Trojan Horse Helps Deliver New Male Contraceptive Compound To Testis

Male Contraceptive Pill

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 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 R ' gine Sitruk-Ware, executive director of product research and development at the Center for Biomedical Research.

Cheng's strategies target the attachment of germ cells onto 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 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 Dr. Dolores Mruk in the 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 given to animals at a high dose orally, however, it caused liver inflammation and muscle atrophy in a small subset of animals. Chang 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. One hurdle they needed to surmount was the fact that the testes are protected by a blood-testis barrier created by the protective Sertoli cells. This blockade prevents immune system cells and foreign substances from entering the testis and damaging sperm.

They overcame the blood-testis barrier by means of a chemical Trojan horse. They attached Adjudin to a version of the follicle-stimulating hormone (FSH). The only FSH receptors in the male body are in the testis. The attachment of FSH delivered the Adjudin directly to the area of the body it was needed, the testis, and also allowed the drug to slip through the blood-testis barrier unnoticed. Using this new approach, the researchers induced infertility in rats using relatively low doses of Adjudin. There were no obvious side effects.

Since the new drug would have been broken down by the body if taken orally, instead it was injected into the rats. Frequent injections would be unacceptable to men, so the researchers are considering other possible delivery systems, such as implants or 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. Cheng's study appeared in a Nature Medicine paper published online on 29 October 2006.