Plasma Calcitonin Concentrations Research Articles

Progression of postoperative residual medullary thyroid carcinoma as monitored by plasma calcitonin levels

Patients operated on for medullary thyroid carcinoma (MTC) frequently have persistent elevated plasma calcitonin concentrations after operation, indicating remaining tumor. The plasma calcitonin concentration in a patient with MTC roughly reflects the endogenous tumor burden. The only effective treatment for MTC is surgical. The decision about whether a patient with persistent MTC should have a repeat operation would be influenced by knowledge of the natural course of the disease. Forty patients with persistently elevated peak plasma calcitonin concentrations after thyroidectomy for MTC were monitored for a mean of 6 years. Serial determinations of plasma calcitonin levels were obtained before and after intravenous injection of calcium and pentagastrin. At the first postoperative test 63% of the patients had undetectable basal calcitonin values, although their stimulated plasma calcitonin concentrations were elevated. The mean annual increase in stimulated plasma calcitonin concentrations was 117%, but plasma calcitonin concentrations were stable in three patients and decreased in one patient. Five patients are known to have experienced distant metastases. MTC is a progressive disease in most patients with persistent hypercalcitoninemia after thyroidectomy. Stimulated peak plasma calcitonin levels are more meaningful than basal levels in the serial postoperative evaluation of patients with persistent hypercalcitoninemia after thyroidectomy for MTC.

Clinical Screening as Compared with DNA Analysis in Families with Multiple Endocrine Neoplasia Type 2A

Multiple endocrine neoplasia type 2A (MEN-2A) is characterized by medullary thyroid carcinoma in combination with pheochromocytoma and sometimes parathyroid adenoma. Missense mutations in the RET proto-oncogene are associated with MEN-2A. Their detection by DNA analysis allows the identification of carriers of the gene, in whom the risk of medullary thyroid carcinoma is 100 percent. We compared the reliability of biochemical tests with that of DNA analysis in identifying carriers of the MEN2A gene. Starting in 1975, we screened 300 subjects in four large families with MEN-2A for expression of the disease, using measurements of plasma calcitonin after stimulation with pentagastrin or calcium and urinary excretion of catecholamines and catecholamine metabolites. We tested for carrier status by DNA analysis, including linkage analysis, and more recently by analysis of mutations in the RET gene. Of 80 MEN2A gene carriers (in 61 of whom carrier status was proved by DNA analysis), 66 had abnormal plasma calcitonin values and medullary thyroid carcinoma. Fourteen young carriers had normal results of plasma calcitonin tests. In 8 of these 14, thyroidectomy revealed small foci of medullary thyroid carcinoma; the remaining 6 have not yet been operated on. Of the other 220 family members, 68 were found by DNA analysis not to carry the MEN2A gene. None of these 68 subjects had medullary thyroid carcinoma or pheochromocytoma; 6 had elevated plasma calcitonin concentrations and underwent thyroidectomy but had only C-cell hyperplasia. Unlike biochemical tests, DNA analysis permits the unambiguous identification of MEN2A gene carriers.

Predictive DNA testing and prophylactic thyroidectomy in patients at risk for multiple endocrine neoplasia type 2A.

Missense germ-line mutations in the RET protooncogene are associated with multiple endocrine neoplasia type 2A (MEN 2A). Detection of these mutant alleles in kindred members predicts disease inheritance and provides the basis for preventative thyroidectomy. A polymerase chain reaction (PCR)-based genetic test for the 19 known RET mutations was designed to study 132 members of 7 kindreds with MEN 2A. Haplotypes also were constructed using genetic markers flanking the MEN 2A locus. Plasma calcitonin (CT) concentrations were determined before and after provocative testing. Direct DNA testing and haplotype analysis showed that 21 of 58 kindred members at risk for disease had inherited a mutation in the RET protooncogene associated with MEN 2A. Plasma CT concentrations were elevated in 9 of the 21 family members, but were normal in 12. After genetic counseling, 13 of the 21 kindred members (6 with normal and seven with elevated plasma CT levels), consented to immediate thyroidectomy. In each patient, the resected thyroid gland showed C-cell hyperplasia with or without medullary thyroid carcinoma. There were no metastases to regional lymph nodes, and postoperative stimulated plasma CT levels were normal. The PCR-based direct DNA test for RET mutations is accurate, rapid, and reproducible. For all 132 individuals evaluated, the results of direct DNA analysis were consistent with haplotype studies. The direct test for mutations in the RET protooncogene is the preferred method for screening MEN 2A kindreds. In family members who have inherited a RET mutation, total thyroidectomy is indicated, regardless of the plasma CT values.

Vitamin D, parathormone, and calcitonin profiles in persons with long-standing spinal cord injury

Rapid immobilization after acute spinal cord injury (SCI) leads to increased bone resorption, net calcium efflux from the bone, hypercalciuria, depressed parathormone (PTH) and increased calcitonin release. However, the effects, if any, of long-standing SCI on calcium regulatory system is not well understood. We measured plasma concentrations of 25 hydroxy (OH) vitamin D, 1,25(OH)2 vitamin D (calcitriol), intact PTH molecule, calcitonin, ionized calcium [Ca++] and phosphorus in 40 clinically stable men with long-standing SCI of 3-year to 50-year duration (22 persons with paraplegia and 18 persons with quadriplegia). The results were compared with those obtained in 14 able-bodied control men. Plasma PTH concentration in the SCI group was significantly lower than that found in the able-bodied controls despite virtually identical concentrations of ionized calcium. Likewise, plasma calcitriol concentration in the SCI group was significantly lower than the value found in the able-bodied control group and lower in persons with quadriplegia than in those with paraplegia. In contrast, plasma calcitonin concentration in the quadriplegic group was significantly higher than that in persons with paraplegia and insignificantly higher than that in the control group. No significant difference was noted in serum ionized calcium between the study groups. PTH and calcitriol levels were positively related to one another (r = 0.35, p < .01) and negatively related to the level of injury (r = −0.43, p < .002 and r = −0.54, p < .001, respectively). In conclusion, long-standing SCI is associated with significant depression of calcitriol and PTH concentrations despite normal ionized calcium concentration. These findings can be explained by an increased calcium release leading to suppression of PTH, which in turn down regulates calcitriol biosynthesis. Negative correlations between the level of injury and both PTH and calcitriol levels suggest bones in the paralyzed structures as the primary source of calcium release in the SCI patients.

Expression of calcitonin gene-related peptide in medullary thyroid cancer.

We studied the expression of calcitonin (CT) and calcitonin gene-related peptide (CGRP) in 18 patients with medullary thyroid cancer (MTC) in the neoplastic (primary or metastatic) tissue by immunohistochemistry and in the plasma by radioimmunoassay. CT immunoreactivity was found in 100% of the primary and metastatic MTC, CGRP was expressed in 66% of the primary tumors and in 73% of the metastases. Both the number of positive cells and the degree of staining were always higher for CT than for CGRP staining. While plasma CT concentrations were always increased in patients with metastases, 3 patients with metastases had undetectable plasma CGRP levels. A positive correlation was found between plasma CT and CGRP levels. These data indicate that CGRP is frequently expressed in MTC sections and that plasma CGRP measurement is an additional marker for MTC, although has no advantage with respect to CT measurements in monitoring the progression of the disease.

Age-related differences in basal and calcium-stimulated plasma calcitonin levels in female rats.

The effects of aging on calcitonin (CT) secretion in female rats were investigated. Old (24 mo) at constant diestrus status and young (2 mo) at diestrus status rats were either ovariectomized (Ovx) or left intact as controls. Ovx rats were injected subcutaneously with estradiol benzoate (25 micrograms/kg body wt) or sesame oil one time per day for 3 days. All rats were infused with CaCl2 (10 mg/ml) at a rate of 2 ml/h for 30 min via a jugular catheter connected to a peristaltic pump. Blood samples (0.5 ml each) were collected at 0, 30, 60, and 120 min. The basal and post-CaCl2 levels of plasma Ca measured with radioimmunoassay were significantly higher (P less than 0.05-0.01) in old than in young female rats. The pre- and post-CaCl2 levels of plasma Ca and CT in young rats were not altered by Ovx or estradiol replacement. In old rats, Ovx caused a higher (P less than 0.01) level in plasma CT at 0 and 30 min after CaCl2 infusion. Both basal and stimulated levels of plasma CT were higher (P less than 0.01) in old Ovx than in young Ovx rats. These results demonstrated that 1) the increase of plasma CT in response to Ca challenge was greater in old than in young female rats, 2) the influence of estradiol and ovarian function on plasma CT concentration increases as a function of age, and 3) estradiol reduced the plasma CT in response to hypercalcemia in old Ovx rats. The sensitivity of the target tissue of young rats may be lower in response to the modulation of estrogen during hypercalcemia without compromising the secretion and hypocalcemic effect of CT in young rats. All suggested an age-related relationship between estrogen and CT secretion in minute-to-minute regulation during Ca infusion in rats.

Bone mineral density in postmenopausal women treated with L-thyroxine

<h3>PURPOSE:</h3> To determine if bone mineral density is decreased in postmenopausal women treated with 1-thyroxine, and, if any decrease is observed, whether it is related to overtreatment with thyroid hormone, to deficiency of calcitonin, or to other factors. <h3>PATIENTS AND METHODS:</h3> The study consisted of 19 postmenopausal women between 50 and 75 years of age treated with 1-thyroxine for 5 years or longer, and 19 matching control subjects with no thyroid disease. Bone mineral density of the spine and hip was measured by dual-photon absorptiometry. Plasma calcitonin concentrations and serum thyroid hormone levels were determined by radioimmunoassays. <h3>RESULTS:</h3> The 1-thyroxine-treated women had lower bone density in the lumbar spine (1.013 g/cm² [95% confidence interval, 0.945 to 1.081] versus 1.134 g/cm² [1.026 to 1.242], p=0.043); in the femoral neck (0.736 g/cm² [0.694 to 0.778] versus 0.809 g/cm² [0.747 to 0.872], p=0.040); in Ward's triangle (0.576 g/cm² [0.530 to 0.623] versus 0.694 g/cm² [0.617 to 0.770], p=0.011); and in the trochanteric area (0.626 g/cm² [0.581 to 0.672] versus 0.722 g/cm² [0.651 to 0.794], p=0.027). The maximal increase in calcitonin following calcium infusion was 1.37 ng/L (95% confidence interval, −0.44 to 3.17) in the 1-thyroxine-treated patients versus 18.8 ng/L (95% confidence interval, 10.0 to 27.5) in normal women, p <0.001. The average dose of 1-thyroxine was 120 μg/day; 16 of the 19 patients had normal serum thyroxine levels. However, TSH levels were low in 13 of the 19, suggesting that 1-thyroxine treatment was supraphysiologic. Seven of the 19 patients had a history of hyperthyroidism in the distant past; these patients, considered separately, had significantly reduced bone density in the hip. The other 12 patients, considered separately, did not have a statistically significant loss of bone density. <h3>CONCLUSIONS:</h3> Long-term 1-thyroxine therapy is associated with decreased density of the spine and hip. Since subclinical hyperthyroidism, decreased calcitonin responsiveness, and a history of hyperthyroidism were demonstrated in some or all of these patients, these factors must be considered as possible causes of the decreased bone density.

Bone mineral density in postmenopausal women treated with L-thyroxine

purpose: To determine if bone mineral density is decreased in postmenopausal women treated with 1-thyroxine, and, if any decrease is observed, whether it is related to overtreatment with thyroid hormone, to deficiency of calcitonin, or to other factors. patients and methods: The study consisted of 19 postmenopausal women between 50 and 75 years of age treated with l-thyroxine for 5 years or longer, and 19 matching control subjects with no thyroid disease. Bone mineral density of the spine and hip was measured by dual-photon absorptiometry. Plasma calcitonin concentrations and serum thyroid hormone levels were determined by radioimmunoassays. results: The l-thyroxine-treated women had lower bone density in the lumbar spine (1.013 g/ cm 2 [95% confidence interval, 0.945 to 1.081] versus 1.134 g/cm 2 [1.026 to 1.242], p = 0.043); in the femoral neck (0.736 g/cm 2 [0.694 to 0.778] versus 0.809 g/cm 2 [0.747 to 0.872], p = 0.040); in Ward's triangle (0.576 g/cm 2 [0.530 to 0.623] versus 0.694, g/cm 2 [0.617 to 0.770], p = 0.011); and in the trochanteric area (0.626 g/cm 2 [0.581 to 0.672] versus 0.722 g/cm 2 [0.651 to 0.794], p = 0.027). The maximal increase in calcitonin following calcium infusion was 1.37 ng/L (95% confidence interval, −0.44 to 3.17) in the l-thyroxine-treated patients versus 18.8 ng/L (95% confidence interval, 10.0 to 27.5) in normal women, p <0.001. The average dose of l-thyroxine was 120 μg/day; 16 of the 19 patients had normal serum thyroxine levels. However, TSH levels were low in 13 of the 19, suggesting that l-thyroxine treatment was supraphysiologic. Seven of the 19 patients had a history of hyperthyroidism in the distant past; these patients, considered separately, had significantly reduced bone density in the hip. The other 12 patients, considered separately, did not have a statistically significant loss of bone density. conclusions: Long-term l-thyroxine therapy is associated with decreased density of the spine and hip. Since subclinical hyperthyroidism, decreased calcitonin responsiveness, and a history of hyperthyroidism were demonstrated in some or all of these patients, these factors must be considered as possible causes of the decreased bone density.

Calcitonin and bone mass status in congenital hypothyroidism

Calcitonin (CT) deficiency and its possible repercussions on bone mass were studied in a group of 9 adult patients (7 females, 2 males) with congenital hypothyroidism of dysgenetic origin. Using a new extraction method (exCT) which considerably improves the sensitivity and the specificity of the assay for CT-monomer, we measured CT levels before and after a short calcium (Ca) stimulation test (2 mg Ca/kg over 5 minutes) to evaluate C-cell secretory reserve. Mean basal plasma CT concentrations were lower in the hypothyroid women (mean +/- SEM: 0.6 +/- 0.1 pg/ml) than in 30 normal female controls (1.7 +/- 0.2 pg/ml, P less than 0.001). Serum calcium increased similarly in the two groups, but postinfusion CT levels were lower in the hypothyroid women, (1.7 +/- 0.2 pg/ml) than in normal women (16.8 +/- 2.9 pg/ml), P less than 0.001. Hypothyroid women showed a 10% reduction in bone mineral content at the diaphyseal site in the radius, 0.840 +/- 0.037 g/cm, compared with normal age-matched controls, 0.930 +/- 0.020 g/cm, (P less than 0.05). Our study demonstrates the existence of a profound CT-monomer deficiency in adult patients with thyroid agenesis or dysgenesis. Both calcitonin deficiency and thyroid hormone treatment could play a role in the observed bone loss. Attention should therefore be paid to bone metabolism during treatment of congenital hypothyroidism to avoid further bone loss.

Phaeochromocytoma--investigation and management of 10 cases.

Since 1960 we have diagnosed phaeochromocytoma (paraganglioma) in 10 children. The cases include a 15 year old girl who over a three year period presented with multiple paragangliomata and an associated malignant carotid body tumour. All children were hypertensive, eight of 10 presenting with severe headaches. Diagnosis was based on finding a raised urinary vanillylmandelic acid excretion and plasma noradrenaline concentration. In addition six of eight children were hypercalcaemic with raised plasma calcitonin concentrations; plasma parathyroid hormone concentrations were high in two of seven and four out of eight children had raised plasma renin activities on presentation. No child, however, was found to have a multiple endocrine neoplasia syndrome. Despite the introduction of newer techniques for the detection of catecholamine producing tumours we found that selective arteriography and venous catecholamine sampling were superior for tumour localisation compared with ultrasound scanning, computed tomography, and metaiodo-benzyl-guanidine (MIBG) scanning.

Secretory Protein 7B2

Mean plasma concentrations of 7B2 in three patients with medullary carcinoma of the thyroid (MCT) (294 +/- 38 pg/ml) were significantly higher than those in age-matched normal subjects (107.2 +/- 7.2 pg/ml, n = 11). The intravenous infusions of pentagastrin (0.5 microgram/kg) markedly increased the plasma concentrations of 7B2 as well as calcitonin in all three MCT patients but it caused no significant rise of the plasma 7B2 concentration in any healthy subjects. The peak times and rates of increase of plasma 7B2 concentrations were different from those of plasma calcitonin concentrations in MCT patients. The plasma 7B2 concentration in one of the patients with MCT showed a marked reduction and no further elevation from the pentagastrin infusion following a total thyroidectomy (preop. 226 pg/ml; postop. 112.1 pg/ml). The above evidence suggests that the increased levels of plasma 7B2 in MCT patients may be attributed to the release from parafollicular cells of thyroid. Therefore, 7B2 is considered to be clinically useful as a tumor marker of MCT.

Plasma concentrations of calcitonin gene‐related peptide increase during haemodialysis: relation to blood pressure*

The authors measured the plasma levels of calcitonin gene-related peptide (CGRP), the most potent vasodilatator known, during sequential ultrafiltration and haemodialysis in 12 patients using a radio-immunoassay method. Mean plasma levels of CGRP were 70.3 +/- 16.5 (mean +/- SE) pmol l-1 at the start of treatment, it increased to 85.3 +/- 17.6 pmol l-1 during ultrafiltration and to 114.5 +/- 25.3 pmol l-1 during dialysis. Systolic blood pressure decreased during haemodialysis. Plasma levels of CGRP were negatively correlated to systolic blood pressure before and at the end of dialysis, and changes in plasma levels of CGRP were strongly correlated to changes in systolic blood pressure. The increase in CGRP levels was not correlated to the fluid removal, toxin removal or changes in osmolality. The increase in plasma levels of CGRP observed during dialysis may be an important cause of dialysis induced vasodilatation and fall in blood pressure.

Effects of oral contraceptive and estrogen administration on plasma calcitonin in pre- and postmenopausal women : J. Bone Miner Res.; 4/1 (89–95)/1989/

Estrogen (E) therapy and administration of oral contraceptives (OCs) reportedly increase plasma calcitonin (CT) concentrations in women effects said to mediate in part the beneficial actions of E on the bone. To further examine this theory the authors tested the effects of 3 cycles of OC therapy in 12 young women comparing them with 10 healthy women before and after 3 normal menstrual cycles. They also determined the effects of 3 months of E therapy (ethinyl estradiol 20 mcg/day 25 of 30 days) in 14 healthy postmenopausal women using a crossover design (studied after 3 months with and 3 months without E). The authors determined CT by radioimmunoassay (antiserum G-1701) in whole plasma (iCT) and silica cartridge extracts of plasma (exCT) after overnight fasting after calcium (Ca) infusion (2 mg Ca/kg over 5 minutes) and during a normal day at 0800 1200 1700 and 2000 hours. In no control study was there a significant diurnal change in iCT or exCT and neither OCs nor E therapy altered this. Similarly OC administration did not affect basal CT levels or the normal iCT and exCT responses to Ca infusion. E therapy induced expected changes in serum Ca phosphorus and alkaline phosphatase and urinary Ca and cAMP excretion; basal and diurnal plasma exCT levels were decreased significantly consonant with the decrement in serum Ca. E did not alter normal iCT and exCT responses to Ca infusion. Thus administration of either OCs or E has no stimulatory effect on CT secretion which suggests that the beneficial actions of E on bone are not mediated through CT-induced inhibition of bone resorption. Interaction of E with CT action at the cellular level is not excluded by these findings but there are no data to support such a proposal. (authors)

Circadian rhythms of calcitonin gene expression in the rat.

The daily changes in rat thyroid calcitonin and its specific mRNA concentrations, and the relationship between their dynamics and the plasma levels of calcitonin, calcium and phosphate over a 24-h period were investigated. The circulating calcitonin concentration rose during the daily dark period when plasma calcium and phosphate levels were minimal, indicating that plasma calcitonin rhythm cannot be generated directly by a linear effect of calcium on hormone secretion. Moreover, we established that the expression of the calcitonin gene also exhibited periodic dynamics observable at the pretranslational level: the gland content of hybridizable specific calcitonin RNA displayed daily rhythms; specific RNA levels peaked during the light period and were minimal during the first part of the dark period. Significant changes in thyroid calcitonin concentrations also occurred over a 24-h period. Statistical analyses which distinguished between variations over the 24-h period and residual variations were performed to test the relationships between the various parameters. The daily rhythms of hybridizable RNA, thyroid calcitonin and plasma minerals appeared to be in phase, while the plasma calcitonin concentration displayed variations out of phase with these rhythms. The implication of the correlations observed on the residual variations is discussed in comparison with the temporal relationship between the daily variations. The results fit the hypothesis that hormone production and secretion are self-oscillating processes. Plasma concentrations of calcium and phosphate might play a role in the synchronization of the calcitonin metabolism periodicity.

Effects of oral contraceptive and estrogen administration on plasma calcitonin in pre- and postmenopausal women.

Estrogen (E) therapy and administration of oral contraceptives (OC) reportedly increase plasma calcitonin (CT) concentrations in women, effects said to mediate in part the beneficial actions of E on bone. To further examine this theory, we tested the effects of three cycles of OC therapy in 12 young women, comparing them to 10 healthy women before and after three normal menstrual cycles. We also determined the effects of 3 months of E therapy (ethinyl estradiol, 20 micrograms/day, 25 of 30 days) in 14 healthy postmenopausal women, using a crossover design (studied after 3 months with and 3 months without E). We determined CT by radioimmunoassay (antiserum G-1701) in whole plasma (iCT) and silica cartridge extracts of plasma (exCT) after overnight fasting, after calcium (Ca) infusion (2 mg Ca/kg over 5 minutes), and during a normal day at 0800, 1200, 1700, and 2000 h. In no control study was there a significant diurnal change in iCT or exCT, and neither OC nor E therapy altered this. Similarly, OC administration did not affect basal CT levels or the normal iCT and exCT responses to Ca infusion. E therapy induced expected changes in serum Ca, phosphorus, and alkaline phosphatase and urinary Ca and cAMP excretion; basal and diurnal plasma exCT levels were decreased significantly, consonant with the decrement in serum Ca. E did not alter normal iCT and exCT responses to Ca infusion. Thus, administration of either OC or E has no stimulatory effect on CT secretion, which suggests that the beneficial actions of E on bone are not mediated through CT-induced inhibition of bone resorption.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of blood calcium on calcitonin receptors in isolated chick osteoclasts.

Isolated osteoclasts obtained from young chickens fed a normal (+Ca) or deficient (-Ca) calcium and vitamin D diet for 3 weeks, were studied for their ability to bind salmon calcitonin (sCT). Osteoclasts obtained from -Ca chickens, when incubated with 0.1 mumol sCT/l, doubled cyclic (c)AMP production and retracted from a glass support, as observed by scanning electron microscopy. The presence of receptors was also demonstrated by autoradiography and competition analysis of 125I-labelled sCT binding. The number of receptors per cell was 0.9 +/- 0.1 x 10(4). In contrast, osteoclasts obtained from +Ca chickens did not increase cAMP production and did not retract in the presence of 0.1 mumol sCT/l. No specific binding of 125I-labelled sCT could be demonstrated on these osteoclasts. Plasma levels of calcium and calcitonin were measured in +Ca and -Ca chickens. The plasma concentration of calcium was markedly lower at 3 weeks in -Ca than in +Ca chickens. The plasma concentration of calcitonin was decreased in -Ca chickens compared with +Ca chickens at the first week and kept decreasing during the 3 weeks. These results strongly support the hypothesis that calcium and vitamin D intake regulate plasma calcitonin levels in chickens, and that calcitonin receptors can be detected on chicken osteoclasts only when blood calcium is decreased by a diet deficient in calcium and vitamin D.

Calcitriol synthesis is decreased in spontaneously hypertensive rats

To investigate the mechanisms of abnormal calcium metabolism, such as hypocalcemia, decreased intestinal calcium absorption and hypercalciuria in spontaneously hypertensive rats (SHR), we have measured the plasma concentration of calcitriol and its synthesis in 5-, 8-, 12-, 16-, and 20-week-old normotensive Wistar Kyoto rats (WKY) and SHR. Metabolic clearance rate (MCR) and production rate (PR) of calcitriol were measured by the constant isotope infusion method. Plasma concentration of calcitriol and PR of calcitriol were decreased in SHR after 12 weeks of age. MCR of calcitriol, however, was not different between WKY and SHR in any age group. Therefore, the decreased synthesis of calcitriol accounts for the lower plasma level of calcitriol in SHR after 12 weeks of age. Metabolic acidosis or decreased renal function could not account for the decreased synthesis of calcitriol, since the blood pH and pCO2 and creatinine clearance were similar between WKY and SHR at times when the calcitriol synthesis was reduced in SHR. Plasma concentration of ionized calcium was also lower in SHR after 12 weeks of age. Plasma concentration of calcitonin was significantly higher in 16-week-old SHR (41.6 +/- 1.5 pg/ml) than in age-matched WKY (30.5 +/- 1.7, P less than 0.001). The values, however, were not different between 8- and 12-week-old WKY and SHR. We believe that the decreased synthesis of calcitriol could be the pathogenetic factor for the development of abnormal calcium metabolism in SHR. Age of animals should be considered when studying the calcium metabolism in SHR.

Plasma calcitonin in rats with renal failure.

To study the effect of the kidney on blood calcitonin (CT), rats were made uremic by either total or partial nephrectomy or bilateral ligation of the ureters. Plasma CT concentrations were measured by radioimmunoassay before and after calcium infusion. Uremia induced by total or partial nephrectomy produced an increase in plasma CT. Rats had higher plasma CT levels (49.3 +/- 1.7 pg/ml, mean +/- SE) after total nephrectomy than after ureteral ligation (30.9 +/- 1.5 pg/ml) even though no significant difference was observed between the blood urea nitrogen (BUN) levels of these two groups. These results indicate that the kidney contributes to the degradation of CT.

Secretion and metabolism of monomeric human calcitonin: effects of age, sex, and thyroid damage.

Some data suggest that human calcitonin (CT) secretion is lower in women than in men, decreases with age and the menopause, and is absent in thyroidectomized persons. To further explore CT secretory physiology, we have studied basal and calcium-stimulated plasma immunoreactive CT (iCT) and silica-extractable monomeric CT concentrations in 148 healthy volunteers and 33 patients with a history of thyroid damage (total or subtotal thyroidectomy, radioiodine treatment for thyrotoxicosis). Both whole-plasma iCT and extractable CT levels were lower basally and after calcium infusion in women than in men, basal levels being reduced about 50% and calcium-stimulated values about 75% from those of male subjects. There were no significant changes in basal iCT or extractable CT concentrations with age, and CT secretory capacity (CT response to calcium infusion) likewise did not change with age. Infusion of monomeric CT to constant concentration in 27 persons permitted estimates of CT metabolic clearance rates (MCRs) and secretion rates (SRs). Calculated MCRs of about 9 ml/min.kg-1 (persons aged 21-30 yr) and 6 ml/min.kg-1 (persons aged 54-70 yr) were in good agreement with published data, and did not differ between the sexes. SRs were dependent upon the assay method used to estimate basal plasma CT concentrations, being highest when whole-plasma iCT values were used. Based on estimates of plasma monomeric CT from the silica extraction procedure, the SR of CT was 59 +/- 6 (SE) ng/d.kg-1 in men, and 22 +/- 3 ng/d.kg-1 in women. Thyroid damage reduced, but did not abolish, apparent CT immunoreactivity, even in silica extracts of plasma. However, all subsets of thyroid-damaged patients had absent-to-markedly-impaired CT secretion in response to calcium infusion. We conclude that CT secretion is substantially lower both basally and after stimulation in women than in men, and that this difference in CT immunoreactivity probably reflects differences in circulating CT bioactivity. The sex difference in plasma CT concentrations probably results from lower rates of CT secretion in women, not increased MCR. There is no age-related decrease of plasma CT concentrations (or CT secretory reserve), calling into question the concept that a progressive deficiency of CT is partly responsible for age-related ("senile") osteoporosis. Surgical or radiation damage to the thyroid gland commonly abolishes C-cell response to calcium; such CT-deficient patients form a population suitable for determining whether or not reduced CT secretion can impair skeletal homeostasis.

Calcitonin deficiency in primary hypothyroidism.

The relative lack of sensitivity and specificity of current assays for plasma calcitonin (CT) have made it difficult to study possible CT deficiency conditions. Using a new extraction method that considerably improves the sensitivity of the assay for CT monomer, CT levels were measured before and after a short calcium (Ca) stimulation test (2 mg Ca/kg over 5 min) to determine C-cell secretory reserve in women with autoimmune primary hypothyroidism and normal women. Mean basal plasma CT concentrations were lower in the hypothyroid women [0.9 +/- 0.1 (+/- SEM) pg/ml] than in the normal women (1.5 +/- 0.2 pg/ml; P less than 0.01). Serum Ca increased similarly in both groups, but postinfusion CT levels were lower in the women with primary hypothyroidism (3.8 +/- 1.3 pg/ml) than in normal women (15.9 +/- 3.0 pg/ml; P less than 0.001). The functional thyroid status at the time of the study did not influence CT levels; both hypothyroid patients (n = 10) and patients who were euthyroid during T4 treatment (n = 11) were CT deficient to the same extent. Unlike that in primary hypothyroidism, CT secretion was normal in four patients with hypothyroidism of pituitary origin. We conclude that the process that causes hypothyroidism in patients with autoimmune thyroid disease can also cause marked CT deficiency. This first demonstration of spontaneous CT deficiency in adults should contribute to the understanding of CT physiology; it also suggests that bone metabolism should be closely monitored during the treatment of primary hypothyroidism.