Work

Sex Steroid Actions in Male Bone

Year: 2014

Type: review

Abstract: Sex steroids are chief regulators of gender differences in the skeleton, and male gender is one of the strongest protective factors against osteoporotic fractures.This advantage in bone strength relies mainly on greater cortical bone expansion during pubertal peak bone mass acquisition and superior skeletal maintenance during aging.During both these phases, estrogens acting via estrogen receptor-␣ in osteoblast lineage cells are crucial for male cortical and trabecular bone, as evident from conditional genetic mouse models, epidemiological studies, rare genetic conditions, genome-wide meta-analyses, and recent interventional trials.Genetic mouse models have also demonstrated a direct role for androgens independent of aromatization on trabecular bone via the androgen receptor in osteoblasts and osteocytes, although the target cell for their key effects on periosteal bone formation remains elusive.Low serum estradiol predicts incident fractures, but the highest risk occurs in men with additionally low T and high SHBG.Still, the possible clinical utility of serum sex steroids for fracture prediction is unknown.It is likely that sex steroid actions on male bone metabolism rely also on extraskeletal mechanisms and cross talk with other signaling pathways.We propose that estrogens influence fracture risk in aging men via direct effects on bone, whereas androgens exert an additional antifracture effect mainly via extraskeletal parameters such as muscle mass and propensity to fall.Given the demographic trends of increased longevity and consequent rise of osteoporosis, an increased understanding of how sex steroids influence male bone health remains a high research priority.(Endocrine Reviews 35: 906 -960, 2014) I. Introduction II.Sex Steroid Physiology in Relation to Bone A. Circulating sex steroids and SHBG B. Local sex steroid metabolism in bone tissue C. Classical androgen and estrogen receptor signaling D. Ligand-independent and nongenomic actions E. Rodent models in the study of sex steroids and bone: a critical appraisal III.Structural Basis of Male Bone Strength A. Favorable cortical bone size and trabecular microstructure in young adult men B. Better maintenance of trabecular and cortical bone structure in men across the lifespan IV.Regulation of Skeletal Sexual Dimorphism A. Estrogen receptor ␣: crucial for peak bone mass B. Estrogen receptor ␤ C. ER␣ AF-1 and AF-2 D. Role of the androgen receptor E. Non-genomic signaling F. Independent effects of gonadotropins V. Target Cells of Sex Steroids in Bone A. Osteoclasts B. Osteoblast lineage C. Chondrocytes D. Conclusions from conditional mouse models VI.Direct Skeletal Target Genes of the Androgen and Estrogen Receptor A. Estrogen receptor target genes B. Androgen receptor target genes VII.Interaction of Sex Steroids with Other Signaling Pathways

Source: Endocrine Reviews

DOI: 10.1210/er.2014-1024