Parathyroid Hormone and Calcium Regulation

By: Abebe T.

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Learning objectives
• After learning this topic you will able to understand
• Parathyroid hormones and action of parathyroid Hormone in
homeostasis of calcium, vitamin D synthesis
• Signaling of parathyroid hormone and regulation of PTH secretion
• Disorder in secretion of parathyroid hormones :hyperparathyroidism
and hypoparathyroidism

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 Parathyroid Hormone
• Parathyroid hormone 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 PTH and has the same effects as PTH.

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 Parathyroid Hormone
• Like most other protein hormones, PTH is synthesized as a
preprohormone.
• After intracellular processing, the biologically active
hormone is packaged within the Golgi into secretory
vesicles, then secreted into blood by exocytosis.
• Parathyroid hormone is secreted as a linear protein of 84
amino acids .

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 Parathyroid Hormone
• PTH is synthesized and secreted by the parathyroid glands
which lie posterior to the thyroid glands.

• The blood supply to the parathyroid glands is from the thyroid

arteries.

• The Chief Cells in the parathyroid gland are the principal site of PTH
synthesis

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 Parathyroid Glands

Chief cells – produce PTH

Oxyphils – function unknown

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 Function of PTH: Regulation of serum calcium

The overall action of PTH is to increase plasma Ca++ levels and decrease
plasma phosphate levels.
PTH acts directly on the
bones to stimulate Ca++ resorption and
kidney to stimulate Ca++ reabsorption in the distal tubule of the kidney
and to inhibit reabsorption of phosphate (thereby stimulating its excretion).
PTH also acts indirectly on intestine by stimulating 1,25-(OH)2-D synthesis.

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 Calcium Homeostasis

• Normal plasma Ca2+ = 10 mg/dl, 5 meq/L = 2.5 mmol/L

• Plasma Ca2+ is existed in 3 forms
1. 40% in combination with –vely charged non-diffusible plasma proteins
2. 10% in combination with anions (citrate, phosphate)
3. 50% in the ionic, free diffusible anions form
Importance of Ca2+ in the body
-Muscle contraction - Blood clotting
-Bone and teeth formation -As a cofactor of enzyme activation
-Synaptic transmission
Hormones involved in calcium homeostasis
-PTH -1, 25 (OH) D3
-Calcitonin
Parathyroid glands Thyroid gland
-Chief cells
-Oxyphilic cells
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 Cont…
• In bone, PTH enhances the release of calcium from the large reservoir
contained in the bones.
• Bone resorption is the normal destruction of bone by osteoclasts, which are
indirectly stimulated by PTH.
• Stimulation is indirect since osteoclasts do not have a receptor for PTH
• Rather, PTH binds to osteoblasts, the cells responsible for creating bone.

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 kidney
• In the kidney, approximately 250 mmol of calcium ions are filtered into
the glomerular filtrate per day.
• Most of this (245 mmol/d) is reabsorbed from the tubular fluid, leaving about
5 mmol/d to be excreted in the urine.
• This reabsorption occurs throughout the tubule (most, 60-70%, of it in the proximal
tubule, except in the thin segment of the loop of Henle.
• Circulating parathyroid hormone only influences the reabsorption that occurs in
the distal tubules and the renal collecting ducts.
• A more important effect of PTH on the kidney is, however, its inhibition of the
reabsorption of phosphate (HPO42−) from the tubular fluid, resulting in a decrease in
the plasma phosphate concentration.
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 Cont…..
• Phosphate ions form water-insoluble salts with calcium.
• Thus, a decrease in the phosphate concentration of the blood plasma (for a
given total calcium concentration) increases the amount of calcium that is
ionized.
• A third important effect of PTH on the kidney is its stimulation of the
conversion of 25-hydroxy vitamin D into 1,25-dihydroxy vitamin D
(calcitriol), which is released into the circulation.
• This latter form of vitamin D is the active hormone which stimulates
calcium uptake from the intestine.

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Intestine
• PTH enhances the absorption of calcium in the intestine by increasing
the production of activated vitamin D.
• Vitamin D activation occurs in the kidney.
• PTH up-regulates 25-hydroxyvitamin D3 ,1-alpha-hydroxylase the
enzyme responsible for 1-alpha hydroxylation of 25-hydroxy vitamin
D, converting vitamin D to its active form (1,25-dihydroxy vitamin D).
• This activated form of vitamin D increases the absorption of calcium
(as Ca2+ ions) by the intestine via calbindin.

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Summary of Ca-homeostasis

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 Regulation of serum phosphate

• PTH reduces the reabsorption of phosphate from the proximal tubule of

the kidney, which means more phosphate is excreted through the urine.
• However, PTH enhances the uptake of phosphate from the intestine and bones into
the blood.
• In the bone, slightly more calcium than phosphate is released from the breakdown
of bone.
• In the intestines, absorption of both calcium and phosphate is mediated by an
increase in activated vitamin D.
• The absorption of phosphate is not as dependent on vitamin D as is that of calcium.
• The end result of PTH release is a small net drop in the serum concentration of
phosphate. 14
Effects of PTH on
Ca2+ and PO4-3

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Vitamin D synthesis

PTH increases the activity of 1-α-hydroxylase enzyme, which converts

25-hydroxycholecalciferol, the major circulating form of inactive
vitamin D, into 1,25-dihydroxycholecalciferol, the active form
of Vitamin D, in the kidney.

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 Regulation of Parathyroid Hormone
Secretion
• Secretion of PTH is inversely related to [Ca2+].
• Maximum secretion of PTH occurs at plasma ionized Ca2+ below 3.5
mg/dL.
• When it is above 5.5 mg/dL, PTH secretion is maximally inhibited.
• PTH secretion responds to small alterations in plasma Ca2+ within
seconds.
• A unique calcium sensing receptor (CaSR) within the parathyroid cell
plasma membrane detect changes in the ECF Ca2+ concentration.
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 Regulation of PTH

• When [Ca2+] is increased a typical G-protein coupled with Ca2+ receptor

that activates phospholipase C and inhibits adenylate cyclase
• increase in intracellular Ca2+ via generation of inositol phosphates and
• decrease in cAMP which prevents exocytosis of PTH from secretory
granules.

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 Regulation of PTH

• When [Ca2+] falls, cAMP rises and PTH is secreted.

• 1,25-(OH)2-D inhibits PTH gene expression, providing
another level of feedback control of PTH.
• Despite close connection between Ca2+ and PO4, no direct
control of PTH is exerted by phosphate levels.

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 Stimulators
• Decreased serum [Ca2+].
• Mild decreases in serum [Mg2+].
• An increase in serum phosphate
• Adrenaline
• Histamine

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Inhibitor
• Increased serum [Ca2+].
• Severe decreases in serum [Mg2+], which also produces symptoms
of hypoparathyroidism (such as hypocalcemia).
• Calcitriol

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 Disorder of PTH Secretion
Primary Hyperparathyroidism
• Hyperparathyroidism is inappropriate over activity of the parathyroid
glands resulting in excess parathyroid hormone (PTH) levels in the blood .
• The presence of excessive amounts of parathyroid hormone in the blood,
occurs in two very distinct sets of circumstances Hyperparathyroidism.
• Primary hyperparathyroidism is the result of parathyroid gland disease,
most commonly due to a parathyroid tumour (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.

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Cont…
• Secondary hyperparathyroidism occurs if the plasma ionized calcium
level does not respond to changes in PTH secretion from normal
glands.
• therefore remains abnormally low (hypocalcemia)
• parathyroid glands respond by secreting large quantities of PTH into
the blood i.e. secondary hyperparathyroidism

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 Cont…
• Hypercalcemia of Malignancy

• The Underlying cause is generally excessive bone resorption

by one of three mechanisms
i.-Increased 1,25-(OH)2-D synthesis by lymphomas
ii.-Local osteolytic hypercalcemia-20% of all hypercalcemia
of malignancy
iii-Over-expression of PTH-related protein (PTHrP)

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 PTH Receptor Defect

• It is rarely occurring disease known as Jansen’s metaphyseal

chondrodysplasia

• Characterized by hypercalcemia, hypophosphotemia, short-

limbed dwarfism
• It is caused due to activating mutation of PTH receptor

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 Hypoparathyroidism

• Hypoparathyroidism is decreased function of the parathyroid glands with

underproduction of parathyroid hormone
• typically results in decreased concentrations of calcium.

• Hypocalcemia is often multi-factorial though it is invariably

associated with hypoparathyroidism

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 Hypoparathyroidism

• 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.

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THANK YOU

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