Effects of estrogen on growth plate senescence and epiphyseal fusion

Estrogen is critical for epiphyseal fusion in both young men and women. In this study, we explored the cellular mechanisms by which estrogen causes th is phenomenon. Juvenile ovariectomized female rabbits received either 70 mu g/kg estradiol cypionate or vehicle i.m. once a week. Growth plates from th e proximal tibia, distal tibia, and distal femur were analyzed after 2, 4, 6, or 8 weeks of treatment. In vehicle-treated animals, there was a gradual senescent decline in tibial growth rate, rate of chondrocyte proliferation , growth plate height, number of proliferative chondrocytes, number of hype rtrophic: chondrocytes, size of terminal hypertrophic chondrocytes, and col umn density. Estrogen treatment accelerated the senescent decline in all of these parameters. In senescent growth plates, epiphyseal fusion was observ ed to be an abrupt event in which all remaining chondrocytes were rapidly r eplaced by bone elements. Fusion occurred when the rate of chondrocyte prol iferation approached zero. Estrogen caused this proliferative exhaustion an d fusion to occur earlier. Our data suggest that (i) epiphyseal fusion is t riggered when the proliferative potential of growth plate chondrocytes is e xhausted; and (ii) estrogen does not induce growth plate ossification direc tly; instead, estrogen accelerates the programmed senescence of the growth plate, thus causing earlier proliferative exhaustion and consequently earli er fusion.