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==Overview== | ==Overview== | ||
The exact [[pathogenesis]] of [[endometriosis]] is not clear and several theories have made an attempt to describe the [[pathogenesis]]. Sampson theory of retrograde [[menstruation]], coelomic [[metaplasia]] theory, [[lymphatic]] and [[vascular]] dissemination theory explain the implantation and invasion of the [[Endometrium|endometrial tissue]] outside the [[uterine cavity]]. [[Immunological|Immunologic]] factors and [[genetic]] factors are also thought play a role in the pathogenesis of [[endometriosis]]. | The exact [[pathogenesis]] of [[endometriosis]] is not clear and several theories have made an attempt to describe the [[pathogenesis]]. Sampson theory of retrograde [[menstruation]], coelomic [[metaplasia]] theory, [[lymphatic]] and [[vascular]] dissemination theory explain the implantation and invasion of the [[Endometrium|endometrial tissue]] outside the [[uterine cavity]]. [[Immunological|Immunologic]] factors and [[genetic]] factors are also thought to play a role in the pathogenesis of [[endometriosis]]. | ||
==Pathophysiology== | ==Pathophysiology== | ||
===Pathogenesis=== | ===Pathogenesis=== | ||
====Translocation of the endometrial cells==== | ====Translocation of the endometrial cells==== | ||
The exact pathogenesis of [[endometriosis]] is still unknown, | The exact pathogenesis of [[endometriosis]] is still unknown. However, several theories were put forward to explain the presence the of viable and hormonally active [[endometrium]] outside the [[uterine cavity]]. The theories proposed include the following:<ref name="Bulun2009">{{cite journal|last1=Bulun|first1=Serdar E.|title=Endometriosis|journal=New England Journal of Medicine|volume=360|issue=3|year=2009|pages=268–279|issn=0028-4793|doi=10.1056/NEJMra0804690}}</ref><ref name="pmid27165051">{{cite journal| author=Greene AD, Lang SA, Kendziorski JA, Sroga-Rios JM, Herzog TJ, Burns KA| title=Endometriosis: where are we and where are we going? | journal=Reproduction | year= 2016 | volume= 152 | issue= 3 | pages= R63-78 | pmid=27165051 | doi=10.1530/REP-16-0052 | pmc=4958554 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27165051 }} </ref><ref name="pmid26949527">{{cite journal| author=Nothnick W, Alali Z| title=Recent advances in the understanding of endometriosis: the role of inflammatory mediators in disease pathogenesis and treatment. | journal=F1000Res | year= 2016 | volume= 5 | issue= | pages= | pmid=26949527 | doi=10.12688/f1000research.7504.1 | pmc=4760268 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26949527 }} </ref><ref name="pmid23416836">{{cite journal| author=Begum T, Chowdhury SR| title=Aetiology and pathogenesis of endometriosis - a review. | journal=Mymensingh Med J | year= 2013 | volume= 22 | issue= 1 | pages= 218-21 | pmid=23416836 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23416836 }} </ref><ref name="pmid22819188">{{cite journal| author=Benagiano G, Habiba M, Brosens I| title=The pathophysiology of uterine adenomyosis: an update. | journal=Fertil Steril | year= 2012 | volume= 98 | issue= 3 | pages= 572-9 | pmid=22819188 | doi=10.1016/j.fertnstert.2012.06.044 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22819188 }} </ref> | ||
*'''Sampson's theory of retrograde menstruation''' | *'''Sampson's theory of retrograde menstruation''' | ||
**The theory postulates that the viable [[Endometrium|endometrial tissue]] passes in a retrograde fashion via the [[fallopian tube]]<nowiki/>s to reach the [[peritoneal cavity]] and subsequently implants onto the pelvic structures and organs. | **The theory postulates that the viable [[Endometrium|endometrial tissue]] passes in a retrograde fashion via the [[fallopian tube]]<nowiki/>s to reach the [[peritoneal cavity]] and subsequently implants onto the pelvic structures and organs. | ||
**Factors favoring the theory include the higher risk of developing [[endometriosis]] in patients with cervical stenosis and congenital outflow obstructions which result in a greater retrograde efflux, and resulting in the implantation of endometrial tissue in the [[peritoneal cavity]]. | **Factors favoring the theory include the higher risk of developing [[endometriosis]] in patients with cervical stenosis and congenital outflow obstructions which result in a greater retrograde efflux, and resulting in the implantation of endometrial tissue in the [[peritoneal cavity]]. | ||
**This theory, however, doesn't explain the disease process in | **This theory, however, doesn't explain the disease process in premenarcheal girls and new borns.<ref name="pmid19344855">{{cite journal| author=Templeman C| title=Adolescent endometriosis. | journal=Obstet Gynecol Clin North Am | year= 2009 | volume= 36 | issue= 1 | pages= 177-85 | pmid=19344855 | doi=10.1016/j.ogc.2008.12.005 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19344855 }} </ref> | ||
*'''Coelomic metaplasia theory''' | *'''Coelomic metaplasia theory''' | ||
**This theory postulates that [[endometriosis]] is a result of [[metaplasia]] of the cells lining the [[Visceral peritoneum|visceral]] and [[parietal peritoneum]] following various [[hormonal]], environmental, or infectious stimuli. | **This theory postulates that [[endometriosis]] is a result of [[metaplasia]] of the cells lining the [[Visceral peritoneum|visceral]] and [[parietal peritoneum]] following various [[hormonal]], environmental, or infectious stimuli. | ||
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====Implantation of the endometrial cells==== | ====Implantation of the endometrial cells==== | ||
* The presence of [[Endometrium|endometrial]] cells alone outside the endometrial tissue is not [[endometriosis]]. The translocated [[Endometrium|endometrial cells]] must attach to the surrounding tissues, survive the [[Immune system|immune defense]] and be receptive to the | * The presence of [[Endometrium|endometrial]] cells alone outside the endometrial tissue is not [[endometriosis]]. The translocated [[Endometrium|endometrial cells]] must attach to the surrounding tissues, survive the [[Immune system|immune defense]] and be receptive to the hormonal changes of [[estrogen]]. This is facilitated by various factors which influence the disease process: | ||
**The [[Endometrium|endometrial]] [[stromal cells]] are essential for the attachment of the [[Endometrium|endometrial cells]] to the surrounding [[tissue]]. | **The [[Endometrium|endometrial]] [[stromal cells]] are essential for the attachment of the [[Endometrium|endometrial cells]] to the surrounding [[tissue]]. | ||
**Ectopic [[Endometrium|endometrial cells]] in [[endometriosis]] are resistant to [[cell mediated immunity]] and have increased proliferative capacity. | **Ectopic [[Endometrium|endometrial cells]] in [[endometriosis]] are resistant to [[cell mediated immunity]] and have increased proliferative capacity. | ||
**The ectopic endometrial cells have an increased [[aromatase]] expression leading to increased [[estrogen]] concentrations. | **The ectopic endometrial cells have an increased [[aromatase]] expression leading to increased [[estrogen]] concentrations. | ||
** | **Aberrant [[integrin]] expression is also been described as a factor involved in the process of implantation. | ||
====Invasion and growth of the endometrial cells==== | ====Invasion and growth of the endometrial cells==== | ||
*The [[Endometrium|endometrial]] glandular cells are involved in the process of invasion.<ref name="pmid27424048">{{cite journal| author=Smarr MM, Kannan K, Buck Louis GM| title=Endocrine disrupting chemicals and endometriosis. | journal=Fertil Steril | year= 2016 | volume= 106 | issue= 4 | pages= 959-66 | pmid=27424048 | doi=10.1016/j.fertnstert.2016.06.034 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27424048 }} </ref> | *The [[Endometrium|endometrial]] glandular cells are involved in the process of invasion.<ref name="pmid27424048">{{cite journal| author=Smarr MM, Kannan K, Buck Louis GM| title=Endocrine disrupting chemicals and endometriosis. | journal=Fertil Steril | year= 2016 | volume= 106 | issue= 4 | pages= 959-66 | pmid=27424048 | doi=10.1016/j.fertnstert.2016.06.034 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27424048 }} </ref> | ||
*Degradation of the [[extracellular matrix]] due to the increased [[proteolytic]] activity allows in the invasion of the [[Endometrium|endometrial]] cells. | *Degradation of the [[extracellular matrix]] due to the increased [[proteolytic]] activity allows in the invasion of the [[Endometrium|endometrial]] cells. | ||
*Numerous [[Proteases|metalloproteases]] and [[plasmin]] help in the degradation of the [[extracellular matrix]] and in establishment of an endometrial lesion outside the [[uterine cavity]]. | *Numerous [[Proteases|metalloproteases]] and [[plasmin]] help in the degradation of the [[extracellular matrix]] and in the establishment of an endometrial lesion outside the [[uterine cavity]]. | ||
====Proliferation of the endometrial cells==== | ====Proliferation of the endometrial cells==== | ||
*The functional [[endometrium]] in the [[uterine cavity]] proliferates in response to the increase in [[estrogen]] levels. The [[estrogen]] levels are dependent on the [[aromatase]] activity which | *The functional [[endometrium]] in the [[uterine cavity]] proliferates in response to the increase in [[estrogen]] levels. The [[estrogen]] levels are dependent on the [[aromatase]] activity which catalyzes the conversion of ovarian [[androstenedione]] into [[estrone]].<ref name="pmid28109841">{{cite journal| author=Patel S| title=Disruption of aromatase homeostasis as the cause of a multiplicity of ailments: A comprehensive review. | journal=J Steroid Biochem Mol Biol | year= 2017 | volume= 168 | issue= | pages= 19-25 | pmid=28109841 | doi=10.1016/j.jsbmb.2017.01.009 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28109841 }} </ref> | ||
*Endometrial cells in patients with [[endometriosis]] have increased levels in the [[aromatase]] levels leading to increased [[estrogen]] levels resulting in excess proliferation. | *Endometrial cells in patients with [[endometriosis]] have increased levels in the [[aromatase]] levels leading to increased [[estrogen]] levels resulting in excess proliferation. | ||
*The endometrial cells also have resistance to [[progesterone]] which controls the [[proliferation]] of the endometrial cells. The resistance to [[progesterone]] results in uncontrolled proliferation. | *The endometrial cells also have resistance to [[progesterone]] which controls the [[proliferation]] of the endometrial cells. The resistance to [[progesterone]] results in uncontrolled proliferation. | ||
| Line 63: | Line 63: | ||
===Genetics=== | ===Genetics=== | ||
*[[Cell-mediated immunity|Cell mediated immunity]] defenses and [[aromatase]] activity | *[[Cell-mediated immunity|Cell mediated immunity]] defenses and [[aromatase]] activity is essential for the growth of the translocated tissue. [[Polymorphisms]] in the [[genes]] coding for them are described in women with [[endometriosis]] explaining the genetic predisposition to develop [[endometriosis]].<ref name="pmid27525656">{{cite journal| author=Fan W, Huang Z, Xiao Z, Li S, Ma Q| title=The cytochrome P4501A1 gene polymorphisms and endometriosis: a meta-analysis. | journal=J Assist Reprod Genet | year= 2016 | volume= 33 | issue= 10 | pages= 1373-1383 | pmid=27525656 | doi=10.1007/s10815-016-0783-4 | pmc=5065559 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27525656 }} </ref><ref name="pmid27252161">{{cite journal| author=Blakemore J, Naftolin F| title=Aromatase: Contributions to Physiology and Disease in Women and Men. | journal=Physiology (Bethesda) | year= 2016 | volume= 31 | issue= 4 | pages= 258-69 | pmid=27252161 | doi=10.1152/physiol.00054.2015 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27252161 }} </ref> | ||
*[[Polymorphisms]] in the genes coding for the [[cytokines]] and toll like receptors are also described to increase the risk of [[endometriosis]]. | *[[Polymorphisms]] in the genes coding for the [[cytokines]] and toll like receptors are also described to increase the risk of [[endometriosis]]. | ||
*Postive family history of [[endometriosis]] in [[first degree relative]] is associated with | *Postive family history of [[endometriosis]] in the [[first degree relative|first-degree relative]] is associated with six times higher risk of developing [[endometriosis]]. | ||
*[[Heterogeneity|Heterogenicity]] of [[chromosome 17]] and [[aneuploidy]] is described in patients with endometriosis. | *[[Heterogeneity|Heterogenicity]] of [[chromosome 17]] and [[aneuploidy]] is described in patients with endometriosis. | ||
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===Gross Pathology=== | ===Gross Pathology=== | ||
*The gross appearance of the lesions | *The gross appearance of the lesions depends on the site, activity, day of the menstrual cycle, duration of the disease, and the presence of [[fibrosis]]. | ||
*On laparoscopy, [[endometriosis]] affecting the pelvic organs appears as raised dark non hemorrhagic lesions. They can also appear brown, black, white, yellow, pink or clear lesions based on the amount of blood supply. | *On laparoscopy, [[endometriosis]] affecting the pelvic organs appears as raised dark non-hemorrhagic lesions. They can also appear brown, black, white, yellow, pink or clear lesions based on the amount of blood supply. | ||
*[[Endometriosis]] of the ovary appears as a dark necrotic tissue and is coined as [[Chocolate cyst of the ovary|"chocolate cyst]]". | *[[Endometriosis]] of the ovary appears as a dark necrotic tissue and is coined as [[Chocolate cyst of the ovary|"chocolate cyst]]". | ||
*Extensive [[endometriosis]] can result in fibrosis of the pelvic structures which can be visualized on [[Laparoscopy|abdominal laparoscopy]]. | *Extensive [[endometriosis]] can result in fibrosis of the pelvic structures which can be visualized on [[Laparoscopy|abdominal laparoscopy]]. | ||
===Microscopic Pathology=== | ===Microscopic Pathology=== | ||
*Microscopy of | *Microscopy of the [[biopsy]] tissue will demonstrate the presence of the [[endometrial]] [[stromal cells]] and [[Glandular|glandular cells]]. | ||
==References== | ==References== | ||
{{Reflist|2}} | {{Reflist|2}} | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Kuchkuntla, M.B.B.S[2]
Overview
The exact pathogenesis of endometriosis is not clear and several theories have made an attempt to describe the pathogenesis. Sampson theory of retrograde menstruation, coelomic metaplasia theory, lymphatic and vascular dissemination theory explain the implantation and invasion of the endometrial tissue outside the uterine cavity. Immunologic factors and genetic factors are also thought to play a role in the pathogenesis of endometriosis.
Pathophysiology
Pathogenesis
Translocation of the endometrial cells
The exact pathogenesis of endometriosis is still unknown. However, several theories were put forward to explain the presence the of viable and hormonally active endometrium outside the uterine cavity. The theories proposed include the following:[1][2][3][4][5]
- Sampson's theory of retrograde menstruation
- The theory postulates that the viable endometrial tissue passes in a retrograde fashion via the fallopian tubes to reach the peritoneal cavity and subsequently implants onto the pelvic structures and organs.
- Factors favoring the theory include the higher risk of developing endometriosis in patients with cervical stenosis and congenital outflow obstructions which result in a greater retrograde efflux, and resulting in the implantation of endometrial tissue in the peritoneal cavity.
- This theory, however, doesn't explain the disease process in premenarcheal girls and new borns.[6]
- Coelomic metaplasia theory
- This theory postulates that endometriosis is a result of metaplasia of the cells lining the visceral and parietal peritoneum following various hormonal, environmental, or infectious stimuli.
- This theory is supported by the evidence that the abdominal, pelvic, and thoracic peritoneum, the Mullerian ducts, the germinal epithelium of the ovary and the endometrium are all derived from the coelomic wall epithelium, explaining the occurrence of endometriosis at these sites.
- Embryonic rest theory
- This theory proposes that endometrial tissue arises from the cells remaining from Mullerian duct migration during embryonic development, following estrogen stimulation.
- The stem cell theory:
- This theory is based on experimental evidence explaining the fact that the endometrial stem cells from the basalis layer and the bone marrow-derived stem cells can travel via the retrograde fashion or via the lymphatic or vascular system resulting in endometriosis.
Implantation of the endometrial cells
- The presence of endometrial cells alone outside the endometrial tissue is not endometriosis. The translocated endometrial cells must attach to the surrounding tissues, survive the immune defense and be receptive to the hormonal changes of estrogen. This is facilitated by various factors which influence the disease process:
- The endometrial stromal cells are essential for the attachment of the endometrial cells to the surrounding tissue.
- Ectopic endometrial cells in endometriosis are resistant to cell mediated immunity and have increased proliferative capacity.
- The ectopic endometrial cells have an increased aromatase expression leading to increased estrogen concentrations.
- Aberrant integrin expression is also been described as a factor involved in the process of implantation.
Invasion and growth of the endometrial cells
- The endometrial glandular cells are involved in the process of invasion.[7]
- Degradation of the extracellular matrix due to the increased proteolytic activity allows in the invasion of the endometrial cells.
- Numerous metalloproteases and plasmin help in the degradation of the extracellular matrix and in the establishment of an endometrial lesion outside the uterine cavity.
Proliferation of the endometrial cells
- The functional endometrium in the uterine cavity proliferates in response to the increase in estrogen levels. The estrogen levels are dependent on the aromatase activity which catalyzes the conversion of ovarian androstenedione into estrone.[8]
- Endometrial cells in patients with endometriosis have increased levels in the aromatase levels leading to increased estrogen levels resulting in excess proliferation.
- The endometrial cells also have resistance to progesterone which controls the proliferation of the endometrial cells. The resistance to progesterone results in uncontrolled proliferation.
- The reduction of excess estrogen and resistance to progesterone forms the basic principle for the medical therapy of endometriosis.
Commonly affected sites in endometriosis
- Endometriosis lesions commonly occur in the dependent areas with ovaries being the most common site.[9]
- Other common sites affected include:
- Pelvic peritoneum lining the uterus
- Posterior cul-de-sac
- Round and broad ligaments of the uterus
- Lymph nodes
- Less common sites affected include:
Genetics
- Cell mediated immunity defenses and aromatase activity is essential for the growth of the translocated tissue. Polymorphisms in the genes coding for them are described in women with endometriosis explaining the genetic predisposition to develop endometriosis.[15][16]
- Polymorphisms in the genes coding for the cytokines and toll like receptors are also described to increase the risk of endometriosis.
- Postive family history of endometriosis in the first-degree relative is associated with six times higher risk of developing endometriosis.
- Heterogenicity of chromosome 17 and aneuploidy is described in patients with endometriosis.
Associated Conditions
Endometriosis is associated with an increased risk of developing ovarian cancer.[17][18]
Gross Pathology
- The gross appearance of the lesions depends on the site, activity, day of the menstrual cycle, duration of the disease, and the presence of fibrosis.
- On laparoscopy, endometriosis affecting the pelvic organs appears as raised dark non-hemorrhagic lesions. They can also appear brown, black, white, yellow, pink or clear lesions based on the amount of blood supply.
- Endometriosis of the ovary appears as a dark necrotic tissue and is coined as "chocolate cyst".
- Extensive endometriosis can result in fibrosis of the pelvic structures which can be visualized on abdominal laparoscopy.
Microscopic Pathology
- Microscopy of the biopsy tissue will demonstrate the presence of the endometrial stromal cells and glandular cells.
References
- ↑ Bulun, Serdar E. (2009). "Endometriosis". New England Journal of Medicine. 360 (3): 268–279. doi:10.1056/NEJMra0804690. ISSN 0028-4793.
- ↑ Greene AD, Lang SA, Kendziorski JA, Sroga-Rios JM, Herzog TJ, Burns KA (2016). "Endometriosis: where are we and where are we going?". Reproduction. 152 (3): R63–78. doi:10.1530/REP-16-0052. PMC 4958554. PMID 27165051.
- ↑ Nothnick W, Alali Z (2016). "Recent advances in the understanding of endometriosis: the role of inflammatory mediators in disease pathogenesis and treatment". F1000Res. 5. doi:10.12688/f1000research.7504.1. PMC 4760268. PMID 26949527.
- ↑ Begum T, Chowdhury SR (2013). "Aetiology and pathogenesis of endometriosis - a review". Mymensingh Med J. 22 (1): 218–21. PMID 23416836.
- ↑ Benagiano G, Habiba M, Brosens I (2012). "The pathophysiology of uterine adenomyosis: an update". Fertil Steril. 98 (3): 572–9. doi:10.1016/j.fertnstert.2012.06.044. PMID 22819188.
- ↑ Templeman C (2009). "Adolescent endometriosis". Obstet Gynecol Clin North Am. 36 (1): 177–85. doi:10.1016/j.ogc.2008.12.005. PMID 19344855.
- ↑ Smarr MM, Kannan K, Buck Louis GM (2016). "Endocrine disrupting chemicals and endometriosis". Fertil Steril. 106 (4): 959–66. doi:10.1016/j.fertnstert.2016.06.034. PMID 27424048.
- ↑ Patel S (2017). "Disruption of aromatase homeostasis as the cause of a multiplicity of ailments: A comprehensive review". J Steroid Biochem Mol Biol. 168: 19–25. doi:10.1016/j.jsbmb.2017.01.009. PMID 28109841.
- ↑ Fritel X (2007). "[Endometriosis anatomoclinical entities]". J Gynecol Obstet Biol Reprod (Paris). 36 (2): 113–8. doi:10.1016/j.jgyn.2006.12.003. PMID 17275210.
- ↑ Park HM, Lee SS, Eom DW, Kang GH, Yi SW, Sohn WS (2009). "Endometrioid adenocarcinoma arising from endometriosis of the uterine cervix: a case report". J Korean Med Sci. 24 (4): 767–71. doi:10.3346/jkms.2009.24.4.767. PMC 2719211. PMID 19654969.
- ↑ Hernández-Ramírez DA, Cravioto-Villanueva A, Barragan-Rincón A (2008). "[Rectal endometriosis: entity difficult to diagnose.]". Rev Gastroenterol Mex. 73 (3): 159–62. PMID 19671503.
- ↑ Collins AM, Power KT, Gaughan B, Hill AD, Kneafsey B (2009). "Abdominal wall reconstruction for a large caesarean scar endometrioma". Surgeon. 7 (4): 252–3. PMID 19736896.
- ↑ Chung MK, Jarnagin B (2009). "Early identification of interstitial cystitis may avoid unnecessary hysterectomy". JSLS. 13 (3): 350–7. PMC 3015962. PMID 19793476.
- ↑ Dirim A, Celikkaya S, Aygun C, Caylak B (2009). "Renal endometriosis presenting with a giant subcapsular hematoma: case report". Fertil Steril. 92 (1): 391.e5–7. doi:10.1016/j.fertnstert.2009.04.013. PMID 19476941.
- ↑ Fan W, Huang Z, Xiao Z, Li S, Ma Q (2016). "The cytochrome P4501A1 gene polymorphisms and endometriosis: a meta-analysis". J Assist Reprod Genet. 33 (10): 1373–1383. doi:10.1007/s10815-016-0783-4. PMC 5065559. PMID 27525656.
- ↑ Blakemore J, Naftolin F (2016). "Aromatase: Contributions to Physiology and Disease in Women and Men". Physiology (Bethesda). 31 (4): 258–69. doi:10.1152/physiol.00054.2015. PMID 27252161.
- ↑ Thomsen LH, Schnack TH, Buchardi K, Hummelshoj L, Missmer SA, Forman A; et al. (2017). "Risk factors of epithelial ovarian carcinomas among women with endometriosis: a systematic review". Acta Obstet Gynecol Scand. 96 (6): 761–778. doi:10.1111/aogs.13010. PMID 27565819.
- ↑ Lassus H, Pasanen A, Bützow R (2015). "[Is endometriosis a premalignant condition to ovarian carcinoma?]". Duodecim. 131 (19): 1777–84. PMID 26638662.