HYPERCALCEMIA IN ASSOCIATION WITH A LEYDIG-CELL TUMOR IN THE RAT - A MODEL FOR TUMOR-INDUCED HYPERCALCEMIA IN MAN

The etiology of tumor-induced hypercalcemia was investigated in a transplantable Leydig cell tumor of the Fischer rat. In this model, serum Ca rose from a baseline of 10.4 .+-. 0.3 mg/dl to 12.5 .+-. 0.4 mg/dl at day 10 and 16.4 .+-. 1.3 mg/dl (P < 0.001) at day 13 post-transplant. Urinary Ca also increased from 1.52 .+-. 0.17 mg/d to 3.52 .+-. 0.72 mg/d (Day 12, P < 0.01). Serum phosphate decreased from a baseline of 7.5 .+-. 0.3 mg/dl to 5.5 .+-. 0.6 mg/dl at day 13 (P < 0.05). At day 13 serum immunoreactive parathyroid hormone levels fell 76% from baseline (P < 0.01). Calcitonin increased from 59 .+-. 2 pg/ml to 88 .+-. 9 pg/ml (P < 0.01). The plasma prostaglandin E metabolite, 13,14-dihydro-15-keto-PGE2 increased from 407 .+-. 103 pg/ml to 647 .+-. 62 pg/ml (P < 0.05) and the active Vit D compound 1,25(OH)2D increased from 94.8 .+-. 5.2 pg/ml to 162.3 .+-. 11.8 pg/ml (P < 0.01). Urinary cAMP did not decrease in parallel with the parathyroid hormone level and, in fact, increased from 146 .+-. 3 nmol/d to 172 .+-. 27 nmol/d (NS). Administration of the cyclooxygenase inhibitor indomethacin (20 mg/kg/d) or hydrocortisone (50 mg/kg/d) did not prevent the development of hypercalcemia. This model is similar to many patients with humoral hypercalcemia of malignancy who demonstrate suppression of parathyroid hormone with elevated urinary cAMP excretion and may prove useful in the understanding of the responsible mechanisms.