Skeletal Sexual Dimorphism: Relative Contribution of Sex Steroids, Growth Hormone - Insulin-Like Growth Factor-I (GH-IGF-I) and Mechanical Loading

Structural gender differences in bone mass - characterized by wider but not thicker bones - are generally attributed to opposing sex steroid actions in men and women. Recent findings have redefined the traditional concept of sex hormones as the main regulators of skeletal sexual dimorphism. Growth hormone (GH) - insulin-like growth factor-I (IGF-I) action is likely to be the most important determinant of sex differences in bone mass. Estrogens limit periosteal bone expansion but stimulate endosteal bone apposition in females, whereas androgens stimulate radial bone expansion in males. Androgens not only act directly on bone through the androgen receptor (AR) but also activate estrogen receptor-alpha or -beta (ERalpha or ERbeta) following aromatization into estrogens. Both AR and ERalpha pathways are needed to optimize radial cortical bone expansion, whereas AR signaling alone is the dominant pathway for normal male trabecular bone development. Estrogen/ERalpha-mediated effects in males may - at least partly - depend on interaction with IGF-I. In addition, sex hormones and their receptors impact on the mechanical sensitivity of the growing skeleton. AR and ERalpha signaling may limit the osteogenic response to loading in males and females, respectively, while ERalpha may stimulate the response of bone to mechanical stimulation in the female skeleton. Overall, current evidence suggests that skeletal sexual dimorphism is not just the end result of differences in sex steroid secretion between sexes, but depends on gender differences in GH-IGF-I and mechanical sensitivity to loading as well.status: publishe