Abstract.Objectives of the present study were to establish and investigate a standardized method for quantifying of intact parathyroid hormone secretion during sequential induction of hypo-and hypercalcaemia, and to explore the applicability to these data of a mathematical model derived from in tritro studies as presented in the literature.Twenty-two healthy volunteers aged 20-80 years participated in one or more experiments. The experiments comprised three different protocols of sequential induction of a regular hypocalcaemic (citrate) clamp followed by increases in blood ionized calcium, ending in a regular hypercalcaemic (calcium) clamp.During protocol I, the induction of hypocalcaemia, blood ionized calcium 0.2 1 mmol 1-(SD 0.01, n = 76) below baseline, the release of serum parathyroid hormone rapidly increased to a concentration of four to seven times above baseline. The serum parathyroid hormone declined gradually to a steady state of about two to three times above baseline. During stepwise increases in blood ionized calcium, the serum parathyroid hormone rapidly declined to new steady state concentrations. When a hypercalcaemia of 0.20 mmol I-' (SD 0.02, n=76) above baseline was reached, serum parathyroid hormone was suppressed to about one-fourth of baseline concentration. Protocol TI, the Cica-clamp, and protocol 111, are short versions of protocol I using a slow and gradual increase in blood ionized calcium from hypo-to hypercalcaemia. Protocol I1 reached a hypocalcaemia of blood ionized calcium 0.22 mmol I-] (SD 0.03, n= 57) below baseline and a hypercalcaemia of 0.19 mmol I-' (SD 0.04, n = 57) above baseline, whereas protocol 111 reached a hypocalcaemia of 0.38 mmol I-' (SD 0.06, n=57) below baseline and a hypercalcaemia of 0.34 mmol 1-' (SD 0.04, n=57) above baseline blood ionized calcium. During protocol TI and I11 we obtained identical results of serum parathyroid hormone compared to protocol I (P>0.70), indicating that serum parathyroid hormone could neither be suppressed nor Blood ionized calcium and serum parathyroid hormone demonstrate an inverse sigmoidal relationship with a blood ionized calcium concentration to the parathyroid hormone-midpoint of 1.1 3 mmol I-' (SD 0.04, n = 19), distinctly different from mean baseline blood ionized calcium, 1.25 mmol I -' (SD 0.04, n = 38). Our data suggest an asymmetrical control of blood ionized calcium by serum Parathyroid hormone with a true calcium set-point corresponding to about 8 5 % inhibition of maximal parathyroid hormone secretion.In conclusion, the present data shows that it is possible to establish a standardized test for sequential induction of hypo-and hypercalcaemia suitably for quantifying of serum parathyroid hormone secretion in vivo. The Cica-clamp test is short, easy to handle, reproducible and without discomfort to normocalcemic subjects. Its clinical usefulness remain to be determined.