Newly found estrogen role in males might lead to contraceptive for men

November 13, 2001

CHAMPAIGN, Ill. -- Researchers tapping into the estrogen pathway that regulates fertility in males have found two independent roles of the hormone, and they may have uncovered a new approach for developing a male contraceptive.

In a paper to appear in the Proceedings of the National Academy of Science, University of Illinois scientists report that estrogen regulates fluid reabsorption in the male reproductive tract by triggering a protein involved in sodium transport. They also detail in the paper - published in the online PNAS Early Edition on Nov. 6 - that estrogen sustains the morphological architecture of the efferent ductules.

"We were not expecting this second role of estrogen," said Rex A. Hess, a professor of reproductive biology and toxicology at the University of Illinois College of Veterinary Medicine. "This structure-sustaining role appears to be independent of estrogen's molecular function of regulating ion transport. This tells us that estrogen is important for the expression of other genes with distinct physiological and morphological functions."

Hess and colleagues had documented in 1997 that estrogen was vital for fluid reabsorption during the transfer of sperm in fluid from the testis through the efferent ductules to the epididymis, where sperm matures and is stored. The PNAS paper provides a molecular picture of what estrogen does.

Efferent ductules are small tubes that produce concentrated semen. In a series of experiments using mice lacking the estrogen receptor or proteins thought to be regulated by estrogen, the scientists showed that when sodium transport did not occur, excess fluid diluted the sperm, leaving mice infertile. However, when estrogen receptor was present, epithelial cells were normal in appearance, even when sodium transport was abolished in the mice lacking the protein NHE3.

Hess and colleagues discovered that NHE3, which is responsible for the transport of sodium into and out of cells, was directly responsible for luminal fluid reabsorption under estrogen regulation. "Thus, blockage of the estrogen receptor could provide a new target for developing the perfect contraceptive in the male," Hess said.

"When we treated animals with a potent anti-estrogen compound, we saw a decline of messenger RNA necessary for sodium transport," said Qing Zhou, a doctoral researcher working with Hess. Zhou used molecular biology and immunohistochemistry methods to document the molecular and physiological changes that occurred in the mice.
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Co-authors were Rong Nie and Kay Carnes, researchers in the UI department of veterinary biosciences, and Benita S. Katzenellenbogen of the department of cell and structural biology and department of molecular and integrative physiology in the UI College of Medicine at Urbana-Champaign.

Contributors from other institutions were Lane Clark of the Dalton Cardiovascular Research Center and University of Missouri at Columbia; Li-Wen Lai and Yeong-Hau H. Lien of the University of Arizona Health Sciences Center in Tucson; Dennis Lubahn of the University of Missouri at Columbia; Allan Verkman of the University of California at San Francisco, and Jane S. Fisher of the Human Reproductive Sciences Unit in Edinburgh, Scotland.

The National Institutes of Health and Kenneth A. Scott Charitable Foundation funded the work through grants to Hess, Clarke and Lien.

University of Illinois at Urbana-Champaign

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