We and others have hypothesized that estrogen helps preserve bone mass by affecting the PTH/vitamin D regulation of skeletal metabolism. To evaluate this theory, we tested the effect of estrogen administration on parathyroid sensitivity to hypocalcemic challenge. Subjects were postmenopausal osteoporotic women recruited from a tertiary care clinic (9 untreated and 12 receiving hormone replacement therapy at the time of the investigation). After baseline serum and urine testing, edetic acid (50 mg/kg) was infused over a 2-h period. Serum and urine samples were obtained over 5 h and 24 h after beginning the infusion. Serum ionized calcium dropped equally in both groups of women. There were overall group differences in PTH-(1-84) secretion (P < 0.02), with a greater peak (P < 0.04) and a longer period of elevation (P < 0.01) in the untreated than in the hormone-treated osteoporotic women. Serum 1,25-dihydroxyvitamin D [1,25-(OH)2D] and phosphorus as well as urinary phosphate and cAMP responded similarly in the two groups of women. Estrogenized osteoporotic women demonstrate a smaller PTH increment to hypocalcemia, indicating that the parathyroid has reduced sensitivity under the influence of estrogen. Despite the smaller PTH increase in estrogenized individuals, renal responses to PTH were the same as those in untreated osteoporotic women, implying an estrogen-mediated increase in the sensitivity of the kidney to PTH.