Twenty normal individuals received 2-h iv infusions of CaCl2 and Na2 ethylenediamine tetra-acetate, with sampling every 15 min. PTH was measured by means of an intact hormone assay (I) and two carboxylterminal assays structured to react mostly with mid (M) or late (L) carboxylterminal fragments. A mathematical model was used to fit the sigmoidal relationship between ionized calcium (CA++) and PTH values. The influence of Ca++ on circulating PTH immunoheterogeneity was assessed via changes in L/I, M/I, and M/L ratios. Results are reported as means +/- SD. Response to hypocalcemia was highest with M (57.8 +/- 26.4 pmol/L, P less than 0.005 vs. L or I) and higher with L (20.1 +/- 5.6 pmol/L; P less than 0.0005 vs. I) than with I (14.1 +/- 6.4 pmol/L). L/I, M/I, and M/L decreased from 2.43 +/- 0.56 to 1.54 +/- 0.19 (P less than 0.0005), 8.44 +/- 2.38 to 4.36 +/- 4.07 (P less than 0.0005), and 3.49 +/- 0.71 to 2.86 +/- 0.76 (P less than 0.005), respectively, during Na2 ethylenediamine tetra-acetate infusion. Nonsuppressible PTH was again higher with M (13.7 +/- 4.8 pmol/L; P less than 0.0005 vs. L or I) and higher with L (2.8 +/- 0.7 pmol/L, P less than 0.0005 vs. I) than with I (0.5 +/- 0.3 pmol/L). L/I, M/I, and M/L ratios increased from 2.47 +/- 0.97 to 5.35 +/- 2.09 (P less than 0.0005), 8.90 +/- 3.10 to 29.56 +/- 14.89 (P less than 0.0005), and 3.62 +/- 0.90 to 5.30 +/- 1.91 (P less than 0.005) during CaCl2 infusion. The set-point for PTH stimulation by calcium was similar for M (1.15 +/- 0.035 mmol/L) and L (1.175 +/- 0.041 mmol/L) but significantly higher with the I assay (1.184 +/- 0.31 mmol/L; P less than 0.0005 vs. M). The M/I, L/I, and M/L ratio set-points were similar at 1.28 +/- 0.01, 1.27 +/- 0.01, and 1.29 +/- 0.02 mmol/L. Thus, even if proportionately more intact PTH and less carboxylterminal fragments are produced and secreted during hypocalcemia, the latter still predominate in the circulation. Furthermore, at high calcium values, secretion of fragments is less well inhibited than that of intact hormone. The lower secretion and higher ratio set-points suggest that the secretion and intracellular degradation of PTH have different sensitivities to inhibition by calcium.