Endometriosis Links to Inflammatory Conditions and Other Diseases

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When treating patients with endometriosis, clinicians should bear in mind the association with serious comorbidities, including immune-related and cardiovascular problems, as well as a small increase in cancer risk.

"Evidence is building that endometriosis does not simply affect gynecologic and reproductive health, but also impacts multiple systems and health across women's lives," said reproductive biologist Stacey A. Missmer, ScD, of Michigan State University in Grand Rapids and Harvard T.H. Chan School of Public Health in Boston. With more than 80% of patients at risk for such non-gynecologic symptoms as fatigue, hypertension, hypercholesterolemia, migraine, fibromyalgia, and joint pain, "gynecologists should be dialoguing with their patients about the many other systems affected," she said.

Immune-Mediated Problems

One of the stronger comorbid associations is with autoimmune disease: "Endometriosis is not considered an autoimmune disease, but it has been consistently associated with several immune system abnormalities – for example, higher rates of peritoneal neutrophils, macrophages, and many antibodies, as well as reduced cytotoxic function of natural killer cells, including aberrant rates of T and B lymphocytes," explained Marina Kvaskoff, PhD, of Paul-Brousse Hospital in Villejuif, France. "However, we don't know whether these anomalies are a cause or a consequence of endometriosis due to the chronic inflammatory response to the presence of endometriosis lesions."

Christine Metz, PhD, of the Feinstein Institutes for Medical Research in Manhasset, New York, pointed to a 2021 study in Nature by Valeria Stella Vanni and colleagues, which found that endometriosis patients with autoimmune disease are likely to have more severe endometriosis than their unaffected counterparts without autoimmune disease. "Clearly, additional research is needed to better understand these associations," Metz said.

It's not clear whether the same underlying pro-inflammatory genetic landscape that predisposes to endometriosis and inhibits the clearance and allows ectopic implantation of extrauterine endometrial cells also predisposes to other immune-related conditions, Missmer said. "Are these manifestations due to a fundamental immune dysfunction that allows the establishment of ectopic endometriotic lesions, or does the local and systemic immune response that directs these lesions also catalyze risk for other conditions? At this point we're not sure."

In terms of the published literature, she said, the strongest studied connection is between endometriosis and rheumatoid arthritis and lupus. "In the real world, asthma and allergies are the most common immune comorbidities, but these have not received as much research attention."

As to the temporal order in which endometriosis versus associated conditions occur, "the reality is that most other conditions are being diagnosed after endometriosis given our current medical system and diagnostic technology and patterns," Missmer said. "We don't yet have the ability to diagnose these before they manifest overtly, but we do know that young adolescents who have asthma are at higher risk of developing endometriosis."

Missmer is co-author of a 2019 systematic review and meta-analysis of studies quantifying an association between endometriosis and several autoimmune diseases. While only five of the 26 eligible studies included could provide high-quality evidence of correlation, four of these supported a statistically significant association with at least one of the following autoimmune disorders: systemic lupus erythematosus Sjogren's syndrome, rheumatoid arthritis, celiac disease, multiple sclerosis, and inflammatory bowel disease.

Examining preliminary results from an analysis of U.K. Biobank data on 273,404 women, the authors found a statistically significantly increased risk of the following autoinflammatory conditions:

• Systemic lupus erythematosus: odds ratio (OR) 1.56 (95% CI 1.10-2.15, P=0.009)

• Multiple sclerosis: OR 1.31 (95% CI 1.00-1.67, P=0.042)

• Inflammatory bowel disease: OR 1.23 (95% CI 1.02-1.46, P=0.023)

• Celiac disease: OR 1.26 (95% CI 0.99-1.58, P=0.048)

• Myasthenia gravis: OR 2.19 (95% CI 1.12-3.85, P=0.012)

• Behcet's syndrome: OR 9.22 (95% CI 3.38-21.51, P<0.001)

• All immunological diseases combined: 9% higher risk, OR 1.09 (95% 1.03-1.14, P=0.002)

Significantly increased risk also emerged for:

• Autoinflammatory diseases: 6%

• Classic autoimmune disease: 15%

• Mixed-pattern autoimmune disease: 19%

Clarifying the association between endometriosis and immunological disease should help shed light on the causes and consequences of both disorders to inform clinical practice and research. Well-designed large prospective cohort studies with confounding control and mediation quantification, as well as genetic and biological studies, are needed to generate further insights into whether endometriosis is a risk factor for, or a consequence of, autoimmune diseases, and whether these two types of disorders share pathophysiological mechanisms even if they arise independently. Researchers foresee opportunities for developing novel non-hormonal medications such as immunomodulators or repurposing of existing immunomodulatory therapies for endometriosis.

Cardiovascular Disease

Endometriosis has been associated with a higher risk of stroke and cardiovascular disease (CVD). According to Missmer, the association is likely attributable both to systemic chronic inflammation and endometriosis treatments. "There is likely interaction between the inflammation and the angiogenic and cholesterol systems. The inflammatory pathway is also being explored by researchers," she said. "But about 40% of heart disease risk is explained by the high rate of early hysterectomy-oophorectomy in endometriosis patients."

In addition, the androgenic, deep menopause-like state produced by some estrogen-suppressing agents may play a role, but the main driver appears to be oophorectomy-related. Add-back hormonal therapy to mitigate bone loss and menopausal symptoms may possibly be of benefit but also has its risks, Missmer said.

In a 2016 prospective study, Missmer and fellow Harvard researchers identified an increased risk of coronary artery disease in women with endometriosis -- particularly those age 40 and younger.

The team analyzed data from the Nurses' Health Study II, which included 116,000 women age 25 to 42 who had no history of heart disease or stroke. Over a 20-year period, nearly 1,500 women in the study developed coronary artery disease. Compared with unaffected women, those who had confirmed endometriosis had:

• 52% greater risk for heart attack

• 91% greater risk of chest pain

• 35% greater risk of undergoing heart surgery

"Since our study, the data have been sparse, but a few have also shown increased risk with endometriosis," Missmer said, noting that in 2021 Li and colleagues reported a 1.64 RR for a transient ischemic attack in women with endometriosis and Wei and co-researchers found a 1.52 RR for a coronary artery disease event.

Also in 2021, in a large population study of U.K. women, Okoth and associates compared CVD risk in women with and without endometriosis and reported the following adjusted hazard ratios for CVD outcomes:

• Composite CVD 1.24 (95% CI 1.13-1.37)

• Ischemic heart disease 1.40 (95% CI 1.22-1.61)

• Cerebrovascular disease 1.19 (95% CI 1.04-1.36)

• Heart failure 0.76 (95% CI 0.54-1.07)

• Arrhythmia 1.26 (95% CI 1.11-1.43)

• Hypertension 1.12 (95% CI 1.07-1.17)

• All-cause mortality 0.66 (95% CI 0.59-0.74)

Interestingly, the study found that the incidence of endometriosis per 10,000 person-years was 12.3 in 1998 and 11.5 in 2017. The prevalence of endometriosis increased from 119.7 per 10,000 population in 1998 to 201.3 per 10,000 population in 2017.

The researchers noted that endometriosis has been linked to factors that also promote heart disease, including chronic inflammation and high levels of low-density lipoprotein cholesterol, and that while endometriosis symptoms often abate after menopause, the risk factors remain.

"Doctors should consider hysterectomy, oophorectomy, and postmenopausal hormone therapy carefully among endometriosis patients given this heightened risk, along with other long-term health risks associated with these procedures/treatments," Kvaskoff said.

Even young women with endometriosis should receive cardiac risk assessment and be advised to reduce their other risk factors, particularly by avoiding tobacco, following a healthy eating plan, and getting at least 30 minutes of moderate exercise daily, she added.

Cancer

Missmer said that although endometriosis is associated with some increase in cancer risk, the relative rise is small and lifetime absolute risk (AR) is very low.

"While there's a slight increase in ovarian cancer risk particularly with endometriomas, removing the ovaries to reduce this risk will increase the far greater risk of heart disease," she said.

There is also a negligible 4% relative rise in breast cancer risk and a more significant 39% rise in thyroid cancer risk. "Interestingly, the risk of cervical cancer is reduced by 32% in endometriosis patients. This is likely due not to any direct cause but to the attentive gynecologic screening and care that pick up early changes in the cervical cells before cancer develops," Missmer explained, adding that it is also possible that estrogen suppression may inhibit cancer development. It's also possible that the higher hysterectomy rates in endometriosis patients contribute to lower cervical cancer, since the cervix is likely to be removed with hysterectomy.

In a 2020 systematic review and meta-analysis of endometriosis and cancer, Kvaskoff and colleagues found the following risk elevations for several cancers compared with women in the general population:

• Ovarian cancer: RR up 5.4%; AR up 1.2% from 1.3% to 2.5%

• Thyroid cancer: RR up 39%; AR up 0.5% from 1.3% to 1.8%

• Breast cancer: RR up 4%; AR up 0.5% from 12.8% to 13.3%

As noted, cervical cancer risk was lower in patients, with an RR decrease of 32%, due likely to early detection of dysplasia during regular gynecologic care. "Not many women with endometriosis will develop cancer. Translated into absolute risks, data suggest that cancer risk is indeed low," said Kvaskoff, noting the following:

• If 1.3 in 100 women in the general female population will develop ovarian cancer in their lifetime, this number goes up to 2.5% among women with endometriosis, which means that 97.5% of endometriosis patients will not develop ovarian cancer

• Breast cancer affects 12.8 in 100 women from the general population and 3.3 in 100 women with endometriosis

• Thyroid cancer affects 1.3 in 100 women from the general population and 13.8 in 100 women with endometriosis

"There is no genetic link between endometriosis and ovarian cancer," said Metz. Approximately 1 in 76 women overall will develop ovarian cancer over their lifetime compared with approximately 1 in 56 women with endometriosis. "These rates are both very low when compared with the genetic-based risk of ovarian cancer for BRCA1 mutation carriers, which is high at 22% to 65%," she said.

Of possible concern, however, is the observation in a review by Amy Dawson and colleagues that mutations present in endometriosis-associated cancers can be found in adjacent endometriotic lesions. "Recent genomic studies, placed in context, suggest that deep-infiltrating endometriosis may represent a benign neoplasm that invades locally but rarely metastasizes," the authors wrote.

Careful research is needed to clarify any connection between endometriosis and a range of malignancies. In the meantime, clinicians should reassure endometriosis patients that their added risk of cancer remains low and even declines for cervical cancer with regular care.

Patients should, however, be made aware of general cancer risk factors and, again, be advised to focus on overall wellness to reduce cancer risk, including not smoking, maintaining a healthy weight, exercising regularly, eating a diet high in fruits and vegetables, minimizing alcohol intake, and using sun protection.

Evolving molecular techniques may soon help clarify the shared link between endometriosis and the above conditions and lead to novel non-hormonal and non-surgical treatments. Better diagnosis is also key. "A non-invasive screening or diagnostic method is seriously needed and would likely significantly improve the diagnosis of endometriosis and reduce the time to diagnosis, which is a major problem for endometriosis patients," Metz said.

Her laboratory is now developing a noninvasive screening method based on assessment of menstrual effluent for predicting endometriosis.

Read previous installments of this series:

Part 1: Endometriosis: Understanding the Pathogenesis and Pathophysiology

Part 2: Diagnosing Endometriosis

Part 3: Managing Endometriosis: Research and Recommendations

Part 4: Case Study: Endometriosis or Hernia?

Part 5: Endometriosis: Fertility and Pregnancy

Part 6: The Latest on What to Know About Managing Endometriomas

Part 7: Enhancing the Doctor-Patient Dialogue About Endometriosis

Part 8: Case Study Mystery: Swollen, Painful Belly Button During Menstruation

Part 9: Endometriosis: Why Is Research Funding So Low?