Endometriosis Subtypes Linked to Distinct Risk Factors and Comorbidities

Endometriosis lesion subtypes display distinct risk factor and comorbidity profiles, according to a pooled cross-sectional analysis of 1,244 surgically confirmed participants published online on August 25, 2026. Researchers found that younger age at menarche and chronic overlapping pain conditions show strong positive associations with specific subtypes.

A pooled cross-sectional analysis of 1,244 participants with surgically confirmed endometriosis and 1,271 control individuals without the condition from three population-based studies—two in the US and one in the UK (A2A, ENDO, and ENDOX)—has revealed that different lesion macrophenotypes carry distinct risk factor and comorbidity profiles. Published online on August 25, 2026, in the American Journal of Obstetrics and Gynecology (doi:10.1016/j.ajog.2026.08.026), the findings point toward underlying differences in etiology or pathophysiology across subtypes, potentially changing how clinicians evaluate symptoms.

Patient Cohort Breakdown and Surgical Classification

The study pooled data from three population-based cohorts. Endometriosis cases were classified based on the surgically visualized lesion macrophenotype as:

Superficial peritoneal endometriosis (SPE) only, accounting for 71% of cases
At least one endometrioma, making up 8%
At least one deep lesion, representing 11%
Both deep lesions and endometriomas, totaling 10%

Distinct Risk Factor And Comorbidity Profiles Tied 2026a1000x6q

Participants completed standardized questionnaires capturing menstrual and reproductive history, early-life factors, and co-existing comorbidities such as chronic overlapping pain conditions and immune-related conditions. Researchers assessed the association between various factors, including menstrual and reproductive characteristics and demographic characteristics, and surgically confirmed endometriosis. Financial support for establishment of and data collection within the A2A cohort was provided by the J. Willard and Alice S. Marriott Foundation. The study was supported by funding in whole or in part by the National Institutes of Health and from the National Institute of Child Health and Human Development, with one author reporting receiving support from the National Institute of Child Health and Human Development. The authors reported having no relevant conflicts of interest.

Menarche Age and Pain Conditions as Subtype Risk Factors

The data demonstrated that a younger age at menarche (≤11 years vs 12 years) was associated with higher odds of endometriosis (odds ratio [OR], 1.35; 95% CI, 1.08-1.68). This risk concentrated particularly in patients with SPE only (OR, 1.29; 95% CI, 1.01-1.65) and deep lesions plus endometriomas (OR, 2.07; 95% CI, 1.11-3.86). Broader evidence indicates that women are also at higher risk for endometriosis if they have a mother, sister, or daughter with endometriosis, have short monthly cycles (less than 27 days), have heavy menstrual periods that last more than 7 days, or are infertile. Some studies suggest that having a lean body mass or low body fat may increase a woman’s risk for endometriosis.

Chronic overlapping pain conditions showed positive associations with specific lesion types. The presence of at least one chronic overlapping pain condition was linked to increased odds of endometriosis overall (OR, 1.66; 95% CI, 1.49-1.85 per condition), SPE only (OR, 1.80; 95% CI, 1.59-2.04 per condition), and deep lesions (OR, 1.76; 95% CI, 1.44-2.15 per condition). In clinical practice, chronic overlapping pain conditions such as migraine, irritable bowel syndrome, bladder pain syndrome, and fibromyalgia frequently coexist with endometriosis, can amplify pain burden, complicate diagnosis, and influence treatment planning, so clinicians often assess for multisystem pain and central sensitization when evaluating persistent pelvic pain. Immune-related conditions were positively associated with SPE only (OR, 1.21; 95% CI, 1.08-1.35 per condition).

Inverse Association With Depression and Divergent Clinical Presentations

What are the risk factors for endometriosis

In an unexpected divergence from other pain comorbidities, depression or mood disorders were inversely associated with endometriomas (OR, 0.49; 95% CI, 0.27-0.87). This association persisted after adjusting for concurrent life-impacting pelvic pain (OR, 0.39; 95% CI, 0.22-0.71). Such variations reinforce the hypothesis that different subtypes manifest through unique biological pathways rather than a uniform disease process.

“[The study] findings provide novel evidence that endometriosis macrophenotypes may have distinct risk factor profiles, suggesting differences in etiology or pathophysiology. The patterns of co-existing conditions also differ by endometriosis macrophenotype, suggesting that clinical manifestation and presentation may differ by macrophenotypes,” the authors wrote.

A woman sits beside her healthcare provider as they consult a medical illustration of the female reproductive system on the — Photo: nichd.nih.gov

The study was led by Naoko Sasamoto, MD, PhD, of the Public Health Sciences Division at the Fred Hutchinson Cancer Center in Seattle, and Amy L. Shafrir of the School of Nursing and Health Sciences at Merrimack College in Andover, Massachusetts.

Methodological Limitations and Next Steps in Research

Despite the robust sample size, the study design carried notable limitations. The study design prevented determination of temporality between some risk factors and diagnosis of endometriosis. Additionally, the control groups might have included undiagnosed endometriosis cases. Future investigations will need to address how these distinct macrophenotypes alter long-term diagnosis and treatment planning in clinical practice.