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1.  Immunoheterogeneity of Parathyroid Hormone in Venous Effluent Serum from Hyperfunctioning Parathyroid Glands 
Journal of Clinical Investigation  1977;60(6):1367-1375.
The immunoreactive parathyroid hormone (iPTH) in the plasma of hyperparathyroid man consists largely of carboxyl (COOH)-terminal fragments of the hormone. Although these fragments have been thought to arise principally or solely from peripheral metabolism of intact human PTH {hPTH(1-84)} secreted from the parathyroid gland, there is disagreement about the source of iPTH fragments in vivo.
To reexamine this question, we fractionated peripheral and thyroid or parathyroid venous effluent sera from four patients with primary hyperparathyroidism using a high-resolution gel filtration system (Bio-Gel P-150 columns run by reverse flow). The column effluents were analyzed using two PTH radioimmunoassays, one directed toward the amino(NH2)-terminal region of the molecule, the other toward the COOH-terminal region.
In all four thyroid or parathyroid venous effluent sera studied, iPTH was 9-180 times higher than in peripheral serum from the same patient; after fractionation, hPTH(1-84) accounted for only a portion of the total iPTH (35-55% with the assay directed toward the COOH-terminal region of hPTH, >90% with the NH2-terminal directed assay.) The remaining iPTH eluted from Bio-Gel P-150 after hPTH(1-84) as NH2-or COOH-terminal hPTH fragments. These results suggest that parathyroid tumors secrete large quantities of hPTH fragments. Based on estimates of their molar concentrations in serum, tumor-secreted COOH-terminal hPTH fragments could account for most of these peptides in peripheral serum if their survival times were, as estimated by several other workers, 5-10 times that of hPTH(1-84).
We conclude that, in contrast to published information, secretory products of hyperfunctioning parathyroid tissue are probably a major source of serum PTH immunoheterogeneity.
PMCID: PMC372494  PMID: 915003
2.  Immunoreactive Forms of Circulating Parathyroid Hormone in Primary and Ectopic Hyperparathyroidism 
Journal of Clinical Investigation  1974;54(1):175-181.
The immunoreactive forms of parathyroid hormone (iPTH) in the plasma of six patients with primary, adenomatous hyperparathyroidism and six patients with ectopic hyperparathyroidism due to non-parathyroid cancer were compared by using gel filtration on columns of Bio-Gel P-150 and radioimmunoassay of iPTH in eluted fractions after concentration. We found much less (p<0.001) small (mol wt<9,500) COOH-terminal fragments of iPTH in plasma samples from ectopic hyperparathyroid patients (0.52±0.13 ng eq/ml) than in samples from primary hyperparathyroid patients (3.70±1.15 ng eq/ml). The quantity of iPTH eluting with or before native bovine PTH [1-84] was the same in both syndromes (ectopic hyperparathyroidism, 0.82±0.22 ng eq/ml; primary hyperparathyroidism, 0.73±0.09 ng eq/ml), and these values correlated positively with plasma calcium concentration (ectopic hyperparathyroidism, r=0.908; primary hyperparathyroidism, r=0.919). In both syndromes, plasma samples had an iPTH component that eluted well before PTH [1-84] (mol wt 9,500), but this component was present in much larger quantities in three patients with ectopic hyperparathyroidism. We conclude that (a) the decreased quantity of biologically inactive COOH-terminal fragments of iPTH circulating in ectopic hyperparathyroidism accounts for the previously reported relatively lower total serum iPTH values in this syndrome as compared with primary hyperparathyroidism (Riggs et al. 1971. J. Clin. Invest. 50: 2079); (b) there appears to be sufficient iPTH with presumed biologic activity to account for the hypercalcemia in both syndromes; (c) a large PTH component, not previously recognized in plasma, is present in both ectopic and primary hyperparathyroidism and may exist as the predominant immunoreactive form of the hormone in some patients with ectopic hyperparathyroidism.
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PMCID: PMC301537  PMID: 4834887
3.  Parathyroid Function in Primary Osteoporosis 
Journal of Clinical Investigation  1973;52(1):181-184.
Two major species of serum immunoreactive parathyroid hormone (iPTH) were measured in 47 untreated patients with primary osteoporosis by using two highly specific radioimmunoassays. Mean iPTH was normal with one antiserum but was lower than normal (P < 0.001) with the other, iPTH values did not correlate with biochemical parameters or with the proportion of bone-resorbing surfaces in iliac crest bone biopsy specimens. These data suggest that the increased bone resorption is not due to increased parathyroid function in most osteoporotic patients. However, seven of our patients (15%) appear to represent a separate population because they had increased values with one or the other of the antisera.
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PMCID: PMC302240  PMID: 4734167
4.  Etiology of Hyperparathyroidism and Bone Disease during Chronic Hemodialysis. III. EVALUATION OF PARATHYROID SUPPRESSIBILITY 
Journal of Clinical Investigation  1973;52(1):173-180.
Parathyroid function was assessed by calcium infusions (4-8 h) in 16 patients with chronic renal insufficiency being treated by long-term hemodialysis. The concentrations of two immunoreactive species of parathyroid hormone in plasma (iPTH-9, mol wt 9500; iPTH-7, mol wt 7000) were estimated by radioimmunoassays utilizing two relatively specific antisera. Control values of the smaller species, iPTH-7, were uniformly high, whereas values of iPTH-9 were normal in 12 of 19 studies. Response of iPTH-7 to calcium infusions was variable, with significant decreases occurring only five times in 27 infusions. Concentrations of iPTH-9, however, decreased during every calcium infusion. In contrast to these acute responses, five of six patients studied during periods of dialysis against both low (< 6 mg/100 ml) and high (7-8 mg/100 ml) calcium concentrations in the dialyzate showed a decrease in values of iPTH-7 during the period of dialysis against the higher calcium concentration. It is concluded that plasma concentrations of iPTH-9 reflect primarily the moment-to-moment secretory status of the parathyroid glands, while concentrations of iPTH-7 reflect more closely chronic parathyroid functional status. It is further concluded that the failure of iPTH-7 to decrease during induced hypercalcemia should not be equated with autonomy of parathyroid gland function.
PMCID: PMC302239  PMID: 4734166
5.  Short- and long-term effects of estrogen and synthetic anabolic hormone in postmenopausal osteoporosis 
Journal of Clinical Investigation  1972;51(7):1659-1663.
In 29 women with postmenopausal osteoporosis, the proportion of total bone surface undergoing resorption or formation was evaluated by microradiography of iliac crest biopsy samples before and after short-term (2½-4 months) and long-term (26-42 months for estrogen and 9-15 months for anabolic hormone) treatment. After estrogen administration, values for bone-resorbing surfaces decreased, although less prominently after long-term than after short-term therapy. The magnitude of this decrease was positively correlated with the pretreatment value for bone-resorbing surfaces (P < 0.001). When the pretreatment value for bone-resorbing surfaces was used as a covariable, estrogen and anabolic hormone appeared to be equally effective. For bone-forming surfaces, short-term therapy with either hormone had no effect but long-term therapy significantly decreased the values. Serum immunoreactive parathyroid hormone (IPTH) increased significantly after estrogen therapy; the change in IPTH was inversely related to the change in serum calcium (P < 0.001, sign test). We conclude that the primary effect of sex hormones in postmenopausal osteoporosis is to decrease the increased level of bone resorption, perhaps by decreasing the responsiveness of bone to endogenous parathyroid hormone. However, this favorable effect, at least in part, is negated after long-term treatment by a secondary decrease in bone formation. Our data are consistent with the concept that the maximal benefit that can be derived from sex hormone therapy in postmenopausal osteoporosis is arrest or slowing of the progession of bone loss.
PMCID: PMC292313  PMID: 4338118
6.  Etiology of hyperparathyroidism and bone disease during chronic hemodialysis 
Journal of Clinical Investigation  1971;50(3):599-605.
Plasma concentration of immunoreactive parathyroid hormone (IPTH) was measured in 18 patients who had been on a hemodialysis program for longer than 6 months. A negative correlation was found between the predialysis plasma concentration of IPTH and the mean concentration of calcium in the dialysate previously used: plasma concentrations of IPTH were higher in patients dialyzed against a calcium concentration between 4.9 and 5.6 mg/100 ml than in patients dialyzed against a calcium concentration of 6.0 mg/100 ml or more. Plasma concentrations of IPTH also were higher in patients with bone disease than in patients without bone disease. Furthermore, a positive correlation was found between predialysis plasma concentrations of IPTH and calcium, and between mean predialysis concentration of IPTH and phosphate. To obviate the possibility that individual differences in susceptibility could have accounted for the observed effects of plasma phosphate and of dialysate calcium, a 2 × 2 factorial study was conducted in seven of these patients to examine the independent effects of perturbation of each of these factors. It was observed that plasma concentration of IPTH was lowest with the combination of high dialysate calcium and low plasma phosphate, highest with the combination of low dialysate calcium and high plasma phosphate, and intermediate with the two other combinations. It is concluded that both dialysate calcium and plasma phosphate are important determinants of parathyroid function in these patients.
PMCID: PMC291968  PMID: 5545122
7.  Etiology of hyperparathyroidism and bone disease during chronic hemodialysis 
Journal of Clinical Investigation  1971;50(3):592-598.
The present study was prompted by the observation that, in patients with chronic renal failure being followed at this center, renal osteodystrophy developed almost exclusively in those who were treated by chronic hemodialysis at home rather than in our center. A systematic comparison was made between the 10 patients with roentgenographic evidence of the bone disease and 18 patients without demonstrable bone disease. The two groups were similar in age, sex, nature of renal disease, and duration of dialysis. The mean duration of kidney disease was almost 2 yr longer in the patients without bone disease than in those with bone disease. Other significant differences related to where the hemodialysis was performed and to the calcium concentration in the dialysate (6.0-7.4 mg/100 ml in the hospital and 4.9-5.6 mg/100 ml at home). If the unknown factors related to where the dialysis was performed were of no consequence, the major factor contributing to the production of bone disease observed in these patients was the use of a dialysate with a calcium concentration less than 5.7 mg/100 ml.
PMCID: PMC291967  PMID: 5101783
8.  Radioimmunoassay of human parathyroid hormone in serum 
A new radioimmunoassay for human parathyroid hormone (PTH) in serum, which can measure the hormone present in 94% of the normal sera tested, is described. It is based on the ability of human PTH to compete with 131I-labeled bovine PTH for binding to an antiserum directed against porcine PTH. This antiserum distinguishes between human PTH extracted from parathyroid adenomata and that present in hyperparathyroid sera. Evidence is given to suggest that this is due to immunochemical changes in the hormone extracted from adenomata and not to immunochemical heterogeneity of the hormone present in serum.
Physiologic data supporting the validity and specificity of the assay are presented. Induced episodes of hypercalcemia and hypocalcemia resulted in appropriate responses in serum immunoreactive PTH (IPTH) in normal subjects and in patients with Paget's disease of bone. In normals, there was a progressive increase in serum IPTH in the late afternoon and evening, suggesting a diurnal secretory rhythm. A negative correlation was found between the serum calcium and serum IPTH over the normal range of serum calcium values; a positive correlation was found between these variables in patients with primary hyperparathyroidism. There was apparent overlap between serum IPTH values in normal subjects and patients with primary hyperparathyroidism, but formal discriminate analysis of values for serum calcium and IPTH demonstrated separation of these two groups, without overlap.
PMCID: PMC291890  PMID: 5543877
9.  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.
PMCID: PMC297020  PMID: 6018750
11.  Internal Medicine—Epitomes of Progress 
Western Journal of Medicine  1978;129(1):50.
PMCID: PMC1238231  PMID: 18748244
12.  Immunologic differentiation of primary hyperparathyroidism from hyperparathyroidism due to nonparathyroid cancer 
Journal of Clinical Investigation  1971;50(10):2079-2083.
Serum immunoreactive parathyroid hormone (IPTH) was measured by radioimmunoassay in 54 patients with primary hyperparathyroidism and in 18 consecutive patients with ectopic hyperparathyroidism due to nonparathyroid cancer without apparent skeletal metastasis. Although serum calcium concentration was higher in the group with ectopic hyperparathyroidism, serum IPTH was lower (rank sum test, P < 0.001) and was undetectable in eight. A second anti-PTH antiserum also differentiated between IPTH in the two groups, although IPTH was undetectable in only 1 of 14 sera. When IPTH values in serial dilutions were plotted, slopes for the two patients with ectopic hyperparathyroidism who had relatively high IPTH were less (P < 0.001) than slopes for standard hyperparathyroid sera. By using differences in either IPTH rank or slope of the dilutional curve of sera, primary hyperparathyroidism could be excluded as a cause of the hypercalcemia in 16 of the 18 patients with ectopic hyperparathyroidism. The data are interpreted as indicating that PTH-like material in the serum of these patients with ectopic hyperparathyroidism is immunologically different from the PTH in the serum of patients with primary hyperparathyroidism.
PMCID: PMC292141  PMID: 4330004

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