Estrogen replacement decreases the set point of parathyroid hormone stimulation by calcium in normal postmenopausal women

Estrogens decrease serum total and ionized calcium (Ca) concentrations in postmenopausal women with or without primary hyperparathyroidism, but cause little or no increase in serum PTH suggesting a modification of the relationship between the two. In order to define this relationship, we studied the effect of conjugated estrogens on total and ionized serum Ca and serum PTH concentrations in five normal postmenopausal women, before and after 3, 11, and 23 weeks of therapy. Dynamic tests of parathyroid gland function, based on 2-h iv infusions of CaCl2 and NaEDTA, were performed at each time. Total and ionized serum Ca and carboxylterminal PTH were measured every 15 min during the infusions, and parathyroid function was evaluated by a nonlinear 4-parameter mathematical model. Estrogen therapy caused decreases in serum total 2.36 +/- 0.04 (SD) mmol/L, baseline vs. 2.19 +/- 0.05 mmol/L, 23 weeks, P less than 0.005) and ionized calcium (1.27 +/- 0.01 mmol/L, baseline vs. 1.21 +/- 0.02 mmol/L, 23 weeks, P less than 0.005]; the decreases were evident at 3 weeks and persisted for the duration of the study. Serum PTH concentrations did not change (8.94 +/- 1.84 pmol/L, baseline vs. 8.98 +/- 2.38 pmol/L, 23 weeks). Three parameters of the parathyroid function, the maximal response to hypocalcemic stimulation, the nonsuppressible fraction of circulating PTH, and the slope of PTH on calcium at the set point were not affected by estrogen treatment. The fourth parameter, the set point of PTH stimulation by serum total calcium (2.16 +/- 0.04 mmol/L, baseline vs. 1.97 +/- 0.07 mmol/L, 23 weeks, P less than 0.0166) or by serum ionized Ca (1.19 +/- 0.04 mmol/L, baseline vs. 1.12 +/- 0.03 mmol/L, 23 weeks, P less than 0.01), was decreased by estrogen treatment. This was evident at the earliest time point studied and persisted thereafter. The decrease in ionized Ca set point only explained 40% of the decrease in total calcium set point, the remaining 60% being related to hemodilution of plasma protein during therapy. We conclude that estrogen replacement can influence parathyroid function in postmenopausal women by resetting the set point of PTH stimulation by ionized Ca. This in turn could contribute to the estrogen-induced changes in their Ca balance.