Index
It is involved in helping regulate the levels of calcium and phosphate in the blood, opposing the action of parathyroid hormone.
This means that it acts to reduce the levels of calcium in the blood.
However, the importance of this role in humans is unclear since patients with very low or very high calcitonin levels show no adverse effects.
Its importance in humans has not been established, and its reputation in other animals, since its function is not generally significant in regulating normal calcium homeostasis. It belongs to the calcitonin type family of proteins.
Calcitonin reduces calcium levels in the blood through two main mechanisms:
It inhibits the activity of osteoclasts, which are the cells responsible for breaking down bones. When the bone is broken down, the calcium contained in the bone is released into the bloodstream.
Therefore, the inhibition of osteoclasts by calcitonin directly reduces the amount of calcium released into the blood. However, this inhibition is short-lived.
It can also decrease the reabsorption of calcium in the kidneys, leading to lower calcium levels in the blood.
The manufactured forms of calcitonin have been administered in the past to treat Paget’s disease of bone and sometimes hypercalcemia and bone pain. However, their use is limited with the introduction of newer drugs, such as bisphosphonates.
Function
Calcitonin is a 32-amino acid hormone secreted by the C cells of the thyroid gland.
In the species in which the structure of calcitonin has been determined, standard features include a disulfide bridge 1-7 amino-terminal with cysteine at positions 1 and 7 and proline at the carboxy terminus.
The divergence is seen inside 10-27 amino acids. Non-mammalian calcitonin, like salmon, has the highest potency. Salmon calcitonin, which differs from human calcitonin by 16 amino acids, has been used to treat hypercalcemia.
The calcitonin gene is found on the short arm of chromosome 11 and encodes calcitonin and the peptide related to the calcitonin gene (CGRP).
It is present in large quantities only in the C cells of the thyroid. In contrast, CGRP, a potent vasodilator, is present in the thyroid and the central and peripheral nervous tissue.
Calcitonin is present in oceanic fish that live in an environment with high calcium content and need to expel calcium.
Calcitonin is, therefore, older than parathyroid hormone (PTH), which was first recognized in the first terrestrial animals when conservation instead of the expulsion of calcium became important.
In addition to modifying increases in serum calcium and increasing production of 1.25D, several potential roles for calcitonin have been suggested, and essential observations have been made on calcitonin.
In azotemic and non-azotic animal models, calcitonin has decreased the magnitude of hypercalcemia during calcium loading.
Studies in the 1980s showed that calcitonin increased renal production of 1.25 D. Unlike other stimuli of production of 1.25 D, such as PTH and hypophosphatemia, 1.25 D occurs. In the convolute proximal tubule, the stimulation of 1.25D by calcitonin occurs in the proximal rectilinear tubule.
Similar to the reciprocal relationships between PTH and 1,25D and FGF23 and 1,25D, calcitonin stimulates the secretion of 1,25D while 1,25D suppresses calcitonin secretion. But during pregnancy and lactation, levels of 1,25D and calcitonin increase.
The effectiveness of calcitonin in treating hypercalcemia is attributed to the reduction of osteoclast activity. However, there is also a subsequent escape of the calcium-lowering effect of calcitonin.
In addition to decreasing the activity of osteoclasts, it has been suggested that calcitonin facilitates the deposition of calcium and phosphorus in bone, especially in the postprandial state.
If calcitonin is stimulated by the ingestion of food through stimulation with gastrin and consequently affects the bone has been a topic of interest.
However, no differences in bone mass have been demonstrated when calcitonin is absent in congenital hypothyroidism, provided that thyroid hormone is replaced.
Gender and age differences in calcitonin have been shown, with women having lower values than men and with decreasing calcitonin values with age in some, but not in all studies.
However, despite several attractive and plausible hypotheses, calcitonin has not been shown to play an essential physiological role in humans more than 50 years after its discovery.
Biosynthesis and regulation
Calcitonin is formed by the proteolytic cleavage of a larger prepropeptide, the product of the CALC1 gene (CALCA). It is functionally antagonistic with parathyroid hormone and vitamin D3.
The CALC1 gene belongs to a superfamily of related protein hormone precursors, including the islet amyloid precursor protein, the peptide related to the calcitonin gene, and the adrenomedullin precursor.
The secretion of calcitonin is stimulated by:
- An increase in serum [Ca2 +].
- Gastonia y pentagastrin.
Effects
The hormone participates in the metabolism of calcium (Ca2 +) and phosphorus. Calcitonin counteracts parathyroid hormone (PTH) and vitamin D in many ways.
More specifically, calcitonin reduces blood Ca2 + levels in two ways:
The main effect: inhibits the activity of osteoclasts in bones.
Minor effect: Inhibits renal tubular reabsorption of Ca2 + and phosphate, allowing it to be excreted in the urine.
High calcitonin concentrations can increase the urinary excretion of calcium and phosphate by actions in the renal tubules leading to marked hypocalcemia. However, this is a minor effect without physiological importance in humans.
It is also a short-lived effect because the kidneys become resistant to calcitonin, as shown by the excretion of calcium not affected by the kidney in patients with thyroid tumors that secrete excessive calcitonin.
Protective mechanisms include the direct inhibition of bone resorption and the indirect effect through the inhibition of prolactin release from the pituitary gland.
The reason is that prolactin induces the peptide release related to the parathyroid hormone that improves bone resorption, but it is still under investigation.
Other effects are the prevention of postprandial hypercalcemia due to Ca2 + absorption.
In addition, calcitonin inhibits food intake in rats and monkeys and may have an action in the central nervous system that involves the regulation of feeding and appetite.
Calcitonin reduces calcium and phosphorus in the blood mainly by inhibiting osteoclasts. Therefore, osteoblasts do not have calcitonin receptors and are not directly affected by calcitonin levels.
However, since bone resorption and bone formation are coupled processes, the inhibition of osteoclast activity by calcitonin leads to more excellent osteoblastic action (as an indirect effect).
Receptor
The calcitonin receptor, found in osteoclasts and the kidney and brain regions, is a G protein-coupled receptor coupled by the alpha Gs subunit to adenylate cyclase and thereby the generation of cyclic adenosine monophosphate in target cells.
History of calcitonin
The discovery of calcitonin (CT), a hormone released in hypercalcemia and decreases serum calcium, was first performed by Copp et al . due to the perfusion of isolated thyroid-parathyroid gland preparations in the anesthetized dog.
Initially, it was mistakenly thought that the source of calcitonin was the parathyroid gland, but later a thyroid origin was established. Pearse showed that the head of calcitonin was the C cells of the thyroid gland.
Potts et al . determined the amino acid sequence of human calcitonin and salmon, which led to the synthesis and commercial use of the most potent salmon calcitonin. The hormone was first called thyrocalcitonin, but it was later called calcitonin.
Since its discovery more than 50 years ago, little progress has been made in understanding its physiopathological role in humans, partly because a deficiency or excess of calcitonin does not lead to abnormalities, except diarrhea, in a few patients with medullary carcinoma. of thyroid
Studies over the past 50 years have shown that calcitonin modifies the development of hypercalcemia. In 1960, it was revealed that calcium infusion in thyroparathyroidectomized dogs resulted in a greater magnitude of hypercalcemia and a longer time to return to baseline than in normal dogs.
Subsequently, Hirsch et al . demonstrated that the calcemic response to the parathyroid extract was more significant in thyroparatiroidectomized rats than in parathyroidectomized or simulated rats that showed the thyroid origin calcitonin.
In rats with hypercalcemia due to metabolic acidosis induced by NH4Cl, the administration of calcitonin decreased the serum concentration of calcium.
As shown in Figure 1, the absence of calcitonin in both azotemic and non-azotemic rats improved the calcemic response to PTH during a PTH infusion of 24 and 48 hours.
Discovery:
Calcitonin was purified in 1962 by Copp and Cheney. Although initially a secretion of the parathyroid glands was considered, it was later identified as the secretion of the C cells of the thyroid gland.
Medical importance
The calcitonin test is used to identify patients with nodular thyroid diseases. It is helpful to make an early diagnosis of medullary thyroid carcinoma.
A malignancy of parafollicular cells, i.e., medullary thyroid cancer, typically produces an elevated serum calcitonin level. The prognosis of medullary thyroid cancer depends on early detection and treatment.
Pharmacology
Salmon calcitonin is used to treat:
- Postmenopausal osteoporosis.
- Hypercalcemia.
- Paget’s disease.
- Bone metastasis .
It has been investigated as a possible non-surgical treatment for spinal stenosis.
General characteristics of the active substance:
Calcitonin is absorbed and eliminated quickly. Maximum plasma concentrations are reached within the first hour of administration.
The bioavailability after subcutaneous and intramuscular injection in humans is high and similar for the two administration routes (71% and 66%, respectively).
Salmon calcitonin degrades primarily and almost exclusively in the kidneys, forming pharmacologically inactive molecule fragments.
Characteristics in patients:
There is a relationship between the subcutaneous dose of calcitonin and the maximum plasma concentrations. After parenteral administration of 100 IU of calcitonin, the maximum plasma concentration is 200 and 400pg / ml.
Treatments
Calcitonin can be used therapeutically for the treatment of hypercalcemia or osteoporosis. In a recent clinical study, subcutaneous calcitonin injections have reduced the incidence of fractures and decreased bone mass in women with type 2 diabetes complicated by osteoporosis.
Subcutaneous injections of calcitonin in patients suffering from mania resulted in a significant decrease in irritability, euphoria, and hyperactivity. Therefore, calcitonin is promising for the treatment of the bipolar disorder.
However, no other papers have been published on this possible application of calcitonin.
Physiological effects of calcitonin
A broad and diverse set of effects has been attributed to calcitonin. Still, in many cases, these were observed in response to pharmacological doses of the hormone, and their physiological relevance is suspect.
However, it seems clear that calcitonin plays a role in calcium and phosphorus metabolism. In particular, calcitonin can decrease calcium levels in the blood, at least in part, by the effects on two well-studied target organs:
Bone: calcitonin suppresses bone resorption by inhibiting the activity of osteoclasts, a type of cell that “digests” the bone matrix and releases calcium and phosphorus into the blood.
Kidney: it prevents calcium and phosphorus from being lost in the urine by resorption in the renal tubules. Calcitonin inhibits the tubular reabsorption of these two ions, which increases the rates of loss in the urine.
It seems clear that there are differences between species in the importance of calcitonin as a factor that affects calcium homeostasis.
In fish, rodents, and some domestic animals, calcitonin plays a vital role in calcium homeostasis. In humans, calcitonin has, at best, a minor role in the regulation of blood calcium levels.
An interesting test to support this claim is that humans with chronically elevated levels (medullary thyroid cancer) or decreased levels (surgical removal of the thyroid gland) of calcitonin in blood generally show no abnormalities in the average serum calcium concentration.
Additional information on the calcitonin and calcium balance can be found in the section Endocrine control of calcium and phosphate homeostasis.
Diagnosis
It can be used diagnostically as a tumor marker for medullary thyroid cancer, in which there may be elevated levels of calcitonin, and high levels after surgery may indicate recurrence.
It can even be used in biopsy samples of suspicious lesions (e.g., swollen lymph nodes) to establish whether they are metastases from original cancer.
It has been suggested that the limits for calcitonin to distinguish cases with medullary thyroid cancer are the following, with a higher value that increases the suspicion of medullary thyroid cancer:
Mujeres: 5ng/L o pg/ml.
Hombres: 12ng/L o pg/ml.
Children under 6 months of age : 40ng / L or pg / ml.
Children between 6 months and three years of age: 15ng / L or pg/ml.
You can use cutoff points for adults when you are over three years.
Increased levels of calcitonin have also been reported for other conditions.
They include C-cell hyperplasia, non-thyroid ovarian cell carcinoma, non-thyroid small cell carcinoma, other non-thyroid malignancies, acute and chronic renal failure, hypercalcemia, hypergastrinemia, and other gastrointestinal disorders and lung disease.
How is calcitonin controlled?
The secretion of both calcitonin and parathyroid hormone is determined by the level of calcium in the blood. Calcitonin is secreted in higher amounts when calcium levels in the blood increase. When calcium levels in the blood decrease, this causes the amount of secreted calcitonin decreases as well.
The secretion of calcitonin is also inhibited by the hormone somatostatin, which can also be released by the C cells in the thyroid gland.
Control of secretion:
Elevated calcium levels in the blood strongly stimulate calcitonin secretion, and secretion is suppressed when the calcium concentration drops below normal.
It has been shown that several other hormones stimulate the release of calcitonin in certain situations, and nerve controls have also been demonstrated.
Disease states:
Many diseases are associated with abnormally increased or decreased calcitonin levels, but the pathological effects of abnormal calcitonin secretion per se are generally not recognized.
There are several therapeutic uses for calcitonin. It is used to treat hypercalcemia caused by various causes and has been a valuable therapy for Paget’s disease, a disorder in bone remodeling. Calcitonin also appears to be an invaluable aid in treating certain types of osteoporosis.
What is the dose?
Injectable calcitonin is injected under the skin or into the muscle. The nasal spray is administered in the nostril. To achieve optimal results, patients with osteoporosis should simultaneously receive adequate calcium and vitamin D.
The recommended regimens for Paget’s disease and postmenopausal osteoporosis are 100 units per day injected into the muscle or under the skin. Postmenopausal osteoporosis can also be treated with one spray (200 units) per day administered in alternative nasal passages.
The increase of calcium in the blood (hypercalcemia) is treated with 4-8 units/kg of calcitonin injection every 6-12 hours.
What happens if I have too much calcitonin?
There is no direct harmful effect on the body due to having too much calcitonin.
Medullary thyroid cancer is a rare type of cancer that arises from the C cells in the thyroid gland that secrete calcitonin. It is sometimes associated with multiple endocrine neoplasia type 2a and multiple endocrine neoplasia type 2b.
Patients with medullary thyroid cancer have high levels of calcitonin in the bloodstream. However, it is essential to note that these high calcitonin levels are a consequence of this condition, not a direct causative factor.
What happens if I have very little calcitonin?
There seems to be no clinical effect on the body due to having very little calcitonin. Patients whose thyroid gland has been removed and have undetectable calcitonin levels in the blood do not show symptoms or adverse signs due to this.
Side effects
It is possible that bone pain increased during the first months of treatment with calcitonin injection. This is not a sign that the medication is not working correctly.
Common side effects may include:
- Redness
- Sickness.
- Vomiting
- Swelling where the injection was given.
