Testosterone on Time

Liz is a staff writer for Science.

When it comes to sex, timing is everything. That's especially true for testosterone production. Now, researchers have discovered that a protein that keeps the body's bile in check does double duty, moderating testosterone output and its affects on the testis, and influencing the onset of fertility.

Testosterone orchestrates the maturation of the male reproductive tract--including the testis, epididymis, and seminal vesicles--and to some extent, of the sperm themselves. Too much of this hormone too soon can disrupt an animal's normal reproductive patterns, leading, for example, to parents producing offspring before they can care for them.

Seeking a better handle on the molecular switches that control testosterone production, David Volle, a postdoc in the lab of Johan Auwerx at the University Louis Pasteur in Strasbourg, France, looked at a protein called small heterodimer partner (SHP). SHP helps regulate the formation of bile in the liver, but it's also present in small amounts in the testis. To learn about SHP's role there, Volle and colleagues compared testosterone production and fertility in mice with and without functional SHP genes.

Testosterone levels were higher, and the epididymis and seminal vesicles grew faster, in the SHP-deficient mice than in mice with the intact gene, the team reports in the 1 February issue of Genes and Development. The researchers' molecular studies showed SHP puts a damper on genes and on a transcription factor protein that spur testosterone manufacture. Moreover, they discovered that SHP plays a second role: reducing the production of retinoic acid to ensure the correct timing of sperm differentiation. SHP-deficient mice were sexually precocious, fertilizing females a week earlier than mice with intact SHP.

Researchers still need to do more work, but the discovery of this new player in maturity suggests a novel way to control male fertility. One day, drugs that interfere with SHP's actions may help improve sperm production in infertile men, suggests Volle. And drugs that promote its activity might be useful for treating premature puberty.

Given how little SHP there is in the testes, it is surprising--but believable--to find a molecule that is so influential in the timing of these key aspects of male reproduction, says Bert O'Malley, a cell biologist at Baylor College of Medicine in Houston, Texas. For male fertility problems, "the work has implications for therapies" by providing a potential new drug target, he says.

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