BCL6 and Fertility: Why a Positive Test Does Not Automatically Mean Endometriosis – or Surgery

By Andrea Vidali, MD

Reproductive Endocrinologist and Endometriosis Surgeon

Endometriosis Surgical Specialists International (ESSI)

The Central Idea

BCL6 is a phenotype marker, not a pathology report. It may signal inflammatory and progesterone-dysregulated endometrial biology, but it does not directly identify an endometriotic lesion. A positive result should prompt clinical thinking—not automatically trigger surgery or medical suppression.

The Answer in One Paragraph

Does a positive BCL6 test mean that a patient has endometriosis? No. Elevated endometrial BCL6 is associated with endometriosis and with inflammatory, progesterone-dysregulated endometrial biology, but it is not a lesion-specific or disease-specific diagnosis. The result is heavily influenced by biopsy timing and progesterone exposure, and the evidence that BCL6-directed surgery or medical suppression improves live birth rates remains limited and inconsistent. A positive result should always be interpreted together with symptoms, expert imaging, embryo quality, uterine findings, age, ovarian reserve, and the patient’s comprehensive reproductive history.

Key Takeaways

• Eutopic, Not Ectopic: BCL6 is measured in the eutopic endometrium (the uterine lining), not inside an external endometriotic lesion.

• Associated, Not Specific: Endometriosis is one important possible cause of elevated BCL6, but BCL6 is not uniquely specific to this disease.

• Signaling, Not Supply: Progesterone resistance means an impaired tissue response to progesterone—it does not simply mean a low serum progesterone level.

• Shared Mechanisms: Endometriosis and adenomyosis are both associated with inflammatory and steroid-receptor abnormalities that can contribute to progesterone resistance.

• Protocol Dependent: Exogenous progesterone and the specific uterine preparation method can substantially drop the measured BCL6 HSCORE.

• No Proven Normalization: No paired study has successfully demonstrated that surgery clears or normalizes endometrial BCL6 expression.

• Inconsistent Data: The original treatment evidence was small and nonrandomized, and later high-quality studies have not consistently reproduced the dramatic live-birth benefit.

• Individualization Over Rules: Insufficient average evidence does not prove that no individual can benefit; it simply means a slightly abnormal biomarker cannot automatically be converted into a universal treatment mandate or a rigid clinical prohibition.

What Is the BCL6 Fertility Test?

B-cell lymphoma 6 (BCL6) is a nuclear transcriptional repressor. In fertility testing, it is assessed by immunohistochemistry in glandular epithelial cells from an endometrial biopsy. The commonly used positive threshold—an HSCORE above 1.4—was derived from comparisons of appropriately timed secretory-phase endometrium in women with endometriosis and fertile controls.

This distinction is fundamental. BCL6 is measured in the uterine lining, not in an endometriotic lesion. It can reflect the molecular and inflammatory state of the endometrium at the time of biopsy, but it cannot directly show whether a lesion exists, where it is located, how extensive it is, or whether it is responsible for a particular patient’s infertility.

Does a Positive BCL6 Test Diagnose Endometriosis?

The association between elevated endometrial BCL6 and endometriosis is biologically credible and has been repeatedly reported in selected infertility cohorts. Foundational studies found increased secretory-phase BCL6 expression in women with surgically confirmed endometriosis and in some women with unexplained infertility or recurrent pregnancy loss.

Association, however, is not specificity. Many surgical studies enrolled patients already enriched for suspected endometriosis. In a high-prevalence population, positive predictive value can look impressive even when a marker is not uniquely linked to one disease. A positive result may reflect endometriosis, another inflammatory pelvic condition, altered endometrial differentiation, hormonal exposure, or a combination of factors. BCL6-positive is not the same as endometriosis-positive.

Can BCL6 Diagnose Adenomyosis?

No. Adenomyosis shares inflammatory, estrogen-dependent, and progesterone-dysregulated biology with endometriosis, making overlap plausible. But BCL6 has not been validated as an adenomyosis diagnostic test. A 2025 tissue study found no significant difference in BCL6 expression between adenomyosis and normal myometrium, although the tissue and assay context differed from the commercial timed endometrial biopsy. Adenomyosis should be evaluated independently through symptoms, expert ultrasound, and MRI when appropriate.

Can BCL6 Diagnose Chronic Endometritis?

No. Chronic endometritis is a histologic diagnosis based on endometrial plasma cells, commonly evaluated with CD138 immunostaining. BCL6 does not identify plasma cells and should not substitute for appropriate histology. In a 2023 multimarker study, overlap between BCL6 positivity and CD138-defined chronic endometritis was limited.

Is BCL6 a Marker of Insulin Resistance or PCOS?

Not clinically. BCL6 participates in metabolic regulation in experimental systems, but its effects are tissue-specific. There is no validated human evidence that an elevated endometrial BCL6 HSCORE diagnoses systemic insulin resistance, hyperinsulinemia, PCOS, or metformin responsiveness. Metabolic dysfunction should be evaluated directly through serum metrics.

Progesterone Resistance Explained

Progesterone resistance does not simply mean low serum progesterone. It means that normal progesterone exposure produces a reduced, incomplete, mistimed, or pathway-specific biological response in the target tissue.

During a normal menstrual cycle, progesterone transforms the estrogen-primed endometrium from a proliferative tissue into a differentiated, implantation-ready environment. It limits estrogen-driven growth, regulates inflammation, supports glandular secretory change, and prepares stromal cells for decidualization. In a progesterone-resistant endometrium, progesterone may be present in adequate amounts while important downstream responses remain impaired.

Potential mechanisms include altered progesterone-receptor expression or isoform balance, abnormal receptor cofactors, chronic inflammatory signaling, epigenetic changes, and disrupted expression of progesterone-responsive genes.

Why Are Endometriosis and Adenomyosis Linked to Progesterone Resistance?

Both conditions are chronic inflammatory and estrogen-dependent. Endometriosis has been associated with altered progesterone-receptor expression, increased estrogen-receptor-beta signaling, inflammatory cytokines, epigenetic changes, and disruption of implantation-related genes. In the proposed BCL6 pathway, inflammatory KRAS/STAT3 signaling increases SIRT1 and BCL6, which can repress GLI1 and Indian Hedgehog signaling involved in progesterone responsiveness.

Adenomyosis also demonstrates abnormal estrogen/progesterone signaling, inflammation, fibrosis, neuroangiogenesis, immune dysfunction, and myometrial remodeling. These changes may contribute to defective decidualization, abnormal uterine contractility, altered implantation biology, and incomplete response to progestin treatment. Progesterone resistance is therefore a shared mechanism—not a diagnosis specific to one condition.

Why Might Progesterone Lower Measured BCL6?

The clinical observation is stronger than the mechanistic proof. Exogenous progesterone exposure is associated with lower measured endometrial BCL6, but no human study has demonstrated a single definitive pathway by which progesterone directly represses the BCL6 gene.

• Progesterone-receptor signaling may reduce upstream inflammatory or proliferative activity that sustains BCL6.

• Progesterone may alter glandular epithelial differentiation, changing the number and intensity of BCL6-positive nuclei that are scored by the pathology lab.

• Progesterone may affect BCL6 transcription, protein stability, or nuclear localization indirectly.

Ultimately, a lower HSCORE may reflect a changed endometrial state without eliminating the underlying disease or inflammatory driver. Progesterone may suppress the measured stain without proving that the underlying pathology has been eradicated.

The Biopsy Protocol Can Change the Answer

Cycle timing is the assay’s Achilles heel. The original threshold was derived from appropriately timed secretory-phase biopsies; it was not validated as a cycle-independent cutoff that can be applied to any endometrial sample.

In a 2023 retrospective study of 244 biopsies, BCL6 positivity above 1.4 occurred in 80.3% of natural cycles, 40.0% of modified-natural cycles with progesterone, and 23.1% of programmed cycles with estrogen and progesterone. Median HSCOR​Es were 3.0, 1.1, and 0.8, respectively. The groups were not paired, so the study does not show how often the same patient would switch classification. Nevertheless, the magnitude of the difference demonstrates that hormonal context completely warps the baseline metrics.

The most scientifically defensible testing conditions are a natural ovulatory cycle, confirmation of ovulation, biopsy approximately 7–10 days after the LH surge or ovulation, and avoidance of exogenous progesterone or ovarian stimulation when the result is being interpreted against the original natural-cycle threshold. A generic label such as “cycle day 21” is completely inadequate because ovulation timing varies. The relevant biological clock is time from ovulation or progesterone exposure—not the calendar day of the cycle.

Does Endometriosis Surgery Lower BCL6?

This has not been demonstrated. The accurate statement is not that surgery has been proven to fail to lower BCL6. It is that the necessary paired preoperative and postoperative study has simply never been performed.

The pivotal 2019 treatment study evaluated pregnancy and live-birth outcomes after laparoscopy or GnRH-agonist suppression. It did not repeat the endometrial biopsy after treatment. Therefore, it did not show that surgery normalized BCL6, that hormonal suppression normalized BCL6, that a lower HSCORE mediated better outcomes, or that repeat testing can be used as a valid test of cure.

How Strong Is the Evidence for BCL6-Directed Interventions?

The widely cited 2019 Likes study included 21 surgically treated patients, 10 patients treated with a GnRH agonist, and 54 untreated BCL6-positive controls. Clinical pregnancy occurred in 13 of 21 after laparoscopy, 6 of 10 after medical suppression, and 8 of 54 untreated controls. Combined live birth was reported in 16 of 31 treated patients versus 4 of 54 untreated.

The signal was striking, but the treatment groups were exceptionally small and completely nonrandomized. The study was highly vulnerable to treatment-selection bias and confounding, and it was not restricted to modern single euploid embryo transfer practice. Surgical and medical interventions were also combined in parts of the analysis even though they are biologically different treatments.

A 2020 multicenter conference abstract reported self-reported outcomes among 143 treated BCL6-positive women, including 40 laparoscopies. However, PGT status was unavailable, some pregnancies were ongoing, and there was no untreated BCL6-positive control group. The author was an employee of Cicero Diagnostics, the ReceptivaDx licensee. This abstract cannot establish a causal benefit of treatment among BCL6-positive patients.

Subsequent evidence has been significantly less supportive of a simple binary treatment model:

• A study of normal responders undergoing single euploid embryo transfer found no association between BCL6 and live birth rates.

• A prospective study of BCL6/SIRT1 in fresh stimulation-cycle biopsies did not find diagnostic or prognostic discrimination and discovered an inverse association between BCL6 and serum progesterone.

• Taggar and colleagues compared treated and untreated BCL6-positive patients and did not find statistically significant differences in implantation, miscarriage, or ongoing pregnancy rates.

The 2026 ASRM committee opinion on recurrent implantation failure states that routine BCL6 testing is not recommended because of conflicting evidence regarding test validity and treatment efficacy. Importantly, it also recognizes limited evidence supporting empiric suppression in selected patients with recurrent implantation failure and known or suspected endometriosis or adenomyosis, while emphasizing the need to identify the population most likely to benefit.

What Does Insufficient Evidence Actually Mean?

Insufficient evidence does not mean that no BCL6-positive patient can benefit from treatment. Clinical studies estimate average treatment effects in heterogeneous populations. A treatment may fail to show a statistically significant average benefit yet still help a biologically selected subgroup. Small or poorly designed studies may also miss a real effect.

But the opposite inference is equally invalid. A mildly elevated BCL6 result cannot automatically be converted into a diagnosis of endometriosis, a recommendation for laparoscopy, or an assumption that several months of suppression will improve live birth. The appropriate response to uncertain evidence is better patient selection—not automatic treatment and not automatic dismissal.

How Should a Positive BCL6 Result Be Interpreted?

Before recommending surgery, suppression, or repeat embryo transfer, four key areas must be evaluated:

1. Was the Test Technically Interpretable?

• Was ovulation officially confirmed?

• Exactly how many days after ovulation or the LH surge was the biopsy taken?

• Was estrogen or progesterone administered ahead of the draw?

• Was this a stimulation or active retrieval cycle?

• Was there recent uterine instrumentation?

• Was the result borderline or markedly elevated?

2. Is There Independent Evidence of Endometriosis or Adenomyosis?

• Severe dysmenorrhea, deep dyspareunia, or cyclic bowel/bladder symptoms.

• Endometrioma, deep endometriosis, or adenomyosis identified on expert imaging scans.

• Fixed or inaccessible ovaries, distorted anatomy, or previous operative documentation.

• A strong clinical phenotype despite negative imaging, recognizing that superficial disease can be completely occult.

3. Have Competing Explanations Been Addressed?

• Embryo aneuploidy and overall embryo quality.

• Adenomyosis, fibroids, polyps, hydrosalpinx, or previous endometrial injury.

• Chronic endometritis assessed with appropriate histological staining.

• Transfer technique and protocol-related variables.

• Metabolic, endocrine, or systemic inflammatory conditions.

4. What Is the Patient’s Complete Reproductive Context?

• Maternal age and current ovarian reserve metrics.

• Number of available embryos and whether they have been genetically tested.

• Previous implantation failures and pregnancy history.

• Symptom burden and patient quality of life.

• Surgical risk, potential ovarian impact, and the timeline costs of treatment delay.

• Patient values and unique treatment preferences.

The ESSI Position on BCL6 Testing

At ESSI, we view BCL6 as potentially useful biological information when it is interpreted inside a complete fertility and endometriosis evaluation. We do not interpret a positive result to mean that every patient has endometriosis, that every patient needs surgery or suppression, or that every negative result excludes disease.

A symptomatic patient with convincing imaging, multiple euploid implantation failures, and strongly abnormal endometrial biology may warrant a very different discussion from an asymptomatic patient with one failed untested transfer and a borderline result obtained after progesterone exposure. BCL6 should inform clinical judgment. It should never dictate it.

Frequently Asked Questions About BCL6

What does a positive BCL6 test mean?

It means that BCL6 staining in the sampled endometrial glandular epithelium exceeded the laboratory threshold. It may reflect an inflammatory and progesterone-dysregulated endometrial phenotype. It does not by itself prove endometriosis, adenomyosis, chronic endometritis, or the absolute need for treatment.

Does BCL6 prove that I have silent endometriosis?

No. Endometriosis is one possible explanation, particularly in a patient with supportive symptoms, imaging, anatomy, or prior surgical findings. But BCL6 is an indirect endometrial marker, not a direct visualization or histologic diagnosis of an endometriotic lesion.

Can a patient have endometriosis with a negative BCL6 test?

Yes. A negative result cannot exclude endometriosis, especially superficial disease. The result may also be influenced by cycle timing, progesterone exposure, assay variability, and the biological heterogeneity of endometriosis.

Can adenomyosis cause a positive BCL6 result?

It is biologically plausible because adenomyosis is associated with inflammation and altered progesterone signaling, but direct clinical validation is lacking. BCL6 should not be used to diagnose or exclude adenomyosis.

When is the best time to test BCL6?

The most defensible protocol is an ovulation-confirmed natural cycle with biopsy approximately 7-10 days after ovulation or the LH surge, without exogenous progesterone or ovarian stimulation when the natural-cycle threshold is being used. Calendar day alone is not sufficient.

Does progesterone lower BCL6?

Clinical studies show lower BCL6 expression in progesterone-exposed protocols. The precise mechanism is not proven and may involve reduced inflammatory signaling, altered glandular differentiation, or changes in BCL6 expression or localization. Lower staining does not necessarily prove that the underlying pathology is gone.

Does surgery lower BCL6?

We do not know. The key treatment study did not repeat BCL6 biopsies after surgery. No validated evidence currently supports using postoperative BCL6 as a test of cure.

Should every BCL6-positive patient have surgery or Lupron suppression?

No. The treatment evidence is limited and inconsistent. Decisions should consider symptoms, imaging, embryo ploidy, uterine pathology, age, reserve, previous outcomes, surgical risk, and patient preferences. Some carefully selected patients may benefit, but the test alone should not dictate treatment.

Commentary from Dr. Andrea Vidali

“The problem with BCL6 is not that the biology is uninteresting. The problem is that an interesting biological signal has too often been converted into a binary clinical command.

BCL6 connects several concepts that matter in fertility care: inflammation, altered progesterone signaling, endometriosis, and potentially a broader abnormal endometrial phenotype. That makes it valuable as a clue. But a clue is not the same as a diagnosis, and a diagnosis is not automatically the same as an indication for surgery.

I am particularly concerned when a slightly elevated BCL6 result—sometimes obtained without rigorous ovulation timing or after hormonal exposure—is used to send an asymptomatic patient directly to laparoscopy or months of suppression. The original treatment evidence was based on very small, nonrandomized groups. Surgery was not shown to lower the biomarker, and later studies have not consistently reproduced the dramatic outcome benefit.

At the same time, I do not believe that incomplete or statistically null average evidence should be converted into a universal clinical prohibition. Population averages do not eliminate biological heterogeneity. Some patients with a convincing endometriosis or adenomyosis phenotype, repeated euploid implantation failure, significant symptoms, abnormal imaging, or a limited number of embryos may still benefit from carefully selected treatment.

The mistake is to let BCL6 become the decision. The test should be one piece of the decision. A thoughtful clinician should ask whether the biopsy was technically valid, whether independent evidence supports endometriosis or adenomyosis, what other explanations have been excluded, and whether the expected benefit of intervention exceeds its cost and risk for this particular patient.

The correct question is not simply, ‘Is BCL6 positive?’ The correct question is, ‘What does this result mean in this patient—and what action, if any, is most likely to improve her outcome?'”

— Andrea Vidali, MD

References

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MEDICAL DISCLAIMER: This article is strictly educational and does not replace individualized medical advice. Decisions about laparoscopy, medical suppression, embryo transfer, or other specialized fertility treatments should only be made after a complete and thorough clinical evaluation with a certified specialist.