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
Introduction
Ovarian cancer is one of the most lethal cancers affecting the female reproductive system. Its high mortality rate is primarily due to the lack of detectable symptoms in the early stages and the absence of effective screening methods. More than 70% of ovarian cancer patients are diagnosed at an advanced stage, where the 5-year survival rates are significantly lower compared to early-stage diagnoses. Early detection is crucial for improving prognosis, and biomarkers play a vital role in achieving this goal.
Cancer antigen 125 (CA125) is the most widely used biomarker for ovarian cancer. However, its sensitivity and specificity are limited, particularly for early-stage ovarian cancer. Approximately 20% of epithelial ovarian cancers (EOCs) do not express CA125, and it can also be elevated in benign gynecological conditions and other malignancies. These limitations highlight the need for more reliable biomarkers.
Human epididymis secretory protein 4 (HE4) has emerged as a promising biomarker for ovarian cancer. It is highly expressed in EOCs, including serous, endometrial, and clear cell carcinomas. Compared to CA125, HE4 demonstrates higher specificity and sensitivity, particularly for early-stage ovarian cancer. Despite its growing clinical use, there is no standardized reference range for HE4 levels, and the factors influencing its concentration in healthy individuals remain unclear. This study aims to evaluate the effects of age and menopausal status on HE4 levels and establish reference values for healthy Chinese women.
Methods
The study was conducted in accordance with the Declaration of Helsinki and approved by the ethics committee of Peking University People’s Hospital. Informed consent was obtained from all participants.
A total of 2,493 healthy women aged 40 years or older were recruited from March 2013 to March 2017 from four medical institutions in Beijing, China. Participants with a history of bilateral ovary resection or malignant tumors were excluded. Demographic data, including age, menopausal status, pregnancy, fertility, and lactation history, were collected. Post-menopausal women were defined as those who had not menstruated for more than one year.
Blood samples were collected and processed according to a standardized protocol. Approximately 5 mL of venous blood was drawn, centrifuged, and stored at -80°C until analysis. Serum levels of HE4 and CA125 were measured using enzyme-linked immunosorbent assay (ELISA) kits.
Statistical analysis was performed using SPSS software. The Wilcoxon rank-sum test was used to analyze the relationships between age, menopausal status, and HE4 or CA125 levels. Stratified analysis was conducted to account for interactions between age and menopausal status. Reference ranges for HE4 were determined using the 5th to 95th percentile cut-offs.
Results
The study population consisted of 2,493 women, including 325 pre-menopausal and 2,168 post-menopausal individuals. The mean age was 58 ± 9 years, with a range of 40 to 91 years. Participants were divided into five age groups: 40–49, 50–59, 60–69, 70–79, and ≥80 years.
Median HE4 levels were significantly higher in post-menopausal women (36.46 pmol/L) compared to pre-menopausal women (24.04 pmol/L). HE4 levels increased significantly with age in post-menopausal women but not in pre-menopausal women. The upper 95th percentile of HE4 levels was 44.63 pmol/L for pre-menopausal women, 78.17 pmol/L for post-menopausal women, and 73.3 pmol/L for all women. In post-menopausal women, HE4 reference ranges increased with age, ranging from 13.15 to 47.31 pmol/L for those aged 40–49 years to 35.71 to 212.37 pmol/L for those aged ≥80 years.
CA125 levels were primarily influenced by menopausal status rather than age. Median CA125 levels were higher in pre-menopausal women (7.78 U/mL) compared to post-menopausal women (4.72 U/mL).
Nineteen individuals had abnormal HE4 levels (≥150 pmol/L), with 18 of these cases occurring in post-menopausal women. The number of individuals with abnormal HE4 levels increased with age in the post-menopausal group. Eighteen individuals had abnormal CA125 levels (≥35 U/mL), with 12 cases occurring in pre-menopausal women.
Discussion
This study demonstrates that both age and menopausal status significantly influence HE4 levels in healthy Chinese women. HE4 levels are higher in post-menopausal women and increase with age in this population. In contrast, HE4 levels remain relatively stable in pre-menopausal women regardless of age. These findings are consistent with previous studies, which have also reported age-related increases in HE4 levels.
The study provides valuable reference ranges for HE4 levels in healthy Chinese women, which differ from those established in Western populations. For example, the upper 95th percentile of HE4 levels in this study was 44.63 pmol/L for pre-menopausal women and 78.17 pmol/L for post-menopausal women, which are lower than the values reported in studies of Western populations. These differences may be attributed to genetic, environmental, or lifestyle factors.
The study also highlights the limitations of CA125 as a biomarker for ovarian cancer. While CA125 levels are influenced by menopausal status, they are not significantly affected by age. This reinforces the need for alternative biomarkers like HE4, which demonstrate higher specificity and sensitivity, particularly for early-stage ovarian cancer.
The findings of this study have important clinical implications. Establishing population-specific reference ranges for HE4 is essential for accurate diagnosis and monitoring of ovarian cancer. The results suggest that age and menopausal status should be considered when interpreting HE4 levels in clinical practice.
Conclusion
This study confirms that age and menopausal status are important factors influencing HE4 levels in healthy Chinese women. HE4 levels are higher in post-menopausal women and increase with age, while they remain stable in pre-menopausal women. The study provides population-specific reference ranges for HE4, which differ from those established in Western populations. These findings underscore the importance of considering demographic factors when interpreting HE4 levels in clinical practice.
doi.org/10.1097/CM9.0000000000000785
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