Uterine adenomyosis: Is there an impact on in vitro fertilization outcomes?

Uterine adenomyosis is a somewhat perplexing disease, with more and more articles describing the different mechanisms involved in its pathogenesis and meta-analyses reporting its impact on in vitro fertilization (IVF) outcomes. In a prospective observational cohort study, Cozzolino et al. (1Cozzolino M. Cosentino M. Loiudice L. Martire F.G. Galliano D. Pellicer A. et al.Impact of adenomyosis on IVF outcomes in women undergoing donor oocyte transfers: a prospective observational study.Fertil Steril. 2024; 121: 480-488Abstract Full Text Full Text PDF Scopus (1) Google Scholar) examined the association of adenomyosis type, location, and severity with reproductive outcomes in a series of 114 patients with adenomyosis undergoing single embryo transfer (SET) using embryos derived from donor oocytes. A comparison was made with 114 infertile women also undergoing SET with donor oocytes. It is true that using a model of oocyte donors allows doctors to focus more on the uterus, and this is what the investigators have done here. The aim was to mitigate the risk of biases because of the wide heterogeneity of female factor infertility in standard IVF-embryo transfer cycles as well as the variability in oocyte quality in these women. Therefore, as suggested by the investigators, it may be considered a good model to demonstrate the possible effect of this uterine pathology. In their study, the primary endpoint was the implantation rate, ascertained using a positive human chorionic gonadotropin value. After SET, the rate was similar in both groups (57% in women with adenomyosis vs. 53% in women without). Secondary endpoints were clinical pregnancy, ongoing pregnancy, and biochemical and clinical miscarriage. Live birth rates (LBRs) were not significantly different between the two groups (36.8% vs. 43.9%), but women with adenomyosis showed a significantly higher miscarriage rate than women without (35.4% vs. 18.1%). It is questionable to observe similar LBRs but significant differences in miscarriage rates in the same cohort study. Although there is indeed a difference in the LBR of >7%, the absence of statistical significance could be because of the relatively small number of patients. When, as stated, the implantation rate was comparable in both groups but the miscarriage rate was higher in women with adenomyosis, we would logically expect a lower LBR. The investigators chose the implantation rate as the primary endpoint. However, from a clinical point of view, the miscarriage rate and LBR are more important, as the birth of a healthy child represents the "final and expected goal" after embryo implantation. In a meta-analysis, the same investigator (2Cozzolino M. Tartaglia S. Pellegrini L. Troiano G. Rizzo G. Petraglia F. The effect of uterine adenomyosis on IVF outcomes: a systematic review and meta-analysis.Reprod Sci. 2022; 29: 3177-3193Crossref PubMed Scopus (27) Google Scholar) concluded that adenomyosis is a statistically significant factor in reducing LBRs and increasing miscarriage rates. Significance was obtained in this large series that compared 839 patients with adenomyosis and 4,649 patients without. Interestingly, in the present article (1Cozzolino M. Cosentino M. Loiudice L. Martire F.G. Galliano D. Pellicer A. et al.Impact of adenomyosis on IVF outcomes in women undergoing donor oocyte transfers: a prospective observational study.Fertil Steril. 2024; 121: 480-488Abstract Full Text Full Text PDF Scopus (1) Google Scholar), the location and severity of adenomyosis were evaluated by an expert in vaginal two-dimensional and three-dimensional echography looking to analyze the risk of miscarriage according to these parameters. The presence of adenomyosis features in the junctional zone (JZ) was associated with more than threefold higher odds of miscarriage. Diffuse adenomyosis in the JZ and severe adenomyosis raised the relative risk of miscarriage twofold, although adenomyosis in the outer myometrium did not impact miscarriage rates. It could therefore be argued that the endometrium, JZ, and inner myometrium all play an important role in invasion by trophoblasts after implantation. One criticism could be that magnetic resonance imaging (MRI) was not used to confirm transvaginal ultrasonography (TVUS) data. As reported by the investigators (1Cozzolino M. Cosentino M. Loiudice L. Martire F.G. Galliano D. Pellicer A. et al.Impact of adenomyosis on IVF outcomes in women undergoing donor oocyte transfers: a prospective observational study.Fertil Steril. 2024; 121: 480-488Abstract Full Text Full Text PDF Scopus (1) Google Scholar), TVUS may offer similar results to MRI to diagnose adenomyosis in experienced hands. However, this is surely not the case in all centers because results from TVUS are operator-dependent and MRI images may be easier to interpret, especially in cases of diffuse adenomyosis in an enlarged uterus. Nevertheless, in the present manuscript, we are confident that the TVUS results are accurate because the corresponding investigator who performed the procedure is a renowned expert in the field. In a previous article, we already corroborated the theory of progesterone resistance as a pathogenic characteristic of this condition and scrutinized the endometrium in patients with adenomyosis to assess endometrial receptivity and the degree of inflammation (3Stratopoulou C.A. Donnez J. Dolmans M.M. Origin and pathogenic mechanisms of uterine adenomyosis: what is known so far.Reprod Sci. 2021; 28: 2087-2097Crossref PubMed Scopus (37) Google Scholar). There is increasing evidence that the endometrium in women with adenomyosis is the site of inflammation, and the presence of M2 macrophages and fibrosis could explain changes in endometrial receptivity (4Stratopoulou C.A. Cussac S. d'Argent M. Donnez J. Dolmans M.M. M2 macrophages enhance endometrial cell invasiveness by promoting collective cell migration in uterine adenomyosis.Reprod Biomed Online. 2023; 46: 729-738Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar). It was recently demonstrated that M2 macrophages, which are more frequently detected in adenomyotic endometrium and stroma, are implicated in the invasion of the myometrium by endometrial glands (4Stratopoulou C.A. Cussac S. d'Argent M. Donnez J. Dolmans M.M. M2 macrophages enhance endometrial cell invasiveness by promoting collective cell migration in uterine adenomyosis.Reprod Biomed Online. 2023; 46: 729-738Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar). M2 macrophages secrete numerous growth factors that may interfere with endometrial receptivity. The presence of M2 macrophages and corresponding inflammation could be to blame also for impaired endometrial receptivity and subsequent subfertility in adenomyosis. This explains why modifying the timing of progesterone administration in IVF treatments does not improve reproductive outcomes in subjects with adenomyosis (1Cozzolino M. Cosentino M. Loiudice L. Martire F.G. Galliano D. Pellicer A. et al.Impact of adenomyosis on IVF outcomes in women undergoing donor oocyte transfers: a prospective observational study.Fertil Steril. 2024; 121: 480-488Abstract Full Text Full Text PDF Scopus (1) Google Scholar). Stratopoulou et al. (4Stratopoulou C.A. Cussac S. d'Argent M. Donnez J. Dolmans M.M. M2 macrophages enhance endometrial cell invasiveness by promoting collective cell migration in uterine adenomyosis.Reprod Biomed Online. 2023; 46: 729-738Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar) attempted to identify whether there were anomalies in the expression of endometrial receptivity markers. Eutopic endometrium from patients with adenomyosis was characterized using abnormal expression of leukemia inhibitory factor, homebox A10 (HOXA10), osteopontin, and progesterone receptor. As witnessed in their study, most anomalies occur in the stromal compartment, demonstrating their pivotal role in endometrial receptivity. Homebox A10 is particularly important because it mediates the expression of other implantation markers like integrins and influences the development of pinopodes. Decreased HOXA10 expression was found to impair endometrial receptivity in endometrial glands in patients with adenomyosis. Because HOXA10 expression depends on the local hormonal milieu, it could be hypothesized that an altered endometrial microenvironment may impact the invasion process of blastocysts after implantation and explain the high rates of miscarriage observed in Cazzolino et al.'s (1Cozzolino M. Cosentino M. Loiudice L. Martire F.G. Galliano D. Pellicer A. et al.Impact of adenomyosis on IVF outcomes in women undergoing donor oocyte transfers: a prospective observational study.Fertil Steril. 2024; 121: 480-488Abstract Full Text Full Text PDF Scopus (1) Google Scholar) study, as well as various meta-analyses (2Cozzolino M. Tartaglia S. Pellegrini L. Troiano G. Rizzo G. Petraglia F. The effect of uterine adenomyosis on IVF outcomes: a systematic review and meta-analysis.Reprod Sci. 2022; 29: 3177-3193Crossref PubMed Scopus (27) Google Scholar). As suggested in one recent research letter (5Donnez J. Donnez O. Dolmans M.M. Evolution of uterine adenomyosis volume during and after GnRH antagonist (linzagolix) treatment: lessons for further clinical trials.Fertil Steril. 2023; 120: 1071-1073Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar), the administration of gonadotropin-releasing hormone antagonists has proved very effective at reducing adenomyotic lesion numbers, volume, and severity. Administration for 12 weeks after oocyte collection and vitrification may offer the possibility of abating inflammation and invasion by macrophages and potentially normalizing endometrial receptivity before embryo transfer. Randomized controlled studies are obviously needed, but it is time to consider different therapeutic approaches to lower the risk of miscarriage in patients with adenomyosis undergoing IVF treatments (5Donnez J. Donnez O. Dolmans M.M. Evolution of uterine adenomyosis volume during and after GnRH antagonist (linzagolix) treatment: lessons for further clinical trials.Fertil Steril. 2023; 120: 1071-1073Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar). Impact of adenomyosis on in vitro fertilization outcomes in women undergoing donor oocyte transfers: a prospective observational studyFertility and SterilityVol. 121Issue 3PreviewTo prospectively examine the association between adenomyosis type, location, and severity with reproductive outcomes in patients undergoing single embryo transfer (SET) with embryos derived from donor oocytes. Full-Text PDF