Parathyroid hormone

Parathyroid hormone, also known as parathormone or parathyrin, is a peptide hormone secreted by the parathyroid glands. It plays a critical role in regulating serum calcium and phosphate levels through its actions on bone, kidneys, and the small intestine. PTH increases serum calcium levels and is opposed by calcitonin. It also promotes the synthesis of calcitriol, the active form of vitamin D.
PTH is secreted in response to low blood serum calcium levels and is a key regulator of bone remodeling, the continuous process of bone resorption and formation. PTH indirectly stimulates osteoclast activity, promoting the release of calcium from the bone matrix to restore serum calcium levels. The bones serve as a reservoir of calcium, releasing it as needed to maintain homeostasis in the face of fluctuating metabolism, stress, and nutritional status.
Produced primarily by the chief cells of the parathyroid glands, PTH is a polypeptide prohormone consisting of 84 amino acids and has a molecular mass of approximately 9500 Da. Its gene is located on chromosome 11 in humans.
PTH exerts its biological effects via two main receptors. The Parathyroid hormone 1 receptor, activated by the 34 N-terminal amino acids of PTH, is highly expressed in bone and kidney cells. The Parathyroid hormone 2 receptor is predominantly found in the central nervous system, pancreas, testes, and placenta. The hormone has a short half-life of approximately 4 minutes. Dysregulation of PTH secretion, as seen in conditions like hypoparathyroidism, hyperparathyroidism, and paraneoplastic syndromes, can result in bone disease, hypocalcemia, or hypercalcemia.

Structure

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

Function

Regulation of serum calcium

Parathyroid hormone regulates serum calcium through its effects on bone, kidney, and the intestine:
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. Binding stimulates osteoblasts to increase their expression of RANKL and inhibits their secretion of osteoprotegerin. Free OPG competitively binds to RANKL as a decoy receptor, preventing RANKL from interacting with RANK, a receptor for RANKL. The binding of RANKL to RANK stimulates osteoclast precursors, which are of a monocyte lineage, to fuse. The resulting multinucleated cells are osteoclasts, which ultimately mediate bone resorption. Estrogen also regulates this pathway through its effects on PTH. Estrogen suppresses T cell TNF production by regulating T cell differentiation and activity in the bone marrow, thymus, and peripheral lymphoid organs. In the bone marrow, estrogen downregulates the proliferation of hematopoietic stem cells through an IL-7 dependent mechanism.
In the kidney, around 250 mmol of calcium ions are filtered into the glomerular filtrate per day. Most of this is reabsorbed from the tubular fluid, leaving about 5 mmol/d to be excreted in the urine. This reabsorption occurs throughout the 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 from the tubular fluid, resulting in a decrease in the plasma phosphate concentration. Phosphate ions form water-insoluble salts with calcium. Thus, a decrease in the phosphate concentration of the blood plasma 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, which is released into the circulation. This latter form of vitamin D is the active hormone which stimulates calcium uptake from the intestine.
Via the kidney, 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. This activated form of vitamin D increases the absorption of calcium by the intestine via calbindin.
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, 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 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.

Interactive pathway map

Regulation of PTH secretion

Secretion of parathyroid hormone is determined chiefly by serum ionized calcium concentration through negative feedback. Parathyroid cells express calcium-sensing receptors on the cell surface. PTH is secreted when is decreased. The G-protein-coupled calcium receptors bind extracellular calcium and may be found on the surface on a wide variety of cells distributed in the brain, heart, skin, stomach, C cells, and other tissues. In the parathyroid gland, high concentrations of extracellular calcium result in activation of the Gq G-protein coupled cascade through the action of phospholipase C. This hydrolyzes phosphatidylinositol 4,5-bisphosphate to liberate intracellular messengers IP3 and diacylglycerol. 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 hypomagnesemia inhibits PTH secretion and also causes resistance to PTH, leading to a form of hypoparathyroidism that is reversible.

Stimulators

Decreased serum .
Mild decreases in serum .
An increase in serum phosphate.
Adrenaline
Histamine
Inhibitors
Increased serum .
Severe decreases in serum , which also produces symptoms of hypoparathyroidism.
Calcitriol
Increase in serum phosphate. Fibroblast growth factor-23 is produced in osteoblasts in response to increases in serum phosphate. 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.
Clinical significance

Disorders

, 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 superimposed on estrogen therapy produced increases in bone mass and reduced vertebral and nonvertebral fractures by 45–65%.

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 ; multiply by 0.1060 to convert from pg/dL to pmol/L.
A US source states the average PTH level to be 8–51 pg/mL. In the UK the biological reference range is considered to be 1.6–6.9 pmol/L. Normal total plasma calcium level ranges from 8.5 to 10.2 mg/dL.
The PTH assay may be liable to interference in rare cases.

Clinical interpretive guide

The intact PTH and calcium normal ranges are different for age; calcium is also different for sex.

Clinical Condition	Intact PTH	Calcium
Normal Parathyroid	Normal	Normal
Hypoparathyroidism	Low or Low Normal	Low
Hyperparathyroidism	-	-
- Primary	High or Normal	High
- Secondary	High	Normal or Low
- Tertiary	High	High
Non-Parathyroid Hypercalcemia	Low or Low Normal	High