Male fertility breakthrough: Scientists identify the trigger that powers sperm

A team of researchers has recently identified the molecular trigger that powers sperm from idle to overdrive. Their work could transform male fertility treatments and enable safe, nonhormonal contraception for men.

“Sperm metabolism is special since it’s only focused on generating more energy to achieve a single goal: fertilization,” said Melanie Balbach, an assistant professor of biochemistry and molecular biology at Michigan State University (MSU) and senior author of the study.

From low power to full throttle

Before ejaculation, mammalian sperm sit in a low energy state. Once in the female reproductive tract, they flip into a high performance mode. They whip their tails harder, their membranes remodel, and they burn through fuel to reach and penetrate an egg. 

Scientists knew this behavioral shift demands a surge of energy. However, they didn’t know how sperm reprogram their metabolism to deliver it.

“Many types of cells undergo this rapid switch from low to high energy states, and sperm are an ideal way to study such metabolic reprogramming,” said Balbach, who joined MSU in 2023 after her pioneering work on sperm biology at Weill Cornell Medicine. 

There, she helped show that temporarily blocking a key sperm enzyme rendered male mice infertile. That proves that nonhormonal, on-demand birth control might be possible.

Tracking fuel, molecule by molecule

In the new study, Balbach’s team teamed up with Memorial Sloan Kettering Cancer Center and the Van Andel Institute to watch sperm metabolism in action. 

The researchers devised a tracer approach to follow glucose – the preferred fuel – through sperm’s biochemical pathways.

Using MSU’s Mass Spectrometry and Metabolomics Core, they mapped how “painted” glucose moved and where it bottlenecked as sperm went from dormant to activated.

“You can think of this approach like painting the roof of a car bright pink and then following that car through traffic using a drone,” Balbach explained. 

“In activated sperm, we saw this painted car moving much faster through traffic while preferring a distinct route and could even see what intersections the car tended to get stuck at.”

The traffic map pointed to a crucial control: the enzyme aldolase. When sperm switches on, aldolase helps shunt glucose through glycolysis – the cell’s turbocharger – so ATP can spike and power stronger swimming. 

The team also found that sperm don’t rely only on the fuel they scavenge. They also tap “on-board” reserves as they launch their run, and other enzymes act like traffic controllers, opening or closing lanes to adjust flow.

A path to male fertility tools 

The findings offer a more complete picture of how sperm fuel their final sprint and why that system can fail. 

With “one in six individuals impacted by infertility globally,” Balbach said, decoding sperm metabolism could sharpen diagnoses and improve assisted reproduction.

It also unlocks a fresh strategy for contraception. Traditional approaches aim upstream, blocking sperm production with hormones that can cause significant side effects. 

By contrast, a metabolism-based method could be nonhormonal, fast-acting, and reversible. By inhibiting a traffic control enzyme at the right moment, sperm never reach full power.

“Better understanding the metabolism of glucose during sperm activation was an important first step, and now we’re aiming to understand how our findings translate to other species, like human sperm,” Balbach said. 

“One option is to explore if one of our ‘traffic-control’ enzymes could be safely targeted as a nonhormonal male or female contraceptive.”

The future of male fertility

Balbach’s lab is now testing how sperm use other fuels, such as fructose, and how different enzymes coordinate the switch from idle to overdrive. 

The goal is twofold: identify metabolic signatures that flag infertility, and pinpoint druggable nodes that could safely throttle sperm motility on demand.

“Right now, about 50% of all pregnancies are unplanned, and this would give men additional options and agency in their fertility,” Balbach said. 

“Likewise, it creates freedom for those using female birth control, which is hormone-based and highly prone to side effects. I’m excited to see what else we can find and how we can apply these discoveries,” she concluded.

The study is published in the journal Proceedings of the National Academy of Sciences.

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