Endocrine Abstracts

In light of the gender differences in bone geometry, sex steroids have been proposed as key regulators of pubertal periosteal bone formation. Sex steroids may affect periosteal bone apposition following activation of sex steroid receptors [androgen receptor (AR), estrogen receptor alpha (ERα) or beta (ERβ)]. Traditionally, it has been assumed that AR-mediated androgen action stimulates periosteal bone formation and thereby determines the larger bone size in males, whereas estrogens suppress periosteal bone formation resulting in a smaller bone size in females. However, optimal periosteal growth in the male is only obtained in the presence of both AR and ER activation as demonstrated in mice with a disruption of the AR gene and in an adolescent man with a mutation in the gene encoding the aromatase enzyme. Moreover, the bone phenotypes of ERα, ERβ and double knock-out mice indicate that the presence of ERα and ERβ increase and decrease periosteal bone expansion, respectively (the former is observed in males and females, the latter only in females). Furthermore, administration of an aromatase inhibitor that blocks the conversion of androgens into estrogens also limits periosteal bone expansion in growing male mice and rats. Beside sex steroids, growth hormone (GH) and insulin-like growth factor-I (IGF-I) are also major determinants of radial skeletal growth. Moreover, sex steroids and GH-IGF-I closely interact in pubertal life in order to obtain optimal stimulation of periosteal bone formation. In this context, targeted disruption of ERα in mice or pharmacological inhibition of aromatization of androgens in mice and rats reduce serum IGF. Such finding raises the question to what extent sex steroids are able to affect periosteal bone formation independently from the GH-IGF-I axis. We therefore studied periosteal bone formation following androgen or estrogen administration in orchidectomized male mice with disrupted growth hormone receptor (GHR). GHR activation appears the main determinant of radial bone expansion, but both GHR signaling and androgen action are independently and cooperatively needed for optimal stimulation of periosteal growth in the male during puberty. Interestingly, estrogen treatment rescued periosteal bone formation in mice with disrupted growth hormone receptor which was explained by a stimulation of IGF-I synthesis in the liver independently from GHR activation.

In conclusion, optimal periosteal bone formation in the male during puberty primarily depends on a functional GH-IGF-I axis, followed by activation of the AR. However, both GH/IGF-I and androgens are independently needed for optimal stimulation of radial bone growth. Moreover, part of the androgen action on periosteal bone may be explained by aromatization and subsequent ERα activation. The latter may interact with GH/IGF-I and may influence periosteal growth by estrogen-related changes in serum IGF-I.