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

Abstract

Background: Human epididymis secretory protein 4 (HE4) is a new ovarian cancer biomarker. The factors influencing HE4 levels are not clear, and the reference data in China are limited. Here, we aim to evaluate the effects of menopause and age on HE4 levels and to provide a possible reference value for HE4 in healthy Chinese people. Methods: A total of 2493 healthy females aged 40 years or older were recruited from March 2013 to March 2017 with the cooperation of four medical institutions across Beijing, China. The serum levels of HE4 and cancer antigen 125 (CA125) were measured by enzyme-linked immunosorbent assay. The Wilcoxon rank-sum test of variance and a stratified analysis were used to analyze the relationships among age, menopausal status, and levels of HE4 or CA125. Confidence intervals (5%–95%) were determined for reference ranges in different populations. Results: There was a statistically significant difference in median HE4 levels between the post-menopausal (n = 2168) and pre-menopausal groups (n = 325) (36.46 vs. 24.04 pmol/L, Z = −14.41, P < 0.001). HE4 increased significantly with age in the post-menopausal groups (H = 408.18, P < 0.001) but not in the pre-menopausal subjects (Z = −0.43, P = 0.67). The upper 95th percentile of HE4 levels were 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 the post-menopausal population, the HE4 reference ranges were 13.15 to 47.31, 14.31 to 58.04, 17.06 to 73.51, 24.50 to 115.25, and 35.71 to 212.37 pmol/L for different age groups from forty divided by decade. The CA125 level was affected mainly by menopausal status and not age. Conclusions: Menopausal status and age were both important factors influencing the level of HE4, and age affected HE4 levels mainly in post-menopausal women. The HE4 level was higher in the post-menopausal population than in the pre-menopausal population and increased with age.

Predictive Value of HE4 in Platinum-Based Chemotherapy for Ovarian Cancer: A Systematic Review

“…This suggested that age may be more important for the effect of HE4 levels. However, Cheng et al (35) concluded that both age and menopausal status are important factors that affect HE4 levels. The difference in the conclusions between the two studies may be because they used different definitions of menopausal status.…”

HE4 as a Biomarker for Endometrial Cancer

“…One of the main limitations for the utilisation of HE4 as a biomarker is that serum levels are significantly influenced by several physiological and demographic variables, making its interpretation more challenging. Several studies investigating the use of HE4 for EC have observed that serum HE4 levels increase with advancing age [ 25 , 60 , 61 , 74 , 124 ]. This has also been observed in studies investigating its use for ovarian cancer [ 125 ].…”

“…Bolstad et al reported that compared to women aged 20 years, the level of serum HE4 was 2%, 9%, 20%, 37%, 63% and 101% higher in women aged 40, 50, 60, 70 and 83 years, respectively [ 127 ]. Serum HE4 is also higher in postmenopausal women compared to those who are pre-menopausal [ 25 , 60 , 68 , 124 ]. However, this association may be secondary to the impact of age on HE4 levels rather than directly related to menopause.…”

Exposure to polycyclic aromatic hydrocarbons and its relationship with increased human epididymal secretory protein 4

“…Second, the enrolled participants with HE4 data in NHANES 2001-2002 dataset were older than 20 years. Menopausal status, which influences the level of HE4, was not excluded in the NHANES database [46]. The median age of our final participants was 45 (31-64) years.…”