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PubMed1990

Cyclic AMP-dependent and calcium-dependent signals in parathyroid hormone function.

Previous work demonstrated that parathyroid hormone (PTH) activates the Ca2+/protein kinase C (PKC) system in addition to cAMP production. Therefore, the authors explored the role of cAMP-dependent and Ca2(+)-dependent signals in the regulation of osteoblastic growth and bone resorption. In exponentially growing UMR 106-01 osteogenic sarcoma cells, PTH (10(-7) M) inhibited [3H] thymidine incorporation by 80%. This effect was reproduced by maximal doses of both dibutyryl-cAMP (dbcAMP) and forskolin. The Ca2+ ionophore ionomycin (10(-7) M) had no effect, whereas phorbol 12-myristate 13-acetate (PMA) was slightly mitogenic. The antimitogenic action of dbcAMP was dose-dependent, with ED0.5 at about 3 X 10(-5) M. Ionomycin enhanced this dbcAMP effect at submaximal doses of the cAMP analog. PMA used in combination with both dbcAMP and ionomycin induced further depression of cell proliferation, indicating synergism with cAMP. Both dbcAMP (10(-4) M) and ionomycin (10(-7) M) stimulated 45Ca release from fetal rat limb bones after five days in culture, although the Ca2+ ionophore was less potent. 1-Oleoyl 2-acetyl-glycerol (2 X 10(-6) M) was ineffective alone, and slightly inhibited the 45Ca release produced by the other second messenger analogs in all combinations. The combination of dbcAMP and ionomycin showed a synergistic effect, and fully reproduced PTH effect. In conclusion, PTH signal transduction for control of cell proliferation and bone resorption is mediated mainly by cAMP. Activation of the Ca2+/PKC message system is nevertheless necessary to express a full hormonal response in both cell and organ culture systems.

Animals↗
PubMed1987

Evidence for transient peripheral resistance to parathyroid hormone in premature infants.

Serum immunoreactive parathyroid hormone (iPTH), ionized calcium, the urinary cyclic AMP/creatinine ratio (cAMP/Cr) and some indices of bone turnover (alkaline phosphatase (AP), serum osteocalcin, and the urinary total hydroxyproline/creatinine ratio (OH-P/Cr)) were measured in 26 preterm infants during the first 4 weeks of life. Despite of stimulated parathyroid gland activity cAMP/Cr, AP, osteocalcin and OH-P/Cr were low during the first week. Thereafter iPTH decreased, whereas cAMP/Cr, and the indices of bone turnover increased, reaching high-normal values (in comparison to full-term infants) during the second and third week of life. Serum iPTH was negatively correlated to cAMP/Cr in the first week (r = -0.61, p less than 0.01), whereas the relationship became positive during the second (r = 0.47, p less than 0.05) and third (r = 0.54, p less than 0.05) week of life indicating maturation of the renal response to PTH. The study supports the concept that in premature infants a transient pseudohypoparathyroid-like state is present during the first week of life reflecting an immaturity of renal and possibly bone response to PTH. This may be an etiological factor in hypocalcemia of prematurity.

Birth Weight↗
PubMedDate not supplied

Parathyroid localization by catheterization of large cervical and mediastinal veins to determine serum concentrations of intact parathyroid hormone.

A success rate of about 90% has been achieved after primary operations for hyperparathyroidism, compared with 60% to 80% in most series of secondary operations. The present reoperative series involved 29 patients who underwent venous catheterization with blood sampling for the determination of intact parathyroid hormone before undergoing repeat parathyroid surgery. Blood samples were taken from the internal jugular veins, innominate veins, and superior caval vein. No attempt was made to perform superselective catheterization of the small neck and mediastinal veins. The reoperations were done by four surgeons who did 1, 2, 13, and 13 of the reoperations, respectively. In all patients, distinct step-ups in parathyroid hormone concentrations were found. On average, the gradient between the highest and lowest value was about 5. Close to the location of the step-ups, diseased parathyroid tissue was found in 27 of the patients. In two cases no parathyroid tissue was found, and these patients remained hyperparathyroid postoperatively. They had been treated by the surgeon who did only two of the operations. When the step-up was observed in the left innominate vein, we could not differentiate mediastinal from low cervical adenomas. No patient developed hypoparathyroidism. To avoid this complication, autotransplantation of diseased parathyroid tissue into the abdominal subcutaneous fat was done in nine patients. No case of recurrent laryngeal nerve paralysis occurred. The introduction of reliable assays for the analysis of parathyroid hormone can make selective catheterization unnecessary when localizing remaining parathyroid glands in patients with persistent hyperparathyroidism.

Adolescent↗
PubMed1976

Effects of parathyroid hormone on sodium and calcium transport in the dog nephron.

1. The effect of purified bovine parathyroid hormone on renal tubular reabsorption of sodium and calcium has been studied by micropuncture in intact and recently thyroparathyroidectomized dogs. 2. Parathyroid hormone increased the rejection of sodium and calcium proportionately at the late proximal tubule in both intact and operated dogs. 3. In both groups of dogs, there was increased delivery of sodium and calcium to the distal tubule after the hormone. However, the Ca/Na ratio decreased, suggesting some selective enhancement of calcium reabsorption before the superficial distal puncture site. 4. In the final urine, the Ca/Na ratio decreased highly significantly in both groups of dogs, indicating a further selective effect of parathyroid hormone on calcium reabsorption in or beyond the distal convoluted tubule.

Absorption↗
PubMed1971

Pathogenesis of hypocalcemia in magnesium depletion. Normal end-organ responsiveness to parathyroid hormone.

Hypocalcemia in the hypomagnesemic state in man is usually attributed to refractoriness of end-organs to the calcemic action of parathyroid hormone. We studied the responsiveness of end-organs to bovine parathyroid extract (PTE) in magnesium-depleted and control dogs by the following three methods after thyroparathyroidectomy: (a) assessment of the calcemic response to a set dose of PTE (0.3 U/kg per hr); (b) assessment of PTE dose required to attain normocalcemia; (c) evaluation of regression lines of plasma calcium concentration on PTE dose. The calcemic response of magnesium-depleted thyroparathyroidectomized puppies to a set dose of PTE was similar to that of control puppies. There was no significant difference in the dose of PTE required to attain normocalcemia nor in the dose-response relations between the plasma calcium concentration and the PTE dose. In a group of magnesium-depleted puppies with intact thyroid and parathyroid glands, the dose of PTE required to attain normocalcemia was similar to that required in thyroparathyroidectomized animals, indicating calcitonin was not a factor contributing to hypocalcemia. We conclude that hypocalcemia in magnesium-depleted puppies is not due to refractoriness of end-organs to the calcium-mobilizing action of parathyroid hormone. Defective synthesis or diminished secretion of parathyroid hormone is suggested as an explanation.

Alkaline Phosphatase↗
PubMed2002

Minimally invasive video-assisted parathyroidectomy and intraoperative parathyroid hormone monitoring. The first 36 cases and some pitfalls.

BACKGROUND: The success of parathyroid surgery depends on the identification and removal of all hyperactive parathyroid tissue. At this writing, bilateral cervical exploration and identification of all parathyroid glands represent the operative standard for primary hyperparathyroidism (pHPT). However, improved preoperative localization techniques and the availability of intraoperative parathyroid hormone monitoring prepare the way for minimally invasive procedures. METHODS: Patients with pHPT and one unequivocally enlarged parathyroid gland on preoperative ultrasound and 99mTc-SestaMIBI scintigraphy underwent minimally invasive video-assisted parathyroidectomy by an anterior approach. Intraoperatively, a rapid chemiluminescense immunoassay was used to measure intact parathyroid hormone (iPTH) levels shortly before and then 5, 10, and 15 min after excision of the adenoma. The operation was considered successful when more than a 50% decrease in preexcision iPTH levels was observed after 5 min. RESULTS: Between October 1999 and November 2001, 36 of 82 patients with pHPT were eligible for a minimally invasive approach. A conversion to open surgery became necessary in five patients because of technical problems. In three cases, intraoperative iPTH monitoring showed no sufficient decrease in iPTH values. In these cases, subsequent cervical exploration showed one double adenoma and two hyperplasias, respectively. In two patients we had difficulty interpreting intraoperative iPTH values, resulting in persistent pHPT. CONCLUSIONS: Despite the use of high-resolution ultrasound and 99mTc-SestaMIBI scintigraphy, the presence of multiple glandular disease cannot be ruled out completely. Intraoperative iPTH monitoring to ensure operative success is indispensible for a minimally invasive approach. Despite our problems with iPTH monitoring in two patients, we believe that in selected cases, minimally invasive parathyroidectomy represents an attractive alternative to conventional surgery.

Adenoma↗
PubMed1980

Parathyroid hormone and the kidney in pseudohypoparathyroidism.

Although a relationship between parathyroid hormone, urinary cyclic AMP and phosphate excretion has been established, the exact molecular sequence which characterizes this cascade is still ambiguous. Consequently, the pathogenesis of inherited forms of hypocalcemia with defective renal responsivity to parathyroid hormone is still conjectural.

Adenylyl Cyclases↗
PubMed1989

Identification and characterization of parathyroid hormone receptors in rat renal cortical plasma membranes using radioligand binding.

Parathyroid hormone (PTH) receptors have been described in renal tissue from several species, but not in the rat. In this study, radioligand binding techniques were used to identify and characterize PTH receptors in rat kidney cortical membranes. The sulfur-free PTH analog [Nle8,18Tyr34]bovine PTH-(1-34)amide was iodinated using the iodogen method. This ligand was suitable for use in identifying PTH receptors in canine renal membranes, but not rat renal membranes. Synthetic, unsubstituted rat PTH-(1-34) was iodinated using the milder, lactoperoxidase technique and was purified by HPLC on a C8 column. [125I]rat PTH-(1-34) bound rapidly to both rat and dog renal membranes. At 22 degrees C reaction reached steady state within 20 minutes, and this level was maintained for at least 3 h. Specific binding was routinely greater than 90% for rat kidney and greater than 95% for dog kidney. Similar results were obtained at 4 degrees C with a longer time required to attain steady state (approximately 45 minutes). Binding was reversible as demonstrated by dissociation of bound ligand after either infinite dilution or displacement with excess nonradioactive PTH. Binding was saturable and of high affinity (rat kidney: Bmax = 2.3 pmol/mg protein, Kd = 3.1 nM, dog kidney: Bmax = 2.1 pmol/mg protein, Kd = 3.7 nM). Rat renal cortical adenylate cyclase activity was stimulated by rat PTH in a dose-dependent manner with an EC50 of 4 nM, a value in good agreement with the binding data. This study demonstrates the feasibility of identifying and characterizing parathyroid hormone receptors in rat renal cortical plasma membranes using radioligand binding techniques.

Adenylyl Cyclases↗
PubMed1985

Paradoxical effects of K+ and D-600 on parathyroid hormone secretion and cytoplasmic Ca2+ in normal bovine and pathological human parathyroid cells.

The effects of K+ and the Ca2+ channel blocker D-600 on parathyroid hormone (PTH) release and cytoplasmic Ca2+ activity (Ca2+i) were measured at different Ca2+ concentrations in dispersed parathyroid cells from normal cattle and from patients with hyperparathyroidism. When the extracellular Ca2+ concentration was raised within the 0.5-3.0 mM range Ca2+i increased and PTH secretion was inhibited. There was also a stimulatory effect of Ca2+ on secretion as indicated by a parallel decrease of Ca2+i and PTH release when extracellular Ca2+ was reduced to less than 25 nM. Addition of 30-50 mM K+ stimulated PTH release and lowered Ca2+i. The effect of K+ was less pronounced in the human cells with a decreased suppressability of PTH release. The Ca2+ channel blocker D-600 had no effect on Ca2+i and PTH release in the absence of extracellular Ca2+. However, at 0.5-1.0 mM Ca2+, D-600 increased Ca2+i and inhibited PTH release, whereas the opposite effects were obtained at 3.0 mM Ca2+. The transition from inhibition to stimulation occurred at a higher Ca2+ concentration in the human cells and the right-shift in the dose-effect relationship for Ca2+-inhibited PTH release tended to be normalized by D-600. It is suggested that K+ stimulates PTH release by increasing the intracellular sequestration of Ca2+ and that the reduced response in the parathyroid human cells is due to the fact that Ca2+i already is lowered. D-600 appears to have both Ca2+ agonistic and antagonistic actions in facilitating and inhibiting Ca2+ influx into the parathyroid cells at low and high concentrations of extracellular Ca2+, respectively. D-600 and related drugs are considered potentially important for the treatment of hyperparathyroidism.

Animals↗
PubMed1993

Clinical usefulness of an intraoperative "quick parathyroid hormone" assay.

BACKGROUND: Intraoperative assays of parathyroid hormone (PTH) in the surgical management of hyperparathyroidism have been limited by an extended "turnaround" time, making it impractical for the operating surgeon. With our modification of a standard immunoradiometric assay for intact PTH, results are reported in 12 minutes. The operative usefulness and the ability of this "quick PTH" assay to predict postoperative serum calcium levels are reported here. METHODS: Quick PTH levels from whole blood samples taken 10 minutes after excision of hyperfunctioning parathyroid glands were compared with preoperative and preexcision samples in patients undergoing 63 parathyroidectomies. Patients were divided into two groups with assay incubation times of 10 and 6 minutes. The latter was clearly not sensitive enough and resulted in a 20% false-negative rate. However, with a 10-minute incubation time, a decrease of 54% or more in quick PTH levels resulted in postoperative normocalcemia in patients with primary hyperparathyroidism. RESULTS: With these criteria used to predict the postoperative return to normocalcemia in 29 patients with primary hyperparathyroidism, the quick PTH assay had a sensitivity of 96%, specificity of 100%, and overall accuracy of 97%. CONCLUSIONS: The quick PTH assay was especially helpful in predicting postoperative calcium levels when multiple excisions were necessary to remove all hyperfunctioning tissue or some normal parathyroid glands were not visualized.

Evaluation Studies as Topic↗
PubMed1978

A sensitive bioassay of parathyroid hormone in plasma.

Understanding of calcium metabolism in health and disease has been retarded by the lack of an adequately sensitive bioassay of parathyroid hormone. The problem of dissociation of bioactivity and immunoactivity, well recognized for other polypeptide hormones, is exaggerated in the case of parathyroid hormone by the disproportionately long half-time in the circulation of the immunoreactive fragments. A new method of assaying the biological activity of parathyroid hormone in plasma has been developed, based on the cytochemical methods which have yielded highly sensitive bioassays of other polypeptide hormones. It depends on the stimulation of glucose 6-phosphate dehydrogenase activity in the distal convoluted tubules of segments of guinea-pig kidney maintained in vitro, and measured by microdensitometry. The limit of sensitivity of the assay is 5 fh/ml (bPTH); the index of precision is 0.09 +/- 0.04 (mean +/- SEM; n = 11).

Animals↗
PubMed1977

Design and synthesis of parathyroid hormone analogues of enhanced biological activity.

Three analogues of bovine parathyroid hormone (bPTH), [Tyr-34]bPTH-(1--34) amide, [Nle-8,Nle-18,Tyr-34]bPTH-(1--34)amide, and [Nle-8,Nle-18, o-NPS-Trp-23,Tyr-34]bPTH-(1--34)amide were synthesized by the solid-phase method. The synthetic peptides were found to be homogeneous in multiple analytical systems. These analogues represent the NH2-terminal one-third of the hormone, previously shown to contain all the structural requirements necessary for biological activity, but containing several structural modifications associated with enhancement and stabilization of biological activity. When tested in the in vitro renal adenylylcyclase assay, in which unsubstituted bPTH-(1--34) has a potency of 5400 MRC Units/mg, [Tyr-34]bPTH-(1--34)amide had a potency of 16,1000 MRC Units/mg, [Nle-8,Nle-18,Tyr-34]bPTH-(1--34)amide was 10,100 MRC Units/mg, and [Nle-8,Nle-18,o-NPS-Trp-23,Tyr-34]bPTH-(1--34)amide was 10,600 MRC Units/mg. The diverse structural features incorporated in these hormone analogues, resulting in a several-fold increase in biological activity in vitro, demonstrate additive effects on biological activity and should prove valuable in certain biological applications, as well as in the design of other parathyroid hormone analogues of enhanced potency.

Adenylyl Cyclases↗
PubMed2004

Age-related changes in the response of intestinal cells to parathyroid hormone.

The concept of the role(s) of parathyroid hormone (PTH), has expanded from that on acting on the classical target tissues, bone and kidney, to the intestine where its actions are of regulatory and developmental importance: regulation of intracellular calcium through modulation of second messengers and, activation of mitogenic cascades leading to cell proliferation. Several causes have been postulated to modify the hormone response in intestinal cells with ageing, among them, alterations of PTH receptor (PTHR1) binding sites, reduced expression of G proteins and hormone signal transduction changes. The current review summarizes the actual knowledge regarding the molecular and biochemical basis of age-impaired PTH receptor-mediated signaling in intestinal cells. A fundamental understanding of why PTH functions are impaired with age will enhance our understanding of its importance in intestinal cell physiology.

Aging↗
PubMed1990

Renal failure, parathyroid hormone and extrarenal disposal of potassium.

Parathyroid hormone (PTH) impairs extrarenal disposal of potassium in both acute and chronic renal failure. This effect is due to the property of the hormone that facilitates entry of calcium into cells since a rise in cytosolic calcium affects cellular permeability to potassium. On the other hand, calcium channel blockers enhance translocation of potassium from extracellular space into cells and this effect of these agents is related to their ability to prevent calcium entry into cells. Since patients with chronic renal failure have elevated blood levels of PTH, the effect of the hormone on extrarenal disposal of potassium should have important clinical implications. Chronic renal failure patients with higher blood levels of PTH may be at a greater risk of hyperkalemia when exposed to a potassium load than those with lower levels of PTH. Thus, in developing dietary regimens for potassium intake to patients with chronic renal failure, their blood levels of PTH should be taken into consideration in such dietary planning.

Animals↗
PubMed1983

The effect of ionized calcium, pH, and temperature on bioactive parathyroid hormone during and after open-heart operations.

Normal myocardial function is dependent on the metabolic balance of a number of electrolytes and hormones. The calcium ion plays a major role in muscle contraction and is rigorously controlled within narrow limits. Open-heart surgery imposes metabolic disturbances on both electrolytes and hormones, especially ionized calcium. Normally, ionized calcium levels are controlled by parathyroid hormone with a negative feedback from the ionized calcium controlling the system, but the results from this study suggest that during open-heart procedures, ionized calcium does not impose its normal negative feedback on bioactive parathyroid hormone secretion. The low blood pH levels that occurred during the operative conditions of the patients studied and the level of hypothermia imposed on the circulating blood during cardiopulmonary bypass appeared to influence the control of parathyroid hormone secretion, causing high levels of hormone to be secreted during this period.

Adult↗
PubMed1999

Reoperative parathyroid surgery in the era of sestamibi scanning and intraoperative parathyroid hormone monitoring.

HYPOTHESIS: Results of reoperative parathyroid surgery (RPS) have improved with the advent of sestamibi parathyroid subtraction scanning and intraoperative parathyroid hormone (IOPTH) monitoring. DESIGN: Retrospective review of patient histories, preoperative localization studies, operative data, including IOPTH monitoring, and outcomes for patients undergoing recent RPS at a single institution. Follow-up was complete (mean, 20 months). SETTING: Tertiary care referral center. PATIENTS: All patients undergoing RPS for benign persistent or recurrent primary hyperparathyroidism during the period 1989 to 1997. MAIN OUTCOME MEASURES: Overall cure rate and operative morbidity from RPS; sensitivity and accuracy of preoperative localization studies; and prediction of cure from IOPTH monitoring. RESULTS: The study group included 124 patients (87 women and 37 men). Hypercalcemia was corrected in 109 patients (88%). Permanent recurrent laryngeal nerve injury occurred in 0.8% and permanent hypoparathyroidism in 13% of patients. Test sensitivities and accuracies, respectively, were as follows: ultrasound with biopsy, 90% and 82%; sestamibi parathyroid subtraction scanning, 82% and 67%; and ultrasound alone, 75% and 65%. Level of IOPTH was predictive of cure in all patients with a 70% or greater fall from baseline at 20 minutes after excision. Persistent multigland disease was the major cause for reoperative failure (73%). CONCLUSIONS: Neither cure rates nor operative morbidity have changed appreciably over the past 2 decades, despite the introduction of sestamibi parathyroid subtraction scanning and IOPTH monitoring. Multigland disease continues to represent the principal cause of failure in RPS despite the routine use of preoperative localization studies. Thus far, increasing the stringency of IOPTH monitoring from a 50% to 70% decline from baseline levels has been predictive of cure, even in multigland disease. Most missed abnormal glands reside in normal anatomic locations, and the need for multiple operations, not just the reoperation, results in the increased morbidity seen with RPS.

Adolescent↗