What the HE4 test shows
HE4 (human epididymis protein 4) is a small glycoprotein, encoded by the WFDC2 gene, that healthy airway and reproductive-tract tissue makes in tiny amounts but that many epithelial ovarian cancers overproduce. Its blood level, in pmol/L, reflects how much of this tumor-associated protein is circulating. StatPearls notes HE4 is detectable in ovarian cancer tissue with a specificity around 96%, which is why it became a standard marker for assessing an ovarian (adnexal) mass and for following women already treated for the disease.
Its job differs from the marker it is almost always ordered with. CA-125 rises in most advanced ovarian cancers but also climbs with menstruation, endometriosis, fibroids, pelvic infection and pregnancy, so alone it produces many false alarms. HE4 is far less swayed by those benign conditions, giving it higher specificity — and because a fifth to a third of ovarian cancers do not raise CA-125, HE4 can flag disease the older marker misses. The two are combined, with menopausal status, in the ROMA score (Risk of Ovarian Malignancy Algorithm) to sort a woman with a pelvic mass into a higher- or lower-risk group.
What HE4 is not is a screening test. The U.S. National Cancer Institute lists it as a marker used to plan treatment, assess progression and monitor for recurrence — not to find cancer in healthy women.
HE4 normal range
HE4 is reported in pmol/L (sometimes written pM; the two are identical). Unlike many blood tests it has no separate conventional and SI unit — pmol/L is used worldwide — so US and European reports mean the same number. What shifts the reference point is menopausal status and age, since HE4 climbs naturally as women get older.
| Group | Orientation, pmol/L (= pM) |
|---|---|
| Women, premenopausal | below ~70 |
| Women, postmenopausal | below ~140 |
| With reduced kidney function | higher — interpret with eGFR |
| Men / children | assay-specific — use your lab’s range |
These are the most widely used cut-offs, but they are assay-dependent (EIA, ECLIA and CMIA platforms differ) and no single range fits every population. HE4 is read mainly through the ROMA score rather than a lone number: a result above the lab’s ROMA threshold marks a higher risk of epithelial ovarian cancer and prompts referral. Reference ranges depend on the lab, sex, age and menopausal status — always read your result against your own report.
Why HE4 is high
For a tumor marker, high is the direction that matters. A raised HE4 is a signal to investigate, never a diagnosis by itself. Causes, roughly by frequency:
- Non-cancer causes are common. Reduced kidney function is the leading benign reason — HE4 is cleared by the kidneys, so it rises step by step as eGFR falls, which is why creatinine is checked alongside it. Older age and smoking also push it up.
- Epithelial ovarian cancer, especially serous and endometrioid subtypes — the reason the test exists; HE4 often rises earlier than CA-125 in early-stage disease.
- Endometrial (uterine) cancer, in which HE4 is frequently elevated.
- Other malignancies: lung adenocarcinoma most notably, and less often breast, pancreatic and gastrointestinal cancers.
- Benign lung, liver or heart disease — pulmonary fibrosis, cirrhosis and heart failure can raise it modestly, since HE4 also tracks fibrosis.
When is it urgent? A pelvic mass with a high HE4, a raised CA-125 and a ROMA score above the lab threshold needs prompt referral to a gynecologic-oncology team. In a woman already treated for ovarian cancer, a rising HE4 trend can be the first sign of recurrence and should reach her oncologist quickly.
Why HE4 is low
A low or normal HE4 is the expected, reassuring finding — no disease pushes it abnormally low, so a low number is not itself a problem. What matters is what a normal value does and does not rule out.
A normal HE4 does not exclude ovarian cancer. Mucinous ovarian carcinomas and germ-cell tumors often secrete little or no HE4, so the marker can read normal while cancer is present. That is exactly why HE4 is never used alone: it is paired with CA-125, and when a mucinous or gastrointestinal tumor is suspected, with CEA and CA 19-9; in younger women with an ovarian mass, AFP is added to catch germ-cell tumors. A normal HE4 with worrying symptoms or a suspicious mass still warrants specialist assessment.
What to test alongside
HE4 is almost never interpreted on its own. It is ordered with:
- CA-125 — its partner marker; combined with HE4 and menopausal status in the ROMA score.
- CEA — helps when a mucinous ovarian or a gastrointestinal primary is suspected.
- CA 19-9 — raised in mucinous ovarian and pancreatic/GI tumors that HE4 may miss.
- AFP — added in younger women to detect germ-cell ovarian tumors.
- CA 15-3 — considered if a breast primary is in the differential.
- creatinine — kidney function; a low eGFR raises HE4 without cancer.
What to do about an abnormal result
- Don’t panic and don’t self-diagnose. A single raised HE4 is not proof of cancer — kidney disease, smoking and age raise it too.
- Interpret it in context. HE4 is read together with CA-125, menopausal status (the ROMA score) and a pelvic ultrasound — not as a stand-alone number — and your doctor weighs kidney function and smoking first. MedlinePlus makes the same point for CA-125: most raised results in otherwise well women are not cancer.
- See the right doctor. Start with your primary care doctor or gynecologist. If a mass looks suspicious or the risk score is high, NICE advises referral to a specialist gynecologic-cancer team — outcomes are better when a gynecologic oncologist leads care.
- During monitoring after ovarian-cancer treatment, a rising trend over several tests matters more than any single value; your oncology team decides on next steps.
- Remember it is not a screening tool. The USPSTF recommends against ovarian-cancer screening in women at average risk, because it does not lower deaths and leads to unnecessary surgery.
Mini-FAQ
Is HE4 a screening test for ovarian cancer?
No. HE4 is not approved to screen healthy women, and the USPSTF advises against ovarian-cancer screening in women at average risk. It is used to assess a known pelvic mass — with CA-125 as the ROMA score — and to monitor women already treated for the disease.
What is a normal HE4 level?
Most labs use below about 70 pmol/L before menopause and below about 140 pmol/L after menopause, but the cut-offs are assay-specific. HE4 also rises with age and with reduced kidney function, so results are read against your own lab’s range.
What does a high HE4 mean?
A raised HE4 is a signal to investigate, not a diagnosis. It is most concerning alongside a pelvic mass and a high ROMA score, but kidney disease, smoking, older age and some lung and other cancers can also raise it.
Can HE4 be normal if I still have ovarian cancer?
Yes. Mucinous and germ-cell ovarian tumors often do not raise HE4, so a normal result cannot rule out cancer. That is why it is paired with CA-125 and, when needed, CEA, CA 19-9 or AFP.
How is HE4 different from CA-125?
Both are ovarian-cancer markers, but HE4 is less often raised by benign conditions such as endometriosis, which makes it more specific. Combining the two in the ROMA score works better than using either marker alone.
