MRI for Diagnosing Intrauterine Adhesions.

OBJECTIVES: To prospectively assess the diagnostic accuracy of MRI and transvaginal ultrasound (TVS) as well as the prognostic value of MRI for intrauterine adhesions (IUAs), using hysteroscopy as the reference standard. DESIGN: Prospective observational study. SETTING: Tertiary medical centre. PATIENT(S): Ninety-two women with amenorrhea, hypomenorrhea, subfertility, or recurrent pregnancy loss who underwent MRI and in whom Asherman's syndrome was suspected upon TVS. INTERVENTION(S): MRI and TVS were conducted approximately 1 week before hysteroscopy. METHODS: Ninety-two patients suspected of having Asherman's syndrome were examined by MRI and TVS within 7 days of an upcoming hysteroscopy. All hysteroscopy procedures were performed during the early proliferative phase of the menstrual cycle. All hysteroscopic diagnoses were performed by an experienced expert. All MRIs were read by 2 experienced, blinded radiologists. RESULTS: MRI was highly accurate (94.57%), sensitive (98.8%), and specific (42.9%) for diagnosing IUAs with a positive predictive value of 95.5% and a negative predictive value of 75%. The diagnostic values of MRI and TVS were significantly different according to McNemar tests. Junctional zone signal and junctional zone alterations correlated with the stage of IUAs. CONCLUSION: MRI is markedly superior to TVS in terms of diagnostic accuracy for IUAs, with total agreement with hysteroscopic findings. However, the main advantage of MRI is that, unlike TVS and hysterosalpingography, it can be used to assess the risk of hysteroscopy and to predict postoperative recovery and future pregnancy based on the uterine junctional zone.

Strategies for managing Asherman's syndrome and endometrial atrophy: Since the classical experimental models to the new bioengineering approach.

Endometrial function is essential for embryo implantation and pregnancy, but managing endometrial thickness that is too thin to support pregnancy or an endometrium of compromised functionality due to intrauterine adhesions is an ongoing challenge in reproductive medicine. Here, we review current and emerging therapeutic and experimental options for endometrial regeneration with a focus on animal models used to study solutions for Asherman's syndrome and endometrial atrophy, which both involve a damaged endometrium. A review of existing literature was performed that confirmed the lack of consensus on endometrial therapeutic options, though promising new alternatives have emerged in recent years (platelet-rich plasma, exosomes derived from stem cells, bioengineering-based techniques, endometrial organoids, among others). In the future, basic research using established experimental models of endometrial pathologies (combined with new high-tech solutions) and human clinical trials with large population sizes are needed to evaluate these emerging and new endometrial therapies.

Perivascular Stem Cell-Derived Cyclophilin A Improves Uterine Environment with Asherman's Syndrome via HIF1α-Dependent Angiogenesis.

Asherman's syndrome (AS) is characterized by intrauterine adhesions or fibrosis resulting from scarring inside the endometrium. AS is associated with infertility, recurrent miscarriage, and placental abnormalities. Although mesenchymal stem cells show therapeutic promise for the treatment of AS, the molecular mechanisms underlying its pathophysiology remain unclear. We ascertained that mice with AS, like human patients with AS, suffer from extensive fibrosis, oligo/amenorrhea, and infertility. Human perivascular stem cells (hPVSCs) from umbilical cords repaired uterine damage in mice with AS, regardless of their delivery routes. In mice with AS, embryo implantation is aberrantly deferred, which leads to intrauterine growth restriction followed by no delivery at term. hPVSC administration significantly improved implantation defects and subsequent poor pregnancy outcomes via hypoxia inducible factor 1α (HIF1α)-dependent angiogenesis in a dose-dependent manner. Pharmacologic inhibition of HIF1α activity hindered hPVSC actions on pregnancy outcomes, whereas stabilization of HIF1α activity facilitated such actions. Furthermore, therapeutic effects of hPVSCs were not observed in uterine-specific HIF1α-knockout mice with AS. Secretome analyses of hPVSCs identified cyclophilin-A as the major paracrine factor for hPVSC therapy via HIF1α-dependent angiogenesis. Collectively, we demonstrate that hPVSCs-derived cyclophilin-A facilitates HIF1α-dependent angiogenesis to ameliorate compromised uterine environments in mice with AS, representing the major pathophysiologic features of humans with AS.

Autologous platelet-rich plasma treatment for moderate-severe Asherman syndrome: the first experience.

PURPOSE: Treatment of Asherman syndrome (AS) presents a significant clinical challenge. Based on our in vitro data showing that PRP could activate endometrial cell proliferation and migration, we hypothesized that intrauterine infusion of autologous platelet-rich plasma (PRP) may improve endometrial regeneration and fertility outcomes in patients with moderate-severe AS. MATERIALS AND METHODS: Subjects with moderate-severe AS were randomized to PRP or saline control administered following hysteroscopic adhesiolysis. Due to relative inability to randomize patients to the control group, after initial randomization of 10 subjects (6 in PRP and 4 in control groups), the remainder were prospectively enrolled in PRP group (n = 9), with 11 historic controls added to control group, for a total of 30 subjects (PRP n = 15; saline control n = 15). Right after hysteroscopy, 0.5-1 mL of PRP or saline was infused into the uterus via a Wallace catheter, followed by estrogen therapy. The primary outcomes were changes in endometrial thickness (EMT, checked in 3 weeks) and in menstrual flow; secondary outcomes were pregnancy and live birth rates. EMT and menstrual bleeding pattern were assessed before and after the intervention. Pregnancy was assessed over a 6-month period. RESULTS: There were no statistically significant differences in age, gravidity/parity, cause of AS, preoperative menses assessment, AS hysteroscopy score, and intrauterine balloon placement between the groups. There was no statistically significant difference (p = 0.79) in EMT pre-PRP infusion for control (5.7 mm, 4.0-6.0) and study arm (5.3 mm, 4.9-6.0). There was no statistically significant change (p = 0.78) in EMT after PRP infusion (1.4 mm, - 0.5-2.4) vs saline (1.0 mm, 0.0-2.5). Patients tolerated the procedure well, with no adverse effects. There was no difference in the predicted likelihood of pregnancy (p = 0.45) between the control (0.67, 0.41-0.85) and study arm (0.53, 0.29-0.76). CONCLUSIONS: PRP was well accepted and tolerated in AS patients. However, we did not observe any significant EMT increase or improved pregnancy rates after adding PRP infusion, compared to standard treatment only. The use of intrauterine PRP infusion may be a feasible option, and its potential use must be tested on a larger sample size of AS patients.

Prevention of de novo adhesion formation in patients with Asherman's syndrome.

OBJECTIVE: To summarize recent data and knowledge of secondary prevention of the recurrence of intrauterine adhesions in patients with Ashermans syndrome. METHODS: Analysis of literature evidence and clinical experience of the authors. RESULTS: Ashermans syndrome is iatrogenic disease with problematic therapy. One of the basic issues is a need for repeated surgical interventions since the recurrence of adhesions is very frequent. Secondary prevention is a crucial factor for successful therapy in these patients. The methods applied include second--look hysteroscopy, hormonal treatment and different types of barriers. To compare their efficacy is difficult and the results of meta-analysis are contradictory. CONCLUSION: There are many different possibilities of secondary prevention of the recurrence of intrauterine adhesions; unfortunately, none of them is perfect. The usage of solid or semi-solid barriers in combination with the support of endometrium regeneration with hormonal therapy seems most reasonable.

Classification systems of Asherman's syndrome. An old problem with new directions.

Intrauterine adhesion (IUA) formation and the resulting Asherman's syndrome (AS) is an unfortunate clinical condition that occurs when the endometrium is damaged as a consequence of trauma, such as vigorous curettage, infection, or some Müllerian anomaly. The most frequent symptoms include hypo/amenorrhea, infertility, and adverse reproductive outcomes. Prevention of IUA formation is essential; however, when present, accurate diagnosis and surgical intervention (hysteroscopic adhesiolysis) are required. The outcome of this treatment is based on the technique and the extent of surgery performed which depends on the severity and complexity of the disease. Hence its classification becomes particularly important to determine a standardized therapy for each case and patient counseling regarding the prognosis. In this article, we aim to describe the IUAs classification systems that have been proposed comparing the merits and demerits of each one.

Comparison of the regenerative effects of bone marrow/adipose-derived stem cells in the Asherman model following local or systemic administration.

PURPOSE: Cell therapy is a promising strategy for the treatment of Asherman's syndrome (AS), but the origin of these cells and injection route influence the therapeutic effect and complications of cell therapy. Herein, we compared the effects of systemic or local intrauterine injection of bone marrow or adipose-derived mesenchymal stem cells (BMSCs/AMSCs) on the endometrium in a rat model of AS. METHODS: After induction of AS in adult Wistar rats, the CM-Dil-positive BMSCs or AMSCs were injected either locally or intravenously. After 3 weeks, endometrial thickness, collagen deposition, cell migration, and VEGF expression were evaluated using histochemistry/immunofluorescence studies. RESULTS: In all stem cell-treated groups, an ameliorative effect on the damaged endometrium was noted. Collagen deposition diminished in both groups (IV and local injection) compared to the AS model. In rats injected locally with MSC, fibrosis decreased compared to the other groups. Moreover, endometrial thickness increased in the groups that received local injection of BMSCs and AMSCs more than the IV-transplanted AMSCs group. Immunofluorescent staining demonstrated that although the systemic transplantation of BMSCs was more effective than the other groups on VEGF expression, it led to the lowest number of CM-Dil+ stem cells in the damaged endometrium. CONCLUSION: Stem cell transplantation may reconstruct the damaged endometrium, but it is recommended to select the most effective stem cells and injection route. Because the removal of the fibrosis and the replacement of the epithelia cells is an effective therapeutic strategy for AS, in this study, we conclude that the local injection of AMSCs is more appropriate than BMSCs to treat AS.

An update on stem cell therapy for Asherman syndrome.

The current treatment for Asherman syndrome is limited and not very effective. The aim of this review is to summarize the most recent evidence for stem cells in the treatment of Asherman syndrome. The advent of stem cell therapy has propagated experimentation on mice and humans as a novel treatment. The consensus is that the regenerative capacity of stem cells has demonstrated improved outcomes in terms of fertility and fibrosis in both mice and humans with Asherman syndrome. Stem cells have effects on tissue repair by homing to the injured site, recruiting other cells by secreting chemokines, modulating the immune system, differentiating into other types of cells, proliferating into daughter cells, and potentially having antimicrobial activity. The studies reviewed examine different origins and administration modalities of stem cells. In preclinical models, therapeutic systemic injection of stem cells is more effective than direct intrauterine injection in regenerating the endometrium. In conjunction, bone marrow-derived stem cells have a stronger effect on uterine regeneration than uterine-derived stem cells, likely due to their broader differentiation potency. Clinical trials have demonstrated the initial safety and effectiveness profiles of menstrual, bone marrow, umbilical cord, and adipose tissue-derived stem cells in resumption of menstruation, fertility outcomes, and endometrial regeneration.

Cellular therapies for the endometrium: An update.

An update on the current state of endometrial cell therapies in terms of cell types, mechanisms of action, delivery, safety, regulatory frameworks and future perspectives. This review focuses on clinical trials using angiogenesis-promoting therapies and stromal therapies piloted in the last 10 years for alleviating Asherman's syndrome and long-term infertility. All studies present promising preliminary results, indicating increased endometrial thickness and resumed menstruation. Further characterization of individual cell products, their mode of action and larger clinical trials will be essential to establishing cell therapy as a viable option for the treatment of infertility and fertility preservation.

Characteristics of Multipotent Mesenchymal Stromal Cells Isolated from the Endometrium and Endometriosis Lesions of Women with Malformations of the Internal Reproductive Organs.

We isolated and characterized cell cultures from eutopic endometrium and endometriotic lesions of women with malformations of the internal reproductive organs. The cells had fibroblast-like shape and intensively expressed CD90, CD73, CD105, CD44, CD146, and CD117 and were capable of induced adipogenic and osteogenic differentiation in vitro. The obtained cultures exhibited properties of multipotent mesenchymal stromal cells; at the same time, they demonstrated in vitro immunophenotypic differences from cell cultures of eutopic and ectopic endometrium of women without developmental abnormalities, which suggests their functional difference. The cells from eutopic endometrium and from ectopic endometriotic lesions can be used as the model for studying of the etiology and pathogenesis of endometriosis and for testing new drugs for this specific group of patients. Markers CD90 and CD117 were identified as promising molecules for the development of minimally invasive diagnostics of endometriosis based on cell cultures from eutopic endometrium.

Effect of stem cell application on Asherman syndrome, an experimental rat model.

PURPOSE: We evaluate the effect of stem cells to induce endometrial proliferation and angiogenesis on Asherman Syndrome (AS). METHODS: The experimental study was performed in stemcell research laboratory. Forty Wistar-Albino rats were divided according to groups. In group1 (n = 10) to establish the model; trichloroacetic acid was injected to right uterine horn. Two weeks later, intrauterine synechia was confirmed. In group2 (n = 10), 2 weeks later, 2 × 106 mesenchymal stem cells (MSC) were injected into right uterine horn followed by three intraperitoneal injections of MSCs. In group3 (n = 10), daily oral estrogen was initiated on the second week. In group4 (n = 10), MSC injections and oral estrogen was given together. The amount of fibrosis, vascularisation, inflammation and immunohistochemical staining with vascular endothelial growth factor (VEGF), proliferating cell nuclear antigen (PCNA) and Ki-67 were evaluated in the uterine tissues. RESULTS: In all treatment groups; fibrosis decreased but vascularisation and immunhistohemical stainings increased in the experimental side. The amount of fibrosis, vascularisation, Ki-67 and PCNA scores were similar between group2 and 3. In group4, comparing to group2, less fibrosis but more Ki-67, PCNA and VEGF staining was observed. CONCLUSION: Stem cells, when added to estrogen, are a highly effective alternative to induce regeneration of endometrium in Asherman Syndrome therapy.

The management of Asherman syndrome: a review of literature.

Asherman syndrome is a debatable topic in gynaecological field and there is no clear consensus about management and treatment. It is characterized by variable scarring inside the uterine cavity and it is also cause of menstrual disturbances, infertility and placental abnormalities. The advent of hysteroscopy has revolutionized its diagnosis and management and is therefore considered the most valuable tool in diagnosis and management. The aim of this review is to explore the most recent evidence related to this condition with regards to aetiology, diagnosis management and follow up strategies.

Regenerating endometrium from stem/progenitor cells: is it abnormal in endometriosis, Asherman's syndrome and infertility?

PURPOSE OF REVIEW: Stem/progenitor cells are present in human and rodent endometrium and have a key role in endometrial regeneration in normal cycling and after parturition. We review emerging evidence of multiple types of endometrial stem/progenitor cells, and that abnormalities in their location and function may contribute to endometriosis. RECENT FINDINGS: Candidate human endometrial stem/progenitors have been identified as clonogenic, Side Population and possessing tissue reconstitution activity. Markers have been identified for human endometrial mesenchymal stem cells, showing their perivascular location in functionalis and basalis endometrium. Human embryonic stem cells can be induced to develop endometrial epithelium, recapitulating endometrial development. In rodent studies, endometrial stem/progenitor cells were identified as label-retaining cells and their role in endometrial repair and regeneration revealed, perhaps via mesenchymal to epithelial transition. Studies of Wnt signalling in the regulation of endometrial stem/progenitor cells may yield insights into their function in endometrial regeneration. Stem/progenitor cells can be isolated from endometrial biopsy or menstrual blood and may be used autologously to regenerate endometrium in Asherman's syndrome. SUMMARY: There is much to be learnt about endometrial stem/progenitor cell biology and their role in endometriosis. Endometrial stem/progenitor cells hold great promise for new treatments for infertility associated disorders, including thin dysfunctional endometrium and Asherman's syndrome.

Antenatal 3-D sonographic features of uterine synechia.

We present a case of uterine synechia diagnosed by conventional 2-D color Doppler, 3-D sonography, and magnetic resonance imaging at 26 weeks' gestation. 3-D sonography clearly revealed umbilical cord prolapse through an oblique transverse uterine synechia. Loops of the umbilical cord were below and the fetus was superior to the uterine synechia. The edge of the umbilical cord loops was attached to the amniotic membrane, and a small echo-free space was noted beneath the attachment. 2-D color Doppler showed arterial blood flow consistent with the maternal heart rate. Magnetic resonance imaging confirmed the oblique horizontal membrane dividing the uterus with umbilical cord prolapse, its attachment to the amniotic membrane, and a small echo-free space in the low, liquor-filled amniotic cavity. We demonstrate how 3-D sonography provided a novel visual depiction of uterine synechia, which greatly helped in prenatal diagnosis and counseling.

Changes in endometrial receptivity in women with Asherman's syndrome undergoing hysteroscopic adhesiolysis.

OBJECTIVE: To determine whether there is any improvement in the endometrial receptivity in infertile women with Asherman's syndrome undergoing hysteroscopic adhesiolysis. MATERIALS AND METHODS: This was a prospective observational clinical analysis of 40 infertile patients who underwent hysteroscopic adhesiolysis for Asherman's syndrome in a tertiary level hospital. Endometrial thickness and blood flow impedance of the uterine spiral artery by transvaginal color pulsed Doppler ultrasound was measured post-menstrual on day 2/3 and post-menstrual on day 21 pre- and post-hysteroscopic adhesiolysis or at a randomly chosen time in patients with amenorrhea. RESULTS: The age of the patients was 18-36 years (mean 29.2 years). The mean duration of infertility was 6.9 years. There were 27 (67.5 %) women with primary infertility and 13 (32.5 %) had secondary infertility. 22 (55 %) women had had genital tuberculosis in the past. A significant improvement in the endometrial thickness was observed on day 2 (p < 0.0001) and day 21 (p < 0.0001) 3 months post-adhesiolysis. The spiral artery RI was statistically significant (p < 0.04) on day 2 pre-adhesiolysis compared to post-adhesiolysis. CONCLUSIONS: A significant improvement in the endometrial thickness was observed post-adhesiolysis. A high blood flow impedance of spiral artery perhaps impairs growth of the endometrium making it unsuitable for successful implantation.

Management of Asherman's syndrome.

Intrauterine adhesions (IUA) or Asherman's syndrome is a multifaceted condition which is being diagnosed with increasing frequency. Although it usually occurs following curettage of the pregnant or recently pregnant uterus, any uterine surgery can lead to IUA. Most women with IUA have amenorrhoea or hypomenorrhoea, but some have normal menses. Those who have amenorrhoea may also have cyclic pelvic pain secondary to 'trapped' menses and the accompanying retrograde menstruation may lead to endometriosis. In addition to menstrual disorders, most women with IUA will present with infertility or recurrent spontaneous abortion. Over the last four decades hysteroscopy has become the standard method to diagnose and treat this condition. Various techniques for adhesiolysis and for prevention of scar reformation have been advocated. The most efficacious appears to be the use of miniature scissors for adhesiolysis and the placement of a balloon stent inside the uterus immediately after surgery. Post-operative oestrogen therapy is prescribed in order to stimulate endometrial regrowth. Follow-up studies to assure resolution of the IUA are mandatory before the patient attempts to conceive as is careful monitoring of pregnancies for cervical incompetence, placenta accreta and intrauterine growth restriction.

Intrauterine infusion of platelet-rich plasma for severe Asherman syndrome: a cutting-edge approach.

Asherman syndrome (AS) consists of intrauterine adhesions development as a consequence of trauma, radiation, or infection in the endometrium. Clinical symptoms include menstrual alterations, infertility, and pregnancy complications, such as recurrent pregnancy loss or abnormal placentation. In this article, we performed a narrative review of the literature, searching electronic databases (i.e., Medline, Pubmed, and Google Scholar) to summarize the available pieces of evidence about epidemiology, pathophysiology, diagnosis, and treatment of AS. Hysteroscopy is essential for diagnosis and treatment, although adhesions may recur. Different postoperative therapies have been proposed to prevent recurrence and restore impaired endometrial function and promote endometrial regeneration, although these effects are usually temporary. We report a case of AS with adhesion recurrence and endometrial atrophy who was successfully treated with intrauterine autologous platelet-rich plasma (PRP) infusion. This therapy allowed endometrial tissue regeneration, leading to increased vascularity and endometrium thickness, and restoration of endometrial function that led to a successful pregnancy. Though there is limited experience supporting the use of PRP to improve endometrial function, it has been safely used in other fields of medicine; besides, it is easy to obtain, not expensive, and harmless being an autologous source. Future studies are encouraged to further assess this approach to treat AS.

[Asherman's syndrome I--history, prevalence, histopathology, classification, ethiology, symtomatology and investigations]. / Ashermanuv syndrom I--historie, prevalence, histopatologie, klasifikace, etiologie, symptomatologie a vysetrovací metody.

OBJECTIVE: To describe the current knowledge of Ashermanes syndrome--its history, prevalence, histopathology, classification, ethiology, symtomatology and investigations. DESIGN: Review article. RESULTS: There is presented the history of definition of Asherman's syndrome. The origin of Asherman's syndrome is in a fibrotisation of endometrium--the ethiologic factors are: an intrauterine trauma in connection with pregnancy, the trauma on nongravid uterus is in minority. There is not certificated that the inflammation without trauma can cause Asherman's syndrome, exception the cases with genital TBC and schistosomiasis. The prevalence of Asherman's syndrome depends on various factors: number of therapeutic and illegal abortions, on incidence of genital inflammation and TBC, on criteria used for diagnosis of IUA and etc. The typical symptomatology of this syndrome consisted of: menstrual abnormalities (hypomenorrhea, amenorrhoea), infertility, repeated pregnancy loss and pregnancy complications. There were described a lot of classifications developed in relation with chosen diagnostic method. The gold standard in diagnosis and therapy is the hysteroscopy, the sonohysterography is very promissing diagnostic method. CONCLUSION: The Asherman's syndrome is very complicated and severe disease that can significantly influence a possibility of woman conceive and give birth to a healthy child.

Suppression of the inflammation and fibrosis in Asherman syndrome rat model by mesenchymal stem cells: histological and immunohistochemical studies.

INTRODUCTION: Asherman syndrome (AS) is a symptomatic intrauterine adhesion caused by endometrial basal layer fibrosis as a result of either uterine cavity surgery or infection leading to many complications. There is a concern to repair the injured tissues by using bone marrow mesenchymal stem cells (BM-MSCs). We aimed in this study to develop an animal model of AS and evaluate the anti-inflammatory and anti-fibrotic effects of BM-MSCs in this model through histological, immunohistochemical, and morphometric studies. MATERIAL AND METHODS: Forty-two adult female adult albino rats were divided into (i) donor group composed of 2 rats used for isolation and propagation of BM-MSCs, and (ii) experimental groups: 40 rats equally divided into 4 groups: GpI (control), GpII (AS model), GpIII (BM-MSCs-treated AS rats), GpIV (untreated AS rats). Histological staining and immunohistochemical (IHC) detection of proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor (VEGF), and nuclear factor-kappa beta (NF-kB) were performed. The results were evaluated by morphometric and statistical analysis. RESULTS: Significant endometrial thinning, fibrosis, and degeneration of the endometrial epithelium with a significant decrease in PCNA and VEGF immunoexpression and a significant increase in NF-kB immunoexpression were detected in GpII and GpIV groups. These changes were substantially reversed in BM-MSCs-treated animals. CONCLUSIONS: BM-MSCs treatment resulted in substantial improvement of intrauterine adhesion in the rat model of Asherman syndrome.