Adjudin is a new drug and an analogue of an old drug known as lonidamine. Lonidamine is an anti-cancer medication whose contraceptive effect was discovered in the 1980s. Researchers did not pursue lonidamine as a male contraceptive because at high doses it caused kidney damage. Since then, a group of scientists at New York’s Population Council, a nonprofit contraceptive research organization, have sought compounds less toxic than, but functionally similar to, lonidamine. Advances in screening technology led to the identification of several promising nontoxic compounds in the late 1990s. One of these compounds – AF-2364 or Adjudin – is moving toward trials in humans.
How does it work?
Adjudin provides contraception by disrupting the process of sperm maturation in the testes. It changes the way Sertoli cells – which divide to produce new sperm cells and then nurse the immature sperm – interact with sperm. In normal sperm production, Sertoli cells remain connected with immature sperm through a series of microscopic bridges and channels. These bridges provide materials and information needed to direct the development of the immature sperm (spermatids).
Spermatids must undergo a series of cellular changes in order to become functional sperm. These changes include packing down the sperm's DNA, shaping the cell for fast swimming, and preparing the cell's membrane to recognize and fuse with an egg. When rats were treated with Adjudin, the bridges between Sertoli cells and spermatids broke before the maturation processes were complete. The prematurely released sperm are molecularly incomplete and never become capable of fertilizing an egg (Population Council 2005).
How is it delivered?
Effective delivery has been one of Adjudin's major development hurdles. The compound has extremely low bioavailability, with less than 0.035% of an oral dose reaching the targeted tissues (Mruk 2006). While grinding the compound extremely fine (micronization) improved oral uptake slightly, injecting the compound into muscle tissue did not (Cheng 2005).
So researchers at the Population Council devised a new delivery mechanism which takes advantage of the body's own delivery system. Researchers attached Adjudin to a slightly modified hormone (follicle stimulating hormone, or FSH). The modified FSH is shaped differently enough that it no longer functions as a hormone, but receptors still recognize and bind to it (Mruk 2006). And here's the hook: the only cells in men that recognize and bind to FSH are Sertoli cells in the testes – the exact target for Adjudin. Thanks to this targeted delivery, an injection of the modified FSH with Adjudin attached is many times more effective than pure Adjudin taken orally. Only a very small dose is needed.
What about side effects & reversibility?
At this low dose, there are no observed side effects in rats. Their hormones, body weight and testes weight all remained normal. When rats treated with a single dose of Adjudin were mated, they had no offspring from 4 to 6 weeks after the injection. Although its long term use has not yet been tested, Adjudin's contraceptive effect has so far proven reversible. All the treated animals regained full fertility within 5 months and had normal pups (Mruk 2006).
Adjudin will not be on the shelf next year
Although certainly promising, Adjudin has many years of development work ahead. The researchers are working to develop a method of delivery which does not involve needles. One idea is a gel that will deliver the modified FSH plus Adjudin across the skin; another is a matchstick-sized implant. With any delivery method, the challenge of bringing down the manufacturing cost of the drug and modified hormone remains critical. The drug has also not yet been tested in men, which is obviously an important development milestone.
- Mruk, D, CH Wong, B Silvestrini and CY Cheng (2006) “A male contraceptive targeting germ cell adhesion.” Nature Medicine advance online publication, October 29.
- Cheng, CY, D Mruk, B Silvestrini, M Bonanomi, CH Wong, MK Siu, NP Lee, WY Lui and MY Mo (2005) “AF-2364 [1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide] is a potential male contraceptive: a review of recent data.” Contraception 72(4): 251-61.
- Population Council (2005) “Probing Studies in Male Contraception.” Online at www.popcouncil.org/biomed/Probing.html