Age and Menopausal Status Impact Serum HE4 Levels: A Large Study of Healthy Chinese Women

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Age and Menopausal Status Impact Serum HE4 Levels: A Large Study of Healthy Chinese Women

Ovarian cancer is the deadliest cancer of the female reproductive system, with over 70% of cases diagnosed at an advanced stage when survival rates plummet. Early detection is critical—but the most widely used marker, CA125, misses half of early-stage cancers and isn’t specific enough. Enter HE4 (human epididymis secretory protein 4), a newer biomarker approved by the U.S. FDA in 2009 for monitoring ovarian cancer. But until now, little was known about how age and menopause affect HE4 levels in healthy Chinese women—and whether current reference ranges work for this population.

A team of researchers from Peking University People’s Hospital, Peking University Third Hospital, and other top Beijing institutions set out to change that. Between 2013 and 2017, they analyzed serum HE4 and CA125 levels in 2493 healthy women aged 40 and older. The goal? To clarify how age and menopausal status influence HE4—and provide tailored reference ranges for Chinese women.

What the Study Found

The results, published in the Chinese Medical Journal in 2020, offer key insights for both doctors and women:

1. Menopause Drives Higher HE4 Levels

Post-menopausal women (those who hadn’t had a period in over a year) had significantly higher HE4 levels than pre-menopausal women. The median HE4 level for post-menopausal women was 36.46 pmol/L—compared to 24.04 pmol/L for pre-menopausal women. This difference held even when researchers looked at women of the same age: for example, 40–49-year-old post-menopausal women had higher HE4 than 40–49-year-old pre-menopausal women.

2. Age Matters Most for Post-Menopausal Women

Age didn’t affect HE4 levels in pre-menopausal women. But in post-menopausal women, HE4 rose steadily with age. The median HE4 level for post-menopausal women:

  • 40–49 years: 27.18 pmol/L
  • 50–59 years: 32.38 pmol/L
  • 60–69 years: 39.35 pmol/L
  • 70–79 years: 52.24 pmol/L
  • 80+ years: 70.27 pmol/L

This means a 70-year-old post-menopausal woman’s HE4 level should not be compared to a 40-year-old’s—current FDA guidelines (which set a single 150 pmol/L upper limit) don’t account for this.

3. New HE4 Reference Ranges for Chinese Women

The study established age- and menopause-specific reference ranges (using the 5th to 95th percentiles, the “normal” range for 90% of healthy people):

  • Pre-menopausal women: 10.89–44.63 pmol/L (upper limit: 44.63 pmol/L)
  • Post-menopausal women:
    • 40–49: 13.15–47.31 pmol/L
    • 50–59: 14.31–58.04 pmol/L
    • 60–69: 17.06–73.51 pmol/L
    • 70–79: 24.50–115.25 pmol/L
    • 80+: 35.71–212.37 pmol/L

For all women combined, the upper limit was 73.3 pmol/L—far lower than the FDA’s 150 pmol/L cutoff.

4. CA125 Is Mostly About Menopause, Not Age

The study also looked at CA125, the older ovarian cancer marker. Pre-menopausal women had higher CA125 levels (median: 7.78 U/mL) than post-menopausal women (4.72 U/mL). Age had little impact—unlike HE4.

Why This Matters for Women and Doctors

Right now, many labs use the FDA’s one-size-fits-all 150 pmol/L limit for HE4. But this study shows that’s too high for most healthy Chinese women—especially pre-menopausal ones. For example:

  • A pre-menopausal woman with an HE4 level of 50 pmol/L would be “abnormal” by the FDA’s standard but normal by the study’s pre-menopausal range (up to 44.63 pmol/L).
  • A 70-year-old post-menopausal woman with an HE4 level of 100 pmol/L is within the study’s 70–79 range (up to 115.25 pmol/L) but would be flagged as high by the FDA.

For doctors, this means tailoring HE4 interpretations to a woman’s age and menopause status. For women, especially post-menopausal ones, it means understanding that HE4 levels rise naturally with age—no need to panic if your level is higher than a younger woman’s.

How This Compares to Other Studies

The findings align with some research (like a 2012 U.S. study that found HE4 rises with age) but differ in one key way: the U.S. study suggested age, not menopause, drove HE4 levels. The Chinese study, however, used a stricter definition of menopause (1+ years without a period) and included more age groups—so it’s more precise about how menopause and age interact.

Another difference: Chinese women had lower HE4 levels than U.S. women in similar studies. For example, the U.S. study found a median HE4 of 57.6 pmol/L in post-menopausal women, while the Chinese study found 36.46 pmol/L. This highlights why racial and regional differences matter—one global reference range doesn’t fit all.

Limitations and Next Steps

The study only included women from Beijing, so results may not apply to women in other parts of China. Future research should expand to more regions and include factors like body mass index (BMI) or kidney function (which may affect HE4 levels).

Key Takeaways

  • HE4 levels are influenced by both age and menopause—post-menopausal women have higher levels, and age matters more after menopause.
  • Current FDA HE4 limits are too broad—doctors should use age- and menopause-specific ranges for Chinese women.
  • CA125 is less useful for older women—it’s higher in pre-menopausal women, often due to benign conditions like uterine fibroids.

For women, this study is a win: it provides clearer guidelines for what’s “normal” when it comes to HE4. For doctors, it’s a reminder that personalized medicine—considering a patient’s age and life stage—leads to better care.

Cheng HY, Zeng L, Ye X, et al. Age and menopausal status are important factors influencing the serum human epididymis secretory protein 4 level: a prospective cross-sectional study in healthy Chinese people. Chin Med J 2020;133:1285–1291. doi:10.1097/CM9.0000000000000785

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