Endometriosis has no single, definitive cause. Despite affecting roughly 10% of reproductive-age women worldwide (about 190 million people), the condition remains one of the most poorly understood in reproductive health. What researchers do know is that several biological processes likely work together: reversed menstrual flow, immune system dysfunction, genetic predisposition, hormonal influences, and possibly environmental exposures. Most experts believe endometriosis develops when multiple factors converge in the same person, which helps explain why diagnosis still takes an average of 5 to 12 years from the time symptoms begin.
Retrograde Menstruation: The Oldest Theory
The most widely cited explanation is retrograde menstruation, the idea that during a period, some menstrual blood flows backward through the fallopian tubes and into the pelvic cavity instead of leaving the body. This blood carries fragments of the uterine lining, which then attach to pelvic organs and tissues and begin growing outside the uterus.
The problem with this theory on its own is that retrograde menstruation happens in up to 90% of menstruating women, yet only about 10% develop endometriosis. So backward flow alone doesn’t explain the disease. Something else has to determine why certain women’s bodies allow those displaced tissue fragments to implant, survive, and grow, while most women’s bodies simply clear them away.
The Immune System’s Role
That “something else” appears to involve the immune system. In women with endometriosis, the body’s cleanup crew doesn’t work the way it should. Normally, immune cells called natural killer cells and macrophages would recognize misplaced tissue and destroy it. In endometriosis, both of these cell types are dysfunctional. Natural killer cells have reduced ability to kill abnormal cells, and macrophages shift into a repair-and-growth mode instead of a search-and-destroy mode.
At the same time, the immune environment around endometriosis lesions is flooded with inflammatory signaling molecules. Some of these signals promote inflammation and pain, while others suppress the immune response that would normally eliminate the displaced tissue. This contradictory mix of inflammation and immune suppression creates conditions where endometrial-like tissue can survive in places it doesn’t belong, build its own blood supply, and keep growing. Some researchers have even found that the body produces autoantibodies (immune proteins that mistakenly target the body’s own tissue), which has led some to frame endometriosis as a condition with autoimmune-like features.
Genetics and Family Risk
Endometriosis runs in families, and the numbers are striking. Women who have a mother or sister with surgically confirmed endometriosis are 5 to 7 times more likely to develop it themselves. One study found that 8.1% of sisters of affected women had the disease, compared to just 0.9% of women with no family connection. In cases of severe endometriosis, the relative risk for sisters climbs even higher, up to 15 times the baseline risk. Even cousins show a modestly elevated risk, about 1.5 times the general population.
No single “endometriosis gene” has been identified. Instead, large-scale genetic studies have found dozens of small genetic variations, each contributing a small amount of risk. Many of these variations are in genes involved in hormone signaling, cell growth, and immune regulation. This genetic complexity means endometriosis is not inherited in a simple, predictable pattern. Having a family history raises your risk significantly, but it doesn’t guarantee the disease will develop.
Epigenetic Changes in Endometriosis Tissue
Beyond the DNA you’re born with, the way genes are switched on or off also matters. Researchers have found widespread differences in these chemical “switches” (called DNA methylation patterns) when comparing endometriosis lesions to normal uterine lining. In general, endometriosis tissue shows abnormal activation of genes involved in cell adhesion, cell growth, and response to hormones, while genes that would normally keep tissue growth in check are silenced.
For example, endometriosis lesions show changes in the activity of genes that control how cells respond to progesterone, a hormone that normally counterbalances estrogen’s growth-promoting effects. When progesterone signaling is dialed down, tissue becomes more responsive to estrogen and more prone to unchecked growth. Researchers have also found that genes controlling enzymes responsible for tissue remodeling are abnormally activated in lesions, which may help explain how endometriosis invades surrounding tissue. These epigenetic changes could be influenced by hormones, inflammation, or environmental exposures, tying multiple causal theories together.
Cell Transformation and Stem Cells
Not all endometriosis can be explained by menstrual tissue landing in the wrong place. The condition has been found in rare cases in people who have never menstruated, including in men and in girls before puberty. This led to an alternative theory: that cells lining the pelvic cavity can transform into endometrial-like tissue on their own, a process called coelomic metaplasia. The idea is grounded in embryology. The uterine lining and the tissue lining the pelvis both originate from the same type of cell during fetal development, so under certain conditions, pelvic lining cells may “switch” back to behaving like uterine cells.
A newer theory focuses on stem cells. The uterine lining contains stem cells that regenerate it every month after a period. These stem cells, along with stem cells from bone marrow, may travel to ectopic sites through the fallopian tubes, the bloodstream, or the lymphatic system. Once there, they can differentiate into the various cell types found in endometriosis lesions, including glandular cells, stromal cells, and even smooth muscle cells. This stem cell theory helps explain how endometriosis can appear in distant, unusual locations like the lungs or brain, places that retrograde menstruation alone cannot account for.
Estrogen and Hormonal Drivers
Regardless of how endometriosis starts, estrogen is the fuel that keeps it going. Endometriosis lesions are estrogen-dependent, meaning they grow and become more active when estrogen levels are high and tend to shrink when estrogen is low (such as after menopause). What makes this worse is that endometriosis lesions can produce their own estrogen locally, creating a self-sustaining cycle of growth even when the ovaries are producing normal hormone levels.
At the same time, endometriosis tissue often shows reduced sensitivity to progesterone, the hormone that normally opposes estrogen and limits tissue growth in the uterus. This combination of excess estrogen signaling and progesterone resistance is one of the central hormonal imbalances driving the disease. It also explains why many treatments for endometriosis work by suppressing estrogen or mimicking progesterone’s effects.
Environmental Exposures
A growing body of research links endometriosis risk to environmental chemicals that interfere with the body’s hormone system. These endocrine-disrupting chemicals mimic or block natural hormones, particularly estrogen, and are found in everyday products and industrial byproducts.
- Dioxins: Byproducts of industrial processes like paper bleaching and fossil fuel combustion. A potential link to endometriosis was first identified in 1993 when the disease appeared in a colony of dioxin-exposed monkeys. Human studies have been inconsistent, but the association remains an active area of investigation.
- Bisphenol A (BPA): Found in plastics, food container linings, and thermal receipts. Women with ovarian endometriosis have been found to have higher urinary BPA concentrations. Animal studies show that even low-level BPA exposure can enhance the development of endometriosis lesions.
- Phthalates: Used in plastics, personal care products, and fragrances. Multiple studies report an association between phthalate exposure and endometriosis.
- DES (diethylstilbestrol): A synthetic estrogen prescribed to pregnant women from the 1940s to 1970s. Some evidence suggests women exposed to DES in the womb have a slightly increased risk of endometriosis.
None of these chemicals has been proven to cause endometriosis on its own. The concern is that chronic, low-level exposure to multiple hormone-disrupting chemicals may tip the balance in women who are already genetically or immunologically susceptible.
Why There’s No Single Answer
Endometriosis is almost certainly not caused by one mechanism. The current understanding is that it arises from a combination of factors: menstrual tissue reaching the wrong location (through retrograde flow, blood vessels, or lymphatic channels), an immune system that fails to clear it, a genetic background that makes someone more vulnerable, hormonal conditions that feed tissue growth, and possibly environmental exposures that worsen the whole picture. Different combinations of these factors may also explain the wide variation in how the disease presents, from mild, incidental findings to severe, deeply invasive lesions that cause debilitating pain and infertility. This complexity is a major reason why endometriosis remains so difficult to diagnose quickly, with most patients waiting 5 to 12 years from symptom onset to confirmation.