- Open Access
Is adenomyosis the neglected phenotype of an endomyometrial dysfunction syndrome?
© The Author(s) 2011
- Received: 16 November 2011
- Accepted: 24 November 2011
- Published: 28 December 2011
Since the dissociation between adenomyoma and endometriosis in the 1920s and the laparoscopic progress in the diagnosis and surgery of endometriosis, the literature has been greatly focused on the disease endometriosis. The study of adenomyosis, on the other hand, has been neglected as the diagnosis remained based on hysterectomy specimens. However, since the introduction of magnetic resonance and sonographic imaging techniques in the 1980s, the myometrial junctional zone has been identified as a third uterine zone and interest in adenomyosis was renewed. This has also been the start for the interest in the role of the myometrial junctional zone dysfunction and adenomyosis in reproductive and obstetrical disorders.
Endometriosis and adenomyosis are both defined by the presence of ectopic endometrial-like tissue, respectively outside the uterus and in the myometrium. Although both disorders were described under the common name of “adenomyoma” by early authors  and extensively studied by Cullen  as one condition, today they are considered two different diseases. The dissociation practiced in the 1920s by Frankl  and Sampson  is largely a consequence of the limitations in diagnostic tools that have existed up to the mid-1980s. Today, new insights in the structural and functional characteristics of the endometrium and myometrial junctional zone (the “endomyometrium”), in women with adenomyosis and endometriosis, provide increasing evidence that they are frequently associated and both are characterized by an aberrant function of the endomyometrium. Data indicating that they could well represent two phenotypes of a similar endomyometrial dysfunction syndrome rather than two different diseases have been accumulated—thanks to current imaging techniques, functional, and molecular investigations. In addition, evidence has also been gathered that the endomyometrial dysfunction has major repercussion on reproductive functions. The present review first describes the history and clinical background of the two anomalies; subsequently, it outlines reproductive dysfunctions existing in both disorders and, finally, tries to define clinical features of the syndrome.
Although already in the 40s, Novak and de Lima  linked again adenomyosis and endometriosis, stating “one cannot resist the feeling that there is some common denominator between endometrial hyperplasia and adenomyosis, and possibly also pelvic endometriosis”, it was only over the last two decades that the search for the underlying link between endometriosis and adenomyosis received a major booster. The development that provided the first important lead was the introduction of magnetic resonance (MR) imaging; using this technique, the “myometrial junctional zone” (JZ) was identified as a functional uterine zone to form with the endometrium the endomyometrium unit . Shortly after, numerous molecular studies showed that the endometrium in endometriosis and adenomyosis is characterized by impaired cellular responses to ovarian sex steroids , as well as by a number of other metabolic aberrations.
Notwithstanding, these important developments, a major stumbling block remained since the histological diagnosis of endometriosis is based on a simple biopsy obtained at the time of laparoscopy or laparotomy, while the diagnosis of adenomyosis traditionally required a hysterectomy specimen. Indeed, to this day, almost all studies involving adenomyosis have been carried out on uteri removed at surgery. This has major scientific consequences. First, according to Scopus, the number of publications in 2011 on endometriosis is 22,730 and on adenomyosis 2,368, a tenfold difference. Secondly, endometriosis is frequently diagnosed in its early stage by the presence of variable or scarred peritoneal endometriosis, while adenomyosis is rarely diagnosed during the early reproductive life, its identification being made only after the appearance, in older women, of symptoms of abnormal menstrual bleeding and/or dysmenorrhea, severe enough to necessitate hysterectomy. Consequently, endometriosis risks to be overdiagnosed, while adenomyosis is neglected or overlooked.
In the normal human pregnancy, the remodeling of the spiral arteries involves both their myometrial and decidual segments. There is growing evidence that a pre-pregnancy disorder of the myometrial junctional zone is at the basis of defective deep placentation which, in turn, is associated with major reproductive and obstetrical complications . Comparative studies on placentation show that the human is not unique among primates in showing deep trophoblast invasion , although recent investigations indicate that the baboon, with no appreciable trophoblast invasion of the myometrium is not an appropriate model for the study of either endometriosis  or preeclampsia . On the other hand, there are case reports showing that preeclampsia may occur in chimpanzees and gorillas where trophoblast invasion and spiral artery remodeling are basically similar to the human [37, 38].
Today, the investigation of reproductive outcomes in young women with junctional zone abnormalities and/or adenomyosis has become possible—thanks to MR imaging and ultrasonography; using these techniques, an improved and clinically useful correlation with histology-based diagnosis for adenomyosis has been accomplished [39, 40]—thanks also to the analysis of the myometrial junctional zone. The importance of myometrial junctional zone research in reproductive medicine is frequently underestimated: indeed, the inner myometrium is the critical zone for the adequate transformation of spiral arteries supplying maternal blood to intervillous spaces of the placenta and a defective transformation of myometrial spiral arteries in the placental bed has been associated with major obstetrical syndromes .
The disappearance of the distinct myometrial zonal anatomy very early during pregnancy on MR imaging has also been observed in a unique case report by Turnbull et al. . This may correspond to the early decidualization process of the myometrial spiral arteries in the placental bed well before the zone is colonized by intravascular and interstitial trophoblast [43, 44].
Impaired follicular function
A recent MR imaging study by Kunz and Beil  suggests that the uterine junctional zone may be of significance with respect to the early process of human reproduction. In 113 infertile women, the diameter of the anterior and posterior JZ myometrium was documented by MR imaging prior to the use of in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI). Each group of women was also subdivided according to the presence [metaphase I (MI)/germinal vesicle (GV) >0%] or absence (MI/GV = 0%) of MI and GV oocytes. The MRI measurements were related to these and further parameters like expansion of the cumulus oophorus, pronuclei stages, embryo morphology, and pregnancy rates. The authors found that in all women with MI/GV = 0%, the JZ myometrium was significantly enlarged (p < 0.004) and the clinical pregnancy rate was significantly lower (p < 0.025) compared to that of women with MI/GV >0%. The authors suggested that the JZ, as documented by MR imaging, might interfere with follicular function.
Implantation failure and miscarriage
In a prospective clinical-imaging study including 152 patients, Maubon et al.  have explored the influence of the uterine junctional zone thickness (as measured on pelvic MR imaging), on implantation rates during IVF. They measured average and maximal junctional zone thickness values and implantation outcomes were correlated with these values and with infertility subtypes (endometriosis, tubal, dysovulation, male, and unexplained). A junctional zone thickness increase was significantly correlated with implantation failure at IVF: implantation failure rate was 95.8% for patients with an average junctional zone greater than 7 mm and a maximal junctional zone greater than 10 mm, versus 37.5% in other patient groups (p < 0.0001), independently from cause of infertility or patients’ age. The authors concluded that a pelvic MR scan showing a thickened uterine junctional zone has a negative predictive factor for embryo implantation after IVF.
Tremellen and Russell  reported that in four women who had previously undergone multiple unsuccessful in vitro fertilization attempts, inactivation of adenomyosis by an ultra-long pituitary downregulation regime, promptly resulted in successful pregnancy for all four women. In women with endometriosis, Mijatovic et al.  found no significant differences for any of the IVF/ICSI outcomes between women with and without concomitant adenomyosis after pretreatment with GnRH agonist for 3 to 26 months. Clearly, further prospective controlled studies are required to clarify the impact of adenomyosis on implantation following IVF.
Martinez-Conejero et al.  evaluated the effect of adenomyosis on endometrial gene expression and reproductive outcome in an oocyte donation program. The clinical and molecular data indicate that implantation is not affected by adenomyosis, but higher rates of miscarriage were associated with this condition leading to lower term pregnancies.
Major obstetrical syndromes
On the basis of pre-pregnancy imaging, Juang et al.  reported that adenomyosis is an important risk factor for spontaneous preterm delivery. Other recent studies have shown that endometriosis is associated with preterm delivery and other major obstetrical syndromes, such as small for gestation age in the absence of hypertension, preterm delivery, and obstetrical abnormal bleeding [50–52]. In evaluating the significance of these investigations, once again the question arises whether adenomyosis may not be a critical confounding factor in the endometriosis studies as long as adenomyosis or junctional zone hyperplasia is not systematically excluded by imaging scan. In addition, advanced maternal age is not only an important confounding factor for the likelihood of pregnancy complications, but is also associated with structural changes in JZ anatomy as demonstrated by Kunz et al. . Indeed, observational studies suggest that perturbations in JZ structure or functions prior to conception predispose towards impaired deep trophoblast invasion that underpins a spectrum of obstetrical complications, including preterm birth [53–55]
While the link between endometriosis and endometriosis has been puzzling, the role of the myometrial junctional zone appears in both conditions to be associated with several pathologically and clinically recognizable features. Therefore, the presence of either endometriosis or adenomyosis should alert the physician to the possible presence of the other. Both tend to have a range of possible etiologies that could create a set of reproductive and obstetrical disorders. Although the reason that they occur together has not yet been discovered, they have several molecular aberrations of the endometrium and myometrial junction zone in common. As a consequence, these features can justify the introduction of the endomyometrium dysfunctional syndrome.
Finally, there are several practical implications for research and clinical management. It is clear that, from now on, biochemical and clinical studies of the eutopic endometrium in women with endometriosis need to document the presence or absence of myometrial junctional zone abnormalities and uterine adenomyosis.
Conflicts of interest
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
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