May 2007, Vol. 13, No. 1

Reproductive Health
Chemical Postmaster Helps Deliver Contraceptive to Testis

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 biomedical scientists in the Population  Council’s Reproductive Health program. 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 prevents conception without interfering with hormones secreted by the hypothalamus, pituitary gland, and testis.

“The hormones of the hypothalamic– pituitary–testicular axis regulate male sex drive and maintain the health of other tissues, 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 a man’s libido intact,” says Régine Sitruk-Ware, the Population Council’s executive director of product research and development.

Cheng’s strategies target the attachment of germ cells to Sertoli cells in the testis. A disruption of germ cell–Sertoli cell attachment leads to the premature release of germ cells, and the net result is a reversible male contraceptive. Sertoli cells are the “nurse” cells of the testis. Their main function is to nurture the developing sperm.

Following a lead
Cheng was first put on the trail of Adjudin more than 15 years ago through the work of Professor Bruno Silvestrini, a colleague 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. Adjudin is one such analog that was shown—using assays established by cell biologist Dolores Mruk in Cheng’s laboratory—to deplete germ cells from the testis.

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 when they are immature and incapable 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 hormones produced by the hypothalamus, pituitary gland, or testis.

When Adjudin was administered orally at a high dose, however, it caused liver inflammation and muscle atrophy in a small subset of animals. To remedy this, Cheng and his colleagues set out to develop a way of delivering the drug directly to the testis, so that it would not interfere with these other systems. This would also allow them to use a lower dose.

A chemical “postmaster”
One hurdle Cheng and his colleagues needed to surmount was the blood–testis barrier created by the protective Sertoli cells. This barrier prevents immune system cells and foreign substances from entering the testis and damaging sperm. They overcame this blockade by means of a chemical “postmaster,” a synthesized variant of follicle-stimulating hormone (FSH). Adjudin was attached to the variant FSH. Because FSH slips through the blood–testis barrier without difficulty, it is able to deliver Adjudin directly to the testis. Using this new approach, the researchers induced temporary infertility in rats using relatively low doses of Adjudin. There were no obvious side effects.

“These results show that it may be possible to develop a class of male contraceptives with few side effects by interfering with cell-to-cell attachment in the testis,” says Cheng.

Because the new low doses would have been broken down by the body if taken orally, the researchers instead injected Adjudin into the rats. Frequent injections may be unacceptable to men, so the researchers are considering other delivery systems, such as a nasal spray, gel, implant, or transdermal patch.

Sources
Mruk, Dolores D., Ching-Hang Wong, Bruno Silvestrini, and C. Yan Cheng. 2006. “A male contraceptive targeting germ cell adhesion,” Nature Medicine 12(11): 1323–1328. Epub 2006 Oct 29. (offsite abstract)

Wong, Ching-Hang, Dolores D. Mruk, Will M. Lee, and C. Yan Cheng. 2007. “Targeted and reversible disruption of the blood–testis barrier by an FSH mutant–occludin peptide conjugate,” The FASEB Journal 21(2): 438–448.

Outside funding
National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health (NIH) and the CONRAD program

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See Also

• Project description: “Probing Studies in Male Contraception”

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