Calcium-lowering action of glucocorticoids in adrenalectomized-parathyroidectomized rats. Specificity and relative potency of natural and synthetic glucocorticoids.

The specificity and potency of glucocorticoids to lower serum calcium (Ca) in rats after parathyroidectomy (PTX) and adrenalectomy (ADX) were examined. Rats fasted overnight were given sc injections of various steroids immediately after the operations. The fall in serum calcium 5 h after PTX-ADX in rats given hypocalcemic doses of corticosterone was compared to that after injection of a test steroid. At high doses, progesterone, estradiol, testosterone, and aldosterone were inactive, whereas glucocorticoids were consistently hypocalcemic. These results indicate that the Ca-lowering effect is specific for steroids with glucocorticoid activity. Potency estimates were made by comparing the dose-response of natural and synthetic glucocorticoids to that of corticosterone, the major glucocorticoid in rats. The mean potency of hydrocortisone was 8.2 times that of corticosterone. Prednisolone was about 9.6, triamcinolone 33, betamethasone 109, and dexamethasone 301 times as potent as corticosterone. Thus, the use of the calcium-lowering action as a bioassay has provides a specific and rapid in vivo method to compare potencies of glucocorticoids consistent with those obtained by anti-inflammatory and glycogen deposition assays. The importance of this interesting calcitonin-like action of glucocorticoids in normal physiology of calcium metabolism is not yet established.

Hypocalcemic effect of physiological concentrations of corticosterone in adrenalectomized-parathyroidectomized rats.

We have confirmed the serum calcium-raising effect of adrenalectomy in young male rats 5-6 h after parathyroidectomy that was first observed by others many years ago. (The phenomenon has also been reported in cats, dogs, and mice.) In addition, we have shown that adrenalectomy raises the serum ionized calcium as well as total calcium and that the effect occurs in young female as well as in young male rats. Furthermore, we have found that the serum calcium-raising effect of adrenalectomy occurs if the adrenalectomy is performed several days before parathyroidectomy or 6 h after parathyroidectomy, as well as at the same time as the parathyroidectomy. When the rats were adrenalectomized 7-9 days before parathyroidectomy and given small daily life-maintaining doses of corticosterone or cortisone acetate, this glucocorticoid treatment did not reverse the adrenalectomy effect. This led us to think at first that the effect of adrenalectomy must be due to the loss of an unknown adrenal factor rather than to loss of glucocorticoid. Additional experiments, however, in which corticosterone or hydrocortisone was administered by continuous release pellets, demonstrated conclusively that a small continuous supply of corticosterone (within the physiological range as determined by immunoassay of plasma) was sufficient to reverse the adrenalectomy effect. The results with hydrocortisone were similar at even lower doses than of corticosterone. Somewhat higher doses of corticosterone or hydrocortisone reduced the serum calcium even below the parathyroidectomy level. In a preliminary investigation of the specificity of the glucocorticoid effect we found that aldosterone, dehydroepiandrosterone, or estradiol had no effect on serum calcium under similar conditions. We conclude that the fall in serum calcium after parathyroidectomy in rats is due in part to the hypocalcemic effect of endogenous corticosterone. Thus, the loss of corticosterone after adrenalectomy explains the serum calcium-raising effect of adrenalectomy in parathyroidectomized rats. These results also suggest that glucocorticoids at physiological levels have a significant effect on calcium metabolism in general.

Gamma-glutamyltranspeptidase levels as an aid in the management of human cancer.

Plasma gamma-glutamyltranspeptidase (GGTP) levels were measured in 435 cancer patients, 120 healthy controls, 15 patients with systemic lupus erythematosis, and 10 patients with rheumatoid arthritis. The mean GGTP activity of all cancer patients studied, with the exception of malignant lymphoma, was significantly elevated compared to control values. Several patient groups were retrospectively analyzed to determine whether GGTP levels correlated with clinical status. Patients who were disease-free had GGTP levels in the normal range, whereas patients with metastases had elevated levels. Serially increasing GGTP levels were associated with disease progression and death. Persons who remained free of disease had serial GGTP levels within the normal range. Furthermore, decreasing levels were associated with response to therapy. These results indicate that GGTP levels may have prognostic value in various human malignancies.

Stimulation of gastrin secretion in the pig by parathyroid hormone and its inhibition by thyrocalcitonin.

Gastrin secretion was studied in 16 young anesthetized pigs weighing 14-26 kg. Test substances were infused (0.1 ml/min x 10-20 min) directly into the gastric antrum via a catheter in the right gastroepiploic artery. Samples were collected from a catheter in the right gastroepiploic vein and plasma gastrin was measured by radiommunoassay. The following results were observed: 1) basal gastrin in antral venous blood was 10-5 times that in peripheral blood (620+/-222 pg/ml vs. 41+/-10 pg/ml, 2) native bovine parathyroid hormone (PTH) and synthetic human 1-34 PTH (0.02-4U/min) produced rapid (within 10-30 min) and pronounced (approximately 10-fold) increases in gastrin release with no increase in plasma calcium and, in several animals, in the face of a falling plasma calcium concentration, 3) neither acute thyroidectomy nor infusion of porcine thyrocalcitonin (TCT), 0.5-2.5 U/min) consistently altered basal gastrin secretion (N=3-6), and 4) infusion of TCT (0.5 U/min)along with PTH (2U/min) significantly suppressed the 10-11-fold increase in gastrin release observed when PTH subsequently was infused alone in each pig (N=6). The results demonstrate that PTH can stimulate gastrin secretion in the pig and that TCT can suppress this effect.

Calcium metabolism during lactation: enhanced effects of thyrocalcitonin.

Lactating rats were compared with nonlactating controls, with regard to the intake and absorption of calcium, serum calcium level, and te protective effect of thyroacalcitonin (TC) against hypercalcemia and hyperphosphatemia. While consuming a commercial diet, intact, nonfasted lactating rats maintained a serum calcium level of approximately 9 mg/100 ml, which was 1 mg/100 ml lower than that of nonlactating controls. The level rose to that of the controls within one day after removal of the litters from the mother. Compared with nonlactating rats, lactating rats had a three-fold higher calcium intake and a six-fold higher rate of net absorption of calcium. After intragastric calcium (10 mg/100 g body wt) the increase in serum calcium was small (1 mg/100 ml) 2 h later in both groups of sham-operated rats but was markedly increased in thyroparathyroidectomized groups, with the lactating rats showing a significantly greater increase than the nonlactating rats. The injection of a small dose of porcine thyrocalcitonin completely counteracted this hypercalcemia in lactating rats, but did not have any effect on nonlactating controls. Protection by the thyroid gland against hyperphosphatemia after intragastric calcium also was significant in both lactating and nonlactating rats. The results show that TC is much more effective in lactating than in nonlactating rats, suggesting that TC may be of particular importance in lactation by restricting elevations of serum calcium and phosphorus levels after eating, thereby aiding in conservation of these ions.