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 Regine Sitruk-Ware, executive director of contraceptive development at the Center for Biomedical Research.
Cheng's strategies target the movement of germ cells, a critical component of sperm development. Germ cells mature into sperm as they travel from the outer layer of seminiferous tubules to the cavity at the center of the tubules. This migration is facilitated by the constant disruption and regeneration of specialized attachments between cells within the testis.
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. …