The dream of developing a contraceptive pill for men is alive and well. Researchers have experimented for years to elucidate the changes in how sperm wriggle to develop ways to prevent them from reaching and merging with the egg. Researchers in the United States published experiments showing that plant triterpenoids plus testosterone and hydrocortisone slows down the penetration of sperm. A new study could not replicate this. However, the researchers think that modifying an existing drug could provide a new and safe contraceptive for men.
Moving the fastest is not the only criteria. After a long and challenging journey through the cervix, uterus and fallopian tube, a sperm with powerful rhythmic wriggling and rolling must break through a thick protective layer around the egg itself. Researchers are attempting to prevent sperm motility and thereby enable men to take a pill to avoid getting a woman pregnant. This may sound easy, but new research shows that this journey, like the sperm’s, is long and uncertain with many obstacles.
“Researchers in the United States published promising results claiming that plant triterpenoids plus testosterone and hydrocortisone can inhibit sperm motility. However, both we and researchers in Germany have tried unsuccessfully to replicate these results. But we found that an approved drug has this desired effect. By modifying it slightly, we expect to be able to amplify the effect and thus create a contraceptive that can effectively and safely make the sperm unable to fertilize the egg,” explains Anders Rehfeld, Postdoctoral Fellow, Department of Biomedical Sciences and Department of Drug Design and Pharmacology, University of Copenhagen and Department of Growth and Reproduction, Rigshospitalet.
Investigating two plant triterpenoids
Several research groups have used varying strategies to prevent sperm motility by disabling the mitochondria or the transport and ion channels on the surface. The current experiments focus on the ion channels by attempting to inhibit the sperm-specific Ca2+ channel CatSper, which must be activated to enable the sperm to fertilize a woman’s egg.
“CatSper is an ion channel that is activated by both high pH in the woman’s reproductive tract and progesterone. Preventing this activation keeps the beating pattern of the sperm tail symmetrical. The sperm cells are thus unable to wriggle and therefore cannot penetrate the protective layer of the egg,” says Anders Rehfeld.
Interest was piqued when researchers from the University of California, Berkeley claimed that they had inhibited human CatSper by using steroid-like plant triterpenoids. Cholesterol is a simple triterpenoid, but they are present in myriad variants in plants, including lupeol and pristimerin. The researchers inhibited the activation of CatSper and thus also the ability of sperm to fertilize eggs. The researchers also showed that testosterone and hydrocortisone had the same inhibitory effect on CatSper.
“We tested the effects of various compounds on CatSper and wanted to use lupeol and pristimerin as controls, but we could not replicate these researchers’ results. I contacted them and they instructed me in how to change the procedures for dissolving and testing them, but this did not help. We could not replicate the effect,” explains Anders Rehfeld.
Anders Rehfeld and colleagues, however, were not alone in being unable to replicate the results. A group from University Hospital Münster had unsuccessfully tried to replicate the effect in 2018; the triterpenoids did not inhibit CatSper. In addition, both Anders Rehfeld and the Münster group, unlike the Berkeley group, found that other known human steroids including testosterone and hydrocortisone activated CatSper just like progesterone. Although the Münster researchers performed fluorescence measurements and patch-clamp experiments to measure ion currents, Anders Rehfeld’s group went further.
“I thought creating clarity was important, so we also tested the motility by measuring sperm’s ability to penetrate a viscous barrier of methylcellulose, similar to the mucus in the cervix, after adding various steroids. Again, we did not find the same effect as the Berkeley group. The other steroids all seemed to mimic the effect of progesterone on CatSper and thus the motility of sperm,” says Anders Rehfeld.
The fact that other natural hormones mimic the effect of progesterone on sperm is not inherently surprising. CatSper has previously been shown to be promiscuous, being activated by many chemicals. When this happens, the calcium ions flow through the channel, required for rapidly changing the motility pattern of the sperm, so they can navigate the obstacles in the woman’s reproductive tract and successfully find the egg.
“But we also found another substance that, unlike the triterpenoids, can inhibit the sperm. Unfortunately, for patent-related reasons, I cannot reveal the name now, but it is an existing drug. It is not as effective as the triterpenoids reported by the Berkeley group, but there is huge potential,” explains Anders Rehfeld.
In fact, great effectiveness would have been a great surprise, because then this might have been discovered previously as a side-effect that might be more or less desired. It is effective, however, and now Anders Rehfeld and colleagues hope to strengthen the drug by modifying it chemically so that they can eventually develop a new safe and effective contraceptive for men.
“We clearly still have a long way to go. We need to optimize the modifications to ensure that the drug enhances the effectiveness on CatSper without any side-effects. We have the advantage that this drug, unlike the plant triterpenoids used by the Berkeley group, is not hormone-like, but we must still develop it in pill form and in a chemical form that can be transported across the intestinal wall, through the bloodstream, and to the seminal fluid. The second option is as a suppository for women, but right now we are chasing the big dream – The Pill for men,” concludes Anders Rehfeld.