Administration Of Parathyroid Extract Research Articles

Effect of parathyroid extract on renin release in the dog.

1. A rapid increase in plasma renin activity occurred in dogs after intravenous administration of parathyroid extract. 2. This was not seen after injection of a purer parathormone preparation, or the solution used to dilute the parathyroid extract or calcitonin. 3. A vasoactive compound in parathyroid extract appears to provide the most likely explantation of this effect.

Changes in the electroencephalogram in acute uremia. Effects of parathyroid hormone and brain electrolytes.

Studies were carried out in order to evaluate the effects of changes in brain calcium and the influence of parathyroidectomy and administration of parathyroid extract on the electroencephalogram (EEG) of normal and uremic dogs. Manual analysis of frequency and power distribution of the EEG in uremic dogs revealed a significant increase in both the percentage distribution and the area or power occupied by frequencies below 5 Hz. In addition, high amplitude bursts of delta activity were apparent in the uremic dog. These changes were largely prevented by parathyroidectomy before the induction of uremia, but the administration of parathyroid extract to either normal dogs, or to previously parathyroidectomized uremic dogs, induced EEG changes similar to those noted in uremic animals with intact parathyroid glands. In all groups of animals which showed EEG changes, brain content of calcium was significantly higher than in either normal dogs or previously parathyroidectomized uremic dogs. Changes in arterial pH and bicarbonate, or in the concentrations of Na+, K+, urea, or creatinine in plasma or cerebrospinal fluid were similar in uremic animals with intact parthyroid glands and in previously parathyroidectomized uremia dogs. The results indicate that the EEG changes found in dogs with acute renal failure require the presence of excess parathyroid hormone in blood, and they may be related to the observed changes in brain content of calcium.

Responsiveness of Urinary Cyclic AMP and Phosphate to Paraghyroid Extract in Patients with Parathyroid Disorders

Responsiveness of urinary cyclic AMP and phosphate to 200 units of parathyroid extract was evaluated in 5 normal subjects, 2 patients with idiopathic hypoparathyroidism, 4 patients with pseudohypoparathyroidism and 3 patients with primary hyperparathyroidism. Among them, 3 patients with pseudohypoparathyroidism were examined prior to and during therapy with vitamin D. Two patients with primary hyperparathyroidism were examined before and after removal of adenomas. In control subjects, percent increase in cyclic AMP after parathyroid extract administration was 7265 plus or minus 3312%, and in phosphate 290 plus or minus 72%. It was found that in idiopathic hypoparathyroidism the response of cyclic AMP was in the normal range, though that of phosphate was higher than normal. In pseudohypoparathyroidism, as distinguished from what Drezner et al. called pseudohypoparathyroidism type II, the response of cyclic AMP was uniformly low, while that of phosphate was variable. Similar results were obtained during treatment with vitamin D. In primary hyperparathyroidism, the responses of both cyclic AMP and phosphate were lower than normal. After removal of adenomas, the response of phosphate became norma., but the response of cyclic AMP rose to a subnormal level in one patient, and remained low in the other. For the diagnosis of pseudohypoparathyroidism, the response in cyclic AMP was considered to be a more reliable index than that in phosphate whether the patient was being treated with vitamin D or not.

Effect of parathyroid extract (PTE) on electrolytes, phosphorus and protein content of parotid saliva

The excretion pattern of calcium (Ca), magnesium (Mg), potassium (K), sodium (Na), phosphorus (P) and protein of the parotid saliva was studied before and during PTE administration in 6 normal subjects aged 24 to 32 years. The Stensen's duct was cannulated and the flow rate of saliva measured before and after stimulation by lemon juice. After a control period, 50 U of PTE were given i.v. followed by an infusion of 2 U/min. for 60 to 90 min. In the absence of any change in serum Ca and P, PTE induced a significant increase of salivary Ca (p< 0.001), P (p< 0.005) and protein (p< 0.001) concentrations. These changes were independent of the flow rate. Na excretion was also increased (p< 0.005) but only at high flow rates. PTE had no significant effect on Mg and K concentrations. These results provide evidence that PTE acts on the parotid gland by affecting Ca and P transport and protein secretion.

Indentification of an intestinal sodium and calcium-dependent phosphatase stimulated by parathyroid hormone.

Previous reports suggest that the site of the energy-dependent intestinal calcium transport against an electropotential and concentration gradient is located along the basal-lateral membrane of the mucosal cell. Accordingly, basal-lateral membranes were prepared from rat intestinal homogenates in order to identify the enzyme mediating this step in the transport process. An alkaline phosphatase was delineated which utilized ATP as a substrate and was dependent on both Na(-) and Ca(++) with optimum enzyme activity at 200 mM and 0.04 mM, respectively. Furthermore, the activity of the enzyme was demonstrated to decrease with the advance in age of the animal and to decrease with removal of the parathyroid glands, consistent with a decreased rate of (45)Ca release from mucosal cells under the same experimental conditions. Calcium binding to basal-lateral membrane fragments was also sodium dependent and enhanced by the prior administration of parathyroid extract. The consistent correlation between the rate of calcium transport across the basal-lateral membrane of the mucosal cell and the activity of this Na, Ca-dependent phosphatase under a variety of experimental conditions suggest that this enzyme may mediate the parathyroid hormone-sensitive active transport of calcium across the intestine.

Calcium metabolism of brain in acute renal failure. Effects of uremia, hemodialysis, and parathyroid hormone.

Studies were carried out to evaluate the changes in content of calcium and magnesium in brain during acute uremia in dogs. Ca content in gray and white matter of brain increased significantly after 3 days of acute uremia and this increment was prevented by thyroparathyroidectomy (TPTX). The administration of parathyroid extract (PTE) to normal dogs and TPTX uremic animals produced a significant rise in brain Ca. These changes were not related to alteration in the concentration of Ca in plasma or cerebrospinal fluid, to changes in calcium-phosphorus product, or to changes in blood pH. Furthermore, the infusion of large amounts of phosphate to vitamin D2-treated animals with suppressed parathyroid gland activity produced marked elevation in calcium-phosphorus product but no significant change in brain Ca. Also, uremia in vitamin D2-treated TPTX dogs failed to increase calcium content in brain despite marked elevation in calcium-phosphorus product. Hemodialysis significantly reduced Ca content of brain but the values were still significantly higher than normal. Mg content increased modestly only in the white matter of uremic dogs with intact parathyroid glands and in normal dogs and TPTX uremic dogs receiving PTE. The results indicate that (a) acute uremia of 3 days is associated with a marked rise of Ca content of brain and modest increment of Mg in certain parts of the brain, and (b) these alterations are not related to uremia, per se, but are dependent on the presence of excess parathyroid hormone. It is suggested that the neurological abnormalities noted in acute uremia may be related in part to the rise in the Ca content of brain.

Micropuncture studies of phosphate transport in the proximal tubule of the dog. The relationship to sodium reabsorption.

Micropuncture studies were performed in the dog to examine the relationship between sodium and phosphate transport in the proximal tubule. In hydropenic, thyroparathyroidectomized animals, administration of parathyroid extract, saline, or acetazolamide resulted in a fall in proximal tubule fluid-to-plasma (TF/P) inulin ratio as well as a rise in tubule fluid-to-plasma ultrafilterable (TF/UF) phosphate ratio. A correlation was found between the changes in fractional reabsorption of sodium and phosphate but the phosphate changes were generally greater than those of sodium. Also, a high distal phosphate delivery in the face of low fractional excretion of phosphate in the urine in thyroparathyroidectomized dogs suggests significant phosphate reabsorption in the distal nephron. On the other hand, calcium chloride infusion to saline-loaded, normal dogs to suppress endogenous parathyroid hormone reduced proximal TF/UF phosphate without change in TF/P inulin, while both parameters remained unchanged in saline-loaded, thyroparathyroidectomized dogs after calcium infusion. An increase in proximal TF/UF phosphate associated with unchanged TF/P inulin was also demonstrated by administration of highly purified parathyroid hormone to saline-loaded, thyroparathyroidectomized dogs. It was concluded that although proximal tubule phosphate transport is generally closely related to that of sodium, the two can dissociate under certain experimental conditions, especially under the influence of parathyroid hormone. These observations also indicate that the effect of parathyroid hormone on proximal tubule phosphate transport is not solely dependent upon its effect on sodium transport.

Pathogenesis of osteopetrosis in the ia rat: reduced bone resorption due to reduced osteoclast function.

AbstractOsteopetrosis, a skeletal condition characterized by excessive accumulation of bone, is an inherited disease in man, rats and mice. In ia rats the condition undergoes spontaneous permanent remission beginning 30 to 50 days after birth, in contrast to the disease in mice and men. Thus, the ia rat offers a unique opportunity to analyze factors suspected of causing the skeletal condition.In the present investigation bone formation and bone resorption have been measured at various ages in ia rats and normal littermates. Bone matrix formation, measured by 3H‐proline uptake, was decreased slightly during the first three postnatal weeks and elevated slightly thereafter. Bone resorption, stimulated by injection of parathyroid extract, was determined in vivo as the rate of release of 3H from bone after incorporation of 3H‐proline. Bone resorption was reduced 20% at two weeks and elevated 20% by three weeks. Administration of parathyroid extract or thyroxine, or a deficiency of thyrocalcitonin produced by thyroidectomy (supplemented with thyroxine), did not hasten remission. An abnormally high cytoplasmic concentration of acid phosphatase activity was observed in ia osteoclasts during the first two weeks. The skeletal signs of spontaneous remission, appearing between 30 and 50 days after birth, were preceded by a normal response of the serum calcium to exogenous parathyroid extract, by increased bone resorption and by a more normal cytoplasmic distribution of acid phosphatase activity during the third postnatal week.These observations are interpreted to indicate that the osteopetrotic condition of ia rats is not due to deficiencies of parathyroid hormone or thyroxine or an excess of thyrocalcitonin but results from failure of osteoclasts to respond to stimuli promoting resorption. Specifically, these cells seem able to synthesize but not release normal amounts of the lysosomal enzyme acid phosphatase.

Calcium and phosphorus metabolism parathyroid hormone, calcitonin and bone histology in pseudohypoparathyroidism.

Abstract. High blood levels of immunreactive parathyroid hormone and normal levels of calcitonin were detected in a 14‐yearoIdgirl suffering from pseudohypoparathyroidism. Antibodies to parathyroid hormone have not been detected. Normalization of the serum calcium concentration suppressed parathyroid hormone and stimulated calcitonin secretion to a reproducible extent. Prolonged administration of parathyroid extract induced an increase ofphosphaturia and subsequently normalized the serum calcium level, while intestinal absorption of calcium did not improve. High values for the exchangeable calcium pool and the bone accretion rate of calcium were found. Histologically the iliac crest bone showed a deficient degree of mineralization and a high osteoclastic activity. Treatment with die hydrotachysterol for over a year did not normalize the respons‐of urinary excretion of phosphate and cyclic AMP to administration of parathyroid extract. The data presented are compatible with a relative resistance of the renal tubules, the bone tissue and probably the gut to parathyroid hormone and with the co‐existence of a moderate degree of osteomalacia and secondary hyperparathyroidism.

Effects of porcine calcitonin in osteogenesis imperfecta tarda

The effect of the administration of porcine calcitonin to two children with osteogenesis imperfecta tarda was evaluated by means of calcium and phosphorus balance studies, urinary hydroxyproline excretion, tubular reabsorption of phosphorus, and phosphate clearance before and after administration of parathyroid extract. The balance studies indicated that calcitonin was effective in causing retention of calcium and phosphorus and decrease in hydroxyproline excretion. These improvements suggest that calcitonin may be of therapeutic value in osteogenesis imperfecta by decreasing bone resorption.

Renal effects of calcitonin and parathyroid extract in man. Studies in hypoparathyroidism.

To clarify the controversial renal action of calcitonin (CT) and a possible interrelationship between CT and parathyroid hormone, eight patients with untreated surgical hypoparathyroidism were studied. Various calcitonins, i.e. extracted porcine, synthetic porcine, synthetic human, and synthetic salmon CT in doses of 150 Medical Research Council U or 1.5 mg were infused over a 3 hr period. Subsequently, six of the same subjects received 500 USP U parathyroid extract (PTE) (Eli Lilly & Co., Indianapolis, Ind.) in 3 hr and later a combination of CT and PTE. In addition, two patients were given an infusion of ammonium phosphate with the aim of producting a phosphaturia of comparable degree as seen after CT and PTE, thus differentiating hormonal from nonhormonal influences on cation excretion. A protocol of serial clearance (C) studies using the patients as their own controls was followed. Serum and urinary inorganic phosphate (P), calcium (Ca), magnesium (Mg), sodium (Na), potassium (K), and creatinine (Cr) were determined and the clearance values calculated. All CT peptides caused a uniform, immediate and significant increase of C(P), C(Na), C(K), C(Ca), and C(Mg), PTE evoked a rise of C(P), C(Na), and C(K), but C(Ca) and C(Mg) were reduced, the Ca and Na figures being not statistically significant. The administration of both CT and PTE resulted in a summation of individual hormone effects on Ca and Mg excretion. Phosphate infusion on the other hand induced an isolated phosphaturia but no concomitant changes of the urinary cations.The hypoparathyroid data demonstrate that calcitonin enhances urinary elimination of P, Na, K, Ca, and Mg independently of parathyroid action, CT and PTE act qualitatively similarly on P, Na, and K excretion, while an antagonism seems to exist for the renal handling of Ca and Mg.

Ultrastructure and Acid Phosphatase Cytochemistry of Odontoclasts: Effects of Parathyroid Extract

Deciduous teeth extracted from mongrel puppies were decalcified and prepared for electron microscopy. Teeth were extracted before and after administration of parathyroid extract to determine its effects on the fine structure of odontoclasts and the distribution of acid phosphatase activity. Odontoclasts demonstrated cytoplasmic processes entering dentinal tubules, extracellular dense bodies showing acid phosphatase activity, and intracellular localization of this enzyme within digestive vacuoles and the Golgi apparatus. Parathyroid extract apparently affected only the extracellular dense bodies by increasing their number.

Differential stimulation by parathyroid hormone of bone and kidney ribonucleic acid synthesis.

SUMMARY The effects of parathyroid extract (PTE) on the synthesis in vivo of free nucleotide and RNA were compared in rat metaphysial bone and kidney. The incorporation of 32P into chromatographically pure acid-soluble 5′-AMP and purified bulk RNA was examined at various times after PTE administration. Pulse-labelled RNA was further characterized by sedimentation in sucrose density gradients and by ribomononucleotide analysis. In both organs the labelling of 5′-AMP and its turnover were accelerated after administration of the hormone. The pool size of free AMP of kidney was approximately 3 times that of bone; neither was affected by PTE. The specific activity of pulse-labelled kidney AMP was always greater, and hormonal stimulation of its labelling was more rapid than in bone. Despite more extensive precursor labelling, the stimulation of renal RNA synthesis was negligible, and was delayed for several hours, the overall hormonal effect being inseparable from its effect on phosphate entry into the nucleotide precursor pool. In bone, the hormonal stimulation of RNA labelling was immediate, and continued to increase at a linear rate for up to 12 h. Initially, stimulation of RNA polymerization accounted for the total hormonal effect, while after 4 h an increasing proportion of the total increase in RNA labelling was attributable to enhanced precursor labelling. Newly synthesized bone RNA differed qualitatively from kidney RNA in its sedimentation properties and composition. Although the labelling of all RNA species and RNA-nucleotides in bone was stimulated by PTE, there was a proportionately greater effect on the labelling of ribosomal RNA, and an apparent shift towards GMP-rich molecules, neither change being manifest in kidney. It is concluded that while bone and kidney share certain mechanisms, they show changes in RNA biosynthesis in response to parathyroid hormone which are both quantitatively and qualitatively different and which are in accord with the RNA requirements for the respective physiological response of each.

Effect of parathyroid function on absorption and excretion of calcium, magnesium and phosphate by rats.

The effects of parathyroidectomy, of parathyroid extract administration and of vitamin D on calcium, phosphate and magnesium metabolism by adult male rats have been studied. Parathyroidectomy had no effect on net calcium absorption or calcium balance but the administration of parathyroid gland extract to parathyroidectomized rats decreased them. Parathyroidectomy also had no significant effect on net phosphate absorption or balance. The administration of parathyroid gland extract to parathyroidectomized rats did not change net phosphate absorption but lowered phosphate balance as a consequence of hyperphosphaturia. The secretion of calcium or phosphate into the intestinal tract was unaffected by the parathyroid status or the serum levels of calcium or phosphate. Supplemental vitamin D increased calcium absorption and balance by parathyroidectomized rats much more than by their controls; it had no significant effect on phosphate absorption by intact rats but increased absorption by parathyroidectomized rat...

Effect of the oral administration of ammonium chloride, sodium phosphate, cellulose phosphate and parathyroid extract on the activity product of brushite in urine

The formation of renal calculi of calcium phosphate origin probably requires a state of supersaturation of urine with respect to brushite (CaHPO 4 · 2H 2O). The reduction in the degree of saturation of urine with respect to this phase should therefore be one of the basic aims of medical therapy for the patient in whom kidney stones form. This hypothesis was tested in eleven patients who had a history of passage of recurrent calcium-containing renal calculi by repeated estimation of the degree of saturation of urine from the urinary activity product of divalent calcium ions (Ca ++) and divalent phosphate ions (HPO 4 −). In ten of the eleven patients urine specimens were supersaturated, largely attributable to a high urine pH or an abnormally high urinary calcium content. The administration of ammonium chloride lowered the activity product of Ca ++ and HPO 4 − in the urine of two patients who responded with a satisfactory degree of urinary acidification. In a patient with renal tubular acidosis, this therapy resulted in a marked increase in the activity product. Orally administered sodium phosphate significantly increased the degree of saturation of urine with respect to brushite in five patients, probably by increasing the urinary excretion of phosphorus (P). (Urinary and serum orthophosphate is expressed in units of elemental phosphorus.) During the administration of cellulose phosphate the urine became less supersaturated in all nine patients tested; in six of them, it became undersaturated. These effects of cellulose phosphate probably resulted from a significant decrease in urinary calcium in the face of an only moderate increase in urinary phosphorus excretion. The administration of parathyroid extract greatly increased the activity product of Ca ++ and HPO 4 −. Surgical removal of parathyroid adenoma or hyperplasia in three patients markedly lowered the degree of saturation of urine with respect to brushite.

Serum calcium concentration and the average evoked response

The effect of serum calcium concentration on the visual average evoked response (AER) was studied in twenty-four patients with disorders of calcium metabolism and in six normal volunteers given parathyroid extract. Low serum calcium concentrations (below 8 mg/100 ml) were associated with greater amplitude and shorter latency evoked responses that were high serum calcium concentrations (above 12 mg/100 ml). Administration of parathyroid extract in doses that affected the serum calcium minimally had no effect on the AER latency or amplitude. AER latency and amplitude changes were correlated with serum calcium concentration rather than with the patient's diagnostic category.

Effects of parathyroidectomy on the development of nephrocalcinosis and calcium, phosphorus and magnesium balance in rats.

SUMMARY Rats of different strains raised on a semipurified casein—sugar diet, develop a nephrocalcinosis in which deposits composed principally of calcium and phosphorus accumulate at the corticomedullary junction of the kidney. To determine whether the development of this nephrocalcinosis was in any way related to the activity of the parathyroid glands, female weanling 21-day-old rats were parathyroidectomized (PTX) or sham-operated and fed the semipurified diet for 3 weeks. Absorption, retention and excretion of Ca, P and Mg were studied during a 14-day balance period. The effects of injecting PTX rats with a small amount of parathyroid extract (15 U.S.P. units Lilly Para-thor-mone, every 12 h for 1 week) were examined. Compared with sham-operated animals PTX rats showed: lower serum Ca and higher P concentrations; a lower urinary excretion (% intake) of Ca, P and Mg; a higher retention (% intake) of P and Mg; a higher concentration of Mg in bone (% femur ash). Administration of parathyroid extract (PTE) tended to reverse changes induced by parathyroidectomy but PTE-treated animals remained slightly hypocalcaemic. Sham-operated and PTE-treated PTX rats developed nephrocalcinosis but untreated PTX rats did not do so. The results indicate that nephrocalcinosis did not develop in rats fed the semipurified diet in the absence of parathyroid hormone. It is postulated that although some activity of the parathyroid glands is needed for mineral deposition in the renal tubules, excessive activity is not necessarily a prerequisite to the development of this type of renal calcification.

A Case of Pseudo-Pseudohypoparathyroidism

In 1942 Albright and Burnett1) described a group of patients who have a round face, short stature, shortening of metacarpals and metatarsals, ectopic ossifications, with elevated serum phosphorus and low serum calcium values as the term pseudohypoparathyroidism (referred to as here-after) and differentiated it from idiopathic hypoparathyroidism. Difference was the failure to respond with a phosphate diuresis to parenteral administration of parathyroid extract. Ten years later the designation of pseudopseudohypoparathyroidism (referred to as here-after) was introduced by Albright, Forbes, and Henneman2) to the patients who had most of the clinical features of PH but in whom the values for serum phosphorus and serum calcium were normal. Since 1952, many PPH cases were reported throughout the world, and 78 cases, including 18 males, 56 females and 4 unknown sex distinction, were reported in Western countries. In Japan, however, there is only one report of Morisaki et al.3) in 1967. Authors had an opportunity to observe a young girl who had features of PPH and PH.

The role of parathyroid hormone in the gastro-intestinal absorption of calcium.

1. Gastrointestinal calcium absorption was studied in six normal subjects and in one patient with idiopathic hypoparathyroidism during a control period and during treatment with parathyroid extract. 2. In all subjects there was a small increase in the gastro-intestinal absorption of calcium during the administration of parathyroid extract.

Changes in serum and urinary calcium during phosphate depletion: studies on mechanisms.

The changes in serum calcium and the renal handling of this ion were evaluated during phosphate depletion. 96 renal clearance studies were carried out in 10 dogs before and after prolonged phosphate depletion (30-160 days) and after repletion. Depletion was produced by reducing phosphate intake and administering aluminum hydroxide gel while intakes of sodium, calcium, and magnesium were constant. With phosphate depletion, serum phosphorus fell to less than 1.0 mg/100 ml and diffusible serum calcium either remained unchanged or rose transiently. Glomerular filtration rate (GFR) fell by 15 to 53%. Despite the reduced filtered load of calcium, its fractional excretion increased in most experiments. This hypercalciuria was not dependent upon changes in sodium or magnesium excretion, or the urinary concentration of complexing anions, and persisted after sodium restriction. Phosphate repletion reversed the effects on GFR and calcium excretion. The intravenous infusion of small quantities of phosphate (0.04 mmole/min) into either intact or thyroparathyroidectomized (T-PTX), phosphate-depleted animals caused a significant reduction in fractional excretion of calcium, but the intrarenal infusion of 0.02 mmole/min of phosphate into one kidney failed to produce an ipsilateral effect. The administration of parathyroid extract reduced fractional calcium excretion, but the latter remained significantly elevated. After T-PTX, fractional calcium excretion did not increase in the phosphate-depleted animals. Furthermore, serum calcium was normal after T-PTX until serum phosphorus increased slightly, and only then did hypocalcemia develop. These observations indicate that (a) phosphate depletion produces hypercalciuria through a reduction in tubular reabsorption of calcium which is not due to changes in the tubular reabsorption of other ions; this effect is not reversed by the direct intrarenal infusion of phosphate; (b) a state of functional hypoparathyroidsm occurs during phosphate depletion which may, in part, cause reduced tubular reabsorption of calcium; (c) other extra renal mechanism(s), possibly related to events occurring in bone as a result of phosphate depletion, may have an effect on urinary calcium excretion; and (d) in the phosphatedepleted state, parathyroid hormone is not required for the maintenance of a normal level of serum calcium.