PARTHYROID

HORMONE & Vit. D

Dr. Hina Sadaf
Assistant Professor Physiology
 Learning Objectives
At the end of lecture, students should be able to:
• Describe mechanism of formation of Parathyroid Hormone
• Discuss the stimulus for PTH secretion.
• Explain the types of receptors present on Parathyroid gland
for detection of Ca concentration.
• Understand the target organs for PTH & its physiological
effects
• Discuss the regulation of PTH.
 Physiologic Anatomy of the Parathyroid Glands
• Normally there are four parathyroid glands in humans;
• they are located immediately behind the thyroid gland-one
behind each of the upper and each of the lower poles of
the thyroid.
• Each parathyroid gland is about 6 millimeters long, 3
millimeters wide, and 2 millimeters thick and has a
macroscopic appearance of dark brown fat.
• The parathyroid glands are difficult to locate during
thyroid operations because they often look like just
another lobule of the thyroid gland.
• For this reason, before the importance of these glands
was generally recognized, total or subtotal thyroidectomy
frequently resulted in removal of the parathyroid glands as
well.
 Physiologic Anatomy of the Parathyroid Glands
• The parathyroid gland of the adult human
being, contains mainly:
• chief cells and
• oxyphil cells.
The chief cells are believed to secrete most
of the PTH.
• The function of the oxyphil cells is not
certain, but the cells are believed to be
modified or depleted chief cells that no
longer secrete hormone
 Synthesis of PTH
• PTH has been isolated in a pure form.
• It is first synthesized on the ribosomes in the form of a preprohormone,
a polypeptide chain of 110 amino acids.
• This is cleaved first to a prohormone with 90 amino acids,
• then to the hormone itself with 84 amino acids by the endoplasmic
reticulum and Golgi apparatus, and finally packaged in secretory
granules in the cytoplasm of the cells.
• The final hormone has a molecular weight of about 9500. Smaller
compounds with as few as 34 amino acids adjacent to the N terminus of
the molecule have also been isolated from the parathyroid glands that
exhibit full PTH activity.
STIMULUS FOR SECRETION of PTH

• When ever plasma Ca concentration decreases in

ECF , it is sensed out by the receptors present on
Parathyroid hormone & within short time it
increases the Ca concentration in ECF.
 Parathyroid Hormone Increases Calcium
and Phosphate Absorption from the Bone
• PTH has two effects on bone in causing absorption of calcium and phosphate.
• One is a rapid phase that begins in minutes and increases progressively for several
hours.
• This phase results from activation of the already existing bone cells (mainly the
osteocytes) to promote calcium and phosphate absorption.
• The second phase is a much slower one, requiring several days or even weeks to
become fully developed; it results from proliferation of the osteoclasts, followed by
greatly increased osteoclastic reabsorption of the bone itself, not merely absorption
of the calcium phosphate salts from the
 Rapid Phase of Calcium and Phosphate
Absorption from Bone-Osteolysis
• Histological and physiological studies have shown that PTH causes
removal of bone salts from two areas in the bone:
• (1) from the bone matrix in the vicinity of the osteocytes lying within the
bone itself and
• (2) in the vicinity of the osteoblasts along the bone surface
 Rapid Phase of Calcium and Phosphate
Absorption from Bone-Osteolysis
• Studies have shown that the osteoblasts and osteocytes form a system of
interconnected cells that spreads all through the bone and over all the bone
surfaces except the small surface areas adjacent to the osteoclasts .
• In fact, long, filmy processes extend from osteocyte to osteocyte
throughout the bone structure, and these processes also connect with the
surface osteocytes and osteoblasts. This extensive system is called the
osteocytic membrane system, and it is believed to provide a membrane
that separates the bone itself from the extracellular fluid.
 Rapid Phase of Calcium and Phosphate Absorption
from Bone-Osteolysis
• Between the osteocytic membrane and the bone is a small amount of bone fluid.
• Experiments suggest that the osteocytic membrane pumps calcium ions from the
bone fluid into the extracellular fluid, creating a calcium ion concentration in the
bone fluid only one-third that in the extracellular fluid.
• When the osteocytic pump becomes excessively activated, the bone fluid calcium
concentration falls even lower, and calcium phosphate salts are then absorbed from
the bone.
• This effect is called osteolysis, and it occurs without absorption of the bone's
fibrous and gel matrix. When the pump is inactivated, the bone fluid calcium
concentration rises to a higher level and calcium phosphate salts are redeposited in
the
 Rapid Phase of Calcium and Phosphate Absorption from
Bone-Osteolysis
• the cell membranes of both the osteoblasts and the osteocytes have receptor
proteins for binding PTH.
• PTH can activate the calcium pump strongly, thereby causing rapid removal of
calcium phosphate salts from those amorphous bone crystals that lie near the cells.
• PTH is believed to stimulate this pump by increasing the calcium permeability of
the bone fluid side of the osteocytic membrane, thus allowing calcium ions to
diffuse into the membrane cells from the bone fluid.
• Then the calcium pump on the other side of the cell membrane transfers the
calcium ions the rest of the way into the extracellular fluid.
 Slow Phase of Bone Absorption and Calcium
Phosphate Release-Activation of the Osteoclasts
• A much better known effect of PTH and one for which the
evidence is much clearer is its activation of the osteoclasts.
• Yet the osteoclasts do not themselves have membrane receptor
proteins for PTH.
• Instead, it is believed that the activated osteoblasts and
osteocytes send secondary "signals" to the osteoclasts.
• major secondary signal is osteoprotegerin ligand,
• which activates receptors on preosteoclast cells and transforms
them into mature osteoclasts that cause demineralization of bone
 Slow Phase of Bone Absorption and Calcium
Phosphate Release-Activation of the Osteoclasts
• After a few months of excess PTH, osteoclastic resorption of
bone can lead to weakened bones and secondary stimulation
of the osteoblasts that attempt to correct the weakened state.
• Therefore, the late effect is actually to enhance both
osteoblastic and osteoclastic activity.
• Still, even in the late stages, there is more bone absorption
than bone deposition in the presence of continued excess
PTH
 Slow Phase of Bone Absorption and Calcium
Phosphate Release-Activation of the Osteoclasts
• Bone contains such great amounts of calcium in comparison
with the total amount in all the extracellular fluids (about
1000 times as much) that even when PTH causes a great rise
in calcium concentration in the fluids, it is impossible to
discern any immediate effect on the bones.
• Prolonged administration or secretion of PTH-over a period
of many months or years-finally results in very evident
absorption in all the bones and even development of large
cavities filled with large, multinucleated osteoclasts.
 Parathyroid Hormone Decreases Calcium Excretion
and Increases Phosphate Excretion by the Kidneys
• Administration of PTH causes rapid loss of phosphate in the
urine owing to the effect of the hormone to diminish proximal
tubular reabsorption of phosphate ions. PTH also increases
renal tubular reabsorption of calcium at the same time that it
diminishes phosphate reabsorption.
• The increased calcium absorption occurs mainly in the late
distal tubules, the collecting tubules, the early collecting ducts.
• By opening up of Calcium Channels on luminal membrane &
on basilar membrane by secondary active transport of Ca by Na
Ca exchange mechanism.
 Parathyroid Hormone Increases Intestinal
Absorption of Calcium and Phosphate
• PTH greatly enhances both calcium and phosphate absorption from the
intestines by increasing the formation in the kidneys of 1,25-
dihydroxycholecalciferol from vitamin D
 Vitamin D
• Vitamin D has a potent effect to increase calcium
absorption from the intestinal tract;
• it also has important effects on bone deposition and bone
absorption, as discussed later. However, vitamin D itself
is not the active substance that actually causes these
effects.
• Instead, vitamin D must first be converted through a
succession of reactions in the liver and the kidneys to the
final active product, 1,25-dihydroxycholecalciferol, also
called 1,25(OH)2D3.
 Cholecalciferol (Vitamin D3) Is Formed in the
Skin
• Several compounds derived from sterols
belong to the vitamin D family, and they all
perform more or less the same functions.
• Vitamin D3 (also called cholecalciferol) is the
most important of these and is formed in the
skin as a result of irradiation of 7-
dehydrocholesterol, a substance normally in
the skin, by ultraviolet rays from the sun.
• Consequently, appropriate exposure to the sun
prevents vitamin D deficiency. The additional
vitamin D compounds that we ingest in food
are identical to the cholecalciferol formed in
the skin.
 Storage of Vit. D
• This controlled conversion of vitamin D3 to 25-hydroxycholecalciferol
conserves the vitamin D stored in the liver for future use.
• Once it is converted, it persists in the body for only a few weeks, whereas
in the vitamin D form, it can be stored in the liver for many months
 Formation of 1,25-Dihydroxycholecalciferol in the
Kidneys and Its Control by Parathyroid Hormone

• In the proximal tubules of the kidneys of 25-

hydroxycholecalciferol to 1,25-dihydroxycholecalciferol.
• This latter substance is by far the most active form of
vitamin D
• Therefore, in the absence of the kidneys, vitamin D loses
almost all its effectiveness
 Formation of 1,25-Dihydroxycholecalciferol in the
Kidneys and Its Control by Parathyroid Hormone

• The conversion of 25-hydroxycholecalciferol to 1,25-

dihydroxycholecalciferol requires PTH.
• In the absence of PTH, almost none of the 1,25-
dihydroxycholecalciferol is formed.
• Therefore, PTH exerts a potent influence in determining the
functional effects of vitamin
 Actions of Vitamin D
• The active form of vitamin D, 1,25-dihydroxycholecalciferol, has several
effects on the intestines, kidneys, and bones that increase absorption of
calcium and phosphate into the extracellular fluid and contribute to
feedback regulation of these substances.
 Vit. D receptors
• Vitamin D receptors are present in most cells in the body and are located
mainly in the nuclei of target cells.
• Similar to receptors for steroids and thyroid hormone, 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, and this complex binds to DNA and
activates transcription in most instances. In some cases, however, vitamin
D suppresses transcription. Although 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.
 "Hormonal" Effect of Vitamin D to Promote
Intestinal Calcium Absorption
• 1,25-Dihydroxycholecal-ciferol itself functions as a type of "hormone" to promote
intestinal absorption of calcium.
• It does this principally by increasing, over a period of about 2 days, formation of
calbindin, a calcium-binding protein, in the intestinal epithelial cells.
• This protein functions in the brush border of these cells to transport calcium into the
cell cytoplasm.
• Then the calcium moves through the basolateral membrane of the cell by facilitated
diffusion.
• The rate of calcium absorption is directly proportional to the quantity of this
calcium-binding protein. Furthermore, this protein remains in the cells for several
weeks after the 1,25-dihydroxycholecalciferol has been removed from the body, thus
causing a prolonged effect on calcium absorption.
 Other effects of Vitamin D

• Other effects of 1,25-dihydroxycholecalciferol that

might play a role in promoting calcium absorption are
the formation of
• (1) a calcium-stimulated ATPase in the brush border of
the epithelial cells and
• (2) an alkaline phosphatase in the epithelial cells.
 Vitamin D Promotes Phosphate
Absorption by the Intestines
• Although phosphate is usually absorbed easily, phosphate flux
through the gastrointestinal epithelium is enhanced by vitamin
D.
• It is believed that this results from a direct effect of 1,25-
dihydroxycholecalciferol, but it is possible that it results
secondarily from this hormone's action on calcium absorption.
 Vitamin D Decreases Renal Calcium and
Phosphate Excretion
• Vitamin D also increases calcium and phosphate
reabsorption by the epithelial cells of the renal tubules,
thereby tending to decrease excretion of these substances in
the urine.
• However, this is a weak effect and probably not of major
importance in regulating the extracellular fluid
concentration of these substances
 Effect of Vitamin D on Bone and Its Relation to
Parathyroid Hormone Activity
• Vitamin D plays important roles in both bone absorption and bone
deposition.
• The administration of extreme quantities of vitamin D causes
absorption of bone. In the absence of vitamin D, the effect of PTH
in causing bone absorption is greatly reduced or even prevented.
• The mechanism of this action of vitamin D is not known, but it is
believed to result from the effect of 1,25-dihydroxycholecalciferol
to increase calcium transport through cellular membranes.
 Cyclic Adenosine Monophosphate Mediates the
Effects of Parathyroid Hormone
• A large share of the effect of PTH on its target organs is mediated by
the cyclic adenosine monophosphate (cAMP) second messenger
mechanism.
• Within a few minutes after PTH administration, the concentration of
cAMP increases in the osteocytes, osteoclasts, and other target cells.
This cAMP in turn is probably responsible for such functions as
osteoclastic secretion of enzymes and acids to cause bone reabsorption
and formation of 1,25-dihydroxycholecalciferol in the kidneys.
• Other direct effects of PTH probably function independently of the
second messenger mechanism
 Control of Parathyroid Secretion by Calcium
Ion Concentration
• Even the slightest decrease in calcium ion concentration in the extracellular fluid
causes the parathyroid glands to increase their rate of secretion within minutes; if
the decreased calcium concentration persists, the glands will hypertrophy,
sometimes fivefold or more.
• For instance, the parathyroid glands become greatly enlarged
• in rickets, in which the level of calcium is usually depressed only a small
amount.
• They also become greatly enlarged in pregnancy, even though the decrease in
calcium ion concentration in the mother's extracellular fluid is hardly measurable,
• and they are greatly enlarged during lactation because calcium is used for milk
 Control of Parathyroid Secretion by
Calcium Ion Concentration
• conditions that increase the calcium ion concentration above
normal cause decreased activity and reduced size of the
parathyroid glands. Such conditions include
• (1) excess quantities of calcium in the diet,
• (2) increased vitamin D in the diet, and
• (3) bone absorption caused by factors other than PTH (e.g.,
bone absorption caused by disuse of the bones
 Mechanism of action for secretion of PTH
• Changes in extracellular fluid calcium ion concentration are detected by a
calcium-sensing receptor (CaSR) in parathyroid cell membranes. The
CaSR is a G protein-coupled receptor that, when stimulated by calcium
ions, activates phospholipase C and increases intracellular inositol 1,4,5-
triphosphate and diacylglycerol formation.
• This stimulates release of calcium from intracellular stores, which, in
turn, decreases PTH secretion.
• Conversely, decreased extracellular fluid calcium ion concentration
inhibits these pathways and stimulates PTH secretion.
• This contrasts with many endocrine tissues in which hormone secretion is
stimulated when these pathways are activated.