"Stuck in the middle with you(terus): Another look at the impact of intramural leiomyomas on endometrium"

Uterine leiomyomas are the most common benign pelvic tumors in women of reproductive age, with a prevalence of up to 70% in White women and up to 80% in women of African ancestry. Uterine leiomyomas can vary greatly in both size and location within the uterus, and are typically classified simply as submucosal (protruding into the uterine cavity), intramural (within the muscle layer), or subserosal (on the outer surface of the uterus). It is well established that submucosal leiomyomas or large leiomyomas that alter the shape of the endometrial cavity have adverse effects on reproductive outcomes. There is fair evidence that hysteroscopic myomectomy for submucosal leiomyomas improves clinical pregnancy rates, and the American Society for Reproductive Medicine Practice Committee recommends that asymptomatic women with cavity-distorting leiomyomas (submucosal or intramural with a submucosal component), may be considered to undergo myomectomy (open, laparoscopic, or hysteroscopic) to improve pregnancy rates. However, it is less clear if intramural leiomyomas that do not distort the endometrial cavity have any deleterious effect on reproduction as multiple studies have shown conflicting results.

A secondary analysis of the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation clinical trial demonstrated that clinical pregnancy rates were reduced significantly in patients with noncavity-distorting leiomyomas compared to those without leiomyomas in conception cycles; however, there were no differences in the live birth rates. In contrast, other studies demonstrate significantly decreased cumulative pregnancy rates, live birth rates, and decreased ongoing pregnancy rates. Thus, the management of these noncavity distorting intramural leiomyomas remains controversial, and the American Society for Reproductive Medicine Practice Committee states that myomectomy is generally not advised to improve the pregnancy rates in infertile women with these types of lesions.

This then leads to the question—how do intramural leiomyomas that do not distort the cavity contribute to fertility issues? Even if the endometrial cavity is not distorted directly, an intramural leiomyoma could theoretically still physically affect it by decreasing the distensibility of the uterus. Could it possibly impact the endometrium at the molecular level, with effects on endometrial receptivity? Some recent studies have examined that. Microarray analysis of the midsecretory endometrium from women with noncavity-distorting uterine leiomyomas (patients with a single leiomyoma <5 cm, a single leiomyoma ><5 cm, two leiomyomas <5 cm, or three leiomyomas <5 cm) when compared with women without leiomyomas showed no differences in endometrial receptivity.

Further, a study compared endometrial gene expression signatures of the endometrium from subjects with noncavity-distorting leiomyomas to the genes on the Endometrial Receptivity Array platform and overall found minimal differences between the two. However, there were still a large number of significantly dysregulated genes between the two groups in the midsecretory phase. These studies, nevertheless, did not address the specific type of intramural fibroids based on their distance from the endometrium.

A major limitation of many studies examining the relationship between intramural leiomyomas and the endometrium, including the ones mentioned above, is that the exact number and location of the intramural leiomyomas are either unknown or not reported. Even in the subset class of intramural leiomyomas, there can be quite a bit of heterogeneity in the location in the myometrium, which could contribute to the conflicting results reported in the literature. If intramural leiomyomas, indeed, do have an adverse effect on the overlying endometrium, it would be advantageous and clinically relevant to specifically examine the leiomyomas that are in closest proximity to the endometrium without distorting it.

The investigators found that the expression and localization of metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) in the endometrium contralateral to type 3 leiomyomas were significantly altered. Metalloproteinases and TIMPs are involved in extracellular matrix remodeling, and their dysregulation, could contribute to aberrant tissue remodeling processes with collagen deposition and fibrosis in the endometrium. This abnormal collagen deposition and fibrosis may carry consequences for proper endometrial function. The investigators went even further to show that MMPs and TIMPs were altered at a protein level, something that many other studies fail to do. Whether this finding has any clinical merit is another question, as clinical studies still do not agree about the effect of intramural fibroids on fertility, if any. The next logical steps would be to specifically correlate the dysregulation of extracellular matrix components to endometrial receptivity, decidualization, and maybe even compaction and contractility function or dysfunction.

Governini et al. collected endometrial biopsies during the proliferative phase of the menstrual cycle via hysteroscopy. Interestingly and remarkably, the endometrial tissue was biopsied on the contralateral region in regard to the type 3 leiomyoma. This is potentially advantageous compared to other studies, where biopsies were obtained blindly with either a pipelle or with curettage. Moreover, the decision to obtain biopsies on the contralateral side is valuable, with the assumption that the ipsilateral endometrium overlying the type 3 leiomyoma is more ''affected.'' The downside, obviously, is the absence of the comparative analysis with the endometrium immediately overlying the fibroid. It would be intriguing to take the investigators' approach a step further and take multiple directed biopsies throughout the endometrial cavity to ''map out'' differences in gene expression in relation to an underlying type 3 leiomyoma.

"Endometrial receptivity array testing based on endometrial biopsies obtained blindly with a pipelle assumes that the endometrium is a homogenous entity. Perhaps the endometrium is more heterogeneous than previously thought, and these ''receptivity maps'' could open new avenues for reproductive management not only in the setting of leiomyomas but also with endometrial polyps and endometriosis/adenomyosis. Imagine the future, where we could directly transfer an embryo to a specific point in the endometrial cavity with the greatest receptivity, away from a type 3 leiomyoma or a scarred/atrophic island, rather than subjecting a patient to complex abdominal surgeries and potentially repeated implantation failures. This article is helping to make a small step toward that future."

Source: https://doi.org/10.1016/j.fertnstert.2021.09.004