Alterations in the sensitivity of the parathyroid gland to both stimulative and suppressive stimuli may be partially responsible for skeletal changes that occur with age, estrogen deficiency, osteoporosis, and estrogen treatment of osteoporosis. We sought to define the changes in intact PTH-(1-84) secretion in normal premenopausal and postmenopausal, osteoporotic and estrogen-treated osteoporotic women during the infusion of human (h) PTH-(1-34). hPTH-(1-34) was infused at 0.55 U/kg.h for 24 h, with serum sampling every 4 h. Serum was analyzed for calcium (ionized and total), hPTH-(1-34), and PTH-(1-84). Basal chemistries were no different among groups, except for serum phosphorus, which was highest in osteoporotic women (1.31 vs. 1.07 mmol/L in premenopausal; P less than 0.02), and hPTH-(1-34), which was slightly higher in normal postmenopausal women (19.31 vs. 13.24 ng/L in estrogen treated; P less than 0.02). No differences in PTH-(1-84) were found among groups. hPTH-(1-34) rose similarly in all patient groups, while the calcemic response was somewhat more sluggish in estrogen-treated women, although statistically significant differences were not found. PTH-(1-84) declined rapidly in all patient groups, although estrogen-treated women had a smaller maximal decrease in PTH-(1-84), and the slope of the decremental change in PTH-(1-84) was lower in estrogen-treated women than in osteoporotic or normal postmenopausal women. Untreated osteoporotic women had less suppression of PTH-(1-84) than normal postmenopausal women at every calcium level. Estrogen treatment decreases the calcemic effects of infused hPTH-(1-34) and at the same time reduces calcium-induced suppression of parathyroid secretion. It is possible that such changes in the set-point of the gland contribute to the alterations in bone turnover that result in osteoporosis and the mechanisms by which estrogen prevents bone loss.