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MEDIA CENTER Chemical Postmaster Helps Deliver New Contraceptive NEW YORK, NY (31 October 2006) — The development of effective, reversible, and safe contraceptives for men has lagged far behind the availability of methods for women, largely because scientists lack sufficient knowledge about male reproductive physiology. Improving this state of affairs has been a key aim of scientists at the Population Council’s Center for Biomedical Research. In one of the Council’s labs, biochemist and cell biologist C. Yan Cheng and his colleagues have found a way to target a new drug, known as Adjudin, to the testis in rats. This method induces reversible infertility without interfering with hormones secreted by the hypothalamus, pituitary gland, and testis. “The hormones of the hypothalamus-pituitary-testicular axis regulate male sex drive and maintain the health of other targets, including bone, muscle, and the sex organs. Male contraceptives that bypass this hormonal system would be welcome because they would be likely to leave these organs and libido intact,” says Régine Sitruk-Ware, executive director of product research and development at the center. Cheng’s strategies target the attachment of germ cells to Sertoli cells in the testis. A disruption of germ cell attachment leads to the premature release of germ cells, and the net result is infertility. Cheng was first put on the trail of one promising compound, AF-2364, through the work of a colleague, Professor Bruno Silvestrini at the University of Rome, who was studying an anticancer drug, lonidamine. One side effect of lonidamine was a temporary, profound disruption of spermatogenesis. Because of its toxic side effects, lonidamine could not be used as a contraceptive. However, Cheng speculated that if he could synthesize nontoxic analogs of lonidamine, they might work as a male contraceptive. AF-2364, now known as Adjudin, is one such analog that was shown to induce germ cell depletion from the testis using assays established by cell biologist Dolores Mruk in Cheng’s laboratory. Adjudin interferes with the adhesion of germ cells to the supportive Sertoli cells that surround them. When this attachment is disrupted, germ cells are released before they mature and become capable of fertilizing an egg. Cheng’s research has shown Adjudin to be a potent, effective, and reversible male contraceptive in laboratory animals. Normal fertility returns a few months after treatment with Adjudin stops. The compound does not influence the hypothalamus-pituitary-testicular axis. When Adjudin was administered at a high dose orally, however, it caused liver inflammation and muscle atrophy in a small subset of animals. Cheng and his colleagues then set out to develop a way of delivering the drug directly to the testis at a lower dose, so that it would not interfere with these other systems. To deliver the drug directly to the testis, the scientists used a chemical postmaster, a version of the follicle-stimulating hormone (FSH). FSH naturally attaches to a molecule known as the FSH receptor. The only FSH receptors in the male body are in the testis. By attaching FSH to Adjudin, the drug was delivered directly to the area of the body where it was needed, the testis. Using this new approach, the researchers induced infertility in rats using relatively low doses of Adjudin. There were no obvious side effects. Because the new drug would have been broken down by the body if taken orally, it was instead injected into the rats. Frequent injections may be unacceptable to men, so the researchers are considering other delivery systems, such as implants and patches. “These results show that a class of male contraceptives with potentially few side effects can be developed by interfering with cell-to-cell attachments in the testis,” says Cheng. This work was supported in part by grants from the National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health (NIH) and the CONRAD program. A paper by Cheng and colleagues describing this research appeared in Nature Medicine, published online on 29 October 2006. About the Population Council ### Media contacts Population Council
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