PTH (7-84) has antagonistic effects on the calcemic and phosphaturic actions of PTH (1-84) whole molecule (bioPTH). Human plasma contains bioPTH and PTH (7-84)-like fragments. Using bioPTH-specific and nonspecific assays, we found that the patients with pseudohypoparathyroidism (PHP) type I with PTH-resistant hypocalcemia and hyperphosphatemia had the increased plasma levels of bioPTH and PTH (7-84)-like fragments than normal subjects (26.8 +/- 13.2 vs. 2.37 +/- 0.75 pmol/liter, P < 0.01 and 16.2 +/- 8.8 vs. 0.82 +/- 0.47 pmol/liter, P < 0.01, respectively). Calcitriol treatment increased phosphaturic response to PTH (1-34) (P < 0.05), and there was a negative correlation between phosphaturic response and the PTH levels (P < 0.05). These results suggested that the increased bioPTH and PTH (7-84)-like fragment levels may be related to the impaired phosphaturic response to PTH (1-34) in PHP type I. We also examined bioPTH-calcium dynamics in PHP type Ib patients and found that set-point calcium was 0.928 +/- 0.045 mmol/liter and the baseline to maximal ratio of bioPTH was 0.96 +/- 0.04. Calcitriol treatment increased set-point calcium to 1.129 +/- 0.028 mmol/liter (P < 0.01) and suppressed baseline to maximal ratio of bioPTH to 0.35 +/- 0.21 (P < 0.01). These bio-PTH calcium dynamics studies revealed the maximally stimulated baseline PTH secretion in PHP type Ib and demonstrated the effects of calcitriol on PTH-calcium curve shift and the degree of relative stimulation of baseline secretion.

Parathyroid hormone (PTH) transiently increases urinary excretion of the lysosomal enzyme, N-acetyl-beta-D-glucosaminidase, which is distributed mainly in proximal tubules. The response is reduced in pseudohypoparathyroidism (PHP) type I, which is characterized by target-organ resistance to PTH. Evidenced by normal calcium resorption, distal tubule sensitivity to PTH has been believed to be normal in this disorder. This hypothesis was tested through a search for another marker of distal nephron sensitivity to PTH. In the human kidney, cathepsin D was expressed predominantly in distal segments of the nephron, cortical and medullary thick ascending limbs of Henle's loop, distal convoluted tubules, and connecting tubules and in cortical collecting ducts and medullary collecting ducts. PTH infusion transiently increased cathepsin D excretion in normal subjects. The cathepsin D response to PTH was reduced in the patients with PHP type I. The decrease in cathepsin D response in PHP type I indicates a resistance to PTH in the distal nephron (cortical thick ascending limbs of Henle's loop, distal convoluted tubules, and connecting tubules) and cortical collecting ducts. These observations suggest that the preservation of renal tubular sensitivity to PTH in this disorder may be confined to PTH-dependent calcium resorption in distal tubules.

Stanniocalcin (STC) is a calcium (Ca)‐regulating hormone that was originally discovered in the fish Stannius body, which is a unique endocrine organ. Hypercalcemia increases STC secretion, which inhibits Ca uptake by the gills and normalizes serum Ca level. In this study we investigated the STC expression in human normal and abnormal adrenal cells. Immunohistochemistry using monoclonal antibody against STC revealed specific staining in zona glomerulosa and medulla of normal human adrenal glands. STC was also detected in human adrenal tumors, such as pheochromocytoma, differentiated neuroblastoma, and aldosterone‐producing adenoma, and cultured adrenal tumor cells (rat pheochromocytoma PC‐12 cells and human neuroblastoma NB‐1 cells). However, undifferentiated human adrenal neuroblastoma was negative for STC staining. Reverse transcription polymerase chain reaction demonstrated STC mRNA expression in cultured PC‐12 cells and NB‐1 cells. Following several studies indicating that zona glomerulosa cells of adrenal glands express neuroendocrine properties, STC expression in normal and abnormal adrenal cells provides additional evidence to support the neuroendocrine differentiation of these cells. In conclusion, STC may be useful as a new cell marker of adrenal glands under physiological and pathological conditions.

Omeprazole is an inhibitor of gastric H+,K(+)-ATPase. Although the major proton transport of osteoclast is mediated by a vacuolar-type H(+)-ATPase which is different from the gastric H+,K(+)-ATPase, in vitro studies have demonstrated that omeprazole inhibits bone resorption. In this study, the effect of omeprazole on bone resorption was evaluated in patients who had a history of gastric ulcer and were treated with maintenance doses of H2 blocker without any gastric complaints at the study time. H2-blocker administration was changed to omeprazole treatment in the study group and to no treatment in the control group. Urinary excretion of hydroxyproline and calcium decreased after omeprazole treatment in the study group. Serum intact PTH, alkaline phosphatase, osteocalcin, and tartrate-resistant acid phosphatase (TRAP) increased in this group. In the control group, there were not any changes in these parameters. The discrepancy between serum TRAP and urinary excretion of hydroxyproline and calcium in the study group was thought to be due to the suppression of bone resorption by omeprazole, which probably interfered the acidification at resorption lacunae and resulted in the inactivation of TRAP and other lysosomal enzymes. The results of our study suggest the possibility that the specific inhibitors of the osteoclastic proton pump (such as bafilomycins) will more effectively suppress bone resorption and be useful for the treatment of metabolic bone diseases with increased bone resorption.

Urinary excretion of calcium (Ca) was measured in 9 patients with pseudohypoparathyroidism (PHP) type I—3 with Albright's hereditary osteodystrophy (AHO): AHO(+) and 6 without AHO: AHO(−)—and in 13 with idiopathic hypoparathyroidism (IHP), treated with active vitamin D3 (1,25(OH)2D3 or 1αOHD3) to maintain serum Ca levels at 8.4–9.5 mg/dl. Fasting urinary excretion of Ca in PHP was significantly lower than that in IHP. Moreover, fasting urinary excretion of Ca in PHP AHO(+) was lower than that in PHP AHO(−). This difference was also seen in the urine after oral loading of Ca. Urinary excretion, of sodium (Na) was not different between PHP AHP(+) and PHP AHO(−). Serum levels of immunoreactive PTH in PHP AHO(+) were higher than those in PHP AHO(−). The difference in urinary excretion of Ca between PHP AHO(+) and PHP AHO(−) may come from the difference in the circulating levels of PTH.

Synthetic human parathyroid hormone (1–34) (hPTH(1–34) infusion test has been utilized in the differential diagnosis of hypoparathyroidism by examining the incremental response of urinary phosphate and cyclic adenosine monophosphate (AMP). The response of plasma levels of 1,25-dihydroxyvitamin D (1,25(OH)2D) in parathyroid hormone (PTH) infusion test was studied as a new criterion for the differential diagnosis of idiopathic hypoparathyroidism (IHP) and pseudohypoparathyroidism (PHP). Fourteen patients with IHP, 4 patients with PHP, and five control subjects were studied. All subjects received an intravenous infusion of 30 μg hPTH(1–34) over 5 minutes. The basal levels of plasma 1,25(OH)2D in patients with IHP and PHP were significantly lower than those in control subjects, but there was no significant difference between the levels in patients with IHP and in patients with PHP. The plasma levels of 1,25(OH)2D increased after the infusion of hPTH(1–34) and reached a peak 6 to 24 hours afterward. The 1,25(OH)2D increase at 24 hours after the infusion (Δ1,25(OH)2D) in control subjects and in patients with IHP were 18.1±3.91 (mean±SEM) and 24.1±2.80 pg/ml, respectively. There was no significant increase in patients with PHP (Δ1,25(OH)2D=4.9±1.97 pg/ml). From these results, the measurement of Δ1,25(OH)2D in hPTH(1–34) infusion test is useful as a criterion for the differential diagnosis of hypoparathyroidism.

N-acetyl-beta-D-glucosaminidase (NAG) is a lysosomal enzyme predominantly located in renal proximal tubules. In idiopathic hypoparathyroidism (IHP), 100 Units of human PTH (1-34) increased urinary excretion of NAG from 0.029 +/- 0.027 to 0.173 +/- 0.035 U/lGF (p less than 0.05) in two patients before treatment and from 0.025 +/- 0.004 to 0.189 +/- 0.092U/lGF (p less than 0.02) in four patients during treatment with active vitamin D3 (1,25(OH)2D3 or 1 alpha OHD3). In pseudohypoparathyroidism (PHP), PTH did not significantly increase the urinary excretion of NAG in one patient with before treatment (0.048 to 0.025 U/lGF) and four patients during treatment with active vitamin D3 (0.018 +/- 0.008 to 0.036 +/- 0.015 U/lGF). Increase in urinary excretion of NAG after injection of PTH may be a new indicator of renal effect of PTH.

Plasma 1,25-dihydroxyvitamin D (1,25-(OH)2D) level, which is considered to be an indicator of parathyroid function, is possibly modified by the level of vitamin D. In the present study, we have investigated parathyroid function in terms of enhancement of the plasma levels of 1,25-(OH)2D after oral administration of 100 micrograms of 25-hydroxyvitamin D3 (25OHD3) in 9 cases of primary hyperparathyroidism (1 degree HPT), 7 cases of hypoparathyroidism (HP), 2 cases of pseudohypoparathyroidism (PHP) and 6 normal subjects. The plasma levels of 25-hydroxyvitamin D (25OHD) increased and reached a peak at 6-12 hours after the administration of 25OHD3. The plasma levels of 1,25-(OH)2D slightly increased but remained within the normal range after 25OHD3 administration in 3 of the normal subjects whose basal levels were rather low, but the increase in plasma 1,25-(OH)2D in control subjects was not statistically significant. In cases of 1 degrees HPT, the plasma 1,25-(OH)2D level rose significantly in all cases (P less than 0.05), although the pattern of the increase was not uniform. These increases were remarkable in the patients whose basal levels were low. On the other hand, an increase in the level was rarely observed in any of the cases of HP and in one of the cases of PHP. In another case, normocalcemic PHP, the plasma 1,25-(OH)2D level rose.(ABSTRACT TRUNCATED AT 250 WORDS)

Three cases from two families with idiopathic hypoparathyroidism and progressive sensorineural deafness are described. Cases 1 and 2 were siblings. Case 3 was one of four siblings from another family. All of them had both idiopathic hypoparathyroidism and progressive sensorineural hearing loss. There was no evidence to suggest involvement of autoimmune mechanism in these cases except for the associated Graves' hyperthyroidism in case 3. Human leukocyte antigen A9 and A11 were positive in both families. The sensorineural hearing loss was progressive even after the treatment for hypoparathyroidism. As the familial idiopathic hypoparathyroidism is a very rare entity, it is unlikely that this disease is associated with familial progressive sensorineural deafness by chance. The combination of these two diseases may compose a new syndrome.

Several problems in the measurement of plasma cyclic AMP (PcAMP) and nephrogenous cyclic AMP were studied using a YAMASA RIA Kit (YAMASA Shoyu, Choshi, Japan). In this assay method, cAMP in plasma is directly succinylated without prior deproteinization, and then it is bound to antibody in an imidazole buffer. So far as the blood samples were obtained with EDTA-4Na at least 5.0 mM in the final concentration, PcAMP was not reduced until 16 hours after the blood samples were drawn. Even without EDTA, the reductions in PcAMP were not detected within 1 hour after the blood samples were drawn. This assay method for PcAMP showed parallelism in the dilution curve. Recovery was almost complete. Intra- and interassay variations were low. When plasma was incubated at 37 degrees C for 24 hours, PcAMP became negligible. Furthermore, the values of PcAMP measured with this direct assay system almost agreed with those obtained after the purification by deproteinization and Dowex column chromatography through an anion-exchange resin. The normal values of PcAMP were 13.6 +/- 3.62 pmol/ml [mean +/- SD, n = 43]. Nephrogenous cAMP expressed as a function of GFR never did show any negative values in various clinical situations. From the data of basal levels and the oral calcium tolerance test, nephrogenous cAMP appeared to be more useful than total urinary cAMP in the diagnosis of parathyroid disorders, especially hyperparathyroidism.

UNAKAMI, H., FURUKAWA, Y., SOHN, H.E., YUMITA, S., MIURA, R., SASAKI, A., KOKUBUN, M., MIURA, Y., YOSHINAGA, K. and NAKANOME, C. 1, 25-Dihydroxyvitamin D Production Stimulated by Dibutyryl 3', 5'-Cyclic AMP in Normal Subjects and a Patient with Pseudohypoparathyroidism. Tohoku J. exp. Med., 1982, 138 (4), 411-418-Dibutyryl 3', 5'-cyclic AMP (DBcAMP) was infused in 4 normal subjects and a patient with pseudohypoparathyroidism (PHP) to study its effect on the production of 1, 25-dihydroxyvitamin D [1, 25(OH)2D]. In normal subjects, 2.5mg/kg of DBcAMP increased plasma 1, 25(OH)2D. reaching the peak at 6hr after infusion, while, 6.0mg/kg of DBcAMP delayed the peak to 12hr. The maximal increment of plasma 1, 25(OH)2D was 19.7±2.8pg/ml (mean±S.D.) in normals with 6.0mg/kg of DBcAMP and 12.2±1.0pg/ml (mean±S.D.) with 2.5 mg/kg, respectively. There was a significant difference between the doses (p<0.01). Plasma 24, 25-dihydroxyvitamin D [24, 25(OH)2D] showed no significant change after DBcAMP infusion in normal subjects. In a patients with PHP, however, 2.5mg/kg of DBcAMP markedly increased plasma 1, 25(OH)2D to reach the peak (48.9pg/ml) at 14hr and plasma 24, 25(OH)2D was decreased reciprocally. After DBcAMP infusion, depression of serum P, slight decrease in %TRP and the elevation of IRI were proved in normal subjects, while in a patient with PHP, there was a marked depression of %TRP. It is suggsted that the increments of plasma 1, 25(OH)2D by infusion of DBcAMP is dose-dependent in normal subjects, and that the 1, 25(OH)2D productivity by DBcAMP may be accelerated in a patient with PHP.

Plasma gastric inhibitory polypeptide (GIP), insulin, glucagon concentrations and blood glucose levels in response to the ingestion of 100 g glucose were measured in 5 patients with hyperparathyroidism in order to elucidate the effect of hypercalcemia on the release of these hormones. In addition, the effect of acute hypercalcemia on the release of these hormones in response to glucose ingestion was investigated in normal subjects. Fasting plasma GIP concentration in patients with hyperparathyroidism was significantly greater than the value in seventeen normal subjects. Significantly higher responses of plasma GIP and insulin were observed after the glucose ingestion in the patients with hyperparathyroidism as compared with the values in the normal subjects, and integrated GIP and insulin responses to the glucose ingestion for 120 min in the patients with hyperparathyroidism were significantly greater than the values in the normal subjects. On the other hand, plasma glucagon concentration after the glucose ingestion in the patients with hyperparathyroidism remained unchanged, although plasma glucagon concentrations after the glucose ingestion decreased significantly from the basal value in the normal subjects. Blood glucose levels after the glucose ingestion in two groups increased significantly from the basal value in the same manner. In nine normal subjects calcium infusion (4 mg/kg bolus injection followed by continuous infusion of 4 mg/kg/hr for 3 hr) caused a significantly high concentration of plasma calcium (11.5 approximately 13.0 mg/dl) from the basal value. Significantly higher responses of plasma GIP and insulin to the glucose ingestion were observed during calcium infusion as compared with the values during saline infusion. On the other hand, plasma glucagon concentration after the glucose ingestion was not significantly changed during calcium infusion in contrast with a significant decrease of plasma glucagon after the glucose ingestion during saline infusion. Consequently, calcium was considered to play a major part in the release of GIP and insulin. The characteristic response of plasma glucagon during calcium infusion was considered, at least in part, to protect the hypoglycemia caused by hyperinsulinemia.

Parathyroid extract (PTE) or synthetic 1-34 human parathyroid hormone (1-34 hPTH) was injected intravenously as a bolus in 4 normal subjects, 4 patients with PTH deficient hypoparathyroidism (HP) and 3 patients with pseudohypoparathyroidism (PHP). In normal subjects and HP, plasma 1,25(OH)2D was markedly increased at 6 hr and reached the peak at 12 or 14 hr after administration of 200 units of PTE or 20 to 30 micrograms of 1-34hPTH. On the other hand, 500 units of PTE or 20 micrograms of 1-34hPTH failed to increase plasma 1,25(OH)2D in PHP. However, 2.5 mg/kg of dibutyryl cAMP remarkably increased plasma 1,25(OH)2D in a patient with PHP. Maximal increments of plasma 1,25(OH)2D in 3 patients with HP(21.7 +/- 5.6 pg/ml, mean +/- S.D.) were nearly as high as in normal subjects (20.6 +/- 7.0 pg/ml), whereas those in 3 patients with PHP (2.3 +/- 2.3 pg/ml) were distinctly lower than in normal subjects or HP. It is suggested that 1,25(OH)2D production by PTH is intact in HP, but is impaired in PHP mainly due to a defect in the activation of adenylate cyclase system.

The effects of calcium injection (3 mg/Kg/10 min) or oral calcium administration (calcium lactate 7.7 g) on plasma iPTH and Nephrogenous cyclic AMP (NcAMP) were studied in 6 normal controls and 13 patients with primary hyperparathyroidism. In the control subjects, plasma iPTH determined by a predominantly carboxyl-terminal antiserum was less than 0.3 ng/ml before and after both calcium loads, whereas 41 approximately 98% (mean 67%) of NcAMP was rapidly and uniformly suppressed to a level lower than the normal value. In 2 patients with primary hyperparathyroidism, iPTH was clearly reduced from 8.0 to 4.6 ng/ml and 1.6 to 0.96 ng/ml, respectively, by the calcium load. However, in the other 7 patients with primary hyperparathyroidism who showed only a slight elevation of iPTH: less than 0.3 approximately 0.9 ng/ml, the reductions in iPTH were not detected after the calcium load: less than 0.3 approximately 0.7 ng/ml. In contrast, 30 approximately 54% (1.02 approximately 3.85 nmol/dl GF) of NcAMP, which was greater than the diurnal variation, was suppressed after calcium injection in 5 patients with primary hyperparathyroidism (2 of 4 patients with urological, and 3 of 5 patients with chemical hyperparathyroidism). But NcAMP was not suppressed in all 4 patients with skeletal hyperparathyroidism including one with proximal renal tubular dysfunction whose basal iPTH was elevated markedly but reduced clearly by the calcium load. In general, suppression of NcAMP was followed by a decrease of phosphate excretion. On the other hand, even in a patient with primary hyperparathyroidism whose NcAMP was not suppressed at all after the calcium injection, calcium infusion (15 mg/Kg/3h) resulted in some (23%) decrease in NcAMP. Oral calcium administration resulted in responses which were almost the same as those produced by calcium injection. These results suggest that NcAMP provides a useful index in the parathyroid suppression test in patients with primary hyperparathyroidism, especially those who display a rather mild elevation of iPTH. This is not the case, however, in a few patients who show a marked elevation of iPTH and/or proximal renal tubular dysfunction.