Parathyroid secretion

It may seem disturbing that 1,25-(OH)2D3 can be considered a hormone with two signals (low calcium and low phosphoms) and two functions (calcium mobilization and phosphate mobilization). It would appear that a specific correction of the signal would not be possible. However, the calcium signal causes parathyroid secretion thus parathyroid hormone accompanies 1,25-(OH)2D3 in this circumstance, permitting mobilization of bone calcium and renal reabsorption of calcium. The effect of 1, 2S-(0H)2D3 on serum phosphate is negated by the parathyroid hormone induced loss of phosphate in urine. The composite effect of the low calcium signal is to elevate serum calcium but not phosphate ... 

It is well known that strontium brings about a vitamin D-resistant rickets and markedly reduces intestinal calcium absorption It is now clear that the feeding of strontium represses the renal 25-OH-D3-la-hydroxylase and that the administration of 1,25-(0H)2D3 to strontium-fed animals will restore their ability to absorb calcium Thus at least in part the metabolic basis for strontium-induced rickets has been solved. Recent results suggest that strontium suppresses the 1-hydroxylase by suppressing parathyroid secretion ... 

Calcium ion activity in blood is strictly regulated by a hormonal feedback mechanism. When the activity tends to decrease, the parathyroids secrete parathyroid hormone (PTH), which stimulates renal tubular reabsorption of Ca , K , and Na and decreases the reabsorption of phosphate. The net effect is a decreased excretion of Ca , Na" ", and K and an increased excretion of phosphate. PTH stimulates the hydroxylase activity in the kidney, and there is a negative feedback system which means that an increased amount of 1,25(OH)2D3 inhibits this hydroxylation procedure. Other hormones such as prolactin, estrogen, and growth hormone also stimulate hydroxylase activity, as does as a low serum phosphate concentration [6]. 

A peritoneal lavage technique was developed which permitted study of the effect of calcium and phosphate on the parathyroid. Parathyroid activity is measured by counting the development of osteoblasts in bone. Using calcium-free and phosphate-free lavage, investigators established that the calcium levels of serum control parathyroid secretion directly, and that any effect of the phosphate is indirect on parathormone secretion. 

Effect on Electrolytes. The administration of human growth hormone raises the intracellular levels of electrolytes, leads to a loss of bone calcium, and reduces urinary levels of phosphorus, potassium, and sodium. The increase in intracellular electrolytes may result from an increase in the cellular mass. Mobilization of bone calcium leads to osteoporosis in acromegaly and calciuria. Two explanations offered for this are (1) increased glomerular filtration combined with inhibition of tubular reabsorption, and (2) stimulation of parathyroid secretion. 

Spontaneous muscular spasms in the wrists and ankles, resulting when the parathyroid secretion is deficient, causing the amount of calcium in the blood to drop and the phosphorus to increase. 

Although it is being found that vitamin D metaboUtes play a role ia many different biological functions, metaboHsm primarily occurs to maintain the calcium homeostasis of the body. When calcium semm levels fall below the normal range, 1 a,25-dihydroxy-vitainin is made when calcium levels are at or above this level, 24,25-dihydroxycholecalciferol is made, and 1 a-hydroxylase activity is discontiaued. The calcium homeostasis mechanism iavolves a hypocalcemic stimulus, which iaduces the secretion of parathyroid hormone. This causes phosphate diuresis ia the kidney, which stimulates the 1 a-hydroxylase activity and causes the hydroxylation of 25-hydroxy-vitamin D to 1 a,25-dihydroxycholecalciferol. Parathyroid hormone and 1,25-dihydroxycholecalciferol act at the bone site cooperatively to stimulate calcium mobilization from the bone (see Hormones). Calcium blood levels are also iafluenced by the effects of the metaboUte on intestinal absorption and renal resorption. 

Three hormones regulate turnover of calcium in the body (22). 1,25-Dihydroxycholecalciferol is a steroid derivative made by the combined action of the skin, Hver, and kidneys, or furnished by dietary factors with vitamin D activity. The apparent action of this compound is to promote the transcription of genes for proteins that faciUtate transport of calcium and phosphate ions through the plasma membrane. Parathormone (PTH) is a polypeptide hormone secreted by the parathyroid gland, in response to a fall in extracellular Ca(Il). It acts on bones and kidneys in concert with 1,25-dihydroxycholecalciferol to stimulate resorption of bone and reabsorption of calcium from the glomerular filtrate. Calcitonin, the third hormone, is a polypeptide secreted by the thyroid gland in response to a rise in blood Ca(Il) concentration. Its production leads to an increase in bone deposition, increased loss of calcium and phosphate in the urine, and inhibition of the synthesis of 1,25-dihydroxycholecalciferol. 

PTH is the most important regulator of bone remodelling and calcium homeostasis. PTH is an 84-amino acid polypeptide and is secreted by the parathyroid glands in response to reductions in blood levels of ionised calcium. The primary physiological effect of PTH is to increase serum calcium. To this aim, PTH acts on the kidney to decrease urine calcium, increase mine phosphate, and increase the conversion of 25-OH-vitamin D to l,25-(OH)2-vitamin D. PTH acts on bone acutely to increase bone resorption and thus release skeletal calcium into the circulation. However, due to the coupling of bone resorption and bone formation, the longer-term effect of increased PTH secretion is to increase both bone resorption and bone formation. 

Nemeth EF (2002) Pharmacological regulation of parathyroid hormone secretion. Curr Pharm Des 8 2077-2087... 

In the periphery, dopamine receptor levels are generally lower than those observed in brain, particularly in comparison to striatal dopamine receptor levels. Due to these low levels, knowledge of receptor distribution in the periphery is not yet comprehensive. Nevertheless, Dl-like receptors have been reported in the parathyroid gland and in the tubular cells of the kidney. D2-like dopamine receptors have also been observed in the kidney. In addition, dopamine D2 and D4 receptors have been found in the adrenal cortex, where they modulate aldosterone secretion. The... 

Parathyroid Hormone (PTH) Is Secreted as an 84-Amino-Acid Peptide... 

Figure 42-13. Structure of bovine preproparathyroid hormone. Arrows indicate sites cieaved by processing enzymes in the parathyroid giand (1-5) and in the iiver after secretion of the hormone (4-5). The bioiogicaiiy active region of the moiecuie is fianked by sequence not required for activity on target receptors. (Slightly modified and reproduced, with permission, from Habener JF Recent advances in parathyroid hormone research. Clin Biochem 1981 14 223.)...

Parathyroid hormone also exists in storage vesicles. As much as 80-90% of the proPTH synthesized is degraded before it enters this final storage compartment, especially when Ca + levels are high in the parathyroid cell (see above). PTH is secreted when Ca is low in the parathyroid cells, which contain a several-hour supply of the hormone. 

The management of secondary hyperparathyroidism involves correction of serum calcium and phosphorus levels, and decreasing parathyroid hormone secretion. 

Cinacalcet is a calcimimetic that increases the sensitivity of receptors on the parathyroid gland to serum calcium levels to reduce PTH secretion. Cinacalcet maybe beneficial in patients with an increased Ca-P product who have elevated PTH levels and cannot use vitamin D therapy. Because the effects of cinacalcet on PTH can reduce serum calcium levels and result in hypocalcemia, cinacalcet should not be used if serum calcium levels are below normal. 

The delicate balance maintained by these factors is altered in patients with cancer by two principal mechanisms tumor production of humoral factors that alter calcium metabolism (humoral hypercalcemia) and local osteolytic activity from bone metastases.27 Humoral hypercalcemia causes around 80% of all hypercalcemia cases and is mediated primarily by systemic secretion of parathyroid hormone-related protein... 

Secondary hyperparathyroidism Increased secretion of parathyroid hormone from the parathyroid glands caused by hyperphosphatemia, hypocalcemia, and vitamin D deficiency that result from decreased kidney function. It can lead to bone disease (renal osteodystrophy). 

The final mechanism of action of PTH involves the activation of vitamin D3 through the stimulation of la-hydroxylase in the kidney. In the gastrointestinal tract, vitamin D3 is essential for the absorption of calcium. Enhanced absorption of calcium from dietary sources serves to further increase the concentration of calcium in the blood. Many foods, in particular, dairy products, which are rich in calcium, are fortified with vitamin D. The release of PTH from the parathyroid glands is regulated by plasma calcium levels through negative feedback. A decrease in the level of calcium in the blood stimulates the secretion of PTH and an increase in the calcium level in the blood inhibits it. 

Calcium-phosphorus balance is mediated through a complex interplay of hormones and their effects on bone, GI tract, kidney, and parathyroid gland. As kidney disease progresses, renal activation of vitamin D is impaired, which reduces gut absorption of calcium. Low blood calcium concentration stimulates secretion of parathyroid hormone (PTH). As renal function declines, serum calcium balance can be maintained only at the expense of increased bone resorption, ultimately resulting in renal osteodystrophy (ROD) (Fig. 76-7). 

Calcitriol, 1,25-dihydroxyvitamin D3, directly suppresses PTH synthesis and secretion and upregulates vitamin D receptors, which ultimately may reduce parathyroid hyperplasia. The dose depends on the stage of CKD and type of dialysis (Table 76-4). 

High phosphate diets cause decreased Ca absorption, secondary hyperparathyroidism, accelerated bone resorption and soft tissue calcification in some animals, but not in normal humans. Although phosphates may decrease Ca absorption in man at very high (> 2000 mg/day) Ca intakes, they do not do so at more moderate Ca levels and enhance Ca absorption at very low levels (< 500 mg/day). Phosphates increase renal tubular reabsorption and net retention of Ca. At low Ca intakes, phosphates stimulate parathyroid hormone (PTH) secretion without causing net bone resorption. 

In rats, infusion of the insulin secretagogues arginine and glucose induced a calciuria proportional to serum insulin levels. Suppression of insulin secretion by mannoheptulose or streptozotocin prevented the calciuria. Parathyroidectomy did not affect arginine-induced hypercalciuria in the rat, so insulin is not inhibiting parathyroid hormone secretion or activity. 

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