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Thyrocalcitonin and the response to parathyroid hormone.

1) In the absence of the thyroid gland, the infusion of parathyroid hormone leads to a prompt rise in plasma calcium and to prompt increase in the rate of excretion of calcium in the urine.2) In the presence of the thyroid gland, the parathyroid hormone-induced rise in plasma calcium is less marked; the rate of urinary calcium excretion falls initially and rises only after 20 to 30 hours of continuous parathyroid hormone infusion.3) The infusion of exogenous thyrocalcitonin along with the parathyroid hormone into a thyroparathyroidectomized animal leads to a pattern of response similar to that seen in the animal with an intact thyroid gland.4) Thyrocalcitonin has little apparent effect upon the immediate changes in renal function induced by parathyroid hormone.5) We conclude that bone is a major site of action of thyrocalcitonin and that it probably inhibits bone resorption.

Animals↗

An alternative analysis of intraoperative parathyroid hormone data may improve the ability to detect multiglandular disease.

HYPOTHESIS: A nomogram based on regression analysis of intraoperative parathyroid hormone level decay discriminates single gland disease from multiglandular (MG) disease more accurately than the currently used 50% rule. DESIGN: Retrospective case series. SETTING: Academic health center. PATIENTS: Two hundred thirty-five patients (222 patients with single gland disease and 13 patients with MG disease) who underwent parathyroidectomy. INTERVENTIONS: Intraoperative parathyroid hormone level analysis at baseline, time 1 (about 5 minutes), and time 2 (about 10 minutes) after excision of the first gland. MAIN OUTCOME MEASURES: The mean slope was calculated at time 1 and time 2 and analyzed using one-way analysis of variance and the Fisher least significance difference post hoc tests using data normalized to baseline intraoperative parathyroid hormone levels to compare patients with single gland disease with patients with MG disease. A regression-based nomogram was created to analyze individual kinetic decay data. RESULTS: The mean (SEM) single gland disease slope was significantly steeper than the MG disease slope at both time 1 (-0.91 [0.02] vs -0.66 [0.05]; P<.01) and time 2 (-0.77 [0.01] vs -0.56 [0.05]; P<.01). When the standard threshold rule of a 50% decrease from baseline was used, only 23% of the patients with MG disease were correctly predicted by intraoperative parathyroid hormone values (77% false-positive result rate) at time 1. However, the nomogram correctly predicted 54% of the patients with MG disease at time 1 (46% false-positive result rate). At time 2, the standard threshold 50%-rule method correctly predicted 38% of the patients with MG disease (62% false-positive result rate), while the nomogram still correctly classified 54% of the patients with MG disease (46% false-positive result rate). CONCLUSIONS: A regression-based nomogram incrementally improves prediction of MG disease compared with the standard 50%-rule method and accounts for variability in the exact timing of samples. Slope analysis suggests that the earliest time point best isolates the kinetics of the excised gland. The nomogram will need to be validated prospectively.

Academic Medical Centers↗

Early increase in plasma parathyroid hormone levels following liver transplantation.

BACKGROUND/AIMS: The pathogenesis of post-transplantation bone loss is poorly understood, although glucocorticoid therapy is believed to play an important role. In the present study we have measured plasma parathyroid hormone concentrations in the first few months after orthotopic liver transplantation, in order to examine the potential contribution of hyperparathyroidism to bone disease. PATIENTS AND METHODS: Twenty-seven patients aged 32-54 years, 12 male, undergoing liver transplantation were studied prospectively before and for 3 months after operation. Plasma parathyroid hormone and serum 25-hydroxyvitamin D concentrations were measured by radioimmunoassay. RESULTS: Plasma parathyroid hormone levels were normal in all but two patients prior to transplantation. There was a highly significant increase in plasma parathyroid hormone concentrations at 1 and 2 months (p < 0.0005 and 0.001, respectively, versus baseline); by 3 months, values were close to those obtained preoperatively. Serum 25-hydroxyvitamin D concentrations showed no significant change over the study period. However, 74% of the patients had subnormal values at baseline. CONCLUSIONS: An early and transient increase in plasma parathyroid hormone after liver transplantation may be responsible for the high rates of bone loss which occur during the first few post-operative months. Prevention of post-transplantation bone disease is most likely to be achieved by peri-operative intervention with an anti-resorptive agent.

Adult↗

Zinc(II)-mediated enhancement of the agonist activity of histidine-substituted parathyroid hormone(1-14) analogues.

Previous studies on parathyroid hormone (PTH)(1-14) revealed that residues (1-9) played a dominant role in stimulating PTH-1 receptor-mediated increases in cAMP formation. In the present study, we examined the effects of installing a metal-binding motif in the (10-14) region of rat PTH(1-14) on the peptide's agonist activity. We found that substitution of histidine for the native asparagine at position 10 of PTH(1-14) provided a peptide that was approx. 8-fold more potent as an agonist in the presence of divalent zinc salts than it was in the absence of the metal. This enhancement in potency was dependent on the native histidine at position 14, the concentration of Zn(II) utilized, and did not occur with other divalent metal ions. The zinc-activated [His(10)]-PTH(1-14) peptide was blocked by a classical PTH-1 receptor antagonist, PTHrP(7-36), and did not activate the PTH-2 receptor. The zinc-mediated enhancing effect did not require the large N-terminal extracellular domain of the PTH-1 receptor. Although we were able to demonstrate that [His(10)]-PTH(1-14) binds Zn(II) using (1)H-NMR, our spectroscopic studies (circular dichroism and nuclear magnetic resonance) were not consistent with the notion that zinc enhanced the activity of [His(10)]-PTH(1-14) simply by inducing a helical structure in the 10-14 region. Rather, the data suggest that the enhancement in cAMP potency arises from the formation of a ternary complex between [His(10)]-PTH(1-14), a zinc atom, and the extracellular loop/transmembrane domain region of the PTH-1 receptor.

Animals↗

Peripheral metabolism of [35S]parathyroid hormone in vivo: influence of alterations in calcium availability and parathyroid status.

Parathyroid hormone (PTH) is rapidly metabolized, mainly by liver and kidney, to smaller fragments that are believed to be biologically inactive. The significance of this peripheral metabolism in the overall actions of PTH is unclear. Generation of circulating biologically active amino-terminal PTH fragments during metabolism in vivo has been suggested by certain observations in vitro, and what are believed to be amino-terminal fragments may be detectable in blood under pathological circumstances in vivo (such as renal failure and coexistent hyperparathyroidism) when highly sensitive assays are employed. We recently reported, however, that administration to normal rats of [35S]bovine PTH ([35S]bPTH) directly labelled at amino-terminal methionines, followed by high-resolution chromatographic analysis of extracted [35S]peptides, does not result in appearance of radioactive amino-terminal fragments in blood, even when the tracer is continuously infused to near-physiological plasma concentrations. We have now employed these techniques to address a second question regarding hormonal metabolism: is hormonal metabolism modified during metabolic perturbations such as changing calcium availability or altered levels of calciotrophic hormones? Metabolism of [35S-Met]bPTH (900 Ci/mmol), either alone or together with [3H-Pro]bPTH, however, did not lead to alterations in the rate of hormonal clearance nor to detectable circulating amino-terminal fragments, either in calcium-deprived or thyroparathyroidectomized rats or when animals were first rendered intoxicated with vitamin D or maintained on a high calcium intake. Likewise, tissue localization and specific cleavage patterns of intact hormone in liver or kidney were all unaltered by these various manoeuvres.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Comparison of the effects of daily and intermittent-dose calcitriol on serum parathyroid hormone and ionized calcium concentrations in normal cats and cats with chronic renal failure.

BACKGROUND: Chronic renal failure is complicated by secondary hyperparathyroidism, which traditionally has been controlled by dietary restriction of phosphorus and administration of phosphorus binders. Early treatment of patients with chronic renal failure with calcitriol may be indicated because once established, parathyroid gland hyperplasia does not readily resolve with therapy. HYPOTHESIS: Daily and intermittent dosing of calcitriol will decrease plasma parathyroid hormone concentration in normal cats and cats with chronic renal failure without causing ionized hypercalcemia. ANIMALS: Ten normal cats; 10 cats with chronic renal failure. METHODS: Phase 1 was daily calcitriol administration (2.5 ng/kg PO q24h) for 14 days. Phase 2 was intermittent calcitriol administration (8.75 ng/kg PO q84h) for 14 days. A 7-day washout period separated phases 1 and 2. Before each phase, calcitriol, parathyroid hormone, and ionized calcium concentrations were measured. On days 1, 2, and 3 of both phases, serum ionized calcium concentrations were measured. On the last day of both phases, calcitriol, parathyroid hormone, and ionized calcium concentrations were measured 0, 2, 4, and 6 hours after calcitriol administration. RESULTS: Overall, serum parathyroid hormone concentrations were significantly higher in cats with chronic renal failure than in normal cats (P = .022), but serum parathyroid hormone concentrations for both normal cats and cats with chronic renal failure were not significantly different before and after 14 days of treatment with calcitriol, regardless of whether calcitriol was administered daily or intermittently. Adverse effects of calcitriol administration (specifically ionized hypercalcemia) were not seen in either feline group during either phase of the study over the 3-day evaluation after calcitriol administration was initiated. CONCLUSIONS AND CLINICAL IMPORTANCE: At the dosages used, calcitriol treatment did not result in significant differences in serum parathyroid hormone concentrations before and after treatment in both normal cats and cats with chronic renal failure. With these dosages, adverse affects of calcitriol administration were not seen. Potential reasons for lack of apparent effect include small sample size, insufficient duration of study, insufficient dosage of calcitriol, problems with formulation or administration of calcitriol, and variable gastrointestinal absorption of calcitriol.

Administration, Oral↗

Effects of calcitonin and parathyroid hormone on the distribution of F-actin in the clear zone of osteoclasts in vivo.

To elucidate the relation between the distribution of F-actin bands in the clear zone and the bone-resorbing activity of osteoclasts in vivo, the endocranial surfaces of calvariae from 7-day-old Wistar rats were stained with F-actin-specific fluorescein isothiocyanate-labeled phalloidin (FITC-phalloidin) with and without the intraperitoneal injection of the calcium-regulating hormones, calcitonin (CT), and parathyroid hormone (PTH). Some specimens were double-stained with FITC-phalloidin and a monoclonal antibody, ED1, which stained monocytes and macrophages. In normal rats, almost 80% of the osteoclasts showed ring-shaped F-actin bands in the clear zone, and the remaining 20% showed arch- or line-shaped F-actin bands. From 15 min to 1 h after the injection of CT (salmon, 10 mg/kg), the number of osteoclasts with ring-shaped F-actin bands decreased significantly. At 1 h, few F-actin bands were detected in osteoclasts, which were still stained by ED1. However, these F-actin bands recovered to the normal level at 6 h. On the other hand, from 15 min to 6 h after the injection of PTH (bovine, 50 mg/kg), the number of osteoclasts with arch- or line-shaped F-actin bands decreased significantly. These results indicate that osteoclasts with arch- or line-shaped F-actin bands in the clear zone had lower bone-resorbing activity than those with ring-shaped F-actin bands, and that the formation of bands could be controlled by calcium-regulating hormones over the course of a few hours. Observation of the endocranial surfaces of calvariae might be useful for examining factors which affect the activities of osteoclasts in vivo.

Actins↗

Nephrogenous cyclic AMP and plasma parathyroid hormone in hypercalcaemia: the influence of renal function.

Immunoreactive parathyroid hormone (PTH) levels and nephrogenous cyclic adenosine monophosphate (cAMP) have been reported to be useful parameters in the diagnosis of hyperparathyroidism. Measurements in hyperparathyroid patients usually give values above the normal range when PTH is measured with a carboxyterminal radioimmunoassay and when nephrogenous cAMP is related to glomerular filtration rate. We tested these two parameters in two groups of hypercalcaemic patients (twelve cases of primary hyperparathyroidism and fourteen cases of hypercalcaemia of non-parathyroid origin) and in two groups of normocalcaemic subjects (twenty-one young healthy volunteers and fourteen elderly subjects without parathyroid disease). Slight impairment of renal function caused elevated values of immunoreactive parathyroid hormone in a carboxyterminal radioimmunoassay and also of nephrogenous cAMP when related to glomerular filtration rate. We found that elevated nephrogenous cAMP without parathyroid disease could be attributed to renal insufficiency and to the mode of expression generally used for the nephrogenous cAMP.

Adolescent↗

Are preoperative serum calcium, parathyroid hormone, and adenoma weight predictive of postoperative hypocalcemia?

The objective of this study is to determine whether preoperative serum calcium, parathyroid hormone, or adenoma weight is predictive of postoperative hypocalcemia after removal of a parathyroid adenoma. A retrospective chart review was performed for consecutive parathyroidectomy patients over a 6-year period at a community-based teaching institution. Patients with renal failure (serum creatinine >1.7), hyperplastic disease, and parathyroid carcinoma were excluded. The outcome measures were postoperative serum calcium and the presence of signs or symptoms such as paresthesias, anxiety, or Chvostek's sign. One hundred forty-one patients underwent parathyroidectomy during the study period. Fifty-four patients were excluded as a result of hyperplastic disease, renal failure, carcinoma, or unavailable records. Of the remaining 87 patients 25 (28.7%) developed hypocalcemia (serum calcium < 8.0), and ten patients (11.5%), developed symptoms. The mean preoperative calcium levels for the normocalcemic and hypocalcemic groups were 10.9 and 10.6, respectively (P < 0.217). The mean preoperative parathyroid hormone levels (normal 10-54) were 214 and 139, respectively (P < 0.305), and the mean adenoma weights were 1.059 and 1.337 g respectively (P < 0.343). This study demonstrates no statistically significant difference in the mean preoperative serum calcium levels, parathyroid hormone levels, or adenoma weight between normocalcemic and hypocalcemic patients postoperatively.

Adenoma↗

The degradation of bovine parathyroid hormone by leukocytes.

Human peripheral leukocytes catalyse an elastase-like cleavage of bovine parathyroid hormone, with an identical specificity to that previously observed with a neutral proteinase (EC 3.4.21-) isolated from the outer surface of plasma membranes from human leukocytes. Parathyroid hormone is not hydrolysed by human erythrocytes, and polymorphonuclear leukocytes are much more effective in hormone degradation than lymphocytes. Despite the fact that purified human leukocyte granular elastase (EC 3.4.21.37) catalyses an identical cleavage reaction, the hydrolysis observed with intact cells is clearly not due to proteinases secreted by the cells. The reaction is inhibited by human serum and by purified human alpha-1-antitrypsin, but not by antibodies to human leukocyte granular elastase. The possible significance of these phenomena to the in vivo metabolism of parathyroid hormone are discussed.

Amino Acids↗

Parathyroid hormone assay. Unreliable and overused.

The records of 100 patients operated on for primary hyperparathyroidism, from Jan 21, 1982 to June 11, 1984, were reviewed. In each patient, hypercalcemia had been documented on at least two separate occasions. A history, physical examination, chest roentgenogram, complete blood cell count with differential, 18-factor automated blood chemistry analysis, and urinalysis were used to screen for other causes of hypercalcemia. Of the 100 patients who had surgery, 88 had a preoperative parathyroid hormone level determination. Preoperative parathyroid hormone levels were normal in 41% of patients with parathyroid disease demonstrated at surgery. Parathyroid hormone assays produce variable results even from the best laboratories. A serum calcium determination remains the best test for diagnosing primary hyperparathyroidism.

Adenoma↗

Morphometric analysis of compartments concerned with secretion of parathyroid hormone in male and female rats.

Parathyroid cells responded to estradiol application in rats by increment in surface area of the compartments concerned with parathyroid hormone secretion, i.e. the rough endoplasmic reticulum, Golgi complex and secretory granules. We thus compared the morphology of parathyroids of male rats with those of females of the same age and same weight, respectively. Morphometric analysis revealed that (i) the mean cell volume was significantly larger and, consequently, the number of parathyroid cells lower expressed per 1 mm3 tissue and (ii) the surface area of the Golgi complex was larger expressed per mean parathyroid cell volume and per 1 mm3 tissue in female rats than in males. Diversity in cell volume seems to depend on age rather than on sex, whereas diversity in the Golgi complex is considered to be sex related. The physiological implications remain to be clarified.

Aging↗

Serum parathyroid hormone: a double antibody radioimmunoassay.

A radioimmunoassay for parathyroid hormone (PTH) using a double antibody system is described. Because of the immunolgoical heterogeneity of the hormone in human serum, the standard used has been serum from a patient with parathyroid carcinoma. With the use of the synthetic 34 amino acid N-terminal fragment of PTH, the anti-PTH antiserum was determined to react primarily with the N-terminal end of the molecule. PTH was detectable in the sera of 25% of normal subjects and elevated in 18 of 19 patients with parathyroid adenoma and carcinoma. Serum PTH levels were elevated in 3 of 5 patients with parathyroid hyperplasia.

Adenoma↗

Effect of dialysate calcium concentration on plasma parathyroid hormone during hemodialysis.

The effect of changes in the dialysate calcium concentration on calcium fractions and parathyroid hormone species in plasma during hemodialysis has been examined. C-terminal immunoreactive parathyroid hormone was suppressed when plasma calcium increased by greater than 25% whereas N-terminal fragments demonstrated an increase. The significance of this is discussed in light of present knowledge of parathyroid hormone metabolism.

Adult↗

Cytochemical bioassay of parathyroid hormone: characteristics of the assay and analysis of circulating hormonal forms.

A cytochemical bioassay for parathyroid hormone (PTH) was used for the characterization of the biological activity of circulating forms of the hormone. PTH-stimulated glucose-6-phosphate dehydrogenase activity in distal convoluted tubule cells was quantitated by integrating microdensitometry and the response to native bovine (b)PTH(1-84) was found to be linear between graded doses of hormone from 5 fg/ml to 5 pg/ml. Synthetic bPTH(1-34) and human (h)PTH(1-34) elicited a parallel and equimolar response; however calcitonin, ACTH, glucagon, epinephrine, vasopressin, and insulin failed to significantly stimulate the enzyme in doses up to 100,000 times greater than the lowest concentration of bPTH used. The assay was capable of distinguishing hormonal activity in normal, hypoparathyroid, and hyperparathyroid human plasma. After gel chromatography, bioactivity in plasma of hyperparathyroid patients with skeletal disease but normal kidney function coeluted mainly with bPTH(1-84), whereas bioactivity in plasma of hyperparathyroid patients with skeletal disease but severe uremia coeluted in approximately equivalent amounts with bPTH(1-84) and hPTH(1-34). Despite the abundance of small molecular-weight bioactivity in the peripheral circulation in uremia, approximately 85% of the bioactivity in the parathyroid venous effluent coeluted with bPTH(1-84). The results therefore demonstrate the sensitivity and specificity of the assay for PTH and its utility in measuring the hormone in human parathyroid disorders. The results furthermore demonstrate the importance of entities cochromatographing with bPTH(1-84) in comprising the circulating bioactive hormone in hyperparathyroidism, and support the concept of a biological role for smaller forms of PTH, at least in chronic renal failure.

Animals↗

Formation and serum disappearance of fragments of parathyroid hormone in the infused dog.

Radioiodinated parathyroid hormone [125I-PTH(1-84)] was infused into intact dogs. At various times venous samples were chromatographed to determine the levels of intact hormone (1-84) and large fragments in the circulation. Both bioactive (electrolytically iodinated) and inactive (chloramine-T-labeled) preparations were used. In both instances, plateau concentrations of intact hormone and of large metabolite(s) were quickly reached. After cessation of infusion the levels of intact hormone and metabolite(s) quickly declined. Clearly, in the dog, the peripheral formation and disappearance of large fragments of exogenous PTH occur at rates comparable to the clearance of the intact hormone itself.

Animals↗

A possible mechanism whereby parathyroid hormone stimulates phospholipid synthesis in canine renal tubules.

Incubation of canine renal cortical tubules with parathyroid hormone and [3H]glycerol stimulated incorporation of tracer into phosphatidylinositol 4-phosphate and decreased phosphatidic acid labelling but did not affect phosphatidylinositol, phosphatidylcholine/phosphatidylserine, phosphatidylethanolamine/phosphatidylglycerol, 1,2-diacyl- or triacylglycerol labelling. The hormone did not change the activity of glycerol 3-phosphate acyltransferase or of phosphatidate phosphohydrolase measured in tubule homogenates. However, parathyroid hormone induced a rapid increase in phosphatidylinositol kinase activity associated with a decrease in Km of the enzyme for ATP in homogenized tubules. These findings suggest a possible mechanism whereby parathyroid hormone increases phospholipid synthesis in the renal cortex.

1-Phosphatidylinositol 4-Kinase↗

Cardiac electrophysiologic effects of parathyroid hormone in the guinea pig.

The cardiac electrophysiologic effects of parathyroid hormone (PTH) were studied in three different experimental models. Purified synthetic human parathyroid hormone (hPTH 1-84), at a dose of 30 ng/g body weight (BW), prolonged the QT interval of surface ECGs in intact guinea pigs. To further clarify the mechanisms of the QT prolongation caused by hPTH, the action potentials of guinea pig papillary muscle were recorded by conventional microelectrode techniques. hPTH (10(-7)M) prolonged the action potential duration without changing the action potential amplitude, resting potential, maximal upstroke velocity of the action potential, or maximal repolarization rate. hPTH affected only the plateau phase, in a concentration-dependent fashion. The half-maximum concentration was 6.8 x 10(-8)M for action potential duration at 30% repolarization (APD30), 3.2 x 10(-8)M for APD50, and 2.1 x 10(-8)M for APD90. In isolated single guinea pig ventricular cells, the patch clamp method was used to record the slow inward calcium current (ICa) and delayed rectifier potassium current (IK) responsible for the action potential plateau phase. hPTH increased the peak amplitude of ICa at + 10mV by an average of 42%, and increased IK at + 10mV by 85%. These results indicate that, in ventricular muscle, hPTH prolongs the action potential duration and QT interval by the balance of the prolongation effect on APD by enhancing the slow inward calcium current and the shortening effect on APD by enhancing the delayed rectifier potassium current.

Action Potentials↗