SCIENTISTS ISOLATE STEROID-RESPONSE MOLECULES THAT MAY LEAD TO NEW FERTILITY DRUGS
20 February 2003 - University of Texas at Austin

The findings, which will be published in two papers in the March 4 issue of Proceedings of the National Academy of Sciences, end more than 20 years of scientific effort to identify these molecules. They reside on the outer membrane of sperm cells and certain other cells, where they respond to the presence of specific steroid hormones by changing the internal workings of the cells in as little as 30 seconds.

The molecules, called membrane receptors, may serve unique functions from their previously discovered, slower-acting counterparts, which occur inside cells. Information the researchers obtained on their underlying genes could produce novel tests and treatments for fertility and other medical conditions.

“These genes produce proteins that carry out a wide variety of vital functions in the body so that our genetic findings could result in biomedical advances for treating certain conditions,” said Dr. Peter Thomas, the lead researcher and a marine scientist at The University of Texas at Austin.

Fertility treatments are an example. The membrane receptor on fish sperm triggers changes that improve sperm motility and thus improve fertility. A related receptor likely does the same for human sperm because men with low fertility have low levels of the receptor. As a result, developing drugs to ramp up the activity of the human gene identified in this research may improve men’s receptor level and fertility. Conversely, other drugs could be developed as contraceptives that dampen the gene’s activity.

In the first paper, Thomas’ group isolated the gene that produces the membrane receptor in spotted seatrout that responds to steroids called progestins. This was done by individually exposing proteins that were produced from hundreds of thousands of the fish’s genes to marker antibodies. The antibodies were selected to specifically recognize unique features of the membrane receptor.

The researchers performed further studies on a handful of candidate genes to determine if one produced a protein with the right characteristics to be the cell membrane receptor. They identified a gene whose protein product occurred on the surface of cells in the brain and reproductive tissues, and responded to progestin hormone by producing rapid changes inside cells grown in test tubes. In addition, the protein this gene produced was needed for fish eggs to complete maturation, a process the protein is involved in.

In the second paper, Thomas and his colleagues identified 13 other genes that represent three different classes of progestin membrane receptors in other animals. Related genes were identified in humans, mice, pigs and frogs, among others. The human and mouse versions produced membrane receptors that responded as anticipated to progesterone, the progestin steroid hormone in mammals.

Further study of the human genes showed that one class of the receptors was active in reproductive tissues, another in the brain and another predominantly in the kidneys and intestinal tissues.

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