Serologic Signals of Nerve Injury in Endometriosis

Neurofilament light chain elevation supports neuropathic-like mechanisms in endometriosis pain

Key Points

Highlights:

• Serum neurofilament light chain (NfL),  a biomarker of ongoing neuronal injury, was elevated in patients with endometriosis compared with healthy controls. 

Importance:

• Endometriosis-associated pain has traditionally been considered predominantly nociceptive, although increasing evidence suggests neuropathic and neuroinflammatory mechanisms may contribute in some patients. 
• Objective blood-based biomarkers reflecting neuronal injury could help improve understanding of pain heterogeneity in endometriosis.
• These findings further support the emerging concept that endometriosis-associated pain may involve peripheral nerve pathology beyond visible pelvic lesions.

What’s done here:

• In this retrospective multicohort study, investigators measured serum neurofilament light chain concentrations in patients with fibromyalgia (n=60), endometriosis (n=61), small fibre neuropathy (n=24), and healthy controls (n=30).
• Neuropathic-like pain was assessed using the painDETECT questionnaire in fibromyalgia and endometriosis cohorts and the NeuPSIG grading system in small fibre neuropathy patients.
• Serum neurofilament light chain levels were quantified using the ultra-sensitive Simoa SR-X platform and analyzed using both absolute concentrations and age/BMI-adjusted z-scores.

Key results:

• Serum neurofilament light chain concentrations were significantly elevated in fibromyalgia and small fibre neuropathy, while endometriosis demonstrated intermediate but significantly elevated levels compared with healthy controls. 
• Neuropathic-like pain criteria were met by 26% of endometriosis patients, compared with 44% in fibromyalgia and 96% in small fibre neuropathy.
• Neurofilament light chain levels were not directly associated with neuropathic-like pain severity, suggesting that neuronal injury and pain perception may not fully overlap.

Strengths and Limitations: 

• Strengths are the inclusion of multiple chronic pain cohorts, use of an objective blood-based neuronal injury biomarker, and comparative analysis across traditionally nociceptive and neuropathic pain conditions.
• Limitations are the retrospective design, modest cohort size, heterogeneity in pain phenotyping, lack of anatomical localization of nerve pathology, and absence of universally standardized neurofilament light chain assessment methods.

From the Editor-in-Chief – EndoNews

"This study adds important serologic evidence to the evolving discussion surrounding nerve involvement in chronic pain disorders traditionally classified outside the classical neuropathic spectrum. While fibromyalgia demonstrated the strongest signal of ongoing neuronal injury, the intermediate neurofilament light chain profile observed in endometriosis is particularly noteworthy. These findings suggest that, in at least a subset of patients, endometriosis-associated pain may involve biological processes extending beyond nociceptive inflammation alone.

Importantly, the study does not establish definitive neuropathy in endometriosis, nor does it demonstrate a direct correlation between neurofilament light chain levels and neuropathic-like pain severity. Rather, it highlights the complexity and heterogeneity of chronic pelvic pain biology. The dissociation between objective serologic markers and patient-reported neuropathic symptoms further emphasizes that neuronal injury, pain perception, sensitization, and clinical symptom expression may represent overlapping but distinct processes.

Another notable contribution of this work is its use of a measurable blood-based neuronal injury marker across multiple chronic pain conditions. Objective biomarkers capable of reflecting peripheral or central nerve involvement remain limited in chronic pain medicine, particularly in endometriosis, where pain mechanisms are increasingly recognized as multidimensional and patient-specific.

Notably, the concepts explored in this paper strongly parallel the scientific themes emphasized during the recent EndoFound Medical Conference “Endometriosis 2026: A Nerve-centric Disease” and the Patient-day “Mapping Pain: Pelvis to Brain,” both of which highlighted the growing recognition of neuroimmune and neuroinflammatory mechanisms in endometriosis-associated pain.

At the same time, caution is essential. Neurofilament light chain is not specific to endometriosis or peripheral nerve injury alone, and the retrospective multicohort design limits anatomical and mechanistic interpretation. Nevertheless, the findings support the growing need to investigate endometriosis-associated pain through integrated neuroimmune, inflammatory, and sensory frameworks rather than purely lesion-based paradigms."

Lay Summary

Patients with fibromyalgia demonstrated serologic evidence of ongoing neuronal injury comparable to small fibre neuropathy, according to a new study published in Pain Reports.

The study also showed that patients with endometriosis exhibited an intermediate neurofilament light chain (NfL) profile, with levels higher than healthy controls but lower than those observed in fibromyalgia and small fibre neuropathy cohorts.

These findings further support the growing concept that nerve pathology and neuropathic-like mechanisms may contribute to chronic pain conditions traditionally considered predominantly nociceptive.

To investigate circulating markers of neuronal injury across chronic pain conditions, a research team led by Dr. Annina B. Schmid from the Nuffield Department of Clinical Neurosciences at the University of Oxford analyzed serum neurofilament light chain concentrations in 175 participants, including patients with fibromyalgia (n=60), endometriosis (n=61), small fibre neuropathy (n=24), and healthy controls (n=30). Neurofilament light chain, a structural neuronal protein released during axonal injury, was measured using an ultra-sensitive digital immunoassay platform. The investigators additionally assessed neuropathic-like pain using validated questionnaires and grading systems across cohorts.

The results demonstrated significantly elevated serum neurofilament light chain levels in both fibromyalgia and small fibre neuropathy compared with healthy controls. Endometriosis patients showed intermediate elevations, suggesting possible nerve involvement despite endometriosis traditionally being classified as a nociceptive pain condition. Approximately 44% of fibromyalgia patients and 26% of endometriosis patients met criteria for likely neuropathic-like pain, whereas 96% of small fibre neuropathy patients fulfilled probable or definite neuropathic pain criteria. Interestingly, neurofilament light chain levels were not directly associated with neuropathic-like pain severity, indicating that structural neuronal injury and pain perception may not completely overlap.

The authors concluded that elevated neurofilament light chain levels may reflect ongoing axonal injury in subsets of chronic pain patients and emphasized the need for further mechanistic and phenotypic studies, particularly in endometriosis, to better understand the role of peripheral nerve pathology in chronic pelvic pain.

Research Source: https://pubmed.ncbi.nlm.nih.gov/41890134/