Heat triggers sperm activation for fertilization in mammals

In mammals - including us humans - sperm are surprisingly picky about temperature, thriving best in conditions a few degrees cooler than normal body temperature. But, given that the female reproductive tract is warmer than normal body temperature, how do these heat-sensitive swimmers manage to fertilize an egg in such a toasty environment?

Research from Washington University School of Medicine in St. Louis has an answer: warmer temperatures - such as those of the female reproductive tract - trigger a specific signal that activates sperm, changing their behavior from the relatively smooth motions used for navigation to the thrashing and twisting motions needed to enter the egg for fertilization. The discovery of that trigger provides a possible target for male contraceptives and treatments for male infertility.

Studying mice, the researchers showed that a specific protein common to all mammals triggers a hyperactive state in sperm when the surrounding temperature matches that of the female reproductive tract. The findings, published in Nature Communications April 17, also help explain the evolution of mammalian anatomy.

That hyperactive state in sperm is key for successful fertilization, and no one knew exactly how temperature triggers it. Our work has identified a temperature-controlled switch in sperm that triggers these increased movements precisely when they are needed during fertilization."

Polina Lishko, PhD, a BJC Investigator and professor of cell biology and physiology at WashU Medicine

All mammals share a particular protein embedded in the surface of sperm called CatSper. It controls the entry of particles needed to power the hyperactive movements in the tail-like flagella that propel the sperm forward. Temperature activation of CatSper was not known, however it had been believed to be activated by a combination of the pH level in the female reproductive channel and, in primates, by progesterone, a female reproductive hormone. The theory didn't entirely hold up, said Lishko, because most mammalian sperm do not respond to progesterone, so there had to be another controlling factor to flip the CatSper switch.

Temperature seemed a likely culprit. Mammalian evolution has developed ingenious ways to keep male reproductive organs at or below 34 degrees Celsius (93.2 degrees Fahrenheit). Dolphins, for instance, lower the temperature of blood destined for their internal testes by first passing it through their dorsal fin; elephants use a similar system that cools blood through their ears. Most other mammals, humans included, create and store sperm in testicles outside of their body. Animals without these cooling adaptations for their male reproductive organs, such as birds, lack the CatSper proteins on their sperm.

Using micron-scaled tools and techniques originally developed to study brain cells, Lishko's team observed the pattern of electric charges distinctive to CatSper's activation in individual sperm cells, measuring clear spikes when the temperature surrounding the cell surpassed 38 degrees Celsius (100.4 degrees Fahrenheit). With CatSper activated, the sperm's behavior switched from the relatively smooth motions they use for navigation to the hyperactive movements needed for them to enter the egg for fertilization.

Lishko said that understanding temperature's role in fertility may help to improve male contraception and treatments for infertility. Because CatSper only appears in sperm, targeting it would not affect other bodily functions. There have been attempts to develop contraceptives that deactivate the channel, but Lishko said those have not been very effective so far. The insights from this discovery might point to new approaches.

"Instead of creating inhibitors, it might be possible to activate CatSper with temperature thus, prematurely switching on this channel to drain the sperm of energy, so that by the time the sperm cell is ready to do its job and enter the egg cell, it is powerless," she said.

Swain DK, Vergara C, Castro-Arnau J, Lishko PV. The essential calcium channel of sperm CatSper is temperature-gated. Nature Communications. April 17, 2025. DOI: 10.1038/s41467-025-58824-0

This work was supported by the BJC Investigator fund.