Zavesca

Alas, it seems that Zavesca – also known as miglustat, N-butyldeoxynojirimycin or NB-DNJ – is a contraceptive for a particular type of laboratory mouse, but not for men. Researchers at Oxford GlycoSciences, the pharmaceutical company Schering, and the University of Washington have all confirmed that Zavesca’s contraceptive effects are either greatly diminished or nonexistent in other species of mice, rabbits and humans.

The drug showed promise as a potential true male pill. It was originally developed by Oxford GlycoSciences to treat Gaucher disease, a rare genetic disorder. In trials with their laboratory mice, the researchers found that the drug had a reliable and reversible contraceptive effect (van der Spoel 2002). Because the process of sperm production is similar in many mammals, they hoped the drug would be an effective contraceptive in humans, too.

What's so special about these mice?

Initial tests of Zavesca were promising. Male mice fed a small amount of Zavesca each day had abnormally shaped sperm incapable of fertilizing an egg. However, these mice had normal sperm counts, showed typical mating behavior, and had no changes in body or testes weight. Tests also showed that the genetic material in the treated sperm was normal. It took three weeks for the contraceptive effect to kick in, and the same amount of time for fertility to return in short-term trials (van der Spoel 2002). At the end of a longer-term trial, mice treated with Zavesca for 1 year recovered full fertility within 9 weeks (Walden 2006). The mouse pups conceived after the end of treatment were normal.

However, the contraceptive effect of the drug was more specific than researchers had realized. The type of mouse used in Zavesca experiments – a strain known as C57BL/6 – turns out to be uniquely suited to using the drug as a male contraceptive. When researchers fed an equivalent contraceptive dose to other related mouse strains, they saw no effects. Only at a dose three times higher did Zavesca begin to show some disruption of sperm production (spermatogenesis) in these strains of mice. Unrelated mouse species showed even less response to the drug. And the results were even more disappointing for other animals: even at 17 times the equivalent contraceptive dose for C57BL/6 mice, Zavesca had no effect on rabbits (Bone 2006).

Exactly how Zavesca works as a contraceptive for male C57BL/6 mice is a matter of speculation. The drug alters the way the body breaks down and stores a component of cell membranes, a molecule known as a glycosphingolipid (a carbohydrate attached to a fatty carbon chain and a protein-alcohol molecule called sphingosine). There are different types of glycolipid molecules in sperm, as well as other tissues of all mammals.

Researchers propose that glycosphingolipids play an important role in the function of sperm cell membranes. During sperm production, the proper formation of the membrane is a crucial step. Components of the membrane start a chain reaction leading to the ability of the sperm to swim. Given that a drug which disrupts sperm membrane glycosphingolipid function in one animal has no effect on another, it is clear that these molecules are structured differently, or perhaps function differently in different animal species. These differences are not well understood.

Any hope for men?

As researchers in Europe conducted tests of Zavesca in mice and rabbits, a group in the US was testing it in men. They found similarly disappointing results: Zavesca had no measurable effect on human sperm production or shape (Amory 2006). Both groups of researchers concluded their reports by calling for a better understanding of how glycolipids function in sperm across different species.

Researchers studying which genes affect spermatogenesis are already helping to answer this question. Genes are functional groups of DNA that are read by other pieces of cellular machinery like blueprints for the creation of all kinds of proteins, including enzymes. The loss of a gene which codes for an enzyme called ß-Glucosidase 2 (GBA2) had interesting effects on the fertility of the male mice. The enzyme GBA2 is found in the Sertoli cells of the testes, brain and 14 other body tissues of male mice. The enzyme acts as a molecular-sized pair of scissors, snipping up glycolipids for transport (Roy 2006).

Knocking out the production of this enzyme in mice resulted in some symptoms similar to Gaucher’s disease – which Zavesca was created to treat. Male mice lacking GBA2 couldn’t properly process certain glycolipids, and one of them in particular (glucosylceramide) accumulated in various organs, including the testes. Though an unknown mechanism, this accumulation affected the production of new sperm. Their sperm were abnormally shaped, and their membranes were jumbled. Male mice also made 40% fewer sperm, and overall had one third the normal fertility level. Female mice lacking GBA2 had normal fertility levels. And unlike people with Gaucher disease, the mice did not show enlarged organs or any neurological symptoms (Yildiz 2006).

Will researchers find a drug to block the function of GBA2? It’s possible that Zavesca functioned in mice partly by doing just that. Is it possible that other animals with blocked GBA2 would also have impaired fertility? No conclusive answers yet, but we do know that the mouse gene for GBA2 shares 83% of its sequence with the human gene.

It does seem possible that further understanding of the functions of sperm membrane components like glycolipids could lead to new male contraceptive leads, especially if the molecules occur only in the male reproductive system. However – particularly after so much initial excitement about the Zavesca results in mice – researchers pursuing these approaches will now likely avoid general statements about the applicability of their findings to other animals, men included.

• Amory, JK, CH Muller, ST Page, E Leifke, ER Pagel, A Bhandari, B Subramanyam, W Bone, A Radlmaier and WJ Bremner (2006) “Miglustat has no apparent effect on spermatogenesis in normal men.” Human Reproduction. Epub ahead of print, October 25.
• Bone, W, AC van der Spoel, U Gottwald, FM Platt (2006) “The effect of miglustat on male fertility, sperm morphology and motility is strain/species specific.” Presented at 10th International Symposium on Spermatology, September 17-22, Madrid, Spain.
• Roy, A, YN Lin and MM Matzuk (2006) “Shaping the sperm head: an ER enzyme leaves its mark.” Journal of Clinical Investigation 116: 2860-2863.
• Suganuma, R, CM Walden, TM Butters, FM Platt, RA Dwek, R Yanagimachi and AC van der Spoel (2005) “Alkylated imino sugars, reversible male infertility-inducing agents, do not affect the genetic integrity of male mouse germ cells during short-term treatment, despite induction of sperm deformities.” Biology of Reproduction 72(4): 805-813.
• van der Spoel, AC, M Jeyakumar, TD Butters, HM Charlton, HD Moore, RA Dwek, FM Platt (2002) “Reversible infertility in male mice after oral administration of alkylated imino sugars: A nonhormonal approach to male contraception.” Proceedings of the National Academy of Sciences of the United States of America 99(26): 17173-17178.
• Walden, CM, TD Butters, RA Dwek, FM Platt and AC van der Spoel (2006) “Long-term non-hormonal male contraception in mice using N-butyldeoxynojirimycin.” Human Reproduction 21(5): 1309-15.
• Yildiz, Y, H Matern, B Thompson, JC Allegood, RL Warren, DMO Ramirez, RE Hammer, FK Hamra, S Matern and DW Russell (2006) “Mutation of β-glucosidase 2 causes glycolipid storage disease and impaired male fertility.” Journal of Clinical Investigation 116: 2985-2994.