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Cyclic AMP production in rat calvaria in vitro: interaction prostaglandins with parathyroid hormone.

We studied the cAMP response of cultured rat calvaria to parathyroid hormone (PTH) and prostaglandins (PG) in order to test the hypothesis that PTH action is mediated by PG. PTH and PGE1 each caused an 8-fold increase in tissue cAMP during 15 min incubation. There was an additive response to the combination of the two agonists at maximally effective individual concentrations. Similar results were obtained when adenylate cyclase activity in bone homogenates were measured. Calvaria incubated for 60 min with PGE1 were desensitized to further stimulation by PGE1, but responded normally to PTH. Indomethacin, aspirin and phenylbutazone, 10(-5)M, had no effect on the cAMP response to PTH. At millimolar concentration these agents did block the hormone response; however, the response to exogenous PGE1 and the fluoride-sensitive adenylate cyclase were also inhibited. Thus, it appears that the effects of high concentrations of the anti-inflammatory drugs on cAMP formation are non-specific. Our results suggest that receptors in bone for PTH and prostaglandins are separate and independent, and that the cAMP response to PTH is not mediated by prostaglandins.

Adenylyl Cyclases↗

NMR solution structure of the [Ala26]parathyroid-hormone-related protein(1-34) expressed in humoral hypercalcemia of malignancy.

The structure of the biologically active N-terminal domain of human parathyroid-hormone-related protein (residues 1-34) containing an Ala substituted for a His in position 26 was studied by two-dimensional proton NMR spectroscopy. Unambiguous NMR assignments of all backbone and side-chain hydrogens were made with the aid of totally correlated spectroscopy experiments, which provided through-bond 1H-1H connectivities, and NOE spectroscopy, which provided through-space and sequential backbone connectivities. The NMR data were utilized in distance-geometry algorithms to generate a family of structures. The major structural features include two segments of alpha-helix extending from Glu4 to Lys13 and from Leu27 to Thr33, with two turns from Gln16 to Arg19 and Phe22 to His25. A salt-bridge appears likely between Arg20 and Glu30 which may be critical for holding the receptor-binding domain together.

Amino Acid Sequence↗

Is there low-dimensional chaos in pulsatile secretion of parathyroid hormone in normal human subjects?

In many biological systems information is transferred by hormonal ligands, and it is assumed that these hormonal signals encode developmental and regulatory programs in mammalian organisms. The specificity of the biological response on activation by a hormone has so far been located within the interaction of a specific conformation of the ligand with the corresponding receptor structure. According to these classical explanations, the constant circulating hormonal pool described by the rate of its production and metabolic clearance is a major determinant of this interaction. Recently it has become apparent that hormone pulses contribute to this hormonal pool. Phase-space analysis of dynamic parathyroid hormone (PTH) secretion allowed the definition (in comparison to normal subjects) of a relatively quiet "low dynamic" secretory pattern in osteoporosis, and a "high dynamic" state in hyperparathyroidism. We now investigate whether this pulsatile secretion of PTH in healthy humans exhibits characteristics of low-dimensional deterministic chaos. Our findings suggest that this indeed appears to be the case. PTH secretion thus seems to be a first example of a chaotic hormonal rhythm in human physiology.

Adult↗

Parathyroid hormone secretion after operation for primary hyperparathyroidism.

BACKGROUND: Primary hyperparathyroidism (pHPT) is associated with a defective regulation of the secretion of parathyroid hormone (PTH). Thus in pHPT, higher than normal calcium concentrations are required to inhibit PTH release. However, it is not known if this defective regulation is normalized by removal of the parathyroid adenoma (i.e., whether the regulation of PTH secretion is normal in the remaining glands). In this study we therefore investigated the PTH secretion in patients operated on for parathyroid adenoma 1 year after operation. METHODS: Na2 ethylenediamine tetraacetic acid and CaCI2 were infused at constant rates in six patients operated on for parathyroid adenoma and six healthy individuals. Serum levels of intact PTH and ionized calcium were determined during the infusions. RESULTS: No significant differences between the two groups were found in baseline levels of serum ionized calcium and PTH. Furthermore, no significant differences between patients and control subjects were found in the maximum serum PTH levels during the hypocalcemic infusion of ethylenediamine tetraacetic acid or in the minimum serum PTH levels during the calcium infusion. In contrast, the set point (the calcium concentration required for half-maximal inhibition of PTH secretion) was significantly lower in the patients (1.20 +/- 0.01 mmol/L) compared with control subjects (1.22 +/- 0.01 mmol/L; p < 0.05). CONCLUSIONS: We conclude that the elevation of set point in patients with parathyroid adenoma is corrected by successful operation. This suggests a monoclonal origin of parathyroid adenomas.

Adenoma↗

Changes in parathyroid hormone in diabetic patients on long-term hemodialysis.

Changes in parathyroid hormone (PTH) and osteocalcin over 3 years were studied in hemodialyzed patients with diabetic nephropathy (HD/DM) and hemodialyzed patients without diabetes (HD/non-DM). In HD/DM patients, concentrations of the carboxyl terminal regions of PTH and osteocalcin in the serum did not change significantly, but in HD/non-DM patients, both concentrations increased significantly. In patients in both groups, the mean concentration of the mid-region of PTH increased significantly. Secondary hyperparathyroidism in HD/DM develops slower than in HD/non-DM.

Female↗

Effects of parathyroid hormone in vivo on the protein kinase activity in rat kidney.

Parathyroid hormone (PTH) was infused into thyroparathyroidectomized rats, and the protein kinase activity of the kidney was studied. When the tissue was homogenized in a buffer containing 5 mM potassium phosphate (pH 7.0), 2 mM EDTA, 1 mM mercaptoethanol, and 5 mM theophylline, the total protein kinase activity (measured in the presence of 5 muM cAMP) in the cytosol was decreased by the infusion of PTH, exhibiting an inverse relationship to cAMP level in the renal tissue. The decrease of total activity was accounted for by a decrease of cAMP-dependent kinase activity, and such a change was induced also by the infusion of calcitonin or dibutyryl cAMP. A substantial enzyme activity was solubilized from the particulate fraction with a buffer containing KC1. The infusion of PTH increased the kinase activity (activities measured in both the presence and absence of cAMP) solubilized from the particulate fraction, suggesting the translocation of activated enzyme from cytosol to some particulate cell component(s). However, when KC1 was added to the homogenization buffer in concentrations up to 150 mM or even higher, the total protein kianse activities in the cytosols of control and PTH rats were similar and there was simply an increase in the fraction of cAMP -independent activity. These observations indicate that the hormonally-induced increase of cAMP in vivo activates protein kinase of the kidney, and the activation of kinase results in apparent translocation of the enzyme from the soluble to the particulate fraction when the tissue is homogenized in buffers of low ionic strength. The physiological significance of this phenomenon, however, cannot be evaluated, due to the fact that the increased association of activated kinase with particulate component(s) is reversed by employing a homogenization buffer containing what is probably a physiological concentration of salt.

Animals↗

Elevated serum parathyroid hormone concentration during treatment with high ceiling diuretics.

Serum concentrations of parathyroid hormone (s-PTH) calcium, phosphorus and alkaline phosphatase were measured during treatment with furosemide or bumetanide for congestive heart failure. Significant elevations both of s-PTH and alkaline phosphatase were found, whereas serum calcium concentration was decreased. The changes were not related to the dose of drug or to the duration of treatment. It is concluded that treatment with furosemide or bumetanide may cause hypocalcaemia, resulting in elevation of s-PTH. The increased concentration of alkaline phosphatase may indicate accelerated bone remodelling, as found in primary hyperparathyroidism.

Adult↗

[Human parathyroid hormone (1-34) as a new therapeutic agent for osteoporosis].

Human parathyroid hormone (PTH) is used clinically for severe osteoporosis in North America and Europe. The clinical trial is now in progress in Japan. In this review, I introduce the additive effects of PTH with bone resorption inhibitors, the different effects on bone structure and quality between PTH and bone resorption inhibitor, and the bone-increasing effects of PTH involved in IGF/IRS, AP-1 and Wnt pathways. I focus on new topics including the presentations in ASBMR (American Society for Bone and Mineral Research) 2004.

Alendronate↗

Minimal-access parathyroid surgery using intraoperative parathyroid hormone assay.

OBJECTIVES: Review the most current preoperative localization imaging techniques in patients with primary hyperparathyroidism and demonstrate their applicability to targeted tumor removal with intraoperative parathyroid hormone (PTH) monitoring. STUDY DESIGN: Retrospective review of 40 consecutive patients undergoing parathyroid surgery with intraoperative PTH assay as the principal determinant of correction of the hyperparathyroid state. Details of the technology, cost analysis, and comparison with other management methods are discussed. METHODS: The standard intact PTH chemiluminescent assay (Nichols Diagnostics) and modifications to allow accelerated intraoperative results are discussed in detail. The time intervals between completion of parathyroid excision and postremoval assay and subsequent laboratory investigation present a practical therapeutic algorithm. RESULTS: Forty consecutive patients with hyperparathyroidism were treated surgically with intraoperative PTH as the determinant of satisfactory resolution of the disease state. In most instances, the surgical field was reduced to the targeted pathology identified by preoperative localization, and all patients became eucalcemic when this method was employed. Approximately half of eligible patients were treated under local anesthesia. CONCLUSIONS: Intraoperative PTH assay has added a new dimension to primary and revision parathyroid surgery. It is cost-effective and accurate and may reduce the morbidity of surgical intervention in revision procedures.

Adenoma↗

Reversible resistance to the renal action of parathyroid hormone in human vitamin D deficiency.

1. The response to exogenous parathyroid hormone (PTH) was tested in normal subjects and patients with osteomalacia due to vitamin D deficiency; 200 MRC units of bovine PTH were administered intravenously. 2. The rise in plasma adenosine 3':5'-cyclic monophosphate (cyclic AMP) and the increase in urinary excretion of cyclic AMP were reduced in the patients with vitamin D deficiency. After treatment with vitamin D the responses returned to normal. 3. It is suggested that this reversible resistance is due to the secondary hyperparathyroidism associated with vitamin D deficiency.

25-Hydroxyvitamin D 2↗

Regulation of NaPi-IIa mRNA and transporter protein in chronic renal failure: role of parathyroid hormone (PTH) and dietary phosphate (Pi).

Chronic renal failure (CRF) is associated with a high fractional phosphate excretion (FEPi), secondary hyperparathyroidism, and resistance to parathyroid hormone (PTH). This study was undertaken to characterize the role of PTH and dietary Pi in the regulation of PTH/PTH-related peptide receptor (PTHrP-R) mRNA and NaPi-IIa mRNA and protein in CRF. The following groups of rats were studied: (1) sham-operated (control); (2) CRF: 6 weeks after 5/6 nephrectomy (NPX); (3) NPX and parathyroidectomy (NPX + PTX); (4) NPX rats fed a low-Pi diet (NPX + LP); (5) sham-operated rats fed a low-Pi diet (control + LP); (6) sham-operated after PTX (control + PTX). Expression of NaPi-IIa mRNA and PTH/PTHrP-R mRNA was determined in the renal cortex by Northern hybridization. NaPi-IIa protein abundance was determined in cortical brush border membranes by immunoblotting. In NPX rats creatinine clearance decreased to 40 +/- 4%, PTH/PTHrP-R mRNA to 52.1 +/- 2% and NaPi-IIa mRNA to 41.2 +/- 5.5% of control. The PTH/PTHrP-R and NaPi-IIa mRNA in the NPX + PTX and NPX + LP group was similar to that in NPX. NaPi-IIa protein abundance was reduced in NPX compared with control, but was increased dramatically in NPX + PTX and NPX + LP compared to NPX, paralleled by a decrease in FEPi. These findings suggest that the elevated FEPi in CRF is maintained by decreased NaPi-IIa mRNA and NaPi-IIa protein abundance. In contrast, the observed decrease in FEPi with PTX or LP diet in CRF is mediated, at least partly, by increased NaPi-IIa protein abundance with no change in NaPi-IIa mRNA, suggesting post-transcriptional regulation of the NaPi-IIa transporter.

Administration, Oral↗

Observations on the effect of parathyroid hormone on environmental blood lead concentrations in humans.

The effect of parathyroid hormone (PTH) on blood lead (Pb) concentrations was observed preliminarily in three different situations. Of 342 healthy bus drivers with no unusual exposure to Pb, 25 drivers with the highest and 25 with the lowest blood Pb were compared for serum PTH concentrations. There was no association between blood Pb and serum PTH concentrations. Eight women with postmenopausal osteoporosis enrolled in an experimental protocol to increase bone mass received daily PTH (1-34 fragment) for 1 week, calcitonin for the next 2 weeks, and oral calcium for the subsequent 10 weeks. This cycle was repeated four times during the year. Initial blood Pb concentrations averaged 6.0 micrograms/dl (range 2.1-8.9). Mean blood Pb concentrations decreased by 1.7 micrograms/dl over 1 year of therapy. The confidence interval for this change excluded zero, the mean change was significantly different from the mean change for comparative population (P less than 0.050), and paired changes were statistically significant (P = 0.045). Lastly, a single subject with hyperparathyroid disease and no unusual exposures to lead demonstrated stabilized blood Pb concentrations that were 50% lower after removal of his hyperplastic parathyroid glands. These observations suggest that the effect of PTH on increasing bone turnover and releasing Pb into blood is not easily detected at low physiologic amounts of PTH, but that with pathologic increases of PTH in hyperparathyroid disease, elevation of blood Pb from bone or increased gastrointestinal absorption may be possible. Likewise, either bone building therapies (PTH + calcitonin + calcium) may move Pb from blood into bone or supplemental calcium may decrease Pb gastrointestinal absorption, thereby explaining the observed lower blood Pb concentrations.

Adult↗

Serum intact parathyroid hormone levels in elderly Chinese females with hip fracture.

Serum intact parathyroid hormone (PTH), 25 hydroxyvitamin D(25OHD), 1,25 dihydroxyvitamin D (1,25(OH)2D), albumin, and ionized calcium were measured in 61 Chinese female patients with hip fracture and 61 control subjects. Hip fracture patients had low albumin, ionized calcium, and 250HD levels. Serum PTH and 1,25(OH)2D values were not different between the two groups. We conclude that although 250HD level in hip fracture patients is low, there is no evidence of secondary hyperparathyroidism, suggesting that the low 250HD levels may be a secondary phenomenon in response to the fracture.

Aged↗

Intraoperative parathyroid hormone assay for management of patients undergoing total thyroidectomy.

BACKGROUND: Rapid parathyroid hormone (PTH) assay has been applied to predict hypocalcemia after thyroidectomy compared with conventional close monitoring of serum calcium levels. We evaluated the reliability of intraoperative intact PTH (ioPTH) assay to predict hypocalcemia after total thyroidectomy and sought to develop an algorithm for the management of postthyroidectomy patients. METHODS: Rapid PTH assays were performed before and after thyroidectomy for 92 new patients receiving total thyroidectomy. Preoperative and postoperative serum calcium and standard PTH levels were serially obtained to 6 months after surgery RESULTS: Postoperative hypocalcemia developed in 34 of 92 patients (37%), who showed significantly lower ioPTH values compared with those of normocalcemic patients (mean 9.2 pg/mL vs 31.3 pg/mL). The ioPTH levels were significantly correlated with standard PTH levels (p < .001, r > 0.62), but not with early serum calcium levels within 8 hours after the operation. Sensitivity and specificity of ioPTH levels of <15.0 pg/mL for the prediction of postoperative hypocalcemia were 85% and 84%, respectively. A value of >15.0 pg/mL and <70% decline in ioPTH after thyroidectomy can reliably identify normocalcemic patients during thyroidectomy or patients requiring close monitoring and early calcium supplement CONCLUSIONS: Rapid ioPTH assay can reliably monitor parathyroid function after thyroidectomy and predict postoperative hypocalcemia. The proposed algorithm based on rapid PTH levels will lead to improved prediction of normocalcemic patients.

Adolescent↗