Endometriosis is a chronic, incurable systemic inflammatory disease that affects approximately 10% of women of reproductive age. Although it is best known to cause severe pelvic pain, its symptoms can also include migraine, digestive problems, anxiety, and depression, which may be interpreted as unrelated conditions.

The broad range of symptoms and difficulty in establishing a diagnosis contribute to substantial underdiagnosis and diagnostic delays that can last for years. The condition can, therefore, have a profound effect on physical and mental health and quality of life.

To better understand the varied ways endometriosis can present, researchers at the Institut de Recerca Sant Pau in Barcelona, Spain, analyzed clinical and health data from women with endometriosis enrolled in the US-based All of Us research program, one of the world’s largest population-based biobanks. These findings were published in Human Reproduction.

Diagnostic Challenges

Speaking with Univadis Spain, part of the Medscape Professional Network, Dora Koller, PhD from the Perinatal and Women’s Health research group at Institut de Recerca Sant Pau, and lead author of the study, said, “The definitive diagnosis of endometriosis has traditionally relied on laparoscopy, a surgical procedure that allows lesions to be visualized but is invasive and carries risks, costs, and a long recovery period. Many women do not have access to it. Transvaginal ultrasound and MRI are now also used; although useful for some forms of the disease, they have limitations in detecting superficial lesions.”

Endometriosis presents a second challenge: a delayed diagnosis. “There is a delay of between 4 and 11 years in diagnosis caused by several factors: Symptoms vary greatly from one woman to another and are often downplayed or attributed to nonspecific causes. For example, severe menstrual pain has long been considered normal. Furthermore, when digestive, neurologic, or psychological symptoms predominate, they are not linked to endometriosis, and the patient is referred to various specialists without a common explanation. Added to this is the fact that a definitive diagnosis used to depend on invasive surgery and that historically, women’s pain has been trivialized and stigmatized,” Koller said.

Widespread Underdiagnosis

Sex bias, limitations in diagnostic techniques, and prolonged delays in diagnosis contribute to widespread underdiagnosis. “Official estimates indicate that around 10% of women of reproductive age, some 190 million worldwide, have endometriosis. However, in our study, only 1.92% of patients had a clinically confirmed diagnosis. This figure increased to 5.67% when we included cases self-reported by the patients themselves. Even in a large database, the disease appears to be far below its actual prevalence, reflecting underdiagnosis. That is why self-reported data are so valuable: Patients correctly identify their condition about 84% of the time,” said Koller.

Given these diagnostic challenges, symptom assessment is increasingly recommended as the starting point because endometriosis can present with a wide range of symptoms.

The researchers identified distinct symptom patterns and examined how they relate to quality of life and disease severity. “We used data from All of Us, one of the largest population-based biobanks in the US. We included 22,438 women with endometriosis documented in their medical records or self-reported data. From this group, we defined a subgroup of 5542 premenopausal women aged 18-45 years to reduce confounding from menopause. We also analyzed two additional subgroups: 1797 women with clinically confirmed endometriosis without adenomyosis and 643 with endometriosis and adenomyosis. However, we were unable to analyze adenomyosis alone because the sample size was insufficient for robust analysis,” said Koller.

Four Symptom Patterns

The analysis included 19 symptoms and comorbidities associated with endometriosis, including chronic pelvic pain, abdominal pain, gastrointestinal symptoms, migraine, anxiety, depression, chronic fatigue, infertility, and irritable bowel syndrome.

Four major symptom patterns were identified in this study. The first group, comprising 18.8% of women, reflected a high disease burden with severe pain, gastrointestinal symptoms, and mood disturbances. The second group, accounting for 30%, had moderate symptoms, mainly involving pain and emotional distress. The third group, comprising 29.6%, was characterized by psychological and neurologic symptoms, including anxiety, depression, and migraine. The fourth group, comprising 20.6%, had a much lower symptom burden.

“These results were consistent with our initial hypothesis. We expected to find profiles dominated by pain and high symptom burden, which was what we observed. However, these findings were unexpected. First, we identified a distinct psychological and neurologic profile characterized by migraine, anxiety, and depression. This was particularly striking because it challenges the view of endometriosis as a purely gynecologic disease and suggests that some young women with these symptoms may remain undiagnosed. Second, among women of reproductive age, most had well-defined symptom profiles, while fewer had an ‘asymptomatic’ profile than expected. We were also surprised that the low symptom burden profile was almost absent among women with associated adenomyosis, with almost all having a high symptom burden,” said Koller.

These findings suggest that endometriosis may present in ways that do not fit the typical focus on pelvic or menstrual pain. “Endometriosis does not always present the way we expect, and these symptoms may first appear in women seeking care for other physical symptoms. If we continue to focus solely on pelvic or menstrual pain, we risk overlooking many patients,” Koller said.

Clinical Implications

Identifying distinct symptom patterns could help reduce underdiagnosis and shorten the time to diagnosis. When gastrointestinal, neurologic, or psychological symptoms are the main complaints, their potential connection to endometriosis may be overlooked. This can lead to repeated consultations with different specialists before the symptoms are recognized as part of the same condition.

An individual may initially seek care for recurrent migraine, digestive discomfort, anxiety, fatigue, or chronic pain, without these symptoms being linked to endometriosis. As a result, an individual may visit several specialists before receiving a definitive diagnosis.

“Many patients spend years searching for an explanation for symptoms that are evaluated in isolation. Recognizing that endometriosis can manifest in very different ways could help identify it earlier and reduce years of uncertainty for many women,” said Koller.

“One of the main lessons from the study is the need to adopt a more comprehensive view of the disease. If a woman experiences menstrual pain along with migraine, digestive symptoms, or mental health issues, it is important to consider whether these manifestations are connected. Often, they are evaluated separately, even though they may be part of the same clinical picture. Greater awareness of this clinical diversity could lead to earlier recognition of the condition, particularly in primary care, where initial consultations typically occur. It could also facilitate faster referral to appropriate specialists and shorten the time between symptom onset and treatment, ultimately improving the quality of life for women with this condition,” concluded Koller.

Koller reported having no relevant conflicts of interest. The authors’ conflicts of interest are reported in the original study publication. 

This story was translated from Univadis Spain.