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Endometriosis

Gianna Russo

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            Endometriosis is chronic inflammatory disease that affects approximately 1 in 10 women of reproductive age. Where endometrial tissue lining the inside of the uterus  ordinarily evolves throughout the monthly duration of the menstrual cycle within the uterus, in endometriosis, this tissue undergoes these changes ectopically, or outside of the uterus. In this disease, ectopic endometrial tissue may deposit and grow anywhere outside of the uterus, typically within the abdominopelvic cavity, inhabiting the surface of reproductive structures including the ovaries or uterine tubes, as well as other structures such as those of the gastrointestinal (GI) tract. Ectopic endometrial cells can form lesions where they deposit.

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            Just like typical uterine endometrium, ectopic endometrium can progress through the menstrual cycle, which is facilitated changes in hormone regulation. These processes that endometrial cells normally undergo can cause major damage when displaced outside of the uterus. This is because normal endometrial tissue that develops as the innermost layer of the uterus is typically expelled from the body during menses, or “period”, however, shedding ectopic endometrium has no outlet. Inflammatory cells like macrophages are recruited to the site of foreign tissue. Normally, these red blood cells and endometrial cells are phagocytized by macrophages. In patients with endometriosis, however, dysregulation in hormone signaling or cell signaling between macrophages, endometrial cells, endothelial cells, and abdominal epithelial cells may allow the formation of a lesion. This is characterized by adhesion to the peritoneum, migration of cells, proliferation, and invasion into the peritoneal tissue by endometrial cells.

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            Formation of a lesion can cause unusually severe menstrual cramps, long-term lower back or pelvic pain, heavy bleeding during menses, painful intercourse, and fatigue, as well as other symptoms, depending where the lesion is formed. Endometriosis can lead to the development of other complications, including bowel and urinary problems, infertility, ovarian cysts, and certain forms of cancer. Causes of endometriosis are currently unknown, however, several theories have circulated regarding how these cells find their way outside of the uterus. Certain risk factors have been implicated including heredity, immune dysfunction, oxidative stress, and hormone dysregulation. Some current treatments of endometriosis include hormone therapy, such as birth control, pain medication, changes in diet, exercise, and surgical procedures. Infertility is a common complication associated with endometriosis. Although the pathogenesis of endometriosis has not been definitively identified, modern research implicates macrophage activity, particularly tie-2 expressing macrophages, low levels of progesterone, and high levels of ERβ activity to the pathogenesis of endometriosis. Other studies, discovered an he overexpression of the Frizzled/Wnt/β-catenin pathway in endometrial cells. Analyzing the characteristics of this disease via cell signaling dysregulation may be the key to understanding the pathogenesis of this disease and future breakthroughs in treatment.

a-medical-illustration-of-endometriosis-

Endometriosis: Symptoms

 

Endometriosis is typically characterized by:

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  • Unusually severe menstrual cramps

  • Heavy bleeding during menses

  • Bleeding between periods

  • Period lasting longer than 7 days

  • Long-term lower-back and/or pelvic pain

  • Painful intercourse

  • Fatigue

  • Bloating

 

Ectopic endometrial tissue growing on

gastrointestinal organs can cause:

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  • Constipation

  • Diarrhea

    • Alternating constipation & diarrhea

  • Painful bowel movements

  • Intestinal cramping

  • Nausea and/or vomiting

  • Bloody stool (old dark brown or mucousy)

**Relative bowel symptoms are prevalent in most cases of endometriosis, but ectopic growth directly on bowels is   only prevalent in a small fraction of cases. Therefore, bowel symptoms may derive from inflammatory mediators (such as cytokines, TNF, interleukins, & prostaglandins) seeping into bowel tissues from endometrial tissue elsewhere.

 

Other complications that may arise in those with endometriosis:

  • Sciatic nerve pain

  • Infertility

  • Ovarian cancer

Diagnosis

 

  • Pelvic exam

  • Ultrasound

  • MRI

  • Laparoscopy

    • Only definitive diagnosis
       

Treatment

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  • Hormones

    • Contraceptives

    • Hormone therapy

    • Aromatase inhibitors

  • Self-care

  • Surgical treatment and medical procedures

    • Hysterectomy

  • Pain medication

  • Fertility treatment

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”Subway Map” of Typical Endometrial Cell Signaling Pathways throughout 7 Phases: (1) Regeneration, (2) Breakdown, (3) Migration, (4) Angiogenesis, (5) Proliferation, (6) Decidualization, and (7) Implantation

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Menstrual Cycle Hormone Regulation

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Endometriosis Cell Signaling: Macrophages

 

  • Estrogens during proliferative phase cause rapid growth of vasculature, which provides oxygen and nutrients to tissues

    • mitogen-activated protein kinase (MAPK)

      • Encourages growth, proliferation, migration

    • phosphatidylinositide-3-kinase/protein kinase B (PI3K/AKT)

      • Encourages proliferation and survival

    • nuclear factor-kappa B (NF-κB)

      • Encourages anti-apoptosis, pro-inflammatory factors, and cytokine production; recruiting inflammatory cells

    • Estrogens act on macrophages, encouraging macrophage production of vascular endothelial growth factor (VEGF), inducing vessel remodeling and recruitment of inflammatory cells

      • VEGFs increases endothelial cell (cells lining the interior surface of blood and lymphatic vessels) proliferation, migration, organization into tubules, and increased permeability = Angiogenesis!

  • Progesterone secreted by the corpus luteum during the secretory phase of normal eutopic endometrial tissue stimulates maturation of the capillary sub-epithelial plexus and growth of spiralized arterioles

    • Luteinizing Hormone (LH) secreted by the anterior pituitary gland activates progesterone secretion of corpus luteum

    • In the late secretory phase, the corpus luteum dies and, thus, progesterone levels drop suddenly

      • Endometrial tissue reacts by secreting endometrial prostaglandin (PG), PGE2, and PGE2alpha, serving as a potent vasoconstrictor of spiral arterioles

      • This induces local hypoxia (poor oxygen supply). Altogether, this environment encourages the production of chemokines IL-8 (CXCL8) and CXC chemokine ligand 12 (CXCL12) [a.k.a. stromal cell derived factor (SDF-1)]

      • This further stimulates ER-beta receptors, which induces growth and proliferation

    • Local hypoxia induces vessel remodeling in damaged a regenerative tissues

      • Hypoxic conditions causes hypoxia-inducible transcription factor-1alpha (HIF1α) to translocate to nucleus to help facilitate transcription of response elements:

        • angiopoietin 2 (Ang-2), CXCL12, & VEGF

          • Recruits macrophages and other inflammatory cells, increases angiogenesis, cell survival, proliferation, and migration

            • CXC12 activates MAPK and PI3K/AKT Signaling

              • Encourages cellular migration

            • VEGFs activate MAPK, PI3K/AKT signaling

            • Ang-2 inhibits Tie-2 cell membrane receptors, which, when active, inhibits NF-κB. Therefore, when Ang-2 is activate, Tie-2 activity is inhibited, and NF-κB pathway is activated

              • NF-κB leads to: anti-apoptosis (survival), pro-inflammatory factors, cytokine production → recruitment of more macrophages

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FZD/Wnt/β-catenin Pathway in Endometriosis

 

            Some research has indicated an upregulation in the Wnt/β-catenin pathway in endometrial cells of patients with endometriosis. This has been successfully modeled in experiments using mice, where overexpression of the Frizzled 7 gene of these cells as well as β-catenin were observed. The evidence also indicated low levels of microRNA-488 in these cells, which serve as inhibitors of FZD7, thus, stifling the activity of the Wnt/β-catenin pathway. Further, research suggests that an increased levels of miRNA-488 inhibited proliferation, migration, and invasion of ectopic endometrial cells via the Wnt/β-catenin pathway. Exploitation of this information could be a viable option for future treatment of this disease.

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Discussion

 

            Research on cell signaling relative to patients with endometriosis suggests elevated activity in several cell signaling pathways. These pathways most notably include those involving the Wnt/β-catenin and NFκb pathways. The Wnt/β-catenin pathway helps regulate cellular activities including proliferation and migration. Upregulation of the Wnt/β-catenin pathway has be evidenced in endometrial tissues of patients with this disease, thus, this pathway helps facilitate proliferation, migration, and invasion of endometrial cells, resulting in formation of endometriotic lesions. Upregulation of the NFκb pathway has also been observed in these diseased tissues, encouraging these cells to produce inflammatory factors and cytokines (such as TNF-ɑ), recruiting more macrophages to the site, as well as preventing their own destruction via apoptosis. This production of TNF-ɑ activates the NFκb pathway of neighboring cells and acts in a positive feedback loop.

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            Diseased tissue of ectopic lesions also exhibit upregulated estrogen receptor β (ERβ) activity. ERβ is stimulated by the binding of 17β-estradiol (E2), a form of estrogen. When translocated to the nucleus and bound to the estrogen response element (ERE), encourages cell growth and proliferation. Estrogen binding can promote the production vascular endothelial growth factor (VEGF), which encourages endothelial cells of nearby blood vessels to proliferate, migrate, and grow, causing that tissue to become more vascularized via angiogenesis. This supplies nutrients and oxygen to not only those local tissues, such as peritoneal tissue, but also the ectopic endometrial cells of, further promoting the viability of the lesion.

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            Endometrial tissue of endometriosis is also characterized by low levels of progesterone. Progesterone encourages the growth of spiralized vessels in endometrial tissues, so when these levels drop these vessels diminish, leaving the remaining tissue lacking in adequate oxygen and nutrients. This creates a hypoxic of environment. The cell responds to this by translocating HIF1α to the nucleus, leading to the production of VEGF, CXCL12, and Ang-2. CXCL12 promotes cell chemotaxis, while Ang-2 reception via tie-2 receptor expressing macrophages results in increased NFκb activity. Therefore, this environment combats hypoxia by promoting vascularization of contaminated tissue, encouraging the survival of endometriosis lesions.

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            Considering all of these confounding signals, one can understand how displaced endometrial cells, possibly through “retro menstruation”, set up camp in ectopic areas. The production of inflammatory molecules and cytokines result in local inflammation, which can be painful. The secretion of these molecules further recruits macrophages to the site. Since endometriosis lesions are usually formed on the outside of the uterus, ovaries, fallopian tubes, or in the peritoneal cavity, it makes sense why endometriosis patients often experience severe back pelvic and/or back pain, especially during menses, when progesterone levels drastically drop. Fatigue can result since the body’s energy is directed towards sustaining the lesion, since the ectopic endometrial cells are resistant to apoptosis and macrophages help facilitate angiogenesis to the area.

References

 

Andrade, S. S., Azevedo, A. D., Monasterio, I. C., Paredes-Gamero, E. J., Gonçalves, G. A., Bonetti, T. C., . . . Silva, I. D. (2013). 17β-Estradiol and steady-state concentrations of H2O2: Antiapoptotic effect in endometrial cells from patients with endometriosis. Free Radical Biology and Medicine,60, 63-72. doi:10.1016/j.freeradbiomed.2013.01.034

Makieva, S., Giacomini, E., Ottolina, J., Sanchez, A., Papaleo, E., & Viganò, P. (2018). Inside the Endometrial Cell Signaling Subway: Mind the Gap(s). International Journal of Molecular Sciences, 19(9), 2477. doi:10.3390/ijms19092477

 

Andrade, S. S., Azevedo, A. D., Monasterio, I. C., Paredes-Gamero, E. J., Gonçalves, G. A., Bonetti, T. C., . . . Silva, I. D. (2013). 17β-Estradiol and steady-state concentrations of H2O2: Antiapoptotic effect in endometrial cells from patients with endometriosis. Free Radical Biology and Medicine,60, 63-72. doi:10.1016/j.freeradbiomed.2013.01.034

 

Mueller, M. D., Vigne, J. L., Minchenko, A., Lebovic, D. I., Leitman, D. C., & Taylor, R. N. (2000). Regulation of vascular endothelial growth factor (VEGF) gene transcription by estrogen receptors alpha and beta. Proceedings of the National Academy of Sciences of the United States of America, 97(20), 10972–10977. doi:10.1073/pnas.200377097

 

Ota, H., Igarashi, S., Hatazawa, J., & Tanaka, T. (1999). Immunohistochemical assessment of superoxide dismutase expression in the endometrium in endometriosis and adenomyosis. Fertility and Sterility,72(1), 129-134. doi:10.1016/s0015-0282(99)00152-1

 

Xiao-Qiu Wang, Wen-Jie Zhou, Xue-Zhen Luo, Yu Tao, Da-Jin Li; Synergistic effect of regulatory T cells and proinflammatory cytokines in angiogenesis in the endometriotic milieu, Human Reproduction, Volume 32, Issue 6, 1 June 2017, Pages 1304–1317, https://doi.org/10.1093/humrep/dex067

 

Zhu H, Cao X‐X, Liu J, Hua H. MicroRNA‐488 inhibits endometrial glandular epithelial cell proliferation, migration, and invasion in endometriosis mice via Wnt by inhibiting FZD7. J Cell Mol Med. 2019;00:1–12. https://doi.org/10.1111/jcmm.14078

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