Sexual dimorphism in cortical bone size and strength but not density is determined by independent and time-specific actions of sex steroids and IGF-1: Evidence from pubertal mouse models

Abstract

Although it is well established that males acquire more bone mass than females, the underlying mechanism and timing of this sex difference remain controversial. The aim of this study was to assess the relative contribution of sex steroid versus growth hormoneinsulin-like growth factor 1 (GH-IGF-1) action to pubertal bone mass acquisition longitudinally in pubertal mice. Radial bone expansion peaked during early puberty (3 to 5 weeks of age) in male and female mice, with significantly more expansion in males than in females (þ40%). Concomitantly, in 5 week old male versus female mice, periosteal and endocortical bone formation was higher (þ70%) and lower (À47%), respectively, along with higher serum IGF-1 levels during early puberty in male mice. In female mice, ovariectomy increased radial bone expansion during early puberty as well as the endocortical perimeter. In male mice, orchidectomy reduced radial bone expansion only during late puberty (5 to 8 weeks of age), whereas combined androgen and estrogen deficiency modestly decreased radial bone expansion during early puberty, accompanied by lower IGF-1 levels. GHRKO mice with very low IGF-1 levels, on the other hand, showed limited radial bone expansion and no skeletal dimorphism. From these data we conclude that skeletal sexual dimorphism is established during early puberty and depends primarily on GH-IGF-1 action. In males, androgens and estrogens have stimulatory effects on bone size during late and early puberty, respectively. In females, estrogens limit bone size during early puberty. These longitudinal findings in mice provide strong evidence that skeletal dimorphism is determined by independent and time-specific effects of sex steroids and IGF-1. ß

Defective signaling, osteoblastogenesis and bone remodeling in a mouse model of connexin 43 C-terminal truncation

“…These findings suggest the intriguing possibility that, beyond the disparate roles of Cx43 in the cortical and trabecular bone compartments, the effects of Cx43 on bone are sexually dimorphic. In female mice, estrogens are known to inhibit periosteal apposition and stimulate endocortical bone apposition; these effects may counteract the action of Cx43 to stimulate periosteal apposition and endocortical resorption (Callewaert et al, 2010b). However, to systematically address the sexually dimorphic skeletal phenotype in these mice, studies should be conducted comparing estrogen-replete and estrogen-deficient mice.…”

Sexual Difference in Bone Geometry of Adult Patients with Classical Congenital Adrenal Hyperplasia: Data Using Peripheral Quantitative Computed Tomography

“…Androgens enhance osteoblast differentiation and influence osteoclast activity. In both sexes androgens may stimulate periosteal apposition [35]. In males with lower levels of estrogens, periosteal apposition might be upregulated, whereas in females endogenous estrogens may inhibit periosteal apposition through interaction with IGF-1 [36].…”

Inactivation of the androgen receptor in bone-forming cells leads to trabecular bone loss in adult female mice

“…9,12 A full AR knockout has been shown to exhibit increased bone turnover and reduced trabecular and cortical bone volume in male mice. [13][14][15][16] Further elimination of estrogen receptor a (ERa) caused an additional reduction in cortical bone mass. 14 In another full AR knockout model, the bone growth and composition of knockout female mice were indistinguishable from those of wild-type (WT) mice at 8 weeks of age, 17 suggesting that the AR is not important during the early development or rapid growth phase of the female skeleton.…”