It is generally well accepted that the pubertal surge in estrogen is responsible for the rapid bone accretion that occurs during puberty and that this effect is mediated by an estrogen-induced increase in GH/IGF action. To test the cause and effect relationship between estrogen and GH/IGF, we evaluated the consequence of ovariectomy (OVX) in prepubertal mice (C57BL/6J mice at 3 weeks of age) on skeletal changes and GH/IGF axis during puberty. Contrary to our expectations, OVX increased body weight (12 to 18%), bone mineral content (11%), bone length (4%), bone size (3%), and serum, liver and bone IGF-I (30 to 50%) and decreased total body fat (18%) at 3 weeks post-surgery. To determine if estrogen is the key ovarian factor responsible for these changes, we performed a second experiment in which OVX mice were treated with placebo or estrogen (E) implants. In addition to observing similar results compared with our first experiment, estrogen treatment partially rescued the increased body weight and bone size and completely rescued body fat and IGF-I levels. The increased bone accretion in OVX mice was due to increased bone formation rate (as determined by bone histomorphometry) and increased serum procollagen peptide. In conclusion, contrary to the known estrogen effect as an initiator of GH/IGF surge and thereby pubertal growth spurt, our findings demonstrate that loss of estrogen and/or other hormones during the pre-pubertal growth period effect leads to an increase in IGF-I production and bone accretion in mice.