Gender-based political correctness continues in vogue - up to a point. One striking example is contraception: Why do all forms of pregnancy curtailment - whether the pill, skin patches, vaginal inserts, whatever - remain in the hands of females? Why is there no male contraceptive on the market?

It's not for lack of trying - by industry and academia.

"A lot of work has been done on hormonal male contraceptives, and they definitely do work in humans," observed cell biologist Aarnoud van der Spoel, at the University of Oxford, UK. "Mostly, what is administered these days is a progestin combined with a synthetic testosterone. The result is reduced testosterone production in the testes, and lowering of those two essential reproductive hormone levels. That effectively suppresses spermatogenesis, which of course means sterility.

"The consequence of this hormonal therapy," van der Spoel continued, "is that the males who will receive this form of contraceptive need testosterone replacement to maintain their secondary male-sex characteristics - hair growth, increased muscle mass and many other things. Administration of these testosterones is something of intense current research interest. Most of them cannot be taken orally but must be injected or implanted subdermally.

"Of course the testosterone replacement comes with a number of possible side effects - augmented muscle weight, increased acne, mood changes; possibly the HDL cholesterol might be affected. It all depends on which combination of hormones is used. But all this is in development, so things can change in the future."

A senior research associate at Oxford's Glycobiology Institute, van der Spoel, is lead author of a paper in the Proceedings of the National Academy of Sciences (PNAS), released Dec. 10, 2002. Its title: "Reversible infertility in male mice after oral administration of alkylated imino sugars: A nonhormonal approach to male contraception." Its senior author is the Institute's glycobiologist, Frances Platt.

Human Pre-Evaluation Gives Drug Leg Up

"Serendipitously," van der Spoel told BioWorld Today, "we identified the property of a novel compound that appears to act as the contraceptive male pill in mice. The attractive thing is that this drug has already been evaluated in a number of mammalian species, including humans. And it's about to become available for treating patients with Gaucher's disease. Those are our two main findings," he summed up. "It's a drug that acts as a contraceptive in male mice, and still needs to be evaluated in people for this property. But the fact that it has been evaluated in humans already differentiates it from all other such compounds, which may have been tested only in animals."

The compound is an alkylated imino sugar sporting the chemical name: N-butyldeoxynojirimycin - NB-DNJ for short.

"NB-DNJ has recently been approved by the European Medicines Evaluation Agency," van der Spoel noted, "with a positive recommendation for the use of this compound. It is designated to treat patients with Gaucher's disease, for whom the established therapy, which is enzyme replacement, is not suitable or acceptable to recipients. It is expected that this drug will become available for this purpose in the next year.

"Before Gaucher's," he went on, "NB-DNJ was, for a while, tested in the U.S. as an AIDS therapeutic. That was actually its first use in humans. Heavily HIV-infected individuals were tested in this study. The drug appeared not to be effective against AIDS, but that was before we knew of this compound's effects on sphingolipid biosynthesis. We don't know at the moment the mechanism of its contraception in human males. Our present hypothesis is that it affects the metabolism of glucosphingolipids. These sugar-fat molecules are essential for spermatogenesis. We propose that the NB-DNJ compound causes infertility in males."

Pending impending human trials, the Oxford co-authors put sexually vigorous male mice through the contraceptive effects of oral NB-DNJ., starting four years ago. "We obtained the drug as a very fine crystalline powder," van der Spoel recounted, "mixed with powdered mouse chow. In this way the animals took it in quite well. The compound itself has a very bitter taste, but it didn't seem to deter the mice from eating their experimental food. Several control animals consumed the powdered mouse chow straight."

Reviewing the overall results of their in vivo experimentation, he went on: "Above a certain dose of NB-DNJ, 100 percent of the treated mice became sterile. We assessed their fertility status by first placing the males six to a cage, eating drug-spiked food. After five weeks of treatment, we transferred each animal to a separate cage. Then, along with every male mouse we put four untreated females, and left them together for nine days. During three weeks we recorded the females' litter sizes if any. Also, while the male was still in there, we checked for the presence of mucus plugs in the female vaginas, which are evidence of copulation - of a mating. NB-DNJ had no effect on sexual behavior, but rendered the male mice completely infertile at doses 10 times lower than those used to treat Gaucher's patients. Four weeks after being taken off the drug, male sterility and lack of sperm motility were fully reversed. The sperm of mice fed the drug exhibited a number of defects, including abnormally shaped nuclei, unusual distribution of mitochondria, and in some cases, tails coiled around sperm heads. NB-DNJ also caused a large increase in defective acrosomes, organelles that normally help sperm penetrate the egg's protective coating."

Sterility, Sperm Immobility, Promptly Reversible

"The mice were infertile after at least three weeks of drug consumption," the paper recorded. "They regained fertility after three weeks off drug, and sired normal-sized litters that developed normally to adulthood.

"At this moment," van der Spoel observed, "we do not know if NB-DNJ will have the same contraceptive efficacy in human males as it did in male mice. The outlook for clinical testing of its effects," he allowed, "is that trials with normal human volunteers will likely be done. Those plans are still under study, but the intention is there.

"Before we submitted our paper to the journal," van der Spoel pointed out, "the university had already applied for a patent covering this work, which is very amenable to patenting. Its principal inventors," he concluded, "are the Oxford Institute co-authors on the PNAS manuscript."