Widespread distribution of hormones in an animal permits certain

hormones, such as growth hormone from the vertebrate pituitary

gland, to affect most, if not all, cells during specific stages of cellular
differentiation. Whether hormones produce widespread responses or
highly specific responses only in certain cells and at certain times
depends on the presence of receptor molecules on or in target cells. A
hormone engages only those cells that display the receptor that, by
virtue of its specific molecular shape, binds with the hormone mole-
cule. Other cells are insensitive to the hormone's presence because
they lack specific receptors. Hormones act through membrane-bound
receptors: nuclear receptors and cytoplasmic receptors.
Membrane-Bound Receptors
and the Second-Messenger Concept
Many hormones, such as most amino acid derivatives, and peptide
hormones that are too large, or too polar, to pass through plasma mem-
branes, bind to transmembrane proteins (see Figure 3.6, p. 40) that act

as receptor sites on the surfaces of target-cell membranes. The hor -

mone and receptor form a complex that triggers a cascade of molecu-
lar events within a cell. The hormone thus behaves as a first messenger
that causes activation of a second-messenger system in the cyto-
plasm. At least six different molecules have been identified as second
messengers. Each works via a specific kinase, which causes activa-
tion or inactivation of rate-limiting enzymes (see Chapter 4, p. 59) that
modify the direction and rate of cytoplasmic processes (Figure 34.2).
Since many molecules are activated at each level in the second-
messenger system cascade after a single hormone molecule has been
bound, the message is amplified, perhaps many thousands of times.
Second-messenger systems known to participate in hormone
actions are cyclic AMP (cAMP), cyclic GMP (cGMP), Ca ++/
calmodulin, inositoltrisphosphate (IP 3), and diacylglycerol
(DAG). Cyclic AMP was the first to be investigated, and it has been
shown to mediate actions of many peptide hormones, including
parathyroid hormone, glucagon, adrenocorticotropic hormone
(ACTH), thyrotropic hormone (TSH), melanophore-stimulating
hormone (MSH), and vasopressin. It also mediates action of epi -
nephrine (also called adrenaline), an amino acid derivative.

nterestingly, the same hormone may activate different second-

messenger systems in each type of target cell, such that a single
hormone produces multiple actions within an animal.
Other membrane-bound receptors possess kinase activity
themselves and are activated when the hormone binds to the recep-
tor, for example, the insulin and insulin-like growth factor mem -
brane receptors.

Nuclear Receptors
Unlike peptide hormones and epinephrine, which are much too large
to pass through plasma membranes, steroid hormones (for example,
estrogen, testosterone, and aldosterone) are lipid-soluble molecules
that readily diffuse through plasma membranes. Once inside the
cytoplasm of target cells, steroid hormones bind selectively to recep-
tor molecules. While these receptor molecules may be located in
either cytoplasm or nucleus, their ultimate site of activity is nuclear.
The hormone-receptor complex, now called a gene regulatory pro-
tein, then activates or inhibits specific genes. As a result, gene tran-
scription is altered (see Chapter 5, p. 88), since messenger RNA
molecules are synthesized on specific sequences of DNA. Stimulation
or inhibition of mRNA formation modifies production of key
enzymes, thus setting in motion a hormone’s observed effect
(Figure 34.2). Thyroid hormones and the insect-molting hormone,
ecdysone (a steroid, p. 24), also act through nuclear receptors.
Thyroid hormones first bind to a transmembrane protein-transport
molecule (p. 46) that uses ATP to move the hormones into the cell.
Compared with peptide hormones that act indirectly through
second-messenger systems, steroids and thyroid hormones have a
direct effect on protein synthesis because they bind a nuclear recep-
tor that modifies specific gene activity.

Cytoplasmic Receptors
Lipid-soluble hormones, such as estrogen, are now known to interact
not only with nuclear receptors but also with cytoplasmic receptors
that are either membrane bound or free within the cytoplasm. Once
activated, these hormone-receptor complexes interact with second-
messenger systems within the cytoplasm (much like peptide hor -
mones) or through a cascade of events activate factors that enter the
nucleus either to stimulate or to inhibit transcription processes
(p. 88). Thus, lipid-soluble hormones provide multiple and complex
control of target cells.

Control of Secretion Rates of Hormones

Hormones influence cellular functions by altering rates of many dif-
ferent biochemical processes. Many affect enzymatic activity and
thus alter cellular metabolism, some change membrane permeability,
some regulate synthesis of cellular proteins, and some stimulate
release of hormones from other endocrine glands. Because these are
all dynamic processes that must adapt to changing metabolic
demands, they must be regulated, not merely activated, by appropri-
ate hormones. This regulation is achieved by precisely controlled
release of a hormone into the blood or surrounding tissue.
Concentration of a hormone in body fluid depends on two factors: its
rate of secretion and the rate at which it is inactivated and removed
from the circulation. Consequently, if secretion is to be correctly
controlled, an endocrine gland requires information about the level
of its own hormone(s) in the plasma.
Most hormones are controlled by negative feedback systems
that operate between the glands secreting hormones and the outputs
or products of target cells (Figure 34.3). A feedback pattern is one in
which output is constantly compared with a setpoint, like a thermo-
stat. For example, CRH (corticotrophin-releasing hormone), secreted
by the hypothalamus, stimulates the pituitary (containing target
cells) to release ACTH. ACTH stimulates the adrenal gland (contain-
ing target cells) to secrete cortisol. As the level of ACTH rises in the
plasma, it acts on, or “feeds back” on, the hypothalamus to inhibit
release of CRH. Similarly, as cortisol levels rise in the plasma,
it “feeds back” on the hypothalamus and pituitary to inhibit release
of both CRH and ACTH, respectively. Thus any deviation from the
setpoint (a specific plasma level of each hormone) leads to corrective
action in the opposite direction (Figure 34.3). Such a negative feed-
back system is highly effective in preventing extreme oscillations in
hormonal output. However, hormonal feedback systems are more
complex than a rigid “closed-loop” system such as a thermostat that
controls a house’s central heating system, because hormonal

feedback may be altered by input from the nervous system or by

metabolites or other hormones.
Extreme oscillations in hormone output do sometimes occur
under natural conditions. However, because they have the potential
to disrupt finely tuned homeostatic mechanisms, such extreme oscil-
lations, as a result of positive feedback, are highly regulated and
possess an obvious shutoff mechanism. During positive feedback,
the signal (or output of the system) feeds back to the control system
and causes an increase in the initial signal. In this way the initial
signal becomes progressively amplified to produce an explosive
event. For example, hormones controlling parturition (birth) become
elevated from their normal setpoint and are shut off by birth of off-
spring from the uterus.

INVERTEBRATE HORMONES

All invertebrate taxa produce hormones, and cnidarians, nematodes,

and annelids possess endocrine cells that act autonomously and are
not organized into glands. Endocrine glands appear in molluscs and
arthropods, with the latter being more complex. In most invertebrate
phyla these chemical signals must move from source to target cells via
body fluids other than circulating blood. Invertebrate hormones are
peptides (often neuropeptides), steroids, or terpenoids (lipid-soluble
organic molecules), but peptides and neuropeptides are the most com-
mon among different invertebrate groups. Some hormones are verte-
bratelike in structure and function (for example, steroids), but there is
much greater diversity in invertebrate endocrine function than in that
of vertebrates. Invertebrate hormones regulate color changes, growth,
reproduction, and internal homeostatic mechanisms, such as metabo-
lism, metabolic fuel levels, and osmoregulation.
In many animal phyla, the principal source of hormones is
neurosecretory cells, specialized nerve cells capable of synthesiz-
ing and secreting hormones. Their products, called neurosecretory
hormones or neurohormones, are discharged directly into body flu-
ids, and serve as a crucial link between the nervous and endocrine
systems.
Peptides and neuropeptides have been shown to regulate many
physiological processes in invertebrates. In Crustacea, cardioactive
peptide increases heart rate. Hormones that regulate metabolism of
carbohydrates, fats, and amino acids belong to the crustacean
hyperglycemic hormone family (CHH) in Crustacea and to the
adipokinetic hormone family in insects. Diuretic hormones stim-
ulate the secretion of fluid in insect Malpighian tubules (p. 666). A
family of small neuropeptides called FMRFamide-related pep -
tides (FaRPs) appears to have evolved as early as bilateral symmetry,
and their functions seem to have been conserved across phyla.
Peptides of this family are known to regulate muscular tissues of the
body, and digestive and reproductive processes in many inverte-
brates, as well as osmoregulatory processes in nematodes, annelids,
molluscs, and insects, and arterial hemolymph flow in crustaceans.
They are now being isolated and characterized in vertebrates.
An extensively studied neurosecretory process in invertebrates is
control of development and metamorphosis of insects. In insects, as
in other arthropods, growth is a series of steps in which the rigid,
nonexpansible exoskeleton is periodically discarded and replaced
with a new, larger one. Most insects undergo a process of metamor-
phosis (p. 456), in which a series of juvenile stages, each requiring
formation of a new exoskeleton, end with a molt.

Insect physiologists discovered that molting and metamorphosis

(see Chapter 21, p. 456) are primarily controlled by interaction of two
hormones, one favoring growth and differentiation of adult structures
and another favoring retention of juvenile structures. These two hor-
mones are molting hormone or ecdysone, a steroid produced by the
prothoracic gland, and juvenile hormone, a terpenoid produced by
the corpora allata (Figure 34.4).
Ecdysone is controlled by prothoracicotropic hormone or
PTTH. This hormone is a polypeptide (molecular weight about 5000)
produced by neurosecretory cells of the brain, and transported by
axons to the corpora cardiacum where it is stored. At intervals during
juvenile growth, release of PTTH into the blood stimulates the protho-
racic gland to secrete ecdysone. Ecdysone bound to its nuclear recep-
tor acts directly on the chromosomes as a gene regulatory protein
(Figure 34.2) to cause a molt, and subsequent development of adult
structures. It is held in check, however, by juvenile hormone, which
favors retention of juvenile characteristics. During juvenile life, juve-
nile hormone predominates and each molt yields another larger

750 PART FOUR Activity of Life

juvenile (Figure 34.4). Finally output of juvenile hormone decreases,
allowing final metamorphosis to the adult stage.
Juvenile hormone appears to be important, at least in some
insects, during diapause (or arrested development), which can
occur at any stage of metamorphosis. Diapause usually occurs due
to seasonal changes in environmental conditions, such as cold tem-
peratures or changes in day length. In some insects high levels of
juvenile hormone inhibit release of PTTH, and thus ecdysone levels
remain low and development to the next stage is arrested. In other
insects diapause is due to a decrease in brain neurosecretory activity
and a direct reduction of PTTH, or to a direct effect of temperature
on the prothoracic glands, causing decreased ecdysone secretion.
Juvenile hormone is also present in adult insects, where it is involved
in regulation of egg development in females. In addition, low levels
cause decreased reproductive function during adult diapause (or
dormancy), which occurs during winter months in some insects.
Based on the extensive study of all aspects of endocrine regulation
in insects, scientists have synthesized many different endocrine

disruptors designed to regulate insect populations, such as potent analogs

of juvenile hormone, which induce abnormal final molts or prolong or
block development. Unlike chemical insecticides, they are highly spe-
cific, but given the conservation of hormone functions across invertebrate
groups, they are less ecologically benign than originally thought.

VERTEBRATES GLANDS AND HORMONES

We describe some of the best understood and most important verte-

brate hormones, including a brief overview of mammalian hormonal
mechanisms (because laboratory mammals and humans have always
been the objects of the most intensive research) and discussion of
some important differences in functional roles of hormones among
different vertebrate groups.
Hormones of the Hypothalamus
and Pituitary Gland
The pituitary gland, orhypophysis, is a small gland (0.5 g in humans)
lying in a depression in the floor of the cranium (Figure 34.5). It is a
two-part gland having a double embryological origin. The anterior
pituitary (adenohypophysis) is derived embryologically from the

roof of the mouth. The posterior pituitary (neurohypophysis) arises

from a ventral portion of the brain, the hypothalamus, and is con -
nected to it by a stalk, the infundibulum. Although the anterior
pituitary lacks any anatomical connection to the brain, it is function-
ally connected to it by a special portal circulatory system. A portal
circulation is one that delivers blood from one capillary bed to
another (Figures 34.5 and 34.6). In this case, the portal circulation
provides a link between neurosecretory cells of the hypothalamus
and endocrine cells of the anterior pituitary gland.
Hypothalamus and Neurosecretion
Because of the strategic importance of the pituitary in influencing
most hormonal activities in the body, the pituitary was once called

the “master gland.” This description is not appropriate, however,

because anterior pituitary hormones are regulated by a higher
council, the neurosecretory centers of the hypothalamus. The
hypothalamus is itself under ultimate control by inputs from other
regions of the brain. The hypothalamus contains groups of neuro-
secretory cells, which are specialized nerve cells (Figures 34.5
and 34.6) that manufacture neurohormones. Those that regulate
the anterior pituitary are called releasing hormones or release-
inhibiting hormones (or “factors”). These neurohormones travel
down nerve axons to their endings in the median eminence. Here
they enter a capillary network to complete their journey to the
anterior pituitary by way of the hypothalamic-pituitary portal sys-
tem. The hypothalamic hormones then stimulate or inhibit release
of various anterior pituitary hormones. Several hypothalamicre-
leasing and release-inhibiting hormones have been discovered,
characterized chemically, and isolated in pure state (Table 34.1),

although the identification and action of some of the hypotha-

lamic hormones listed in Table 34.1 is still tentative. Other hypo-
thalamic neurosecretory cells possess nerve axons that travel
down the infundibulum and have their nerve endings in the poste-
rior pituitary. These secrete neurohormones directly into the gen-
eral blood circulation and not into the hypothalamic-pituitary
portal system (Figure 34.5).
Anterior Pituitary
The anterior pituitary consists of an anterior lobe (pars distalis)
as shown in Figure 34.5, and an intermediate lobe (pars interme-
dia), which is absent in some animals (including humans).
The anterior pituitary produces seven hormones, and in those
animals with an intermediate lobe, all but one are released by the
anterior lobe.

The anterior pituitary produces four hormones that regulate

other endocrine glands, collectively called tropic hormones (from
the Greek tropē, to turn toward) (Table 34.1). Thyroid-stimulating
hormone (TSH) or thyrotropin stimulates production of thyroid
hormones by the thyroid gland. Two tropic hormones, commonly
called gonadotropins, act on the gonads (ovaries of females, testes
of males). These are follicle-stimulating hormone (FSH) > and
luteinizing hormone (LH). FSH promotes egg production and
secretion of estrogen in females, and supports sperm production in
males. LH induces ovulation, corpus luteum production, and secre-
tion of female sex steroids, progesterone and estrogen. In males, LH
promotes production of male sex steroids (primarily testosterone).
It once was called interstitial cell stimulating hormone (ICSH) in
males, before it was discovered to be identical to LH in females.
The hormonal control of reproduction is extensively discussed in
Chapter 7. The fourth tropic hormone, adrenocorticotropic hor-
mone (ACTH), increases production and secretion of steroid hor-
mones from the adrenal cortex.
Prolactin and the structurally related growth hormone (GH)
are proteins. Prolactin is essential for preparing mammary glands
for lactation; after birth it is required for production of milk.
Prolactin also is implicated in parental behavior in a wide variety of
vertebrates. Beyond its more traditional role in reproductive pro-
cesses, prolactin regulates water and electrolyte balance in many
species. Prolactin has also been shown to be a chemical mediator of
the immune system and is important in formation of new blood
vessels (angiogenesis). Unlike tropic hormones, prolactin acts
directly on its target tissues rather than through other hormones.
GH (also called somatotropin) performs a vital role in
governing body growth through its stimulatory effect on cellular
mitosis, on synthesis of messenger RNA and protein, and on metab-
olism, especially in new tissue of young vertebrates. Growth hor-
mone acts directly on growth and metabolism, as well as indirectly
through a polypeptide hormone, insulin-like growth factor (IGF)
or somatomedin, produced by the liver.
The only anterior pituitary hormone produced by the
intermediate lobe is melanocyte-stimulating hormone (MSH). In
cartilaginous and bony fishes, amphibians, and nonavian reptiles,
MSH is a directacting hormone that promotes dispersion of the
pigment melanin within melanocytes, causing darkening of the
skin. In birds and mammals, MSH is produced by cells in the ante-
rior pituitary rather than the intermediate lobe, but its physiological
function remains unclear. MSH appears unrelated to pigmentation
in endotherms, although it causes darkening of the skin in humans
if injected into the circulation. MSH has been isolated from spe-
cific regions of the hypothalamus, where it has been linked to reg-
ulation of ingestive behaviors and metabolism in adult mammals.
MSH and ACTH are derived from a precursor molecule (pro-
opiomelanocortin or POMC) that is transcribed and translated from a single gene.

Posterior Pituitary
The hypothalamus is the source of two hormones of the posterior
lobe of the pituitary (Table 34.1). They are formed in neurosecre-
tory cells in the hypothalamus, whose axons extend down the infun-
dibular stalk and into the posterior lobe. The hormones are secreted
from axon terminals ending close to blood capillaries, which the

w w w . m h h e . c o m / h i c k m a n i p z 1 7 e CHAPTER 34 Chemical Coordination: Endocrine System 753

hormones enter when released (Figure 34.5). In a sense the poste-
rior lobe is not a true endocrine gland, but a storage and release
center for hormones manufactured entirely in the hypothalamus.
The two posterior-lobe hormones of mammals, oxytocin and vaso-
pressin, are chemically very much alike. Both are polypeptides con-
sisting of eight amino acids (octapeptides, Figure 34.7). These
hormones are among the fastest-acting hormones, since they
can produce a response within seconds of their release from the
posterior lobe.
Oxytocin has two important specialized reproductive functions
in adult female mammals. It stimulates contraction of uterine smooth
muscles during parturition (birth of young). In clinical practice, oxy-
tocin is used to induce delivery during prolonged labor and to pre-
vent uterine hemorrhage after birth. A second action of oxytocin is
that of milk ejection by the mammary glands in response to suckling.
A role for oxytocin in pair-bonding behavior in both sexes in some
monogamous vole species has now been established.
Vasopressin, the second posterior-lobe hormone, acts on col -
lecting ducts of the kidney to increase water reabsorption and thus
restrict urine flow, as already described on page 671. It is therefore
often called antidiuretic hormone or ADH. Vasopressin also
increases blood pressure through its generalized constrictor effect on
smooth muscles of arterioles, and acts centrally to increase thirst,
and therefore, drinking behavior. Finally, vasopressin has been linked
to pair-bonding behavior in some monogamous vole species.
All jawed vertebrates secrete two posterior-lobe hormones that
are quite similar to those of mammals. All are octapeptides, but their
structures vary because of amino-acid substitutions in three of eight
aminoacid positions in the molecule.
Of all posterior-lobe hormones, vasotocin (Table 34.1) has
the widest phylogenetic distribution and is considered the parent
hormone from which other octapeptides evolved. It occurs in all
vertebrate classes except mammals. It is a water-balance hor -
mone in amphibians, especially toads, in which it acts to con -
serve water by (1) increasing permeability of skin (to promote
water absorption from the environment), (2) stimulating water
reabsorption from the urinary bladder, and (3) decreasing urine
flow. Action of vasotocin is best understood in amphibians, but it
appears to play some water-conserving role in birds and nonavian
reptiles as well.

Pineal Gland
In all vertebrates the dorsal part of the brain, the diencephalon
(Figure 33.13, p. 731), gives rise to a saclike evagination called the
pineal complex, which lies just beneath the skull in a midline
position. In ectothermic vertebrates the pineal complex contains
glandular tissue and a photoreceptive sensory organ involved in pig-
mentation responses and in light-dark biological rhythms. In lam -
preys, many amphibians, lizards, and tuataras (Sphenodon, p. 578),
the median photoreceptive organ is so well developed, containing
structures analogous to the lens and cornea of lateral eyes, that it is
often called a third eye. In birds and mammals, the pineal complex
is an entirely glandular structure called the pineal gland. The pineal
gland produces the hormone melatonin. Melatonin secretion is
strongly affected by exposure to light. Its production is lowest
during daylight hours and highest at night. In nonmammalian verte-
brates, the pineal gland is responsible for maintaining circadian
rhythms—self-generated (endogenous) rhythms that are about
24 hours in length. A circadian rhythm serves as a biological clock
for many physiological processes that follow a regular pattern.
In mammals, an area of the hypothalamus called the
suprachiasmatic nucleus has become the primary circadian pace-
maker, although the pineal gland still produces melatonin nightly
and serves to reinforce the circadian rhythm of the suprachiasmatic
nucleus. In birds and mammals in which seasonal rhythms in repro-
duction are regulated by photoperiod, melatonin plays a critical
role in timing gonadal activity. In long-day breeders, such as horses,
ferrets, hamsters, and deer mice, reduced light stimulation with
shortening day length in the autumn increases melatonin secretion,
and in these species reproductive activity is suppressed during win-
ter months. Lengthening days in the spring have the opposite effect,
and reproductive activities are resumed. Short-day breeders, such as
white-tailed deer, silver fox, spotted skunk, and sheep, are stimu-
lated by reduced day length in the autumn; increasing melatonin
levels at this time are associated with increased reproductive activ-
ity. The role of melatonin is an indirect one in both cases because
melatonin itself does not stimulate or inhibit the reproductive axis.
The pineal gland produces subtle effects on circadian and
annual rhythms in nonphotoperiodic mammals (such as humans).
For example, melatonin secretion has been linked to a sleeping and
eating disorder in humans called seasonal affective disorder (SAD).
Some people living in northern latitudes, where day lengths are
short in winter and when melatonin production is elevated, become
depressed in winter, sleep long periods, and may have eating binges.
Often this wintertime disorder can be treated by exposure to
sunlamps with full-spectrum light; such exposure depresses
melatonin secretion by the pineal gland. Disturbed physiological
rhythms associated wit h jet lag, shift work, and aging also are
linked to inappropriate melatonin rhythms. Circadian-rhythm prob-
lems may also be linked to psychiatric disorders, metabolic syn -
drome (simultaneous occurrence of high blood pressure, elevated
insulin levels, excess body fat around the waist, or elevated choles-
terol levels), and increased cancer risks.

Prostaglandins and Cytokines

Prostaglandins
Prostaglandins are derivatives of long-chain unsaturated fatty acids
that were discovered in seminal fluid in the 1930s. At first they were
thought to be produced only by the prostate gland (hence the name)
but now they have been found in virtually all mammalian tissues.
Prostaglandins often act as local hormones and have diverse actions
on many different tissues, making generalizations about their effects
difficult. Many of their effects, however, involve smooth muscle. In
some tissues prostaglandins regulate vasodilation or vasoconstriction

by their action on smooth muscle in walls of blood vessels. They are

known to stimulate contraction of uterine smooth muscle during
childbirth. There also is evidence that overproduction of uterine
prostaglandins is responsible for painful symptoms of menstruation
(dysmenorrhea) experienced by many women, and inhibitors of
prostaglandins may provide relief from these symptoms. Among
other actions of prostaglandins is their intensification of pain in
damaged tissues, mediation of the inflammatory response (see
Chapter 35, pp. 767–769), and involvement in fever.
Cytokines
For some years we have known that cells of the immune system com-
municate with one another and that this communication was crucial to
the immune response. Now we understand that a large group of poly-
peptide hormones called cytokines (p. 771) mediate communication
between a wider variety of cells and can affect the cells that secrete
them, can affect nearby cells, and like other hormones, can affect cells
in distant locations. Their target cells bear specific receptors for the
cytokine bound to the surface membrane. Cytokines coordinate a com-
plex network, with some target cells being activated, stimulated to
divide and often to secrete their own cytokines. The same cytokine that
activates some cells may suppress division of other target cells.
Cytokines also are involved in formation of blood, and in regulation of
energy balance by the central nervous system. Many cytokines that are
secreted by adipose tissue, termed adipokines, have become a focus of
research on the regulation of energy balance and obesity. It appears that
secretion of these hormones elicits an inflammatory response (see
Chapter 35, p. 767) within adipose tissue and other organs that medi-
ates many of the symptoms associated with obesity.

Hormonal Regulation of Calcium Metabolism

Closely associated with the thyroid gland and, in some animals, bur-
ied within it are parathyroid glands. These tiny glands occur as two
pairs in humans but vary in number and position in other vertebrates.
In birds and mammals, including humans, removal of the parathyroid
glands rapidly decreases the level of calcium in the blood, leading to
a serious increase in nervous-system excitability, severe muscular
spasms, tetany, and finally death. Parathyroid glands secrete a hor -
mone, parathyroid hormone (PTH), which is essential to mainte -
nance of calcium homeostasis. Calcium ions are extremely important
for formation of healthy bones. In addition, they are needed for a
multitude of functions, such as neurotransmitter and hormone release,
muscle contraction, intracellular signaling, and blood clotting.
Before considering how hormones maintain calcium homeostasis,
it is helpful to summarize mineral metabolism in bone, a densely
packed storehouse of both calcium and phosphorus (see Chapter 29,
p. 645, for bone structure and function). Bone contains approximately

98% of the calcium and 80% of the phosphorus in humans. Although

bone is second only to teeth as the most durable material in the body (as
evidenced by survival of fossil bones for millions of years), it is in a
state of constant turnover in living vertebrates. Bone-building cells
(osteoblasts) synthesize organic fibers and glycoproteins of bone
matrix, which becomes mineralized with a form of calcium phosphate
called hydroxyapatite. Bone-resorbing cells (osteoclasts) are giant,
multinucleated cells that dissolve the bony matrix, releasing calcium
and phosphate into the blood. These opposing activities allow bone
constantly to remodel itself, especially in a growing animal, producing
structural improvements to counter new mechanical stresses on the
body. They additionally provide a vast and accessible reservoir of min-
erals that can be withdrawn as needed for general cellular requirements.
One of the more prominent ideas for the evolution of bone in fishes was
that it might have served as a reservoir for calcium to support heart
muscle contractions in fish that colonized freshwater.
The level of calcium in the blood is maintained by three hormones
that coordinate absorption, storage, and excretion of calcium ions. If
blood calcium should decrease slightly, the parathyroid gland increases
its secretion of PTH. This increase stimulates osteoclasts to dissolve
bone adjacent to them, thus releasing calcium and phosphate into the
bloodstream and returning blood calcium level to normal. PTH also
decreases the rate of calcium excretion by the kidney and increases
production of the hormone 1,25-dihydroxyvitamin D 3. PTH levels
vary inversely with blood calcium level, as shown in Figure 34.11.
A second hormone involved in calcium metabolism in all tetra-
pods is derived from vitamin D3. Vitamin D3, like all vitamins, is a
dietary requirement. But unlike other vitamins, vitamin D 3 may also
be synthesized in the skin from a precursor by irradiation with ultra-
violet light from the sun. Vitamin D3 is then converted in a two-step
oxidation to a hormonal form, 1,25-dihydroxyvitamin D3. This ste-
roid hormone is essential for active calcium absorption by the gut
(Figure 34.12). Production of 1,25-dihydroxyvitamin D3 is stimulated
by low plasma phosphate as well as by an increase in PTH secretion.
In humans, a deficiency of vitamin D3 causes rickets, a disease
characterized by low blood calcium and weak, poorly calcified
bones that tend to bend under postural and gravitational stresses.
Rickets has been called a disease of northern winters, when sunlight

is minimal. It once was common in the smoke-darkened cities of

England and continental Europe.
A third calcium-regulating hormone, calcitonin, is secreted by
specialized cells (C cells) in the thyroid gland of mammals and in the
ultimobranchial glands of other vertebrates. Calcitonin is released in
response to elevated levels of calcium in the blood. It rapidly sup-
presses calcium withdrawal from bone, decreases intestinal absorp-
tion of calcium, and increases excretion of calcium by the kidneys.
Calcitonin therefore protects the body against an increase in level of
calcium in the blood, just as parathyroid hormone protects it from a
decrease in blood calcium (Figure 34.12). Calcitonin has been iden-
tified in all vertebrate groups, but its importance is uncertain in
humans because replacement of calcitonin is not required for

maintenance of calcium homeostasis, if the thyroid gland is surgi-

cally removed (also removing the C cells). It seems to be fairly
important in fishes, because fishes do not have discrete parathyroid
glands and thus use calcitonin more for calcium regulation.
Hormones of the Adrenal Cortex
The mammalian adrenal gland is a double gland composed of two
unrelated types of glandular tissue: an outer region of adrenocorti-
cal cells, or cortex, and an inner region of specialized cells, the
medulla (Figure 34.13). In nonmammalian vertebrates homologs
of adrenocortical and medullary cells are organized quite differ-
ently; they may be intermixed or distinct, but never arranged in a
cortexmedulla relationship as in mammals.
At least 30 different compounds have been isolated from adreno-
cortical tissue, all of them closely related steroids. Only a few of these
compounds are true steroid hormones; most are various intermediates
in synthesis of steroid hormones from cholesterol (Figure 34.14).
Corticosteroid hormones are commonly classified into two groups,
according to their function: glucocorticoids and mineralocorticoids.
Glucocorticoids, such as cortisol (Figure 34.14) and corticos-
terone, influence food metabolism, inflammation, and stress. They
promote synthesis of glucose from compounds other than carbohy-
drates, particularly amino acids and fats. The overall effect of this
process, called gluconeogenesis, is to increase the level of glucose
in the blood, thus providing a quick energy source for muscle and
nervous tissue. Glucocorticoids are also important in diminishing
the immune response to various inflammatory conditions. Because
several diseases of humans are inflammatory diseases (for example,

allergies, hypersensitivity, and rheumatoid arthritis), these cortico-

steroids have important medical applications.
Synthesis and secretion of glucocorticoids are controlled
principally by ACTH of the anterior pituitary (see Figure 34.6), while
ACTH is controlled in turn by corticotropin-releasing hormone (CRH)
of the hypothalamus (Table 34.1). As with pituitary control of the
thyroid, negative feedback exists between CRH, ACTH, and the adre-
nal cortex (see Figure 34.3). An increase in release of glucocorticoids
suppresses output of CRH and ACTH; the resulting decline in blood
level of CRH and ACTH then inhibits further release of glucocorti-
coids from the adrenal cortex. An opposite sequence of events hap-
pens should the blood level of glucocorticoids drop: CRH and ACTH
output increases, which in turn stimulates secretion of glucocorticoids.
CRH is known to mediate stressful stimuli through the adrenal axis.

Mineralocorticoids, the second group of corticosteroids, are

those that regulate salt balance. Aldosterone (Figure 34.14) is by far
the most important steroid of this group. Aldosterone promotes
tubular reabsorption of sodium and tubular secretion of potassium by
the kidneys. Since sodium usually is in short supply in diets of many
animals and potassium is in excess, mineralocorticoids play vital
roles in preserving the correct balance of blood electrolytes.
The salt-regulating action of aldosterone is controlled by the renin-
angiotensin system, and by blood levels of potassium ions described
on page 670.
Adrenocortical tissue also produces androgens (Gr. andros,
man, + genesis, origin), which, as the name implies, are similar in
effect to the male sex hormone, testosterone. Adrenal androgens pro-
mote some developmental changes, such as the growth spurt, that
occur just before puberty in human males and females. Development
of anabolic steroids, synthetic hormones related to testosterone, has
led tHormones of the Adrenal Medulla
Adrenal medullary cells secrete two structurally similar hormones:
epinephrine (adrenaline) and norepinephrine (noradrenaline).
The adrenal medulla is derived embryologically from the same tissue
that gives rise to postganglionic sympathetic neurons of the auto-
nomic nervous system (p. 732). Norepinephrine serves as a neu -
rotransmitter at the endings of sympathetic nerve axons. Thus
functionally, as well as embryologically, the adrenal medulla can be
considered a very large sympathetic ganglion.
It is not surprising, then, that adrenal medullary hormones and
the sympathetic nervous system have the same general effects on the
body. These effects center on responses to emergencies, such as fear
and strong emotional states, flight from danger, fighting, lack of oxy-
gen, blood loss, and exposure to pain. Walter B. Cannon, of homeosta-
sis fame (p. 661), termed these “fight or flight” responses that are
appropriate for survival. We are familiar with the increased heart rate,
tightening of the stomach, dry mouth, trembling muscles, general feel-
ing of anxiety, and increased awareness that attends sudden fright or
other strong emotional states. These effects are attributable to increased
activity of the sympathetic nervous system and to rapid release into the
blood of epinephrine and norepinephrine from the adrenal medulla.o widespread abuse of steroids among
athletes.

Activation of the adrenal medulla by the sympathetic nervous system

prolongs the effects of sympathetic-system activation.
Epinephrine and norepinephrine have many other effects of
which we are not as aware, including constriction of arterioles
(which, together with increased heart rate, increases blood pressure),
mobilization of liver glycogen and fat stores to release glucose and
fatty acids for increased energy availability, increased oxygen con-
sumption and heat production, hastening of blood coagulation, and
inhibition of the gastrointestinal tract. These changes prepare the
body for emergencies and are activated in stressful conditions.
organ.

Growth Hormone and Metabolism

Growth hormone (GH) is a particularly important metabolic hor-
mone in young animals during growth and development. It acts
directly on long bones to promote cartilaginous growth and bone
formation by cell division and protein synthesis, thus producing an
increase in length and density of bone. GH also acts indirectly on
growth via stimulation of insulin-like growth factor (IGF) or
somatomedin release from the liver. This polypeptide hormone
promotes mobilization of glycogen from liver stores and release of fat
from adipose tissue stores necessary for growth processes. Thus, GH
is considered a diabetogenic hormone, since oversecretion leads to
an increase in blood glucose and can cause insulin insensitivity or
diabetes mellitus type 2. If produced in excess, GH causes giantism.
A deficiency of this hormone in a human child leads to dwarfism.

Hormones from Islet Cells of the Pancreas

The pancreas is both an exocrine and an endocrine organ (Figure34.15).
The exocrine portion produces pancreatic juice, a mixture of digestive
enzymes and bicarbonate ions conveyed by a duct (or ducts) to the
digestive tract (see Chapter 32). Scattered within the extensive exocrine
portion of the pancreas are numerous small islets of tissue, called islets
of Langerhans (Figure 34.15 and photograph on p. 746). This endo -
crine portion of the pancreas is only 1% to 2% of the total weight of the
organ. The islets are without ducts and secrete their hormones directly
into blood vessels that extend throughout the pancreas.
Several polypeptide hormones are secreted by different cell
types within the islets: insulin and amylin, produced by beta cells;
glucagon, produced by alpha cells; somatostatin, produced by
delta cells; and pancreatic polypeptide (PP), produced by

gamma cells. Insulin and glucagon have antagonistic actions of

great importance in metabolism of carbohydrates and fats. Meals
rich in carbohydrates stimulate insulin and amylin release as blood
glucose levels rise following digestion and absorption of the meal
(p. 713). Insulin is essential for uptake of blood-borne glucose by
cells, especially skeletal-muscle cells. Insulin promotes entry of glu-
cose into body cells through its action on a glucose-transporter mol-
ecule found in cell membranes. Amylin's actions appear to enhance
insulin's actions. Although insulin dependent glucose-transporter
molecules have been demonstrated on neurons of the central nervous
system, neurons do not require insulin for glucose uptake. This inde-
pendence from insulin is very important because unlike other cells
of the body, neurons almost exclusively use glucose as an energy
source. The exact role of insulin-dependent glucose transporters in
the brain is not clear, but insulin is important in central regulation of
food intake and body weight. Cells of the rest of the body, however,
require insulin to use glucose; without insulin the level of glucose in
the blood rises to abnormally high levels, a condition called hyper-
glycemia. When this level exceeds the transport maximum of the
kidney (see note on p. 670), sugar (glucose) appears in urine. Insulin
deficiency also inhibits uptake of amino acids by skeletal muscle,
and fats and proteins in muscle are metabolized to provide energy.
Body cells starve while the urine abounds in the very substance the
body craves. The disease of insulin deficiency, called diabetes mel-
litus type 1, afflicts nearly 5% of humans in varying degrees of
severity. If left untreated, it can lead to severe damage to kidneys,
eyes, and blood vessels, and it can greatly shorten life expectancy.
Humans can also develop insulin insensitivity or diabetes mellitus
type 2, with similar symptoms to type 1 diabetes mellitus. This dis-
ease is occurring at an increasing rate as more individuals become
overweight and obese (see Chapter 32, p. 714). In 2000, a global
estimate of humans with type 2 diabetes was 171 million, with a
projected increase to 366 million by 2030. An increase in exercise
levels and a change in diet can help to decrease insulin levels and to
alleviate symptoms in such individuals.

The first extraction of insulin in 1921 by two Canadians,

Frederick Banting and Charles Best, was one of the most dramatic
and important events in the history of medicine. Many years earlier
two German scientists, J. Von Mering and O. Minkowski, had discov-
ered that surgical removal of the pancreas of dogs invariably caused
severe symptoms of diabetes, causing the animal's death within a few
weeks. Many attempts were made to isolate the diabetes preventive
factor, but all failed because powerful protein-splitting digestive
enzymes in the exocrine portion of the pancreas destroyed the hor-
mone during extraction procedures. Following a hunch, Banting, in
collaboration with Best and his physiology professor J. J. R. Macleod,
tied shut the pancreatic ducts of several dogs. This caused the exo-
crine portion of the gland with its hormone-destroying enzyme to

degenerate, but it left the islets' tissues healthy long enough for
Banting and Best to extract insulin successfully from these glands.
Injected into another dog, the insulin immediately lowered the level
of sugar in the blood (Figure 34.16). Their experiment paved the way
for commercial extraction of insulin from slaughterhouse animals. It
meant that millions of people with diabetes, previously fated to dis-
ability or death, could look forward to more normal lives.
Glucagon, another hormone of the pancreas, has several effects
on carbohydrate and fat metabolism that are opposite to the effects of
insulin. Low blood glucose levels and absorption of amino acids into
the blood following digestion (p. 714) stimulate glucagon secretion.
For example, glucagon raises the blood glucose level (by converting
liver glycogen to glucose), whereas insulin lowers blood glucose.
Glucagon and insulin do not have the same effects in all vertebrates,
and in some, glucagon is lacking altogether.
Somatostatin, from pancreatic delta cells, inhibits secretion of
other pancreatic hormones, reduces the rate of gastric emptying,
and inhibits pancreatic exocrine secretion. Somatostatin is also
secreted from the hypothalamus (here termed growth hormone
release–inhibiting hormone) and inhibits growth hormone release
from the anterior pituitary (see p. 752).
Pancreatic hormone, PP, is released after a meal and reduces
appetite. It appears to have a physiological role in regulating gastric
secretions, and it decreases secretions from the pancreatic exocrine
gland and gallbladder, and inhibits intestinal motility. But because its
administration to mice and humans reduces food intake, it has
become a focus of research in the fight against obesity.
SYNTHESIS OF THYROID HORMONES

Slide 4:

Thyroid hormones are derived from the amino acid tyrosine and are synthesized through
sequential iodination of the tyrosine phenol rings. First, iodine is added to the phenol ring meta
positions, resulting in monoiodotyrosine if a single site is iodinated or diiodotyrosine if two sites
are iodinated. This is followed by the coupling of one iodinated phenol group to another,
resulting in a diphenyl ether. The coupling of two diiodotyrosines formsT4 (which contains two
iodine residues on both the inner and outer rings) while the coupling of a monoiodotyrosine and
a diiodotyrosine forms T3 (which contains two iodine residues on the inner ring but only one
iodine residue on the outer ring).

Reverse T3, a product of peripheral deiodination of T4, contains two iodine residues on the outer
ring and a single iodine on the inner ring.
Of the compounds shown on this slide, T4 and T3 are the biologically active hormones while the
others are nonfunctional.

Slide 5:

Thyroid hormone synthesis is controlled by the hypothalamic-pituitary-thyroid axis, with initial

stimulation coming from the hypothalamus in the form of thyrotropin releasing hormone, or
TRH. TRH signals the anterior pituitary to release thyroid stimulating hormone, or TSH. TSH in
turn stimulates the thyroid to produce primarily T4, with smaller amounts of T3.

To prevent uncontrolled production of T4 and T3, free T4 (the small fraction of T4 not bound by
carrier proteins, to be discussed later in the presentation) feeds back primarily on the pituitary
and suppresses TSH production. Lower plasma TSH concentrations result in decreased
production of T4 and T3 by the thyroid, thereby decreasing circulating free T4 concentrations.
Conversely, in response to high metabolic demand, peripheral tissues increase their rate of T4
uptake and conversion of T4 to T3. This decreases the circulating concentrations of free T4,
stimulating TSH production by the pituitary, which increases T4 and T3 production by the
thyroid gland. This continuous communication between peripheral tissues, the thyroid gland and
the pituitary keeps free T4 concentrations within the physiologically appropriate range.

Slide 7:

The first, and rate limiting, step in thyroid hormone synthesis is the active transport of negatively
charged iodide from circulating plasma into thyroid follicular cells. Stimulated by TSH binding
to TSH receptors on the follicular cell surface, transport is performed by the sodium-iodide
symporter against a concentration gradient in which iodide concentrations are typically 30-40
times higher in thyroid follicular cells relative to circulating plasma. Notably, iodide uptake is
inhibited by lithium (which competes with sodium) but is not inhibited by antithyroid
medications, such as methimazole and propylthiouracil that block subsequent steps in thyroid
hormone synthesis.

Slide 8:

In the second step, also stimulated by TSH, iodide is transported through the follicular cell and
into the colloid by pendrin, a transporter protein located at the follicular cell surface. Once in the
colloid, iodide is oxidized (or “organified”) by thyroperoxidase to form an iodine radical, with
hydrogen peroxide serving as the electron acceptor.

Slide 9:

In the third step, organified iodine is incorporated into thyroglobulin tyrosine residues by thyroid
peroxidase to form diiodotyrosine and lesser amounts of monoiodotyrosine. These iodinated
tyrosine residues are then coupled, also by thyroid peroxidase, to form predominantly T4 with
smaller amounts of T3. T4 is formed by coupling two diiodinated tyrosines while T3 is formed
by coupling a monoiodotyrosine and a diiodotyrosine.

To illustrate the importance of thyroglobulin in thyroid hormone synthesis, thyroglobulin is the

dominant protein product of thyroid follicular cells and is estimated to account for approximately
75% of the total protein content of the thyroid gland.

Slide 10:

In the fourth step, also stimulated by TSH, colloid is taken up by thyroid follicular cells by
pinocytosis, the colloid vesicle is fused with a primary lysosome and thyroglobulin is digested,
releasing T4, T3, diiodotyrosine, monoiodotyrosine and non-iodinated amino acids. T4 and T3
are released into circulation while the remaining thyroglobulin degradation products are
recycled.

Slide 11:

The last step in thyroid hormone synthesis occurs outside the thyroid gland and consists of
peripheral deiodination of T4 to T3 and reverse T3. T4 is often referred to as a “prohormone”
because it has 10-fold lower biological activity than T3.

Approximately 40% of T4 is converted to the more biologically active T3 by removal of an

iodine from the outer ring and 45% of T4 is inactivated by conversion to reverse T3 by removal
of an iodine from the inner ring. The vast majority of T3 (around 80%) is formed from peripheral
deiodination and only 20% is produced and secreted directly by the thyroid gland.

The conversion of T4 to T3 or reverse T3 is largely determined by the body’s desired metabolic

rate. For a high metabolic rate, T4 is preferentially converted to T3 rather than reverse T3. By
contrast, for a low metabolic rate, T4 is preferentially converted to reverse T3 rather than T3.

Slide 12:
Once in circulation, T4 and T3 are either protein-bound or free and the overwhelming majority
of T4 and T3 is protein-bound. 99.97% of T4 and 99.7% of T3 is bound to carrier protein,
leaving only 0.03% of T4 and 0.3% of T3 free. This is important because free hormone is what
the body “sees” as the pool of hormone available for use. For this reason, the concentration of
free T4 typically correlates more closely with patient symptoms than does total T4.

Thyroid hormones exert their biological activity by binding to specific intranuclear receptors
(TRα and TRβ) that recognize DNA sequences in the regulatory regions of target genes.
Following binding to these regulatory regions, TRs recruit cellular machinery that increases or
decreases the rate of transcription of thyroid hormone-responsive genes.

Slide 13:

There are three proteins responsible for binding T4 and T3 in circulation: thyroxine-binding
globulin, or TBG, transthyretin, also known as prealbumin due to its migratory properties during
serum protein electrophoresis and albumin. TBG is present at the lowest concentration but binds
T4 with the highest affinity, while at the other end of the spectrum, albumin is present at the
highest concentration but binds T4 with the lowest affinity. Transthyretin represents the middle
ground, as it is present at intermediate concentrations and binds T4 with modest affinity.
Factors that affect the half-lives of the thyroid binding proteins can have an important impact on
thyroid hormone concentrations. For instance, estradiol prolongs the half-life of TBG, resulting
in increased total thyroid hormone concentrations while testosterone shortens TBG’s half-life,
resulting in decreased total thyroid hormone concentrations.

Importantly, TBG has a 10-fold higher binding affinity for T4 relative to T3, which means that
most T4 is tightly bound while a relatively larger proportion of T3 exists in a loosely bound state.
As a result, T4 has a relatively long half-life of 5-7 days while that of T3 is only 1 day.

Slide 14:

As discussed in a previous slide, free T4 typically correlates more closely with patient symptoms
than total T4. This is due largely to the fact that the concentrations and binding capacities of
thyroid hormone binding proteins can change in response to other drugs. For instance, estrogen
increases the concentration of TBG. This increased number of thyroid hormone binding sites
briefly reduces the free T4 concentration and stimulates the thyroid to produce larger amounts of
T4 to maintain free T4 concentrations within the physiologically appropriate range. During
pregnancy, when TBG concentrations remain elevated due to high concentrations of estradiol,
total T4 concentrations increase while free T4 remains within the non-pregnant reference
interval.

Free T4 concentrations within the reference interval can also be observed in the context of a
decreased total T4 in patients whose TBG concentrations are suppressed by excess androgens or
glucocorticoids, or in patients treated with compounds that compete with T4 for carrier protein
binding sites, including salicylates and phenytoin.
FUNCTIONS

Slide 2:

Thyroid hormones play important roles in a number of different biological functions. Their
primary role is to regulate the basal metabolic rate, which they do primarily by stimulating
mitochondrial respiration. Thyroid hormones also enhance synthesis and breakdown of
carbohydrates, proteins and lipids, stimulate CNS development and physical growth in the
developing fetus and throughout childhood and adolescence, increase heart rate, support
reproductive health and promote drug clearance, as well as many other activities too numerous to
list here. It’s important to note that both thyroid hormone excess and insufficiency can lead to
abnormalities in these biological processes.

Slide 3:

Thyroid hormones are secreted by the thyroid gland, which is a butterfly shaped, bilobal
structure typically located anterior to the trachea. Pictured here is follicle, the functional unit of
the thyroid gland. The thyroid gland is composed of millions of these repeating units. Follicles
are defined by an outer membrane of follicular cells, which produce and secrete thyroxine (T4)
and a smaller amount of triiodothyronine (T3). At the interior of the follicle is colloid, an
amorphous substance composed almost entirely of thyroglobulin, which serves as the protein
backbone for thyroid hormone synthesis.

The thyroid gland also contains parafollicular cells or C-cells, which are interspersed between
follicles. Parafollicular cells aren’t involved in thyroid hormone synthesis but they do secrete
calcitonin, which is a protein involved in calcium homeostasis that is most frequently measured
clinically as a tumor marker for patients with medullary thyroid cancer.

Hypothyroidism
What is hypothyroidism? In short, your thyroid gland can’t make enough hormones to function
well. The thyroid gland controls every aspect of your body’s metabolism. In hypothyroidism, the
gland’s hormone production slows. This, in turn, slows your metabolism, which can lead to
weight gain. Hypothyroidism is common, and affects about 4.6 percentTrusted Source of the
U.S. population.

According to the American Thyroid Association, there’s no cure for hypothyroidism. However,
there are medications that can treat the disease. The goal of the medication is to improve your
body’s thyroid function, restore hormone levels, and allow you to live a normal life.

Hashimoto’s thyroiditis is the most common cause of hypothyroidism. With this condition, your
body attacks its own immune system. Over time, this attack causes the thyroid to stop producing
hormones as it should which leads to hypothyroidism. Like many autoimmune diseases,
Hashimoto’s thyroiditis occurs more frequently in women than men.
Hyperthyroidism
As its name suggests, hyperthyroidism occurs when your body makes too much of the thyroid
hormones, thyroxine (T4) and triiodothyronine (T3), and becomes overactive. If you have
hyperthyroidism, you may experience a fast heartbeat, increased appetite, anxiety, sensitivity to
heat, or sudden weight loss.

Hyperthyroidism most commonly occurs in three ways:

 thyroiditis, or
an inflammation of the thyroid
 a thyroid nodule
that produces too much T4 hormone
 an autoimmune
condition known as Graves’ disease

In hyperthyroidism, an irritation of your thyroid known as thyroiditis allows too much thyroid
hormone to enter your blood. This can lead to pain and discomfort. Thyroiditis can also occur as
the result of pregnancy. This is usually short-term.

Thyroid nodules are common in both hypothyroidism and hyperthyroidism. More often than not,
these nodules are benign. In hyperthyroidism, these nodules can lead to an increase in your
thyroid’s size or produce too much T4 thyroid hormone. Doctors don’t always know why this
happens.

Graves’ disease causes the body to attack itself. This attack allows the thyroid gland to produce
too much thyroid hormone. This autoimmune disease is often the underlying cause of
hyperthyroidism. Graves’ disease causes your thyroid to make too much thyroid hormone.

Medications, radioactive iodine, or surgery are treatment options of hyperthyroidism. If left

untreated, hyperthyroidism can cause bone loss or an irregular heartbeat. Both Hashimoto’s
thyroiditis and Graves’ disease can run in families.