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The effects of sex steroids on bone via extraskeletal actions

The major role of sex steroids is the development of sexual characteristics. Testosterone, which is the main male sex steroid is produced by the Leydig cells in the testicle and is responsible for the differentiation of the male sex organs during the embryogenesis and the acquisition of secondary sexual characteristics, such as deep voice, sexual hair growth and penile enlargement during puberty. On the other hand, estradiol is the major female sex steroid and is synthetized mainly in the granulosa and theca cells in the follicles of the ovary, and plays a key role in the female sexual development and the growth of the female reproductive organs. Both estrogens and androgens are synthetized from cholesterol and their activation takes place within specific tissues such as bone. They are present in both sexes and are responsible for the differences of the male and female skeleton. Particularly estrogens are related with the epiphyseal maturation, the normal bone mineral accretion and the pubertal growth spurt. The strong correlation between sex steroids and bone physiology became obvious during the study of osteoporosis, which is a very common metabolic disorder in older ages. Bone loss is a physiological characteristic of the ageing process but some people lose bone density faster and suffer greater risk of fractures. Women during menopause for example lose approximately 10% of bone mass and the decrease of estrogen levels plays a critical role in this condition. Sex steroid levels have direct effect on bone and they influence bone resorption and bone production via regulation of osteoclastic and osteoblastic activity. They directly reduce the number of osteoclasts on bone surfaces either by inhibiting the differentiation of osteoclasts or by promoting their apoptosis. Due to those antiosteoclastogenic properties, estrogens are used during menopause to prevent bone loss and hormone replacement therapy was a cornerstone in the treatment of osteoporosis in the past few decades. Apart from the direct effect of sex steroids on osteoclasts, osteoblasts and osteocytes, estrogens and adrogens can also affect bone via extraskeletal actions. The aim of this article is to provide a contemporary summary of those actions. The key systems that will be analyzed are the immune system, the muscle cells, the adipose tissue and reactive oxygen species and how the actions of sex steroids on those tissues influence the bone. Abstract Sex steroids have direct effect on bone via their action on the estrogen and androgen receptors of bone cells. However, there is emerging evidence that their indirect actions on bone can play also important role in the pathogenesis of osteoporosis and bone loss in inflammatory diseases. The tissues that are involved in the extraskeletal actions of sex hormones and are better studied in the past few decades are adipose tissue, muscle tissue and the immune system. Key regulators on those complex pathways are molecules such as cytokines, adipokines and reactive oxygen species.