Estrogen's Emerging Manly Alter Ego

Estrogen is usually described as the animal kingdom's primary female sex hormone. That's a gross oversimplification, however. Even that quintessentially male preserve -- the sperm -- depends on estrogen, scientists report this week. Without estrogen, males are infertile.

 The new study, by Rex A. Hess at the University of Illinois at Urbana-Champaign and his colleagues, focuses on estrogen's role in male reproductive function. Nevertheless, the researchers observe that their findings also suggest a mechanism by which DDT and other estrogen-mimicking pollutants could wreak havoc on fertility. If these weak estrogens displace the body's more potent natural ones, they might diminish estrogen exposure -- and sperm activity.

 Hess and his colleagues study mutant mice. These animals were bred to produce estrogen normally, but they lack the gene for an estrogen receptor -- a protein that allows cells to take up the hormone. As a result, the mice cannot respond to the estrogen in their bodies.

 Since this hormone plays a pivotal feminizing role in development, the scientists expected that mutant females would develop abnormally. "The big surprise," notes Patricia M. Saling, a reproductive cell biologist at Duke University Medical Center in Durham, N.C., was the finding 4 years ago that the males were infertile. Since then, Hess and others have been probing why.

 Last year, Mitch Eddy of the National Institute of Environmental Health Sciences (NIEHS) in Research Triangle Park, N.C., and his colleagues showed that although the mutant males initially make sperm, their testes quickly degenerate. They traced the problem to a backup of excess seminal fluid.

 In the Dec. 4 Nature, Hess and his colleagues uncover the cause of the backup. It's not overproduction of the secreted fluid, as many had suspected. Instead, it's a drainage problem: The tubes running from the testes to the epididymis, where sperm mature and acquire the ability to fertilize eggs, are unable to drain off the excess liquid. 

 Besides damaging the testes, this excess fluid "also results in a very dilute ejaculate," notes Hess' colleague Kenneth S. Korach of NIEHS, a developer of the mutant strain of mice. If sperm are not packed densely in seminal fluid, fertility is impaired.

 The tubes -- known as efferent ducts -- and the epididymis have never been considered "dominant in terms of making or breaking fertility," Saling says. The new study suggests otherwise. In fact, she says, "if manipulating the epididymal environment can lead to whopping amounts of infertility, this would suggest a new organ to target in the development of [male] contraceptives."

 Ineffective fluid removal may not explain all of the mutant males' fertility problems, however. Eddy's team found that any sperm produced fail to mature and become capable of fertilization. Yet excess fluid might play a role here, too, speculates Richard M. Sharpe of the Medical Research Council in Edinburgh. In a commentary accompanying the Nature report, he says that ". . . the abnormal amounts of fluid will effectively dilute [any maturing agents] secreted within the epididymis."

 What the new data clearly demonstrate, Korach states, is the essential role of estrogen in male reproductive health. Indeed, Sharpe adds, "Suddenly, the idea of 'male' and 'female' hormones begins to look thin."

 Hess' team argues that the new data also raise "further concern over the potential direct effects of environmental estrogens on male reproduction and reported declines in sperm counts."

 After analyzing 61 studies, Danish scientists reported an apparent downward trend in human sperm counts 5 years ago. Since then, others have challenged their assessment, arguing that the data -- collected in different regions, over different times, and using different criteria -- are not comparable. 

 Not so, concludes a major reanalysis. 

"I think we were the only group that actually got all of the original data," says Shanna H. Swan of the California Department of Health Services in Emeryville. Her group analyzed the data using a series of alternative statistical techniques to see if the decline originally reported was an artifact of the way the data had been analyzed.

 In the just-published November Environmental Health Perspectives, Swan's team reports that all its analyses show a decline in sperm counts since 1970 for men in Western countries. Indeed, Swan observes, the statistical representations that best fit the data detected an even stronger drop than the Danes had reported. 

 The new declines average more than 1 percent annually -- or about 1.5 million sperm per milliliter per year in the United States and 3 million sperm per milliliter per year in Europe.