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Functional Anatomy of the Thyroid and Parathyroid Glands

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Title: Functional Anatomy of the Thyroid and Parathyroid Glands


1
Functional Anatomy of the Thyroid and Parathyroid
Glands The thyroid gland is located in the
____, in close approximation to the first part of
the trachea. In humans, the thyroid gland has a
"butterfly" shape, with two lateral lobes that
are connected by a narrow section called the
isthmus. Most animals, however, have
____separate glands on either side of the
trachea. Thyroid glands are __________________
in color.

2
Close examination of a ______ gland will reveal
one or more small, light-colored nodules on or
protruding from its surface - these are
_________glands (meaning "beside the thyroid").
The image shows a canine thyroid gland and one
attached parathyroid gland.

3

4
Occasionally, a person is born with one or more
of the parathyroid glands embedded in the
thyroid, the thymus, or elsewhere in the chest.
In most such cases, however, the glands function
normally.

5
Though their names are similar, the thyroid and
parathyroid glands are _________________glands,
each producing distinct hormones with specific
______________.
6
Parathyroid hormone ____ is the most important
endocrine regulator of ______ and __________
concentration in extracellular fluid. This
hormone is secreted from cells of the parathyroid
glands and finds its major target cells in
____and _____. Another hormone,
______________________________, binds to the same
receptor as parathyroid hormone and has major
effects on ________.

7
Parathyroid hormone Like most other protein
hormones,____ is synthesized as a
________hormone. After intracellular
processing, the mature hormone is packaged within
the Golgi into secretory vesicles, the secreted
into blood by ________. PTH is secreted as a
linear protein of ___ aa.

8
Although the __ parathyroid glands are quite
small- have a very rich _______ supply.
IMPORTANT- they are required to monitor the
calcium level in the blood ____hours a day. As
the blood filters through the parathyroid glands,
they detect the amount of ______ present in the
blood and react by making more or less
parathyroid hormone (__). When the calcium level
in the blood is too low, the cells of the
parathyroids sense it and make more PTH Once PTH
is released into the blood, it circulates to act
in a of places to increase the amount of
calcium in the blood.

9
When the _____ level in the blood is too high,
the cells of the parathyroids make less ____ (or
stop making it altogether), thereby allowing
______ levels to decrease. This feed-back
mechanism runs constantly, thereby maintaining
_____ (and PTH) in a very narrow "normal" range.
In a normal person with normal parathyroid
glands, their parathyroid glands will turn on and
off _________ times per day...in an attempt to
keep the _______ level in the normal range so our
brain and muscles function properly.

10

11
Physiologic Effects of Parathyroid
Hormone Function for ____ is straightforward
if _______ ion concentrations in extracellular
fluid fall below normal, bring them back within
the normal range. In conjunction with increasing
calcium concentration, the concentration of
________ ion in blood is _______.

12
Parathyroid Hormone Receptors PTH and its cousin
_________ are critical controllers of c_____and
p______ balance. The receptors for these ___
hormones are of high interest to drug companies,
because such understanding may facilitate
development of antagonists for treatment of a
number of important diseases, including
_________and hypercalcemia associated with some
types of _______.

13
Parathyroid Hormone Receptors
Type __ PTH receptor PTH and ____________
peptides of PTHrP. G protein-coupled receptor

Type __ PTH receptor Binds PTH, but has very
____affinity for PTHrP. only expressed in a few
tissues- its structure and physiologic
significance are poorly characterized. Like the
type 1 receptor, it is coupled to ______ and
ligand binding induces a rise in intracellular
concentration of _______.
14
Physiologic Effects of Parathyroid
Hormone Parathyroid hormone accomplishes its job
by stimulating at least three processes
Mobilization of _____ from _____ Although the
mechanisms remain obscure, a well-documented
effect of parathyroid hormone is to stimulate
__________to reabsorb bone mineral, liberating
calcium into _______.

15
Physiologic Effects of Parathyroid
Hormone Enhancing absorption of ______ from the
___________ Facilitating calcium absorption from
the small intestine would clearly serve to
elevate blood levels of calcium. Parathyroid
hormone stimulates this process, but indirectly
by stimulating production of the active form of
________ in the kidney. Vitamin D induces
synthesis of a calcium-binding protein in
intestinal epithelial cells that facilitates
efficient absorption of calcium into ______.
16
Physiologic Effects of Parathyroid
Hormone Parathyroid hormone accomplishes its job
by stimulating at least three processes
Suppression of ______ loss in urine In
addition to stimulating fluxes of calcium into
blood from ____ and _____, parathyroid hormone
puts a brake on __________________ in urine, thus
conserving ______in blood. This effect is
mediated by stimulating tubular reabsorption of
calcium. Another effect of parathyroid hormone on
the kidney is to stimulate loss of _______ ions
in urine.
17
(No Transcript)
18
Control of Parathyroid Hormone Secretion PTH
is released in response to ___________
concentrations of free ________ Changes in blood
phosphate concentration can be associated with
changes in PTH secretion, but this appears to be
an indirect effect and phosphate per se is __ a
significant ________of this hormone.

19
Control of Parathyroid Hormone Secretion When
calcium concentrations fall below the normal
range, there is a steep ______in secretion of
PTH. Low levels of the hormone are secreted even
when blood calcium levels are ____. The figure
depicts PTH release from cells cultured in vitro
in differing concentrations of calcium. The
parathyroid cell monitors extracellular free
______concentration via an integral membrane
protein that functions as a ___________________

20
Extracellular Calcium-Sensing Receptor Maintainin
g tight control over the concentration of
c_______ in blood and extracellular fluid is a
critical task. It stands to reason that a
calcium sensor would evolve as a component of the
system responsible for calcium _________.
Considering its involvement in modulating so many
physiologic processes, calcium itself can be
thought of as a type of ______, and the
__________ as its receptor. The DNA sequence
encoding the extracellular calcium sensor was
originally isolated from bovine ____________.
Since then, corresponding sequences have been
isolated from a broad range of species, enabling
serious study of this intriguing membrane
protein.
21
The ____________ receptor is a member of the G
protein-coupled receptor family. Like other
family members, it contains ______and is present
in___. The large (600 amino acids) extracellular
domain is known to be critical to interactions
with ____________________. The receptor also has
a rather large (200 amino acids) cytosolic tail.
-intracellular domain has _______________________
__ sites.
22
The __________ is expressed in a broad range of
cells, including _______ and __ cells in the
thyroid gland, indicating its involvement in
controlling the synthesis and secretion of ______
and _________. Functional studies and
investigation of animals with mutations in the
calcium sensor gene have confirmed that the
_________ directly affects secretion of these two
hormones.

23
Calcitonin _______ is a hormone involved in
calcium and phosphorus metabolism. In mammals,
the major source of ________ is from the
parafollicular or __ cells in the _______gland,
but it is also synthesized in a wide variety of
other tissues. Calcitonin is a __ aa peptide
cleaved from a larger ___hormone. It contains a
single disulfide bond, which causes the amino
terminus to assume the shape of a ring.

24
Calcitonin Calcitonin is a hormone involved in
calcium and phosphorus metabolism. Alternative
splicing of the calcitonin pre-mRNA can yield a
mRNA encoding calcitonin gene-related peptide
that peptide appears to function in the nervous
and vascular systems. The _________ receptor has
been cloned and shown to be a member of the
_______________________ receptor family.

25
Calcitonin Physiologic Effects of Calcitonin A
large and diverse set of effects has been
attributed to ___________, but in many cases,
these were seen in response to pharmacologic
doses of the hormone, and their physiologic
relevance is ________. It is clear however, that
calcitonin plays a role in _______ and
___________ metabolism.

26
Calcitonin Physiologic Effects of
Calcitonin calcitonin has the ability to
________blood calcium levels at least in part by
effects on two well-studied target organs
_______ Calcitonin suppresses resorption of
_____ by inhibiting the activity of ___________,
a cell type that "digests" bone matrix, releasing
calcium and phosphorus into blood._______
Calcium and phosphorus are prevented from being
lost in urine by reabsorption in the __________.
Calcitonin inhibits tubular reabsorption of these
two ____, leading to increased rates of their
loss in _____.

27
Calcitonin There are ______ differences in the
importance of calcitonin as a factor affecting
calcium homeostasis. In ___, rodents and some
domestic animals, calcitonin appears to play a
__________ role in calcium homeostasis. In
humans, ______ has at best a _______ role in
regulating blood concentrations of calcium. One
interesting piece of evidence to support this
statement is that humans with chronically
increased (medullary thyroid cancer) or decreased
(surgical removal of the thyroid gland) levels of
calcitonin in blood usually do not show
alterations from normal in serum calcium
concentration.

28
Calcitonin Control of Calcitonin Secretion The
most prominent factor controlling calcitonin
secretion is the extracellular concentration of
ionized calcium. Elevated blood calcium levels
strongly __________ calcitonin secretion, and
secretion is suppressed when calcium
concentration falls below normal. A number of
other _________ have been shown to stimulate
calcitonin release in certain situations, and
nervous controls also have been demonstrated.

29
Calcitonin Disease States A large number of
diseases are associated with abnormally increased
or decreased levels of calcitonin, but
____________ effects of abnormal calcitonin
secretion per se are not generally recognized.

30
Endocrine Control of Calcium and Phosphate
Homeostasis It would be very difficult to name
a physiologic process that does not depend, in
one way or another, on ________ critical to
maintain blood calcium concentrations within a
______ normal range. Deviations above or below
the normal range frequently lead to
_______disease.
31
Endocrine Control of Calcium and Phosphate
Homeostasis _________ refers to low blood
calcium concentration. Clinical signs of this
disorder reflect increased neuromuscular
excitability and include muscle spasms, tetany
and cardiac dysfunction. _______ indicates a
concentration of blood calcium higher than
normal. The normal concentration of calcium and
phosphate in blood and extracellular fluid is
near the saturation point elevations can lead to
diffuse precipitation of calcium phosphate in
tissues, leading to widespread organ dysfunction
and damage. Preventing hypercalcemia and
hypocalcemia is largely the result of robust
_________ control systems.

32
Body Distribution of Calcium and Phosphate 3
major pools of calcium in the body __________
A large majority of calcium within cells is
sequestered in _______and ____. Intracellular
free calcium concentrations fluctuate greatly,
from roughly 100 nM to greater than 1 uM, due to
release from cellular stores or influx from
extracellular fluid. These fluctuations are
integral to calcium's role in intracellular
signaling, enzyme activation and muscle
contractions.

33
Body Distribution of Calcium and Phosphate 3
major pools of calcium in the body
_______________ Roughly ____ of the calcium in
blood is bound to proteins. The concentration of
ionized calcium in this compartment is normally
almost invariant at approximately 1 mM, or 10,000
times the basal concentration of free calcium
within cells. Also, the ___________of phosphorus
in blood is essentially identical to that of
calcium. ______ A vast majority of body
calcium is in ____. Within bone, ___ of the
calcium is tied up in the mineral phase, but the
remaining __ is in a pool that can rapidly
exchange with ___________ calcium.

34
Endocrine Control of Calcium and Phosphate
Homeostasis Fluxes of Calcium and
Phosphate Maintaining constant concentrations of
calcium in blood requires frequent adjustments,
which can be described as fluxes of calcium
between blood and other body compartments. Three
organs participate in supplying calcium to blood
and removing it from blood when necessary The
_________ is the site where dietary ______ is
absorbed. Importantly, efficient absorption of
calcium in the small intestine is dependent on
expression of a calcium-binding protein Bone
serves as a _______ of calcium. Stimulating net
resorption of bone mineral releases calcium and
phosphate into blood, and suppressing this effect
allows calcium to be deposited in bone.

35
Endocrine Control of Calcium and Phosphate
Homeostasis Fluxes of Calcium and
Phosphate The ____ is critically important in
_______homeostasis. Under normal blood calcium
concentrations, almost all of the calcium that
enters glomerular filtrate is reabsorbed from the
tubular system back into blood, which preserves
blood calcium levels. If tubular reabsorption of
calcium decreases, calcium is lost by excretion
into _________.

36

37
Hormonal Control Systems Maintaining normal
blood calcium and phosphorus concentrations is
managed through the concerted action of
_____________________ that control fluxes of
calcium in and out of blood and extracellular
fluid

38
Hormonal Control Systems ____ serves to increase
blood concentrations of calcium. Mechanistically,
____ preserves blood calcium by several major
effects Stimulates production of the
biologically-active form of _____ within the
kidney. Facilitates mobilization of _____ and
phosphate from bone. To prevent detrimental
increases in phosphate, _____ also has a potent
effect on the kidney to eliminate phosphate
(phosphaturic effect). Maximizes tubular
reabsorption of ________ within the kidney.
This activity results in minimal losses of
______ in _______.

39
Hormonal Control Systems _______ acts also
function to increase blood concentrations of
calcium. It is generated through the activity of
PTH within the kidney. Far and away the most
important effect of ________ is to facilitate
absorption of calcium from the _______. In
concert with PTH, vitamin D also enhances fluxes
of calcium out of bone. _______ is a hormone
that functions to reduce blood calcium levels.

40
Vitamin D (Cholecalciferol, Calcitriol) ________
is a steroid hormone that has long been known for
its important role in regulating body levels of
calcium and phosphorus, and in mineralization of
bone. More recently, it has become clear that
receptors for vitamin D are present in a wide
variety of cells, and that this hormone has
biologic effects which extend ____________________
________________
41
Structure and Synthesis-Vitamin D The term
vitamin D actually refers to a ___________
molecules. Vitamin D3, also known as
cholecalciferol is generated in the s___of
animals when light energy is absorbed by a
precursor molecule 7-dehydrocholesterol.
_______ is thus not a true vitamin, because
individuals with adequate exposure to ________ do
not require dietary supplementation. There are
dietary sources of vitamin D, including ____,
fish oil and a number of _____. The plant form
of vitamin D is called vitamin D2 or ergosterol.
However, natural diets typically do not contain
adequate quantities of vitamin D, and exposure to
sunlight or consumption of foodstuffs
purposefully supplemented with vitamin D are
necessary to prevent deficiencies.

42
Vitamin D, as either D3 or D2, does not have
_________________________________________ Rather,
it must be ______ within the _____ to the
hormonally-active form. This transformation
occurs in ___steps, as depicted in the diagram on
the next slide Within the ______, cholecalciferal
is hydroxylated to 25-hydroxycholecalciferol by
the enzyme 25-hydroxylase. Within the______,
25-vitamin D serves as a substrate for
1-alpha-hydroxylase, yielding 1,25-dihydroxycholec
alciferol, the biologically active form of
vitamin D.

43

44
Each of the forms of _______ is _________ and is
transported in blood bound to carrier proteins.
The major carrier is called, appropriately,
vitamin D-binding protein. The half-life of
25-hydroxycholecalciferol is several weeks, while
that of 1,25-dihydroxycholecalciferol is only a
________s.

45
Control of Vitamin D Synthesis Hepatic synthesis
of 25-hydroxycholecalciferol is only loosely
regulated, and blood levels of this molecule
largely reflect the amount of amount of vitamin D
produced in the ____ or ______. In contrast, the
activity of 1-alpha-hydroxylase in the _____ is
tightly regulated and serves as the major control
point in production of the active hormone. The
major inducer of 1-alpha-hydroxylase is _____ it
is also induced by low blood levels of phosphate.

46
The Vitamin D Receptor and Mechanism of
Action The active form of vitamin D binds to
intracellular receptors that then function as
___________ to modulate gene expression. Like
steroid hormones and thyroid hormones, the
_________ receptor has hormone-binding and
DNA-binding domains. The vitamin D receptor
forms a complex with another intracellular
receptor, the retinoid-X receptor (RXR), and that
________ is what binds to DNA. In most cases
studied, the effect is to activate transcription,
but situations are also known in which vitamin D
suppresses transcription. The vitamin D receptor
binds several forms of cholecalciferol. Its
affinity for 1,25-dihydroxycholecalciferol is
roughly 1000 times that for 25-hydroxycholecalcife
rol, which explains their relative biological
potencies.

47
Physiological Effects of Vitamin D Vitamin D is
well known as a hormone involved in ______
metabolism and ______ growth. Its most dramatic
effect is to facilitate _______ absorption of
calcium, although it also stimulates absorption
of phosphate and magnesium ions. In the absence
of vitamin D, dietary calcium is not absorbed at
all efficiently. Vitamin D stimulates the
expression of a number of proteins involved in
transporting calcium from the lumen of the
intestine, across the epithelial cells and into
blood. The best-studied of these calcium
transporters is _______, an intracellular protein
that ferries calcium across the intestinal
epithelial cell.

48
Physiological Effects of Vitamin D Numerous
effects of vitamin D on bone have been
demonstrated. As a transcriptional regulator of
bone matrix proteins, it induces the expression
of osteocalcin and suppresses synthesis of type I
collagen. In cell cultures, vitamin D stimulates
differentiation of osteoclasts. However, studies
of humans and animals with vitamin D deficiency
or mutations in the vitamin D receptor suggest
that these effects are perhaps not of major
physiologic importance, and that the crucial
effect of vitamin D on bone is to provide the
proper balance of calcium and phosphorus to
support mineralization. vitamin D receptors are
present in most if not all cells in the body.
Additionally, experiments using cultured cells
have demonstrated that vitamin D has potent
effects on the growth and differentiation of many
types of cells. Hence, vitamin D has physiologic
effects much ______ that a role in mineral
homeostasis bone function.

49
Disease States Vitamin D deficiency The
classical manifestations of vitamin D deficiency
is ________, which is seen in children and
results in bony deformaties including bowed long
bones.

50
Disease States Deficiency in adults leads to the
disease osteomalacia. Both rickets and
osteomalacia reflect impaired mineralization of
newly synthesized bone matrix, and usually result
from a combination of inadequate exposure to
______and decreased dietary intake of
_________________.

51
Disease States Vitamin D deficiency or
insufficiency occurs in several other situations,
which you might predict based on the synthetic
pathway described above Genetic defects in the
________ receptor a number of different
mutations have been identified in humans that
lead to hereditary ________ resistance.Severe___
__ or ______ disease this can interfere with
generation of the biologically-active form of
vitamin D.

52
Disease States Vitamin D deficiency or
insufficiency occurs in several other situations,
which you might predict based on the synthetic
pathway described above Insufficient
exposure to _________ Elderly people that stay
inside and have poor diets often have at least
subclinical deficiency.

53
Disease States Ironically, it appears that
hypovitaminosis D is very common in some of the
most sunny countries in the world - the cause of
this problem is the cultural dictate that women
be heavily veiled when outside in public.
Sunscreens, especially those with SPF ratings
greater than 8, effectively block synthesis of
vitamin D in the skin. However, people that use
such sunscreens usually live in industrial
countries where many foods are supplemented with
vitamin D, and vitamin D deficiency is thereby
averted by dietary intake.

54
Disease States Vitamin D toxicity Excessive
exposure to sunlight does not lead to
overproduction of ________. Vitamin D toxicity is
inevitably the result of overdosing on vitamin D
_______. Don't do this! Ingestion of milligram
quantities of vitamin D over periods of weeks of
months can be severely ______ to humans and
animals. In fact, baits laced with vitamin D are
used very effectively as _____________.

55

56
Disease States Both and
secretion of PTH are recognized as causes of
serious disease in man and animals. Excessive
secretion of parathyroid hormone is seen in
______ forms

57
______ Is the result of parathyroid gland
disease, most commonly due to a parathyroid tumor
(adenoma) which secretes the hormone without
proper regulation. Common manifestations of
this disorder are chronic elevations of blood
______ concentration (hypercalcemia), ______
and decalcification of bone.

58
hypercalcemia is what usually signals the doctor
that something may be wrong with the parathyroid
glands. In ______ of people with this disorder,
a benign tumor (adenoma) has formed on one of the
parathyroid glands, causing it to become
overactive. In most other cases, the excess
hormone comes from two or more enlarged
parathyroid glands, a condition called
hyperplasia. Very rarely, hyperparathyroidism is
caused by cancer of a parathyroid gland. This
excess ______ triggers the release of too much
calcium into the bloodstream. The bones may lose
calcium, and too much calcium may be absorbed
from food. The levels of calcium may increase in
the urine, causing kidney stones. PTH also acts
to lower blood phosphorous levels by increasing
excretion of phosphorus in the ______.

59
Why Are Calcium and Phosphorous So
Important? Calcium is essential for good health.
It plays an important role in ______
development and in maintaining bone strength. It
is also important in ______ Phosphorous is found
in ______ Combined with calcium, it gives
strength and rigidity to your bones and teeth.
60
What Causes Hyperparathyroidism? In most cases
______. The vast majority of cases occur in
people with no family history of the disorder.
Only about ______ of cases can be linked to an
inherited problem. Familial (multiple) endocrine
neoplasia type I is one rare inherited syndrome
that affects the parathyroids as well as the
pancreas and the pituitary gland. Another rare
genetic disorder, familial hypocalciuric
hypercalcemia, is sometimes confused with typical
hyperparathyroidism.

61
How Common Is Hyperparathyroidism? In the
U.S., about 100,000 people develop the disorder
each year. Women outnumber men ______ to 1, and
risk increases with ______. In women 60 years and
older, 2 out of 1,000 will get hyperparathyroidism
.

62
What Are the Symptoms of Hyperparathyroidism? may
have ______ symptoms, subtle ones, or none at
all. Increasingly, routine blood tests that
screen for a wide range of conditions including
______ levels are alerting doctors to people who,
though symptom-free, have mild forms of the
disorder. When symptoms do appear, they are
often mild and nonspecific, such as a feeling of
weakness and fatigue, depression, or aches and
pains. With more severe disease, a person may
have a loss of ______, nausea, vomiting,
constipation, confusion or impaired thinking
______, and increased ______ .
Patients may have thinning of the bones without
symptoms, but with risk of fractures. Increased
calcium and phosphorous excretion in the urine
may cause ______. Patients with
hyperparathyroidism may be more likely to develop
peptic ulcers, high blood pressure, and
pancreatitis.

63
How Is Hyperparathyroidism Diagnosed? Hyperparathy
roidism is diagnosed when tests show that blood
levels of calcium as well as PTH are too high.
Other diseases can cause high blood calcium
levels, but only in hyperparathyroidism is the
elevated calcium the result of too much PTH.
______ has simplified the diagnosis of
hyperparathyroidism. Once the diagnosis is
established, other tests may be done to assess
complications. Because high PTH levels can cause
bones to weaken from calcium loss, a measurement
of ______ may be done to assess bone loss and the
risk of fractures. Abdominal radiographs may
reveal the presence of kidney stones and a
24-hour urine collection may provide information
on kidney damage and the risk of stone formation.

64
How Is Hyperparathyroidism Treated? Surgery to
remove the enlarged gland(s) is the only
treatment for the disorder and cures it in ______
of cases. However, some patients who have mild
disease may not need immediate treatment,
according to a panel of experts convened by the
National Institutes of Health in 1990. Patients
who are symptom-free, whose blood ______ is only
slightly elevated, and whose kidneys and bones
are normal, may wish to talk to their doctor
about long-term monitoring.
65
How Is Hyperparathyroidism Treated? In the
panel's recommendation, monitoring would consist
of clinical evaluation and measurement of ______
levels and ______ function every 6 months, annual
abdominal x-ray, and bone mass measurement after
1 to 2 years. If the disease shows no signs of
worsening after 1 to 3 years, the interval
between exams may be lengthened. If the patient
and doctor choose long-term followup, the patient
should try to ______, and get plenty of exercise.
Immobilization and gastrointestinal illness with
vomiting or diarrhea can cause calcium levels to
rise, and if these conditions develop, patients
with hyperparathyroidism should seek medical
attention
66
Are There Any Complications Associated With
Parathyroid Surgery? Surgery for
hyperparathyroidism is highly successful with a
low complication rate when performed by surgeons
experienced with this condition. About 1 of
patients undergoing surgery have damage to the
nerves controlling the vocal cords, which can
affect speech. 1-5 of patients develop chronic
low calcium levels, which may require treatment
with calcium and/or vitamin D. The complication
rate is slightly higher for hyperplasia than it
is for adenoma since more extensive surgery is
needed. .
67
Are Parathyroid Imaging Tests Needed Before
Surgery? NOPE The NIH panel recommended against
the use of expensive imaging tests to locate
benign tumors before initial surgery. Research
shows that such tests do not improve the success
rate of surgery, which is about ______ when
performed by experienced surgeons. Localization
tests are useful in patients having a second
operation for recurrent or persistent
hyperparathyroidism. .
68
Secondary hyperparathyroidism is the situation
where disease outside of the parathyroid gland
leads to excessive secretion of parathyroid
hormone. A common cause of this disorder is
kidney disease - if the kidneys are unable to
reabsorb calcium, blood calcium levels will fall,
stimulating continual secretion of parathyroid
hormone to maintain normal calcium levels in
blood. Secondary hyperparathyroidism can also
result from inadequate nutrition - for example,
diets that are deficient in calcium or vitamin D,
or which contain excessive phosphorus (e.g. all
meat diets for carnivores).A prominent effect
of secondary hyperparathyroidism is
decalcification of bone, leading to pathologic
fractures or "rubber bones".

69
There is no doubt that chronic secretion or
continuous infusion of PTH leads to
decalcification of bone and loss of bone mass.
However, in certain situations, treatment with
PTH can actually stimulate an increase in bone
mass and bone strength. This seemingly
paradoxical effect occurs when the hormone is
administered in pulses (e.g. by once daily
injection), and such treatment appears to be an
effective therapy for diseases such as
osteoporosis.

70
Inadequate production of parathyroid hormone
______ - typically results in decreased
concentrations of calcium and increased
concentrations of phosphorus in blood. Common
causes of this disorder include surgical removal
of the parathyroid glands and disease processes
that lead to destruction of parathyroid glands.
The resulting ______ often leads to tetany and
convulsions, and can be acutely life-threatening.
Treatment focuses on restoring normal blood
calcium concentrations by calcium infusions, oral
calcium supplements and vitamin D therapy.

71
Parathyroid Hormone-Related Protein Parathyroid
hormone-related protein (PTHrP) is actually a
family of protein hormones produced by most if
not all tissues in the body. A segment of PTHrP
is closely related to PTH, hence its name, but
these peptides have a much broader spectrum of
effects. PTH and some of the PTHrP peptides bind
to the same receptor, but PTHrP peptides also
bind to several other receptors.

72
Parathyroid Hormone-Related Protein . PTHRP
was discovered as a protein secreted by certain
tumors that caused hypercalcemia (elevated blood
calcium levels) in affected patients. It was
soon shown that the uncontrolled secretion of
PTHRP by many tumor cells induces hypercalcemia
by stimulating resorption of calcium from bone
and suppressing calcium loss in urine, similar to
what is seen with hyperparathyroidism. However,
it quickly become apparent that PTHRH had many
activities not seen with PTH.

73
Hormone Structures, Receptors and Sources ______
is encoded by a single gene that is highly
conserved among species. It should probably be
described as a polyhormone, because a family of
peptide hormones are generated by ______ of the
primary transcript and through use of alternative
post-translational cleavage sites. To make
matters even more complex, some cells appear to
use alternative translational initiation codons
to produce forms of the protein that are targeted
either for secretion or nuclear localization. The
figure below shows one of the characterized
processing patterns of the PTHrP preprohormone,
in this case yielding 3 bioactive peptides.

74
Parathyroid Hormone-Related Protein The diverse
activities of PTHrP result not only from
processing of the precursor into multiple
hormones, but from use of multiple receptors. It
is clear that amino-terminal peptides of PTHrP
share a receptor with PTH, but they also bind to
a type of receptor in some tissues that does not
bind PTH. Moreover, it is almost certain that
the midregion and osteostatin peptides bind
other, unique receptors. In addition to the
secreted forms, there is considerable evidence
that a form of PTHrP is generated in some cells
that is not secreted and, via nuclear targeting
sequences, is translocated to the nucleus, where
it affects ______.

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Parathyroid Hormone-Related Protein Moreover,
it is almost certain that the midregion and
osteostatin peptides bind other, unique
receptors. In addition to the secreted forms,
there is considerable evidence that a form of
PTHrP is generated in some cells that is not
secreted and, via nuclear targeting sequences, is
translocated to the nucleus, where it affects
nuclear function. The consequences of this
"intracrine" mode of action are not yet well
characterized, but may modulate such important
activities as programmed cell death.

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Parathyroid Hormone-Related Protein PTHrP is
secreted from a large and diverse set of cells,
and during both fetal and postnatal life. Among
tissues known to secrete this hormone are several
types of epithelium, mesenchyme, vascular smooth
muscle and central nervous system. Although
PTHrP is found in serum, a majority of its
activity appears to reflect paracrine signaling.

77
Physiologic Effects of Parathyroid
Hormone-Related Protein One thing to recognize
about PTHrP is that its name is ______ Like PTH,
some of the effects of PTHrP result from its
effects on transepithelial fluxes of calcium, but
many of its actions have nothing to do with
______. Most prominently, PTHrP peptides exert
significant control over the proliferation,
differentiation and death of many cell types.
They also play a major role in development of
several tissues and organs.

78
Physiologic Effects of Parathyroid
Hormone-Related Protein . Much of our
understanding of the biologic effects of PTHrP
comes from experiments with ______ Mice with
targeted deletions in the PTHrP gene (knockout
mice), mice that overexpress PTHrP in specific
tissues (transgenic mice), and crosses between
knockout and transgenic mice have been critical
in delineating many effects of this hormone.
Humans with mutations in the PTHrP gene or the
parathyroid receptor have also played a role in
confirming the activity of PTHrP. Some of the
physiologic effects of PTHrP garnered from these
studies are indicated on next few slides

79
Physiologic Effects of Parathyroid
Hormone-Related Protein ______ Mice null for
PTHrP gene die at birth, if not earlier. A
developmental defect in proliferation and
differentiation of cartilage. These and other
types of studies indicate that PTHrP stimulates
the proliferation of chondrocytes and suppresses
their terminal differentiation. These effects of
PTHrP appear due to interaction of the PTH-like
peptide with the PTH receptor.

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Physiologic Effects of Parathyroid
Hormone-Related Protein . Mammary Development
and Lactation The mammary glands of female mice
with homozygous inactivation of the PTHrP gene
fail to develop, except for the earliest stages.
Development of the mammary gland depends upon a
complex interaction between epithelial and
mesenchymal cells that apparently requires PTHrP.
In normal animals, mammary epithelial cells
secrete large amounts of PTHrP, which suggests a
role of this hormone in adapting maternal
metabolism to the calcium demands of lactation.
Placental Transfer of Calcium The "midregion"
peptide of PTHrP (see above) has been shown to
control the normal maternal-to-fetal pumping of
calcium across the placenta. In the absence of
fetal PTHrP, this gradient is not established.

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Physiologic Effects of Parathyroid
Hormone-Related Protein ______ PTHrP is secreted
from smooth muscle usually in response to
stretching. It acts to relax smooth muscle,
thereby serving, among other things, as a
vasodilating hormone. Transgenic mice that
express PTHrP in vascular smooth muscle manifest
hypotension. PTHrP may also have effects on
contraction of muscle in the bladder, uterus and
heart.

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Physiologic Effects of Parathyroid
Hormone-Related Protein ______ PTHrP is
highly expressed in skin. Transgenic mice that
overexpress PTHrP in skin show alopecia, and
treatment of mice with a PTHrP antagonist leads
to increased numbers of hair follicles and a
shaggy appearance. Another interesting defect in
PTHrP-null mice is that teeth develop normally,
they fail to erupt. Finally, both PTHrP and its
receptors are widely expressed in the CNS, and
appear to influence neuronal survival by several
mechanisms. It should be clear from the above
examples that PTHrP hormones have profound
effects on a large number of physiologic
processes. Ongoing research on this polyhormone
is certain to reveal additional effects in this
already complex system.

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