Sex steroids, or androgens, in men have well known functions in reproduction and fertility, specifically the ‘male’ hormone testosterone. A lesser known function is the effect of testosterone and other steroid hormones on the development of the skeleton. In the March 4, 2011, issue of the scientific journal Cell, a group led by researchers at Columbia University reported a previously unknown bidirectional regulation between the gonads and skeleton in men.
As shown by these University of Michigan biomechanics course materials, human skeletal bone is made of a matrix of connective tissue that becomes mineralized (for example, with calcium and potassium). The bone matrix is laid down by cells called osteoblasts (“osteo” meaning bone). One protein produced by osteoblasts is osteocalcin, which makes up 10 percent of the non-connective tissue proteins in bone. Osteocalcin was discovered in the mid 1970s and found to be abundant in mineralized bone as it is a calcium-binding protein. The protein is considered a cell marker for osteoblasts, though its actual structure was not elucidated until 2003 and its interactions with minerals in the bone are still being discovered. However, among the discoveries for this protein is a role outside the skeletal system - the new research findings highlight a role for osteocalcin as a regulator of male fertility.
In the male testes, testosterone is produced by Leydig cells, also known as the interstitial cells of Leydig. Using mice, the Columbia research team found a G-protein coupled receptor on Leydig cells (known as Gprc6a) that binds osteocalcin, resulting in a CREB-dependent expression of enzymes that are needed to synthesize testosterone. In more simple terms, they showed that the bone hormone binds cells in the testes and induces gene expression involved in the synthesis of testosterone. The result of this expression was germ cell survival and spermatogenesis (production of sperm), indicating a role for the regulation in fertility. Conversely, an absence of osteocalcin resulted in decreased testosterone levels, decreased sperm count, half as many litters with breeding partners, and fewer pups per litter.
The hormone had no effect on estrogen production, the female correlate in fertility. Thus, osteocalcin is involved in male fertility specifically, through an influence on the system regulating the production of sperm. This study is the first to show an endocrine role for the skeletal system in reproduction. The research is said to have been spurred by the observation that mice lacking osteocalcin were poor breeders. The results still need to be confirmed in humans, but it may explain the low testosterone levels involved in some cases of human infertility.