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PubMed1988

Diagnostic limitations of region-specific parathyroid hormone assays in the investigation of hypercalcaemia.

Assays for N-terminus, C-terminus and mid-molecule parathyroid hormone have been assessed with respect to their sensitivity and specificity in the diagnosis of primary hyperparathyroidism (1 degree HPT). The mid-molecule assay was the most sensitive method studied and only failed to identify one out of 30 patients with histologically proven 1 degree HPT. In all three assays there was some degree of overlap between results observed in 1 degree HPT and in patients with non-parathyroid hypercalcaemia, with results in the latter group sometimes falling well within the hyperparathyroid range. This study highlights the limitations of currently available methods and emphasises the need for caution in the interpretation of parathyroid hormone (PTH) measurements.

Adult↗
PubMed1999

1Alpha,25-dihydroxy-3-epi-vitamin D3, a natural metabolite of 1alpha,25-dihydroxyvitamin D3, is a potent suppressor of parathyroid hormone secretion.

1Alpha,25(OH)2D3 is an important negative regulator of parathyroid hormone (PTH) gene transcription. In parathyroid cells, as in other target tissues, 1alpha,25(OH)2D3 is degraded by side chain oxidation by the inducible 24-hydroxylase. We have previously shown that one metabolite of this pathway, 1alpha,23(S),25-(OH)3-24-oxo-D3, potently suppresses PTH synthesis and secretion in cultured bovine parathyroid cells (bPTC). Further examination of the metabolites of 1alpha,25(OH)2D3 in bPTC has revealed another compound that is less polar than 1alpha,25(OH)2D3. By HPLC analysis and mass spectrometry, this metabolite was identified as 1alpha,25(OH)2-3-epi-D3. The activity of this metabol ite on PTH gene transcription was assessed by the steady-state PTH secretion by bPTC after 72-h treatment with concentrations from 10(-11) M to 10(-7) M. 1Alpha,25(OH)2-3-epi-D3 was found to be only slightly, but not significantly, less active than the native 1alpha,25(OH)2D3 in suppressing PTH secretion despite having 30 times lower affinity for the bPTC VDR. Both 1alpha,25(OH)2D3 and 1alpha,25(OH)2-3-epi-D3 maximally suppressed PTH secretion by 50%. Along with 1alpha,25(OH)2-3-epi-D3, the activities of the other two A-ring diastereomers were assessed. 1beta,25(OH)2D3 suppressed PTH only at 10(-7) M with a decrease of only 30%, in good agreement with its low VDR affinity. Surprisingly, 1beta,25(OH)2-3-epi-D3 stimulated PTH secretion by 30-50% at concentrations from 10(-11) M to 10(-8)M and fell to control (untreated) rates at 10(-7) M. The mechanism for this increase in PTH secretion is under investigation. Metabolism studies performed in bPTC cells using high concentrations of 1alpha,25(OH)2D3 substrate showed that in some incubations, the concentration of 1alpha,25(OH)2-3-epi-D3 was even higher than that of the parent substrate 1alpha,25(OH)2D3. This finding indicates a slower rate of metabolism for this diastereomer. Thus, production and accumulation of 1alpha,25(OH)2-3-epi-D3, as a major stable metabolite of 1alpha,25(OH)2D3 in parathyroid glands, may contribute to the prolonged suppressive effect of 1alpha,25(OH)2D3 on PTH gene transcription.

Animals↗
PubMed1986

Parathyroid hormone and calcitonin modify inositol phospholipid metabolism in fetal rat limb bones.

Inositol-containing phospholipids are believed to be intimately involved in the first steps of cellular signalling by certain hormones and neurotransmitters. We examined whether parathyroid hormone (PTH) and calcitonin (CT), two hormones that affect bone physiology, would elicit changes in inositol-phospholipid metabolism in cultured bone. [3H]inositol readily entered into the tissue phospholipid pool in fetal rat limb bones, and incorporated into phosphatidylinositol (92.9%), phosphatidylinositol-4-P (4.5%), and phosphatidylinositol-4,5-P2 (2.6%). PTH enhanced the incorporation of inositol into PtdIns in limb bones following 2- or 24-h hormone treatments. The effect of PTH was dose dependent (EC50 of 0.3-0.4 nM) and occurred in a concentration range similar to that for hormone-stimulated bone resorption. In contrast, 24-h treatment with CT-inhibited inositol incorporation, also in a dose-dependent manner. Two-hour CT treatment had variable effects on labeling. CT inhibited the stimulatory effect of PTH at both 2 and 24 h. The effects induced by PTH and CT were specific for PtdIns and were independent of the [3H]inositol pool size. These results indicate that inositol-phospholipid turnover can be modified during the action of these hormones on bone tissue. Although the time course of hormone-stimulated inositol incorporation observed here is slower than that found in other tissues, the change in phosphatidylinositol metabolism could mediate delayed effects of PTH or CT. Alternatively, alterations induced by PTH and CT in bone cell membranes, cell populations, or in the mineralized matrix could conceivably result in secondary changes in phosphatidylinositol metabolism.

Animals↗
PubMed1987

Identification of an antigenic determinant in the amino-terminal sequence of parathyroid hormone.

The application of a hydrophilicity plot to define an antigenic determinant in the amino-terminal sequence of human parathyroid hormone is reported. The data obtained were compared to specificity studies of three antibodies, one polyclonal and two monoclonal, against the same portion of the molecule. Results were coincident. These data support the use of the hydrophilicity plot in the prediction of antigenic sites in the parathyroid hormone molecule.

Antibodies↗
PubMed1981

In vivo demonstration of receptors in rat liver to the amino-terminal region of parathyroid hormone.

The specific binding of the amino-terminal region of parathyroid hormone (PTH) to liver has been assessed by in vivo radioautography employing a biological active 125I-labeled synthetic bPTH analog ([Nle-8,18, Tyr-34]bPTH-(1-34) amide) as a probe. Two minutes after intrajugular injection of the labeled analog into rats, free hormone was separated from that bound to cells by intracardiac perfusion with buffer (30 sec), followed by perfusion-fixation with glutaraldehyde. By light and electron microscope radioautography, the distribution of silver grains over the liver sections revealed localization over the periphery of hepatocytes as well as over endothelial cells. In simultaneous control experiments, the unlabeled synthetic active fragment bPTH-(1-34) and unlabeled intact native bPTH-(1-84) significantly inhibited binding of the labeled analog to liver hepatocytes but not to endothelial cells. Greater uptake of the 125I-labeled bPTH analog was found in rat liver (28% of the injected dose) than in kidney, bone, or other organs examined. In parallel experiments using purified plasmalemma fractions from hepatocytes, both bPTH-(1-34) and intact bPTH-(1-84) demonstrated a dose-dependent activation of adenylate cyclase which was less than that of glucagon but greater than that of epinephrine. The combined results support the concept of the liver as a target organ for the amino-terminal biologically active region of PTH.

Adenylyl Cyclases↗
PubMed2005

Intraoperative parathyroid hormone testing improves cure rates in patients undergoing minimally invasive parathyroidectomy.

BACKGROUND: Intraoperative parathyroid hormone (iPTH) testing often is used during minimally invasive parathyroidectomy for primary hyperparathyroidism (1 degrees HPT). However, several investigators report that these assays are not cost effective and do not improve outcomes significantly. METHODS: To determine the impact of iPTH testing on the outcomes of patients with 1 degrees HPT, we reviewed our experience. From January 1990 to June 2004, there were 345 consecutive patients with 1 degrees HPT and positive localization studies for a single parathyroid adenoma who were candidates for minimally invasive parathyroidectomy. Group 1 patients (n = 157) underwent parathyroid exploration without iPTH testing and group 2 patients (n = 188) had an operation with iPTH testing. RESULTS: Of the group 1 patients, 15 (10%) still were hypercalcemic postoperatively owing to additional unidentified hyperfunctioning parathyroid glands. In contrast, among 188 group 2 patients, 170 (90%) had resection of a single parathyroid adenoma, a greater than 50% decrease in iPTH levels, and were cured. The remaining 18 (10%) patients did not have an adequate reduction in iPTH levels and underwent bilateral neck exploration with resection of additional parathyroids. Of these 18 patients, 9 had double adenomas and 9 had 3- or 4-gland hyperplasia. Importantly, all patients in group 2 were cured. CONCLUSIONS: iPTH testing improves cure rates in patients undergoing minimally invasive parathyroidectomy. iPTH testing allowed intraoperative recognition and resection of additional hyperfunctioning parathyroids missed by preoperative imaging studies. Consequently, we strongly advocate the routine use of iPTH testing in patients who undergo minimally invasive parathyroidectomy for 1 degrees HPT.

Adenoma↗
PubMed1995

Intermittent treatment with human parathyroid hormone (hPTH[1-34]) increased trabecular bone volume but not connectivity in osteopenic rats.

Previous studies have determined that intermittent parathyroid hormone (PTH) therapy increases bone mass and improves biomechanical strength in osteopenic animal models. The purpose of this investigation was to determine if intermittent human parathyroid hormone (hPTH[1-34]) therapy increased trabecular bone volume and connectivity in a rat model of established osteopenia using three-dimensional (3D) ex vivo in situ morphometry by X-ray tomographic methods (XTM). Six-month-old retired Sprague-Dawley breeder rats were used. Thirty animals were ovariectomized (OVX) and six were Sham operated. On day 56, post-OVX, a prePTH-treatment OVX groups was sacrificed. The remaining OVX animals were randomized into four groups of six animals each, given injections 5 out of every 7 days for 28 days of either vehicle or hPTH(1-34) at 4, 40, or 400 microg/kg of body weight (BW)/day and were sacrificed on day 84 post-OVX. At sacrifice, the left proximal tibias were harvested for XTM scans. hPTH(1-34) at medium and high doses significantly increased trabecular bone volume and trabecular thickness compared with ovariectomized animals treated with vehicle (p<0.05). The trabecular bone volume was equal to or greater than the Sham-operated animals in both hPTH(1-34) 40 and 400 microg/kg of BW treatment groups. Trabecular bone connectivity decreased by nearly 50% compared to the S ham-operated group at day 84 post-OVX and did not increase with any of the hPTH(1-34) treatments. Intermittent hPTH(1-34) treatment is osteopenic OVX rats increased trabecular bone volume to control levels or higher by thickening existing trabeculae. Human PTH(1-34) did not re-establish connectivity when therapy was started after 50% of the trabecular connectivity was lost. We hypothesize that to re-establish trabecular connectivity, a therapeutic intervention would have to be given before a significant distance between trabeculae has developed. Further studies will need to be done to refute or confirm our hypothesis.

Animals↗
PubMed1990

Characterization of the major parathyroid hormone target cell in the endosteal metaphysis of rat long bones.

The majority of in vivo competitive binding of parathyroid hormone (PTH) in the endosteal metaphysis of rat long bones was recently shown to be localized in the intertrabecular tissue to a cell that is distinct from a differentiated osteoblast. In the present report we have further characterized this cell, termed a parathyroid hormone target (PT) cell, by light and electron microscopy using radioautography and histochemical techniques. These studies demonstrate that the PT cell is a mononuclear cell with a large cell body located at times between clusters of differentiated osteoblasts, as well as in other regions of the intertrabecular tissue. Its long cytoplasmic processes extend from the bone matrix through the intertrabecular region toward vascular structures, interdigitating with various cells of the endosteum. A distinctive tubular structure originating in the Golgi system and often associated with long mitochondria and glycogen particles extends throughout the cytoplasmic processes of the PT cell. Based on its capacity to incorporate [3H]thymidine, the PT cell appears to divide rather slowly. The identification of occasional hybrid cells with ultrastructural features of both the PT cell and the differentiated osteoblast and the presence of histochemical evidence for alkaline phosphatase activity suggest that the PT cell is of the osteoblast lineage. These studies therefore morphologically define a major osseous target cell for PTH that, although of the osteoblast lineage, is not a differentiated osteoblast and provide in vivo evidence that characteristics of the "osteoblast phenotype" are not restricted to a sole osseous cell type.

Animals↗
PubMed1990

Parathyroid hormone related peptide can function as an autocrine growth factor in human renal cell carcinoma.

Parathyroid hormone related peptide (PTHrP) has been implicated in the cause of the hypercalcemia associated with a number of malignant tumours. The data presented here suggests that PTHrP (in addition to its known role of mediating hypercalcemia) may be involved in the autocrine regulation of growth of some tumours. Polyclonal PTHrP antiserum almost totally inhibited the growth of a human renal cell carcinoma cell line, known to secrete PTHrP, in vitro and growth was significantly inhibited by the competitive PTH antagonist PTH (3-34)NH2.

Carcinoma, Renal Cell↗
PubMed2002

Biosynthesis and secretion of parathyroid hormone are sensitive to proteasome inhibitors in dispersed bovine parathyroid cells.

Preproparathyroid hormone (prepro-PTH) is one of the proteins abundantly synthesized by parathyroid chief cells; yet under normal growth conditions, little or no prepro-PTH can be detected in these cells. Although this may be attributed to effective cotranslational translocation and proteolytic processing, proteasome-mediated degradation of PTH precursors may be important in the regulation of the levels of these precursors and hence PTH secretion. The effects of N-acetyl-Leu-Leu-norleucinal, N-acetyl-Leu-Leu-methional, carbobenzoxy-Leu-Leu-leucinal (MG132), benzyloxycarbonyl-Ile-Glu(t-butyl)-Ala-leucinal (proteasome inhibitor I), and lactacystin on the biosynthesis and secretion of PTH were examined in dispersed bovine parathyroid cells. We demonstrate that treatment of these cells with proteasome inhibitors caused the accumulation of prepro-PTH and pro-PTH. Compared with mock-treated cells, the processing of pro-PTH to PTH was delayed, and the secretion of intact PTH decreased in proteasome inhibitor-treated cells. Relieving the inhibition of the proteasome by chasing MG132-treated cells in medium without the inhibitor led to the rapid disappearance of the accumulated prepro-PTH, and the rate of PTH secretion was restored to levels comparable to those in mock-treated cells. Furthermore, overexpression of the Hsp70 family of molecular chaperones was observed in proteasome inhibitor-treated cells, and we show that PTH/PTH precursors interact with these molecular chaperones. These data suggest the involvement of parathyroid cell proteasomes in the quality control of PTH biosynthesis.

Acetylcysteine↗
PubMed1978

Effects of parathyroid hormone on the osteoclastic pool, bone resorption and formation in rat alveolar bone.

The osteoclast number and its relation to parathyroid hormone have been studied in rat alveolar bone by quantitative histology and fluorescent labeling. The osteoclast number decreases 60 h after parathyroidectomy and remains constant for the next 132 h. Parathyroid hormone administration to parathyroidectomized animals 96 h after the operation induces an increase in osteoclast number within 12 h to somewhat above those of control animals. The elevated osteoclast counts remain constant for 60 h then rapidly fall over the next 24 h to the level seen in untreated parathyroidectomized animals. As determined by fluorescent labeling, normal alveolar bone resorption and formation were disturbed by parathyroidectomy, such that significant bone formation occurred for only 6 days after surgery, after which a quiescent state followed.

Alveolar Process↗
PubMedDate not supplied

[Hypoparathyroidism following total thyroidectomy: prognostic value of intraoperative parathyroid hormone assay].

Transient and definitive hypoparathyroidism represent a frequent complication after thyroid surgery. Recently some authors proposed the use of intraoperative parathyroid hormone assay for the rapid detection of this complication. In this paper the authors describe the data obtained from 42 total thyroidectomies with intraoperative measurements of parathyroid hormone. When parathormone decrement was over 75% during thyroidectomy, the hypocalcemic symptomatology was found in all cases during postoperative observation. The authors emphasize intraoperative PTH dosage for immediate identification of patients at risk for postoperative hypoparathyroidism. In this cases parathyroid autotransplantation is suggested to prevent postoperative hypoparathyroidism.

Adult↗
PubMed1980

The effect of parathyroid hormone on technetium-99m pyrophosphate distribution in rats.

Sprague-Dawley rats were treated with varying quantities of parathyroid hormone for 1--3 days, then sacrificed at periods ranging from 1--6 h after administration of 99mTc-pyrophosphate. Very little increase in bone accumulation of tracer occurred with this treatment. A small, but obvious decrease occurred in the blood levels of 99mTc-pyrophosphate and a smaller and less consistent decrease was affected in the muscle levels of the radiopharmaceutical. The overall result was an improvement in the bone/blood and bone/muscle ratios. It is suggested that the basis of the "supernormal" bone scan of hyperparathyroidism is achieved by this mechanism and that the increased bone uptake of other ions in response to parathyroid hormone is not shared by 99mTc-pyrophosphate.

Animals↗
PubMed1976

[Effect of parathyroid hormone and thyrocalcitonin on the cell membrane Na, K-ATP-ase of rat brain and kidney].

The influence of parathyroid hormone (PH) and thyrocalcitonine (TCT) on the enzymatic activity of ATP-ase systems of the membrane specimens of the cerebral cortex and renal cortex was investigated in experiments on rats. It was found that parathyroid hormone increased the activity of Na, K-ATP-ase and Ca-activated ATP-ase transport of the membranes in the brain and the kidneys both in vivo and in vitro. TCT caused analogous, but less expressed changes of the ATP-ase activity. Both hormones showed no influence on the Mg-ATP-ase activity of the both organs. It is supposed that the PH hormone influenced the membrane structures with the ATP-ase activity directly, while the action of TCT on them was mediated.

Adenosine Triphosphatases↗
PubMed1991

Effects of guanine nucleotides and parathyroid hormone on inositol 1,4,5-trisphosphate metabolism in canine renal cortical tubular cell membranes.

Parathyroid hormone (PTH) and guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma S) increase levels of the second messenger inositol 1,4,5-triphosphate (IP3) and other inositol phosphates (IP) in several membrane preparations of PTH-responsive cells. We present evidence here indicating that in a membrane preparation of canine renal cortical tubular cells bPTH-(1-84), bPTH-(1-34), [N-Leu8,18Tyr34]bPTH-(3-34)NH2, and the human PTH related peptide fragment hPTHrP-(1-34)NH2 all increase levels of inositol phosphate (IP) but [Tyr34]-bPTH-(7-34)NH2 and hPTHrP-(7-34)NH2 have no significant effects on IP accumulation. Increases in IPs are generally attributed to increased formation of IPs and appear to be mediated by a G protein. However, increased levels of IPs may also result from inhibition of the phosphatases are responsible for their metabolism. We investigated the effect of PTH and GTP-gamma S on the metabolism of IP3 in canine renal cortical tubular membranes. These membranes rapidly metabolize [3H]IP3 (47% at 15 s). Decreases in [3H]IP3 at all time points are accounted for quantitatively by increases in the sum of its breakdown products: [3H]IP2, [3H]IP1, and [3H]inositol. After 5 minutes of exposure to membranes, the vast majority of [3H]IP3 (84%) is converted to its terminal metabolite, [3H]inositol. GTP-gamma S (100 microM) inhibits the amount of [3H]IP3 metabolized in 15 s by 70% and reduces the amount of [3H]inositol ultimately formed in 5 minutes by 64%. ATP-gamma S, ATP, and 2,3-bisphosphoglycerate (100 microM) also inhibit [3H]IP3 hydrolysis in this preparation.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3-Diphosphoglycerate↗
PubMed1987

[Effects of parathyroid hormone on the cardiovascular system].

It has been well accepted that the bone and kidney are the principal organs of parathyroid hormone (PTH) actions, but there has been little work on the cardiovascular system. We evaluated the effect of PTH on the cardiovascular system of rats. In thiobutabarbital anesthetized rats, synthetic bovine parathyroid hormone, containing the amino acid (b-PTH 1-34) in dose of 0.1-10 micrograms/kg iv, caused dose related decrease in mean arterial blood pressure (MAP). On the other hand, there were significantly increase in heart rate (HR) and left ventricular contractile force. With the doses of 10 micrograms/kg, PTH decreased the MAP from 104.3 to 55.5 mmHg, left ventricular pressure (LVP) 122.1 to 96.4 mmHg, left ventricular end diastolic pressure (LVEDP) from 6.70 to 6.37 mmHg and LV dp/dt max 5,684 to 4,736 mmHg/sec. The HR, LV dp/dt/p and Vmax increase from 399.7 to 410.0 bpm, 95.5 to 108.4/sec, 98.2 to 107.4/sec, respectively. The propranolol, phentolamine, atropine and promethazine did not affect these actions of PTH. On the basis of these findings, we conclude that PTH has the directory vasodepressive action and the effect of augmentation of the left ventricular contractile force.

Animals↗
PubMed1993

Mineral and parathyroid hormone inter-relationships in normal pregnancy and pregnancy-induced hypertension.

The serum of calcium, other involved minerals and parathyroid hormone (PTH) were studied in non-pregnant women, during pregnancy and in pregnancy-induced hypertension (PIH). In pregnant women, serum creatinine, total calcium, total protein, albumin, inorganic phosphorus and magnesium declined, while parathyroid hormone levels increased significantly when compared to non-pregnant women. In PIH cases, serum total proteins, albumin and inorganic phosphorus were further reduced, while PTH levels were further increased when compared to normal pregnant women. Serum ionised calcium and sodium levels were similar in all the three groups. No significant relationship between blood pressure, PTH and involved minerals was observed in this study.

Adolescent↗
PubMed1998

Inactivating mutation in the human parathyroid hormone receptor type 1 gene in Blomstrand chondrodysplasia.

A single homozygous nucleotide exchange in exon E3 of the gene encoding the parathyroid hormone receptor type 1 (PTHR1) was identified in an infant with Blomstrand chondrodysplasia born to consanguineous parents. This alteration changes a strictly conserved proline residue at position 132 in the receptor's amino terminal extracellular domain to leucine. COS-1 cells expressing the mutant receptor did not accumulate cyclic adenosine 3',5'-monophosphate in response to PTH or PTH-related peptide (PTHrP) and did not bind the radiolabeled ligand. Expression of the mutant protein on the cell surface of transiently transfected COS-1 cells and in growth plate chondrocytes derived from the affected infant suggests that proline 132 is critical for the receptor's intrinsic binding activity. These findings suggest that the Blomstrand form of human short-limbed dwarfism arises from defective PTHR1 signaling in the developing cartilaginous skeleton.

Amino Acid Sequence↗