Adenomyosis and infertility in 2024 – update with literature review

1. Introduction

Adenomyosis is a benign uterine condition marked by the infiltration of endometrial glands and stroma into the myometrium, resulting in the hypertrophy and hyperplasia of the myometrial smooth muscle cells. This condition was initially described in 1860 by the German pathologist Karl von Rokitansky⁽¹⁾.

Adenomyosis can manifest as either a diffuse or focal lesion (adenomyoma) affecting the inner or outer myometrium. Typically, lesions originate near the endometrial-myometrial junction and may extend outward into the myometrial layers, with varying depths of infiltration, from superficial to full-thickness involvement. The condition is common, with a prevalence estimated at 20-30% among women⁽²⁾. Adenomyosis significantly affects the quality of life in women due to its debilitating symptoms, which include severe pelvic pain, heavy menstrual bleeding, and an association with infertility. Additionally, it can lead to obstetric complications, even in naturally conceived pregnancies, such as pre­eclampsia, preterm birth, fetal growth restriction, and postpartum hemorrhage⁽³⁾.

Adenomyosis has received growing attention from researchers, signaling a shift toward a more comprehensive understanding of its impact, especially regarding infertility risk in women of reproductive age. While past studies primarily focused on diagnostic methods, current research is advancing towards molecular-level diagnostic approaches, which hold potential for transformative treatment options for this complex condition. Traditionally, adenomyosis has been viewed as a pathology mainly affecting older, multiparous women, particularly those with a history of invasive uterine procedures, aligning with established risk factors. However, new studies reveal a significant presence of adenomyosis among younger women, often in relation to primary infertility.

Given the rising prevalence of infertility and the strong correlation between adenomyosis and reduced fertility rates, we highlight the latest advancements in diagnostic and treatment approaches that offer potential improvements both in symptoms’ management and in the implementation of assisted reproduction protocols. These updates aim to enhance patient outcomes by addressing adenomyosis impact on reproductive health, particularly for those undergoing assisted reproductive techniques (ART).

2. Materials and method

We searched PubMed for relevant full-text articles published in English between January 2024 and November 2024, using the following keywords: ‘‘adenomyosis’’ and “infertility”. Filters applied: free full text, English language. We found 43 articles, of which 13 discuss treatment options (hormonal therapies, minimally invasive therapies, surgical techniques), eight focus on molecular and epigenetic mechanisms, seven address the implications of this pathology within assisted reproductive techniques, six explore newly discovered risk factors in the onset of adenomyosis, and five propose new diagnostic criteria.

3. Results

Diagnosis

Researchers sought to examine the relationship between adenomyosis type and severity with symptoms and fertility outcomes, using ultrasound assessments in affected patients. The findings revealed differences between focal and diffuse adenomyosis, particularly in relation to patients’ age, menstrual bleeding patterns, infertility rates, and miscarriage incidence. While no direct correlation was found between symptoms’ severity and disease extent, the study noted that diffuse adenomyosis was more commonly observed in older women experiencing heavy menstrual bleeding. In contrast, focal adenomyosis was linked to higher rates of infertility and miscarriage. Additionally, severe diffuse adenomyosis was associated with intense dysmenorrhea and menorrhagia⁽⁴⁾.

The MUSA (Morphological Uterus Sonographic Assessment) consensus, released in 2015, established standardized terminology and uniform criteria to improve the accuracy of ultrasound diagnosis for adenomyosis⁽⁵⁾. Following the release of the MUSA criteria in 2018, a pilot study found that inter-rater reliability in using these features to assess ultrasound images of adenomyosis was low, even among both highly and moderately experienced evaluators. This inconsistency was likely due to ambiguities in the definitions of specific ultrasound characteristics⁽⁶⁾. In 2021, the MUSA criteria were revised by a panel of experts to improve diagnostic clarity for adenomyosis using a Delphi procedure. The revised criteria classify ultrasound markers as direct (e.g., myometrial cysts, hyperechoic islands) and indirect signs (e.g., asymmetrical thickening, globular uterus). The diagnosis requires at least one direct sign, which indicates ectopic endometrial tissue, while indirect signs suggest related myometrial changes. Although direct signs have high specificity, their sensitivity remains low. In uncertain cases, 3D-TVUS evaluation of the junctional zone can help exclude adenomyosis if the zone appears intact⁽⁷⁾.

At present, transvaginal ultrasound (TVUS) is the primary diagnostic tool for adenomyosis, demonstrating significantly higher accuracy compared to the trans­abdominal approach. This method is direct, minimally invasive, cost-effective, widely accessible, and has no contraindications. Additionally, the development of three-dimensional ultrasound (3D-TVUS) marks a valu­able improvement, especially for assessing the junctional zone, making it particularly beneficial in the evaluation of adenomyosis⁽⁸⁾.

In the most recent article regarding the correlation between symptoms and ultrasound findings of adenomyosis, Biasioli et al. found that, apart from peri­ovulatory pain, there were no major clinical differences between patients with direct ultrasound markers of adenomyosis and those with only indirect signs. In highly symptomatic patients, indirect signs alone might result from obscured direct markers due to extensive myometrial changes. Their findings suggest that, while new diagnostic criteria are not stricter, diagnosing ade­nomyosis should combine clinical and imaging data. In asymptomatic patients, indirect signs alone can rule out adenomyosis, minimizing overdiagnosis. However, in symptomatic cases, a holistic clinical approach remains essential, with further studies needed to validate these insights⁽⁹⁾.

Also, a study demonstrates that subendometrial lines and buds were the most common direct feature of adenomyosis, detected in 7.1% of women. These features align with the MUSA criteria for irregularities and are considered one of the most accurate ultrasound markers for diagnosing adenomyosis. The study also observed that women with endometriosis were more likely to present altered junctional zones, with the likelihood of adenomyosis features being nearly three times higher in these women. However, the revised MUSA criteria suggest that some direct features could also be considered indirect, potentially leading to an overestimation of indirect features. Additionally, the junctional zones may appear irregular or interrupted due to fibrosis or artifacts, which may not necessarily indicate adenomyosis. Translesional vascularity is often used to rule out fibroids and typically appears alongside other indirect features like a globular uterus or fan-shaped shadowing. They found that 1 in 10 women preparing for their first ART procedure displayed direct or pathognomonic signs of adenomyosis on both 2D and 3D-TVUS. It suggests that routine 2D and 3D-TVUS exams, using standardized diagnostic criteria for adenomyosis, should be integrated into everyday clinical practice⁽¹⁰⁾.

In light of this, Tandulwadkar et al. proposed a classification system based on the size, location and distance of the adenomyoma from the endometrial cavity, as well as the presence of associated endometriosis, developed through a study of 100 women with adenomyosis undergoing in vitro fertilization (IVF)⁽¹¹⁾. Based on their classification, 56% of the women were categorized in grade 1, 24% in grade 2, 8% in grade 3, and 12% in grade 4 adenomyosis. Pregnancy rates were 71% for grade 1, 66% for those receiving medical management, and 33% for those undergoing surgical treatment in grade 2. Women with grade 3 were recommended surrogacy, while those with grade 4 had a pregnancy rate of 66%.

Adenomyosis and infertility

For successful spontaneous conception, the normal function of both the endometrium and fallopian tubes is essential, as it creates a physiologically optimized environment for fertilization and early embryonic development⁽¹²⁾. Adenomyosis associated with subfertility presents a challenging dilemma for clinicians, as treatment options remain highly debated, and there is no clear consensus on the role of conservative surgery, with or without medical management, in improving reproductive outcomes. 

The exact mechanism linking adenomyosis to infertility remains unclear, but several factors have been proposed. One factor involves intrauterine abnormalities, such as increased uterine peristalsis and inflammation, which can lead to anatomical distortions and adhesions that impair sperm migration and embryo transport⁽¹³⁾. Another contributing factor is the abnormal endometrial function, where altered steroid metabolism, heightened inflammation and increased oxidative stress affect the uterine environment, making it less receptive to implantation⁽¹⁴⁾. Inflammation can also impair implantation by reducing the expression of adhesion molecules and markers necessary for embryo attachment, such as leukemia inhibitory factor (LIF) and HOXA10, a gene important for embryonic development⁽¹⁵⁾. Additionally, chronic endometritis resulting from uterine infections may further compromise fertility in women with adenomyosis.

Another aspect that was investigated is the link between chronic endometritis (CE) and reproductive complications, including recurrent implantation failure following IVF and embryo transfer, recurrent miscarriage, and unexplained infertility⁽¹⁶⁾. A multicenter cohort study conducted in Japan observed a higher incidence of uterine infections in patients with diffuse adenomyosis, potentially leading to the development of chronic endometritis in these women⁽¹⁷⁾. While the causal relationship between CE and embryo implantation failure remains debated, existing evidence suggests that chronic endometritis adversely impacts reproductive outcomes. A recent study provides clinical evidence showing that CE occurs at varying rates in women with different forms of adenomyosis, including focal, diffuse, intrinsic, and extrinsic types. These findings suggest that the presence of chronic endometritis in various adenomyosis subtypes may contribute to poor fertility outcomes⁽¹⁸⁾. The negative impact of adenomyosis on fertility may stem from several biological factors, including local inflammation caused by the condition, disruptions in uterotubal sperm transport, altered endometrial function and receptivity, and a disturbance in local hormonal metabolism, leading to a hyperestrogenic environment. Recent research suggests that inflammation in the endometrium may lead to damage of the microvilli and axonemal alterations in the apical endometrial cells, potentially explaining the link between adenomyosis and poor fertility outcomes. These findings could provide valuable insights for clinicians when counseling symptomatic patients with adenomyosis who are considering future pregnancies⁽¹⁹⁾.

ART in the context of adenomyosis

Research indicates that heightened uterine contractions during embryo transfer in IVF cycles are associated with lower pregnancy success rates⁽²⁰⁾. Oxytocin receptor antagonists, which bind to oxytocin receptors with higher affinity than oxytocin itself, reduce uterine contractions by lowering prostaglandin production and limiting calcium influx into cells⁽²¹⁾. While some studies have reported a notable increase in clinical pregnancy rates when using atosiban during embryo transfer compared to controls⁽²²⁾, other studies have not found similar benefits⁽²³⁾.

Building on these findings, Lin et al. hypothesized that administering an oxytocin receptor antagonist during embryo transfer might improve IVF outcomes in women with adenomyosis. Their study revealed a positive association between the use of an oxytocin receptor antagonist and reduced early miscarriage rates among women affected by adenomyosis⁽²⁴⁾.

Regarding the medical treatment for improving the success rate of IVF, Ansaripour et al. conducted a trial that compared the ultra-long GnRH agonist protocol versus standard downregulation for frozen-thawed embryo transfer in women with adenomyosis. They found that, in women with adenomyosis undergoing frozen-thawed embryo transfer (FET) cycles, extended GnRH agonist downregulation did not enhance chemical or clinical pregnancy rates compared to the standard GnRH agonist protocol. These findings suggest that, for women with adenomyosis (and no endometriosis history), the standard GnRH agonist downregulation protocol may be more effective in achieving higher clinical and chemical pregnancy rates, positioning it as a preferred approach for FET⁽²⁵⁾. However, for patients with poor ovarian function, the ultralong protocol should be applied cautiously. In fresh embryo transfer cycles, the ultralong protocol appeared to enhance pregnancy outcomes; however, the extended duration and higher dosage of gonadotropins resulted in increased costs. In contrast, the use of long-acting GnRHa in frozen-thawed embryo transfer (FET) cycles showed no impact on pregnancy success. A combination of long, short, or antagonist protocols in fresh embryo transfer cycles, along with a flexible FET approach, may offer a promising strategy for patients with adenomyosis and diminished ovarian reserve⁽²⁶⁾.

For patients with severe adenomyosis, the literature offers hope that there are cases of success in achieving and maintaining a pregnancy, even after surgical treatment of this condition. A Japanese team reported the case of a 35-year-old woman with uterine adenomyosis who underwent preoperative gonadotropin analog treatment before a laparoscopic adenomyomectomy, guided by intraoperative elastography. The surgery successfully removed the adenomyotic tissue while preserving the endometrium, and postoperative MRI confirmed no residual adenomyosis. Following in vitro fertilization and double blastocyst transfer, the patient achieved a twin pregnancy. Although she required hospitalization for preterm labor prevention, she delivered healthy twins by caesarean section at 32 weeks. This case marks the first reported successful twin pregnancy after vitrified-warmed embryo transfer post-elastography-guided adenomyomectomy. The technique offers precise tissue resection and reduces risks of uterine rupture and placenta-related complications, though further research is needed to confirm its safety and efficacy⁽²⁷⁾.

In ART, platelet-rich plasma (PRP) presents a promising option for addressing endometrial complications related to fertility treatments. While they remain a useful adjunct, further standardization of preparative strategies and large-scale studies are needed to confirm their effectiveness across patient groups. Uterine absorption, which leverages PRP’s regenerative properties, may offer a targeted approach to improve endometrial receptivity and health in future ART treatments⁽²⁸⁾.

Medicine is not about the disease, it’s about the patient

Lastly, a topic often considered taboo in the medical field, regardless of the pathology being treated, is the importance of the relationship between healthcare providers and patients. This is especially relevant in cases of conditions such as adenomyosis or other infertility-related disorders, where the emotional impact on the patient is considerably stronger. Studies examining the doctor-patient relationship indicate that the perception of a patient’s condition can take on a different meaning depending on how both the progression of the disease and treatment options are communicated.

The focus of endometriosis research has shifted from improving pathological classification to exploring pa­tient-reported outcomes, revealing a growing disconnec­tion between doctors and their patients. This highlights the need for a more compassionate, patient-centered approach in healthcare. It is essential that medical professionals not only rely on their scientific knowledge, but also understand the individual experiences of patients by listening, addressing their unique needs, and considering their personal values when making treatment decisions. These principles should be embedded in medical education and practiced as part of a professional ethical responsibility.

For individuals with endometriosis, the quality of care has been directly linked to higher treatment satisfaction, and incorporating human-centered practices has been shown to improve clinical results. Doctors, who are not just providers of medical treatment but also a source of care, must be aware that their approach and attitude play a crucial role in determining their patients’ overall well-being and quality of life⁽²⁹⁾.

4. Conclusions

Recent advancements in the diagnosis and treatment of adenomyosis mark a shift toward minimally invasive approaches, particularly for younger women experiencing primary infertility. Current research emphasizes the importance of high-precision diagnostic methods such as transvaginal ultrasound (TVUS) and three-dimensional TVUS (3D-TVUS), based on refined MUSA criteria. These techniques aim to distinguish between direct and indirect ultrasound markers, which is crucial for accurate diagnosis and reducing the risks of overdiagnosis, particularly in asymptomatic patients. Emerging diagnostic criteria and refined imaging techniques now enable earlier and more precise detection of adenomyosis, which is especially useful in younger patients experiencing primary infertility. Early diagnosis allows for tailored treatment strategies that may improve ART success.  There is a growing body of evidence supporting pre-ART treatments, such as hormonal therapies (e.g., GnRH agonists) or minimally invasive interventions, that aim to control adenomyotic lesions and reduce uterine inflammation. These treatments have shown promise in enhancing ART success rates by improving the endometrial environment. Conservative treatment approaches, such as HIFU, PMWA and RFA, demonstrate potential for symptoms’ management while preserving fertility. Advances in molecular research have shed light on the role of epigenetic changes and inflammatory markers associated with adenomyosis, which can hinder embryo implantation. These findings suggest that targeted anti-inflammatory treatments or hormonal therapies may improve ART outcomes for women with adenomyosis. However, further research is necessary to establish standardized treatment guidelines. Overall, a patient-centered approach that integrates compassio­nate, individualized care with evidence-based practice is essential to optimize the management of adenomyosis and improve patients’ outcomes.   

CORRESPONDING AUTHOR: Ioana Păvăleanu E-mail: ioana_pavaleanu@yahoo.com

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.