Estrogen treatment improves calcium malabsorption induced by surgical or natural menopause, but the mechanisms involved are still under debate, with both increased production of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] and improved peripheral responsiveness to the steroid having been proposed. To address this issue, we studied the effect of short term administration of 1,25-(OH)2D3 (1 microgram/day for 7 days) on intestinal fractional absorption of 47Ca (47Ca FA) and vertebral bone density, measured by dual photon absorptiometry, in 14 premenopausal women (aged 31-50 yr) before and 6 months after oophorectomy. After surgery, patients were randomly allocated to a 6-month treatment with either conjugated estrogens (0.625 mg/day; n = 7) or placebo (n = 7). Oophorectomy caused a decrease in both basal 47Ca FA (-40.8 +/- 23.4%; P = 0.004) and vertebral bone density (-7.21 +/- 1.20%; P less than 0.001) in the placebo group. Estrogen replacement prevented these changes and increased basal serum 1,25-(OH)2D3 (+10.3 +/- 10.9%; P = 0.047), whereas a detectable but not significant decrease was observed in the control group (-8.8 +/- 10.5%; P = 0.07). Assessment of 47Ca FA before and after 1,25-(OH)2D3 administration revealed a similar degree of responsiveness to the steroid in the estrogen-treated women before and at the end of the study period (45.8 +/- 6.9% vs. 42.9% +/- 14.9% from basal, respectively; P = 0.142), but a blunted response to 1,25-(OH)2D3 was observed in the placebo group at 6 months (27.9 +/- 17.7%) compared to the result obtained before surgery (36.7 +/- 9.1%; P = 0.032). Multifactor analysis of variance revealed that the effects of estrogen and 1,25-(OH)2D3 on 47Ca FA were independent of basal serum 1,25-(OH)2D3 levels. On the other hand, calcitriol administration increased serum 1,25-(OH)2D3 to a similar extent before and 6 months after surgery in the placebo group (24.2 +/- 18.3% vs. 34.7 +/- 16.7% from basal, respectively; P = 0.484) as well as in the estrogen-treated women (34.2 +/- 17.2% vs. 26.6 +/- 15.45%; P = 0.302). The significant impairment of 1,25-(OH)2D3 stimulation of 47Ca FA in spite of increased levels of circulating 1,25-(OH)2D3 in the untreated women is suggestive of an end-organ resistance to the vitamin D metabolite in a hypoestrogenic condition, which can be prevented by hormone replacement, and supports the hypothesis of a vitamin D-independent action of estrogen on intestinal calcium absorption.