Mini-Abstract: DHEA may be useful in the treatment of PMO. Our present study has found the preferable stimulatory effect of DHEA on bone, different from the proliferative effects of E2 on endometrium and uterus, which suggests the more potential clinical values of DHEA than estrogens in prophylaxis and therapeutics for PMO. Introduction: A series of findings raise the possibility that DHEA may be useful in the treatment of PMO. Our present study thus aimed at the differential effects of DHEA and E2 on bone and uterus in the ovariectomized mice, and involvements of aromatase, ERα, ERβ, and AR in the effects. Materials and methods: The ovariectomized and sham BALB/c mice were given daily treatment with either vehicle, DHEA or E2 for three months, respectively. BMD were determined by DEXA after the last treatment. Mice were necropsied in 3 months after the treatment, femur OBs ultrastructure were analyzed by TEM; DHEA, DHEAS and E2 levels were assayed by EIA; production in vitro of E2 in uterus or tibia was assayed to evaluate the profile of P450arom activity; ERα and ERβ mRNA levels in uterus and tibia were determined by real-time PCR. The primary murine OBs were treated with DHEA and E2, respectively for 72h. Real-time PCR and Western blot was carried out to evaluate aromatase, ERα, ERβ and AR expression in OBs. Results: Both DHEA and E2 significantly improved bone mineral density (BMD) and OB ultrastructure; E2 but not DHEA has significantly increased uterus wet weight, endometrium epithelial and gland thickness. DHEA not only increased serum and femoral DHEA, DHEAS and E2 concentration, but also increased uterine DHEA and DHEAS other than E2 concentration in site; while E2 only increased serum, uterine and femoral E2 concentration, but failed to alter the concentrations of DHEA and DHEAS. Moreover, DHEA significantly increased tibia P450arom enzyme activity; while E2 increased uterine and tibia aromatase activity. Furthermore, DHEA increased uterine ERβ and ERα, and ERβ transcription in tibia; while E2 increased ERα transcription in uterus and tibia. DHEA increased aromatase, ERα, ERβ and AR expression in OB, and increased significantly, but E2 apparently decreased the ratio of ERβ/ERα. Conclusions: Although both DHEA and E2 augment BMD, the proliferative effects of E2 on endometrium and uterus reflect the different modes of action on bone and uterus, which indicates that the preferable stimulatory effect of DHEA on bone appears to the more potential clinical values than estrogens in prophylaxis and therapeutics for PMO. But applicability of the findings from rodents in humans needs further study.