Human Parathyroid Hormone IMMUNOLOGICAL CHARACTERIZATION OF ANTIBODIES AGAINST A GLANDULAR EXTRACT AND THE SYNTHETIC AMINO-TERMINAL FRAGMENTS 1-12 AND 1-34 AND THEIR USE IN THE DETERMINATION OF IMMUNOREACTIVE HORMONE IN HUMAN SERA

Fischer, Jan A.; Binswanger, U; Dietrich, Felix M.

doi:10.1172/jci107885

Cited by 88 publications

(35 citation statements)

References 33 publications

(142 reference statements)

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“…4). The 7'000 mol wt COOH-terminal fragment described in the literature (15,17,30,31) as an important circulating form was hardly visualized, unless the shoulder trailing from the intact PTH peak represented part of it. In this instance, the CPD donor blood had undetectable PTH.…”

Section: Methodsmentioning

confidence: 94%

“…PTH in column effluent fractions and in serum was determined radioimmunologically with ['"I] bPTH-(1-84) as the ligand and a IWO pure extract of human parathyroid tumors as standard (hPTH-(1-84)G-100) (3,15). Antibodies were obtained in a goat on day 848 (goat 16, day 848), which was immunized with seven injections of hPTH-(TCA) totalling 24 mg (or 0.24 mg immunoreactive PTH), followed by two injections of 0.01 mg bPTH-(I-84); the same bPTH-(1-84) was used as the ligand.…”

Section: Methodsmentioning

confidence: 99%

“…Columns of Bio-Gel P-150 (100-200 mesh) (Bio-Rad Laboratories, Richmond, CA), 1.6 x 100 cm were used for gel filtration of a 1% pure ureatrichloroacetic acid extract (hPTH-(TCA)) of human parathyroid tumors previously described (15), as well as of serum samples. The columns were equilibrated with eluant consisting of 0.2 M ammonium acetate (pH 4.7) and human serum albumin (Swiss Red Cross, Berne, Switzerland) (2.5 mg/ml) at 4°C.…”

Section: Gel Filtration Of Parathyroid Hormone or Seramentioning

confidence: 99%

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Parathyroid Hormone Response in Newborn Infants during Exchange Transfusion with Blood supplemented with Citrate and Phosphate: Effect of iv Calcium(37)

et al. 1979

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SummaryWe studied secretory parathyroid function in 16 newborn infants, aged 34-137 hr, before, during, and after exchange transfusion with a radioimmunoassay recognizing mainly intact human parathyroid hormone-(1-84) ). Before the exchange transfusion, serum calcium was normal or decreased, whereas parathyroid hormone (PTH) was within or above the range of normal adults. Serum P T H approached a maximum at decreased serum ionized and total calcium levels which were close to the normal range. During the early period of the exchange transfusion, serum ionized calcium was decreased as a result of the administration of considerable amounts of phosphate and citrate i n the donor-blood and P T H was raised to levels seen in hypocalcemic infants before the exchange transfusion. Thereafter, serum ionized calcium remained low, whereas mean PTH concentrations were below basal levels. These inappropriately low P T H levels in relation to lowered serum-ionized calcium concentrations are probably the result of inadequate P T H secretion, which is enhanced by withdrawal of large-amounts of presumably biologically active PTH-(1-84) during the exchange transfusion. Serum total calcium.. .on the other hang, was rais& during the exchange transfusion probably as a result of calcium mobilization, and the net calcium balance expressed as the difference of calcium administered and in the withdrawn blood was negative. Even though serum ionized calcium decreased to levels below 2.5 mg/dl during the exchange transfusion, tetany was never observed, iv injections of calcium during the exchange transfusion caused temporary increases in total, but not i n ionized calcium levels and shortening of Q-oTc intervals lasting for less than 1 min. We, therefore, advocate that iv calcium injections at regular time intervals during the exchange transfusion with donor blood preserved in citrate and phosphate should no longer be recommended as a prophylactic measure for preventing the decrease in serum-ionized calcium. SpeculationParathyroid secretory function is inversely related to serum calcium concentrations i n newborn infants. Serum PTH secretion is maximal at serum-ionized and total calcium concentrations close to the normal range despite further reduction to more markedly hypocalcemic levels. ran sit or^ hypoparathyroidism occurs during exchange transfusion as a result of the removal of considerable amounis of biologically active PTH-(1-84).Evidence obtained by David and Anast (10) indicates that serum PTH is low or undetectable during the first 48 hr of life, whereas after 48 hr, there are parallel increases in PTH as well as in total and ionized calcium levels. In newborn infants, exchange transfusion with donor blood preserved in citrate, or citrate and phosphate are used to relieve hyperbilirubinemia (12,21,35,36). This results in a decrease in ionized (1 1, 27, 33) and in a slight increase in total calcium concentrations (1 1, 27). The available evidence indicates that a fall in ionized rather than in total calcium is responsible for a s...

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Section: Methodsmentioning

confidence: 94%

Section: Methodsmentioning

confidence: 99%

Section: Gel Filtration Of Parathyroid Hormone or Seramentioning

confidence: 99%

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Parathyroid Hormone Response in Newborn Infants during Exchange Transfusion with Blood supplemented with Citrate and Phosphate: Effect of iv Calcium(37)

et al. 1979

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“…Dilution curves of the tissue culture stsndard and hyperparathyroid sera, using GP-1 M antiporcine PTH (32), were superimp osable, which indicated immunologic similarity (8). The level of CAMP in urine was determined according t o the method oaf Brown et al (3).…”

Section: Methodsmentioning

confidence: 99%

Excessive Thyrotropin Response to Thyrotropin-releasing Hormone in Pseudohypoparathyroidism

et al. 1975

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ExtractIn 8 of 10 patients with pseudohypoparathyroidism, confirmed by increased immunoreactive plasma parathyroid hormone concentrations and/or defective urinary excretion of adenosine 3',5'-monophosphate (CAMP) after parathyroid extract infusion, excessive plasma thyrotropin (thyroid-stimulating hormone) (TSH) response to thyrotropin-releasing hormone (TRH) injection was found. On the other hand, in all seven cases with idiopathic true hypoparathyroidism the TSH response was normal. In two of three patients with pseudopse~dohypoparathyroidisrn, with normal or slightly low plasma calcium, normal or slightly high immunoreactive plasma parathyroid hormone concentration, and intermediate response of cAMP to parathyroid extract, the TSH response to TRH was increased. The results indicate that moderate primary hypothyroidism is frequently present in pseudohypoparathyroidism. Thyroid dysfunction may only be detectable with the use of TSH stimulation by TRH, since clinical signs and other studies of thyroid function did not definitely suggest hypothyroidism in our patients. The rise of TSH is suppressible by thyroxine treatment, but is not influenced by vitamin D treatment. The TSH response to TRH is significantly correlated with the decrease of tubular reabsorption of phosphate after parathyroid extract infusion in with pseudo-and pseudopseudohypoparathyroidism. Speculation TSH stimulation by TRH may be a useful test for the further delineation of biochemical variants of pseudohypoparath yroidism.The occasional association of hypothyroidism with pseudohypoparathyroidism had been suspected for several years (5, 22), but it was only proven in 1960 in a chiId described by Cohen and Donne11 (5). Hypothyroidism was attributed to TSH deficiency, because the ' I uptake by the thyroid gland was increased markedly after TSH administration. Subsequent reports confirmed this finding in additional patients (24,25,27). Recently, however, a mother and her 11-year-oId daughter, who both suffered from pseudohypoparathyroidism, were found to have increased plasma immunoreactive TSH concentrations, which suggested a primary thyroid disorder rather than TSH deficiency (19). In the mother an excessive TSH response to TRH infusion was demonstrated. A similar observation in a child (1 7) prompted the present study of TSH stimulation by TRH in children and adults with pseudohypoparathyroidism. For comparison, TRH tests were also performed in patients with pseudopseudohypoparathyroidism and idiopathic true hypoparathyroidism.

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“…Based on these difficulties and on the evolution of knowledge on PTH structure and peptide synthesis, two new approaches were used to develop new antibodies against human PTH: the use of human parathyroid adenoma extracts and synthetic peptides. Fischer et al (11) were the first to describe the production of antibodies against PTH synthetic peptides, and the preparation of antisera against peptides obtained from human adenoma extracts was first described by Manning et al (12). Synthetic sequences with a tyrosine added were used for iodine labeling, resulting in more stable, specific and reproductive assays.…”

Section: First Phase: Competitive Assaysmentioning

confidence: 99%

Evolution of PTH assays

Vieira

Kunii

Nishida

2006

Arq Bras Endocrinol Metab

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PTH metabolism is complex and the circulating forms include the intact 1-84 molecule as well as several carboxyl-terminal fragments. The first generation of PTH assays included several types of competitive assays, with specificities that spanned carboxyl, mid-region and amino-terminal portions of the molecule. The limitations of these assays and the methodological evolution led to the description of 2 nd generation non-competitive immunometric assays for PTH in the late 80's, based on the recognition of the PTH molecule by two different antibodies, one directed against de amino-terminal and other against the carboxyl-terminal segments. The observation that in some circumstances "long" carboxyl-terminal segments were also measured by 2 nd generation assays led to the development of 3 rd generation assays based on amino-terminal specific antibodies that are specific for the first amino acids, measuring only the molecular forms that activate PTH1R. The practical and cost-benefit advantages of these assays are still debatable. The recent observation that carboxyl-terminal fragments of PTH have biological activity via a distinct receptor than PTH1R, points to the future need of more than one assay in order to evaluate parathyroid hormone function. RESUMO Evolução dos Ensaios para Paratormônio.O metabolismo do PTH e complexo e as formas circulantes incluem o PTH 1-84, assim como fragmentos C-terminal. A primeira geração de ensaios para o PTH incluía vários ensaios competitivos com especificidades para as regiões carboxi, meio da molécula e amino-terminal. A limitação destes ensaios e a evolução metodológica, levaram ao desenvolvimento dos ensaios não competitivos de 2ª. geração no final dos anos 80, baseados no reconhecimento por dois anticorpos diferentes, contra a porção amino e carboxi-terminal respectivamente. A observação que em algumas circunstâncias segmentos carboxiterminais longos também eram detectados, levou ao desenvolvimento dos ensaios de 3ª. geração, baseados em anticorpos específicos para a porção aminoterminal com maior especificidade para os primeiros aminoácidos, e assim mensurando apenas a forma molecular que ativa o PTH1R. As vantagens práticas e o custo-benefício deste ensaio ainda e motivo de debate. A observação recente de que fragmentos carboxiterminais têm atividade biológica via receptor distinto, aponta para a necessidade futura de mais de um ensaio para avaliar a função do paratormônio.

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Human Parathyroid Hormone IMMUNOLOGICAL CHARACTERIZATION OF ANTIBODIES AGAINST A GLANDULAR EXTRACT AND THE SYNTHETIC AMINO-TERMINAL FRAGMENTS 1-12 AND 1-34 AND THEIR USE IN THE DETERMINATION OF IMMUNOREACTIVE HORMONE IN HUMAN SERA

Cited by 88 publications

References 33 publications

Parathyroid Hormone Response in Newborn Infants during Exchange Transfusion with Blood supplemented with Citrate and Phosphate: Effect of iv Calcium(37)

Parathyroid Hormone Response in Newborn Infants during Exchange Transfusion with Blood supplemented with Citrate and Phosphate: Effect of iv Calcium(37)

Excessive Thyrotropin Response to Thyrotropin-releasing Hormone in Pseudohypoparathyroidism

Evolution of PTH assays

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