Phenotypes of Endometriosis and Adenomyosis

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1		Marwan Habiba	--	1404	2024-01-11 22:07:57	\|
2	layout	Jessie Wu	Meta information modification	1404	2024-01-12 03:56:55	\|

This entry is adapted from the peer-reviewed paper 10.3390/biom14010032

The link between endometriosis and adenomyosis has been suggested in theories that identified endometrial abnormalities in instances where both conditions coexist, particularly in patients with infertility. When—during the second half of the 19th century—the presence of epithelial cells on the peritoneal surface and within the myometrium was first identified, endometriosis (except for ovarian endometriomas) and adenomyosis were considered under the common name ‘adenomyoma’. Subsequently, in the 1920s, as they came to be regarded as separate entities, the terms adenomyosis and endometriosis gained wide acceptance. Interestingly, the term endometriosis also came to be used as an overarching term that encompasses instances where endometrial tissue is present outside the lining of the uterus. Adenomyosis came to be referred to as endometriosis interna to distinguish it from cases where the aberrant endometrium is present outside the uterus, which was referred to as endometriosis externa.

adenomyosis endometriosis pathogenesis KRAS epidemiology

1. Introduction

Endometriosis is now more clearly recognized as entailing the presence of endometrial epithelium and stroma at ectopic sites outside the uterus. The most recent definition from the World Health Organization reads, “Endometriosis is a disease in which tissue similar to the lining of the uterus grows outside the uterus. It can cause severe pain in the pelvis and make it harder to get pregnant” ^[1]. However, beyond this seemingly clear definition, developing a unified theory of endometriosis has been elusive because of the diversity of locations and clinical phenotypes. The implications of the condition differ based on a number of factors, such as whether it affects the ovary, the peritoneal surface, is deeply infiltrating, or affects peritoneal (or even extra-peritoneal) organs. Thus, even framing the diverse clinical manifestations of the disease under a unified pathogenetic theory is in itself quite challenging; for this reason, a call has been made for “reclassifying endometriosis as a syndrome.”

However, it has been long argued that the various phenotypes of endometriosis cannot be explained by a single theory. Indeed, whereas for peritoneal and ovarian variants the most widely accepted theory involves a retrograde flux of menstruation, as first proposed by Sampson ^[2], Sampson himself classified endometriosis into several phenotypes, each having a separate pathogenetic mechanisms ^[3]:

-: A variant recognized today as adenomyosis, where the ectopic endometrial tissue raises by direct extension into the uterine wall.
-: A type resulting from retrograde menstruation, namely, the peritoneal and ovarian implantation of endometrial cells and stroma.
-: The transplantation of the ectopic tissue as a consequence of dissemination due to surgical wounds.
-: A “metastatic” variant as a consequence of lymphatic or hematogenous microembolization of endometrial cells.
-: A developmentally determined variant where the presence of ectopic endometrium is the consequence of embryonic remnants.

Features of the “metastatic” phenotype have been recently reviewed ^[4]^[5] (Table 1).

Table 1. Reported sites of extra-pelvic endometriosis.

Affection of the Abdominal Wall	Primary Abdominal Wall Endometriosis (No Previous Scar)
	Scar endometriosis
	Umbilical endometriosis
	Inguinal endometriosis
Perineal endometriosis	Primary (no previous surgery)
	Following scarring
Visceral endometriosis	Kidney
	Liver
	Pancreas
	Biliary tract
	Diaphragm
Thoracic endometriosis	Diaphragm
	Pleura pneumothorax
	Lung parenchyma
Nose
Central nervous system	Brain
	Lumbar vertebrae
	Conus medullaris
Extra-pelvic muscles
Peripheral nerves

2. Phenotypes of Endometriosis

Endometriosis can affect different sites in the peritoneum, the ovary, or the rectovaginal septum (as well as more distant sites, such as the lungs). Histological investigations have suggested that peritoneal endometriosis, ovarian endometrioma and rectovaginal endometriosis are three separate entities with different pathogeneses ^[6]. There are similarities between proliferative eutopic endometrium and red peritoneal nodules; in more advanced disease, these evolve into black lesions and eventually into plaques of old collagen ^[7]. Black lesions rarely demonstrate typical progestational changes ^[6]. Affections of the rectovaginal septum contain aggregates of smooth muscle and may represent a form of deep-infiltrating endometriosis, now renamed deep endometriosis (DE) ^[8], or adenomyotic nodules originating from Müllerian rests ^[6].

A theory that links endometriosis and adenomyosis needs to take into account these differing phenotypes.

3. Phenotypes of Adenomyosis

Adenomyosis is characterized by the presence of endometrial glands and stroma within the myometrium. This can be localized or diffuse, and have different depths, distributions, and densities of myometrial involvement.

It has been proposed that intrinsic (also known as ‘internal’) adenomyosis characterized by increased JZ thickness and tiny mono- or multi-focal cystic structures proximal to the endometrium on magnetic resonance imaging (MRI) and extrinsic (or ‘external’) adenomyosis, which features lesions in the outer portion of the myometrium close to the peritoneal lining, are distinct entities ^[9]^[10]. As mentioned, external adenomyosis is often associated with posterior, anterior or lateral DE lesions. This raises the possibility that the external variant may be the product of invasion of the myometrium by DE lesions, but it is also possible that external adenomyosis penetrates through the peritoneum and expands to surrounding structures, causing DE ^[11].

As summarized in Table 2, using MRI, Kishi et al. ^[12] distinguished four subtypes of adenomyosis: subtype I (intrinsic) involves lesions directly connected to the eutopic endometrium and is characterized by a thickened JZ; subtype II (extrinsic) refers to cases in which lesions are found in the outer myometrium, and where the JZ seems to be intact on MRI; subtype III (intramural) is the variant in which foci are separated from the JZ and from the serosa; and subtype IV (indeterminate adenomyosis) includes cases that do not conform to any of the above criteria.

Table 2. MRI Classification of Adenomyosis according to Kishi et al. ^[12].

Subtype	Description
I	Adenomyosis that occurs in the uterine inner layer without affecting the outer structures.
II	Adenomyosis that occurs in the uterine outer layer without affecting the inner structure
III	Adenomyosis that occurs solitarily without relationship to structural components
IV	Adenomyosis that did not satisfy the above criteria

Irrespective of origin, different subtypes of adenomyosis seem to have different clinical manifestations, a point initially noted by Kishi et al. ^[12]. According to Bourdon et al. ^[13], the clinical profile of women with external adenomyosis differs from that of those with internal adenomyosis. In the former variant, subjects are significantly younger (mean ± SD; 31.9 ± 4.6 vs. 33.8 ± 5.2 years; p = 0.006), more often nulligravid (p ≤ 0.001), and more likely to exhibit an associated endometriosis (p < 0.001). Women with internal adenomyosis are more likely to have a history of previous uterine surgery (p = 0.002) and heavy menstrual bleeding (HMB) (p < 0.001). There were no differences in pain scores (i.e. dysmenorrhea, non-cyclic pelvic pain, and dyspareunia) between the two groups. One important implication is that the different phenotypes may reflect a different pathogenesis.

Recent studies have linked HMB in women with adenomyosis with endometrial fibrosis ^[14]^[15]^[16]. As adenomyotic lesions progress to become more fibrotic, pro-fibrogenic molecules produced by lesions permeate into neighboring JZ and then endometrium, effectively propagating endometrial fibrosis. This increases tissue stiffness or rigidity, which suppresses PGE2 signaling, hypoxia signaling, glycolysis and endometrial HDAC3 expression ^[14]^[15]^[16]. Endometrial downregulation of HDAC3 would, in and of itself, upregulate collagen I, leading to increased endometrial fibrosis ^[17]. Subsequently, endometrial repair is impaired, resulting in HMB ^[16]. Thus, it is conceivable that the adenomyotic lesions closer to endometrium, such as internal adenomyosis, are more likely to propagate fibrosis to the neighboring endometrium and, thus, are more likely to impair endometrial repair and cause HMB.

On the other hand, lesions proximal to the serosa, such as external adenomyosis, are unlikely to exert the same effect on the endometrium, and the course could be more protracted. This provides a plausible explanation for the link between superficial adenomyosis and HMB (and likely infertility). Given that the extent of lesional fibrosis correlates positively with the amount of menstrual blood loss in women with adenomyosis who complain of HMB, it is possible that women with internal adenomyosis who do not have HMB have “softer” lesions or fewer adenomyotic foci, with little impact on the endometrium. External adenomyosis is perhaps more closely associated with DE and would be associated more with dysmenorrhea and chronic pelvic pain but less with HMB.

There is an ongoing debate about whether DE represents a variant of adenomyosis or endometriosis. Differences in biomarker expression seem to show a link between DE and extrinsic adenomyosis ^[11]^[18]^[19]. The physical proximity between these two types of lesions also suggests a causal relationship.

In conclusion, just as with endometriosis, adenomyosis has several distinct subtypes or variants with possibly different etiology and clinical manifestations. Type I adenomyosis is associated with the history of iatrogenic uterine procedures and often manifests with HMB and possibly infertility. In contrast, Type II adenomyosis is associated with DE and often manifests with dysmenorrhea and pelvic pain. It is unclear whether Type II is the cause or consequence of DE.

References

World Health Organization. Endometriosis. Available online: https://www.who.int/news-room/fact-sheets/detail/endometriosis (accessed on 28 April 2023).
Sampson, J.A. Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. Am. J. Obstet. Gynecol. 1927, 14, 422–469.
Sampson, J.A. Metastatic or Embolic Endometriosis, due to the Menstrual Dissemination of Endometrial Tissue into the Venous Circulation. Am. J. Pathol. 1927, 3, 93–110.43.
Andres, M.P.; Arcoverde, F.V.L.; Souza, C.C.C.; Fernandes, L.F.C.; Abrao, M.S.; Kho, R.M. Extrapelvic Endometriosis: A Systematic Review. J. Minim. Invasive Gynecol. 2020, 27, 373–389.
Hirata, T.; Koga, K.; Osuga, Y. Extra-pelvic endometriosis: A review. Reprod. Med. Biol. 2020, 19, 323–333.
Nisolle, M.; Donnez, J. Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities. Fertil. Steril. 1997, 68, 585–596.
Brosens, I.A. Is mild endometriosis a progressive disease? Hum. Reprod. 1994, 9, 2209–2211.
Koninckx, P.R.; Martin, D.C. Deep endometriosis: A consequence of infiltration or retraction or possibly adenomyosis externa? Fertil. Steril. 1992, 58, 924–928.
Togashi, K.; Nishimura, K.; Itoh, K.; Fujisawa, I.; Noma, S.; Kanaoka, M.; Nakano, Y.; Itoh, H.; Ozasa, H.; Fujii, S.; et al. Adenomyosis: Diagnosis with MR imaging. Radiology 1988, 166 Pt 1, 111–114.
Bazot, M.; Darai, E. Role of transvaginal sonography and magnetic resonance imaging in the diagnosis of uterine adenomyosis. Fertil. Steril. 2018, 109, 389–397.
Donnez, J.; Spada, F.; Squifflet, J.; Nisolle, M. Bladder endometriosis must be considered as bladder adenomyosis. Fertil. Steril. 2000, 74, 1175–1181.
Kishi, Y.; Suginami, H.; Kuramori, R.; Yabuta, M.; Suginami, R.; Taniguchi, F. Four subtypes of adenomyosis assessed by magnetic resonance imaging and their specification. Am. J. Obstet. Gynecol. 2012, 207, 114.e1–114.e17.
Bourdon, M.; Oliveira, J.; Marcellin, L.; Santulli, P.; Bordonne, C.; Maitrot Mantelet, L.; Millischer, A.E.; Plu Bureau, G.; Chapron, C. Adenomyosis of the inner and outer myometrium are associated with different clinical profiles. Hum. Reprod. 2021, 36, 349–357.
Huang, Q.; Liu, X.; Critchley, H.; Fu, Z.; Guo, S.-W. How does the extent of fibrosis in adenomyosis lesions contribute to heavy menstrual bleeding? Reprod. Med. Biol. 2022; in press.
Mao, C.; Liu, X.; Guo, S.W. Decreased Glycolysis at Menstruation is Associated with Increased Menstrual Blood Loss. Reprod. Sci. 2023, 30, 928–951.
Mao, C.; Liu, X.; Guo, S.W. Reduced endometrial expression of histone deacetylase 3 in women with adenomyosis who complained of heavy menstrual bleeding. Reprod. Biomed. Online 2023, 47, 103288.
Kim, T.H.; Yoo, J.Y.; Choi, K.C.; Shin, J.H.; Leach, R.E.; Fazleabas, A.T.; Young, S.L.; Lessey, B.A.; Yoon, H.G.; Jeong, J.W. Loss of HDAC3 results in nonreceptive endometrium and female infertility. Sci. Transl. Med. 2019, 11, eaaf7533.
Khan, K.N.; Fujishita, A.; Koshiba, A.; Kuroboshi, H.; Mori, T.; Ogi, H.; Itoh, K.; Nakashima, M.; Kitawaki, J. Biological differences between intrinsic and extrinsic adenomyosis with coexisting deep infiltrating endometriosis. Reprod. Biomed. Online 2019, 39, 343–353.
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Subjects: Obstetrics & Gynaecology

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Marwan Habiba

Sun-Wei Guo

Giuseppe Benagiano

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Update Date: 16 Jan 2024

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1. Introduction

2. Phenotypes of Endometriosis

3. Phenotypes of Adenomyosis

References