麻豆传媒

"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this 12-part journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

Endometriosis, in which tissue of the type that normally lines the uterus instead grows outside of it, is a somewhat enigmatic high-morbidity disease affecting an estimated 5-10% of women of reproductive age worldwide -- and likely a higher percentage of women in Asia -- and up to 3% of . The condition is thought to peak in prevalence at ages 25 to 35, although with increasing awareness of the disease, women are presenting at earlier ages and in adolescence; endometriosis has also been found in women who have had a . The historical histological definition has been the presence of endometrial glans and stroma outside the uterus, sometimes with hemosiderosis.

Despite a growing body of research, the exact etiology and pathogenesis of this estrogen-dependent condition are unclear. It is becoming evident, however, that genetic factors and physiologic environmental conditions triggering complex immunologic interactions within the pelvic cavity are implicated.

Historically, the main precipitating of endometriosis were considered to be endometrial glans and stroma that escape the uterus via the fallopian tubes during retrograde menstruation, possibly because of uterine anatomical anomaly or trauma. Recent research, however, is suggesting a complex range of underlying and synergistic contributors to the pathogenesis of a multifactorial disease, and the classic pelvic-centered description no longer reflects the condition's broad scope.

According to a 2021 review in by Hugh Taylor, MD, and colleagues at Yale School of Medicine in New Haven, Connecticut, clinical presentation can be varied, the presence of pelvic lesions is heterogeneous, and manifestations outside of the female reproductive tract remain poorly understood.

"Endometriosis is now considered a systemic disease rather than a disease predominantly affecting the pelvis," the authors wrote. The condition affects metabolism in liver and adipose tissue, leads to systemic inflammation, and alters gene expression in the brain leading to pain hypersensitization and mood disorders, which are more common in affected women. "Recognition of the full scope of the disease will facilitate clinical diagnosis," Taylor and colleagues said.

Endometriosis is a chronic, systemic disease, with multifactorial effects throughout the body. Moreover, the current gold-standard surgical approach to diagnosis does little to help early identification of the disorder and prevent long-term sequelae. An estimated 65% of women are initially misdiagnosed.

With regard to the classic pelvic presentation, however, "any uterine anomaly where the outflow tract is obstructed can lead to retrograde menstruation, including cervical stenosis, congenital absence of the cervix, or an obstructed vagina," said Chantel I. Cross, MD, of Johns Hopkins Medicine in Baltimore. This reflux can occur spontaneously, or may be due to uterine anatomical abnormalities.

Moreover, even the normal uterine contractions that facilitate menses can cause some blood to reflux and leave via the fallopian tubes, she noted. "Presumably, everyone has some degree of retrograde flow, but not everyone gets endometriosis."

Furthermore, retrograde flow does not explain the presence of endometrial tissue in distant sites like the lung, heart, and brain, Cross added. "Newer thinking has it that bone marrow-derived stem cells intended for the uterus get lost in blood on the way and lead to endometriotic implants at other sites."

has suggested a growing range of underlying and synergistic contributors to the pathogenesis of this multifactorial disease, and theories abound, as enumerated in a recent overview. It has been posited, they said, that ectopic endometrial-like tissue develops de novo from different sites such as the multipotential peritoneal epithelium, the germinal epithelium of the ovary, or from remnants of the primordial Wolffian or Müllerian ducts in the female embryo.

Another theory is that the exfoliated endometrial cells that arrive in the pelvic cavity secrete active substances that then stimulate the peritoneal epithelium to transform into endometrial tissue. For these abnormal cells to flourish and expand, other favorable factors must come into play.

Stem Cells

Endometrial stem cells from bone marrow and other sources have been shown to contribute to the development of endometriosis when transported to the pelvis. Compared with those without endometriosis, affected women have higher numbers of basalis-like cells during menses, and these cells can differentiate into endometriotic structures.

These progenitor stem cells are likely to be important in establishing ectopic lesion, Taylor and co-authors noted. Testimony to the significance of such cells is that endometriosis can be found in women without a uterus, in female fetuses, and even in men, indicating that retrograde menstruation is far from the only developmental route.

Immunological Interactions

The immune system and its relationship with the mesothelial milieu of the pelvic cavity are increasingly recognized as having an important etiologic role.

For example, according to a review by the proinflammatory lipid prostaglandin E2, is upregulated in the endometriotic peritoneum, where it is produced by macrophages and ectopic endometrial cells. This fatty compound is thought to be involved in the pathophysiology of the disease and elicits cell signals via several receptor types.

Furthermore, prostaglandin E2 increases estrogen synthesis by upregulating steroidogenic acute regulatory protein and aromatase. Prostaglandin E2 also inhibits cell apoptosis and increases levels of fibroblast growth factor-9, promoting cell proliferation and leukocyte infiltration, leading to angiogenesis via the effects on estrogen and upregulation of vascular endothelial growth factor.

Recent have that women with advanced endometriosis may have higher plasma levels of which is involved in antibody production, hematopoiesis, and . Endometriosis appears to be associated with a higher risk of asthma -- for example, a found that about 24% of women with endometriosis had asthma, compared with about 13% of unaffected women.

Moreover, certain adhesion molecules in the peritoneum are thought to enhance the of migratory endometrium to the peritoneum.

Beyond the pelvis, endometriosis expands the systemic landscape for inflammation -- increasing, for example, the presence of pro-inflammatory cytokines and causing shifts in the circulating immune cell population, Taylor and co-authors explained. In addition, a greater prevalence of systemic disease than predicted in affected patients has been documented, with potential neurological, cardiovascular, metabolic, and immune implications. The Nurses' Health study, for example, found an association between endometriosis and a greater risk of heart disease.

Genetic Markers of Endometriosis

Researchers recently identified a familial gene that predisposes women to have more severe endometriosis. Variants in the inflammation- and asthma-associated neuropeptide S receptor 1 (NPSR1) gene on chromosome 7p13-15 have been linked to . Even so, despite genome-wide association studies and the large number of genetic variants identified in these studies, the variants detected account for only a small proportion of the described, and there is currently no single endometriosis gene.

These mutations may be future targets for inhibition with medical therapy, according to Jeffrey Rogers, PhD, of Baylor College of Medicine's Human Genome Sequencing Center in Houston. "Other genes, all related to sex steroid hormone pathways and metabolism, are being investigated," he noted. These include mutations in estrogen receptor 1 (ESR1), linked to metastatic breast cancer, and follicle-stimulating hormone subunit beta (FSHB).

In addition, ongoing are investigating pathogenetic mechanisms linked to cellular proliferation, differentiation, and migration, as well as to tumor suppression and growth, apoptosis, angiogenesis, and inflammation.

Another gene, the lymphoma-linked proto-oncogene BCL6, which is associated with inflammation, is in endometriosis tissue and the endometrium of affected women. "BCL6 can be identified via the ReceptivaDx assay, but is used not to detect but to instead rule out the presence of endometriosis in the setting of infertility," Rogers said.

While there are many biomarkers associated with endometriosis, these are not typically diagnostically tested for in clinical practice, Cross noted. In addition, while endometriotic lesions express a range of cancer-driver and angiogenetic genes, it is important to recognize that endometriosis is an overall benign condition, he explained. Women with endometriosis, however, are known to be at a somewhat higher (although still overall low) risk for ovarian cancer.

Epigenetic and Environmental Factors

An array of environmental and lifestyle contributors to endometriosis, including smoking, body mass index (BMI), nulliparity, diet, and alcohol, have all been suggested as having some association with endometriosis. "But study findings have varied, and no definitive environmental risk factors have been established," Cross said.

While alcohol consumption and cigarette smoking have been associated with a reduced risk of endometriosis, developmental exposure to diethylstilbestrol and exposure to soy formula in early infancy, as well as alcohol consumption in adulthood, have been linked to an increased risk for the disease, Polak and co-authors noted in their review.

In addition, higher rates of red meat consumption were found to increase risk in the .

Women with endometriosis are at , which is felt to be due to the on genes associated with .

Recent epidemiologic and biomonitoring studies have investigated a potential role for exposure to . For example, it is known that environmental toxicants can bind with and activate the estrogen receptor, dysregulate steroid metabolism, and act as anti-androgenic substances, which has led to a theory that exposure to environmental toxicants may increase the risk of endometriosis.

In a 2020 review, explained that while epidemiologic studies provide only weak evidence of an association, animal and cell culture models point to biologically plausible mechanisms between toxicant exposures and endometriosis, and it is too soon to rule out a causal relationship.

Sorting out the complex synergy of factors that promote endometriosis will take time but may eventually lead to effective medical interventions as well as protective or mitigating measures.

Next up: Diagnosing Endometriosis