There may be new hope in the search for "the pill" for men, a male contraceptive that would more effective than condoms and more easily reversible than vasectomy. A compound called JQ1, which was originally developed as a cancer therapy, can also cause reversible infertility in male mice without apparent side effects in rodents or their offspring, the researchers report today. The compound is not ready for testing in healthy men, but it offers a promising avenue in the search for an improved male contraceptive. "I am delighted to see a new potential approach," explains reproduction biologist William Bremner of the University of Washington School of Medicine in Seattle, who was not involved in the study.
Scientists have struggled for decades to find ways to block reversibly and safely male fertility. Bremner said several key challenges stand in the way: First, men produce millions of sperm a day compared to typical single egg of a woman produces each month. Second, there is a "blood-testis barrier" which blocks many blood-borne compounds from reaching the area in which sperm are produced. Finally, any potential drug should be extremely safe and will not cause lasting genetic damage to sperm cells or their precursors.
JQ1 was originally developed as an anticancer agent, says James Bradner, a chemical biologist at Dana-Farber Cancer Institute in Boston and one of the authors of the article. It was designed to inhibit a protein called BRD4, which helps regulate cell division and is known to be involved in a type of aggressive skin cancer. Bradner has high hopes that inhibitors of Brd4 as JQ1 become cancer therapies, but he and his colleagues knew that BRD4 is also closely linked to a protein called BRDT, which helps control cell division in the testes. So they collaborated with Martin Matzuk, a reproduction biologist at the Baylor College of Medicine in Houston, Texas, to test JQ1 as a potential contraceptive in mice.
The researchers report today in Cell that after 6 weeks of daily injections of sperm JQ1 The numbers of animals was reduced by almost 0%. Only 5% of the remaining spermatozoa were able to swim correctly, compared to 85% of the spermatozoa in the control mice. After 3 months of treatment, none of the mice were able to produce offspring, although their sexual behavior was normal. The compound had no apparent effect on the production of testosterone and other hormones produced by the testicles. Researchers have also shown that the effect is reversible. One or two months after stopping treatment, all the mice were again able to father as many smaller than control mice and testicular size and sperm of animals counts returned to normal levels between 1 and 3 months after stopping treatment. The treatment did not cause obvious side effects in mice, and the offspring of treated animals revealed no abnormalities.
The compound appears to target sperm development both before and after meiosis, the special cell division that form sperm and eggs, said Matzuk. This means that fewer sperm precursor cells in the testicles, and some of those who go to produce functional sperm.
Bradner, father of twins 18 months, jokes that he took "one gram per day" JQ1 recently. But he and Matzuk caution that researchers need to find a new compound that interacts with only testicular BRDT protein and has no impact BRD4 or related proteins that are present in most cells of the body, before clinical trials can begin. "We need one which is extraordinarily specific" Bradner said. Matzuk said that the crystal structure of BRDT interacting with JQ1, which colleagues from the University of Oxford have developed, will provide valuable clues.
Debra Wolgemuth, a reproduction biologist at Columbia University Medical Center, who studied BRDT, agrees. "If you take the healthy people in their twenties and giving them a drug, you want to be very sure that this does not affect anything else," she said. "The bar for safety and efficiency is as high as you can get." She and her colleagues tested compounds that disrupt vitamin A metabolism, which have also shown promise as male contraceptives. However, she noted that mouse lives are not sufficient to test the possible long-term effects of drugs that people might want to be able to take decades. primate experiments, meanwhile, are prohibitive, and funding is scarce. "I am very excited when new developments come along a field that has been terribly neglected for too long," she said. "The more goals we pursue, the better."
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