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PubMed2001

Molecular mechanisms of ligand recognition by parathyroid hormone 1 (PTH1) and PTH2 receptors.

The mammalian parathyroid hormone (PTH) / PTH receptor family includes PTH1 and PTH2 receptors and three related ligands (PTH, PTH-related protein (PTHrP) an d tuberoinfundibular peptide of 39 residues (TIP39)). Here we comparatively and systematically review the pharmacological properties of PTH receptors and ligands, structure of the ligands, and molecular mechanisms of receptor-ligand interaction. The PTH1 receptor is activated by PTH and PTHrP but not by TIP39. The PTH2 receptor is activated by TIP39 but not by PTHrP. PTH strongly activates the human PTH2 receptor but is a weak partial agonist for rat and zebrafish PTH2 receptors. Receptor-G-protein interaction increases the receptor binding selectivity of PTHrP and TIP39. Despite different primary structures, the secondary structures of PTH, PTHrP and TIP39 are quite similar. Each ligand contains an N-terminal and a C-terminal alpha-helix in secondary structure-inducing conditions. Receptor-bound ligand structure is less well-characterized. The orientation of receptor-ligand interaction is highly similar for PTH and PTHrP binding to the PTH1 receptor and TIP39 interaction with the PTH2 receptor. Ligands bind according to a 'two-site' mechanism, in which the C-terminal portion of the ligand binds the extracellular N-terminal domain of the receptor (N-interaction), and the N-terminal ligand portion binds to the juxtamembrane receptor domain (J-interaction). The N-interaction provides most of the PTH1-receptor binding energy for PTH and PTHrP but provides less energy for PTH2 receptor-TIP39 interaction. The J-interaction stimulates G-protein activation. For the PTH-PTH1 receptor interaction, the efficacy-generating component of the J-interaction is independent of the N-domain of the receptor and C-terminal portion of the ligand. This finding suggests that it might be possible to design low molecular-weight PTH1 receptor agonists, which could be bone anabolic agents and used for the treatment of osteoporosis.

Amino Acid Sequence↗
PubMed1977

Inhibition of parathyroid hormone secretion by isoproterenol.

Intravenous infusion of the beta-adrenergic agonist isoproterenol produced a fall in the serum concentration of parathyroid hormone. It also produced a pronounced fall in the serum phosphate concentration, and significant increases in blood glucose and serum insulin concentration and in pulse rate. The fall in serum parathyroid hormone was abolished by beta-adrenergic blockage with propranolol. Oral glucose loads produced a pronounced fall in serum phosphate concentration, comparable to the fall after isoproterenol infusion, but no significant changes in serum parathyroid hormone. It is concluded that the fall in serum parathyroid hormone after isoproterenol is due to a beta-adrenergic effect. It is unknown, if isoproterenol acts directly on the parathyroid hormone secreting cell, or the fall in serum parathyroid hormone is secondary to the effect of isoproterenol on other endocrine glands or the cardiovascular system.

Adult↗
PubMed1989

Effect of vitamin D intake on seasonal variations in parathyroid hormone secretion in postmenopausal women.

Vitamin D intake should be sufficient to maintain calcium absorption and prevent increased parathyroid secretion throughout the year. To determine the level of intake that achieved the latter in elderly women, we studied the interrelations among vitamin D intake, serum 25-hydroxyvitamin D (25(OH)D) levels, and parathyroid hormone concentrations in a cross-sectional study of 333 healthy, white, postmenopausal women with low median calcium (408 mg a day) and vitamin D (112 IU a day) intakes who lived in Massachusetts. The overall inverse relation between serum parathyroid hormone and 25(OH)D levels was found to be dependent on vitamin D intake. In women whose estimated intake of vitamin D was less than or equal to 220 IU a day, the mean (+/- SD) serum parathyroid hormone values were lowest in those studied between August and October (30 +/- 11 ng per liter; n = 72) and highest in those studied between March and May (37 +/- 16 ng per liter; n = 54); the respective serum 25(OH)D levels were 93 +/- 32 and 63 +/- 21 nmol per liter. At vitamin D intakes of more than 220 IU a day, the mean serum parathyroid hormone and 25(OH)D levels did not vary with the season. The correlation between vitamin D intake and serum 25(OH)D concentration, although significant in all women (r = 0.29; P less than 0.001), was highest in those studied between March and May (r = 0.65; P less than 0.001) and lowest in those studied between August and October (r = 0.13; P greater than 0.10). The estimated serum 25(OH)D level associated with a vitamin D intake of 220 IU a day between March and May was 95 nmol per liter. Mean serum calcium values were similar at all times in both groups. We conclude that the dietary intake of more than 220 IU of vitamin D a day by postmenopausal women in Massachusetts may be sufficient to maintain constant serum 25(OH)D and parathyroid hormone concentrations throughout the year. Such an intake prevents a seasonal increase in parathyroid hormone secretion, with its possible deleterious skeletal effects.

Calcium↗
PubMed2001

Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis.

BACKGROUND: Once-daily injections of parathyroid hormone or its amino-terminal fragments increase bone formation and bone mass without causing hypercalcemia, but their effects on fractures are unknown. METHODS: We randomly assigned 1637 postmenopausal women with prior vertebral fractures to receive 20 or 40 microg of parathyroid hormone (1-34) or placebo, administered subcutaneously by the women daily. We obtained vertebral radiographs at base line and at the end of the study (median duration of observation, 21 months) and performed serial measurements of bone mass by dual-energy x-ray absorptiometry. RESULTS: New vertebral fractures occurred in 14 percent of the women in the placebo group and in 5 percent and 4 percent, respectively, of the women in the 20-microg and 40-microg parathyroid hormone groups; the respective relative risks of fracture in the 20-microg and 40-microg groups, as compared with the placebo group, were 0.35 and 0.31 (95 percent confidence intervals, 0.22 to 0.55 and 0.19 to 0.50). New nonvertebral fragility fractures occurred in 6 percent of the women in the placebo group and in 3 percent of those in each parathyroid hormone group (relative risk, 0.47 and 0.46, respectively [95 percent confidence intervals, 0.25 to 0.88 and 0.25 to 0.861). As compared with placebo, the 20-microg and 40-microg doses of parathyroid hormone increased bone mineral density by 9 and 13 more percentage points in the lumbar spine and by 3 and 6 more percentage points in the femoral neck; the 40-microg dose decreased bone mineral density at the shaft of the radius by 2 more percentage points. Both doses increased total-body bone mineral by 2 to 4 more percentage points than did placebo. Parathyroid hormone had only minor side effects (occasional nausea and headache). CONCLUSIONS: Treatment of postmenopausal osteoporosis with parathyroid hormone (1-34) decreases the risk of vertebral and nonvertebral fractures; increases vertebral, femoral, and total-body bone mineral density; and is well tolerated. The 40-microg dose increased bone mineral density more than the 20-microg dose but had similar effects on the risk of fracture and was more likely to have side effects.

Bone Density↗
PubMed1984

An investigation of the biological activity of parathyroid hormone in pseudohypoparathyroidism: comparison with vitamin D deficiency.

Circulating parathyroid hormone was studied in patients with pseudohypoparathyroidism and compared with that in normal subjects and patients with hypocalcaemia due to postsurgical or idiopathic hypoparathyroidism or vitamin D deficiency. The cytochemical bioassay was used to measure bioactivity and an amino-terminal specific immunoradiometric assay was used to measure immunoreactivity. In normal subjects (n = 12) the concentration of bioactive parathyroid hormone was 1.1-5.9 pg/ml. It was higher in patients with newly diagnosed, untreated pseudohypoparathyroidism (n = 4, range 20-53 pg/ml) and similarly raised in patients with untreated vitamin D deficiency (n = 9, range 23-74 pg/ml). The degree of hypocalcaemia was similar in these two groups of patients. By contrast, the concentration of bioactive parathyroid hormone was low (less than 0.6 pg/ml) in four patients with untreated postsurgical or idiopathic hypoparathyroidism. Restoration of normocalcaemia reduced the concentrations of bioactive PTH in both pseudohypoparathyroidism and vitamin D deficiency. Thus, in this respect the parathyroid glands in both conditions appeared to respond to the circulating calcium concentration. Immunoreactive PTH was also raised in patients with untreated pseudo-hypoparathyroidism and vitamin D deficiency, but restoration of normocalcaemia did not always reduce immunoreactive PTH to normal in these patients. Thus, there can be dissociation between bioactivity and immunoreactivity even when the PTH is measured in an amino-terminal specific assay.

Adolescent↗
PubMed2003

Postoperative parathyroid hormone level as a predictor of post-thyroidectomy hypocalcemia.

OBJECTIVES: To evaluate levels of parathyroid hormone following total thyroidectomy in order to ascertain its ability to predict postoperative hypocalcemia. To establish standardized criteria permitting the safe discharge of total thyroidectomy patients within 13 hours of surgery. METHODS: This is a prospective study in which parathyroid hormone levels were tested in 54 consecutive patients who underwent total thyroidectomy. Levels were measured postoperatively at 6, 12, and 20 hours. Corrected calcium levels were also measured at 6, 12, and 20 hours in accordance with the preexisting protocol. RESULTS: Statistical analysis demonstrates that patients with corrected calcium levels greater than or equal to 2.14 mmol/L and parathyroid hormone levels greater than or equal to 28 ng/L at 12 hours post-thyroidectomy can be discharged without further need for calcium monitoring. The analysis also demonstrates that patients with 12-hour parathyroid hormone levels less than or equal to 20 ng/L are at significant risk of developing hypocalcemia. CONCLUSION: Parathyroid hormone levels in conjunction with corrected calcium values are accurate predictors of the calcium trends of post-thyroidectomy patients. Implementation of this protocol can result in shorter hospital stays for the majority of post-thyroidectomy patients, which can translate into substantial cost savings for the health care system.

Adult↗
PubMed1976

Renal adenylate cyclase and the interrelationship between parathyroid hormone and vitamin D in the regulation of urinary phosphate and adenosine cyclic 3',5'-monophosphate excretion.

This study examined the role of cyclic AMP in the phosphaturic response to parathyroid hormone in vitamin D-deficient rats. Infusion of purified bovine parathyroid hormone (13.3 mug/h) into control, D-fed, or D-deficient, thyroparathyroidectomized rats produced a sixfold increase in renal phosphate and cyclic AMP excretion in D-fed rats, but only a two- to threefold increase in both parameters in D-deficient animals. Intravenous injection of parathyroid hormone over the dosage range from 1-50 mug/kg resulted in a dose-dependent increase in phosphate and cyclic AMP excretion with both D-fed and D-deficient thyroparathyroidectomized rats. However, the D-deficient rats responded to these injections of parathyroid hormone with a two- to threefold increase in both renal phosphate and cyclic AMP excretion at the highest dose of 50 mug/kg, whereas the D-fed animals' response was 35-fold and 11-fold over control excretion levels of phosphate and cyclic AMP, respectively. To directly examine the role of the renal cortical adenylate cyclase system in the blunted phosphaturic and urinary cyclic AMP responses to parathyroid hormone in D-deficient rats, we prepared a plasma membrane fraction enriched in this enzyme activity from the renal cortex of D-fed and D-deficient thyroparathyroidectomized rats. The renal cortical adenylate cyclase of D-deficient rats showed significantly (P less than 0.001) less activation by parathyroid hormone over the hormone concentration range from 0.3 to 7.0 mug/ml than was observed with the enzyme prepared from D-fed animals. Basal adenylate cyclase activity and the fluoride-stimulated enzyme activity were not altered by the state of D-deficiency. These experiments demonstrate that the blunted phosphaturic response to parathyroid hormone observed in D-deficient rats is associated with the reduced responsiveness of the renal cortical adenylate cyclase to the hormone. Moreover, the defect in the renal membrane adenylate cyclase system appears to be localized at the level of PTH binding to membrane receptors or, alternatively, at the level of transmission of the hormone-receptor binding signal to the catalytic moiety of this membrane enzyme.

Adenylyl Cyclases↗
PubMed1980

Parathyroid hormone alters collagen synthesis and procollagen mRNA levels in fetal rat calvaria.

Parathyroid hormone decreased the incorporation of [3H]proline into collagenase-digestible protein in cultured 21-day fetal rat calvaria but had little effect on the labeling of noncollagen protein. After 24 hr of culture, there was a 50% reduction in collaghen synthesis and a 40% decrease in the level of functional procollagen mRNA as measured in a reticulocyte lystate translation assay. The effect of parathyroid hormone on both parameters was detectable after 6 hr of treatment. In these cultures, there was also a substantial degradation or release of newly synthesized collagen from the calvaria, but parathyroid hormone had little effect on the release of collagen into the medium. These results suggest that parathyroid hormone inhibits collagen synthesis primarily by decreasing the steady-state level of procollagen mRNA.

Animals↗
PubMed1995

[Diagnosis of dysfunctions of replanted parathyroid gland tissue by bilateral analysis of intact parathyroid hormones in cubital vein blood. A prospective study].

AIM: In a prospective long-term follow-up study after operative therapy of hyperparathyroidism the value of bilateral determination of parathyroid hormone levels in cubital venous blood after total parathyroidectomy/autologous parathyroid gland reimplantation (musculus brachioradialis) for diagnosis of dysfunctioning grafted tissue is evaluated. PATIENTS AND MATERIAL: From August, 1, 1987 to March, 31, 1994 68 of 243 patients operated on for hyperparathyroidism underwent total parathyroidectomy. Autologous reimplantation of parathyroid gland was carried out simultaneously in 64 patients. Twice delayed reimplantation of cryopreserved tissue was carried out, and there was no reimplantation in two patients up to this day. Three patients were operated on for hyperfunctioning parathyroid autograft after former total parathyroidectomy/reimplantation. RESULTS: During follow-up 5 patients developed dysfunction of (reimplanted) parathyroid gland. Because of low or unprovable levels of intact parathormone the gradients of intact parathyroid hormone between grafted and nongrafted forearm were about 1:1 in postoperative hypoparathyroidism as well as in hypofunction of parathyroid gland. After successful replantation of cryopreserved parathyroid tissue gradients of intact parathyroid hormone increased (> 1:10). In hyperfunction of grafted parathyroid tissue hormone gradients were high (> 1:20 to 1:45,3) because of excessive high levels of intact parathormone in the cubital vein of the graft bearing arm. Successful reduction of parathyroid graft was followed by decrease of parathyroid hormone gradients. CONCLUSION: Regular follow-up of intact parathormone gradients together with intact parathyroid hormone levels and serumcalcium analysis allow the determination of parathyroid graft function. Also differentiation between graft dependent hyperparathyroidism and hyperfunctioning parathyroid tissue in the neck or mediastinum seems to be possible by bilateral determination of intact parathormone. Normal values or a normal range for intact parathyroid hormone gradients can not yet be defined.

Adult↗
PubMed1975

Influence of calcium infusion on calcitonin and parathyroid hormone concentrations in normal and hemodialyzed subjects.

Plasma calcitonin and parathyroid hormone concentrations were compared before and after calcium infusion in both hemodialyzed patients and control subjects. Levels of both hormones were significantly higher in patients with chronic renal failure. In the uremic group, calcium infusion inhibited parathyroid hormone secretion but did not affect calcitonin. In the control group, calcium infusion stimulated calcitonin secretion but had no effect on parathyroid hormone.

Adult↗
PubMed2000

Absence of response to human parathyroid hormone in athymic mice grafted with human parathyroid adenoma, hyperplasia or parathyroid cells maintained in culture.

In athymic mice we have developed a model of long-term human PTH hypersecretion, using xenotransplantation of respectively parathyroid gland fragments obtained from patients with primary (primary) or secondary (secondary) uremic hyperparathyroidism (HPT), and parathyroid cells maintained in culture from patients with secondary uremic HPT. Both grafted parathyroid tissue fragments and cultured cells induced prolonged and marked secretion of human intact PTH (iPTH) in nude mice. Despite extremely high plasma iPTH levels, hypercalcemia or hypophosphatemia was not observed. Moreover, PTH secretion was not significantly modified by low-calcium, high-phosphate diet for 3 weeks. Four mice which had a mean plasma human iPTH level of 237+/-152 pg/ml for more than 9 months and 4 age-matched, sham-grafted control mice with undetectable human iPTH levels underwent bone histomorphometry examination. No difference was found between the two groups with respect to active bone resorption surface or number of osteoclasts/mm2. We hypothesize that the characteristic deficit of T cell function and of cytokine and growth factor production may protect nude mice with chronic hypersecretion of human PTH from hypercalcemia and bone lesions. We suggest that this strain of mice could be used for better understanding the relationship between cytokines and bone turnover.

Adenoma↗
PubMed2003

Transcervical endoscopic-assisted mediastinal parathyroidectomy with intraoperative parathyroid hormone monitoring.

Ectopic mediastinal parathyroid adenomas are rare lesions that typically necessitate either median sternotomy or thoracotomy. More recently, video-assisted thoracoscopy has been used to excise mediastinal parathyroid adenomas. Herein we describe a novel technique in which we used a minimally invasive transcervical endoscopic-assisted approach to excise an anterior mediastinal parathyroid adenoma in a young man with a history of spontaneous pneumothorax. Intraoperative parathormone monitoring confirmed the excision of all hypersecreting parathyroid tissue, thereby obviating the need for a conventional neck exploration.

Adenoma↗
PubMed1983

Solution synthesis of [ASN76]-human parathyroid hormone (1-84).

Human parathyroid hormone, hPTH(1-84), was synthesized by the conventional solution procedure applying the maximal-protection approach. All protecting groups were removed simultaneously by the HF method. The product was purified by CM-cellulose column chromatography, gel-filtration on Sephadex G-50 and in the final stage, by reversed phase HPLC. The structure of the final product was confirmed not only by HPLC analysis but also by peptide mapping of tryptic digests on HPLC. The present product showed 350(249-480) IU/mg on in vitro rat renal adenylate cyclase assay.

Adenylyl Cyclases↗
PubMedDate not supplied

Humoral hypercalcemia of hepatocellular carcinoma associated with elevated levels of parathyroid-hormone-related-peptide.

Parathyroid-hormone-related-peptide (PTHrP) has been shown to be important in the pathogenesis of hypercalcemia of malignancy. The malignancies most commonly associated with hypersecretion of PTHrP include squamous cell carcinoma and breast cancer. The pathogenesis of hypercalcemia associated with hepatocellular carcinoma was evaluated in this study. Two male patients with hepatocellular carcinoma were found to have severe hypercalcemia at initial presentation. PTHrP was measured with radioimmunoassay in these two patients before treatment as well as in nine other patients with hepatocellular carcinoma but without hypercalcemia. The levels were markedly elevated in the two patients with hypercalcemia (29.3 and 32.1 pM), but were less than 5 pM in the nine patients without hypercalcemia. These results suggest that PTHrP was important in the pathogenesis of hypercalcemia associated with hepatocellular carcinoma in these men.

Journal Article↗
PubMed1991

Preoperative localization of enlarged parathyroid glands with ultrasonically guided fine needle aspiration for parathyroid hormone assay.

For preoperative localization of enlarged parathyroid glands, several imaging techniques have been used. In this study we demonstrate the feasibility of using ultrasonography with fine needle aspiration for parathyroid hormone assay as a preoperative localization procedure in 21 patients with primary hyperparathyroidism. A single adenoma was found in 18 patients while 3 patients had multiglandular disease. Ultrasonically guided fine needle biopsy was possible in 11 cases. In 8 of these aspirates, a high parathyroid hormone content was found. In all 8 cases the localization was confirmed at surgery. We conclude that the efficiency to preoperatively localize enlarged parathyroid glands is enhanced by fine needle aspiration.

Adult↗