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In a nutshell
- Sperm have a temperature-sensitive “thermostat” called CatSper that activates when temperatures exceed 33.5°C (92.3°F), explaining why testicles need to stay cooler than body temperature.
- Seminal fluid contains spermine, which protects sperm from premature heat activation after ejaculation until they reach their destination in the female reproductive tract.
- This discovery explains why conditions that increase testicular temperature (like varicocele) can cause infertility and why mammals evolved external testicles.
ST. LOUIS — Men’s testicles hang outside the body for a good reason – and scientists have finally figured out why they need to stay cool. Researchers from the Washington University School of Medicine have discovered that sperm cells contain a molecular “thermostat” that activates when temperatures rise too high.
The finding solves a longstanding mystery about why mammals evolved external testicles and helps explain certain types of male infertility.
The Heat-Sensitive Channel That Controls Fertility
The discovery centers on a protein channel called CatSper, which allows calcium to flow into sperm cells. According to the new study in Nature Communications, CatSper acts like a temperature-sensitive switch that flips on when temperatures exceed 33.5°C (92.3°F). This temperature threshold sits just below normal body temperature, suggesting that testicles must remain cooler to prevent premature activation of this critical channel.
“These results emphasize the need to maintain testes below 34°C for optimal fertility and advance understanding of CatSper regulation in male fertility,” the researchers write in their paper.
To investigate this question, the research team measured tiny electrical currents flowing through individual sperm cells. By controlling the temperature around these cells with precision, they observed how CatSper channels responded to heat.
The results were dramatic. When temperatures rose from room temperature to body temperature (around 38°C), calcium flow through CatSper channels increased significantly. This effect disappeared in sperm cells from mice genetically engineered to lack functional CatSper channels, confirming this protein as the key temperature sensor.
Natural Safeguards: How The Body Protects Sperm
When sperm are stored in the epididymis (the tube where they mature before ejaculation), they’re kept in an acidic environment that helps suppress CatSper activity despite the cool temperatures.
Upon ejaculation, sperm enter the female reproductive tract, which is warmer and less acidic – conditions that would normally trigger massive CatSper activation. But nature has a safeguard: seminal fluid contains high levels of a compound called spermine, which blocks CatSper’s heat response. This protection keeps sperm from activating too quickly after ejaculation.
Only after several hours in the female reproductive tract, when sperm undergo their final maturation process called capacitation, does spermine’s effect wear off, allowing CatSper to respond to temperature.
After this final maturation, sperm actually become less temperature-sensitive. This adaptation allows them to survive longer in the warm female reproductive tract while awaiting an egg.
Evolution and Implications for Fertility
The research explains why some common causes of infertility impair sperm function. Conditions like varicocele – enlarged veins in the scrotum that raise testicular temperature – likely cause premature CatSper activation, triggering sperm dysfunction.
Looking at the animal kingdom, species with internal testes, such as birds, have typically lost their CatSper genes entirely during evolution. Meanwhile, marine mammals with internal testes (like whales and seals) have evolved specialized cooling systems to protect their sperm from heat.
For men, the takeaway is clear: keeping the testicles cool isn’t just about comfort – it’s essential for preserving the precise timing of sperm activation. This molecular thermostat must remain off until sperm reach their final destination, where the right temperature helps them make their final push toward an egg.
Paper Summary
Methodology
Researchers used whole-cell patch-clamp techniques to record electrical currents directly from mouse sperm cells under varying temperature conditions. They isolated sperm from the cauda epididymis of wild-type mice and CatSper1-knockout mice (lacking functional CatSper channels). By establishing electrical contact with individual sperm cells, they measured calcium currents through CatSper channels while precisely controlling temperature using an in-line heater with thermal probes positioned near the recorded cells. They conducted experiments with both monovalent (cesium) and divalent (barium) ion solutions to characterize CatSper’s electrical properties under different conditions, including varying pH and exposure to spermine (a component of seminal fluid). They also examined how sperm capacitation affects temperature sensitivity by incubating sperm in capacitation medium for 45-90 minutes before recording.
Results
The study found that CatSper functions as a temperature-gated ion channel with a thermal threshold of 33.5°C and a temperature coefficient (Q10) of 5.1, indicating high temperature sensitivity. When temperatures exceeded this threshold, CatSper channels opened much more readily in response to voltage changes, causing increased calcium influx. This temperature-dependent activation was completely absent in CatSper1-knockout sperm. The researchers discovered that acidic conditions (pH 6.0) and spermine exposure significantly inhibited CatSper’s temperature response, providing protective mechanisms against premature activation. After capacitation, sperm showed reduced temperature sensitivity, suggesting adaptation to the warm environment of the female reproductive tract. The research confirms CatSper as the primary temperature-sensitive ion channel in sperm, with other temperature-sensitive channels (TRPV4, TRPM3, TRPV1) showing no significant contribution to this response.
Limitations
The study was conducted primarily in mice, so direct application to human fertility requires further investigation, though CatSper is known to be essential for male fertility across mammalian species. The research focused on isolated sperm cells under laboratory conditions, which may not fully replicate the complex environment of the reproductive tract. While the researchers examined how different conditions affect CatSper temperature sensitivity, they acknowledge that other molecular factors in vivo might influence this response.
Funding and Disclosures
This research was supported by the BJC Investigator fund to Dr. Polina V. Lishko, the senior author. The authors declared no competing interests that could have influenced the study design or results.
Publication Information
The paper titled “The essential calcium channel of sperm CatSper is temperature-gated” was published in Nature Communications on April 17, 2025 (volume 16, article number 3657). The research was conducted by Dilip K. Swain, Citlalli Vergara, Júlia Castro-Arnau, and Polina V. Lishko at Washington University in St. Louis School of Medicine.
