CT is a 32 amino acid hormone secreted by the C-cells of the thyroid gland. In species in which the structure of CT has been determined, common features include a 1—7 amino terminal disulfide bridge with cysteine at positions 1 and 7 and proline at the carboxy-terminal [ 6 ].
Divergence is seen in the interior 10—27 amino acids. Non-mammalian CTs such as salmon have the greatest potency. Salmon CT, which differs from human CT in 16 amino acids, has been used for treatment of hypercalcemia. CT is primarily metabolized by the kidney [ 8 — 10 ].
CT is present in large amounts only in the C-cells of the thyroid while CGRP, a potent vasodilator, is present not only in the thyroid, but also in central and peripheral nervous tissue. CT is present in ocean fish which live in a high calcium environment with the need to expel calcium. CT is thus older than parathyroid hormone PTH which was first recognized in early land-dwelling animals when conservation rather than expulsion of calcium became important.
Besides modifying increases in serum calcium and increasing 1,25D production, several potential roles for CT have been suggested and important observations about CT have been made. In azotemic and non-azotemic animal models, CT has been shown to decrease the magnitude of hypercalcemia during calcium loading [ 1 — 3 , 11 ]. Studies in the s showed that CT increased renal production of 1,25D [ 12 , 13 ]. In contrast to other stimuli of 1,25D production such as PTH and hypophosphatemia in which 1,25D production occurs in the convoluted proximal tubule, stimulation of 1,25D by CT occurs in the straight proximal tubule [ 12 ].
But during pregnancy and lactation, both 1,25D and CT levels are increased [ 16 — 18 ]. The effectiveness of CT in the treatment of hypercalcemia is attributed to reducing osteoclast activity [ 19 ]. But there is also a subsequent escape from the calcium-lowering effect of CT [ 20 ]. Besides decreasing osteoclast activity, CT has been suggested to facilitate deposition of calcium and phosphorus in bone especially in the post-prandial state [ 21 ].
Whether CT is stimulated by the ingestion of food through gastrin stimulation and consequently affects bone has been a subject of interest [ 21 , 22 ]. However, no differences in bone mass has been shown when CT is absent in congenital hypothyroidism provided thyroid hormone is replaced [ 23 , 24 ]. Gender and age differences in CT have been shown with women having lower values than men and with decreasing CT values with age in some, but not all studies [ 9 , 25 ]. CT screening has been shown to be a useful tool for the diagnosis of medullary thyroid carcinoma [ 26 ].
However, despite several attractive and plausible hypotheses, CT has not been shown to have an important physiologic role in humans more than 50 years after its discovery. Studies during the past 50 years have shown that CT modifies the development of hypercalcemia. In , a calcium infusion in thyroparathyroidectomized dogs was shown to result in a greater magnitude of hypercalcemia and a longer time to return to baseline values than in normal dogs [ 27 ]. Subsequently, Hirsch et al.
In rats with hypercalcemia from NH 4 Cl-induced metabolic acidosis, CT administration decreased the serum calcium concentration [ 28 ]. In the CT receptor knockout mouse, 1,25D-induced hypercalcemia was greater than in the control mouse [ 29 ].
In a mouse study consisting of PTH knockout, PTH and calcium-sensing receptor CaSR double knockouts, and wildtype mice, it was shown that both CaSR-mediated CT secretion and enhanced renal calcium excretion were important for preventing the development of hypercalcemia while inhibition of PTH secretion was not required for a robust defense against hypercalcemia [ 30 ]. In summary, strong evidence exists that CT is an important modifier of the hypercalcemic effect of acute calcium loading.
Reprinted with permission from Kidney International. The mechanisms for the opposite effects downstream from the CaSR are still poorly understood.
The CT response to hypercalcemia is a sigmoidal curve opposite in direction to the sigmoidal curve of the PTH response to hypocalcemia [ 32 — 34 ]. In one animal study, a rapid induction of hypercalcemia resulted in a greater CT response than a slow induction of hypercalcemia of similar magnitude [ 35 ].
Also, as PTH secretion is suppressed by the induction of hypercalcemia, CT secretion in both control and CKD patients is suppressed by the induction of hypocalcemia [ 34 ]. In a study of normal and CKD subjects, a maximal CT response was seen after an increase in ionized calcium of 0.
Many more studies of the PTH response to hypocalcemia have been performed than of the CT response to hypercalcemia. Interestingly, while every normal and azotemic subject in studies of PTH secretion has shown a sigmoidal response to hypocalcemia, studies in normal and azotemic humans and animals have shown that some patients and animals fail to increase CT secretion in response to hypercalcemia induced by a calcium infusion [ 34 , 36 ].
In a study in cats, a strong correlation was found between the number of CT-positive cells in the thyroid gland and the plasma CT concentration induced by hypercalcemia [ 36 ]. Finally, both in azotemic patients and rats, baseline CT values have been shown to be increased compared with normal [ 32 , 34 , 37 ] and also to stimulate more during the induction of hypercalcemia [ 34 ]. Similar to PTH secretion, CT secretion also appears to adapt to the ambient or existing serum calcium concentration [ 38 ].
In Deftos et al. CT values were shown to increase before hypercalcemia developed. In a subsequent study in normal young male subjects, oral calcium loading that increased serum calcium to higher, but still normal values resulted in increases in serum CT that correlated with the increase in serum calcium [ 22 ].
In a study in normal, parathyroidectomized, and azotemic rats with the latter divided by a serum calcium less or greater than 8. Finally, Messa et al. When hypocalcemia was present PTX and RF a , the calcitonin response to an increase in serum calcium began before hypercalcemia developed shifting the set point for calcitonin secretion to the left [ 32 ].
The adapting of PTH and CT secretion to the existing serum calcium concentration is an interesting phenomenon that may reflect a broader concept of physiologic adaptation. For example, adaptation to cold and hot weather as well as oxygen adaptation to high altitude in Himalayan mountain climbers is well known.
However, adaptation of hormonal effects and secretion is less well appreciated. In type 1 diabetic patients, an unawareness of hypoglycemia is associated with prolonged insulin therapy and frequent episodes of hypoglycemia [ 39 ]. After resection of the insulinoma, these same responses became similar to those in normal subjects.
Besides adaptation to hypercalcemia, other causes for changes in CT secretion are also possible. Raue and associates have shown that chronic hypercalcemia resulted in a decrease in CT content of the thyroid gland and a diminished CT response to acute calcium stimulation while basal serum CT levels remained unchanged [ 40 ]. Also, it was shown that 1,25D-induced hypercalcemia failed to stimulate CT secretion [ 40 ] which may be related to the presence of 1,25D receptors on C cells [ 41 ] and a 1,25D decrease in CT gene transcription [ 14 , 15 , 42 ].
In an in vitro study with rat C cells, repetitive calcium stimulation led to a decline in CT release, but 2 h after reversing the calcium concentration in the media to basal values, the CT response to a calcium stimulus was restored [ 43 ].
In the cat, the CT response to hypercalcemia correlated with the number of CT-positive cells in the thyroid [ 36 ]. Also, it was shown that several cats failed to increase CT in response to hypercalcemia.
Chronic hypocalcemia induced by parathyroidectomy in rats has resulted in increased thyroidal CT content after 50 days and longer, but interestingly not at 32 days [ 44 , 45 ]. Such a finding could explain an enhanced CT response to calcium loading in chronic hypocalcemia [ 23 ].
However, in the study by Torres et al. Several studies have evaluated CT secretion in primary hyperparathyroidism which is characterized by chronic hypercalcemia.
In one study, a gender difference was observed. Males, but not females had elevated baseline CT values and a further increase in CT values during a calcium infusion [ 46 ]. In a subsequent study, men and women with primary hyperparathyroidism had normal serum CT levels and the CT response to a calcium infusion was indistinguishable between men and women with primary hyperparathyroidism and normal men and women [ 47 ].
In another study performed in post-menopausal women with primary hyperparathyroidism, all the patients had normal serum CT levels and a blunted response to a calcium stimulus as compared with normal women [ 48 ]. In a study in horses, the rapid induction of hypercalcemia increased CT values by 6-fold, but CT values returned to baseline values before hypercalcemia resolved [ 49 ].
Thus, the question remains whether the lack of a CT response to hypercalcemia in primary hyperparathyroidism is due to a depletion of CT stores or a reset of the set point for CT secretion. When dogs were subjected to hypocalcemia, repetitive cycles of the induction of and recovery from hypocalcemia done without pause, whether for 30 or 60 min, produced the same PTH response on the second as the first cycle Figure 3 A and B [ 38 ].
Also, the PTH value for the same serum calcium concentration was greater during the induction of than the recovery from hypocalcemia Figure 3 C and greater during the recovery from than the induction of hypercalcemia not shown [ 38 ]. This phenomenon, known as hysteresis, is not unique to PTH secretion, but is seen with other physiologic phenomenon [ 38 ].
But for PTH secretion, hysteresis may be important in preventing an overcorrection during the restoration of a normal serum calcium concentration [ 38 ]. Another interesting observation has been that an episodic versus a linear induction of hypocalcemia of the same magnitude over the same time period resulted in differences in PTH secretion [ 50 ].
Finally, it was shown that metabolic acidosis stimulates and metabolic alkalosis inhibits PTH secretion in the rat and dog [ 51 — 54 ]. Moreover, because calcium suppresses PTH secretion and stimulates CT secretion, the effects of acidosis and alkalosis may be reversed from that of PTH with alkalosis stimulating and acidosis suppressing CT secretion. When blood calcium levels drop below a certain point, calcium-sensing receptors in the parathyroid gland are activated to release parathyroid hormone PTH into the blood.
PTH modulates calcium and phosphate homeostasis, as well as bone physiology. PTH has effects antagonistic to those of calcitonin by increasing blood calcium levels by stimulating osteoclasts to break down bone and release calcium. PTH also increases gastrointestinal calcium absorption by activating vitamin D, and promotes calcium conservation by re-absorption in the kidneys.
The parathyroid glands are small, pea-sized endocrine glands located on the rear side of the thyroid gland. When blood calcium levels drop below a certain point, the calcium-sensing receptors in the parathyroid gland are activated, and the parathyroid glands release parathyroid hormone PTH into the blood.
PTH is a small protein hormone that is integral to the regulation of the level of calcium in the blood via the bone, kidneys, and intestines. PTH works in concert with another hormone, calcitonin, that is produced by the thyroid to maintain calcium homoeostasis. When bone is broken down, the calcium contained in the bone is released into the bloodstream.
Therefore, the inhibition of the osteoclasts by calcitonin directly reduces the amount of calcium released into the blood. However, this inhibition has been shown to be short-lived. It can also decrease the resorption of calcium in the kidneys , again leading to lower blood calcium levels.
How is calcitonin controlled? What happens if I have too much calcitonin? What happens if I have too little calcitonin? Last reviewed: Feb Prev. Related Endocrine Conditions. Osteoporosis Hypercalcaemia Thyroid cancer Rickets Paget's disease Multiple endocrine neoplasia type 2A Multiple endocrine neoplasia type 2B Familial medullary thyroid cancer View all Endocrine conditions.
In birds, fish and amphibians, calcitonin is secreted from the ultimobrachial glands. Calcitonin is a 32 amino acid peptide cleaved from a larger prohormone. It contains a single disulfide bond, which causes the amino terminus to assume the shape of a ring.
Alternative splicing of the calcitonin pre-mRNA can yield a mRNA encoding calcitonin gene-related peptide; that peptide appears to function in the nervous and vascular systems.
The calcitonin receptor has been cloned and shown to be a member of the seven-transmembrane, G protein-coupled receptor family. A large and diverse set of effects has been attributed to calcitonin, but in many cases, these were seen in response to pharmacologic doses of the hormone, and their physiologic relevance is suspect.
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