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Male fertility is in the bones

Cell Press

Researchers have found an altogether unexpected connection between a hormone produced in bone and male fertility. The study in the February 18th issue of Cell, a Cell Press publication, shows that the skeletal hormone known as osteocalcin boosts testosterone production to support the survival of the germ cells that go on to become mature sperm.

The findings in mice provide the first evidence that the skeleton controls reproduction through the production of hormones, according to Gerard Karsenty of Columbia University and his colleagues.

Bone was once thought of as a "mere assembly of inert calcified tubes," the researchers explained. But in the last ten years, scientists have gained a much more dynamic picture of bone as a bona fide endocrine organ with links to energy metabolism and reproduction.

Prior work on skeletal ties to reproduction had focused primarily on the reproductive organs as a regulator of bone remodeling. That led Karsenty's team to wonder whether the influence might go the other way as well. Given the links between menopause and osteoporosis, his team anticipated such a connection would more likely turn up in females. But that's not what they found at all.

"We found that the bones do control reproduction, but only in males," Karsenty said. "That was obviously a surprise, but that's the finding."

Osteocalcin produced by the bone-building cells known as osteoblasts induces testosterone production by the testes, but fails to influence estrogen production by ovaries, the researchers report.

Matings between normal females and osteocalcin-deficient males produced smaller and less frequent litters than those between typical males and females. Males lacking a second gene that inhibits osteocalcin's endocrine functions showed just the opposite: larger (though not significantly larger) and more frequent litters.

The researchers further showed that osteocalcin works through a receptor found on testosterone-producing Leydig cells in the testes.

The newly identified osteocalcin receptor is already known to be expressed in human testes but not ovaries. Osteocalcin has also been shown to influence glucose metabolism in both mice and humans, suggesting that it does act as a hormone in humans.

The new discovery may lead to answers for some men who now suffer from unexplained infertility.

"Male subfertility with no apparent cause is a well-known condition," Karsenty said. He added that researchers may now begin looking for evidence that mutations in osteocalcin or its receptor might be responsible in some of those cases.

Karsenty says his team intends to continue studying the effects of bone on male fertility in greater detail, and they may yet find other links to female fertility that are independent of osteocalcin.

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