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.

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.

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

_________________glands, each producing distinct hormones with specific

______________.

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 ________.

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.

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.

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.

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 _______.

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

_______.

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 _______.

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 _______.

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 ______.

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.

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.

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 ___________________

Extracellular Calcium-Sensing Receptor

Maintaining 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.

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.

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.

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.

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.

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.

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 _____.

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.

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.

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.

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.

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.

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.

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.

Endocrine Control of Calcium and Phosphate Homeostasis

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:

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 proteinBone 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.

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 _________.

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:

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 _______.

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.

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 ____________________________________

Structure and Synthesis-Vitamin DThe 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.

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-dihydroxycholecalciferol, the

biologically active form of vitamin D.

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.

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 ____ 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.

The Vitamin D Receptor and Mechanism of ActionThe 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-hydroxycholecalciferol, which explains their relative

biological potencies.

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.

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.

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.

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

_________________.

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.

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.

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.

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

_____________.