Several studies indicate that estrogen may enhance the effects of mechanical loading on bone mineral density in elderly women. This stimulating effect of estrogen could be due to increased sensitivity of bone cells to mechanical stress in the presence of estrogen. The present study was performed to determine whether 17-estradiol (E₂) enhances mechanical stress-induced prostaglandin production and cyclooxygenase (COX)-2 mRNA expression. We subjected bone cells from seven nonosteoporotic women between 56 and 75 yr of age for 1 h to pulsating fluid flow (PFF) in the presence or absence of 10¹¹ M E₂ and measured prostaglandin production and COX-1 and COX-2 mRNA expression. One hour of PFF stimulated prostaglandin (PG)E₂ production threefold, PGI₂ production twofold, and COX-2, but not COX-1, mRNA expression 2.9-fold. Addition of E₂ further enhanced PFF-stimulated PGE₂ production by 1.9-fold but did not significantly affect PGI₂ production or COX-2 or COX-1 mRNA expression. E₂ by itself did not affect any of the parameters measured. These results suggest that estrogen modulates bone cell mechanosensitivity via the prostaglandin synthetic pathway independently of COX mRNA expression.