Testing the Endometrium: BCL-6, Uterine NK Cells & Immune Profiling Explained by a Reproductive Immunologist

UPDATED ON 10 JUNE 2025

When I see patients dealing with recurrent IVF failure or unexplained pregnancy loss, one of the first things I look into—if structural and genetic causes have been ruled out—is the condition of the endometrium, the inner lining of the uterus where the embryo implants. 

Testing the endometrium for immune-related causes can provide crucial insights, but it must be approached with both precision and purpose.

Let me walk you through the three key tests we consider: BCL-6, uterine natural killer (uNK) cells, and immune profiling.

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When Is the Right Time to Test the Endometrium?

We usually perform endometrial testing in the mid-luteal phase of your cycle—this typically falls around day 20 to 24 in a 28-30 day cycle.

Why this phase? Because it’s closest to when implantation naturally occurs, giving us the most accurate view of your endometrium’s immune environment.

However, it is very important to understand that, for practical purposes, we do not prefer to do this test when the lady is in her menstrual phase. In every other phase, we can actually test the endometrium, and usually, we may end up getting a slightly collaborative and accurate report.

How Is the Test Done?

The procedure is simple and outpatient:

• We use a thin, flexible instrument called a pipelle to collect a small sample of the endometrium.

• This sample is sent for biopsy, often evaluated using a technique called immunohistochemistry (IHC). Apart from the immunohistochemistry, in certain situations where we are trying to find out the concentration of uterine natural killer cells.

• In some advanced cases, we also use flow cytometry or Next Generation Sequencing (NGS) for a deeper immune marker analysis.

What Are We Looking For? Understanding the Endometrial Immunology Tests

There are many different ways to test the endometrium, especially when we’re looking for signs of inflammation. Most of these tests aim to detect pro-inflammatory markers, which can impact how well an embryo implants.

But here’s the challenge:

👉 There are no standard, universal guidelines for which markers to test or how to interpret them.

👉 Different clinics may use different tests based on what’s available in their lab or their individual approach.

That’s why it can feel overwhelming or even contradictory at times. My goal is to help you understand what each test means and whether it’s truly useful in your unique situation.

BCL-6 Testing: A Marker for Inflammation and Endometriosis

BCL-6 is a pro-inflammatory marker. Elevated levels often point toward:

• Endometriosis (even if it’s silent)
• Chronic endometritis
• Adenomyosis (diffuse or focal)

Women who have repeated implantation failures or recurrent miscarriages—and especially those with a history of endometriosis or suggestive ultrasound findings—are prime candidates for BCL-6 testing.

📌 A result is considered abnormal if the H-score is above 1.4.

What’s Next If BCL-6 Is Elevated?

We may:

• Recommend diagnostic laparoscopy or detailed pelvic ultrasound
• Consider GNRH agonist therapy or immunotherapy

But this isn’t a one-size-fits-all. Every treatment decision is made case by case, only after evaluating your history and pelvic mapping. 

One of the tests that we advise is the testing for BCL6. This is a test, which is a pro-inflammatory test of the endometrium and is typical in picking up endometriosis as well as endometritis. Elevation levels of BCL6 often correlate with the presence of endometriosis in the tissue in the pelvis, and very often.

We would recommend that these patients have a diagnostic laparoscopy or have a detailed ultrasound in order to rule out endometriosis.

Apart from that, it being a pro-inflammatory marker is also useful to be tested in patients in whom there is repeated implantation failure as well as recurrent abortions, especially if some of them have had a past history of endometriosis as well as an ultrasound picture that is suggestive of a focal or a diffuse adenomyosis, which is present inside the uterus. 

BCL6 is a test that, typically in immunohistochemistry, requires an adequate sample of the endometrium, and the presence or absence of BCL6 in the sample, along with its quantification, is important to make further decisions. 

Uterine Natural Killer (uNK) Cell Testing

Let’s clear up a common myth: uNK cells are not the same as blood NK cells. While both are immune cells, they behave very differently:

• uNK cells support implantation but can become overactive in a pro-inflammatory state
• We assess these via CD56 staining using IHC

Uterine NK cells and peripheral NK cells are grossly different from each other. Both of them are usually elevated in situations when there is an inflammatory response, but there is a characteristic signature expressed by both of them that contributes predominantly to the different types of functions that they play in the environment in which they are in. 

For example, it is the uterine NK cells that play one of the most important roles as far as implantation and acceptance of the semi-allogenic embryo are concerned.

🔍 A uNK cell count over 300 per sample is considered to be very severe as far as pro-inflammatory markers in the uterine endometrium are concerned.

But—here’s the catch:

• uNK levels vary from cycle to cycle
• They’re influenced by infections (like chronic endometritis), structural problems, and even stress

Because of this, we don’t rely solely on uNK testing. It’s only part of the puzzle.

Endometrial Profiling for Immunology

Now we have to understand one thing that the biopsy to take out the endometrium is going to be the same. It is the immune profiling which gives you a much more detailed report as far as the exhibition of various immune markers which are present in the endometrium at that point in time 

This is going to be predominantly looking at the presence of T cells as well as tumour necrosis factors which is called as TNF alpha and gamma as well as IL8, which is interleukin eight and the expression of other cytokines which is related to the pro-inflammatory state, which is present in the uterus.

TH1/TH2 ratio, which is present inside the endometrium can also be found out with this testing and may add some benefit. 

This profiling can reveal whether your endometrium is in a pro-inflammatory or anti-inflammatory state at the time of biopsy.

💡 BUT: Immune profiling is an expensive test (costing around ₹25,000 in India), and results can vary between cycles. That’s why I’m very selective in recommending it.

In cases where we suspect chronic endometritis, I prefer to do a MUM1 biopsy—a simpler, more specific test for plasma cells, which are often elevated in endometrial inflammation.

Final Thoughts: When and Why We Test?

Not every patient needs these tests. In fact, many don’t.

If you’ve had recurrent miscarriages or failed IVF cycles—and standard tests haven’t provided answers—then immune-related causes might be worth exploring. But I always

• Start with pelvic mapping to rule out visible structural or inflammatory causes
• Use evidence-based decision-making to avoid unnecessary tests
• Tailor therapy only when truly indicated

Immune testing of the endometrium can be a game-changer—but only when used judiciously and interpreted by a specialist in reproductive immunology.

If you’re wondering whether immune testing could help you, let’s talk with me, Dr. Jay Mehta. My role isn’t just to treat, but to guide, explain, and walk this journey with you. Let’s uncover what your body is truly telling us—and build a plan together.

AUTHOR

CONDITION

Repeated Miscarriages

Failed IVF Cycles

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