesterol is esterifi ed and stored in lipid droplets.
Cholesterol ester hydrolase catalyzes the formation of free
cholesterol in the lipid droplets ( Figure 20–9 ). Th e cholesterol
is transported to mitochondria by a sterol carrier protein. In
the mitochondria, it is converted to pregnenolone in a reaction
catalyzed by an enzyme known as cholesterol desmolase
or side-chain cleavage enzyme. Th is enzyme, like most of the
enzymes involved in steroid biosynthesis, is a member of the
cytochrome P450 superfamily and is also known as P450scc
or CYP11A1. For convenience, the various names of the
enzymes involved in adrenocortical steroid biosynthesis are
summarized in Table 20–3 .
Pregnenolone moves to the smooth endoplasmic reticulum,
where some of it is dehydrogenated to form progesterone
in a reaction catalyzed by 3β-hydroxysteroid
dehydrogenase. Th is enzyme has a molecular weight of 46,000
and is not a cytochrome P450. It also catalyzes the conversion
of 17α-hydroxypregnenolone to 17α-hydroxyprogesterone,
and dehydroepiandrosterone to androstenedione ( Figure
22–7 ) in the smooth endoplasmic reticulum. Th e 17α-
hydroxypregnenolone and the 17α-hydroxyprogesterone are
formed from pregnenolone and progesterone, respectively
( Figure 20–7 ) by the action of 17α-hydroxylase. Th is is
another mitochondrial P450, and it is also known as P450c17
C O
HO
HO
O
CH2OH
CH2
C O
O
HO HC
O
CH2OH
Cortisol
and
sex steroids
Cholesterol
Pregnenolone
Progesterone
Deoxycorticosterone
Corticosterone
18-Hydroxycorticosterone
Aldosterone
Aldosterone
synthase
Aldosterone
synthase
ANG II
Aldosterone
synthase
ACTH
ANG II
FIGURE 208 Hormone synthesis in the zona glomerulosa.
The zona glomerulosa lacks 17α-hydroxylase activity, and only the
zona glomerulosa can convert corticosterone to aldosterone because
it is the only zone that normally contains aldosterone synthase. ANG
II, angiotensin II.
CLINICAL BOX 20–1
Synthetic Steroids
As with many other naturally occurring substances, the activity
of adrenocortical steroids can be increased by altering
their structure. A number of synthetic steroids are available
that have many times the activity of cortisol. The relative
glucocorticoid and mineralocorticoid potencies of the natural
steroids are compared with those of the synthetic steroids
9α-fl uorocortisol, prednisolone, and dexamethasone
in Table 20–2 . The potency of dexamethasone is due to its
high affi nity for glucocorticoid receptors and its long halflife.
Prednisolone also has a long half-life.
TABLE 201 Principal adrenocortical hormones in adult humans. a
Name Synonyms
Average Plasma Concentration
(Free and Bound) a μg/dL)
Average Amount Secreted
(mg/24 h)
Cortisol Compound F, hydrocortisone 13.9 10
Corticosterone Compound B 0.4 3
Aldosterone 0.0006 0.15
Deoxycorticosterone DOC 0.0006 0.20
Dehydroepiandrosterone sulfate DHEAS 175.0 20
a All plasma concentration values except DHEAS are fasting morning values after overnight recumbency.
sheep, monkeys, and humans secrete predominantly cortisol.
In humans, the ratio of secreted cortisol to corticosterone is
approximately 7:1.
STEROID BIOSYNTHESIS
Th e major paths by which the naturally occurring adrenocortical
hormones are synthesized in the body are summarized
in Figures 20–7 and 20–8 . Th e precursor of all steroids
is cholesterol. Some of the cholesterol is synthesized from
acetate, but most of it is taken up from LDL in the circula-
CHAPTER 20 The Adrenal Medulla & Adrenal Cortex 361
or CYP17. Located in another part of the same enzyme is
17,20-lyase activity that breaks the 17,20 bond, converting
17α-pregnenolone and 17α-progesterone to the C 19 steroids
dehydroepiandrosterone and androstenedione.
Hydroxylation of progesterone to 11-deoxycorticosterone
and of 17α-hydroxyprogesterone to 11-deoxycortisol occurs
in the smooth endoplasmic reticulum. Th ese reactions are
catalyzed by 21β-hydroxylase, a cytochrome P450 that is also
known as P450c21 or CYP21A2.
11-deoxycorticosterone and the 11-deoxycortisol move back
to the mitochondria, where they are 11-hydroxylated to form corticosterone
and cortisol. Th ese reactions occur in the zona fasciculata
and zona reticularis and are catalyzed by 11β-hydroxylase, a
cytochrome P450 also known as P450c11 or CYP11B1.
In the zona glomerulosa there is no 11β-hydroxylase but a
closely related enzyme called aldosterone synthase is present.
Th is cytochrome P450 is 95% identical to 11β-hydroxylase
and is also known as P450c11AS or CYP11B2. Th e genes
that code CYP11B1 and CYP11B2 are both located on chromosome
8. However, aldosterone synthase is normally found
only in the zona glomerulosa. Th e zona glomerulosa also lacks
17α-hydroxylase. Th is is why the zona glomerulosa makes
aldosterone but fails to make cortisol or sex hormones.
Furthermore, subspecialization occurs within the inner
two zones. Th e zona fasciculata has more 3β-hydroxysteroid
dehydrogenase activity than the zona reticularis, and the
zona reticularis has more of the cofactors required for the
17,20-lyase activity of 17α-hydroxylase. Th erefore, the zona
fasciculata makes more cortisol and corticosterone, and the
zona reticularis makes more androgens. Most of the dehydroepiandrosterone
that is formed is converted to dehydroepiandrosterone
sulfate (DHEAS) by adrenal sulfokinase, and
this enzyme is localized in the zona reticularis as well.
ACTION OF ACTH
ACTH binds to high-affi nity receptors on the plasma membrane
of adrenocortical cells. Th is activates adenylyl cyclase
via G s . Th e resulting reactions ( Figure 20–9 ) lead to a prompt
increase in the formation of pregnenolone and its derivatives,
with secretion of the latter. Over longer periods, ACTH also
increases the synthesis of the P450s involved in the synthesis
of glucocorticoids.
ACTIONS OF ANGIOTENSIN II
Angiotensin II binds to AT 1 receptors (see Chapter 38 ) in the
zona glomerulosa that act via a G protein to activate phospholipase
C. Th e resulting increase in protein kinase C fosters
the conversion of cholesterol to pregnenolone ( Figure 20–8 )
and facilitates the action of aldosterone synthase, resulting in
increased secretion of aldosterone.
ENZYME DEFICIENCIES
Th e consequences of inhibiting any of the enzyme systems
involved in steroid biosynthesis can be predicted from
Figures 20–7 and 20–8 . Congenital defects in the enzymes lead
to defi cient cortisol secretion and the syndrome of congenital
adrenal hyperplasia. Th e hyperplasia is due to increased ACTH
secretion. Cholesterol desmolase defi ciency is fatal in utero
because it prevents the placenta from making the progesterone
necessary for pregnancy to continue. A cause of severe congenital
adrenal hyperplasia in newborns is a loss of function mutation
TABLE 202 Relative potencies of corticosteroids
compared with cortisol.a
Steroid
Glucocorticoid
Activity
Mineralocorticoid
Activity
Cortisol 1.0 1.0
Corticosterone 0.3 15
Aldosterone 0.3 3000
Deoxycorticosterone 0.2 100
Costisone 0.7 0.8
Prednisolone 4 0.8
9α-Fluorocortisol 10 125
Dexamethasone 25 –0
a Values are approximations based on liver glycogen deposition or antiinfl
ammatory assays for glucocorticoid activity, and eff ect on urinary Na + /K + or
maintenance of adrenalectomized animals for mineralocorticoid activity. The last
three steroids listed are synthetic compounds that do not occur naturally.
LDL
Cholesteryl
esters
Cholesterol
Cortisol Preg
11-Deoxycortisol
17-OH
preg
cAMP Protein
kinase A
ATP
CEH
SER
Lipid
droplet
Mitochondrion
ACTH
R
GS AC
FIGURE 209 Mechanism of action of ACTH on cortisolsecreting
cells in the inner two zones of the adrenal cortex. When
ACTH binds to its receptor (R), adenylyl cyclase (AC) is activated
via Gs. The resulting increase in cAMP activates protein kinase A,
and the kinase phosphorylates cholesteryl ester hydrolase (CEH),
increasing its activity. Consequently, more free cholesterol is formed
and converted to pregnenolone. Note that in the subsequent steps in
steroid biosynthesis, products are shuttled between the mitochondria
and the smooth endoplasmic reticulum (SER). Corticosterone is also
synthesized and secreted.
362 SECTION III Endocrine and Reproductive Physiology
of the gene for the steroidogenic acute regulatory (StAR) protein.
Th is protein is essential in the adrenals and gonads but not
in the placenta for the normal movement of cholesterol into the
mitochondria to reach cholesterol desmolase, which is located
on the matrix space side of the internal mitochondrial membrane
(see Chapter 16 ). In its absence, only small amounts of
steroids are formed. Th e degree of ACTH stimulation is marked,
resulting eventually in accumulation of large numbers of lipoid
droplets in the adrenal. For this reason, the condition is called
congenital lipoid adrenal hyperplasia. Because androgens are
not formed, female genitalia develop regardless of genetic sex
(see Chapter 22 ). In 3β hydroxysteroid dehydrogenase defi -
ciency, another rare condition, DHEA secretion is increased.
Th is steroid is a weak androgen that can cause some masculinization
in females with the disease, but it is not adequate to
produce full masculinization of the genitalia in genetic males.
Consequently, hypospadias, a condition where the opening of
the urethra is on the underside of the penis rather than its tip, is
common. In fully developed 17α-hydroxylase defi ciency, a third
rare condition due to a mutated gene for CYP17, no sex hormones
are produced, so female external genitalia are present.
However, the pathway leading to corticosterone and aldosterone
is intact, and elevated levels of 11-deoxycorticosterone and other
mineralocorticoids produce hypertension and hypokalemia.
Cortisol is defi cient, but this is partially compensated by the glucocorticoid
activity of corticosterone.
Unlike the defects discussed in the preceding paragraph,
21β-hydroxylase defi ciency is common, accounting for 90%
or more of the enzyme defi ciency cases. Th e 21β-hydroxylase
gene, which is in the human leukocyte antigen (HLA) complex
of genes on the short arm of chromosome 6 (see Chapter 3 ) is
one of the most polymorphic in the human genome. Mutations
occur at many diff erent sites in the gene, and the abnormalities
that are produced therefore range from mild to severe.
Production of cortisol and aldosterone are generally reduced,
so ACTH secretion and consequently production of precursor
steroids are increased. Th ese steroids are converted to
androgens, producing virilization. Th e characteristic pattern
that develops in females in the absence of treatment is the
adrenogenital syndrome. Masculization may not be marked
until later in life and mild cases can be detected only by laboratory
tests. In 75% of the cases, aldosterone defi ciency causes
appreciable loss of Na + ( salt-losing form of adrenal hyperplasia).
Th e resulting hypovolemia can be severe.
In 11β-hydroxylase defi ciency, virilization plus excess
secretion of 11-deoxycortisol and 11-deoxycorticosterone
take place. Because the former is an active mineralocorticoid,
patients with this condition also have salt and water retention
and, in two-thirds of the cases, hypertension ( hypertensive
form of congenital adrenal hyperplasia).
Glucocorticoid treatment is indicated in all of the virilizing
forms of congenital adrenal hyperplasia because it repairs
the glucocorticoid defi cit and inhibits ACTH secretion, reducing
the abnormal secretion of androgens and other steroids.
Expression of the cytochrome P450 enzymes responsible
for steroid hormone biosynthesis depends on steroid factor-1
(SF-1), an orphan nuclear receptor. If Ft2-F1, the gene for SF-1,
is knocked out, the gonads as well as adrenals fail to develop
and additional abnormalities are present at the pituitary and
hypothalamic level.
TRANSPORT, METABOLISM,
& EXCRETION OF
ADRENOCORTICAL HORMONES
GLUCOCORTICOID BINDING
Cortisol is bound in the circulation to an α globulin called
transcortin or corticosteroid-binding globulin (CBG). A
minor degree of binding to albumin also takes place. Corticosterone
is similarly bound, but to a lesser degree. Th e halflife
of cortisol in the circulation is therefore longer (about
60–90 min) than that of corticosterone (50 min). Bound steroids
are physiologically inactive (see Chapter 16 ). In addition,
relatively little free cortisol and corticosterone are found in the
urine because of protein binding.
Th e equilibrium between cortisol and its binding protein
and the implications of binding in terms of tissue supplies
and ACTH secretion are summarized in Figure 20–10 . Th e
bound cortisol functions as a circulating reservoir of hormone
that keeps a supply of free cortisol available to the tissues.
TABLE 203 Nomenclature for adrenal steroidogenic enzymes and their location in adrenal cells.
Trivial Name P450 CYP Location
Cholesterol desmolase; side-chain cleavage enzyme P450SCC CYP11A1 Mitochondria
3β-Hydroxysteroid dehydrogenase . . . . . . SER
17α-Hydroxylase, 17,20-lyase P450 C 17 CYP17 Mitochondria
21β-Hydroxylase P450 C 21 CYP21A2 SER
11β-Hydroxylase P450 C 11 CYP11B1 Mitochondria
Aldosterone synthase P450 C 11AS CYP11B2 Mitochondria
SER, smooth endoplasmic reticulum.
CHAPTER 20 The Adrenal Medulla & Adrenal Cortex 363
Th e relationship is similar to that of T 4 and its binding protein
(see Chapter 19 ). At normal levels of total plasma cortisol
(13.5 μg/dL or 375 nmol/L), very little free cortisol is present
in the plasma, but the binding sites on CBG become saturated
when the total plasma cortisol exceeds 20 μg/dL. At higher
plasma levels, binding to albumin increases, but the main
increase is in the unbound fraction.
CBG is synthesized in the liver and its production is
increased by estrogen. CBG levels are elevated during pregnancy
and depressed in cirrhosis, nephrosis, and multiple
ACTH
Anterior
pituitary
Tissue
cortisol
Protein-bound
cortisol in plasma
(13 μg/dL)
Adrenal
cortex
Free cortisol
in plasma
(~0.5 μg/dL)
FIGURE 2010 The interrelationships of free and bound
cortisol. The dashed arrow indicates that cortisol inhibits ACTH
secretion. The value for free cortisol is an approximation; in most
studies, it is calculated by subtracting the protein-bound cortisol
from the total plasma cortisol.
O
HO
C O
OH
Δ4-Hydrogenase;
NADPH
Cortisol
Cortisone Tetrahydrocortisol
glucuronide
Dihydrocortisol Tetrahydrocortisol
17-Ketosteroids
Tetrahydrocortisone glucuronide
17-Ketosteroids
11β-Hydroxysteroid
dehydrogenase
Glucuronyl transferase;
uridine-diphosphoglucuronic
acid
3α-Hydroxysteroid
dehydrogenase;
NADPH or NADH
CH2OH
C O
OH
CH2OH
C O
OH
CH2OH
C O
OH
CH2OH
C O
OH
CH2OH
O
O
O
HO
H HO H
HO
HC O H
HO
HCOH
HOCH
HCOH
HC O
COO–
FIGURE 2011 Outline of hepatic metabolism of cortisol.
myeloma. When the CBG level rises, more cortisol is bound,
and initially the free cortisol level drops. Th is stimulates ACTH
secretion, and more cortisol is secreted until a new equilibrium
is reached at which the bound cortisol is elevated but the free
cortisol is normal. Changes in the opposite direction occur
when the CBG level falls. Th is explains why pregnant women
have high total plasma cortisol levels without symptoms of
glucocorticoid excess and, conversely, why some patients with
nephrosis have low total plasma cortisol without symptoms of
glucocorticoid defi ciency.
METABOLISM & EXCRETION
OF GLUCOCORTICOIDS
Cortisol is metabolized in the liver, which is the principal site
of glucocorticoid catabolism. Most of the cortisol is reduced to
dihydrocortisol and then to tetrahydrocortisol, which is conjugated
to glucuronic acid ( Figure 20–11 ). Th e glucuronyl transferase
system responsible for this conversion also catalyzes the
formation of the glucuronides of bilirubin (see Chapter 28 )
and a number of hormones and drugs. Competitive inhibition
takes place between these substrates for the enzyme system.
Th e liver and other tissues contain the enzyme 11β
hydroxysteroid dehydrogenase. Th ere are at least two forms of
this enzyme. Type 1 catalyzes the conversion of cortisol to cortisone
and the reverse reaction, though it functions primarily
as a reductase, forming cortisol from corticosterone. Type 2
catalyzes almost exclusively the one-way conversion of cortisol
to cortisone. Cortisone is an active glucocorticoid because it is
364 SECTION III Endocrine and Reproductive Physiology
converted to cortisol, and it is well known because of its extensive
use in medicine. It is not secreted in appreciable quantities
by the adrenal glands. Little, if any, of the cortisone formed in
the liver enters the circulation, because it is promptly reduced
and conjugated to form tetrahydrocortisone glucuronide. Th e
tetrahydroglucuronide derivatives (“conjugates”) of cortisol
and corticosterone are freely soluble. Th ey enter the circulation,
where they do not become bound to protein. Th ey are
rapidly excreted in the urine.
About 10% of the secreted cortisol is converted in the
liver to the 17-ketosteroid derivatives of cortisol and cortisone.
Th e ketosteroids are conjugated for the most part to sulfate
and then excreted in the urine. Other metabolites, including
20-hydroxy derivatives, are formed. Th ere is an enterohepatic
circulation of glucocorticoids and about 15% of the secreted
cortisol is excreted in the stool. Th e metabolism of corticosterone
is similar to that of cortisol, except that it does not form a
17-ketosteroid derivative (see Clinical Box 20–2).
ALDOSTERONE
Aldosterone is bound to protein to only a slight extent, and its
half-life is short (about 20 min). Th e amount secreted is small
( Table 20–1 ), and the total plasma aldosterone level in humans
is normally about 0.006 μg/dL (0.17 nmol/L), compared with a
cortisol level (bound and free) of about 13.5 μg/dL (375 nmol/L).
Much of the aldosterone is converted in the liver to the tetrahydroglucuronide
derivative, but some is changed in the liver and
in the kidneys to an 18-glucuronide. Th is glucuronide, which is
unlike the breakdown products of other steroids, is converted
to free aldosterone by hydrolysis at pH 1.0, and it is therefore
oft en referred to as the “acid-labile conjugate.” Less than 1% of
the secreted aldosterone appears in the urine in the free form.
Another 5% is in the form of the acid-labile conjugate, and up
to 40% is in the form of the tetrahydroglucuronide.
17KETOSTEROIDS
Th e major adrenal androgen is the 17-ketosteroid dehydroepiandrosterone,
although androstenedione is also secreted.
Th e 11-hydroxy derivative of androstenedione and the
17-ketosteroids formed from cortisol and cortisone by side
chain cleavage in the liver are the only 17-ketosteroids that
have an =O or an —OH group in the 11 position (“11-oxy-
CLINICAL BOX 20–2
Variations in the Rate of Hepatic Metabolism
The rate of hepatic inactivation of glucocorticoids is depressed
in liver disease and, interestingly, during surgery
and other stresses. Thus, in stressed humans, the plasmafree
cortisol level rises higher than it does with maximal
ACTH stimulation in the absence of stress.
17-ketosteroids”). Testosterone is also converted to a
17-ketosteroid. Because the daily 17-ketosteroid excretion in
normal adults is 15 mg in men and 10 mg in women, about
two thirds of the urinary ketosteroids in men are secreted by
the adrenal or formed from cortisol in the liver and about one
third are of testicular origin.
Etiocholanolone, one of the metabolites of the adrenal
androgens and testosterone, can cause fever when it is unconjugated
(see Chapter 17 ). Certain individuals have episodic
bouts of fever due to periodic accumulation in the blood of
unconjugated etiocholanolone (“etiocholanolone fever”).
EFFECTS OF ADRENAL
ANDROGENS & ESTROGENS
ANDROGENS
Androgens are the hormones that exert masculinizing
eff ects and they promote protein anabolism and growth (see
Chapter 23 ). Testosterone from the testes is the most active
androgen and the adrenal androgens have less than 20% of
its activity. Secretion of the adrenal androgens is controlled
acutely by ACTH and not by gonadotropins. However, the
concentration of DHEAS increases until it peaks at about
225 mg/dL in the early 20s, and then falls to very low values
in old age ( Figure 20–12 ). Th ese long-term changes are
not due to changes in ACTH secretion and appear to be due
instead to a rise and then a gradual fall in the lyase activity of
17α-hydroxylase.
All but about 0.3% of the circulating DHEA is conjugated
to sulfate (DHEAS). Th e secretion of adrenal androgens is
nearly as great in castrated males and females as it is in normal
males, so it is clear that these hormones exert very little masculinizing
eff ect when secreted in normal amounts. However,
they can produce appreciable masculinization when secreted
600
500
400
300
200
100
0
0 10 20 30 40 50 60 70 80
Age (years)
DHEAS (μg/dL)
Males
Females
FIGURE 2012 Change in serum dehydroepiandrosterone
sulfate (DHEAS) with age. The middle line is the mean, and the
dashed lines identify ±1.96 standard deviations. (Reproduced, with
permission, from Smith MR, et al: A radioimmunoassay for the estimation of serum
dehydroepiandrosterone sulfate in normal and pathological sera. Clin Chim Acta
1975;65:5.)
CHAPTER 20 The Adrenal Medulla & Adrenal Cortex 365
in excessive amounts. In adult males, excess adrenal androgens
merely accentuate existing characteristics, but in prepubertal
boys they can cause precocious development of the secondary
sex characteristics without testicular growth (precocious
pseudopuberty). In females they cause female pseudo-hermaphroditism
and the adrenogenital syndrome. Some health
practitioners recommend injections of dehydroepiandrosterone
to combat the eff ects of aging (see Chapter 1 ), but results
to date are controversial at best.
ESTROGENS
Th e adrenal androgen androstenedione is converted to testosterone
and to estrogens (aromatized) in fat and other peripheral
tissues. Th is is an important source of estrogens in men
and postmenopausal women (see Chapters 22 and 23 ).
PHYSIOLOGIC EFFECTS
OF GLUCOCORTICOIDS
ADRENAL INSUFFICIENCY
In untreated adrenal insuffi ciency, Na + loss and shock occurs
due to the lack of mineralocorticoid activity, as well as abnormalities
of water, carbohydrate, protein, and fat metabolism
due to the lack of glucocorticoids. Th ese metabolic abnormalities
are eventually fatal despite mineralocorticoid treatment.
Small amounts of glucocorticoids correct the metabolic
abnormalities, in part directly and in part by permitting other
reactions to occur. It is important to separate these physiologic
actions of glucocorticoids from the quite diff erent eff ects produced
by large amounts of the hormones.
MECHANISM OF ACTION
Th e multiple eff ects of glucocorticoids are triggered by binding
to glucocorticoid receptors, and the steroid–receptor
complexes act as transcription factors that promote the transcription
of certain segments of DNA (see Chapter 1 ). Th is, in
turn, leads via the appropriate mRNAs to synthesis of enzymes
that alter cell function. In addition, it seems likely that glucocorticoids
have nongenomic actions.
EFFECTS ON INTERMEDIARY
METABOLISM
Th e actions of glucocorticoids on the intermediary metabolism
of carbohydrate, protein, and fat are discussed in
Chapter 24. Th ey include increased protein catabolism and
increased hepatic glycogenesis and gluconeogenesis. Glucose
6-phosphatase activity is increased, and the plasma glucose
level rises. Glucocorticoids exert an anti-insulin action in
peripheral tissues and make diabetes worse. However, the brain
and the heart are spared, so the increase in plasma glucose
provides extra glucose to these vital organs. In diabetics, glucocorticoids
raise plasma lipid levels and increase ketone body
formation, but in normal individuals, the increase in insulin
secretion provoked by the rise in plasma glucose obscures
these actions. In adrenal insuffi ciency, the plasma glucose level
is normal as long as an adequate caloric intake is maintained,
but fasting causes hypoglycemia that can be fatal. Th e adrenal
cortex is not essential for the ketogenic response to fasting.
PERMISSIVE ACTION
Small amounts of glucocorticoids must be present for a number
of metabolic reactions to occur, although the glucocorticoids
do not produce the reactions by themselves. Th is eff ect
is called their permissive action. Permissive eff ects include
the requirement for glucocorticoids to be present for glucagon
and catecholamines to exert their calorigenic eff ects (see above
and Chapter 24 ), for catecholamines to exert their lipolytic
eff ects, and for catecholamines to produce pressor responses
and bronchodilation.
EFFECTS ON ACTH SECRETION
Glucocorticoids inhibit ACTH secretion, which represents a
negative feedback response on the pituitary. ACTH secretion
is increased in adrenalectomized animals. Th e consequences
of the negative feedback action of cortisol on ACTH secretion
are discussed below in the section on regulation of glucocorticoid
secretion.
VASCULAR REACTIVITY
In adrenally insuffi cient animals, vascular smooth muscle
becomes unresponsive to norepinephrine and epinephrine.
Th e capillaries dilate and, terminally, become permeable to
colloidal dyes. Failure to respond to the norepinephrine liberated
at noradrenergic nerve endings probably impairs vascular
compensation for the hypovolemia of adrenal insuffi ciency
and promotes vascular collapse. Glucocorticoids restore vascular
reactivity.
EFFECTS ON THE
NERVOUS SYSTEM
Changes in the nervous system in adrenal insuffi ciency that
are reversed only by glucocorticoids include the appearance
of electroencephalographic waves slower than the normal
β rhythm, and personality changes. Th e latter, which are mild,
include irritability, apprehension, and inability to concentrate.
EFFECTS ON WATER METABOLISM
Adrenal insuffi ciency is characterized by an inability to excrete
a water load, causing the possibility of water intoxication. Only
glucocorticoids repair this defi cit. In patients with adrenal
366 SECTION III Endocrine and Reproductive Physiology
insuffi ciency who have not received glucocorticoids, glucose
infusion may cause high fever (“glucose fever”) followed by
collapse and death. Presumably, the glucose is metabolized, the
water dilutes the plasma, and the resultant osmotic gradient
between the plasma and the cells causes the cells of the thermoregulatory
centers in the hypothalamus to swell to such an
extent that their function is disrupted.
Th e cause of defective water excretion in adrenal insuffi
ciency is unsettled. Plasma vasopressin levels are elevated
in adrenal insuffi ciency and reduced by glucocorticoid treatment.
Th e glomerular fi ltration rate is low, and this probably
contributes to the reduction in water excretion. Th e selective
eff ect of glucocorticoids on the abnormal water excretion is
consistent with this possibility, because even though the mineralocorticoids
improve fi ltration by restoring plasma volume,
the glucocorticoids raise the glomerular fi ltration rate to a
much greater degree.
EFFECTS ON THE BLOOD
CELLS & LYMPHATIC ORGANS
Glucocorticoids decrease the number of circulating eosinophils
by increasing their sequestration in the spleen and lungs.
Glucocorticoids also lower the number of basophils in the circulation
and increase the number of neutrophils, platelets, and
red blood cells ( Table 20–4 ).
Glucocorticoids decrease the circulating lymphocyte
count and the size of the lymph nodes and thymus by inhibiting
lymphocyte mitotic activity. Th ey reduce secretion of
cytokines by inhibiting the eff ect of NF-κB on the nucleus.
Th e reduced secretion of the cytokine IL-2 leads to reduced
proliferation of lymphocytes (see Chapter 3 ), and these cells
undergo apoptosis.
RESISTANCE TO STRESS
Th e term stress as used in biology has been defi ned as any change
in the environment that changes or threatens to change an existing
optimal steady state. Most, if not all, of these stresses activate
TABLE 204 Typical effects of cortisol on the white
and red blood cell counts in humans (cells/ μL).
Cell Normal Cortisol-Treated
White blood cells
Total 9000 10,000
PMNs 5760 8330
Lymphocytes 2370 1080
Eosinophils 270 20
Basophils 60 30
Monocytes 450 540
Red blood cells 5 million 5.2 million
processes at the molecular, cellular, or systemic level that tend to
restore the previous state, that is, they are homeostatic reactions.
Some, but not all, of the stresses stimulate ACTH secretion.
Th e increase in ACTH secretion is essential for survival when
the stress is severe. If animals are then hypophysectomized, or
adrenalectomized but treated with maintenance doses of glucocorticoids,
they die when exposed to the same stress.
Th e reason an elevated circulating ACTH, and hence glucocorticoid
level, is essential for resisting stress remains for the
most part unknown. Most of the stressful stimuli that increase
ACTH secretion also activate the sympathetic nervous system,
and part of the function of circulating glucocorticoids
may be maintenance of vascular reactivity to catecholamines.
Glucocorticoids are also necessary for the catecholamines to
exert their full FFA-mobilizing action, and the FFAs are an
important emergency energy supply. However, sympathectomized
animals tolerate a variety of stresses with relative impunity.
Another theory holds that glucocorticoids prevent other
stress-induced changes from becoming excessive. At present,
all that can be said is that stress causes increases in plasma glucocorticoids
to high “pharmacologic” levels that in the short
run are life-saving.
It should also be noted that the increase in ACTH, which
is benefi cial in the short term, becomes harmful and disruptive
in the long term, causing among other things, the abnormalities
of Cushing syndrome.
PHARMACOLOGIC & PATHOLOGIC
EFFECTS OF GLUCOCORTICOIDS
CUSHING SYNDROME
Th e clinical picture produced by prolonged increases in
plasma glucocorticoids was described by Harvey Cushing
and is called Cushing syndrome ( Figure 20–13 ). It
may be ACTH-independent or ACTH-dependent. Th e
causes of ACTH-independent Cushing syndrome include
glucocorticoid-secreting adrenal tumors, adrenal hyperplasia,
and prolonged administration of exogenous glucocorticoids
for diseases such as rheumatoid arthritis. Rare but
interesting ACTH-independent cases have been reported
in which adrenocortical cells abnormally express receptors
for gastric inhibitory polypeptide (GIP) (see Chapter 25 ),
vasopressin (see Chapter 38 ), β-adrenergic agonists, IL-1, or
gonadotropin-releasing hormone (GnRH; see Chapter 22 ),
causing these peptides to increase glucocorticoid secretion.
Th e causes of ACTH-dependent Cushing syndrome include
ACTH-secreting tumors of the anterior pituitary gland
and tumors of other organs, usually the lungs, that secrete
ACTH (ectopic ACTH syndrome) or corticotropin releasing
hormone (CRH). Cushing syndrome due to anterior pituitary
tumors is oft en called Cushing disease because these tumors
were the cause of the cases described by Cushing. However,
it is confusing to speak of Cushing disease as a subtype of
CHAPTER 20 The Adrenal Medulla & Adrenal Cortex 367
Cushing syndrome, and the distinction seems to be of little
more than historical value.
Patients with Cushing syndrome are protein-depleted as
a result of excess protein catabolism. Th e skin and subcutaneous
tissues are therefore thin and the muscles are poorly
developed. Wounds heal poorly, and minor injuries cause
bruises and ecchymoses. Th e hair is thin and scraggly. Many
patients with the disease have some increase in facial hair and
acne, but this is caused by the increased secretion of adrenal
androgens and oft en accompanies the increase in glucocorticoid
secretion.
Body fat is redistributed in a characteristic way. Th e
extremities are thin, but fat collects in the abdominal wall,
face, and upper back, where it produces a “buff alo hump.” As
the thin skin of the abdomen is stretched by the increased subcutaneous
fat depots, the subdermal tissues rupture to form
prominent reddish purple striae. Th ese scars are seen normally
whenever a rapid stretching of skin occurs, but in normal
individuals the striae are usually inconspicuous and lack
the intense purplish color.
Many of the amino acids liberated from catabolized proteins
are converted into glucose in the liver and the resultant
hyperglycemia and decreased peripheral utilization of glucose
may be suffi cient to precipitate insulin-resistant diabetes mellitus,
especially in patients genetically predisposed to diabetes.
Hyperlipidemia and ketosis are associated with the diabetes,
but acidosis is usually not severe.
Th e glucocorticoids are present in such large amounts
in Cushing syndrome that they may exert a signifi cant mineralocorticoid
action. Deoxycorticosterone secretion is also
elevated in cases due to ACTH hypersecretion. Th e salt and
water retention plus the facial obesity cause the characteristic
plethoric, rounded “moon-faced” appearance, and there
may be signifi cant K + depletion and weakness. About 85%
Moon face
Red cheeks
Bruisability
with ecchymoses
Thin skin
Poor muscle
development
Poor wound
healing
Striae
Pendulous
abdomen
Fat pads
FIGURE 2013 Typical fi ndings in Cushing syndrome.
(Reproduced with permission from Forsham PH, Di Raimondo VC: Traumatic Medicine
and Surgery for the Attorney. Butterworth, 1960.)
of patients with Cushing syndrome are hypertensive. Th e
hypertension may be due to increased deoxycorticosterone
secretion, increased angiotensinogen secretion, or a direct glucocorticoid
eff ect on blood vessels (see Chapter 32 ).
Glucocorticoid excess leads to bone dissolution by
decreasing bone formation and increasing bone resorption.
Th is leads to osteoporosis, a loss of bone mass that leads eventually
to collapse of vertebral bodies and other fractures. Th e
mechanisms by which glucocorticoids produce their eff ects on
bone are discussed in Chapter 21 .
Glucocorticoids in excess accelerate the basic electroencephalographic
rhythms and produce mental aberrations
ranging from increased appetite, insomnia, and euphoria
to frank toxic psychoses. As noted above, glucocorticoid
defi ciency is also associated with mental symptoms, but
the symptoms produced by glucocorticoid excess are more
severe.
ANTIINFLAMMATORY &
ANTIALLERGIC EFFECTS
OF GLUCOCORTICOIDS
Glucocorticoids inhibit the infl ammatory response to tissue
injury. Th e glucocorticoids also suppress manifestations of
allergic disease that are due to the release of histamine frommast
cells and basophils. Both of these eff ects require high
levels of circulating glucocorticoids and cannot be produced
by administering steroids without producing the other manifestations
of glucocorticoid excess. Furthermore, large doses
of exogenous glucocorticoids inhibit ACTH secretion to the
point that severe adrenal insuffi ciency can be a dangerous
problem when therapy is stopped. However, local administration
of glucocorticoids, for example, by injection into an
infl amed joint or near an irritated nerve, produces a high local
concentration of the steroid, oft en without enough systemic
absorption to cause serious side eff ects.
Th e actions of glucocorticoids in patients with bacterial
infections are dramatic but dangerous. For example, in pneumococcal
pneumonia or active tuberculosis, the febrile reaction,
the toxicity, and the lung symptoms disappear, but unless
antibiotics are given at the same time, the bacteria spread
throughout the body. It is important to remember that the
symptoms are the warning that disease is present; when these
symptoms are masked by treatment with glucocorticoids,
there may be serious and even fatal delays in diagnosis and the
institution of treatment with antimicrobial drugs.
Th e role of NF-κB in the anti-infl ammatory and antiallergic
eff ects of glucocorticoids has been mentioned above
and is discussed in Chapter 3 . An additional action that combats
local infl ammation is inhibition of phospholipase A 2 .
Th is reduces the release of arachidonic acid from tissue phospholipids
and consequently reduces the formation of leukotrienes,
thromboxanes, prostaglandins, and prostacyclin (see
Chapter 32 ).
368 SECTION III Endocrine and Reproductive Physiology
OTHER EFFECTS
Large doses of glucocorticoids inhibit growth, decrease
growth hormone secretion (see Chapter 18 ), induce PNMT,
and decrease thyroid-stimulating hormone (TSH) secretion.
During fetal life, glucocorticoids accelerate the maturation of
surfactant in the lungs (see Chapter 34 ).
REGULATION OF
GLUCOCORTICOID SECRETION
ROLE OF ACTH
Both basal secretion of glucocorticoids and the increased secretion
provoked by stress are dependent upon ACTH from the
anterior pituitary. Angiotensin II also stimulates the adrenal
cortex, but its eff ect is mainly on aldosterone secretion. Large
doses of a number of other naturally occurring substances,
including vasopressin, serotonin, and vasoactive intestinal
polypeptide (VIP), are capable of stimulating the adrenal
directly, but there is no evidence that these agents play any role
in the physiologic regulation of glucocorticoid secretion.
CHEMISTRY & METABOLISM
OF ACTH
ACTH is a single-chain polypeptide containing 39 amino
acids. Its origin from proopiomelanocortin (POMC) in the
pituitary is discussed in Chapter 18 . Th e fi rst 23 amino acids
in the chain generally constitute the active “core” of the molecule.
Amino acids 24–39 constitute a “tail” that stabilizes the
molecule and varies slightly in composition from species to
species Th e ACTHs that have been isolated are generally active
in all species but antigenic in heterologous species.
ACTH is inactivated in blood in vitro more slowly than in
vivo; its half-life in the circulation in humans is about 10 min. A
large part of an injected dose of ACTH is found in the kidneys,
but neither nephrectomy nor evisceration appreciably enhances
its in vivo activity, and the site of its inactivation is not known.
EFFECT OF ACTH
ON THE ADRENAL
Aft er hypophysectomy, glucocorticoid synthesis and output
decline within 1 h to very low levels, although some hormone
is still secreted. Within a short time aft er an injection of ACTH
(in dogs, less than 2 min), glucocorticoid output is increased.
With low doses of ACTH, the relationship between the log of
the dose and the increase in glucocorticoid secretion is linear.
However, the maximal rate at which glucocorticoids can be
secreted is rapidly reached, and this “ceiling on output” also
exists in humans. Th e eff ects of ACTH on adrenal morphology
and the mechanism by which it increases steroid secretion
have been discussed above.
4 8 24
Time (h)
0 2
10
20
30
40
50
ACTH IV
N
DX
CST
HI
Plasma cortisol (μg/dL)
FIGURE 2014 Loss of ACTH responsiveness when ACTH
secretion is decreased in humans. The 1- to 24-amino-acid
sequence of ACTH was infused intravenously (IV) in a dose of 250 μg
over 8 h. CST, long-term corticosteroid therapy; DX, dexamethasone
0.75 mg every 8 h for 3 days; HI, anterior pituitary insuffi ciency;
N, normal subjects. (Reproduced with permission from Kolanowski J, et al:
Adrenocortical response upon repeated stimulation with corticotropin in patients
lacking endogenous corticotropin secretion. Acta Endocrinol [Kbh] 1977;85:595.)
ADRENAL RESPONSIVENESS
ACTH not only produces prompt increases in glucocorticoid
secretion but also increases the sensitivity of the adrenal to
subsequent doses of ACTH. Conversely, single doses of ACTH
do not increase glucocorticoid secretion in chronically hypophysectomized
animals and patients with hypopituitarism, and
repeated injections or prolonged infusions of ACTH are necessary
to restore normal adrenal responses to ACTH. Decreased
responsiveness is also produced by doses of glucocorticoids
that inhibit ACTH secretion. Th e decreased adrenal responsiveness
to ACTH is detectable within 24 h aft er hypophysectomy
and increases progressively with time ( Figure 20–14 ).
It is marked when the adrenal is atrophic but develops before
visible changes occur in adrenal size or morphology.
CIRCADIAN RHYTHM
ACTH is secreted in irregular bursts throughout the day and
plasma cortisol tends to rise and fall in response to these
bursts ( Figure 20–15 ). In humans, the bursts are most frequent
in the early morning, and about 75% of the daily production
of cortisol occurs between 4:00 am and 10:00 am.
Th e bursts are least frequent in the evening. Th is diurnal
(circadian) rhythm in ACTH secretion is present in patients
with adrenal insuffi ciency receiving constant doses of glucocorticoids.
It is not due to the stress of getting up in the morning,
traumatic as that may be, because the increased ACTH
secretion occurs before waking up. If the “day” is lengthened
experimentally to more than 24 h, that is, if the individual
is isolated and the day’s activities are spread over more than
24 h, the adrenal cycle also lengthens, but the increase in
ACTH secretion still occurs during the period of sleep. Th e
CHAPTER 20 The Adrenal Medulla & Adrenal Cortex 369
biologic clock responsible for the diurnal ACTH rhythm is
located in the suprachiasmatic nuclei of the hypothalamus
(see Chapter 14 ).
THE RESPONSE TO STRESS
Th e morning plasma ACTH concentration in a healthy resting
human is about 25 pg/mL (5.5 pmol/L). ACTH and cortisol
values in various abnormal conditions are summarized
in Figure 20–16 . During severe stress, the amount of ACTH
secreted exceeds the amount necessary to produce maximal
glucocorticoid output. However, prolonged exposure to ACTH
in conditions such as the ectopic ACTH syndrome increases
the adrenal maximum.
Increases in ACTH secretion to meet emergency
situations are mediated almost exclusively through the
200
180
160
140
120
100
80
60
40
20
0
25
20
15
10
5
0
Noon 4 PM 8 PM Mid- Noon
night
4 AM 8 AM
Lunch Dinner Snack Sleep B'kfast
Snack
Plasma ACTH (pg/mL)
Plasma 11-OHCS (μg/dL)
FIGURE 2015 Fluctuations in plasma ACTH and
glucocorticoids throughout the day in a normal girl (age 16). The
ACTH was measured by immunoassay and the glucocorticoids as
11-oxysteroids (11-OHCS). Note the greater ACTH and glucocorticoid
rises in the morning, before awakening. (Reproduced, with permission,
from Krieger DT, et al: Characterization of the normal temporal pattern of plasma
corticosteroid levels. J Clin Endocrinol Metab 1971;32:266.)
hypothalamus via release of CRH. Th is polypeptide is
produced by neurons in the paraventricular nuclei. It is
secreted in the median eminence and transported in the
portal-hypophysial vessels to the anterior pituitary, where it
stimulates ACTH secretion (see Chapter 18 ). If the median
eminence is destroyed, increased secretion in response to
many diff erent stresses is blocked. Aff erent nerve pathways
from many parts of the brain converge on the paraventricular
nuclei. Fibers from the amygdaloid nuclei mediate
responses to emotional stresses, and fear, anxiety, and
apprehension cause marked increases in ACTH secretion.
Input from the suprachiasmatic nuclei provides the drive for
the diurnal rhythm. Impulses ascending to the hypothalamus
via the nociceptive pathways and the reticular formation
trigger increased ACTH secretion in response to injury
( Figure 20–16 ). Th e baroreceptors exert an inhibitory input
via the nucleus of the tractus solitarius.
GLUCOCORTICOID FEEDBACK
Free glucocorticoids inhibit ACTH secretion, and the degree
of pituitary inhibition is proportional to the circulating glucocorticoid
level. Th e inhibitory eff ect is exerted at both the
pituitary and the hypothalamic levels. Th e inhibition is due
primarily to an action on DNA, and maximal inhibition takes
several hours to develop, although more rapid “fast feedback”
also occurs. Th e ACTH-inhibiting activity of the various steroids
parallels their glucocorticoid potency. A drop in resting
corticoid levels stimulates ACTH secretion, and in chronic
adrenal insuffi ciency the rate of ACTH synthesis and secretion
is markedly increased.
Th us, the rate of ACTH secretion is determined by two
opposing forces: the sum of the neural and possibly other
stimuli converging through the hypothalamus to increase
ACTH secretion, and the magnitude of the braking action of
glucocorticoids on ACTH secretion, which is proportional to
their level in the circulating blood ( Figure 20–17 ).
Normal, morning
Normal, evening
Normal, dexamethasone
Normal, metyrapone
Normal, stress
Addison disease
Hypopituitarism
Congenital adrenal hyperplasia
Cushing, hyperplasia
Cushing, dexamethasone
Cushing, postadrenalectomy
Cushing, ectopic ACTH syndrome
Cushing, adrenal tumor
0 5 50 500 5000
5 50 500 5000
0
0 0
12 25 50 100
12 25 50 100
Condition
Plasma ACTH
(pg/mL)
Plasma cortisol
(μg/dL)
FIGURE 2016 Plasma concentrations of ACTH and cortisol in various clinical states. (Reproduced with permission from Williams RH [editor]:
Textbook of Endocrinology, 5th ed. Saunders, 1974.)
370 SECTION III Endocrine and Reproductive Physiology
Th e dangers involved when prolonged treatment with
anti-infl ammatory doses of glucocorticoids is stopped deserve
emphasis. Not only is the adrenal atrophic and unresponsive
aft er such treatment, but even if its responsiveness is restored
by injecting ACTH, the pituitary may be unable to secrete normal
amounts of ACTH for as long as a month. Th e cause of the
defi ciency is presumably diminished ACTH synthesis. Th ereaft
er, ACTH secretion slowly increases to supranormal levels.
Th ese in turn stimulate the adrenal, and glucocorticoid output
rises, with feedback inhibition gradually reducing the elevated
ACTH levels to normal ( Figure 20–18 ). Th e complications of
sudden cessation of steroid therapy can usually be avoided by
slowly decreasing the steroid dose over a long period of time.
CRH
Trauma via
nociceptive
pathways
Systemic
effects
Cortisol
Afferents
from NTS
Emotion via
limbic system
Drive for
circadian
rhythm
ACTH
Hypothalamus
Anterior
pituitary
Adrenal
cortex
FIGURE 2017 Feedback control of the secretion of cortisol
and other glucocorticoids via the hypothalamic-pituitary-adrenal
axis. The dashed arrows indicate inhibitory eff ects and the solid
arrows indicate stimulating eff ects. NTS, nucleus tractus solitarius.
0 2 4 6 8 10 12
ACTH
Cortisol
Months after stopping
glucocorticoid treatment
High
Normal
Low
Plasma concentration FIGURE 20
18 Pattern of plasma ACTH and cortisol values
in patients recovering from prior long-term daily treatment with
large doses of glucocorticoids. (Courtesy of R Ney.)
45
40
35
98
96
94
92
90
80
70
400
300
200
60
40
20
0
0 30 60 80 110 140 170 200 230 260
Time (min)
Aldosterone
Creatinine clearance
K+ excretion
Percent filtered K+
reabsorbed
Percent filtered Na+ reabsorbed
Na+ excretion
Percent
mL/min
μeq/min
FIGURE 2019 Eff ect of aldosterone (5 μg as a single dose
injected into the aorta) on electrolyte excretion in an adrenalectomized
dog. The scale for creatinine clearance is on the right.
EFFECTS OF
MINERALOCORTICOIDS
ACTIONS
Aldosterone and other steroids with mineralocorticoid activity
increase the reabsorption of Na + from the urine, sweat, saliva,
and the contents of the colon. Th us, mineralocorticoids cause
retention of Na + in the ECF. Th is expands ECF volume. In the
kidneys, they act primarily on the principal cells (P cells) of
the collecting ducts (see Chapter 37 ). Under the infl uence of
aldosterone, increased amounts of Na + are in eff ect exchanged
for K + and H + in the renal tubules, producing a K + diuresis
( Figure 20–19 ) and an increase in urine acidity.
MECHANISM OF ACTION
Like many other steroids, aldosterone binds to a cytoplasmic
receptor, and the receptor–hormone complex moves to the
nucleus where it alters the transcription of mRNAs. Th is in turn
increases the production of proteins that alter cell function.
Th e aldosterone-stimulated proteins have two eff ects—a rapid
eff ect, to increase the activity of epithelial sodium channels
(ENaCs) by increasing the insertion of these channels into the
cell membrane from a cytoplasmic pool; and a slower eff ect to
increase the synthesis of ENaCs. Among the genes activated by
aldosterone is the gene for serum- and glucocorticoid regulated
kinase (sgk), a serine-threonine protein kinase. Th e gene for
sgk is an early response gene, and sgk increases ENaC activity.
Aldosterone also increases the mRNAs for the three subunits
CHAPTER 20 The Adrenal Medulla & Adrenal Cortex 371
that make up ENaCs. Th e fact that sgk is activated by glucocorticoids
as well as aldosterone is not a problem because glucocorticoids
are inactivated at mineralocorticoid receptor sites.
However, aldosterone activates the genes for other proteins
in addition to sgk and ENaCs and inhibits others. Th erefore,
the exact mechanism by which aldosterone-induced proteins
increase Na + reabsorption is still unsettled.
Evidence is accumulating that aldosterone also binds
to the cell membrane and by a rapid, nongenomic action
increases the activity of membrane Na + –K + exchangers. Th is
produces an increase in intracellular Na + , and the second messenger
involved is probably IP 3 . In any case, the principal eff ect
of aldosterone on Na + transport takes 10–30 min to develop
and peaks even later ( Figure 20–19 ), indicating that it depends
on the synthesis of new proteins by a genomic mechanism.
RELATION OF
MINERALOCORTICOID TO
GLUCOCORTICOID RECEPTORS
It is intriguing that in vitro, the mineralocorticoid receptor
has an appreciably higher affi nity for glucocorticoids than the
glucocorticoid receptor does, and glucocorticoids are present
in large amounts in vivo. Th is raises the question of why glucocorticoids
do not bind to the mineralocorticoid receptors
in the kidneys and other locations and produce mineralocorticoid
eff ects. At least in part, the answer is that the kidneys
and other mineralocorticoid-sensitive tissues also contain
the enzyme 11β-hydroxysteroid dehydrogenase type 2. Th is
enzyme leaves aldosterone untouched, but it converts cortisol
to cortisone ( Figure 20–11 ) and corticosterone to its 11-oxy
derivative. Th ese 11-oxy derivatives do not bind to the receptor
(Clinical Box 20–3).
OTHER STEROIDS THAT
AFFECT NA + EXCRETION
Aldosterone is the principal mineralocorticoid secreted by
the adrenal, although corticosterone is secreted in suffi cient
amounts to exert a minor mineralocorticoid eff ect ( Tables 20–1
and 20–2 ). Deoxycorticosterone, which is secreted in appreciable
amounts only in abnormal situations, has about 3% of
the activity of aldosterone. Large amounts of progesterone and
some other steroids cause natriuresis, but there is little evidence
that they play any normal role in the control of Na + excretion.
EFFECT OF ADRENALECTOMY
In adrenal insuffi ciency, Na + is lost in the urine; K + is retained,
and the plasma K + rises. When adrenal insuffi ciency develops
rapidly, the amount of Na + lost from the ECF exceeds
the amount excreted in the urine, indicating that Na + also
must be entering cells. When the posterior pituitary is
intact, salt loss exceeds water loss, and the plasma Na + falls
( Table 20–5 ). However, the plasma volume is also reduced,
resulting in hypotension, circulatory insuffi ciency, and,
CLINICAL BOX 20–3
Apparent Mineralocorticoid Excess
If 11β-hydroxysteroid dehydrogenase type 2 is inhibited or
absent, cortisol has marked mineralocorticoid eff ects. The
resulting syndrome is called apparent mineralocorticoid
excess (AME). Patients with this condition have the clinical
picture of hyperaldosteronism because cortisol is acting on
their mineralocorticoid receptors, and their plasma aldosterone
level as well as their plasma renin activity is low. The
condition can be due to congenital absence of the enzyme.
THERAPEUTIC HIGHLIGHTS
Prolonged ingestion of licorice can also cause an increase
in blood pressure. Outside of the United States,
licorice contains glycyrrhetinic acid, which inhibits
11β-hydroxysteroid dehydrogenase type 2. Individuals
who eat large amounts of licorice have an increase
in MR-activated sodium absorption via the epithelial
sodium channel ENaC in the renal collecting duct, and
blood pressure can rise.
eventually, fatal shock. Th ese changes can be prevented to a
degree by increasing dietary NaCl intake. Rats survive indefinitely
on extra salt alone, but in dogs and most humans,
the amount of supplementary salt needed is so large that it
is almost impossible to prevent eventual collapse and death
unless mineralocorticoid treatment is also instituted (see
Clinical Box 20–4).
REGULATION OF
ALDOSTERONE SECRETION
STIMULI
Th e principal conditions that increase aldosterone secretion
are summarized in Table 20–6 . Some of them also increase
glucocorticoid secretion; others selectively aff ect the output
TABLE 205 Typical plasma electrolyte levels in
normal humans and patients with adrenocortical
diseases.
State
Plasma Electolytes (mEq/L)
Na + K + Cl – HCO 3 –
Normal 142 4.5 105 25
Adrenal insuffi ciency 120 6.7 85 25
Primary
hyperaldosteronism
145 2.4 96 41
372 SECTION III Endocrine and Reproductive Physiology
CLINICAL BOX 20–4
Secondary Eff ects of Excess
Mineralocorticoids
A prominent feature of prolonged mineralocorticoid excess
( Table 20–5 ) is K + depletion due to prolonged K + diuresis.
H + is also lost in the urine. Na + is retained initially, but the
plasma Na + is elevated only slightly if at all, because water
is retained with the osmotically active sodium ions. Consequently,
ECF volume is expanded and the blood pressure
rises. When the ECF expansion passes a certain point, Na +
excretion is usually increased in spite of the continued action
of mineralocorticoids on the renal tubules. This escape
phenomenon ( Figure 20–20 ) is probably due to increased
secretion of ANP (see Chapter 38 ). Because of increased excretion
of Na + when the ECF volume is expanded, mineralocorticoids
do not produce edema in normal individuals and
patients with hyperaldosteronism. However, escape may
not occur in certain disease states, and in these situations,
continued expansion of ECF volume leads to edema (see
Chapters 37 and 38 ).
of aldosterone. Th e primary regulatory factors involved are
ACTH from the pituitary, renin from the kidney via angiotensin
II, and a direct stimulatory eff ect on the adrenal cortex
of a rise in plasma K + concentration.
EFFECT OF ACTH
When fi rst administered, ACTH stimulates the output of
aldosterone as well as that of glucocorticoids and sex hormones.
Although the amount of ACTH required to increase
aldosterone output is somewhat greater than the amount that
stimulates maximal glucocorticoid secretion ( Figure 20–21 ),
TABLE 206 Conditions that increase
aldosterone secretion.
Glucocorticoid secretion also increased
Surgery
Anxiety
Physical trauma
Hemorrhage
Glucocorticoid secretion unaff ected
High potassium intake
Low sodium intake
Constriction of inferior vena cava in thorax
Standing
Secondary hyperaldosteronism (in some cases of congestive heart
failure, cirrhosis, and nephrosis)
it is well within the range of endogenous ACTH secretion. Th e
eff ect is transient, and even if ACTH secretion remains elevated,
aldosterone output declines in 1 or 2 days. On the other
hand, the output of the mineralocorticoid deoxycorticosterone
remains elevated. Th e decline in aldosterone output is partly
due to decreased renin secretion secondary to hypervolemia,
but it is possible that some other factor also decreases the conversion
of corticosterone to aldosterone. Aft er hypophysectomy,
the basal rate of aldosterone secretion is normal. Th e
increase normally produced by surgical and other stresses is
absent, but the increase produced by dietary salt restriction is
unaff ected for some time. Later on, atrophy of the zona glomerulosa
complicates the picture in long-standing hypopituitarism,
and this may lead to salt loss and hypoaldosteronism.
Normally, glucocorticoid treatment does not suppress
aldosterone secretion. However, an interesting recently
described syndrome is glucocorticoid-remediable aldosteronism
(GRA). Th is is an autosomal dominant disorder in which
the increase in aldosterone secretion produced by ACTH is no
longer transient. Th e hypersecretion of aldosterone and the
accompanying hypertension are remedied when ACTH secretion
is suppressed by administering glucocorticoids. Th e genes
encoding aldosterone synthase and 11β-hydroxylase are 95%
identical and are close together on chromosome 8. In individuals
with GRA, there is unequal crossing over so that the 5΄-
regulatory region of the 11βhydroxylase gene is fused to the
coding region of the aldosterone synthase gene. Th e product of
this hybrid gene is an ACTH-sensitive aldosterone synthase.
EFFECTS OF ANGIOTENSIN II
& RENIN
Th e octapeptide angiotensin II is formed in the body from
angiotensin I, which is liberated by the action of renin on circulating
angiotensinogen (see Chapter 38 ). Injections of angiotensin
II stimulate adrenocortical secretion and, in small doses,
aff ect primarily the secretion of aldosterone ( Figure 20–22 ).
Th e sites of action of angiotensin II are both early and late in the
steroid biosynthetic pathway. Th e early action is on the conversion
of cholesterol to pregnenolone, and the late action is on
the conversion of corticosterone to aldosterone ( Figure 20–8 ).
Angiotensin II does not increase the secretion of deoxycorticosterone,
which is controlled by ACTH.
Renin is secreted from the juxtaglomerular cells that surround
the renal aff erent arterioles as they enter the glomeruli
(see Chapter 38 ). Aldosterone secretion is regulated via the
renin–angiotensin system in a feedback fashion ( Figure 20–23 ).
A drop in ECF volume or intra-arterial vascular volume leads
to a refl ex increase in renal nerve discharge and decreases renal
arterial pressure. Both changes increase renin secretion, and the
angiotensin II formed by the action of renin increases the rate of
secretion of aldosterone. Th e aldosterone causes Na + and, secondarily,
water retention, expanding ECF volume, and shutting
off the stimulus that initiated increased renin secretion.
Hemorrhage stimulates ACTH and renin secretion. Like
hemorrhage, standing and constriction of the thoracic inferior
CHAPTER 20 The Adrenal Medulla & Adrenal Cortex 373
vena cava decrease intrarenal arterial pressure. Dietary sodium
restriction also increases aldosterone secretion via the renin–
angiotensin system ( Figure 20–24 ). Such restriction reduces
ECF volume, but aldosterone and renin secretion are increased
before any consistent decrease in blood pressure takes place.
Consequently, the initial increase in renin secretion produced
by dietary sodium restriction is probably due to a refl ex
increase in the activity of the renal nerves. Th e increase in circulating
angiotensin II produced by salt depletion upregulates
the angiotensin II receptors in the adrenal cortex and hence
150
100
50
0
6 Serum K+
(meq/L)
Serum Na+
(meq/L)
4
DOCA 10 mg IM every 12 h
300
200
100
0
150
130
Intake
Intake
60
58
56
Days 1
Body weight
(kg)
3 5 7 9 11 13 15 17
11.40 L
4.26 L
1.14 L
3.12 L
9.14 L
3.55 L
1.48 L
2.07 L
ECF
TBV
RCV
PV
Urinary Na+
(meq/24 h)
Urinary K+
(meq/24 h)
Male, age 29
Bilateral adrenalectomy
Dexamethasone, 0.25 mg/6 h
FIGURE 2020 “Escape” from the sodium-retaining eff ect of desoxycorticosterone acetate (DOCA) in an adrenalectomized patient.
ECF, extracellular fl uid volume; PV, plasma volume; RCV, red cell volume; TBV, total blood volume. (Courtesy of EG Biglieri.)
12 40
10
Change in 8
17-hydroxycorticoid
output
(μg/min)
Change in
aldosterone
output
(ng/min)
6
4
2
0
30
25
20
15
10
5
0
2 5 10 100 1000
Dose of ACTH
(mU)
No. of dogs (4) (8) (6) (3) (10)
FIGURE 2021 Changes in adrenal venous output of steroids
produced by ACTH in nephrectomized hypophysectomized dogs.
increases the response to angiotensin II, whereas it downregulates
the angiotensin II receptors in the blood vessels.
ELECTROLYTES &
OTHER FACTORS
An acute decline in plasma Na + of about 20 mEq/L stimulates
aldosterone secretion, but changes of this magnitude are rare.
However, the plasma K + level need increase only 1 mEq/L to
stimulate aldosterone secretion, and transient increases of this
8
Change in
17-hydroxycorticoid
(μg/min)
Change in
aldosterone
output
(ng/min)
6
4
2
0
25
20
15
10
5
0
0.042 0.083 0.167 0.42 1.67
Dose of angiotensin II
(μg/min)
No. of dogs (5)* (2) (8) (7) (7)
*Aldosterone values in 3 dogs
FIGURE 2022 Changes in adrenal venous output of
steroids produced by angiotensin II in nephrectomized
hypophysectomized dogs.
374 SECTION III Endocrine and Reproductive Physiology
magnitude may occur aft er a meal, particularly if it is rich in K + .
Like angiotensin II, K + stimulates the conversion of cholesterol
to pregnenolone and the conversion of deoxycorticosterone to
aldosterone. It appears to act by depolarizing the cell, which
opens voltage-gated Ca 2+ channels, increasing intracellular
Ca 2+ . Th e sensitivity of the zona glomerulosa to angiotensin II
and consequently to a low-sodium diet is decreased by a lowpotassium
diet.
In normal individuals, plasma aldosterone concentrations
increase during the portion of the day that the individual
is carrying on activities in the upright position. Th is
increase is due to a decrease in the rate of removal of aldosterone
from the circulation by the liver and an increase in
aldosterone secretion due to a postural increase in renin
secretion. Individuals who are confi ned to bed show a circadian
rhythm of aldosterone and renin secretion, with
the highest values in the early morning before awakening.
Atrial natriuretic peptide (ANP) inhibits renin secretion
and decreases the responsiveness of the zona glomerulosa to
angiotensin II (see Chapter 38 ). Th e mechanisms by which
ACTH, angiotensin II, and K + stimulate aldosterone secretion
are summarized in Table 20–7 .
ROLE OF MINERALOCORTICOIDS
IN THE REGULATION
OF SALT BALANCE
Variations in aldosterone secretion is only one of many factors
aff ecting Na + excretion. Other major factors include the
glomerular fi ltration rate, ANP, the presence or absence of
osmotic diuresis, and changes in tubular reabsorption of Na +
independent of aldosterone. It takes some time for aldosterone
to act. When one rises from the supine to the standing
position, aldosterone secretion increases and Na + is retained
from the urine. However, the decrease in Na + excretion develops
too rapidly to be explained solely by increased aldosterone
Angiotensinconverting
enzyme
Angiotensinogen Renin
Angiotensin I
Angiotensin II
Aldosterone Decreased Na+
(and water) excretion
Increased extracellular
fluid volume
Increased renal arterial
mean pressure, decreased
discharge of renal nerves
Juxtaglomerular
apparatus
Adrenal
cortex
FIGURE 2023 Feedback mechanism regulating aldosterone secretion. The dashed arrow indicates inhibiition.
secretion. Th e primary function of the aldosterone-secreting
mechanism is the defense of intravascular volume, but it is
only one of the homeostatic mechanisms involved in this
regulation.
SUMMARY OF THE EFFECTS OF
ADRENOCORTICAL HYPER &
HYPOFUNCTION IN HUMANS
Recapitulating the manifestations of excess and defi ciency of
the adrenocortical hormones in humans is a convenient way
to summarize the multiple and complex actions of these steroids.
A characteristic clinical syndrome is associated with
excess secretion of each of the types of hormones.
Excess androgen secretion causes masculinization
(adrenogenital syndrome) and precocious pseudopuberty or
female pseudohermaphroditism.
Excess glucocorticoid secretion produces a moon-faced,
plethoric appearance, with trunk obesity, purple abdominal
striae, hypertension, osteoporosis, protein depletion, mental
abnormalities, and, frequently, diabetes mellitus (Cushing
syndrome). Excess mineralocorticoid secretion leads to K +
depletion and Na + retention, usually without edema but with
weakness, hypertension, tetany, polyuria, and hypokalemic
alkalosis (hyperaldosteronism). Th is condition may be due to
primary adrenal disease (primary hyperaldosteronism; Conn
syndrome) such as an adenoma of the zona glomerulosa, unilateral
or bilateral adrenal hyperplasia, adrenal carcinoma, or
by GRA. In patients with primary hyperaldosteronism, renin
secretion is depressed. Secondary hyperaldosteronism with
high plasma renin activity is caused by cirrhosis, heart failure,
and nephrosis. Increased renin secretion is also found in individuals
with the salt-losing form of the adrenogenital syndrome
(see above), because their ECF volume is low. In patients with
elevated renin secretion due to renal artery constriction, aldosterone
secretion is increased; in those in whom renin secretion
CHAPTER 20 The Adrenal Medulla & Adrenal Cortex 375
TABLE 207 Second messengers involved in
the regulation of aldosterone secretion.
Secretagogue Intracellular Mediator
ACTH Cyclic AMP, protein kinase A
Angiotensin II Diacylglycerol, protein kinase C
K + Ca 2+ via voltage-gated Ca 2+ channels
150
140
130
120
15
10
400
300
200
100
2000
0
1500
1000
500
0
15
20
10
5
0
5
0
2.0
2.5
1.5
1.0
0.5
0
Low Normal High
Sodium intake
Plasma vasopressin
(pg/mL)
Plasma renin activity
(ng AI/mL/h)
Plasma Na+
(mmol/L)
Plasma aldosterone
(pmol/L)
Urinary Na+
excretion
(mmol/day)
Plasma ANP
(pg/mL)
FIGURE 2024 Eff ect of low-, normal-, and high-sodium
diets on sodium metabolism and plasma renin activity,
aldosterone, vasopressin, and ANP in normal humans. (Data
from Sagnella GA, et al: Plasma atrial natriuretic peptide: Its relationship to
changes in sodium in-take, plasma renin activity, and aldosterone in man.
Clin Sci 1987;72:25.)
is not elevated, aldosterone secretion is normal. Th e relationship
of aldosterone to hypertension is discussed in Chapter 32 .
Primary adrenal insuffi ciency due to disease processes
that destroy the adrenal cortex is called Addison disease. Th e
condition used to be a relatively common complication of
tuberculosis, but now it is usually due to autoimmune infl ammation
of the adrenal. Patients lose weight, are tired, and
become chronically hypotensive. Th ey have small hearts, probably
because the hypotension decreases the work of the heart.
Eventually they develop severe hypotension and shock (addisonian
crisis). Th is is due not only to mineralocorticoid defi -
ciency but to glucocorticoid defi ciency as well. Fasting causes
fatal hypoglycemia, and any stress causes collapse. Water is
retained, and there is always the danger of water intoxication.
Circulating ACTH levels are elevated. Th e diff use tanning of
the skin and the spotty pigmentation characteristic of chronic
glucocorticoid defi ciency are due, at least in part, to the melanocyte-
stimulating hormone (MSH) activity of the ACTH in
the blood. Pigmentation of skin creases on the hands and the
gums are common. Minor menstrual abnormalities occur in
women, but the defi ciency of adrenal sex hormones usually has
little eff ect in the presence of normal testes or ovaries.
Secondary adrenal insuffi ciency is caused by pituitary
diseases that decrease ACTH secretion, and tertiary adrenal
insuffi ciency is caused by hypothalamic disorders disrupting
CRH secretion. Both are usually milder than primary adrenal
insuffi ciency because electrolyte metabolism is aff ected to a
lesser degree. In addition, there is no pigmentation because in
both of these conditions, plasma ACTH is low, not high.
Cases of isolated aldosterone defi ciency have also been
reported in patients with renal disease and a low circulating
renin level (hyporeninemic hypoaldosteronism). In addition,
pseudohypoaldosteronism is produced when there is
resistance to the action of aldosterone. Patients with these syndromes
have marked hyperkalemia, salt wasting, and hypotension,
and they may develop metabolic acidosis.
CHAPTER SUMMARY
■ Th e adrenal gland consists of the adrenal medulla that
secretes dopamine and the catecholamines epinephrine
and norepinephrine, and the adrenal cortex that secretes
steroid hormones.
■ Norepinephrine and epinephrine act on two classes of
receptors, α- and β-adrenergic receptors, and exert metabolic
eff ects that include glycogenolysis in liver and skeletal muscle,
mobilization of FFA, increased plasma lactate, and stimulation
of the metabolic rate.
■ Th e hormones of the adrenal cortex are derivatives of
cholesterol and include the mineralocorticoid aldosterone, the
glucocorticoids cortisol and corticosterone, and the androgens
dehydroepiandrosterone (DHEA) and androstenedione.
■ Androgens are the hormones that exert masculinizing eff ects,
and they promote protein anabolism and growth. Th e adrenal
androgen androstenedione is converted to testosterone
and to estrogens (aromatized) in fat and other peripheral
376 SECTION III Endocrine and Reproductive Physiology
tissues. Th is is an important source of estrogens in men and
postmenopausal women.
■ Th e mineralocorticoid aldosterone has eff ects on Na + and
K + excretion and glucocorticoids aff ect glucose and protein
metabolism.
■ Glucocorticoid secretion is dependent on ACTH from the
anterior pituitary and is increased by stress. Angiotensin II
increases the secretion of aldosterone.
MULTIPLECHOICE QUESTIONS
For all questions, select the single best answer unless otherwise
directed.
1. Which of the following is produced only by large amounts of
glucocorticoids?
A. Normal responsiveness of fat depots to norepinephrine
B. Maintenance of normal vascular reactivity
C. Increased excretion of a water load
D. Inhibition of the infl ammatory response
E. Inhibition of ACTH secretion
2. Which of the following are incorrectly paired?
A. Gluconeogenesis : Cortisol
B. Free fatty acid mobilization : Dehydroepiandrosterone
C. Muscle glycogenolysis : Epinephrine
D. Kaliuresis : Aldosterone
E. Hepatic glycogenesis : Insulin
3. Which of the following hormones has the shortest plasma halflife?
A. Corticosterone
B. Renin
C. Dehydroepiandrosterone
D. Aldosterone
E. Norepinephrine
4. Mole for mole, which of the following has the greatest eff ect on
Na + excretion?
A. Progesterone
B. Cortisol
C. Vasopressin
D. Aldosterone
E. Dehydroepiandrosterone
5. Mole for mole, which of the following has the greatest eff ect on
plasma osmolality?
A. Progesterone
B. Cortisol
C. Vasopressin
D. Aldosterone
E. Dehydroepiandrosterone
6. Th e secretion of which of the following would be least aff ected
by a decrease in extracellular fl uid volume?
A. CRH
B. Arginine vasopressin
C. Dehydroepiandrosterone
D. Estrogens
E. Aldosterone
7. A young man presents with a blood pressure of 175/110 mm
Hg. He is found to have a high circulating aldosterone but
a low circulating cortisol. Glucocorticoid treatment lowers
his circulating aldosterone and lowers his blood pressure to
140/85 mm Hg. He probably has an abnormal
A. 17α-hydroxylase.
B. 21β-hydroxylase.
C. 3β-hydroxysteroid dehydrogenase.
D. aldosterone synthase.
E. cholesterol desmolase.
8. A 32-year-old woman presents with a blood pressure of
155/96 mm Hg. In response to questioning, she admits that
she loves licorice and eats some at least three times a week. She
probably has a low level of
A. type 2 11β-hydroxysteroid dehydrogenase activity.
B. ACTH.
C. 11β-hydroxylase activity.
D. glucuronyl transferase.
E. norepinephrine.
9. In its action in cells, aldosterone
A. increases transport of ENaCs from the cytoplasm to the cell
membrane.
B. does not act on the cell membrane.
C. binds to a receptor excluded from the nucleus.
D. may activate a heat shock protein.
E. also binds to glucocorticoid receptors.
CHAPTER RESOURCES
Goldstein JL, Brown MS: Th e cholesterol quartet. Science
2001;292:1510.
Goodman HM (editor): Handbook of Physiology, Section 7: Th e
Endocrine System. Oxford University Press, 2000.
Larsen PR, Kronenberg HM, Melmed S, et al. (editors). Williams
Textbook of Endocrinology, 9th ed. Saunders, 2003.
Stocco DM: A review of the characteristics of the protein required
for the acute regulation of steroid hormone biosynthesis: Th e
case for the steroidogenic acute regulatory (StAR) protein. Proc
Soc Exp Biol Med 1998;217:123.
White PC: Disorders of aldosterone biosynthesis and action. N Engl
J Med 1994;331:250.
377
O B J E C T I V E S
After studying this chapter,
you should be able to:
■ Understand the importance of maintaining homeostasis of body calcium and
phosphate concentrations, and how this is accomplished.
■ Describe the body pools of calcium, their rates of turnover, and the organs that
play central roles in regulating movement of calcium between stores.
■ Delineate the mechanisms of calcium and phosphate absorption and excretion.
■ Identify the major hormones and other factors that regulate calcium and
phosphate homeostasis and their sites of synthesis as well as targets of their action.
■ D efi ne the basic anatomy of bone.
■ Delineate cells and their functions in bone formation and resorption.
liver and kidneys. Its primary action is to increase calcium
absorption from the intestine. Calcitonin, a calcium-lowering
hormone that in mammals is secreted primarily by cells in
the thyroid gland, inhibits bone resorption. Although the role
of calcitonin seems to be relatively minor, all three hormones
probably operate in concert to maintain the constancy of the
calcium level in the body fl uids. Phosphate homeostasis is
likewise critical to normal body function, particularly given
its inclusion in adenosine triphosphate (ATP), its role as a
biological buff er, and its role as a modifi er of proteins, thereby
altering their functions. Many of the systems that regulate
calcium homeostasis also contribute to that of phosphate,
albeit sometimes in a reciprocal fashion, and thus will also be
discussed in this chapter.
Hormonal Control of C H A P T E R
Calcium & Phosphate
Metabolism & the
Physiology of Bone 21
INTRODUCTION
Calcium is an essential intracellular signaling molecule and
also plays a variety of extracellular functions, thus the control
of body calcium concentrations is vitally important. Th e
components of the system that maintains calcium homeostasis
include cell types that sense changes in extracellular calcium
and release calcium-regulating hormones, and the targets of
these hormones, including the kidneys, bones, and intestine,
that respond with changes in calcium mobilization, excretion,
or uptake. Th ree hormones are primarily concerned with the
regulation of calcium homeostasis. Parathyroid hormone
(PTH) is secreted by the parathyroid glands. Its main action is
to mobilize calcium from bone and increase urinary phosphate
excretion. 1,25-Dihydroxycholecalciferol is a steroid hormone
formed from vitamin D by successive hydroxylations in the
CALCIUM & PHOSPHORUS
METABOLISM
CALCIUM
Th e body of a young adult human contains about 1100 g
(27.5 moles) of calcium. Ninety-nine per cent of the calcium is
in the skeleton. Plasma calcium, normally at a concentration
of around 10 mg/dL (5 mEq/L, 2.5 mmol/L), is partly bound to
protein and partly diff usible ( Table 21–1 ). Th e distribution of
calcium inside cells and the role of Ca 2+ as a second messenger
molecule is discussed in Chapter 2 .
It is the free, ionized calcium (Ca 2+ ) in the body fl uids that
is a vital second messenger and is necessary for blood coagulation,
muscle contraction, and nerve function. A decrease
in extracellular Ca 2+ exerts a net excitatory eff ect on nerve
Ganong_Ch21_377-390.indd 377 1/4/12 1:08:20 PM
378 SECTION III Endocrine and Reproductive Physiology
and muscle cells in vivo (see Chapters 4 and 5). Th e result
is hypocalcemic tetany , which is characterized by extensive
spasms of skeletal muscle, involving especially the muscles of
the extremities and the larynx. Laryngospasm can become so
severe that the airway is obstructed and fatal asphyxia is produced.
Ca 2+ also plays an important role in blood clotting (see
Chapter 31 ), but in vivo, fatal tetany would occur before compromising
the clotting reaction.
Because the extent of Ca 2+ binding by plasma proteins is
proportional to the plasma protein level, it is important to know
the plasma protein level when evaluating the total plasma calcium.
Other electrolytes and pH also aff ect the free Ca 2+ level.
Th us, for example, symptoms of tetany appear at higher total
calcium levels if the patient hyperventilates, thereby increasing
plasma pH. Plasma proteins are more ionized when the pH
is high, providing more protein anions to bind with Ca 2+ .
Th e calcium in bone is of two types: a readily exchangeable
reservoir and a much larger pool of stable calcium that
TABLE 211 Distribution (mg/dL) of calcium
in normal human plasma.
Total diff usible 5.36
Ionized (Ca 2+ ) 4.72
Complexed to HCO 3 – , citrate, etc 0.64
Total nondiff usible (protein-bound) 4.64
Bound to albumin 3.68
Bound to globulin 0.96
Total plasma calcium 10.00
Diet
25 mmol
GI
tract
Feces
22.5 mmol
Absorption
15 mmol
Secretion
12.5 mmol
Reabsorption
247.5 mmol
ECF
35 mmol
Glomerular
filtrate
250 mmol
Urine
2.5 mmol
Rapid
exchange
Accretion
500 mmol
7.5 mmol
Reabsorption
7.5 mmol
Bone
Exchangeable
100 mmol
Stable
27,200 mmol
FIGURE 211 Calcium metabolism in an adult human. A typical daily dietary intake of 25 mmol Ca 2+ (1000 mg) moves through many body
compartments. Note that the majority of body calcium is in bones, in a pool that is only slowly exchangeable with the extracellular fl uid (ECF).
is only slowly exchangeable. Two independent but interacting
homeostatic systems aff ect the calcium in bone. One is the system
that regulates plasma Ca 2+ , providing for the movement
of about 500 mmol of Ca 2+ per day into and out of the readily
exchangeable pool in the bone ( Figure 21–1 ). Th e other
system involves bone remodeling by the constant interplay of
bone resorption and deposition (see following text). However,
the Ca 2+ interchange between plasma and this stable pool of
bone calcium is only about 7.5 mmol/d.
Ca 2+ is transported across the brush border of intestinal
epithelial cells via channels known as transient receptor
potential vanilloid type 6 (TRPV6) and binds to an intracellular
protein known as calbindin-D 9k . Calbindin-D 9k sequesters
the absorbed calcium so that it does not disturb epithelial
signaling processes that involve calcium. Th e absorbed Ca 2+
is thereby delivered to the basolateral membrane of the
epithelial cell, from where it can be transported into the
bloodstream by either a Na + /Ca 2+ exchanger (NCX1) or a
Ca2+-dependent ATPase. Nevertheless, it should be noted that
recent studies indicate that some intestinal Ca 2+ uptake persists
even in the absence of TRPV6 and calbindin-D 9k , suggesting
that additional pathways are likely also involved in
this critical process. Th e overall transport process is regulated
by 1,25-dihydroxycholecalciferol (see below). As Ca 2+ uptake
rises, moreover, 1,25-dihydroxycholecalciferol levels fall in
response to increased plasma Ca 2+ .
Plasma Ca 2+ is fi ltered in the kidneys, but 98–99% of
the fi ltered Ca 2+ is reabsorbed. About 60% of the reabsorption
occurs in the proximal tubules and the remainder in the
ascending limb of the loop of Henle and the distal tubule.
Distal tubular reabsorption depends on the TRPV5 channel,
which is related to TRPV6 discussed previously, and whose
expression is regulated by PTH.
CHAPTER 21 Hormonal Control of Calcium & Phosphate Metabolism & the Physiology of Bone 379
PHOSPHORUS
Phosphate is found in ATP, cyclic adenosine monophosphate
(cAMP), 2,3-diphosphoglycerate, many proteins, and other
vital compounds in the body. Phosphorylation and dephosphorylation
of proteins are involved in the regulation of cell
function (see Chapter 2 ). Th erefore, it is not surprising that,
like calcium, phosphate metabolism is closely regulated. Total
body phosphorus is 500–800 g (16.1–25.8 moles), 85–90%
of which is in the skeleton. Total plasma phosphorus is
about 12 mg/dL, with two-thirds of this total in organic compounds
and the remaining inorganic phosphorus (P i ) mostly
in PO 4 3– , HPO 4 2– , and H 2 PO 4 – . Th e amount of phosphorus
normally entering bone is about 3 mg (97 μmol)/kg/d, with an
equal amount leaving via reabsorption.
P i in the plasma is fi ltered in the glomeruli, and 85–90%
of the fi ltered P i is reabsorbed. Active transport in the proximal
tubule accounts for most of the reabsorption and involves
two related sodium-dependent P i cotransporters, NaPi-IIa
and NaPi-IIc. NaPi-IIa is powerfully inhibited by PTH, which
causes its internalization and degradation and thus a reduction
in renal P i reabsorption (see below).
P i is absorbed in the duodenum and small intestine.
Uptake occurs by a transporter related to those in the kidney,
NaPi-IIb, that takes advantage of the low intracellular Na + concentration
established by the Na, K ATPase on the basolateral
membrane of intestinal epithelial cells to load P i against its concentration
gradient. However, the pathway by which P i exits
into the bloodstream is not known. Many stimuli that increase
Ca 2+ absorption, including 1,25-dihydroxycholecalciferol, also
increase P i absorption via increased NaPi-IIb expression and/
or its insertion into the enterocyte apical membrane.
VITAMIN D & THE
HYDROXYCHOLECALCIFEROLS
CHEMISTRY
Th e active transport of Ca 2+ and PO 4 3– from the intestine
is increased by a metabolite of vitamin D . Th e term “vitamin
D” is used to refer to a group of closely related sterols
produced by the action of ultraviolet light on certain provitamins
( Figure 21–2 ). Vitamin D 3 , which is also called
cholecalciferol, is produced in the skin of mammals from
7-dehydrocholesterol by the action of sunlight. Th e reaction
involves the rapid formation of previtamin D 3 , which is then
converted more slowly to vitamin D 3 . Vitamin D 3 and its
hydroxylated derivatives are transported in the plasma bound
to a globulin vitamin D-binding protein (DBP). Vitamin D 3 is
also ingested in the diet.
Vitamin D 3 is metabolized by enzymes that are members
of the cytochrome P450 (CYP) superfamily (see
Chapters 1 and 28). In the liver, vitamin D 3 is converted
to 25-hydroxycholecalciferol (calcidiol, 25-OHD 3 ). Th e
25-hydroxycholecalciferol is converted in the cells of
the proximal tubules of the kidneys to the more active
HO
7-Dehydrocholesterol
7-Dehydrocholesterol
1,25-Dihydroxycholecalciferol
24,25-Dihydroxycholecalciferol 1,25-Dihydroxycholecalciferol
25-Hydroxycholecalciferol
24
25
Vitamin D3
CH2
26
27
HO
CH2
HO OH
OH
KIDNEY
Other
metabolites
LIVER
SKIN
25-Hydroxylase
24-Hydroxylase 1α-Hydroxylase
Vitamin D3
(cholecalciferol)
Previtamin D3
Sunlight
FIGURE 212 Formation and hydroxylation of vitamin D 3 . 25-Hydroxylation takes place in the liver, and the other hydroxylations occur
primarily in the kidneys. The structures of 7-dehydrocholesterol, vitamin D 3 , and 1,25-dihydroxycholecalciferol are also shown in the boxed area.
380 SECTION III Endocrine and Reproductive Physiology
metabolite 1,25-dihydroxycholecalciferol , which is also
called calcitriol or 1,25-(OH) 2 D 3 . 1,25-Dihydroxycholecalciferol
is also made in the placenta, in keratinocytes
in the skin, and in macrophages. Th e normal plasma level
of 25-hydroxycholecalciferol is about 30 ng/mL, and that
of 1,25-dihydroxycholecalciferol is about 0.03 ng/mL
(approximately 100 pmol/L). Th e less active metabolite
24,25-dihydroxycholecalciferol is also formed in the kidneys
( Figure 21–2 ).
MECHANISM OF ACTION
1,25 Dihydroxycholecalciferol stimulates the expression of a
number of gene products involved in Ca 2+ transport and handling
via its receptor, which acts as a transcriptional regulator in
its ligand-bound form. One group is the family of calbindin-D
proteins. Th ese are members of the troponin C superfamily
of Ca 2+ -binding proteins that also includes calmodulin (see
Chapter 2 ). Calbindin-Ds are found in human intestine, brain,
and kidneys. In the intestinal epithelium and many other tissues,
two calbindins are induced: calbindinD 9K and calbindin-
D 28K , with molecular weights of 9000 and 28,000, respectively.
1,25-Dihydroxycholecalciferol also increases the number of
Ca 2+ –ATPase and TRPV6 molecules in the intestinal cells, and
thus, the overall capacity for absorption of dietary calcium.
In addition to increasing Ca 2+ absorption from the intestine,
1,25-dihydroxycholecalciferol facilitates Ca 2+ reabsorption
in the kidneys via increased TRPV5 expression in the
proximal tubules, increases the synthetic activity of osteoblasts,
and is necessary for normal calcifi cation of matrix
(see Clinical Box 21–1). Th e stimulation of osteoblasts
brings about a secondary increase in the activity of osteoclasts
(see below).
REGULATION OF SYNTHESIS
Th e formation of 25-hydroxycholecalciferol does not appear
to be stringently regulated. However, the formation of
1,25-dihydroxycholecalciferol in the kidneys, which is catalyzed
by the renal 1α-hydroxylase, is regulated in a feedback
fashion by plasma Ca 2+ and PO 4
3+ ( Figure 21–3 ). When the
plasma Ca 2+ level is high, little 1,25-dihydroxycholecalciferol
is produced, and the kidneys produce the relatively inactive
metabolite 24,25-dihydroxycholecalciferol instead. Th is eff ect
of Ca 2+ on production of 1,25-dihydroxycholecalciferol is the
mechanism that brings about adaptation of Ca 2+ absorption
from the intestine (see previous text). Conversely, expression
of 1α-hydroxylase is stimulated by PTH, and when the
plasma Ca 2+ level is low, PTH secretion is increased. Th e production
of 1,25-dihydroxycholecalciferol is also increased
by low and inhibited by high plasma PO 4
3– levels, by a direct
inhibitory eff ect of PO 4
3– on the 1α-hydroxylase. Additional
control of 1,25-dihydroxycholecalciferol formation results
from a direct negative feedback eff ect of the metabolite on
1α-hydroxylase, a positive feedback action on the formation
of 24,25-dihydroxycholecalciferol, and a direct action on the
parathyroid gland to inhibit PTH expression.
An “anti-aging” protein called α-Klotho (named aft er
Klotho, a daughter of Zeus in Greek mythology who spins
the thread of life) has also recently been discovered to play
important roles in calcium and phosphate homeostasis, in
part by reciprocal eff ects on 1,25-dihydroxycholecalciferol
levels. Mice defi cient in α-Klotho displayed accelerated
aging, decreased bone mineral density, calcifi cations, and
hypercalcemia and hyperphosphatemia. α-Klotho plays an
important role in stabilizing the membrane localization of
proteins important in calcium and phosphate (re)absorption,
CLINICAL BOX 21–1
Rickets & Osteomalacia
Vitamin D defi ciency causes defective calcifi cation of bone
matrix and the disease called rickets in children and
osteomalacia in adults. Even though 1,25-dihydroxycholecalciferol
is necessary for normal mineralization of bone matrix,
the main defect in this condition is failure to deliver adequate
amounts of Ca 2+ and PO 4 3– to the sites of mineralization. The
full-blown condition in children is characterized by weakness
and bowing of weight-bearing bones, dental defects, and hypocalcemia.
In adults, the condition is less obvious. It used
to be most commonly due to inadequate exposure to the
sun in smoggy cities, but now it is more commonly due to
inadequate intake of the provitamins on which the sun acts
in the skin. These cases respond to administration of vitamin
D. The condition can also be caused by inactivating mutations
of the gene for renal 1α-hydroxylase, or in severe renal
or liver diseases, in which case there is no response to vitamin
D but a normal response to 1,25-dihydroxycholecalciferol
(type I vitamin D-resistant rickets). In rare instances, it
can be due to inactivating mutations of the gene for the
1,25-dihydroxycholecalciferol receptor (type II vitamin Dresistant
rickets) , in which case there is a defi cient response
to both vitamin D and 1,25-dihydroxycholecalciferol.
THERAPEUTIC HIGHLIGHTS
Treatment of these conditions depends on the underlying
biochemical basis, as indicated above. Routine supplementation
of milk with vitamin D has greatly reduced
the occurrence of rickets in Western countries, but the
condition remains among the most common childhood
diseases in developing countries. Orthopedic surgery
may be necessary in severely aff ected children.
CHAPTER 21 Hormonal Control of Calcium & Phosphate Metabolism & the Physiology of Bone 381
such as TRPV5 and Na, K ATPase. Likewise, it enhances
the activity of another factor, fi broblast growth factor
23 (FGF23), at its receptor. FGF23 thereby decreases renal
NaPi-IIa and NaPi-IIc expression and inhibits the production
of 1α-hydroxylase, reducing levels of 1,25-dihydroxycholecalciferol
(Clinical Box 21–1).
THE PARATHYROID GLANDS
ANATOMY
Humans usually have four parathyroid glands: two embedded
in the superior poles of the thyroid and two in its inferior poles
( Figure 21–4 ). Each parathyroid gland is a richly vascularized
disk, about 3 × 6 × 2 mm, containing two distinct types of
cells ( Figure 21–5 ). Th e abundant chief cells , which contain
a prominent Golgi apparatus plus endoplasmic reticulum and
secretory granules, synthesize and secrete PTH . Th e less abundant
and larger oxyphil cells contain oxyphil granules and
Release of calcium
into plasma
Bone
Resorption
Intestine
Calcium absorption
Urinary excretion
of calcium
Plasma
1,25–(OH)2D3
Kidneys
Calcium
reabsorption
1,25–(OH)2D3
formation
Plasma parathyroid hormone
Parathyroid glands
Parathyroid hormone secretion
Plasma calcium
Restoration of plasma calcium toward normal
FIGURE 213 Eff ects of PTH and
1,25-dihydroxycholecalciferol on whole body calcium
homeostasis. A reduction in plasma calcium stimulates parathyroid
hormone secretion. PTH in turn causes calcium conservation and
production of 1,25-dihydroxycholecalciferol in the kidneys, the latter
of which increases calcium uptake in the intestine. PTH also releases
calcium from the readily exchangeable pool in the bone. All of
these actions act to restore normal plasma calcium. (Reproduced with
permission from Widmaier EP, Raff H, Strang KT: Vander’s Human Physiology , 10th ed.
McGraw-Hill, 2006.)
Common
carotid
artery
Right
parathyroids
Pharynx
Recurrent
laryngeal
nerve
Inferior
thyroid
artery
FIGURE 214 The human parathyroid glands, viewed from
behind. The glands are small structures adherent to the posterior
surface of the thyroid gland.
FIGURE 215 Section of human parathyroid ( Reduced 50%
from × 960). Small cells are chief cells; large stippled cells (especially
prominent in the lower left of picture) are oxyphil cells. (Reproduced
with permission from Fawcett DW: Bloom and Fawcett , A Textbook of Histology ,
11th ed. Saunders, 1986.)
large numbers of mitochondria in their cytoplasm. In humans,
few oxyphil cells are seen before puberty, and thereaft er they
increase in number with age. Th eir function is unknown.
Consequences of loss of the parathyroid glands are discussed
in Clinical Box 21–2.
SYNTHESIS &
METABOLISM OF PTH
Human PTH is a linear polypeptide with a molecular weight
of 9500 that contains 84 amino acid residues ( Figure 21–6 ).
It is synthesized as part of a larger molecule containing 115
amino acid residues ( preproPTH ). On entry of preproPTH
382 SECTION III Endocrine and Reproductive Physiology
into the endoplasmic reticulum, a leader sequence is removed
from the amino terminal to form the 90-amino-acid polypeptide
proPTH. Six additional amino acid residues are removed
from the amino terminal of proPTH in the Golgi apparatus,
and the 84-amino-acid polypeptide PTH is packaged in secretory
granules and released as the main secretory product of
the chief cells.
S V S E I Q
A
M H N L G K H L
N V D L K K R L W E V R
F
V
A
L
G A P L A P R D
H Q
N
S
S I V H
L
S
M
E
L
F
S
S I Y
E L S E H S
A
D
K
A
D V D V L
G K
Q
A
Q
T K A
I
I
K S Q
P
P
A
G
G
G S Q
E V L V N D
R P
R
K
K
E
S
5 10 15
20
30 25
35
45
65 60
70
55
75 80
Human Bovine Porcine
50
FIGURE 216 Parathyroid hormone. The symbols above and
below the human structure show where amino acid residues are
diff erent in bovine and porcine PTH. (Reproduced with permission from
Keutmann HT, et al: Complete amino acid sequence of human parathyroid hormone.
Biochemistry 1978;17:5723. Copyright © 1978 by the American Chemical Society.)
CLINICAL BOX 21–2
Eff ects of Parathyroidectomy
Occasionally, inadvertent parathyroidectomy occurs in humans
during thyroid surgery. This can have serious consequences
as PTH is essential for life. After parathyroidectomy, there is a
steady decline in the plasma Ca 2+ level. Signs of neuromuscular
hyperexcitability appear, followed by full-blown hypocalcemic
tetany (see text). Plasma phosphate levels usually rise as
the plasma Ca 2+ level falls. Symptoms usually develop 2–3 days
postoperatively but may not appear for several weeks or more.
The signs of tetany in humans include Chvostek’s sign , a quick
contraction of the ipsilateral facial muscles elicited by tapping
over the facial nerve at the angle of the jaw, and Trousseau’s
sign , a spasm of the muscles of the upper extremity that causes
fl exion of the wrist and thumb with extension of the fi ngers. In
individuals with mild tetany in whom spasm is not yet evident,
Trousseau’s sign can sometimes be produced by occluding the
circulation for a few minutes with a blood pressure cuff .
THERAPEUTIC HIGHLIGHTS
Treatment centers around replacing the PTH that would
normally be produced by the missing glands. Injections
of PTH can be given to correct the chemical abnormalities,
and the symptoms then disappear. Injections of Ca 2+
salts can also give temporary relief.
Th e normal plasma level of intact PTH is 10–55 pg/mL.
Th e half-life of PTH is approximately 10 min, and the secreted
polypeptide is rapidly cleaved by the Kupff er cells in the liver
into fragments that are probably biologically inactive. PTH
and these fragments are then cleared by the kidneys. Currently
used immunoassays for PTH are designed only to measure
mature PTH (ie, 84 amino acids) and not these fragments to
obtain an accurate measure of “active” PTH.
ACTIONS
PTH acts directly on bone to increase bone resorption and
mobilize Ca 2+ . In addition to increasing plasma Ca 2+ , PTH
increases phosphate excretion in the urine and thereby
depresses plasma phosphate levels. Th is phosphaturic action
is due to a decrease in reabsorption of phosphate via eff ects
on NaPi-IIa in the proximal tubules, as discussed previously.
PTH also increases reabsorption of Ca 2+ in the distal
tubules, although Ca 2+ excretion in the urine is oft en increased
in hyperparathyroidism because the increase in the load
of fi ltered calcium overwhelms the eff ect on reabsorption
(Clinical Box 21–3). PTH also increases the formation of
1,25-dihydroxycholecalciferol, and this increases Ca 2+ absorption
from the intestine. On a longer time scale, PTH stimulates
both osteoblasts and osteoclasts.
MECHANISM OF ACTION
It now appears that there are at least three diff erent PTH
receptors. One also binds parathyroid hormone-related protein
(PTHrP; see below) and is known as the hPTH/PTHrP
receptor. A second receptor, PTH2 (hPTH2-R), does not bind
PTHrP and is found in the brain, placenta, and pancreas. In
addition, there is evidence for a third receptor, CPTH, which
reacts with the carboxyl terminal rather than the amino
CHAPTER 21 Hormonal Control of Calcium & Phosphate Metabolism & the Physiology of Bone 383
terminal of PTH. Th e fi rst two receptors are coupled to G s ,
and via this heterotrimeric G protein they activate adenylyl
cyclase, increasing intracellular cAMP. Th e hPTH/PTHrP
receptor also activates PLC via G q , increasing intracellular Ca 2+
concentrations and activating protein kinase C ( Figure 21–7 ).
However, the way these second messengers aff ect Ca 2+ in bone
is unsettled.
In the disease called pseudohypoparathyroidism, the
signs and symptoms of hypoparathyroidism develop but the
circulating level of PTH is normal or even elevated. Because
tissues fail to respond to the hormone, this is a receptor disease.
Th ere are two forms. In the more common form, a congenital
50% reduction of the activity of G s occurs and PTH
fails to produce a normal increase in cAMP concentration. In
a diff erent, less common form, the cAMP response is normal
but the phosphaturic action of the hormone is defective.
REGULATION OF SECRETION
Circulating Ca 2+ acts directly on the parathyroid glands in a
negative feedback fashion to regulate the secretion of PTH.
Th e key to this regulation is a cell membrane Ca 2+ receptor,
CaR. Activation of this G-protein coupled receptor leads to
phosphoinositide turnover in many tissues. In the parathyroid,
its activation inhibits PTH secretion. In this way, when
the plasma Ca 2+ level is high, PTH secretion is inhibited and
Ca 2+ is deposited in the bones. When it is low, secretion is
increased and Ca 2+ is mobilized from the bones.
1,25-Dihydroxycholecalciferol acts directly on the parathyroid
glands to decrease preproPTH mRNA. Increased
CLINICAL BOX 21–3
Diseases of Parathyroid Excess
Hyperparathyroidism due to hypersecretion from a functioning
parathyroid tumor in humans is characterized by hypercalcemia
and hypophosphatemia. Humans with PTH-secreting
adenomas are usually asymptomatic, with the condition detected
when plasma Ca 2+ is measured in conjunction with a
routine physical examination. However, there may be minor
changes in personality, and calcium-containing kidney stones
occasionally form. In conditions such as chronic renal disease
and rickets, in which the plasma Ca 2+ level is chronically low,
stimulation of the parathyroid glands causes compensatory
parathyroid hypertrophy and secondary hyperparathyroidism.
The plasma Ca 2+ level is low in chronic renal disease primarily
because the diseased kidneys lose the ability to form
1,25-dihydroxycholecalciferol. Finally, mutations in the Ca 2+
receptor (CaR) gene cause predictable long-term changes in
plasma Ca 2+ . Individuals heterozygous for inactivating mutations
have familial benign hypocalciuric hypercalcemia, a condition
in which there is a chronic moderate elevation in plasma
Ca 2+ because the feedback inhibition of PTH secretion by Ca 2+
is reduced. Plasma PTH levels are normal or even elevated.
However, children who are homozygous for inactivating mutations
develop neonatal severe primary hyperparathyroidism.
Conversely, individuals with gain-of-function mutations of the
CaR gene develop familial hypercalciuric hypocalcemia due to
increased sensitivity of the parathyroid glands to plasma Ca 2+ .
THERAPEUTIC HIGHLIGHTS
Subtotal parathyroidectomy is sometimes necessary
in patients who develop parathyroid adenoma or hyperplasia
with associated hypercalcemia and resulting
symptoms. However, because parathyroid disease is often
benign or only slowly progressing, surgery remains
controversial in most patients and is typically reserved for
those who have experienced life-threatening complications
of hypercalcemia.
Gs Gq AC PLC
PTHrP PTH
ATP cAMP
PIP2
PTH-R
Diacylglycerol
Protein
kinase C
activation
Intracellular
Ca2+
mobilization
1,4,5-InsP3
FIGURE 217 Signal transduction pathways activated by
PTH or PTHrP binding to the hPTH/hPTHrP receptor. Intracellular
cAMP is increased via G s and adenylyl cyclase (AC). Diacylglycerol
and IP 3 (1,4,5-InsP 3 ) are increased via G q and phospholipase C (PLC).
(Modifi ed and reproduced with permission from McPhee SJ, Lingappa VR, Ganong
WF [editors]: Pathophysiology of Disease , 6th ed. McGraw-Hill, 2010.)
plasma phosphate stimulates PTH secretion by lowering
plasma levels of free Ca 2+ and inhibiting the formation of
1,25-dihydroxycholecalciferol. Magnesium is required to
maintain normal parathyroid secretory responses. Impaired
PTH release along with diminished target organ responses to
PTH account for the hypocalcemia that occasionally occurs
in magnesium defi ciency (Clinical Box 21–2 and Clinical
Box 21–3).
384 SECTION III Endocrine and Reproductive Physiology
PTHrP
Another protein with PTH activity, parathyroid hormonerelated
protein (PTHrP) , is produced by many diff erent tissues
in the body. It has 140 amino acid residues, compared
with 84 in PTH, and is encoded by a gene on human chromosome
12, whereas PTH is encoded by a gene on chromosome
11. PTHrP and PTH have marked homology at their amino
terminal ends and they both bind to the hPTH/PTHrP receptor,
yet their physiologic eff ects are very diff erent. How is this
possible when they bind to the same receptor? For one thing,
PTHrP is primarily a paracrine factor, acting close to where it
is produced. It may be that circulating PTH cannot reach at
least some of these sites. Second, subtle conformational differences
may be produced by binding of PTH versus PTHrP
to their receptor, despite their structural similarities. Another
possibility is action of one or the other hormone on additional,
more selective receptors.
PTHrP has a marked eff ect on the growth and development
of cartilage in utero. Mice in which both alleles of the
PTHrP gene are knocked out have severe skeletal deformities
and die soon aft er birth. In normal animals, on the other
hand, PTHrP-stimulated cartilage cells proliferate and their
terminal diff erentiation is inhibited. PTHrP is also expressed
in the brain, where evidence indicates that it inhibits excitotoxic
damage to developing neurons. In addition, there is
evidence that it is involved in Ca 2+ transport in the placenta.
PTHrP is also found in keratinocytes in the skin, in smooth
muscle, and in the teeth, where it is present in the enamel epithelium
that caps each tooth. In the absence of PTHrP, teeth
cannot erupt.
HYPERCALCEMIA
OF MALIGNANCY
Hypercalcemia is a common metabolic complication of cancer.
About 20% of hypercalcemic patients have bone metastases
that produce the hypercalcemia by eroding bone (local
osteolytic hypercalcemia). Evidence suggests that this erosion
is produced by prostaglandins such as prostaglandin E 2
arising from the tumor. Th e hypercalcemia in the remaining
80% of the patients is due to elevated circulating levels
of PTHrP (humoral hypercalcemia of malignancy). Th e
tumors responsible for this hypersecretion include cancers of
the breast, kidney, ovary, and skin.
CALCITONIN
ORIGIN
In dogs, perfusion of the thyroparathyroid region with solutions
containing high concentrations of Ca 2+ leads to a fall in
peripheral plasma Ca 2+ , and aft er damage to this region, Ca 2+
infusions cause a greater increase in plasma Ca 2+ than they
do in control animals. Th ese and other observations led to
the discovery that a Ca 2+ -lowering as well as a Ca 2+ -elevating
hormone was secreted by structures in the neck. Th e Ca 2+ -
lowering hormone has been named calcitonin. In mammals,
calcitonin is produced by the parafollicular cells of the thyroid
gland, which are also known as the clear or C cells.
SECRETION & METABOLISM
Human calcitonin has a molecular weight of 3500 and contains
32 amino acid residues. Its secretion is increased when
the thyroid gland is exposed to a plasma calcium level of
approximately 9.5 mg/dL. Above this level, plasma calcitonin
is directly proportional to plasma calcium. β-Adrenergic agonists,
dopamine, and estrogens also stimulate calcitonin secretion.
Gastrin, cholecystokinin (CCK), glucagon, and secretin
have also been reported to stimulate calcitonin secretion, with
gastrin being the most potent stimulus (see Chapter 25 ). Th us,
the plasma calcitonin level is elevated in Zollinger–Ellison
syndrome and in pernicious anemia (see Chapter 25 ). However,
the dose of gastrin needed to stimulate calcitonin secretion
is supraphysiological and not seen aft er eating in normal
individuals, so dietary calcium in the intestine probably does
not induce secretion of a calcium-lowering hormone prior to
the calcium being absorbed. In any event, the actions of calcitonin
are short-lived because it has a half-life of less than
10 min in humans.
ACTIONS
Receptors for calcitonin are found in bones and the kidneys.
Calcitonin lowers circulating calcium and phosphate levels. It
exerts its calcium-lowering eff ect by inhibiting bone resorption.
Th is action is direct, and calcitonin inhibits the activity
of osteoclasts in vitro. It also increases Ca 2+ excretion in the
urine.
Th e exact physiologic role of calcitonin is uncertain.
Th e calcitonin content of the human thyroid is low, and aft er
thyroidectomy, bone density and plasma Ca 2+ level are normal
as long as the parathyroid glands are intact. In addition,
aft er thyroidectomy, there are only transient abnormalities of
Ca 2+ homeostasis when a Ca 2+ load is injected. Th is may be
explained in part by secretion of calcitonin from tissues other
than the thyroid. However, there is general agreement that
the hormone has little long-term eff ect on the plasma Ca 2+
level in adult animals and humans. Further, unlike PTH and
1,25-dihydroxycholecalciferol, calcitonin does not appear to
be involved in phosphate homeostasis. Moreover, patients
with medullary carcinoma of the thyroid have a very high
circulating calcitonin level but no symptoms directly attributable
to the hormone, and their bones are essentially normal.
No syndrome due to calcitonin defi ciency has been described.
More hormone is secreted in young individuals, and it may
play a role in skeletal development. In addition, it may protect
the bones of the mother from excess calcium loss during
pregnancy. Bone formation in the infant and lactation are
major drains on Ca 2+ stores, and plasma concentrations of
CHAPTER 21 Hormonal Control of Calcium & Phosphate Metabolism & the Physiology of Bone 385
1,25-dihydroxycholecalciferol are elevated in pregnancy. Th ey
would cause bone loss in the mother if bone resorption were
not simultaneously inhibited by an increase in the plasma calcitonin
level.
SUMMARY OF CALCIUM
HOMEOSTATIC MECHANISMS
Th e actions of the three principal hormones that regulate the
plasma concentration of Ca 2+ can now be summarized. PTH
increases plasma Ca 2+ by mobilizing this ion from bone. It
increases Ca 2+ reabsorption in the kidney, but this may be off set
by the increase in fi ltered Ca 2+ . It also increases the formation of
1,25-dihydroxycholecalciferol. 1,25-Dihydroxycholecalciferol
increases Ca 2+ absorption from the intestine and increases Ca 2+
reabsorption in the kidneys. Calcitonin inhibits bone resorption
and increases the amount of Ca 2+ in the urine.
EFFECTS OF OTHER HORMONES
& HUMORAL AGENTS ON
CALCIUM METABOLISM
Calcium metabolism is aff ected by various hormones in addition
to 1,25-dihydroxycholecalciferol, PTH, and calcitonin.
Glucocorticoids lower plasma Ca 2+ levels by inhibiting osteoclast
formation and activity, but over long periods they cause
osteoporosis by decreasing bone formation and increasing
bone resorption. Th ey decrease bone formation by inhibiting
protein synthesis in osteoblasts. Th ey also decrease the absorption
of Ca 2+ and PO 4 3– from the intestine and increase the renal
excretion of these ions. Th e decrease in plasma Ca 2+ concentration
also increases the secretion of PTH, and bone resorption
is facilitated. Growth hormone increases Ca 2+ excretion
in the urine, but it also increases intestinal absorption of Ca 2+ ,
and this eff ect may be greater than the eff ect on excretion, with
a resultant positive calcium balance. Insulin-like growth factor
I (IGF-I) generated by the action of growth hormone stimulates
protein synthesis in bone. As noted previously, thyroid
hormones may cause hypercalcemia, hypercalciuria, and, in
some instances, osteoporosis. Estrogens prevent osteoporosis
by inhibiting the stimulatory eff ects of certain cytokines on
osteoclasts. Insulin increases bone formation, and there is signifi
cant bone loss in untreated diabetes.
BONE PHYSIOLOGY
Bone is a special form of connective tissue with a collagen
framework impregnated with Ca 2+ and PO 4 3– salts, particularly
hydroxyapatites, which have the general formula
Ca 10 (PO 4 ) 6 (OH) 2 . Bone is also involved in overall Ca 2+ and
PO 4 3– homeostasis. It protects vital organs, and the rigidity it
provides permits locomotion and the support of loads against
gravity. Old bone is constantly being resorbed and new bone
formed, permitting remodeling that allows it to respond to the
stresses and strains that are put upon it. It is a living tissue that
is well vascularized and has a total blood fl ow of 200–400 mL/
min in adult humans.
STRUCTURE
Bone in children and adults is of two types: compact or
cortical bone , which makes up the outer layer of most bones
( Figure 21–8 ) and accounts for 80% of the bone in the body;
and trabecular or spongy bone inside the cortical bone,
which makes up the remaining 20% of bone in the body. In
compact bone, the surface-to-volume ratio is low, and bone
cells lie in lacunae. Th ey receive nutrients by way of canaliculi
that ramify throughout the compact bone ( Figure 21–8 ).
Trabecular bone is made up of spicules or plates, with a high
surface to volume ratio and many cells sitting on the surface
of the plates. Nutrients diff use from bone extracellular fl uid
(ECF) into the trabeculae, but in compact bone, nutrients
are provided via haversian canals ( Figure 21–8 ), which contain
blood vessels. Around each Haversian canal, collagen
is arranged in concentric layers, forming cylinders called
osteons or haversian systems .
Th e protein in bone matrix is over 90% type I collagen,
which is also the major structural protein in tendons and skin.
Th is collagen, which weight for weight is as strong as steel, is
made up of a triple helix of three polypeptides bound tightly
together. Two of these are identical α1 polypeptides encoded
by one gene, and one is an α2 polypeptide encoded by a different
gene. Collagens make up a family of structurally related
proteins that maintain the integrity of many diff erent organs.
Fift een diff erent types of collagens encoded by more than
20 diff erent genes have so far been identifi ed.
BONE GROWTH
During fetal development, most bones are modeled in
cartilage and then transformed into bone by ossifi cation
( enchondral bone formation ). Th e exceptions are the clavicles,
the mandibles, and certain bones of the skull in which
mesenchymal cells form bone directly ( intramembranous
bone formation ).
During growth, specialized areas at the ends of each
long bone ( epiphyses ) are separated from the shaft of the
bone by a plate of actively proliferating cartilage, the epiphysial
plate ( Figure 21–9 ). Th e bone increases in length as
this plate lays down new bone on the end of the shaft . Th e
width of the epiphysial plate is proportional to the rate of
growth. Th e width is aff ected by a number of hormones, but
most markedly by the pituitary growth hormone and IGF-I
(see Chapter 18 ).
Linear bone growth can occur as long as the epiphyses
are separated from the shaft of the bone, but such growth
ceases aft er the epiphyses unite with the shaft (epiphysial
closure). Th e cartilage cells stop proliferating, become
386 SECTION III Endocrine and Reproductive Physiology
hypertrophic, and secrete vascular endothelial growth factor
(VEGF), leading to vascularization and ossifi cation. Th e
epiphyses of the various bones close in an orderly temporal
sequence, the last epiphyses closing aft er puberty. Th e normal
age at which each of the epiphyses closes is known, and
the “bone age” of a young individual can be determined by
X-raying the skeleton and noting which epiphyses are open
and which are closed.
Th e periosteum is a dense fi brous, vascular, and innervated
membrane that covers the surface of bones. Th is layer
consists of an outer layer of collagenous tissue and an inner
layer of fi ne elastic fi bers that can include cells that have the
potential to contribute to bone growth. Th e periosteum covers
all surfaces of the bone except for those capped with cartilage
(eg, at the joints) and serves as a site of attachment of
ligaments and tendons. As one ages, the periosteum becomes
thinner and loses some of its vasculature. Th is renders bones
more susceptible to injury and disease.
BONE FORMATION
& RESORPTION
Th e cells responsible for bone formation are osteoblasts and
the cells responsible for bone resorption are osteoclasts.
Osteoblasts are modifi ed fi broblasts. Th eir early development
from the mesenchyme is the same as that of fi broblasts,
with extensive growth factor regulation. Later, ossifi cationspecifi
c transcription factors, such as Cbfa1/Runx2, contribute
to their diff erentiation. Th e importance of this transcription
Cortical (compact) bone
Lacunae
Trabecular
(cancellous)
bone
Osteons
Canaliculi
Haversian
canal
Resorption
spaces
FIGURE 218 Structure of compact and trabecular bone. The compact bone is shown in horizontal section (top) and vertical section
(bottom). (Reproduced with permission from Williams PL et al (editors): Gray’s Anatomy , 37th ed. Churchill Livingstone, 1989.)
CHAPTER 21 Hormonal Control of Calcium & Phosphate Metabolism & the Physiology of Bone 387
Epiphysis
Epiphysis
Diaphysis
Epiphysial
plate
Marrow
cavity
Compact
bone
Periosteum
Trabecular
bone
FIGURE 219 Structure of a typical long bone before (left)
and after (right) epiphysial closure. Note the rearrangement of
cells and growth of the bone as the epiphysial plate closes (see text
for details).
Bone-resorbing
compartment
Ruffled apical
membrane
Sealing
zone
Integrins
Basolateral
membrane
Bone
matrix
n
n
n
mi
n
FIGURE 2110 Osteoclast resorbing bone. The edges of
the cell are tightly sealed to bone, permitting secretion of acid from
the ruffl ed apical membrane and consequent erosion of the bone
underneath the cell. Note the multiple nuclei (n) and mitochondria
(mi). (Courtesy of R Baron.)
factor in bone development is underscored in knockout mice
defi cient for the Cbfa1/Runx gene. Th ese mice develop to term
with their skeletons made exclusively of cartilage; no ossifi -
cation occurs. Normal osteoblasts are able to lay down type
1 collagen and form new bone.
Osteoclasts, on the other hand, are members of the monocyte
family. Stromal cells in the bone marrow, osteoblasts, and
T lymphocytes all express receptor activator for nuclear factor
kappa beta ligand (RANKL) on their surface. When these
cells come in contact with appropriate monocytes expressing
RANK (ie, the RANKL receptor) two distinct signaling pathways
are initiated: (1) there is a RANKL/RANK interaction
between the cell pairs, (2) mononuclear phagocyte colony
stimulating factor (M-CSF) is secreted by the nonmonocytic
cells and it binds to its corresponding receptor on the monocytes
(c-fi n). Th e combination of these two signaling events
leads to diff erentiation of the monocytes into osteoclasts. Th e
precursor cells also secrete osteoprotegerin (OPG) , which
controls for diff erentiation of the monocytes by competing
with RANK for binding of RANKL.
Osteoclasts erode and absorb previously formed bone.
Th ey become attached to bone via integrins in a membrane
extension called the sealing zone . Th is creates an isolated
area between the bone and a portion of the osteoclast. Proton
pumps (ie, H + -dependent ATPases) then move from endosomes
into the cell membrane apposed to the isolated area,
and they acidify the area to approximately pH 4.0. Similar
proton pumps are found in the endosomes and lysosomes of
all eukaryotic cells, but in only a few other instances do they
move into the cell membrane. Note in this regard that the
sealed-off space formed by the osteoclast resembles a large
lysosome. Th e acidic pH dissolves hydroxyapatite, and acid
proteases secreted by the cell break down collagen, forming
a shallow depression in the bone ( Figure 21–10 ). Th e products
of digestion are then endocytosed and move across the
osteoclast by transcytosis (see Chapter 2 ), with release into the
interstitial fl uid. Th e collagen breakdown products have pyridinoline
structures, and pyridinolines can be measured in the
urine as an index of the rate of bone resorption.
Th roughout life, bone is being constantly resorbed and
new bone is being formed. Th e calcium in bone turns over at
a rate of 100% per year in infants and 18% per year in adults.
Bone remodeling is mainly a local process carried out in
small areas by populations of cells called bone-remodeling
units. First, osteoclasts resorb bone, and then osteoblasts lay
down new bone in the same general area. Th is cycle takes
about 100 days. Modeling drift s also occur in which the
shapes of bones change as bone is resorbed in one location
and added in another. Osteoclasts tunnel into cortical bone
followed by osteoblasts, whereas trabecular bone remodeling
occurs on the surface of the trabeculae. About 5% of
the bone mass is being remodeled by about 2 million boneremodeling
units in the human skeleton at any one time.
Th e renewal rate for bone is about 4% per year for compact
bone and 20% per year for trabecular bone. Th e remodeling
is related in part to the stresses and strains imposed on the
skeleton by gravity.
At the cellular level, there is some regulation of osteoclast
formation by osteoblasts via the RANKL–RANK and the
M-CSF–OPG mechanism; however, specifi c feedback mechanisms
of osteoclasts on osteoblasts are not well defi ned. In a
broader sense, the bone remodeling process is primarily under
endocrine control. PTH accelerates bone resorption, and
estrogens slow bone resorption by inhibiting the production
of bone-eroding cytokines. An interesting new observation
388 SECTION III Endocrine and Reproductive Physiology
FIGURE 2111 Normal trabecular bone (left) compared with
trabecular bone from a patient with osteoporosis (right). The loss
of mass in osteoporosis leaves bones more susceptible to breakage.
1500
1000
500
0
0 20 40 60 80 100
Age (years)
Total body calcium (grams)
I
I
II
III
III
FIGURE 2112 Total body calcium, an index of bone mass,
at various ages in men and women. Note the rapid increase to
young adult levels (phase I) followed by the steady loss of bone with
advancing age in both sexes (phase III) and the superimposed rapid
loss in women after menopause (phase II). (Reproduced by permission
of Oxford University Press from Riggs BL, Melton LJ III: Involutional osteoporosis.
In Evans TG, Williams TF (editors): Oxford Textbook of Geriatric Medicine . Oxford
University Press, 1992.)
is that intracerebroventricular, but not intravenous, leptin
decreases bone formation. Th is fi nding is consistent with
the observations that obesity protects against bone loss and
that most obese humans are resistant to the eff ects of leptin
on appetite. Th us, there may be neuroendocrine regulation of
bone mass via leptin.
BONE DISEASE
Th e diseases produced by selective abnormalities of the cells
and processes discussed above illustrate the interplay of factors
that maintain normal bone function.
In osteopetrosis , a rare and oft en severe disease, the
osteoclasts are defective and are unable to resorb bone in
their usual fashion so the osteoblasts operate unopposed.
Th e result is a steady increase in bone density, neurologic
defects due to narrowing and distortion of foramina through
which nerves normally pass, and hematologic abnormalities
due to crowding out of the marrow cavities. Mice lacking the
protein encoded by the immediate-early gene c- fos develop
osteopetrosis; osteopetrosis also occurs in mice lacking the
PU.1 transcription factor. Th is suggests that all these factors
are involved in normal osteoclast development and
function.
On the other hand, osteoporosis is caused by a relative
excess of osteoclastic function. Loss of bone matrix in this
condition ( Figure 21–11 ) is marked, and the incidence of
fractures is increased. Fractures are particularly common in
the distal forearm (Colles fracture), vertebral body, and hip.
All of these areas have a high content of trabecular bone,
and because trabecular bone is more active metabolically, it
is lost more rapidly. Fractures of the vertebrae with compression
cause kyphosis, with the production of a typical “widow’s
hump” that is common in elderly women with osteoporosis.
Fractures of the hip in elderly individuals are associated with
a mortality rate of 12–20%, and half of those who survive
require prolonged expensive care.
Osteoporosis has multiple causes, but by far the most
common form is involutional osteoporosis. All normal
humans gain bone early in life, during growth. Aft er a plateau,
they begin to lose bone as they grow older ( Figure 21–12 ).
When this loss is accelerated or exaggerated, it leads to
osteoporosis (see Clinical Box 21–4). Increased intake of
calcium, particularly from natural sources such as milk, and
moderate exercise may help prevent or slow the progress of
osteoporosis, although their eff ects are not great. Bisphosphonates
such as etidronate, which inhibit osteoclastic activity,
increase the mineral content of bone and decrease the
rate of new vertebral fractures when administered in a cyclical
fashion. Fluoride stimulates osteoblasts, making bone
more dense, but it has proven to be of little value in the treatment
of the disease.
CHAPTER SUMMARY
Circulating levels of ■ calcium and phosphate ions are controlled
by cells that sense the levels of these electrolytes in the blood
and release hormones, and eff ects of these hormones are
evident in mobilization of the minerals from the bones,
intestinal absorption, and/or renal wasting.
■ Th e majority of the calcium in the body is stored in the bones
but it is the free, ionized calcium in the cells and extracellular
fl uids that fulfi lls physiological roles in cell signaling, nerve
function, muscle contraction, and blood coagulation, among
others.
■ Phosphate is likewise predominantly stored in the bones and
regulated by many of the same factors that infl uence calcium
levels, sometimes reciprocally.
■ Th e two major hormones regulating calcium and phosphate
homeostasis are 1,25-dihydroxycholecalciferol (a derivative
of vitamin D) and parathyroid hormone; calcitonin is also
capable of regulating levels of these ions, but its full physiologic
contribution is unclear.
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