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Habiba, M.; Guo, S.; Benagiano, G. Phenotypes of Endometriosis and Adenomyosis. Encyclopedia. Available online: (accessed on 20 June 2024).
Habiba M, Guo S, Benagiano G. Phenotypes of Endometriosis and Adenomyosis. Encyclopedia. Available at: Accessed June 20, 2024.
Habiba, Marwan, Sun-Wei Guo, Giuseppe Benagiano. "Phenotypes of Endometriosis and Adenomyosis" Encyclopedia, (accessed June 20, 2024).
Habiba, M., Guo, S., & Benagiano, G. (2024, January 11). Phenotypes of Endometriosis and Adenomyosis. In Encyclopedia.
Habiba, Marwan, et al. "Phenotypes of Endometriosis and Adenomyosis." Encyclopedia. Web. 11 January, 2024.
Phenotypes of Endometriosis and Adenomyosis

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).

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.
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.


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  13. 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.
  14. 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.
  15. Mao, C.; Liu, X.; Guo, S.W. Decreased Glycolysis at Menstruation is Associated with Increased Menstrual Blood Loss. Reprod. Sci. 2023, 30, 928–951.
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  17. 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.
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