HE4 Test: Uses, Normal Ranges & What High Levels Mean

When a patient comes to my clinic concerned about pelvic discomfort or a family history of ovarian cancer, I often recommend the HE4 blood test alongside CA-125. HE4, which stands for Human Epididymis Protein 4, is a protein that can be overproduced by certain ovarian cancer cells. Unlike some tumour markers, HE4 is less likely to be elevated by benign gynaecological conditions, making it a valuable tool for risk assessment and monitoring treatment response.

What Is HE4?

HE4 is a glycoprotein encoded by the WFDC2 gene. It was originally identified in the epididymis but is now known to be expressed at low levels in many normal tissues, including the respiratory epithelium and female reproductive tract. In epithelial ovarian cancer—especially the serous and endometrioid subtypes—HE4 production increases significantly and enters the bloodstream.

The test measures the concentration of HE4 in serum or plasma. Laboratories typically report results in picomoles per litre (pmol/L) or in ng/mL, depending on the assay used.

Why Is HE4 Measured?

In my practice, the main reasons for ordering an HE4 test include:

• Ovarian cancer risk assessment: When combined with CA-125 and ultrasound findings, HE4 helps calculate the Risk of Ovarian Malignancy Algorithm (ROMA) score, which stratifies women with pelvic masses into low- or high-risk groups.
• Monitoring treatment: For women already diagnosed with ovarian cancer, serial HE4 levels can indicate how well chemotherapy is working or whether the disease is recurring.
• Distinguishing benign from malignant masses: HE4 is more specific than CA-125 alone because it is rarely elevated in conditions like endometriosis, ovarian cysts, or pelvic inflammatory disease.

Normal Reference Ranges for HE4

Reference intervals vary by laboratory, assay method, and patient demographics. The table below shows commonly used ranges in adults for serum HE4 (pmol/L). Please note that premenopausal women naturally have lower levels than postmenopausal women.

Always interpret results with your clinician. Ranges may differ between laboratories.

What Does a High HE4 Level Mean?

A single elevated HE4 does not automatically mean cancer. Several factors can raise HE4:

Ovarian Cancer

The most concerning cause is epithelial ovarian cancer, especially serous carcinoma. In my experience, levels above 140 pmol/L in postmenopausal women warrant further imaging and possibly biopsy.

Benign Gynaecological Conditions

Uterine fibroids, ovarian cysts, and endometriosis can occasionally cause mild elevations, though much less commonly than with CA-125.

Non-Gynaecological Causes

Chronic kidney disease reduces HE4 clearance, leading to higher levels. Also, lung cancer, pancreatic cancer, and other malignancies can produce HE4. Even some benign lung conditions (e.g., COPD) may raise it slightly.

Other Factors

Age (postmenopausal women naturally have higher levels), pregnancy (usually normal), and certain medications have minimal effects.

HE4 During Pregnancy

Pregnancy does not consistently alter HE4 levels. Most studies show that HE4 remains within the normal premenopausal range throughout gestation. Therefore, if a pregnant woman has symptoms suspicious for ovarian cancer, HE4 can still be used—though imaging is generally preferred.

HE4 vs. CA-125: Which Is Better?

Both tests have strengths and weaknesses. CA-125 is more sensitive for early-stage ovarian cancer but has a higher false-positive rate due to endometriosis, pregnancy, and other conditions. HE4 is more specific, meaning a positive result is more likely to indicate malignancy. In my practice, I use them together in the ROMA algorithm to improve accuracy.

How Is the HE4 Test Performed?

It is a simple blood draw from a vein in your arm. No special preparation like fasting is required. The sample is sent to a lab, and results typically return within a few days.

Limitations of the HE4 Test

HE4 is not a screening test for the general population. It is most useful for women with a pelvic mass or known ovarian cancer. False positives can occur with renal impairment, and false negatives can happen with mucinous or germ cell tumours, which often do not produce HE4.

When Should You Ask Your Doctor About HE4?

If you have persistent bloating, pelvic pain, difficulty eating, or urinary urgency—especially if you are over 50 or have a family history of ovarian or breast cancer—discuss whether an HE4 test (alongside CA-125 and a pelvic ultrasound) is appropriate for you.

Note: This article is for informational purposes only. Always consult your healthcare provider for personalised medical advice.