Parathyroid hormone

PTH
Available structures Gene ontology Molecular function transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding hormone activity parathyroid hormone receptor binding type 1 parathyroid hormone receptor binding protein N-terminus binding receptor ligand activity peptide hormone receptor binding DNA-binding transcription factor activity, RNA polymerase II-specific protein binding Cellular component intracellular anatomical structure extracellular region extracellular space Biological process positive regulation of signal transduction positive regulation of cell proliferation in bone marrow positive regulation of osteoclast proliferation response to fibroblast growth factor hormone-mediated apoptotic signaling pathway cAMP metabolic process response to ethanol response to parathyroid hormone skeletal system development positive regulation of ossification response to lead ion response to nutrient levels G protein-coupled receptor signaling pathway response to vitamin D negative regulation of apoptotic process in bone marrow cell negative regulation of transcription by RNA polymerase II cellular macromolecule biosynthetic process cellular calcium ion homeostasis homeostasis of number of cells within a tissue response to cadmium ion Rho protein signal transduction positive regulation of glucose import positive regulation of glycogen biosynthetic process bone resorption positive regulation of bone mineralization regulation of gene expression positive regulation of transcription by RNA polymerase II cell-cell signaling activation of phospholipase C activity negative regulation of chondrocyte differentiation positive regulation of inositol phosphate biosynthetic process negative regulation of bone mineralization involved in bone maturation regulation of signaling receptor activity adenylate cyclase-activating G protein-coupled receptor signaling pathway calcium ion transport magnesium ion homeostasis bone mineralization phosphate ion homeostasis calcium ion homeostasis negative regulation of calcium ion transport Sources:Amigo / QuickGO
Ensembl ENSG00000152266 ENSMUSG00000059077 UniProt P01270 Q9Z0L6 RefSeq (mRNA) NM_000315 NM_001316352 NM_020623 RefSeq (protein) NP_000306 NP_001303281 NP_065648 Location (UCSC) Chr 11: 13.49 – 13.5 Mb Chr 7: 112.98 – 112.99 Mb PubMed search [3] [4]
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Parathyroid hormone (PTH), also called parathormone or parathyrin, is a peptide

PTH influences

variations. PTH is "a key that unlocks the bank vault" to remove the calcium.

PTH is secreted primarily by the

.

There are two types of PTH receptors. Parathyroid hormone 1 receptors, activated by the 34 N-terminal amino acids of PTH, are present at high levels on the cells of bone and kidney. Parathyroid hormone 2 receptors are present at high levels on the cells of central nervous system, pancreas, testes, and placenta.^[7] The half-life of PTH is about 4 minutes.^[8]

Disorders that yield too little or too much PTH, such as

.

Structure

hPTH-(1-84) crystallizes as a slightly bent, long, helical dimer. The extended helical conformation of hPTH-(1-84) is the likely bioactive conformation.^[9] The N-terminal fragment 1-34 of parathyroid hormone (PTH) has been crystallized and the structure has been refined to 0.9 Å resolution.

Function

Regulation of serum calcium

thyroid gland when the plasma ionized calcium level is high or rising.
The diagram does not show the extremely small amounts of calcium that move into and out of the cells of the body, nor does it indicate the calcium that is bound to the extracellular proteins (in particular the plasma proteins) or to plasma phosphate.^{[11][12][13][14][15]}

Parathyroid hormone regulates

In bone, PTH enhances the release of calcium from the large reservoir contained in the bones.

In the kidney, around 250 mmol of calcium ions are filtered into the

Via the kidney, PTH enhances the absorption of calcium in the

.

PTH was one of the first hormones to be shown to use the G-protein adenylyl cyclase second messenger system.

Regulation of serum phosphate

PTH reduces the reabsorption of phosphate from the proximal tubule of the kidney,^[23] 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 result of PTH release is a small net drop in the serum concentration of phosphate.

Vitamin D synthesis

PTH upregulates the activity of

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.

Interactive pathway map

Regulation of PTH secretion

Secretion of parathyroid hormone is determined chiefly by

(DAG). Ultimately, these two messengers result in a release of calcium from intracellular stores into the cytoplasmic space. Hence a high extracellular calcium concentration leads to an increase in the cytoplasmic calcium concentration. In contrast to the mechanism that most secretory cells use, this high cytoplasmic calcium concentration inhibits the fusion of vesicles containing granules of preformed PTH with the membrane of the parathyroid cell, and thus inhibits release of PTH.

In the parathyroids, magnesium serves this role in stimulus-secretion coupling. A mild decrease in serum magnesium levels stimulates the reabsorptive activity PTH has on the kidneys. Severe

Stimulators

• Decreased serum [Ca²⁺].
• Mild decreases in serum [Mg²⁺].
• An increase in serum phosphate (increased phosphate causes it to complex with serum calcium, forming calcium phosphate, which reduces stimulation of Ca-sensitive receptors (CaSr) that do not sense calcium phosphate, triggering an increase in PTH).
• Adrenaline
• Histamine

Inhibitors

• Increased serum [Ca²⁺].
• Severe decreases in serum [Mg²⁺], which also produces symptoms of hypoparathyroidism (such as hypocalcemia).^[25]
• Calcitriol
• Increase in serum phosphate. Fibroblast growth factor-23 (FGF23) is produced in osteoblasts (from bone) in response to increases in serum phosphate (Pi). It binds to the fibroblast growth factor receptor of the parathyroid and suppresses PTH release. This may seem contradictory because PTH actually helps rid the blood of phosphates but it is also causes release of phosphate into the blood from bone resorption. FGF23 inhibits PTH and then takes its place helping inhibit re-absorption of phosphate in the kidney without the phosphate releasing effect on bones.^[26][27]

Disorders

Hyperparathyroidism, the presence of excessive amounts of parathyroid hormone in the blood, occurs in two very distinct sets of circumstances. Primary hyperparathyroidism is due to autonomous, abnormal hypersecretion of PTH from the parathyroid gland, while secondary hyperparathyroidism is an appropriately high PTH level seen as a physiological response to hypocalcemia. A low level of PTH in the blood is known as hypoparathyroidism and is most commonly due to damage to or removal of parathyroid glands during thyroid surgery.

There are a number of rare but well-described genetic conditions affecting parathyroid hormone metabolism, including pseudohypoparathyroidism, familial hypocalciuric hypercalcemia, and autosomal dominant hypercalciuric hypocalcemia. Of note, PTH is unchanged in pseudopseudohypoparathyroidism. In osteoporotic women, administration of an exogenous parathyroid hormone analogue (teriparatide, by daily injection) superimposed on estrogen therapy produced increases in bone mass and reduced vertebral and nonvertebral fractures by 45 to 65%.^[28]

Measurement

PTH can be measured in the blood in several different forms: intact PTH; N-terminal PTH; mid-molecule PTH, and C-terminal PTH, and different tests are used in different clinical situations. The level may be stated in pg/dL or pmol/L (sometimes abbreviated mmol/L); multiply by 0.1060 to convert from pg/dL to pmol/L.^[29]

A US source states the average PTH level to be 8–51 pg/mL.^[30] In the UK the biological reference range is considered to be 1.6-6.9 pmol/L.^[31] Normal total plasma calcium level ranges from 8.5 to 10.2 mg/dL (2.12 mmol/L to 2.55 mmol/L).^[32]

Interpretive guide

The intact PTH and calcium normal ranges are different for age; calcium is also different for sex.^[33][34]

Condition	Intact PTH	Calcium
Normal Parathyroid	Normal	Normal
Hypoparathyroidism	Low or Low Normal [note 1]	Low
Hyperparathyroidism
- Primary	High or Normal [note 1]	High
- Secondary	High	Normal or Low
- Tertiary[note 2]	High	High
Non-Parathyroid Hypercalcemia	Low or Low Normal [note 1]	High

Medical uses

Recombinant human parathyroid hormone

This section is an excerpt from Recombinant human parathyroid hormone.[edit]

vertebral fractures has been demonstrated.^[39] It is used in combination with calcium and vitamin D supplements.^[35][37]

The most common side effects include sensations of tingling, tickling, pricking, or burning of the skin (paraesthesia); low blood calcium; headache; high blood calcium; and nausea.[36]

Recombinant human parathyroid hormone (Preotact) was approved for medical use in the European Union in April 2006.^[39] Recombinant human parathyroid hormone (Natpara) was approved for medical use in the United States in January 2015, and in the European Union (as Natpar) in February 2017.^[37][40]

Teriparatide

This section is an excerpt from Teriparatide.[edit]

anabolic (promoting bone formation) agent^[42] used in the treatment of some forms of osteoporosis.^[41][43] Teriparatide is a recombinant human parathyroid hormone analog (PTH 1-34).^[41] It has an identical sequence to the 34 N-terminal amino acids of the 84-amino acid human parathyroid hormone.^[41]

See also

• Disorders of calcium metabolism
• Parathyroid hormone family
• Parathyroid hormone-related protein

Footnote

1. Renal stones are, therefore, often a first indication of hyperparathyroidism, especially since the hypercalcuria is accompanied by an increase in urinary phosphate excretion (a direct result of the high plasma PTH levels). Together the calcium and phosphate tend to precipitate out as water-insoluble salts, which readily form solid "stones".^[11][18][19]

References

1. ^ ^{a b c} GRCh38: Ensembl release 89: ENSG00000152266 – Ensembl, May 2017
2. ^ ^{a b c} GRCm38: Ensembl release 89: ENSMUSG00000059077 – Ensembl, May 2017
3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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19. ^ "Symptoms of Hyperparathyroidism and Symptoms of Parathyroid Disease". Parathyroid.com. Norman Parathyroid Center. Retrieved 30 December 2015.
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29. ^ "Parathyroid hormone (PTH) unit conversion (online calculator)". Unitslab.
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31. ^ "Division of Laboratory Medicine: Parathyroid hormone" (PDF). Manchester University NHS Foundation Trust (UK). Archived from the original (PDF) on 2 February 2023. Retrieved 23 April 2022.
32. ^ Zieve D. "MedlinePlus Medical Encyclopedia: Serum calcium". National Library of Medicine, National Institutes of Health. Retrieved 1 February 2009.
33. ^ PTH, Intact and Calcium Test Detail. Quest Diagnostics Lab. Accessed 2019-06-29.
34. LabCorp
    . Accessed 2019-07-02.
35. ^ ^{a b} "Natpara (parathyroid hormone)- parathyroid hormone injection, powder, lyophilized, for solution". DailyMed. Retrieved 8 May 2021.
36. ^ ^{a b} "FDA approves Natpara to control low blood calcium levels in patients with hypoparathyroidism". U.S. Food and Drug Administration (FDA) (Press release). Archived from the original on 30 January 2015. Retrieved 30 January 2015. This article incorporates text from this source, which is in the public domain.
37. ^ ^{a b c} "Natpar EPAR". European Medicines Agency. 18 December 2013. Retrieved 28 December 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
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39. ^ ^{a b c} "Preotact EPAR". European Medicines Agency. 17 September 2018. Retrieved 3 July 2020.
40. ^ "First hormone replacement therapy for parathyroid disorder". European Medicines Agency (EMA) (Press release). 24 February 2017. Retrieved 29 December 2023.
41. ^ ^{a b c d} "Forteo- teriparatide injection, solution". DailyMed. 29 April 2021. Archived from the original on 19 January 2022. Retrieved 8 March 2023.
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Further reading

• Drüeke TB, Massy ZA (2003). "Advanced oxidation protein products, parathyroid hormone and vascular calcification in uremia". Blood Purification. 20 (5): 494–7.
  S2CID 46752152
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• Parfitt AM (October 2002). "Parathyroid hormone and periosteal bone expansion". Journal of Bone and Mineral Research. 17 (10): 1741–3.
  S2CID 37111637
  .
• Martin TJ (March 2004). "Does bone reabsorption inhibition affect the anabolic response to parathyroid hormone?". Trends in Endocrinology and Metabolism. 15 (2): 49–50.
  S2CID 35482527
  .
• Keutmann HT, Sauer MM, Hendy GN, O'Riordan LH, Potts JT (December 1978). "Complete amino acid sequence of human parathyroid hormone". Biochemistry. 17 (26): 5723–9.
  PMID 728431
  .
• Keutmann HT, Niall HD, O'Riordan JL, Potts JT (May 1975). "A reinvestigation of the amino-terminal sequence of human parathyroid hormone". Biochemistry. 14 (9): 1842–7.
  PMID 1125201
  .
• Parkinson DB, Thakker RV (May 1992). "A donor splice site mutation in the parathyroid hormone gene is associated with autosomal recessive hypoparathyroidism". Nature Genetics. 1 (2): 149–52.
  S2CID 24032313
  .
• Handt O, Reis A, Schmidtke J (November 1992). "Ectopic transcription of the parathyroid hormone gene in lymphocytes, lymphoblastoid cells and tumour tissue". The Journal of Endocrinology. 135 (2): 249–56.
  PMID 1474331
  .
• Tonoki H, Narahara K, Matsumoto T, Niikawa N (1991). "Regional mapping of the parathyroid hormone gene (PTH) by cytogenetic and molecular studies". Cytogenetics and Cell Genetics. 56 (2): 103–4.
  PMID 1672845
  .
• Marx UC, Adermann K, Bayer P, Meyer M, Forssmann WG, Rösch P (February 1998). "Structure-activity relation of NH2-terminal human parathyroid hormone fragments". The Journal of Biological Chemistry. 273 (8): 4308–16.
  S2CID 1009667
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• Arnold A, Horst SA, Gardella TJ, Baba H, Levine MA, Kronenberg HM (October 1990). "Mutation of the signal peptide-encoding region of the preproparathyroid hormone gene in familial isolated hypoparathyroidism". The Journal of Clinical Investigation. 86 (4): 1084–7.
  PMID 2212001
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• Nussbaum SR, Gaz RD, Arnold A (November 1990). "Hypercalcemia and ectopic secretion of parathyroid hormone by an ovarian carcinoma with rearrangement of the gene for parathyroid hormone". The New England Journal of Medicine. 323 (19): 1324–8.
  PMID 2215618
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• Ahn TG, Antonarakis SE, Kronenberg HM, Igarashi T, Levine MA (March 1986). "Familial isolated hypoparathyroidism: a molecular genetic analysis of 8 families with 23 affected persons". Medicine. 65 (2): 73–81.
  S2CID 25332134
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• Tregear GW, van Rietschoten J, Greene E, Niall HD, Keutmann HT, Parsons JA, et al. (April 1974). "Solid-phase synthesis of the biologically active N-terminal 1 - 34 peptide of human parathyroid hormone". Hoppe-Seyler's Zeitschrift für Physiologische Chemie. 355 (4): 415–21.
  S2CID 43509130
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• Niall HD, Sauer RT, Jacobs JW, Keutmann HT, Segre GV, O'Riordan JL, et al. (February 1974). "The amino-acid sequence of the amino-terminal 37 residues of human parathyroid hormone". Proceedings of the National Academy of Sciences of the United States of America. 71 (2): 384–8.
  PMID 4521809
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• Andreatta RH, Hartmann A, Jöhl A, Kamber B, Maier R, Riniker B, et al. (1973). "[Synthesis of sequence 1-34 of human parathyroid hormone]". Helvetica Chimica Acta. 56 (1): 470–3.
  PMID 4721748
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• Jacobs JW, Kemper B, Niall HD, Habener JF, Potts JT (May 1974). "Structural analysis of human proparathyroid hormone by a new microsequencing approach". Nature. 249 (453): 155–7.
  S2CID 4226663
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• Vasicek TJ, McDevitt BE, Freeman MW, Fennick BJ, Hendy GN, Potts JT, et al. (April 1983). "Nucleotide sequence of the human parathyroid hormone gene". Proceedings of the National Academy of Sciences of the United States of America. 80 (8): 2127–31.
  PMID 6220408
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• Mayer H, Breyel E, Bostock C, Schmidtke J (1983). "Assignment of the human parathyroid hormone gene to chromosome 11". Human Genetics. 64 (3): 283–5.
  S2CID 35197648
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• Hendy GN, Kronenberg HM, Potts JT, Rich A (December 1981). "Nucleotide sequence of cloned cDNAs encoding human preproparathyroid hormone". Proceedings of the National Academy of Sciences of the United States of America. 78 (12): 7365–9.
  PMID 6950381
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• Hendy GN, Bennett HP, Gibbs BF, Lazure C, Day R, Seidah NG (April 1995). "Proparathyroid hormone is preferentially cleaved to parathyroid hormone by the prohormone convertase furin. A mass spectrometric study". The Journal of Biological Chemistry. 270 (16): 9517–25.
  S2CID 10879253
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External links

• Media related to Parathyroid hormone at Wikimedia Commons
• Parathyroid hormone: analyte monograph - the Association for Clinical Biochemistry and Laboratory Medicine
• Overview of all the structural information available in the PDB for UniProt: P01270 (Parathyroid hormone) at the PDBe-KB.