What causes endometriosis?

Endometriosis is a chronic condition in which tissue similar to the lining of the uterus (endometrium) grows outside the uterine cavity. This misplaced tissue can implant on the ovaries, fallopian tubes, pelvic lining, bladder, intestines and, in rare cases, other organs. Although endometriosis affects up to 10 percent of reproductive-age women, its exact cause remains unclear. Research points to a combination of biological, genetic and environmental factors. Understanding these factors can help explain why endometriosis develops and guide discussions with your healthcare provider.

Causes and Theories
Researchers have proposed several theories to explain the development of endometriosis. No single theory accounts for every case; instead, multiple mechanisms likely act together.

1. Retrograde Menstruation
   • During menstruation, some menstrual blood flows backward through the fallopian tubes into the pelvic cavity rather than out through the vagina.
   • Viable endometrial cells in this blood may attach to peritoneal surfaces and grow.
   • Although most women experience some retrograde flow, only a subset develops endometriosis, implying that additional factors (immune response, genetics) play a role.
   • (Bulun SE. Endometriosis. N Engl J Med. 2009;361:2389–2398.)

2. Coelomic Metaplasia
   • Cells lining the pelvic organs and peritoneum (coelomic epithelium) have the potential to transform into endometrial-like cells under certain stimuli.
   • This conversion could explain rare cases in men or pre-menarchal girls.

3. Müllerian Remnant Theory
   • During embryonic development, tissues destined to become parts of the reproductive tract may be misplaced.
   • These remnants could later differentiate into endometrial tissue.

4. Stem Cell and Bone Marrow Theory
   • Bone marrow–derived stem cells might give rise to endometrial tissue deposits in ectopic locations.
   • Stem cell migration via blood or lymphatic vessels could explain distant implants (e.g., lung, brain).

5. Lymphatic and Vascular Dissemination
   • Endometrial cells can spread through lymphatic channels or blood vessels.
   • This mechanism may account for rare, distant sites of endometriosis.

Risk Factors
Certain factors increase the likelihood of developing endometriosis, although they do not guarantee it:

• Family History
– Having a first-degree relative (mother, sister) with endometriosis raises risk by three- to ninefold (Giudice LC. Clin Pract. Lancet. 2010;364:1789–1799).
• Early Menarche or Short Menstrual Cycles
– More frequent periods lead to more opportunities for retrograde flow.
• Nulliparity or Delayed Childbearing
– Pregnancy and breastfeeding reduce the number of menstrual cycles, potentially lowering risk.
• Heavy or Prolonged Menstrual Flow
– Increases the volume of retrograde menstrual fluid.
• Hormonal Imbalances
– Estrogen dominance promotes growth and survival of ectopic endometrial tissue.
– Progesterone resistance may impair the ability to control tissue proliferation.
• Immune System Dysfunction
– Altered immune surveillance may fail to clear misplaced endometrial cells.
– Chronic inflammation in the pelvic environment can foster implant growth.
• Environmental Exposures
– Some studies suggest a link between exposure to dioxins or other toxins and endometriosis, but data remain inconclusive.

Genetic and Molecular Contributors
Endometriosis has a strong hereditary component, but no single “endometriosis gene” has been identified. Modern techniques (genome-wide association studies) have uncovered multiple susceptibility loci:

• POLYGENIC Inheritance
– Variants in several genes, each with small effect, increase risk.
• Epigenetic Changes
– DNA methylation and histone modifications can alter gene expression without changing DNA sequence.
– These changes may influence estrogen receptors and inflammatory pathways.
• Cytokine and Growth Factor Imbalance
– Elevated levels of pro-inflammatory cytokines (e.g., interleukin-1, tumor necrosis factor) create a local environment favorable to implant survival.
– Increased vascular endothelial growth factor (VEGF) promotes angiogenesis (formation of new blood vessels), nourishing ectopic tissue.

Hormonal Influences
Endometriosis is an estrogen-dependent disease. Estrogen promotes the growth and maintenance of endometrial tissue both inside and outside the uterus. Key points include:

• Local Estrogen Production
– Ectopic implants express aromatase, the enzyme that converts androgens to estrogens, leading to high local estrogen levels even when systemic levels are normal.
• Progesterone Resistance
– Endometrial tissue in endometriosis often shows reduced responsiveness to progesterone, a hormone that normally counterbalances estrogen’s effects.
• Hypothalamic-Pituitary-Ovarian Axis
– Disruptions in this hormonal axis may contribute to abnormal hormone levels and impaired ovulation, exacerbating symptoms.

Immune System and Inflammation
The immune system normally clears misplaced cells, but in endometriosis this surveillance appears defective:

• Reduced Natural Killer (NK) Cell Activity
– NK cells in the peritoneal fluid of women with endometriosis may be less effective at destroying ectopic endometrial cells.
• Macrophage Dysfunction
– Peritoneal macrophages can secrete growth factors and cytokines that support endometrial cell survival and invasion.
• Chronic Inflammation
– Persistent inflammatory milieu causes pain, scarring (adhesions) and can affect fertility.

Environmental and Lifestyle Factors
Although genetics and biology are primary drivers, environmental and lifestyle factors may modulate risk:

• Toxin Exposure
– Animal studies link dioxin exposure to endometriosis-like lesions; human data are mixed.
• Diet and Nutrition
– Diets high in red meat and trans fats may increase risk, while omega-3 fatty acids and fruits/vegetables could have protective effects.
• Physical Activity
– Regular exercise may lower estrogen levels and reduce inflammation, possibly lowering risk.

Putting It All Together
Endometriosis likely arises from the interplay of genetic predisposition, hormonal environment, immune function and environmental exposures. No one cause is responsible; instead, several overlapping mechanisms converge to allow endometrial-like tissue to implant and grow outside the uterus. Key takeaways:

• Multiple Theories: Retrograde menstruation, metaplasia, stem cell spread and lymphovascular dissemination all contribute.
• Genetic Susceptibility: Polygenic inheritance and epigenetic changes heighten risk.
• Hormones: Estrogen dependence and progesterone resistance fuel lesion growth.
• Inflammation: Immune dysfunction and chronic inflammation sustain disease.
• Environment & Lifestyle: Diet, exercise and toxin exposure may modulate development.

If you suspect you may have endometriosis, it’s important to assess your symptoms early. You might consider doing a free, online “symptom check” to help clarify your concerns and guide your next steps.

Remember: only a medical professional can diagnose endometriosis definitively, usually through imaging studies or laparoscopy. Symptoms such as severe pelvic pain, painful periods, pain during intercourse or infertility warrant evaluation. Speak to a doctor about anything that could be life-threatening or seriously affecting your quality of life. A tailored treatment plan—ranging from pain management and hormonal therapy to surgery—can help you regain control and improve your well-being.