1. Parathyroid hormone(Parathormone) Lecture NO: 2nd MBBS
Dr Muhammad Ramzan

2. Parathyroid hormone (PTH) – the definition
A protein hormone from the Parathyroid gland that regulates the metabolism of :
Calcium and phosphorus ions in the body
It is also called as Parathormone (PTH)

3. Parathyroid Glands – the source of Parathormone

4. Parathormone (PTH) – the background ↑ Ca and↓PO4 ions
Parathormone is a protein hormone secreted by the Chief cells of the Parathyroid gland – 84 AAs
It is one of the major hormones regulating the serum and extracellular concentration of :
Calcium and Phosphate Ions and
Activation of Vitamin D in kidneys

5. PTH – the target organs - 3 Bone, kidney and Intestine
10/23/2017
PTH – the target organs - 3 Bone, kidney and Intestine
Target organs are the ones with PTH receptors and include bones, Kidneys and Intestine
These are Osteocytes, Osteoblasts and Renal tubules
No receptors for Intestinal mucosa and Osteoclasts
PTH acts via Osteoblasts, Osteocytes and activated Vitamin D in Kidney to ↑Ca++ absorption from GIT

6. Biosynthesis of PTH – As Pre Prohormone from RER to Golgi
10/23/2017
Biosynthesis of PTH – As Pre Prohormone from RER to Golgi
PTH is synthesized as a Pre Prohormone in the RER of the Chief cells with115 AAs
Pre-Pro PTH is cleaved by signal peptidase to remove 25 AAs and is converted to Pro- PTH
Pro – PTH = 90 amino acids

7. Pro - PTH is transferred to Golgi 6 AAs are removed
10/23/2017
Pro - PTH is transferred to Golgi 6 AAs are removed
Pro - PTH is transferred to the Golgi Complex and 6 AAs are removed by Clipase for PTH = 84 AAs
PTH is packed and stored as secretary vesicles in Chief cells
Hormone Is released to the circulation in response to a proper physiological stimulus like:
Low Ca++ level in serum and ECF

8. Biosynthesis of PTH

9. Regulation of PTH – 2 pathways
10/23/2017
Regulation of PTH – 2 pathways
PTH is regulated through negative feed back mechanism
Regulation is through 2 pathways
Direct and
Indirect pathway

10. Regulation of PTH – Direct pathway No role of Calcitonin
It is the interaction between Ca++ level and PTH secretion
Low serum calcium ions level is sensed by the Calcium sensory receptors of the Chief cells
It ↑ the transcription of mRNA, release of PTH from the Chief cells that ↑ Ca++ level
It is achieved by acting on target organs (bone and Kidneys)
There is no role of Calcitonin

11. Regulation of PTH – Direct pathway

12. PTH Regulation – Indirect pathway ↑ Ca,PTH and Calcitonin
It is interaction B/w high serum Ca++ ,PTH and Calcitonin
High serum Ca++ Induces the following changes
↓Transcription of mRNA for PTH (synthesis)
Auto degradation of the preformed secretary granules that ↓ the release of PTH
Release of Calcitonin to ↓ the Calcium by  its renal excretion and bone resorption `

13. Homeostasis of blood calcium Role of Calcitonin and PTH

14. PTH - Mechanism of Action Activation of GPCR – PTHR1
PTH is a peptide hormone and its action is like the similar ones
PTH binds to the Extracellular domain of the PTHR1 on the membranes of bones and kidneys.
This binding produces conformal changes in the receptor
It activates the intracellular α - subunit of the G protein to produce α – GTP in exchange for α- GDP

15. PTH - Mechanism of action ( PTHR1) activation of adnylate cyclase
10/23/2017
PTH - Mechanism of action ( PTHR1) activation of adnylate cyclase
α- GTP activates the membranous Adenylate Cyclase of the target cells that Acts on the Cytoplasmic ATP :
to form c AMP – the 2nd messenger
C AMP activates the Protein kinas A, that Phosphorylates the specific intracellular enzymes/ proteins
to execute the hormonal effects - ↑in serum Ca++

16. Mechanism of Action of PTH – PTHR1

17. PTH – Alternate mechanism activation of Phospholipase C
An alternate mechanism of action is that :
Activated G- Protein also stimulates the membranous Phospholipase C that converts the :
Membranous Phospholipid PIP2 into IP3 and DAG as 2nd messengers that act on the bone, kidneys and intestine :
To ↑ serum and extracellular Ca++

18. PTH mechanism of action – Dual pathways

19. Metabolic actions of PTH
PTH acts to maintain the serum level of Ca++ B/ W mg/dl and Po4 B/W mg/dl
As well as extracellular Ca++ and Po4 ions
PTH has metabolic actions on :
Bones, Kidneys and Intestine

20. Metabolic role of PTH – the target organs

21. PTH - Metabolic actions on bone
10/23/2017
PTH - Metabolic actions on bone
Bone is a large reservoir of Calcium
PTH enhances the release of Ca and Po4 from the bone by Osteolysis via osteoclasts - a normal process
Osteolysis is also supported by the membranous Ca++ pump and elevated Phosphatases around osteoclasts
Membranous Ca++ pump is activated by PTH

22. Activated Osteoclasts

23. PTH and bone – Role of membranous Ca++ pump
Osteoclasts has no PTH receptors
Act through Osteoblasts and Osteocytes with PTH R1 and
membranous calcium pump
Membranous calcium pump in these bone cells is activated by PTH

24. Membranous Calcium pump – How it works
10/23/2017
Membranous Calcium pump – How it works
Calcium pump causes rapid removal of calcium phosphates from the sites near these cells
Calcium phosphate salts are transported to the extra cellular fluid by :
altering the permeability of Osteocytes to calcium

25. Metabolic action on Kidneys ↑ Cal. Resorption and Po4 e xcretion
PTH ↑ the renal excretion of Phosphates to decrease its plasma concentration and
Enhances the active resorption of Ca and Mg from the distal tubules and ascending loop of Henley 2
This increases Calcium phosphate ratio (3:11) and more free Ca++ions in circulation

26. Metabolic actions on Kidneys cont. Activation of Vit.D for GIT
PTH ↑ the activation of Vitamin D to 1-25 Dehydroxy Cholecalceferol in kidneys (1st hydroxylation in liver 2nd kidneys)
Vita. D promotes calcium absorption from Intestinal mucosa
Intestinal absorption is facilitated by Calbindin (Ca binding protein)
No PTH receptors on Intestinal mucosa
There is no significant effect on Po4 absorption by intestine

27. PTH - secretion abnormalities
Parathormone may be secreted in excess or
there may be deficiency in secretion
Both abnormalities lead to significant clinical conditions

28. PTH excess - hyperparathyroidism
Excess of PTH, increases bone resorption or Osteolysis
2 types of hyperparathyroidism:
Primary and secondary, resulting in:
Osteoporosis, pathological fractures and :
Defective bone formation including Cysts formation

29. PTH deficiency – Hypo para - thyroidism
It is the low level of PTH in blood, caused by inborn metabolism and autoimmune disorders
Hypo parathyroidism results in :
Reduction of Serum calcium
Defects in muscle contraction
Tetany

30. Parathormone
Calcitonin
Site of synthesis
RER of chief cell of parathyroid gland – A protein hormone
RER of Para follicular cells of thyroid gland – A protein hormone
Structure
A Prohormone with 115 AAs – processed in Golgi to 84 AAs
A Prohormone with 115 / 142 as processed in Golgi to 32 AAs.
Target organs
3 – bone, kidney and intestinal mucosa no receptors for Osteoclasts and intestinal mucosa
2 – bones and renal tubular cells – no receptors at Osteoclasts, but present at other bone cells and kidneys
Nature of Action
Increases the calcium from Low to High via osteoclastic activity
Decreases serum Ca level when high Via osteoblastic activity and inhibiting PTH
Regulation of secretion
Direct – interaction B/W low calcium and parathyroid gland
Indirect – interaction B/W high calcium PTH and Calcitonin
Direct – interaction B/W high serum and ECF and Calcitonin
Indirect – interaction B/W low Ca level and Calcitonin and PTH
Stimulates PTH secretion to increase Ca level in serum and ECF
Metabolic Actions
Via 2nd messenger (cAMP)
Maintains the serum concentration of Ca B/W 9.5 – 10.5mg /dl and PO 3.5 – 4.5 mg/dl
Maintains the Ca level in serum and ECF by reducing the Osteoclastic activity when high
Secretion Abnormalities
Excess – hyperparathyroidism osteoporosis, pathological fracture Deficiency low Ca level tetany and defects in muscle contraction
Not significant Excess or Deficiency – used in the treatment of post menopausal osteoporosis and malignancies