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September 2002, Vol. 8, No. 2 Biomedical Research 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 made significant progress in understanding a process that is essential to the formation and development of sperm. Drawing on this knowledge, the team is developing compounds that may eventually be used as new male contraceptive methods. If successful, the methods would induce 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 mass, 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 contraceptive development at the Center for Biomedical Research. Germ-cell migration Cheng was first put on the trail of one 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 is one such analog. The compound 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 AF-2364 to be a potent, effective, and reversible male contraceptive in laboratory animals. Normal fertility returns a few months after treatment with AF- 2364 stops. The compound does not influence the hypothalamus-pituitary-testicular axis. Tests in animals and cell cultures indicate that it is not toxic to the liver, kidney, or other organs and does not cause genetic mutations. Studies to determine whether AF-2364 is toxic to the cardiovascular, respiratory, or central nervous systems are underway. Tests to establish whether the compound is toxic when given in low doses over a long period of time are scheduled to begin in late 2002. “Once these studies are successfully completed, we will be able to apply for Investigational New Drug status for the compound,” says Dolores Mruk, research investigator in Cheng’s laboratory. “Phase 1 clinical trials in humans may begin after that.” Sertoli cells release multiple substances that allow the normal functioning of germ cells in the testis. They also create the blood–testis barrier by tightly adhering to each other near the periphery of the testis. This blockade prevents immune system cells from entering and attacking sperm. Primitive germ cells must migrate past the blood–testis barrier in order to mature. Thus, the barrier must open and close periodically. A number of protein molecules preside over the disassembly and reassembly of the blood–testis barrier that occur during germ cell migration. One of these proteins is occludin. Cheng and his colleagues have recently developed a compound that attaches to occludin and holds the blood–testis barrier open for longer than normal. This allows cells from the immune system to gain access to developing sperm. In laboratory animals receiving this compound, immune cells destroyed immature sperm, temporarily causing infertility. Normal fertility returned in less than two months after treatment was stopped. “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. Sources Cheng, C. Yan, Meng-yun Mo, Josephine Grima, Luciano Saso, Beatrice Tita, Dolores Mruk, and Bruno Silvestrini. 2002. “Indazole carboxylic acids in male contraception,” Contraception 65: 265–268. Cheng, C.Y., B. Silvestrini, J. Grima, M.Y. Mo, L.J. Zhu, E. Johansson, L. Saso, M.G. Leone, M. Palmery, and D. Mruk. 2001. “Two new male contraceptives exert their effects by depleting germ cells prematurely from the testis,” Biology of Reproduction 65: 449–461. Chung, Nancy P.Y., Dolores Mruk, Meng-yun Mo, Will M. Lee, and C. Yan Cheng. 2001. “A 22-amino acid synthetic peptide corresponding to the second extracellular loop of rat occludin perturbs the blood-testis barrier and disrupts spermatogenesis reversibly in vivo,” Biology of Reproduction 65: 1340–1351. Outside funding | |||||||||||||||||||||||||||||||||||||||||||||||
