IUA is an intrauterine lesion resulting from trauma and/or infection of the endometrial basal layer (1, 2). The pathogenesis of IUA remains incompletely understood. Nevertheless, it is commonly thought to be associated with the mutual adhesion between the uterine muscular walls following damage to the basal layer of the endometrium. This process encompasses three stages: the inflammatory stage, the tissue formation stage, and the tissue reconstruction stage (1). Given that the repair of the endometrium mostly involves incomplete regeneration, it eventually results in functional impairment and scar formation. The clinical manifestations of IUA patients mainly include reduced menstrual flow, amenorrhea, dysmenorrhea, infertility, and recurrent miscarriage. The severity of these symptoms is positively correlated with the degree of IUA (3). In severe cases, IUA may have a profound impact on a woman's fertility and mental health (2). Because of this, in recent years, numerous scholars have conducted extensive and in-depth research on the influencing factors of menstrual improvement in patients with moderate to severe IUA (Table 1) (4). This paper aims to review the latest progress of these studies, with the hope of providing more accurate professional guidance for clinical practice.

The Müllerian duct is the simplest basic duct and the cornerstone of the female reproductive tract. This structure consists of an epithelial lumen and the surrounding mesenchymal layer (5). As the fundamental structure of the female reproductive tract, the development of the Müllerian duct is crucial for the formation of the female reproductive system. The uterine morphological and functional abnormalities associated with Müllerian duct anomalies (6) increase the susceptibility of the endometrium to trauma. During the post-trauma repair process, they are more likely to trigger abnormal extracellular matrix deposition and tissue fibrosis, thus significantly elevating the risk of IUA. AMH, also known as Müllerian inhibiting substance (7), plays a very important role in regulating cell differentiation and inhibiting the development of the Müllerian duct (8). In the bodies of adult females, Follicle-Stimulating Hormone can stimulate the expression of AMH. AMH exerts an inhibitory effect by counteracting follicle-stimulating hormone, thus promoting the gradual regression of the Müllerian duct (9). AMH assesses the ovarian reserve function through the quantity and quality of ovarian follicles in women. Its level is positively correlated with the ovarian reserve function (10) but negatively correlated with age (11, 12). Therefore, among patients with moderate to severe IUA, the improvement in menstruation in young women is generally better than that in middle-aged and elderly women. This may be closely related to the good development of the Müllerian duct and the relatively high level of AMH in young women.

MSCs are a type of multipotent stem cells, renowned for their self-renewal and multilineage differentiation potential (13). MSCs have a rich variety of sources, mainly including umbilical cord mesenchymal stem cells, bone marrow mesenchymal stem cells, adipose tissue-derived stromal cells, human amniotic mesenchymal stem cells, placental mesenchymal stem cells, etc. These are all hot topics in research and application (13). Some studies have shown that MSCs can not only promote the repair and regeneration of the endometrium through paracrine action (14) but also increase the vitality of the damaged endometrium via exosomes (15, 16), inhibit and even reverse the process of endometrial fibrosis (17, 18). The specific mechanisms of action may involve multiple aspects such as promoting angiogenesis (19), regulating the inflammatory response (20), and providing nutritional support. These characteristics endow MSCs with unique advantages and potential in the restoration of menstruation in IUA patients. In addition, MSCs can maintain the homeostasis of the uterine internal environment. The balance between self-differentiation and self-renewal of stem cells is crucial for the cyclic regeneration of the endometrium (13). Under physiological conditions, the human body is precisely regulated by the Hypothalamic-Pituitary-Ovarian-Gonadal Axis. As a result, the endometrium undergoes cyclic exfoliation and repair, demonstrating a high regenerative potential. Among them, the level of Estrogen is one of the key factors promoting the repair and regeneration of the endometrium. Some studies have confirmed (21) that the estrogen secreted by MSCs plays a decisive role in therapeutic applications. Estrogen not only promotes the proliferation and migration of MSCs (22) but also inhibits their apoptosis, providing a suitable microenvironment for the survival of MSCs (13). This interaction synergistically promotes angiogenesis in damaged tissues, thereby facilitating the repair and regeneration of the endometrium (23, 24). The endometrium is divided into the superficial functional layer and the deep basal layer. The integrity and continuity of the basal layer are the keys to the cyclic repair and regeneration of the endometrium (25). Some studies have found (26) that when the deep basal layer of the endometrium suffers severe damage, the vast majority of the basal layer is often replaced by a single-layer epithelium and fibrous tissue. This leads to difficulty in the regeneration of the functional layer, a decline in the endometrium's self-repair ability, and the endometrium being in an abnormal state. In this case, even if the Estrogen level in the body is high, due to the reduction in the number of Estrogen receptors or the saturation of their functions, the response to Estrogen stimulation weakens, resulting in an unsatisfactory treatment effect (27). Therefore, for patients with moderate to severe IUA, an adequate Estrogen level and an endometrial basal layer that has not suffered severe damage are two indispensable conditions for achieving menstrual improvement (Figure 1) (28).

With the continuous development and increasing maturity of hysteroscopic technology, the comprehensive treatment method mainly based on hysteroscopy is being increasingly widely applied in patients with moderate to severe IUA (1). Therefore, the impact of hysteroscopic surgery on endometrial and menstrual improvement has become a hot topic in academic and clinical practice.

Hysteroscopic technology (3) is an innovative technique in the field of minimally invasive gynecological diagnosis and treatment (29), its core advantage is in using fiber-source endoscopes for precise inspection and treatment of the uterine cavity. The main operating mechanism of this technology is to insert an endoscope with a light source into the uterine cavity via the vagina and cervix, enabling direct and clear observation of multiple aspects such as the shape of the uterine cavity, the condition of the endometrium, the presence of endometrial polyps, the distribution of abnormal blood vessels, and the state of the bilateral fallopian tube openings (30). Meanwhile, surgical instruments can be introduced through their working channel to perform operations like tissue cutting, separation, and electrocoagulation for hemostasis to treat various intrauterine diseases. Additionally, specimens can be accurately collected under direct vision for pathological examination, providing a reliable basis for diagnosis and treatment (31). Given that the fiber-optic and lens design of the hysteroscope is extremely precise, the damage it causes to the endometrium is minimal, and theoretically, it should not significantly affect a woman's menstrual function. During Transcervical Resection of Adhesion (TCRA) performed under hysteroscopy, the mechanical cold-knife technique is often used to physically separate the adhesive tissue in patients with moderate to severe IUA. Although this process may cause a certain degree of damage to the endometrium, after a period of recovery following the surgery, the endometrial function can return to normal completely, and it will not have a long-term impact on menstrual improvement (32). One study mentioned (33) that it conducted a detailed analysis of the outcomes of hysteroscopic surgery in patients with different degrees of IUA. The results showed that 100% of patients with severe IUA experienced an increase in menstrual volume after hysteroscopic surgery (including a return to normal levels). This result may be closely related to multiple factors such as Surgical Technique, Follow-up Frequency, Barrier Methods, Hormone Therapy, Biological Adjuncts, Innovations (e.g., estrogen stents, HA, PRP, and smart medicine). The following will explore these influencing factors in depth (Figure 2).

Psychological factors play a pivotal role in the improvement of menstrual function in patients with moderate to severe IUA. Due to the long treatment cycles, complex treatment procedures, uncertain treatment efficacy, heavy economic burden, and high recurrence rate of adhesions that IUA patients face, these patients often experience negative emotions such as anxiety and depression (57). Therefore, it is particularly important to develop and implement targeted psychological intervention measures to alleviate patients' psychological burden and improve their quality of life (58). Research shows (57) that a harmonious partner relationship can encourage both spouses to participate in and cooperate during the treatment of IUA, which can effectively relieve the patient's psychological stress. A study by Yuqing Chen, Huan Yang, et al. has found (59) that negative emotions may interfere with sex hormone levels, affect the repair of the endometrium, and thus influence the improvement of menstruation. Mindfulness-Based Stress Reduction, as a method of psychological self-regulation training, has been proven to significantly improve negative emotions such as anxiety and depression in IUA patients during treatment by enhancing the state of mindfulness and adjusting the cognitive level, thus improving their quality of life. Si Jingge and Wang Sha also pointed out that disease-specific follow-up can provide effective guidance and supervision for IUA patients, especially in terms of postoperative adjuvant drug therapy. It can enhance patients' awareness and attention to the disease, avoid unfavorable factors, and standardize subsequent treatment plans. As a result, patients with IUA who receive disease-specific follow-up tend to experience a shorter time to menstrual resumption, a longer menstrual period, and better improvement in menstrual flow (60). In conclusion, psychological factors play a crucial role in the diagnosis and treatment of moderate to severe IUA. The emotional changes in patients are not only triggered by the occurrence of IUA but also, in turn, affect the treatment outcome of IUA (61).

In summary, in the research of the past decade, significant progress has been made in studies on improving menstruation in patients with moderate to severe IUA. This progress is not limited to the common clinical manifestations of IUA patients in traditional cognition, such as reduced menstruation or amenorrhea. The current research horizons are constantly expanding, covering but not limited to the following key areas: exploring the association between Müllerian duct development and AMH levels, the interaction and dynamic changes between MSCs and the endocrine system, and the impact of hysteroscopic surgery on the improvement of the endometrium and menstruation, and the crucial role of psychological factors in the treatment process. These multi-dimensional influencing factors jointly act on the process of improving the menstrual function of patients with moderate to severe IUA. Thus, in young patients with moderate-to-severe IUA, good restoration of menstrual patterns is generally achieved, even if the surgical and subsequent intervention regimen tends to be simplified, because of the maturation of the mullerian ducts, the relatively high levels of AMH and E, and the limited damage to the basal layer of the endothelium. The influencing factors for improving menstruation in patients with moderate to severe IUA involve multiple fields such as biology, endocrinology, and psychology. Considering these factors comprehensively and formulating individualized treatment plans are of great clinical significance in many aspects, including improving treatment efficacy, reducing the risk of re-adhesion, optimizing treatment regimens, enhancing the quality of life of patients, and preventing infertility and miscarriage. However, it cannot be ignored that the research on the influencing factors of menstrual improvement in patients with moderate to severe IUA still faces many challenges. At present, a clear theoretical framework has not been formed regarding the specific directions for improving menstrual function, which restricts the prediction and optimization of treatment effects. Additionally, there is a lack of adequate literature and data to support research on the effects of Müllerian duct development and AMH content on the improvement of menstruation, indicating that further research is needed to fill this knowledge gap. Thus, for patients with moderate to severe IUA, the influencing factors of menstrual improvement are multifaceted and interrelated. Future research needs to further explore the interactions among these factors and how to optimize treatment plans to improve treatment outcomes. At the same time, focusing on the development of individualized treatment strategies is also a key direction for enhancing treatment effectiveness.