PARATHYROID GLANDS

DR Lubna kamil
Reference :endocrie physiology
4th edition. internet
 Anatomy
 Parathyroids are two paired of pea_sized glands located at the top
and bottom posterior borders of the lat. Lobe of the thyroid glands
 The glands are richly vascularized and consist primarly of The chief cells
 The chief cells synthesize and secrete PTH; a polypeptide hormone that
plays a major role in bone remodeling and calcium homeostasis.
 In addition to its central role in the regulation of Ca 2levels and
 bone mass, PTH participates in the renal excretion of phosphate and in the
activation of vitamin D.
Parathyroid hormone biosynthesis
and transport
 PTH is synthesized as a prepropeptide that is rapidly
cleaved to pro-PTH 90-amino-acid and subsequently
the mature form of PTH. Mature and intact PTH consists
of 84 amino acids.
 PTH is degraded by the kidney and the liver to amino-
terminal (PTH 1-34) and carboxy-terminal fragments.
 The amino-terminal fragments constitute approximately
10% of circulating PTH fragments.They are biologically
active but have a short half-life (4–20 minutes).
 the carboxy-terminal fragments, which constitute 80%
of the circulating PTH fragments, have no biologic
activity and have a longer half-life; they are therefore
easier to measure in the plasma.
Regulation of PTH release
 The release of PTH is controlled in a tight feedback
system by plasma Ca 2+concentrations. High calcium
suppresses PTH secretion and low calcium stimulates
hormone release.
 Secretion mainly controlled by ionized calcium levels via
calcium sensing receptors ( CaSR)
 CaSR G protein coupled receptors(Gq/11and Gi) present
on the chief cells its also found in kidney tubules cell and
thyroid c cells
 Activation of the Ca 2+ receptor initiates a signaling
cascade involving phospholipases C, D, and A 2 .The
phosphorylation and activation of phospholipase A 2
activate the arachidonic acid cascade and increase
leukotriene synthesis. The active leukotriene metabolites
During hypocalcemia, the parathyroid Ca 2+ receptor is relaxed, and
PTHsecretion is not restrained. The rapid secretion of preformed PTH
elicited by acute hypocalcemia is rapidly followed by increased stability
of PTH mRNA and the synthesis of new hormone.
 PTH secretion is also controlled by catecholamine levels,
magnesium levels
 In addition the active form of vitamin D [1,25(OH) 2 D] also
contributes to modulation of PTH levels by reducing PTH
gene transcription. Phosphate levels also modulate PTH
release by decreasing phospholipase A2 activity and
arachidonic acid formation,
PARATHYROID HORMONE
TARGET ORGANS
 PTH functions to regulate calcium levels via its actions
on three target organs, the bone, kidney, and gut
 The main physiologic response elicited by PTH is to
plasma Ca2+ level
 increasing Ca2+ renal reabsorption,Ca2+ mobilization
from bone, and intestinal absorption (indirectly via
vitamin D 3 activation).PTH also increases 1α-
hydroxylase activity and renal phosphate excretion
 the effects of PTH are mediated by binding to a cell
membrane receptor in target organs. Three types of PTH
receptors have been identifed (PTHR1, PTHR2, PTHR3)
 All of which are G_protein_coupled receptor the most
important one is PTHR1
 PTH receptor 1
 PTHR1 is expressed in bone osteoblasts and kidney, where it binds
PTH and PTH-related protein (PTHrP). PTHrP differs from PTH in
structure,sharing only 13 amino acids with the amino-terminal of
the hormone. PTHrP is important because it mimics the physiologic
effects of PTH in the bone and kidney.
 PTH bind to Gprotien coupled receptor (PTHR1) leading to
synthesis of 3,5 cAMP and activation of protein kinase A and
phosphorylation of target protein The result is the activation of
preformed proteins, aswell as the induction of gene transcription.
 activation of the PTHR1 can use additional signaling pathways
through Gαq leading to the activation of phospholipase C,
increased intracellular inositol 1, 4, 5-trisphosphate and calcium
Cellular effect of PTH (PTH effect on
renal Ca2+ reabsorbtion
 The transcellular reabsorption of Ca2+ by the distal tubule is
regulated by PTH, 1,25(OH) 2 D, and calcitonin, and by
calcium-sparing drugs such as thiazide diuretics.
 PTH insertion of Ca2+ channels in the apical membrane and
facilitates the entry of Ca2+. Inside the cell, Ca2+ binds to
calbindin-D 28K , a vitamin D-dependent Ca2+ binding
protein that facilitates the cytosolic diff usion of Ca from the
2+

apical influx to the basolateral efflux sites.

(PTH) effects on renal inorganic phosphate
reabsorption.

 Renal reabsorption of Phosphate occur through Na+ /Pi

cotransporters
 3 different Na+ /Pi cotransporters ;l, ll, lll
 Type II cotransporters are expressed in the renal proximal
tubule (type IIa) Type IIa cotransporters are the major target
for PTH
 PTH acutely stimulates internalization of the type IIa
cotransporters, directing them to the lysosomes for
destruction.
PTH effects on bone

PTH binds to osteoblast parathyroid hormone receptor 1

(PTHR1), stimulating the cell surface expression of RANKL,
which binds
to RANK, a cell surface protein on osteoclast precursors.
Binding of RANKL to
RANK activates osteoclast gene transcription
Calcium homeostasis
 Normal plasma concentrations of Ca2+ range between
8.5 and 10.5 mg/dL and are mainly regulated by the
actions of PTH, vitamin D, and calcitonin on 3
tissues:bone, kidney, and intestine.
Actions Of PTH On Blood Calcium Level

Primary action of PTH is to maintain the blood

calcium level within the critical range of 9 to 11
mg/dL.
PTH maintains blood calcium level by:
1. Resorption of Ca from Bones
2. Reabsorption Ca from the renal tubules (Kidney)
3. Absorption of Ca from Gastrointestinal tract.
 ON THE BONE
 PTH enhances the resorption of calcium from the
bones by acting on osteoblasts and
osteoclasts of the bone.
 Immediately after reaching the bone, PTH gets
attached with the receptors on the cell membrane
of osteoblasts and osteocytes.
 The hormone-receptor complex increases the
permeability of membranes of these cells for
calcium ions.
 It accelerates the calcium pump mechanism, so
that calcium ions move out of these bone cells
and enter the blood at a faster rate.
 On Kidney
PTH increases the reabsorption of calcium from
the renal tubules along with magnesium ions an
hydrogen ions.
It increases calcium reabsorption mainly from
distal convoluted tubule and proximal part of
collecting duct.
PTH also increases the formation of 1,25- di-
hydroxycholecalciferol (activated form of
vitamin D) from 25-hydroxycholecalciferol in
kidneys.
 On Gastrointestinal Tract
PTH increases the absorption of calcium ions
from the GI tract indirectly.
It increases the formation of 1,25-
dihydroxycholecalciferol in the kidneys.
This vitamin, in turn increases the absorption of
calcium from GI tract.
Thus, the activated vitamin D is very essential
for the absorption of calcium from the GI tract &
PTH is essential for the formation of activated
vitamin D.
Role of PTH in the activation of
vitamin D
 Vitamin D is very essential for calcium absorption
from the GI tract.
 But vitamin D itself is not an active substance.
 Instead, vitamin D has to be converted into 1, 25-
dihydroxycholecalciferol in the liver and kidney in the
presence of PTH.
 There are various forms of vitamin D.
 But, the most important one is vitamin D3.
 It is also known as cholecalciferol.
 Vitamin D3 is synthesized in the skin from 7-
dehydrocholesterol, by the action of ultraviolet rays
from the sunlight.
 It is also obtained from dietary sources.
The activation of vitamin D3 occurs in
two steps:
 First step
Cholecalciferol (vitamin D3) is converted into
25-hydroxycholecalciferol in the liver
This process is limited and is inhibited by 25-
hydroxycholecalciferol itself by feedback
mechanism
 Second step
25-hydroxycholecalciferol is converted into
1,25- dihydroxycholecalciferol (calcitriol) in
kidney.
This step needs the presence of PTH
 Actions of 1, 25-
Dihydroxycholecalciferol
 It increases the absorption of calcium from the
intestine, by increasing the formation of calcium
binding proteins in the intestinal epithelial cells.
 These proteins act as carrier proteins for facilitated
diffusion, by which the calcium ions are transported.
 The proteins remain in the cells for several weeks
after 1,25-dihydroxycholecalciferol has been removed
from the body, thus causing a prolonged effect on
calcium absorption
It increases the synthesis of calcium-induced
ATPase in the intestinal epithelium
It increases the absorption of phosphate from
intestine along with calcium
 Calcitonin
Calcitonin, a peptide hormone secreted by the thyroid
gland, tends to decrease plasma Ca concentration and,
in general, has effects opposite to those of PTH
Parafollicular cells, or C cells, lying in the interstitial fluid
between the follicles of the thyroid gland
32-amino acid peptide with a molecular weight of about
3400
The primary stimulus for calcitonin secretion is increased
calcitonin decreases blood Ca ion concentration rapidly,
beginning within minutes after injection of the
calcitonin
 Calcitonin
1. The immediate effect is to decrease the absorptive activities
of the osteoclasts and possibly the osteolytic effect of the
osteocytic membrane throughout the bone
Shifting the balance in favor of deposition of calcium in the
exchangeable bone calcium salts - especially significant in young
because of the rapid interchange of absorbed and deposited Ca
2. The second and more prolonged effect of calcitonin is to
decrease the formation of new osteoclasts. Also, because
osteoclastic resorption of bone leads secondarily to osteoblastic
activity - decreased numbers of osteoblasts
the effect on plasma calcium is mainly a transient one, lasting
for a few hours to a few days at most
 Calcitonin
 Calcitonin Has a Weak Effect on Plasma
Calcium Concentration
 in the Adult Human
 Calcitonin - ↓ Ca - ↑ PTH
 Thyroid removed – no calcitonin – no effect
 The effect of calcitonin in children is much
greater because bone remodeling occurs
rapidly in children, with absorption and
deposition of calcium as great as 5 grams or
more per day
Disease of parathyroid hormone
production
 Primary hyperparathyroidism
 Secondary hyperparathrodism
 Hypoparathyroidism
 Pseudohypoparathyroidism
Thank you