3.1.5: Endometriosis
- Page ID
- 94914
\( \newcommand{\vecs}[1]{\overset { \scriptstyle \rightharpoonup} {\mathbf{#1}} } \)
\( \newcommand{\vecd}[1]{\overset{-\!-\!\rightharpoonup}{\vphantom{a}\smash {#1}}} \)
\( \newcommand{\dsum}{\displaystyle\sum\limits} \)
\( \newcommand{\dint}{\displaystyle\int\limits} \)
\( \newcommand{\dlim}{\displaystyle\lim\limits} \)
\( \newcommand{\id}{\mathrm{id}}\) \( \newcommand{\Span}{\mathrm{span}}\)
( \newcommand{\kernel}{\mathrm{null}\,}\) \( \newcommand{\range}{\mathrm{range}\,}\)
\( \newcommand{\RealPart}{\mathrm{Re}}\) \( \newcommand{\ImaginaryPart}{\mathrm{Im}}\)
\( \newcommand{\Argument}{\mathrm{Arg}}\) \( \newcommand{\norm}[1]{\| #1 \|}\)
\( \newcommand{\inner}[2]{\langle #1, #2 \rangle}\)
\( \newcommand{\Span}{\mathrm{span}}\)
\( \newcommand{\id}{\mathrm{id}}\)
\( \newcommand{\Span}{\mathrm{span}}\)
\( \newcommand{\kernel}{\mathrm{null}\,}\)
\( \newcommand{\range}{\mathrm{range}\,}\)
\( \newcommand{\RealPart}{\mathrm{Re}}\)
\( \newcommand{\ImaginaryPart}{\mathrm{Im}}\)
\( \newcommand{\Argument}{\mathrm{Arg}}\)
\( \newcommand{\norm}[1]{\| #1 \|}\)
\( \newcommand{\inner}[2]{\langle #1, #2 \rangle}\)
\( \newcommand{\Span}{\mathrm{span}}\) \( \newcommand{\AA}{\unicode[.8,0]{x212B}}\)
\( \newcommand{\vectorA}[1]{\vec{#1}} % arrow\)
\( \newcommand{\vectorAt}[1]{\vec{\text{#1}}} % arrow\)
\( \newcommand{\vectorB}[1]{\overset { \scriptstyle \rightharpoonup} {\mathbf{#1}} } \)
\( \newcommand{\vectorC}[1]{\textbf{#1}} \)
\( \newcommand{\vectorD}[1]{\overrightarrow{#1}} \)
\( \newcommand{\vectorDt}[1]{\overrightarrow{\text{#1}}} \)
\( \newcommand{\vectE}[1]{\overset{-\!-\!\rightharpoonup}{\vphantom{a}\smash{\mathbf {#1}}}} \)
\( \newcommand{\vecs}[1]{\overset { \scriptstyle \rightharpoonup} {\mathbf{#1}} } \)
\(\newcommand{\longvect}{\overrightarrow}\)
\( \newcommand{\vecd}[1]{\overset{-\!-\!\rightharpoonup}{\vphantom{a}\smash {#1}}} \)
\(\newcommand{\avec}{\mathbf a}\) \(\newcommand{\bvec}{\mathbf b}\) \(\newcommand{\cvec}{\mathbf c}\) \(\newcommand{\dvec}{\mathbf d}\) \(\newcommand{\dtil}{\widetilde{\mathbf d}}\) \(\newcommand{\evec}{\mathbf e}\) \(\newcommand{\fvec}{\mathbf f}\) \(\newcommand{\nvec}{\mathbf n}\) \(\newcommand{\pvec}{\mathbf p}\) \(\newcommand{\qvec}{\mathbf q}\) \(\newcommand{\svec}{\mathbf s}\) \(\newcommand{\tvec}{\mathbf t}\) \(\newcommand{\uvec}{\mathbf u}\) \(\newcommand{\vvec}{\mathbf v}\) \(\newcommand{\wvec}{\mathbf w}\) \(\newcommand{\xvec}{\mathbf x}\) \(\newcommand{\yvec}{\mathbf y}\) \(\newcommand{\zvec}{\mathbf z}\) \(\newcommand{\rvec}{\mathbf r}\) \(\newcommand{\mvec}{\mathbf m}\) \(\newcommand{\zerovec}{\mathbf 0}\) \(\newcommand{\onevec}{\mathbf 1}\) \(\newcommand{\real}{\mathbb R}\) \(\newcommand{\twovec}[2]{\left[\begin{array}{r}#1 \\ #2 \end{array}\right]}\) \(\newcommand{\ctwovec}[2]{\left[\begin{array}{c}#1 \\ #2 \end{array}\right]}\) \(\newcommand{\threevec}[3]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \end{array}\right]}\) \(\newcommand{\cthreevec}[3]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \end{array}\right]}\) \(\newcommand{\fourvec}[4]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \\ #4 \end{array}\right]}\) \(\newcommand{\cfourvec}[4]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \\ #4 \end{array}\right]}\) \(\newcommand{\fivevec}[5]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \\ #4 \\ #5 \\ \end{array}\right]}\) \(\newcommand{\cfivevec}[5]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \\ #4 \\ #5 \\ \end{array}\right]}\) \(\newcommand{\mattwo}[4]{\left[\begin{array}{rr}#1 \amp #2 \\ #3 \amp #4 \\ \end{array}\right]}\) \(\newcommand{\laspan}[1]{\text{Span}\{#1\}}\) \(\newcommand{\bcal}{\cal B}\) \(\newcommand{\ccal}{\cal C}\) \(\newcommand{\scal}{\cal S}\) \(\newcommand{\wcal}{\cal W}\) \(\newcommand{\ecal}{\cal E}\) \(\newcommand{\coords}[2]{\left\{#1\right\}_{#2}}\) \(\newcommand{\gray}[1]{\color{gray}{#1}}\) \(\newcommand{\lgray}[1]{\color{lightgray}{#1}}\) \(\newcommand{\rank}{\operatorname{rank}}\) \(\newcommand{\row}{\text{Row}}\) \(\newcommand{\col}{\text{Col}}\) \(\renewcommand{\row}{\text{Row}}\) \(\newcommand{\nul}{\text{Nul}}\) \(\newcommand{\var}{\text{Var}}\) \(\newcommand{\corr}{\text{corr}}\) \(\newcommand{\len}[1]{\left|#1\right|}\) \(\newcommand{\bbar}{\overline{\bvec}}\) \(\newcommand{\bhat}{\widehat{\bvec}}\) \(\newcommand{\bperp}{\bvec^\perp}\) \(\newcommand{\xhat}{\widehat{\xvec}}\) \(\newcommand{\vhat}{\widehat{\vvec}}\) \(\newcommand{\uhat}{\widehat{\uvec}}\) \(\newcommand{\what}{\widehat{\wvec}}\) \(\newcommand{\Sighat}{\widehat{\Sigma}}\) \(\newcommand{\lt}{<}\) \(\newcommand{\gt}{>}\) \(\newcommand{\amp}{&}\) \(\definecolor{fillinmathshade}{gray}{0.9}\)3.1.5.1 Definition
Endometriosis is the presence of extrauterine functional endometrium-like tissue (glands and stroma). The extrauterine structures commonly involved are the ovaries, pouch of Douglas, uterine ligaments, fallopian tubes, the presacral nerves, the anterior abdominal wall, and/or the diaphragm. It could also involve the peritoneal cavity, periumbilical tissue, and laparotomy scars. When located elsewhere than in the ovary or on the superficial peritoneum, endometriosis is referred to as being deep, usually lying 5 mm below the peritoneum within the bladder, vaginal, or bowel wall
3.1.5.2 Morphological Features
Gross morphological features of endometriosis depend on the duration of the disease, depth of penetration of lesions, localization, and timing of the menstrual cycle. Implants range from small (usually less than 2 cm) to cystic, nodular, or polypoid masses. Lesions vary in color based on the evolution of the disease due to the accumulation of hemosiderin. They could be unpigmented or red, then progress to mature blue or dark-pigmented lesions. They could also become white fibrotic scars. Lesions become more swollen and congested under hormonal stimulation during the menstrual cycle. In severe cases, hemorrhages and the resulting iron accumulation trigger inflammation, leading to fibrosis, scarring, and adhesions, distorting the normal pelvic anatomy and a frozen pelvis. Ovarian endometriotic cysts (endometriomas) are filled with blood and are commonly known as ‘chocolate cysts.’ In more than half of cases, endometriomas are bilateral and typically do not exceed 15 cm in diameter. Endometriomas have fibrotic walls, a smooth lining, and dense, dark brown cyst contents, often adherent to adjacent organs (Figures 3.1.13 and 3.1.14).12
Figure 3.1.13 Macroscopic and microscopic appearance of endometriosis in different sites. Macroscopic picture of ovarian endometrioma with fibrotic wall and a dense, dark brown content (chocolate cyst) (a). Histopathological images of endometriotic implants in intestinal wall, fallopian tube, mesenteric adipose tissue, lymph node and diaphragm (b–f); m: intestinal mucosa; Ft: Fallopian tube; Ly: lymph node. The withe circles and the arrows highlight endometrial implants composed by several endometrial glands and stroma (b–f). Note the presence of hemosiderin-laden macrophages (asterisk) (f). Immunohistochemistry for CD10 shows strong expression in stroma surrounding an ectopic endometrial gland in the diaphragm (f inset). Hematoxylin and eosin stain.
Image Source: Camboni, Alessandra, and Etienne Marbaix. "Ectopic Endometrium: The Pathologist’s Perspective" International Journal of Molecular Sciences 22, no. 20 (2021): 0974. This work is openly licensed via CC BY 4.0 license. doi.org/10.3390/ijms222010974
3.1.14 Histopathology of ovarian endometrioma. The cyst wall is lined by cylindrical endometrial-type epithelium. (H&E) staining method (×10 magnification). Notice the brown hemosiderin deposits.
Image Source: Zucchini, Cinzia, Paola de Sanctis, Chiara Facchini, Nadine di Donato, Giulia Montanari, Valentina Bertoldo, Antonio Farina, Alessandra Curti, and Renato Seracchioli. “Performance of Circulating Placental Growth Factor as a Screening Marker for Diagnosis of Ovarian Endometriosis: A Pilot Study.” International Journal of Fertility and Sterility 9, no. 4 (2016). This work is distributed under a CC BY 2.5 license. ce of Circulating Placental Growth Factor as a Screening Marker for Diagnosis of Ovarian Endometriosis: A Pilot Study.” International Journal of Fertility and Sterility 9, no. 4 (2016). CC BY 2.5
3.1.5.3 Pathogenesis
The exact pathogenesis of the condition is not fully understood. It is proposed that endometriosis originates from uterine endometrial cells through several theories (Figure 3.1.15), including the following:13
- Retrograde menstruation (i.e., regurgitation theory) causes shed endometrial cells to pass through the fallopian tubes and be implanted in the pelvis. These cells demonstrate a cyclical response to ovarian hormones and resist apoptosis with sustained proliferation.
- Benign metastasis theory (lymphovascular dissemination): Endometrial tissue migrates to distant sites through blood vessels and lymphatics.
Alternatively, it is proposed that endometriosis originates from extrauterine cells that can form endometrial cells through the following theories:
3.1.5.3.1 Coelomic Metaplasia Theory
- The mesothelium of the abdomen or pelvis undergoes metaplastic changes to form endometrium. During embryologic development, the Müllerian ducts and the endometrium develop from the mesothelium.
- The mesonephric remnants can differentiate into ectopic endometrial tissue.
3.1.5.3.2 The extrauterine stem cell theory
Stem cells from the bone marrow can differentiate into endometrial tissue.
Figure 3.1.15 Theories of endometriosis pathogenesis. The potential origins of endometriotic lesions include traveling of endometrial tissue through retrograde menstruation and in situ by coelomic metaplasia of the peritoneal lining or from Müllerian remnants. Lymphovascular dissemination contributes to extra-pelvic lesions. Bone marrow-derived stem cells (BMDSCs) can directly differentiate into endometrial cells at ectopic locations in the peritoneal cavity and distant sites, further expanding the hypothesis of retrograde menstruation and lymphovascular dissemination. Invagination theory is characterized by altered endometrial basalis cells invading the uterine myometrium through disruption of the endometrial-myometrial interface (EMI), resulting in endometriosis of uterus. Epigenomic and genomic alterations further explain the aberrant gene expression in endometriotic lesions.
Image Source: Chen, Liang Hsuan, Wei Che Lo, Hong Yuan Huang, and Hsien Ming Wu. “A Lifelong Impact on Endometriosis: Pathophysiology and Pharmacological Treatment.” International Journal of Molecular Sciences, International Journal of Molecular Sciences 24, no. 8 (2023: 7503. This work is openly licensed via CC BY 4.0 license. doi.org/10.3390/ijms24087503
3.1.5.4 Clinicopathological Features
Endometriosis presents with a variety of symptoms throughout the lifespan (Figure 3.1.16). Similar to adenomyosis, it presents with abnormal uterine bleeding, infertility (in approximately 40% of patients), and pelvic pain. Pelvic pain is mainly caused by intrapelvic bleeding and adhesions caused by organized blood.
Figure3.1.16 Endometriosis across the life course. Summary of the symptoms associated with endometriosis, including pain, infertility, and systemic effects. They have a wide range of spectrum and can overlap with these other conditions. The upward arrows represent an increase, and the downward arrows represent a decrease.
Image Source: Chen, Liang Hsuan, Wei Che Lo, Hong Yuan Huang, and Hsien Ming Wu. “A Lifelong Impact on Endometriosis: Pathophysiology and Pharmacological Treatment.” International Journal of Molecular Sciences, International Journal of Molecular Sciences 24, no. 8 (2023: 7503. This work is openly licensed via CC BY 4.0 license. doi.org/10.3390/ijms24087503
3.1.5.5 Treatment
There is a variety of therapeutic options for endometriosis, including hormonal manipulation, surgical procedures, and assisted reproductive technology (ART) for infertility (Figure 3.1.17). COX-2 and aromatase inhibitors are effective treatments
Figure 3.1.17
Image Source: Chen, Liang Hsuan, Wei Che Lo, Hong Yuan Huang, and Hsien Ming Wu. “A Lifelong Impact on Endometriosis: Pathophysiology and Pharmacological Treatment.” International Journal of Molecular Sciences, International Journal of Molecular Sciences 24, no. 8 (2023: 7503. This work is openly licensed via CC BY 4.0 license. doi.org/10.3390/ijms24087503
For detailed treatment options, please refer to Chen, L et al. "A Lifelong Impact on Endometriosis: Pathophysiology and Pharmacological Treatment."63
Glossary Terms
- Adhesions
- a band of scar tissue that joins two surfaces of the body that are usually separate
- Androgens
- male sex hormones; for example, testosterone
- Apoptosis
- programmed cell death
- Aromatase
- enzyme that catalyzes the desaturation (aromatization) of the ring A of C19 androgens and converts them to C18 estrogens. In this process, the 19-methyl is removed
- Cystic
- relating to, formed of, or within a cyst; relating to the bladder or gall bladder
- Diaphragm
- skeletal muscle that separates the thoracic and abdominal cavities and is dome-shaped at rest
- Endometrium
- inner lining of the uterus, part of which builds up during the secretory phase of the menstrual cycle and then sheds with menses
- Extrauterine
- existing, formed, or occurring outside the uterus
- Fallopian tubes
- (uterine tubes or oviducts) ducts that facilitate transport of an ovulated oocyte to the uterus
- Fibrosis
- process in which muscle fibers are replaced by scar tissue
- Gland
- organ of the body that secretes/produces liquid chemicals that have various purposes
- Hemorrhages
- Excessive bleeding
- Hemosiderin
- type of protein that have one or more tightly bound metal ions forming part of their structure
- Inflammation
- basic innate immune response characterized by heat, redness, pain, and swelling
- Laparotomy scars
- scarring from surgical incision made in the wall of the abdomen
- Lesions
- areas of abnormal tissue
- Localization
- the fact of being or becoming located or fixed in a particular place
- Lymphatics
- the system of tubes that transport lymph arond the body
- Metaplasia
- condition in which there is a change of one adult cell type to another similar adult cell type
- Metastasis
- spread of cancer cells from a source to other parts of the body
- Mullerian ducts
- pair of ducts near the Wolffian ducts in a developing embryo
- Nodule
- growth or lump that may be malignant or benign
- Ovaries
- female gonads that produce oocytes and sex steroid hormones (notably estrogen and progesterone)
- Peritoneal cavity
- space enclosed by the peritoneum
- Periumbilical
- region of the body that immediately surrounds the umbilicus
- Polypoid
- organism whose genomes consist of more than two complete sets of chromosomes
- Pouch of Douglas
- (Douglas' Pouch) A sac or recess formed by a fold of the peritoneum
- Presacral
- presacral space is the area between the rectum and lowest part of your the spine, which is called the sacrum. The presacral space is inside the pelvis, behind the rectum and in front of the coccyx and sacrum
- Proliferation
- phase of the menstrual cycle in which the endometrium proliferates
- Retrograde
- a backward movement or a movement that is opposite to the usual direction of flow
- Stroma
- tissue that forms the structure of an organ or body part
- Superficial (peritoneum)
- describes a position nearer to the surface of the body
- Uterine ligaments
- strong bands of dense connective tissue
Footnotes
- Tomassetti, Carla, Neil P. Johnson, John Petrozza, Mauricio S. Abrao, Jon I. Einarsson, Andrew W. Horne, Ted T.M. Lee, et al. “An International Terminology for Endometriosis, 2021.” Journal of Minimally Invasive Gynecology, 2021. doi.org/10.1016/j.jmig.2021.08.032
- Camboni, Alessandra, and Etienne Marbaix. "Ectopic Endometrium: The Pathologist’s Perspective" International Journal of Molecular Sciences 22, no. 20 (2021): 0974. This work is openly licensed via CC BY 4.0 license. doi.org/10.3390/ijms222010974
- Tempest, Nicola, Christopher J. Hill, Alison Maclean, Kathleen Marston, Simon G. Powell, Hannan Al-Lamee, and Dharani K. Hapangama. “Novel Microarchitecture of Human Endometrial Glands: Implications in Endometrial Regeneration and Pathologies.” Human Reproduction Update 28, no. 2 (2022). doi.org/10.1093/humupd/dmab039
- Słopień, Radosław, and Błażej Męczekalski. "Aromatase inhibitors in the treatment of endometriosis". Menopause Review/Przegląd Menopauzalny 15 (1): 43-47. CC BY-NC-SA 4.0 doi:10.5114/pm.2016.58773
Image Acknowledgements
- Camboni, Alessandra, and Etienne Marbaix. "Ectopic Endometrium: The Pathologist’s Perspective" International Journal of Molecular Sciences 22, no. 20 (2021): 0974. This work is openly licensed via CC BY 4.0 license. doi.org/10.3390/ijms222010974
- Chen, Liang Hsuan, Wei Che Lo, Hong Yuan Huang, and Hsien Ming Wu. “A Lifelong Impact on Endometriosis: Pathophysiology and Pharmacological Treatment.” International Journal of Molecular Sciences, International Journal of Molecular Sciences 24, no. 8 (2023: 7503. This work is openly licensed via CC BY 4.0 license. doi.org/10.3390/ijms24087503
- Zucchini, Cinzia, Paola de Sanctis, Chiara Facchini, Nadine di Donato, Giulia Montanari, Valentina Bertoldo, Antonio Farina, Alessandra Curti, and Renato Seracchioli. “Performance of Circulating Placental Growth Factor as a Screening Marker for Diagnosis of Ovarian Endometriosis: A Pilot Study.” International Journal of Fertility and Sterility 9, no. 4 (2016). This work is distributed under a CC BY 2.5 license.