Endometriosis is defined by the presence of tissue resembling the uterine lining, known as the endometrium, in locations outside of the uterus. This misplaced tissue typically grows on organs within the pelvic cavity, such as the ovaries and fallopian tubes, and is associated with chronic pain and inflammation. While the exact origin of endometriosis is not fully understood, the disease is complex and involves a multi-factorial interplay of cellular, hormonal, and immunological processes. Understanding the biological mechanisms, or pathophysiology, behind the initiation and survival of these ectopic lesions is necessary to develop more effective treatments for this common condition.
Theories of Ectopic Tissue Origin
The initial step in the pathophysiology of endometriosis is the establishment of endometrial-like tissue outside of the uterine cavity. The most widely recognized hypothesis for this process is retrograde menstruation, proposed by John Sampson in 1925. This theory suggests that during a menstrual period, some of the shed tissue and menstrual blood flows backward through the fallopian tubes into the pelvic cavity instead of exiting the body. These sloughed cells then implant and adhere to the peritoneal surfaces and organs.
While retrograde menstruation occurs in a large percentage of menstruating women, only a fraction develop endometriosis, suggesting other factors are required for the tissue to survive and grow. Another explanation is the coelomic metaplasia theory, which posits that cells lining the abdominal and pelvic cavities, known as coelomic epithelium, transform into endometrial-like cells. This transformation is thought to be stimulated by hormonal or immunological factors. The metaplasia theory helps explain rare cases of endometriosis found in individuals who have not menstruated or in distant locations.
A third set of theories involves the spread of endometrial cells through the body’s circulatory systems, often referred to as the lymphatic and vascular dissemination theories. This mechanism proposes that endometrial cells, including stem cells from the basal layer of the uterus, travel through the lymph vessels or bloodstream to distant sites. This form of spread can account for the presence of endometriotic tissue in unusual locations, such as the lungs, brain, or lymph nodes. These hypotheses are not mutually exclusive and may represent different pathways by which the disease originates.
Hormonal Dependence and Tissue Survival
Once the ectopic tissue has successfully implanted, its survival and proliferation are dependent on hormonal signaling, particularly the presence of estrogen. Endometriotic lesions are characterized as an estrogen-dependent disease, meaning estrogen promotes the growth and maintenance of the misplaced tissue. This hormonal dependence is supported by the fact that the condition primarily affects women of reproductive age.
A crucial feature of these lesions is their ability to produce estrogen locally, creating a self-sustaining microenvironment. This is achieved through the upregulation of the enzyme aromatase, which converts precursor hormones into the biologically active form of estrogen, estradiol. This local production leads to a hyperestrogenic state within the lesions, which drives cell proliferation and increases inflammation. This local estrogen production can occur even when systemic estrogen levels are suppressed by medication.
The ectopic tissue also exhibits progesterone resistance, which further contributes to its survival. In healthy uterine tissue, progesterone normally acts to limit growth and promote differentiation. However, in endometriotic lesions, there is a failure of progesterone to exert its protective effects, often due to suppressed expression or function of the progesterone receptors. This resistance prevents the normal regulatory balance, allowing the estrogen-driven proliferation and inflammatory responses to continue unchecked.
Immune System Evasion and Dysfunction
For the ectopic tissue to establish itself, it must overcome the normal immune surveillance mechanisms that typically clear misplaced cells and debris. Endometriosis is associated with a local failure of the immune system to recognize and destroy the invading endometrial cells. A primary component of this failure involves the impaired function of Natural Killer (NK) cells, which are part of the innate immune system.
NK cells are responsible for the recognition and destruction of abnormal or misplaced cells. In women with endometriosis, the cytotoxic activity of NK cells, particularly those in the peritoneal fluid, is significantly reduced. This reduced killing capacity allows the endometrial fragments to evade immune destruction and implant on the peritoneal surfaces. The dysfunction is linked to the increased expression of inhibitory receptors on the NK cells, which dampens their ability to eliminate the ectopic tissue.
Macrophage function is also altered in the microenvironment surrounding endometriotic lesions. Macrophages are immune cells that normally clear cellular debris and initiate tissue repair. However, in endometriosis, these macrophages become activated and shift to a pro-inflammatory state, releasing cytokines and growth factors that inadvertently support the lesions. These altered macrophages contribute to the inflammatory environment and promote the growth of new blood vessels, a process called angiogenesis, which is necessary for the lesions to receive nutrients and survive.
The Cycle of Inflammation and Pain
The persistence of the hormone-dependent, immune-evading lesions leads directly to the chronic symptoms associated with endometriosis, primarily inflammation and pain. Like the normal uterine lining, the ectopic tissue bleeds during the menstrual cycle, but this blood has no exit and pools in the confined pelvic cavity. This cyclical bleeding causes localized irritation and triggers a massive inflammatory response.
The inflammatory environment is characterized by the release of high levels of inflammatory mediators, such as prostaglandins and various cytokines, into the peritoneal fluid. Prostaglandins are potent biochemicals that directly stimulate pain-sensing nerve fibers, resulting in the severe, cyclical pain experienced during menstruation (dysmenorrhea). This chronic inflammation also leads to the formation of scar tissue (fibrosis) and the development of adhesions, which are fibrous bands that can tether organs together and cause structural pain.
A significant contributor to chronic pelvic pain is the abnormal growth of new nerve fibers within the endometriotic lesions and the surrounding tissue, a process called neuroangiogenesis. The lesions themselves produce neurotrophic factors that stimulate the sprouting of sensory nerve fibers directly into the ectopic tissue. This dense nerve innervation means the lesions are highly sensitive to the inflammatory mediators, creating a direct link between the physical presence of the lesion and chronic, non-cyclical neuropathic pain. The continuous exposure to inflammation can also sensitize the peripheral and central nervous systems, leading to an amplification of pain signals over time.