HSPA2 and Male Infertility: A Protein Clue Hidden Inside Sperm

In 85 men, lower HSPA2 levels were associated with low sperm counts or varicocele.

Changes in the protein's location were also delayed, offering clues that routine semen analysis cannot capture.

HSPA2, a protein involved in sperm maturation and fertilization, may provide another clue to male infertility. Japanese researchers found lower amounts and altered movement of this protein within sperm from men with low counts or varicocele.

A team at Nagoya City University analyzed semen from 85 men, comparing the amount and distribution of heat shock protein A2, or HSPA2.

Men with abnormalities associated with infertility had relatively less of the protein, as well as differences in its redistribution toward the sperm head.

The study appeared in the Journal of Reproduction and Development on October 1, 2026.

Sperm numbers and movement cannot fully describe fertilizing ability

Routine semen analysis checks whether sperm are sufficiently numerous, active and normally shaped. It does not measure every aspect of their ability to fertilize an egg.

Sperm with normal counts and motility may still have internal functional problems. Conversely, a low measurement does not mean that all sperm have lost fertilizing capability.

HSPA2 plays an important role during sperm formation and maturation. Despite the name “heat shock protein,” its function is broader than responding to heat: it helps other cellular proteins maintain appropriate structure and function.

The researchers examined both the amount of HSPA2 and changes in its position within sperm to investigate possible links with infertility.

Comparing 28 men with normal results and 57 with abnormalities

The study compared semen from 28 men with normal findings under the 2021 WHO framework and 57 men with low sperm counts or varicocele.

Varicocele involves abnormal enlargement of veins around the testis. Changes in temperature or circulation can affect sperm production and function, making it an important consideration in male infertility.

After separating sperm from semen, the team measured HSPA2 and observed its distribution during incubation.

HSPA2 levels were significantly lower in men with low sperm counts than in men with normal results. Reduced levels were also found with varicocele.

Protein amounts were associated with sperm motility and total motile sperm count.

This suggests that reduced motility may relate to internal protein function as well as the physical movement of the tail.

Redistribution toward the acrosome was delayed

Another finding concerned where HSPA2 was located.

The acrosome is a structure at the front of the sperm head that is important in interaction with the egg and fertilization.

The researchers observed HSPA2 localization from immediately after sperm preparation through 24 hours.

Men with low counts or varicocele initially had a lower proportion of sperm showing HSPA2 in the acrosomal region. Its distribution changed over time, but peak acrosomal localization occurred later.

Compared with sperm from men with normal findings, the timing of distribution toward a potentially important location differed.

Similar patterns in low sperm counts and varicocele suggested that the phenomenon might be relevant to functional impairment across more than one condition.

A delay in redistribution alone, however, does not prove a reduction in actual fertilizing ability.

Could molecular testing expand male infertility assessment?

The study provides a clue to abnormalities that routine semen analysis may not reveal.

Conventional assessment chiefly measures visible characteristics: number, movement and shape. Fertilization also requires proteins and other biological functions inside sperm to work appropriately.

Proteins involved in maturation and fertilization, such as HSPA2, could help explain some cases that remain unclear after standard testing.

The findings may interest couples preparing for IVF or ICSI. Injecting a sperm into an egg does not necessarily resolve every internal sperm-function problem.

However, the study did not directly compare fertilization, embryo development, pregnancy or live birth rates.

Low HSPA2 therefore cannot currently be used from these results alone to predict fertilization failure or justify immediate routine clinical testing.

A promising clue that still needs clinical validation

Male infertility includes low sperm counts, poor motility and abnormal morphology, yet conventional testing does not always identify a clear explanation.

Research into DNA damage, oxidative stress and protein expression is trying to characterize internal sperm function more precisely.

This study supports examining molecular functions required for fertilization alongside quantitative semen measures.

Its limitations include a relatively small sample of 85 men and laboratory observations of separated sperm. Further work must establish whether low HSPA2 causes impaired function or reflects damage that has already occurred.

Larger studies linking HSPA2 changes with actual fertilization and birth outcomes could clarify its potential diagnostic or treatment value.

The central question extends beyond how many sperm there are and how actively they move to whether the internal proteins needed for fertilization are functioning appropriately.

Study source

Akiko Natsume, Yasuhiko Ozaki and colleagues at Nagoya City University: “Role of dynamic changes in human sperm heat shock protein A2 in male infertility.” Journal of Reproduction and Development, volume 72, issue 5, 2026. DOI: 10.1262/jrd.2026-023.

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