['Evidence is accumulating that estradiol metabolites are not merely waste products but may play physiologic and pathophysiologic roles. In the present study, effect of estradiol metabolites on the proliferation of human female osteoblasts was investigated for the first time and compared to effect of their parent substance 17beta-estradiol.', 'Osteoblasts from female hipbone were incubated with estradiol and estradiol metabolites at dosages of 10(-9), 10(-7) and 10(-5) M for 7 days. Cell proliferation was measured using a cell counter.', 'Estradiol had no effect on cell proliferation at the tested concentrations. In contrast, the A-ring metabolites 2-hydroxyestrone, 2-hydroxyestradiol, 2-hydroxyestriol, 4-hydroxyestrone and 4-hydroxyestradiol displayed significant increases in cell proliferation, although only at high physiologic or pharmacologic dosages. Methylation ofthese metabolites completely abolished their proliferating property. For the D-ring metabolites estrone, estriol, estetrol and 16alpha-hydroxyestrone, no significant changes in cell proliferation were observed.'] Do endogenous estradiol metabolites stimulate the in vitro proliferation of human osteoblastic cells?