Endometriosis Is Not One Disease: Landmark Multi-Omics Study Confirms the Pelvic Overlap Spectrum
By Endometriosis Surgical Specialists International (ESSI) | Commentary by Dr. Andrea Vidali
A new Nature Genetics study gives molecular weight to what many complex endometriosis patients—and the clinicians who care for them—have been saying for years: endometriosis is not one disease, and it cannot be fully explained by lesion location, stage, or surgical appearance alone.
The study analyzed nearly 1.4 million women, including 105,869 cases, and identified 80 genomic regions associated with endometriosis risk, including 37 newly identified loci. It then integrated transcriptomic, epigenetic, and proteomic data to connect genetic risk to real biological pathways, including immune regulation, hormonal signaling, inflammation, tissue remodeling, vascular development, and cell differentiation.
For ESSI, this is not simply another genetics paper. It is a major validation of a clinical model Dr. Andrea Vidali has been developing and discussing for years: endometriosis as a heterogeneous, multi-system disorder—the Pelvic Overlap Spectrum.
Figure 1. Study snapshot from the 2026 multi-ancestry GWAS and multi-omics analysis. Alt text: Study snapshot: approximately 1.4 million women analyzed, 105,869 cases, 80 risk regions, and more than 50 putative causal signals.
Key Takeaway: Endometriosis is best understood not as a single pelvic lesion disease, but as a heterogeneous systemic disorder in which genetic, immune, hormonal, vascular, neurologic, inflammatory, and tissue-remodeling pathways interact differently in different patients.
What the New Multi-Omics Study Found
The paper matters because it moves beyond the question, “Which genes are associated with endometriosis?” and asks the more important question: “What biology do these genes point toward?”
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The study included data from eight major cohorts and multiple ancestry groups, creating the largest genetic map of endometriosis to date.
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It identified 80 independent risk regions for endometriosis, 37 of which were newly described.
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Five loci were also associated with adenomyosis, reinforcing that adenomyosis and endometriosis overlap, but are not identical diseases.
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Integrated transcriptomic, epigenetic, and proteomic analyses linked endometriosis risk to immune regulation, hormonal regulation, cell differentiation, tissue remodeling, and inflammation.
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Polygenic risk interacted with abdominal pain, anxiety, migraine, and nausea, showing that symptoms are not separate from the biology of the disease.
The result is a disease map that looks much more like a systems network than a single gynecologic diagnosis. This is precisely the conceptual shift behind the Pelvic Overlap Spectrum.
Figure 2. Multi-omics convergence: multiple data layers point toward a systemic disease network. Alt text: GWAS, transcriptomics, epigenetics, proteomics, and symptom data converge on immune, hormonal, inflammatory, vascular, and cellular remodeling pathways.
Why This Supports the Pelvic Overlap Spectrum
The Pelvic Overlap Spectrum is a clinical framework used by ESSI to understand complex pelvic pain and endometriosis across multiple active domains. It is not a new disease label. It is a better map.
As described in the ESSI Pelvic Overlap Spectrum framework, one patient may have endometriosis or adenomyosis alongside autonomic dysfunction, pelvic venous disorders, immune reactivity, connective-tissue phenotypes, neuropathic pain, GI-microbiome signaling, bladder symptoms, and intestinal motility problems.
The point is not that every patient has every condition. The point is that complex endometriosis often lives at the intersection of several systems, and good care requires asking which systems are active in the individual patient.
Figure 3. Pelvic Overlap Spectrum framework: one patient, multiple active domains. Alt text: Pelvic Overlap Spectrum diagram showing endometriosis and adenomyosis at the center of multiple overlapping domains, including reproductive outcomes, autonomic dysfunction, vascular disorders, immune reactivity, connective tissue phenotypes, neurologic dysfunction, GI axis, bladder hyperactivity, and intestinal motility disorder.
The 2026 multi-omics study strongly supports this approach because it shows that endometriosis risk is not funneled through one biological pathway. Instead, genetic risk converges on multiple pathways that align with what complex endometriosis clinicians see every day: immune dysregulation, hormone responsiveness, vascular remodeling, inflammatory amplification, tissue invasion/remodeling, and symptom networks that extend beyond the reproductive organs.
The Field Is Catching Up to What Patients Have Been Living
For decades, endometriosis was often framed too narrowly: find the lesions, assign a stage, suppress hormones, operate when necessary, and assume the disease had been adequately defined.
Lesions matter. Expert excision matters. But the lesion-only map has never fully explained why some patients have severe symptoms with limited visible disease, why pain can persist after technically successful surgery, why bowel, bladder, vascular, immune, autonomic, and neurologic symptoms cluster together, or why fertility and pregnancy outcomes vary so dramatically.
This is the point ESSI has been making for years. The new science does not suddenly make endometriosis systemic. It gives molecular language to a clinical reality that patients and high-volume endometriosis specialists have been observing all along.
It is encouraging to see the broader field now moving toward a systemic view. But the “bandwagon” only matters if it changes patient care. Endometriosis should not become a buzzword for multi-system disease while patients are still evaluated in one-specialty silos. The Pelvic Overlap Spectrum turns the concept into a practical clinical question: what is driving this patient’s symptoms right now, and what is amplifying them?
How This Aligns with the Martinelli-Vidali Translational Perspective
The 2025 Martinelli-Vidali article, Endometriosis: a cancer-mimicking disease and the need for a translational perspective, argued that endometriosis should not be treated as a uniform benign gynecologic disorder. The authors emphasized that endometriosis can display cancer-like molecular features, including proliferative behavior, angiogenesis, immune evasion, and invasive tissue behavior, and that the disease likely includes multiple biologic subtypes under one umbrella.
That perspective is important here because the new genetics paper identifies pathways that also fit a translational, cancer-mimicking framework: vascular development, tissue remodeling, immune regulation, hormone signaling, and cell-cycle/proliferation-related therapeutic targets.
Why this matters for research: If endometriosis is a heterogeneous disease family, then a single diagnostic marker, a single staging system, or a single treatment algorithm will always miss a large number of patients. The next era should be subtype-aware, symptom-aware, and systems-aware.
Symptoms Are Not “Extra” – They Are Part of the Biology
One of the most important findings in the Nature Genetics paper is that polygenic risk interacted with abdominal pain, anxiety, migraine, and nausea. In the All of Us cohort, these symptoms appeared to attenuate the effect of the endometriosis polygenic risk score, a finding the authors interpret cautiously because it was not statistically replicated in UK Biobank.
Clinically, this is still a powerful idea: severe systemic symptom burden may not be explained by genetics alone. Once disease is established, neuroimmune amplification, inflammatory state, vascular congestion, autonomic dysfunction, gut-bladder cross-talk, and central sensitization may become major drivers of suffering.
That is why a patient with “the same stage” of endometriosis can have a completely different lived experience from another patient. This is also why the Pelvic Overlap Spectrum is a practical clinical tool. It makes space for lesion-driven pain, but it also asks whether pain is being amplified by overlapping systems.
What This Means for Endometriosis Care
Figure 4. Clinical translation: from lesion-only staging to systems-based phenotyping. Alt text: Old map: endometriosis equals lesions. Pelvic Overlap Map: endometriosis equals heterogeneous multi-system disorder requiring layered care.
The takeaway is not that surgery is unimportant. The opposite is true: high-quality, meticulous excision remains essential for patients with surgically treatable disease. But surgery should not be the only map. It should be integrated into a broader systems-based assessment.
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Endometriosis and adenomyosis still require expert surgical and imaging evaluation when indicated.
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Fertility goals, ovarian reserve, miscarriage history, and pregnancy risk should be addressed early.
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Pelvic venous disease and hemodynamic contributors should be considered when symptoms suggest pressure, heaviness, postural worsening, or unexplained persistent pelvic pain.
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Autonomic symptoms such as tachycardia, dizziness, heat intolerance, and brain fog should not be ignored.
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Bladder urgency, IBS-type symptoms, dysmotility, and nausea should be treated as possible parts of a pelvis-gut-brain-immune network rather than incidental complaints.
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Persistent neuropathic pain should prompt evaluation for nerve involvement, central sensitization, and pelvic floor dysfunction.
Commentary by Dr. Andrea Vidali
“For years, I have argued that endometriosis is not one disease. It is a heterogeneous, multi-system disorder that can involve the immune system, the vascular system, the nervous system, the gastrointestinal system, the bladder, fertility, and hormone responsiveness all at once. This Nature Genetics paper is important because it gives molecular support to that reality. It shows that the biology of endometriosis is not linear. It is not simply lesion equals pain. It is a network.
The Pelvic Overlap Spectrum is my way of giving clinicians and patients a better map. It does not mean that every patient has every condition. It means that when a patient presents with endometriosis plus migraine, nausea, fatigue, bladder symptoms, bowel dysmotility, vascular symptoms, dysautonomia, or immune reactivity, we should not dismiss those symptoms as unrelated. We should ask how they interact.
It is interesting to watch the field now moving toward this systemic view. In many ways, everybody is finally jumping on the bandwagon. That is a good thing, but only if it becomes actionable. For too long, endometriosis was discussed as though it were only visible disease in the pelvis. Patients were told that if the lesion burden was small, their suffering should be small. That was never true clinically.
The future of endometriosis care must combine surgical excellence with systems thinking. We need excision when excision is indicated. But we also need to phenotype patients correctly, identify overlapping drivers, and treat the whole disease environment. That is the difference between treating lesions and treating the patient.”
What Patients Should Take From This
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Your symptoms are real, even when they do not fit neatly into one organ system.
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Stage does not always predict pain, infertility, fatigue, bowel symptoms, bladder symptoms, or systemic burden.
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A good endometriosis evaluation should include lesion mapping, but it should also consider overlap domains.
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Precision care means matching treatment to the dominant drivers in the individual patient.
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Genetics may help future research, but polygenic risk scores are not ready to diagnose endometriosis in clinical practice.
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The most important message is that complexity is not confusion. Complexity is information. The job of a modern endometriosis center is to organize that information into a treatment plan.
A Note on Future Treatments
The study also identified drug-repurposing signals involving hormonal, vascular, and cell-cycle pathways, including targets related to ESR1, PGR, KDR, CDKN2A, and TP53. Some candidate drugs are currently used in oncology, contraception, or preterm birth prevention.
These findings should not be interpreted as immediate treatment recommendations. They are research signals. Their value is that they point to druggable pathways beyond traditional empiric suppression and repeated surgery. In the long term, this could help move endometriosis toward biology-guided treatment selection.
FAQ: Endometriosis, Genetics, and the Pelvic Overlap Spectrum
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Is endometriosis genetic? Endometriosis has a genetic component, but it is not caused by one gene. The new study identified many risk regions, supporting a complex polygenic architecture rather than a single inherited cause.
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What is multi-omics? Multi-omics means integrating several layers of biology – such as DNA variation, gene expression, DNA methylation, and proteins – to understand how genetic risk translates into disease mechanisms.
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What is the Pelvic Overlap Spectrum? The Pelvic Overlap Spectrum is an ESSI clinical framework developed around the idea that complex pelvic pain often involves several active domains, including endometriosis, adenomyosis, autonomic dysfunction, vascular disorders, immune reactivity, neurologic pain, GI symptoms, bladder dysfunction, and fertility concerns.
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Does this mean endometriosis surgery is not important? No. Expert excision remains critical when lesions are surgically treatable. The point is that surgery should be integrated into a broader systems-based care plan, especially for patients with complex symptoms.
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Why can symptoms persist after surgery? Persistent symptoms may reflect residual or recurrent disease, but they may also involve overlapping pain conditions, central sensitization, vascular problems, bladder or bowel dysfunction, autonomic dysregulation, immune activation, or pelvic floor dysfunction.
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Is adenomyosis the same as endometriosis? No. The two conditions overlap genetically and clinically, but the new study suggests they are related rather than identical.
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Will genetics soon diagnose endometriosis? Not yet. The study shows important genetic risk architecture, but the authors note that current polygenic risk scores are not sufficient for diagnostic use.
References
[1] Koller D, He J, Lokhammer S, et al. Multi-ancestry genome-wide association and integrated multi-omics analyses of endometriosis and its clinical manifestations. Nature Genetics. 2026.
[2] Martinelli C, Vidali A, Di Chiara F, Mazzarotti G, El Messaoudi S, Alfano L, Ercoli A, Giordano A. Endometriosis: a cancer-mimicking disease and the need for a translational perspective. Annals of Research in Oncology. 2025;5(2):75-94.
[3] Endometriosis Surgical Specialists International. The Pelvic Overlap Spectrum: A New Map for Complex Pelvic Pain. InternationalEndo.com. Published April 28, 2026.
[4] Taylor HS, Kotlyar AM, Flores VA. Endometriosis is a chronic systemic disease: clinical challenges and novel innovations. Lancet. 2021;397:839-852.
[5] Rahmioglu N, et al. The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions. Nature Genetics. 2023;55:423-436.
[6] Bartley EJ. Beyond the Lesions: Unraveling the Multifactorial Nature of Endometriosis and Chronic Overlapping Pain. ARCH Women Health Care. 2024;7(4):1-2.
Medical disclaimer: This article is for educational purposes only and should not replace individualized medical evaluation or treatment advice.
