Semen doesn’t just ferry sperm. It also bears a mystery ingredient that turns on ovulation in some animals and may even pump up fertility in humans as well. The molecule, nerve growth factor, kick-starts egg release and revs up pregnancy-protective hormones in llamas, researchers report online August 20 in the Proceedings of the National Academy of Sciences. Llama semen is loaded with NGF, says study coauthor and veterinarian Gregg Adams of the University of Saskatchewan in Saskatoon, Canada. The protein is also found in the semen of bulls and humans.
“If we find that NGF is also effective in women, it will obviously have huge implications for treating male infertility conditions,” says reproductive biologist Raj Duggavathi of McGill University’s campus in Sainte-Anne-de-Bellevue, Canada. “It could be a big boost for couples.”
NGF is well-known to biologists but not in the context of reproduction. Nerve cells typically spit the protein out to tell neighboring cells to grow.
Previous findings that semen could trigger ovulation in llamas challenged conventional wisdom that the physical movements of sex were what stimulated egg drop in the animals, says Adams. Unlike humans cows, horses and sheep, which ovulate on a regular cycle, some animals rely on a little action to get their eggs moving.
Adams’ team had shown that semen — filtered free of sperm — injected into llamas’ leg muscles could set off ovulation all on its own — no bump-and-grind required. Semen from stallions, cattle, boars and rabbits could also prod llamas to ovulate.
What’s more, in llamas and other animals, the seminal substance nurtured growth of a little yellow gland in the ovary called the corpus luteum. The gland churns out hormones essential for maintaining a pregnancy. Humans rely on it early in gestation, before the placenta plumps up and takes over. A fizzled-out corpus luteum with low-flowing hormones can make women miscarry.
Adams’ team has known since 2005 that some ingredient in llama semen juices up ovulation, but until now, they didn’t know what it was.
To pinpoint NGF’s identity, Adams’ group first collected semen from five llamas. Next, researchers filtered out the sperm, then zeroed in on the special semen substance by injecting increasingly pure portions into female llamas’ legs. Next, Adam’s team followed a step-by-step process to rule out potential molecular suspects.
The molecule’s size, structure and biochemical properties clued researchers in to its identity. “Through a process of elimination, we finally realized it was a very hearty, very tough protein. When we found out that it was NGF, we scratched our heads and said, ‘That’s strange — NGF isn’t supposed to work this way,’” Adams says. Instead of signaling nearby cells, semen NGF goes all the way through the blood vessels to the brain, where it delivers the message to get busy cranking out more hormones.
Adams’ team confirmed that the llama semen substance was NGF by using a technique usually seen in fertility clinics: injections followed by ultrasounds. The researchers gave llamas shots of either the purified semen substance or NGF from mouse salivary glands — a classic source of the protein. Then, they checked the animals’ reproductive organs with daily ultrasounds. Both substances made ovulation rates shoot up.
I’m fairly convinced” that NGF is the ovulation-sparking semen substance, says reproductive biologist Bruce Murphy of the University of Montreal. “It’s a blockbuster paper,” he says. The work is the first to link NGF to reproductive function.
Next, Adams’ team plans to investigate NGF’s role in human semen — to see if it’s connected to fertility in people as well as llamas. Because women, unlike llamas, don’t need semen to ovulate, it’s not clear yet if NGF is also important for people, says reproductive biologist Dan Bernard of McGill University in Montreal. “It’s still early.” But, he says, “I think the fact that they’ve identified the protein will put this work on the map.” The findings should provide fertile ground for other researchers in the field.
Even though human females ovulate regularly, sometimes women’s bodies gear up for egg release at odd times during their cycle. “I want to know what happens if seminal plasma is absorbed at that time,” Adams says. “Will it cause ovulation?” If a timely dose of semen does nudge an egg’s release, he says, “It could be why we sometimes call couples who practice the rhythm method parents.”
In addition to tweaking ovulation timing, NGF could boost growth of the pregnancy-protecting corpus luteum in humans. If NGF can cultivate the gland the way it does in llamas, cattle, and mice, it’s possible that frequent sex — and thus a steady supply of semen — during early pregnancy could help prevent miscarriage.
The idea “is not crazy at all,” Adams says.