ETD

• #Enzian Classification
• 3D Trans-vaginal Ultrasound (3D-TVS)
• classificazione #Enzian.Uterine Malformation
• Deep Infiltrating Endometriosis (DIE)
• ecografia transvaginale 3D (3D-TVS)
• endometriosi profonda infiltrante (DIE)
• Malformazione uterina

Le malformazioni uterine congenite (CUM) sono esiti di un’anomalia dello sviluppo embrionale dell’utero e della vagina e sono riscontrate con maggiore frequenza nelle donne infertili o con esiti riproduttivi avversi. Molte pazienti restano asintomatiche, mentre nelle forme clinicamente manifeste i quadri tipici sono dolore pelvico e amenorrea in età puberale, oppure infertilità, aborti ricorrenti e complicanze ostetriche in età adulta. L’ecografia transvaginale 3D rappresenta oggi la metodica di riferimento per la diagnosi non invasiva delle anomalie uterine, ma la reale prevalenza delle CUM rimane variabile a causa di differenze nei sistemi di classificazione, nei criteri diagnostici e nelle popolazioni studiate. In generale, le CUM sono riportate con frequenza maggiore nelle donne infertili e in quelle con abortività ripetuta, suggerendo un impatto diretto sulla fertilità e sull’andamento della gravidanza. L’endometriosi, caratterizzata da tessuto endometriale ectopico e dolore pelvico cronico, colpisce una quota significativa di donne in età riproduttiva ed è spesso associata a infertilità. Negli ultimi anni, anche per questa patologia la 3D TVS si è affermata come tecnica fondamentale per la diagnosi, affiancata dal sistema di classificazione #Enzian, che consente una mappatura dettagliata delle lesioni in base a sede, estensione e coinvolgimento degli organi adiacenti. Numerose ricerche hanno documentato un’associazione tra CUM ed endometriosi, particolarmente evidente nelle anomalie che determinano ostruzione del deflusso mestruale e che sostengono la teoria della mestruazione retrograda. Tuttavia, sono state descritte correlazioni anche con malformazioni non ostruttive, suggerendo che altri meccanismi — come la disperistalsi uterina e la coesistenza di infertilità — possano contribuire allo sviluppo e alla maggiore severità dell’endometriosi.
In questo contesto, lo scopo di questa tesi è lo studio dell’associazione tra specifiche categorie di malformazioni uterine congenite (secondo la classificazione ESHRE/ESGE) ed endometriosi, individuando le anomalie più frequentemente coinvolte e i compartimenti #Enzian maggiormente interessati, con l’obiettivo di chiarire ulteriormente i legami patogenetici e clinici tra queste condizioni. In questa coorte, 44 pazienti (14,5%) presentavano un utero dismorfico (U1 secondo la classificazione ESHRE), 193 (63,5%) presentavano un utero settato (ESHRE U2), 30 (9,8%) presentavano un utero bicorporeo (ESHRE U3), 35 (11,5%) presentavano un utero emiplegico (ESHRE U4) e 2 (0,6%) presentavano un utero aplastico (ESHRE U5). Su un totale di 304 pazienti, 116 presentavano almeno un segno ecografico di endometriosi/adenomiosi. Nello specifico, 80 pazienti U2 (41,5%) mostravano segni, così come 22 pazienti U1 (50%), 5 pazienti U3 (16,7%), 9 pazienti U4 (25,7%), mentre nessuna delle pazienti U5 presentava segni ecografici di endometriosi/adenomiosi. Analizzando l'incidenza dell'endometriosi/adenomiosi nelle diverse malformazioni, è emerso che U3 ha la correlazione più bassa (OR 0,3). Successivamente, un'analisi di regressione logistica multivariata ha rivelato un'associazione statisticamente significativa tra endometriosi/adenomiosi e U1 (OR 5,0) e U2 (OR 3,5). Analizzando i singoli compartimenti #Enzian, è emerso che U1 è correlato esclusivamente al compartimento FA (OR 7,57), mentre U2 è associato al compartimento DIE (A+B+C+FU) (OR 4,32). Non vi è alcuna correlazione tra U3, U4 o U5 e l'endometriosi/adenomiosi.

Congenital Uterine Malformations (CUM) result from disrupted embryologic development of the uterus and vagina and are more common in women with infertility and poor reproductive outcomes [1]. The true prevalence of uterine anomalies is difficult to determine, as many individuals remain asymptomatic. Symptomatic cases may present at puberty with pelvic pain due to outflow obstruction, endometriosis, or amenorrhea despite normal secondary sexual development. In adults, infertility or adverse reproductive outcomes may be the only indication of Müllerian anomalies [2,3].
Currently, 3D transvaginal ultrasound (3D-TVS) is considered the gold standard for the diagnosis of congenital uterine anomalies. Over the years, several classifications (AFS 1988, ESHRE/ESGE 2016, ASRM 2021) and 3D-TVS parameters have been proposed to enable a precise and consistent diagnosis of these anomalies; however, a universal consensus has yet to be reached [4-11].
Estimates of these malformations prevalence range from 0.1% to 7% of live births, with considerable variation attributed to differences in diagnostic methods, classification systems, and patient populations [12,13]. Nonetheless, CUM are reported in 4–8% of infertile women, 13.3–16.7% of those with recurrent miscarriage, and 24.5% of women experiencing both miscarriage and infertility [14-16].
Endometriosis is a chronic gynecological condition characterized by ectopic endometrial tissue and pelvic pain, affects 6–10% of reproductive-age women, with prevalence rising to 35–50% in those with pelvic pain, infertility, or both [17,18].
Only recently several studies recognized 3D-TVS as the gold standard method for the non-invasive diagnosis of endometriosis [19-23]. At the end of 2020, a new classification system was proposed for the comprehensive mapping of endometriosis, featuring a single classification capable of assessing the anatomical location, lesion size, presence of adhesions, and the degree of involvement of adjacent organs. This system, known as the #Enzian classification, can be used both in surgical settings and for medical management [24-26].
According to several studies this disease is frequently associated with congenital uterine anomalies, particularly in cases involving outflow obstruction and this correlation supports the retrograde menstruation theory of endometriosis pathogenesis [27-31].
Regardless the difference between obstructive and non-obstructive abnormalities, a general association between Müllerian duct anomalies and endometriosis has been supported by research. In 2006, the study of Nawroth et al. [32] suggest a higher incidence of endometriosis in patients with a septate uterus potentially due to uterine dysperistalsis serving as a mechanical contributor to the development of endometriosis, rather than the traditionally proposed mechanism of retrograde menstruation. Uterine anomalies—regardless of whether they are obstructive or non-obstructive—may disrupt normal uterine peristalsis, thereby creating a physiological environment that increases the risk of endometriosis. [33,34].
Matalliotaki et al. [35] reported that 3% of patients with endometriosis had a uterine anomaly, compared to just 0.5% in controls. The most common anomaly observed was a septate uterus, followed by didelphic, unicornuate, and bicornuate uteri. Their findings also highlighted a potential genetic component, as 38% of affected women had a family history of endometriosis.
Similarly, Boujenah et al. [16] found that the prevalence and severity of endometriosis were not linked to the specific class of uterine anomaly. Rather, higher rates of moderate to severe endometriosis -characterized by endometrioma and deep infiltrating endometriosis (DIE) - were observed in anomalies associated with infertility. The study concluded that endometriosis severity may be influenced by infertility in the context of uterine malformations, reinforcing the interconnected nature of these conditions.
Despite extensive research, the precise relationship between Müllerian duct anomalies and endometriosis remains difficult to define. While a strong association has been established in cases involving outflow obstruction - supporting the retrograde menstruation theory - the link between endometriosis and non-obstructive anomalies is less clear.
These observations imply that retrograde menstruation alone may not account for the development of endometriosis in patients with uterine anomalies. Uterine dysperistalsis, a likely characteristic in many CUM cases, has also been proposed as a contributing factor. Moreover, the coexistence of infertility and uterine anomalies may amplify the severity of endometriosis [36].
The aim of the study is to identify the association between endometriosis and ESHRE/ESGE congenital uterine malformations [6], to determine the malformation most commonly associated with endometriosis and to detect the #Enzian [24] compartment most frequently involved. Among this cohort, 44 (14.5%) patients presented a dismorphic uterus (U1 according to ESHRE classification), 193 (63.5%) presented a septate uterus (ESHRE U2), 30 (9.8%) presented a bicorporeal uterus (ESHRE U3), 35 (11.5%) presented a hemi-uterus (ESHRE U4), and 2 (0.6%) presented an aplastic uterus (ESHRE U5). Out of a total of 304 patients, 116 presented with at least one ultrasound sign of endometriosis/adenomyosis. Specifically, 80 U2 patients (41.5%) showed signs, as did 22 U1 patients (50%), 5 U3 patients (16.7%), 9 U4 patients (25.7%), while none of the U5 patients presented any ultrasound signs of endometriosis/adenomyosis. Analyzing the incidence of endometriosis/adenomyosis across different malformations, it emerged that U3 has the lowest correlation (OR 0.3). Subsequently, a multivariate logistic regression analysis revealed a statistically significant association between endometriosis/adenomyosis and U1 (OR 5.0) and U2 (OR 3.5). Analyzing the individual #Enzian compartments, it emerged that U1 is exclusively correlated with FA compartment (OR 7.57), while U2 is associated with DIE compartment (A+B+C+FU) (OR 4.32). There is no correlation between U3, U4, or U5 and endometriosis/adenomyosis.