Adenomyosis Affects Fertility and ART Procedures as Well as Outcomes: An Invited Opinion

Adenomyosis is an enigmatic condition. Defining it separately from endometriosis is crucial for advancing the understanding of this entity. In the previous ICD-10 classification, adenomyosis (N80.03) was a subclassification of endometriosis (N80) (WHO, 2019), but in the recently released ICD-11, the diseases are separated as GA10 and GA11, respectively (WHO, 2024). The way adenomyosis was regarded as a subclassification of endometriosis may partly account for the confusing attribution of the effects or non-effects of adenomyosis on endometriosis and vice versa.

Adenomyosis also has a distinct symptomatology. Dysmenorrhea, or heavy menstrual bleeding, or both, coupled with morphologic abnormalities of the uterus described in imaging studies, are thought to provide a prediction model for the presence of adenomyosis (Tellum et al., 2018).

Despite being an attributable symptom, the clinical prediction model proposed by Tellum in 2018 did not include heavy menstrual bleeding as part of the clinical information collected for correlation with the diagnosis of adenomyosis. Eventually, a recent review by the same author acknowledged that the variety of classification systems based on numerous methods of imaging and histological categorization did little to discern whether the iterations of the disease are clearly associated with a particular outcome (Tellum et al., 2022). Given such heterogeneity, it is not surprising that systematic reviews and meta -analyses of various data sets provide limited association of adenomyosis with poor reproductive outcomes.

Whereas before, various modalities were utilized to diagnose adenomyosis to determine its relationship with subfertility (Maheshwari et al., 2012), standard criteria, an ultrasound imaging system, specifically the Morphological Uterus Sonographic Assessment (MUSA) (Harmsen et al., 2022; Van den Bosch et al., 2015) are currently employed to demonstrate association. Whereas early meta-analysis included studies without clear definitions or classifications of adenomyosis (Younes & Tulandi, 2017), current investigations now utilize the new criteria. Utilizing the MUSA criteria, Mishra et al. were able to determine that only 1 in 10 women with subfertility have isolated adenomyosis (Mishra et al., 2023).

With the advent of these criteria using ultrasound imaging, specifically the MUSA (Harmsen et al., 2022), many stakeholders are encouraged that this promising classification system for adenomyosis is accessible, replicable, non-invasive, and, hopefully, cost-effective. Already there are several studies utilizing these criteria to assess reproductive outcomes and evaluate the efficacy of interventions. The results, however, generally fail to confirm common clinical observations of the impact of adenomyosis on reproduction.

In a prospective cohort study with a sizeable sample ($n=1,228$ eligible participants) and utilizing the MUSA criteria, no effect on live birth rates was noted for women with adenomyosis (Higgins et al., 2021). It should be noted, however, that a large proportion of the sample was diagnosed with adenomyosis with only one of the six sonographic features or markers. This leads one to speculate that while the MUSA is standardized, an evaluation of which marker or combination of markers is more predictive of outcomes has yet to be developed. A similar concern is expressed by the authors of another study using donor oocytes (Dason et al., 2023), where, again, the presence of adenomyosis did not affect outcomes. Is it because the use of the MUSA, where finding just one marker already confirms the diagnosis of adenomyosis, when applied lowered the threshold for the diagnosis of adenomyosis compared with the original assessment? These were the concerns expressed by the author, noting that the MUSA diagnosed adenomyosis in 76% of the samples, higher than the usual prevalence of 30%, and more than thrice the diagnosis of adenomyosis using usual radiologic interpretation. Does the MUSA overdiagnose adenomyosis, increasing false positives and minimizing the impact of “true” positives on reproduction and intervention? This would certainly affect the interpretation of the actual impact of the disease on reproductive outcomes.

Evidence, nevertheless, still exists, as with a recent meta- analysis by Cozzolini (2022), that there is indeed a detrimental effect of adenomyosis on pregnancy and live birth rates among women undergoing assisted reproductive treatment (Cozzolino et al., 2022). Cozzolini also published a prospective observational study (Cozzolino et al., 2024) providing support to the idea that specific attributes of adenomyosis using ultrasound markers. These are, first, the presence of diffuse adenomyosis and, second, the presence of junctional zone lesions. Such lesions increase the likelihood of miscarriage and consequently decrease live births.

This information should now be the basis of future investigations, looking into which specific sonographic marker correlates with outcomes. Those associations observed in earlier papers (Tomassetti et al., 2013) should now be evaluated using standard criteria. Thereafter, any interventions directed to these specific lesions can effectively be evaluated.

In conclusion, we believe adenomyosis of a specific phenotype may be detrimental to reproduction. The use of standard criteria to detect adenomyosis is helpful, but identifying which type of adenomyosis, evaluated using standard imaging of specific lesions, will provide a threshold where the likelihood of poor outcome is expected. Until that threshold is defined, until clear associations are determined, and until unequivocal risk predictions are made, any recommendations toward removing these specific adenomyotic lesions—be it through surgical resection, one of the innovative nonsurgical techniques including uterine artery embolization (UAE), high-intensity focused ultrasound (HIFU), percutaneous microwave ablation (PMWA), or hormonal medical treatment prior to the pursuit of fertility—should be made with caution.

CONFLICT OF INTEREST

The author of this article had received honoraria for incidental expenses for her participation as speaker in industry sponsored symposia organized by Bayer, Abbott, BBraun, and Medtronic.

ORCID

Angela G. Sison-Aguilar  https://orcid.org/0000-0002-1590-2264