HE4
Also known as: Human Epididymis Protein 4
What Does HE4 Measure?
HE4, or Human Epididymis Protein 4, is a protein encoded by the WFDC2 gene that is measured through a blood test. Originally identified in the epididymis (a part of the male reproductive system), it is now known to be expressed in several tissues including the lungs, kidneys, and reproductive organs. The blood test measures the concentration of this protein circulating in the bloodstream, typically reported in picomoles per liter (pmol/L) or units per milliliter (U/mL).
Why Does HE4 Matter?
HE4 is primarily used as a tumor marker for epithelial ovarian cancer, one of the most lethal gynecologic malignancies due to its often late-stage diagnosis. It is particularly valuable because it tends to be elevated in ovarian cancer even when another common marker, CA-125, may be normal, making it a complementary tool for early detection and monitoring. HE4 is also used as part of the ROMA (Risk of Ovarian Malignancy Algorithm) score, which combines HE4 and CA-125 values with menopausal status to stratify a woman's risk of having a malignant pelvic mass. Beyond ovarian cancer, elevated HE4 levels have been associated with endometrial cancer, lung cancer, and chronic kidney disease, expanding its clinical utility.
Normal Ranges
Males
Less than 70 pmol/L (values vary by laboratory; some report <150 pmol/L)
Females
Premenopausal: <70 pmol/L; Postmenopausal: <140 pmol/L (laboratory-specific cutoffs may vary)
Children
Limited reference data; generally not used as a routine marker in pediatric populations
Causes of High Levels
- Epithelial ovarian cancer (particularly serous and endometrioid subtypes)
- Endometrial (uterine) cancer
- Lung cancer (especially non-small cell lung cancer)
- Chronic kidney disease or renal impairment (reduced clearance of HE4)
- Benign conditions such as kidney cysts, endometriosis, or pulmonary fibrosis
- Postmenopausal status (naturally higher baseline levels due to hormonal changes)
Causes of Low Levels
- No clinically significant conditions are associated with abnormally low HE4
- Premenopausal hormonal status is associated with naturally lower HE4 levels
- Effective cancer treatment (surgery, chemotherapy) can reduce previously elevated HE4 back to normal range
How to Improve Your HE4
Diet
- Adopt a Mediterranean-style diet rich in vegetables, fruits, whole grains, and healthy fats to support overall cancer prevention
- Increase consumption of cruciferous vegetables (broccoli, cauliflower, Brussels sprouts) which contain sulforaphane with anti-tumor properties
- Limit processed meats and red meat intake, as these have been associated with increased cancer risk
- Stay well-hydrated and support kidney health with adequate water intake (8-10 glasses per day) to ensure proper HE4 clearance
- Reduce alcohol consumption, as excessive alcohol is linked to elevated cancer risk and hormonal disruption
Supplements
- Vitamin D3 (1,000–2,000 IU/day) — low vitamin D is associated with increased ovarian cancer risk; consult a physician before supplementing
- Omega-3 fatty acids (1,000–2,000 mg EPA/DHA per day) for anti-inflammatory support
- Folate (400–800 mcg/day) for DNA repair and cellular health, particularly relevant for gynecologic health
- Green tea extract (EGCG, 400–800 mg/day) has shown preliminary evidence for anti-cancer properties; consult a healthcare provider
- Note: Supplements should not replace conventional medical treatment; always discuss with your oncologist or physician
Related Biomarkers
Frequently Asked Questions
What is a normal HE4 level, and what level is considered high?
Normal HE4 levels differ based on sex and menopausal status. For premenopausal women, levels below 70 pmol/L are generally considered normal, while postmenopausal women have a higher threshold, typically below 140 pmol/L. Men also have measurable HE4, usually below 70 pmol/L. Elevated levels above these cutoffs may indicate ovarian cancer, endometrial cancer, kidney disease, or other conditions, but a single elevated result does not diagnose cancer — further evaluation by a physician is essential.
Can HE4 detect ovarian cancer early?
HE4 is one of the best available blood markers for ovarian cancer and is especially useful when combined with CA-125 in the ROMA score. It can be elevated in some early-stage ovarian cancers, particularly serous and endometrioid types. However, no single blood test reliably detects all ovarian cancers at an early stage. HE4 is most commonly used to assess the likelihood that a pelvic mass is malignant before surgery, and to monitor response to treatment and detect recurrence in women already diagnosed with ovarian cancer.
What is the ROMA score and how does it use HE4?
The ROMA (Risk of Ovarian Malignancy Algorithm) score is a calculated risk index that combines a woman's HE4 level, CA-125 level, and menopausal status using a specific mathematical formula. The result categorizes women with a pelvic mass into high-risk or low-risk groups for epithelial ovarian cancer. A high ROMA score suggests the mass is more likely to be malignant and may warrant referral to a gynecologic oncologist. It is a decision-support tool, not a definitive diagnostic test.