Functional Anatomy of the Thyroid and Parathyroid Glands

Functional Anatomy of the Thyroid and Parathyroid Glands

The thyroid gland is located in the neck, 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 two separate glands on either side of the trachea.

Thyroid glands are brownish-red in color.

Close examination of a thyroid gland will reveal one or more small, light-colored nodules on or protruding from its surface - these are

parathyroid glands (meaning "beside the thyroid"). The image shows a canine thyroid gland and one attached parathyroid

gland.

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.

Though their names are similar, the thyroid and parathyroid glands are entirely

separate glands, each producing distinct hormones with specific

functions.

Parathyroid hormone (PTH)

PTH is the most important endocrine regulator of calcium and phosphorus concentration in extracellular fluid.

This hormone is secreted from cells of the parathyroid glands and finds its major target

cells in bone and kidney.

Another hormone, parathyroid hormone-related protein, binds to the same receptor as parathyroid hormone and has major effects on development.

http://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/thyroid/phrp.html


Parathyroid hormone

Like most other protein hormones, PTH is synthesized as a preprohormone.

After intracellular processing, the mature hormone is packaged within the Golgi into

secretory vesicles, the secreted into blood by exocytosis.

PTH is secreted as a linear protein of 84 aa.

Although the 4 parathyroid glands are quite small-

have a very rich blood supply.

IMPORTANT- they are required to monitor the calcium level

in the blood 24 hours a day. As the blood filters through the parathyroid

glands, they detect the amount of calcium present in the blood and react by making

more or less parathyroid hormone (PTH).

IMPORTANT- they are required to monitor the calcium

level in the blood 24 hours a day.

When the calcium level in the blood is too low, the cells of the parathyroids

sense it and make more PTHOnce PTH is released into the blood, it

circulates to act in a # of places to increase the amount of calcium in the

blood.

When the calcium level in the blood is too high, the cells of the parathyroids

make less PTH (or stop making it altogether), thereby allowing calcium

levels to decrease. This feed-back mechanism runs

constantly, thereby maintaining calcium (and PTH) in a very narrow "normal"

range.

In a normal person with normal parathyroid glands, their

parathyroid glands will turn on and off dozens of times per day...in an

attempt to keep the calcium level in the normal range so our brain and

muscles function properly.

Physiologic Effects of Parathyroid Hormone

Function for PTH is straightforward: if calcium ion concentrations in

extracellular fluid fall below normal, bring them back within the normal

range.

In conjunction with increasing calcium concentration, the concentration of phosphate ion in blood is reduced.

Parathyroid Hormone Receptors

PTH and its cousin parathyroid hormone-related protein (PTHrP) are critical controllers of calcium and phosphorus

balance.

The receptors for these two 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 osteoporosis and hypercalcemia associated with some types of

cancer.


Parathyroid Hormone Receptors

Type 1 PTH receptor: PTH and amino-

terminal peptides of PTHrP.

G protein-coupled receptor

Type 2 PTH receptor: Binds PTH, but has very low

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

adenylyl cyclase and ligand binding induces a rise in

intracellular concentration of cyclic AMP.


Parathyroid hormone accomplishes its job by stimulating at least three processes:

Mobilization of calcium from bone

Although the mechanisms remain obscure, a well-documented effect of parathyroid hormone is to stimulate osteoclasts to reabsorb bone mineral,

liberating calcium into blood.


Enhancing absorption of calcium from the small intestine: Facilitating calcium absorption from

the small intestine would clearly serve to elevate blood levels of calcium.

PTH stimulates this process, but indirectly by stimulating production of the active form of vitamin D in the kidney. Vitamin D induces synthesis of a calcium-binding protein in

intestinal epithelial cells that facilitates efficient absorption of calcium into blood.

http://arbl.cvmbs.colostate.edu/hbooks/pathphys/endocrine/otherendo/vitamind.html


Parathyroid hormone accomplishes its job by stimulating at least three processes:

Suppression of calcium loss in urine: In addition to stimulating fluxes of calcium into blood from

bone and intestine, PTH puts a brake on excretion of calcium in urine, thus conserving calcium in blood. This effect is mediated by

stimulating tubular reabsorption of calcium. Another effect of PTH on the kidney is to stimulate loss of phosphate ions in urine.

Control of Parathyroid Hormone Secretion

PTH is released in response to low extracellular concentrations of free calcium.

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 not a significant regulator of

this hormone.

Control of Parathyroid Hormone Secretion

When calcium concentrations fall below

the normal range, there is a steep increase in secretion of PTH. Low levels of the hormone are secreted even when blood calcium levels are

high. The figure depicts PTH release from cells cultured in vitro in

differing concentrations of calcium. The parathyroid cell monitors

extracellular free calcium concentration via an integral

membrane protein that functions as a calcium-sensing receptor.

Extracellular Calcium-Sensing Receptor

Maintaining tight control over the concentration of calcium 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 homeostasis.

Considering its involvement in modulating so many physiologic processes, calcium itself can be thought of as a type of hormone,

and the calcium sensor as its receptor.

The DNA sequence encoding the extracellular calcium sensor was originally isolated from bovine parathyroid gland. Since then,

corresponding sequences have been isolated from a broad range of species, enabling serious study of this intriguing membrane

protein.

The calcium-sensing receptor is a member of the G protein-coupled receptor family. Like other family members, it contains 7TMDs and is present in PM. The large (~600 amino acids) extracellular domain is known to be critical to interactions with extracellular calcium. The receptor also has a rather large (~200 amino acids) cytosolic tail. -intracellular domain has kinase phosphorylation

sites.

The calcium sensor is expressed in a broad range of cells, including parathyroid cells and C cells in the thyroid gland, indicating its involvement in

controlling the synthesis and secretion of parathyroid hormone and calcitonin.

Functional studies and investigation of animals with mutations in the calcium sensor gene have

confirmed that the calcium sensor directly affects secretion of these two hormones.

Calcitonin

Calcitonin is a hormone involved in calcium and phosphorus metabolism.

In mammals, the major source of calcitonin is from the parafollicular or C cells in the thyroid gland, but it is

also synthesized in a wide variety of other tissues.

Calcitonin is a 32 aa peptide cleaved from a larger prohormone.

It contains a single disulfide bond, which causes the amino terminus to assume the shape of a ring.

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

calcitonin receptor has been cloned and shown to be a member of the 7TMD, G protein-coupled

receptor family.

Calcitonin

Physiologic Effects of Calcitonin

A large and diverse set of effects has been attributed to calcitonin, but in many cases, these were seen in

response to pharmacologic doses of the hormone, and their physiologic relevance is suspect.

It is clear however, that calcitonin plays a role in calcium and phosphorus metabolism.

Calcitonin

Physiologic Effects of Calcitonin

calcitonin has the ability to decrease blood calcium levels at least in part by effects on two well-studied target organs:

Bone: Calcitonin suppresses resorption of bone by inhibiting the activity of osteoclasts, a cell type that "digests" bone matrix, releasing calcium and phosphorus into blood.

Kidney: Calcium and phosphorus are prevented from being lost in urine by reabsorption in the kidney tubules. Calcitonin inhibits tubular reabsorption of these two ions, leading to increased rates of their loss in urine.

Calcitonin

There are species differences in the importance of calcitonin as a factor affecting calcium homeostasis.

In fish, rodents and some domestic animals, calcitonin appears to play a significant role in calcium

homeostasis. In humans, calcitonin has at best a minor 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.

Calcitonin

Control of Calcitonin Secretion

The most prominent factor controlling calcitonin secretion is the extracellular concentration of

ionized calcium. Elevated blood calcium levels strongly stimulate

calcitonin secretion, and secretion is suppressed when calcium concentration falls below normal. A number of other hormones have been shown

to stimulate calcitonin release in certain situations, and nervous controls have also been

demonstrated.

Calcitonin

Disease States

A large number of diseases are associated with abnormally increased or decreased levels of

calcitonin, but pathologic effects of abnormal calcitonin secretion per se are not generally

recognized.

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

calcium. critical to maintain blood calcium concentrations within a tight normal

range.

Deviations above or below the normal range frequently lead to serious disease.


Hypocalcemia refers to low blood calcium concentration. Clinical signs of this disorder reflect increased

neuromuscular excitability and include muscle spasms, tetany and cardiac dysfunction.

Tetany -the involuntary contraction of muscle caused by diseases and other conditions that increase the action

potential frequency.


TetanyMechanism

When the membrane potential is upset, for instance by low levels of ions (such as Ca++) in the blood (hypocalcemia),

neurons will depolarize too easily. In the case of hypocalcaemia, calcium ions are drawn away

from their association with the voltage-gated sodium channels thus sensitizing them. The upset to membrane

potential is therefore caused by an influx of sodium to the cell, not directly by the hypocalcaemia.

As a result, too many action potentials are sent to muscles causing spasm.


Hypocalcemia refers to low blood calcium concentration. Clinical signs of this disorder reflect increased

neuromuscular excitability and include muscle spasms, tetany and cardiac dysfunction.

Hypercalcemia 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 endocrine control systems.

Body Distribution of Calcium and Phosphate

3 major pools of calcium in the body:

Intracellular calcium: A large majority of calcium within cells is sequestered in mitochondria and ER.

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.



Calcium in blood and extracellular fluid: Roughly half 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 concentration of phosphorus in blood is essentially identical to that of calcium.



Bone calcium: A vast majority of body calcium is in bone. Within bone, 99% of

the calcium is tied up in the mineral phase, but the remaining 1% is in a pool that can

rapidly exchange with extracellular calcium.


Fluxes of Calcium and PhosphateMaintaining 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:


Three organs participate in supplying calcium to blood and removing it from blood when necessary:

The SI is the site where dietary calcium is absorbed. Importantly, efficient absorption of calcium in the SI is dependent on expression of a calcium-binding protein

Bone serves as a vast reservoir 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.


Fluxes of Calcium and Phosphate

The kidney is critically important in calcium 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 urine.

Hormonal Control Systems

Maintaining normal blood calcium and phosphorus concentrations is managed through the

concerted action of three hormones

that control fluxes of calcium in and out of blood and extracellular fluid:

Hormonal Control Systems

PTH serves to increase blood concentrations of calcium. Mechanistically, PTH preserves blood calcium by several major

effects:

Stimulates production of the biologically-active form of vitamin D within the kidney.

Facilitates mobilization of calcium and phosphate from bone. To prevent detrimental increases in phosphate, PTH also has a

potent effect on the kidney to eliminate phosphate (phosphaturic effect).

Maximizes tubular reabsorption of calcium within the kidney.

This activity results in minimal losses of calcium in urine.

Hormonal Control SystemsVitamin D 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 vitamin D is to facilitate absorption of calcium from the small intestine. In

concert with PTH, vitamin D also enhances fluxes of calcium out of bone.

Calcitonin is a hormone that functions to reduce blood calcium levels.

Vitamin D (Cholecalciferol, Calcitriol)

Vitamin D 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 far beyond control of mineral metabolism.

Structure and Synthesis-Vitamin D

The term vitamin D actually refers to a group of steroid molecules. Vitamin D3, also

known as cholecalciferol is generated in the skin of animals when light energy is

absorbed by a precursor molecule 7-dehydrocholesterol.

Structure and Synthesis-Vitamin D

Vitamin D is thus not a true vitamin, because individuals with adequate exposure to sunlight do not require

dietary supplementation.

There are dietary sources of vitamin D, including egg yolk, fish oil and a number of plants.

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.

Vitamin D, as either D3 or D2, does not have significant biological activity.

Rather, it must be metabolized within the body to the hormonally-active form.

This transformation occurs in 2 steps, as depicted in the diagram on the next slide

Within the liver, cholecalciferal is hydroxylated to 25-hydroxycholecalciferol by the enzyme 25-

hydroxylase.

Within the kidney, 25-vitamin D serves as a substrate for 1-alpha-hydroxylase, yielding 1,25-

dihydroxycholecalciferol, the biologically active form of vitamin D.

Each of the forms of vitamin D is hydrophobic 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 few hours.

Control of Vitamin D SynthesisHepatic 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 skin or ingested.

In contrast, the activity of 1-alpha-hydroxylase in the kidney is tightly regulated and serves as the major control point in production of the active hormone. The major inducer of 1-alpha-hydroxylase is PTH: it is also induced

by low blood levels of phosphate.

The Vitamin D Receptor and Mechanism of ActionThe active form of vitamin D binds to intracellular

receptors that then function as transcription factors to modulate gene expression.

Like steroid hormones and thyroid hormones, the vitamin D 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 heterodimer 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-hydroxycholecalciferol, which explains their relative biological

potencies.

Physiological Effects of Vitamin D

Vitamin D is well known as a hormone involved in mineral

metabolism and bone growth. Its most dramatic effect is to

facilitate intestinal 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 calbindin, an intracellular

protein that ferries calcium across the intestinal epithelial cell.


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 culture, 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 broader that a role in mineral homeostasis & bone function.

Disease States

Vitamin D deficiency: The classical manifestations of vitamin D deficiency is rickets, which is seen in children and results in bony deformaties including bowed long

bones.

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 sunlight and decreased dietary intake

of vitamin D.

Disease States

Vitamin D deficiency or insufficiency occurs in several other situations, which you might predict

based on the synthetic pathway

Genetic defects in the vitamin D receptor: a number of different mutations have been

identified in humans that lead to hereditary vitamin D resistance.

Severe liver or kidney disease: this can interfere with generation of the biologically-active form of

vitamin D.

Disease States

Insufficient exposure to sunlight:

Elderly people that stay inside and have poor diets often have at least

subclinical deficiency.

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.

Disease States

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.

Disease States

Vitamin D toxicity: Excessive exposure to sunlight does not lead to overproduction of vitamin D. Vitamin D toxicity is inevitably

the result of overdosing on vitamin D supplements. Don't do this!

Ingestion of milligram quantities of vitamin D over periods of weeks of months can be

severely toxic to humans and animals. In fact, baits laced with vitamin D are used

very effectively as rodenticides.

Disease States

Both increased and decreased secretion of PTH are recognized as causes of serious

disease in man and animals. Excessive secretion of parathyroid hormone

is seen in two forms:

Primary hyperparathyroidism

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 calcium

concentration (hypercalcemia), kidney stones and decalcification of bone.

hypercalcemia is what usually signals the doctor that something may be wrong with the parathyroid glands.

In 85% 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 PTH 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

urine.

Why Are Calcium and Phosphorous So Important?

Calcium is essential for good health. It plays an important role in bone and tooth

development and in maintaining bone strength. It is also important in nerve transmission and

muscle contraction.

Phosphorous is found in every body tissue. Combined with calcium, it gives strength and

rigidity to your bones and teeth.

What Causes Hyperparathyroidism?

In most cases doctors don't know the cause. The vast majority of cases occur in people with no family

history of the disorder. Only about 3-5 % of cases can be linked to an inherited

problem. Familial 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.

How Common Is Hyperparathyroidism?

In the U.S., about 100,000 people develop the disorder each year. Women outnumber men by

2 to 1, and risk increases with age.

In women 60 years and older, 2 out of 1,000 will get hyperparathyroidism.

What Are the Symptoms of Hyperparathyroidism?

may have severe symptoms, subtle ones, or none at all.

Increasingly, routine blood tests that screen for a wide range of conditions including high calcium levels are alerting doctors to people who, though symptom-free, have mild forms of the disorder.

What Are the Symptoms of Hyperparathyroidism?

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 appetite, nausea,

vomiting, constipation, confusion or impaired thinking and memory, and increased thirst and urination. Patients may have thinning of the bones without

symptoms, but with risk of fractures.

Increased calcium and phosphorous excretion in the urine may cause kidney stones. Patients with

hyperparathyroidism may be more likely to develop peptic ulcers, high blood pressure, and pancreatitis.

How Is Hyperparathyroidism Diagnosed?

Hyperparathyroidism 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.

A blood test that accurately measures the amount of PTH has simplified the diagnosis of


How Is Hyperparathyroidism Diagnosed?

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

bone density 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.

How Is Hyperparathyroidism Treated?

Surgery to remove the enlarged gland(s) is the only treatment for the disorder and cures it in 95 % 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 calcium is only slightly elevated, and whose kidneys and bones are

normal, may wish to talk to their doctor about long-term monitoring.

How Is Hyperparathyroidism Treated?

In the panel's recommendation, monitoring would consist of clinical evaluation and measurement of calcium levels and kidney

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 drink lots of water, 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.

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.

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 95 % when performed by experienced surgeons.

Localization tests are useful in patients having a second operation for recurrent or persistent


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".

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.

Inadequate production of parathyroid hormone –

hypoparathyroidism - 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 hypocalcemia 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.

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.

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 PTHRP had many

activities not seen with PTH.

Hormone Structures, Receptors and SourcesPTHrP 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

alternative splicing 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.

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 nuclear function.


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.


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.

Physiologic Effects of Parathyroid Hormone-Related Protein

One thing to recognize about PTHrP is that its name is inadequate to describe its activities.

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 calcium homeostasis.

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.


. Much of our understanding of the biologic effects of PTHrP comes from experiments with transgenic mice.

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


Cartilage and Bone Development: 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.


. 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.


Smooth Muscle Functioning: 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.


Other Effects: 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.

Health & Medicine

Functional Anatomy of the Thyroid and Parathyroid Glands