Live births after Asherman syndrome treatment.

OBJECTIVE: To study the reproductive outcomes after surgical management of women with Asherman syndrome (AS). DESIGN: Cohort study. SETTING: International referral hospital for women with AS. PATIENT(S): A total of 500 women who were diagnosed with and treated for AS between January 2003 and December 2016 and followed for a minimum of 2 years. INTERVENTION(S): Hysteroscopic adhesiolysis using conventional instruments with concomitant fluoroscopy as a guidance method. MAIN OUTCOME MEASURE(S): Live birth rate. RESULT(S): Of the 500 women included in the cohort, 569 pregnancies were achieved within 3 years after surgery. The miscarriage rate was 33.0%, and the live birth rate was 67.4%. Age, the causal procedure, and at least one miscarriage after adhesiolysis strongly predicted the outcome of a live birth. CONCLUSION(S): The overall take-home newborn rate was 67.4% after adhesiolysis in women with AS. Women with AS who are relatively young, with a first-trimester procedure preceding AS, and with low grades of adhesions and no miscarriage after adhesiolysis have the best chance of a newborn delivery.

Adult stem cells in endometrial regeneration: Molecular insights and clinical applications.

Endometrial damage is an important cause of female reproductive problems, manifested as menstrual abnormalities, infertility, recurrent pregnancy loss, and other complications. These conditions are collectively termed "Asherman syndrome" (AS) and are typically associated with recurrent induced pregnancy terminations, repeated diagnostic curettage and intrauterine infections. Cancer treatment also has unexpected detrimental side effects on endometrial function in survivors independently of ovarian effects. Endometrial stem cells act in the regeneration of the endometrium and in repair through direct differentiation or paracrine effects. Nonendometrial adult stem cells, such as bone marrow-derived mesenchymal stem cells and umbilical cord-derived mesenchymal stem cells, with autologous and allogenic applications, can also repair injured endometrial tissue in animal models of AS and in human studies. However, there remains a lack of research on the repair of the damaged endometrium after the reversal of tumors, especially endometrial cancers. Here, we review the biological mechanisms of endometrial regeneration, and research progress and challenges for adult stem cell therapy for damaged endometrium, and discuss the potential applications of their use for endometrial repair after cancer remission, especially in endometrial cancers. Successful application of such cells will improve reproductive parameters in patients with AS or cancer. Significance: The endometrium is the fertile ground for embryos, but damage to the endometrium will greatly impair female fertility. Adult stem cells combined with tissue engineering scaffold materials or not have made great progress in repairing the injured endometrium due to benign lesions. However, due to the lack of research on the repair of the damaged endometrium caused by malignant tumors or tumor therapies, the safety and effectiveness of such stem cell-based therapies need to be further explored. This review focuses on the molecular insights and clinical application potential of adult stem cells in endometrial regeneration and discusses the possible challenges or difficulties that need to be overcome in stem cell-based therapies for tumor survivors. The development of adult stem cell-related new programs will help repair damaged endometrium safely and effectively and meet fertility needs in tumor survivors.

Single cell-derived clonally expanded mesenchymal progenitor cells from somatic cell nuclear transfer-derived pluripotent stem cells ameliorate the endometrial function in the uterus of a murine model with Asherman's syndrome.

OBJECTIVES: Because primary mesenchymal progenitor cells (adult-MPCs) have various functions that depend on the tissue origin and donor, de novo MPCs from human pluripotent stem cells (hPSCs) would be required in regenerative medicine. However, the characteristics and function of MPCs derived from reprogrammed hPSCs have not been well studied. Thus, we show that functional MPCs can be successfully established from a single cell-derived clonal expansion following MPC derivation from somatic cell nuclear transfer-derived (SCNT)-hPSCs, and these cells can serve as therapeutic contributors in an animal model of Asherman's syndrome (AS). MATERIALS AND METHODS: We developed single cell-derived clonal expansion following MPC derivation from SCNT-hPSCs to offer a pure population and a higher biological activity. Additionally, we investigated the therapeutic effects of SCNT-hPSC-MPCs in model mice of Asherman's syndrome (AS), which is characterized by synechiae or fibrosis with endometrial injury. RESULTS: Their humoral effects in proliferating host cells encouraged angiogenesis and decreased pro-inflammatory factors via a host-dependent mechanism, resulting in reduction in AS. We also addressed that cellular activities such as the cell proliferation and population doubling of SCNT-hPSC-MPCs resemble those of human embryonic stem cell-derived MPCs (hESC-MPCs) and are much higher than those of adult-MPCs. CONCLUSIONS: Somatic cell nuclear transfer-derived-hPSCs-MPCs could be an advanced therapeutic strategy for specific diseases in the field of regenerative medicine.

Endometrial Regeneration in Asherman's Syndrome: Clinical and Translational evidence of Stem Cell Therapies.

Asherman's Syndrome or Intrauterine adhesions is an acquired uterine condition where fibrous scarring forms within the uterine cavity, resulting in reduced menstrual flow, pelvic pain and infertility. Until recently, the molecular mechanisms leading to the formation of fibrosis were poorly understood, and the treatment of Asherman's syndrome has largely focused on hysteroscopic resection of adhesions, hormonal therapy, and physical barriers. Numerous studies have begun exploring the molecular mechanisms behind the fibrotic process underlying Asherman's Syndrome as well as the role of stem cells in the regeneration of the endometrium as a treatment modality. The present review offers a summary of available stem cell-based regeneration studies, as well as highlighting current gaps in research.

Bone Marrow Mesenchymal Stem Cells (BMSCs) Restore Functional Endometrium in the Rat Model for Severe Asherman Syndrome.

OBJECTIVE: To investigate the feasibility to restore functional endometrium using bone marrow mesenchymal stem cells (BMSCs) in the Sprague Dawley (SD["SD" has been defined as both "Sprague Dawley" and "standard deviation." Please clarify which one is to be followed.]) rat model for Asherman syndrome (AS). DESIGN: Basic research on treatment of AS utilizing an optimized rat model. SETTING: University research laboratories. ANIMAL(S): Sprague Dawley rat model in which AS was induced in accordance to an optimized protocol. INTERVENTION(S): Bone marrow mesenchymal stem cells were harvested from the rat's bone marrow and labeled with green fluorescent protein (GFP) in the second passage of BMSCs. The fifth passage of GFP-labeled BMSCs was injected systemically through the tail vein in the optimized AS rat model. MAIN OUTCOME MEASURE(S): We examined the reproliferation of the endometrial lining and the expression of markers for endometrium and endometrial receptivity. The localization of engrafted GFP-labeled BMSCs was determined by a laser scanning confocal microscope and a fluorescence microscope. The number of pregnant rats and implanted embryos in each uterus was recorded to evaluate the function of endometrium. RESULT(S): We had demonstrated that in the in vivo experiments on our rat model for AS, the group which received BMSC injection had significantly improved reproductive outcomes-70% of these rats conceived, whereas none of the rats in the control group got pregnant ( P < .01, χ2 test). The mean number of embryos undergoing implantation was 14 ± 1.24 in the sham group and 7 ± 5.70 in the BMSC group (Levene test, P = .001). There was no significant difference between the groups from the time of coitus to conception. To further determine how BMSC injection could have resulted in the improved reproductive outcomes in rats with AS, we employed immunohistochemical techniques to examine the endometrium of these treated rats. On hematoxylin-eosin staining, we noted the reproliferation of all layers of the endometrium and with Masson staining, we noted significant reduction in fibrosis in the damaged endometrium of rats treated with BMSCs. Counterstaining for GFP and cytokeratin-positive cells was noted in the endometrial lining of treated rats, which might suggest the action of BMSCs in regenerating the damaged endometrial lining. The expression of the endometrial receptivity marker, Leukemia inhibitory factor (LIF), in this regenerated endometrial lining could have resulted in the improved reproductive outcomes observed in the AS rat model treated with BMSCs. CONCLUSION: Bone marrow mesenchymal stem cells were likely to play an important role in the reconstruction of the injured endometrium and improvement of reproductive outcomes in the optimized AS rat model.

Asherman's Syndrome: it may not be all our fault.

Asherman's Syndrome (AS) is an acquired condition defined by the presence of intrauterine adhesions (IUA) that cause symptoms such as menstrual abnormalities, pelvic pain, infertility, recurrent miscarriage, abnormal placentation and attendant psychological distress. Classically, AS is considered an iatrogenic disease triggered by trauma to the pregnant uterus. Different factors can cause the destruction of the endometrium, thus affecting the endometrial stem cell niche and creating IUAs. Curettage of the pregnant uterus appears to be the most common source of this destruction. Nevertheless, some AS cases have been associated with congenital uterine abnormalities and infections, and there are some idiopathic cases without any prior surgical procedures, suggesting a putative constitutional predisposition to IUA. Factors reported to cause AS share an underlying inflammatory mechanism leading to defective endometrial healing and vascularization. Interestingly, distinct genetic profiles have been observed in the endometrium of AS patients. These data suggest that AS might not just be an iatrogenic complication, but also the result of a genetic predisposition. Elucidating the possible physiopathological processes that contribute to AS will help to identify patients at risk for this condition, providing an opportunity for prevention.

Fertile ground: human endometrial programming and lessons in health and disease.

The human endometrium is a highly dynamic tissue that is cyclically shed, repaired, regenerated and remodelled, primarily under the orchestration of oestrogen and progesterone, in preparation for embryo implantation. Humans are among the very few species that menstruate and that, consequently, are equipped with unique cellular and molecular mechanisms controlling these cyclic processes. Many reproductive pathologies are specific to menstruating species, and studies in animal models rarely translate to humans. Abnormal remodelling and regeneration of the human endometrium leads to a range of reproductive complications. Furthermore, the processes regulating endometrial remodelling and implantation, including those controlling hormonal impact, breakdown and repair, stem/progenitor cell activation, inflammation and cell invasion have broad applications to other fields. This Review presents current knowledge regarding the normal and abnormal function of the human endometrium. The development of biomarkers for prediction of uterine diseases and pregnancy disorders and future avenues of investigation to improve fertility and enhance endometrial function are also discussed.

Results of centralized Asherman surgery, 2003-2013.

OBJECTIVE: To study the success rate of hysteroscopic adhesiolysis and the spontaneous recurrence rate of intrauterine adhesions (IUAs) in patients with Asherman syndrome. DESIGN: Cohort study. SETTING: University-affiliated hospitals. PATIENT(S): A total of 638 women with Asherman syndrome were included, all diagnosed using hysteroscopy, and operated on between 2003 and 2013. INTERVENTION(S): Hysteroscopic adhesiolysis. MAIN OUTCOME MEASURE(S): Hysteroscopic adhesiolysis was classified as successful if a normalization of menstrual blood flow occurred, along with a restored, healthy, cavity anatomy, free of adhesions, with hysteroscopic visualization of ≥ 1 tubal ostium. Recurrences of adhesions were diagnosed using hysteroscopy after an initial successful procedure. RESULT(S): A first-trimester procedure preceded Asherman syndrome in 371 women (58.2%) and caused adhesions of grades 1-2A. In 243 (38.1%) women, a postpartum procedure caused IUAs of grades 3-5. The procedure was successful in 606 women (95%), and restoration of menstrual blood flow occurred in 97.8%; IUAs spontaneously recurred in 174 (27.3%) of these cases. High grades of adhesions were predictive of a higher chance of spontaneous recurrence of adhesions. CONCLUSION(S): In 95% of women with Asherman syndrome, a healthy uterine cavity was restored with hysteroscopic adhesiolysis, in 1-3 attempts, with a 28.7% recurrence rate of spontaneous IUAs.

Human CD133(+) bone marrow-derived stem cells promote endometrial proliferation in a murine model of Asherman syndrome.

OBJECTIVE: To investigate the engraftment and proliferation of superparamagnetic iron oxide nanoparticles (SPIOs)-labeled human CD133(+) bone marrow-derived stem cells (BMDSCs) in an animal model of Asherman syndrome (AS). DESIGN: Prospective experimental animal study. SETTING: University research laboratories. ANIMAL(S): Nonobese diabetic mice (strain code 394; NOD.CB17- Prkdc(scid)/NcrCrl) in which AS was induced according to a published protocol. INTERVENTION(S): Human CD133(+) BMDSCs were obtained from patients undergoing autologous cell therapy in refractory AS and endometrial atrophy, labeled with SPIOs and injected either intrauterinely (n = 5) or systemically through the tail vein (n = 5) in the animal model. MAIN OUTCOME MEASURE(S): Accumulation of collagen and glycosaminoglycan deposits detected by trichrome staining. Percentage and localization of engrafted human SPIOs-labeled CD133(+) BMDSCs by Prussian blue staining. Cell proliferation assay using Ki67 and reverse transcriptase-polymerase chain reaction (PCR) for specific paracrine factors. RESULT(S): The induction of the AS in the murine model was demonstrated by the accumulation of collagen and glycosaminoglycan deposits in the damaged horns by trichrome staining. Human SPIOs labeled CD133(+) BMDSCs homing represents 0.59% and 0.65% of total number of cells present in the horns after intrauterine or tail vein injections, respectively. Engrafted cells were localized around endometrial blood vessels, inducing proliferation in surrounding cells based on Ki67 and regulation of the paracrine factors thrombospondin 1 and insulin-like growth factor 1. CONCLUSION(S): The injection of human SPIOs labeled CD133(+) BMDSCs in a murine model of AS confirms that these cells engraft around endometrial vessels, inducing proliferation of surrounding cells through paracrine molecules such as thrombospondin 1 and insulin-like growth factor 1. CLINICAL TRIAL REGISTRATION NUMBER: NCT02144987.

Treatment of Asherman's syndrome in an outpatient hysteroscopy setting.

OBJECTIVE: To evaluate the feasibility and success rate of treating Asherman syndrome in an outpatient hysteroscopy unit. DESIGN: Retrospective case series (Canadian Task Force classification III). SETTING: The outpatient hysteroscopy clinic at Ottawa Hospital from November 26, 2008, to January 31, 2014. PATIENTS: Patients undergoing treatment for Asherman syndrome. INTERVENTIONS: All cases of hysteroscopic adhesiolysis were reviewed. MEASUREMENTS AND MAIN RESULTS: Demographic data were collected by a retrospective chart review including patients' age, obstetric history, referring complaint, etiology of Asherman syndrome, antecedent treatment, and outcome measures when available. The severity of Asherman syndrome was determined based on the March classification by the operating surgeon. Analgesia used during the procedure was recorded. Twenty patients were treated for Asherman syndrome in the outpatient hysteroscopy suite. There were a total of 38 procedures (adhesiolysis or diagnostic hysteroscopies) performed for this indication in the patient set. The most common etiologies for intrauterine adhesions were previous curettage (60%) and previous missed abortion (45%). Outcomes were available for 19 patients. All of the patients had normal menses after treatment. Eighty-four percent of patients had either no adhesions or mild adhesions at their final hysteroscopy. Six patients had a spontaneous pregnancy after treatment, and 5 went on to have a term delivery to date. In terms of analgesia used for the procedure, 89% of patients had preoperative nonsteroidal anti-inflammatory drugs, 2.8% required intravenous fentanyl and midazolam, and 5.6% required oral lorazepam. CONCLUSION: This series showed that Asherman syndrome may be successfully treated in an outpatient hysteroscopy setting outside the operating room and without general or regional anesthesia.

Post-abortion hysteroscopy: a method for early diagnosis of congenital and acquired intrauterine causes of abortions.

OBJECTIVE: Recurrent pregnancy loss is often defined as three or more consecutive pregnancy losses but there are no strict criteria for initiation of investigations after a miscarriage. We compared the frequency of uterine anomalies diagnosed by hysteroscopy following one, two and three or more miscarriages. STUDY DESIGN: In our study 151 patients underwent diagnostic hysteroscopy following a missed or an incomplete abortion. Uterine septum, subseptum, arcuate uterus, and uterine hypoplasia are classified as congenital uterine anomalies and polyps, synechia, and submucous myomas are classified as acquired uterine abnormalities. RESULTS: 151 Patients were enrolled in the study. The pregnancy numbers of the patients varied between 1 and 12. Sixty nine (46%) of the patients had one miscarriage, 42 (28%) had two miscarriages and 40 (26%) had three or more miscarriages. Diagnostic hysteroscopy revealed normal uterine cavity in 61.1% of the patients, congenital uterine anomalies in 20.4% and acquired uterine pathologies in 18.5%. Among the congenital anomalies, 14 (9.3%) were uterine septum, 10 (6.6%) were subseptate uterus, 4 (2.6%) were arcuate uterus and 3 (1.9%) were uterine hypoplasia. Among acquired abnormalities 14 (9.3%) were uterine synechia, 12 (7.9%) were endometrial polyps, and 2 (1.3%) were submucous myoma. Among patients who had one miscarriage 64.1% had a normal uterine cavity, 18.2% had congenital abnormalities and 17.7% had acquired uterine pathologies. Of patients with two miscarriages, 52% had a normal uterine cavity, 21.9% had congenital anomalies and 26.1% had acquired uterine pathology. In the three or more miscarriage group, 58.4% had normal uterine cavity, 25.3% had congenital anomalies, and 16.3% had acquired uterine pathology. We did not find any statistically significant difference between the number of miscarriages and pathologic diagnostic hysteroscopy findings. CONCLUSIONS: Post-abortion office hysteroscopy is a simple and efficient tool in the early diagnosis of congenital and acquired uterine pathologies. Diagnostic hysteroscopy can be performed after the first miscarriage in order to determine congenital and acquired uterine pathologies, with regard to the patient's age and anxiety level.

[Intrauterine adhesions--Asherman's syndrome]. / Kohtukiinnikkeet ja Ashermanin oireyhtymä.

Intrauterine adhesions known as Asherman's syndrome evolve after trauma to the basal layer of the endometrium usually secondary to curettage of a recently pregnant uterus. The lesions range from minor to severe cohesive adhesions that affect menstrual function and fertility. Operative hysteroscopy is the mainstay of diagnosis, classification and treatment of the intrauterine adhesions. Significantly obliterated cavity may require multiple hysteroscopic adhesiolysis to achieve a satisfactory anatomical and functional result. Operative hysteroscopy for selective curettage of residual trophoblastic tissue instead of nonselective conventional curettage may prevent intrauterine adhesions.

Successful pregnancy and delivery of a healthy baby after endometrial biopsy treatment in an in vitro fertilization patient with severe Asherman syndrome.

OBJECTIVE: To implement the procedure of endometrial biopsy in a case of severe Asherman syndrome as a possible treatment to increase uterine receptivity. DESIGN: Case report. SETTING: IVF Unit, Kaplan Medical Center, Rehovot, Israel. PATIENT(S): A 29-year-old patient with severe Asherman syndrome, who underwent six operative hysteroscopies combined with hormonal treatment, and no functional receptive endometrium was achieved. INTERVENTION(S): We performed three endometrial biopsies on days 8, 12, and 21 of a progyluton-induced menstrual cycle, and a fourth biopsy on day 21 of the next induced menstrual cycle. After that cycle the patient underwent an IVF treatment. MAIN OUTCOME MEASURE(S): Ultrasound measurement of endometrial thickness, serum beta-hCG, sonography test for the presence of a gestational sac with heartbeat, and pregnancy follow-up until birth. RESULT(S): Biopsy treatment increased the thickness of the endometrium from unobservable by sonography to 7 mm on the day of hCG administration. The next IVF cycle resulted in implantation of an embryo and the birth of a healthy baby boy. CONCLUSION(S): Repeated endometrial biopsies may be used in patients with Asherman syndrome immediately after forming a uterine cavity by hysteroscopy to improve its receptivity.

Factors affecting reproductive outcome of hysteroscopic adhesiolysis for Asherman's syndrome.

OBJECTIVE: To evaluate the outcome of hysteroscopic adhesiolysis in women with Asherman's syndrome. DESIGN: Retrospective clinical study. SETTING: Hysteroscopic center of Fuxing Hospital in Beijing, China. PATIENT(S): Patients with Asherman's syndrome who presented with a history of infertility or recurrent pregnancy loss were included in the study. INTERVENTION(S): The adhesions were divided hysteroscopically by electrode needle or loop under direct vision. A second look hysteroscopy was performed after 3 months. MAIN OUTCOME MEASURE(S): The menstrual pattern, the time interval to conceive, and the reproductive outcome were recorded. RESULT(S): A total of 109 operative procedures were performed in 85 cases. Uterine perforation occurred on one occasion (0.9%). After hysteroscopic adhesiolysis, the chances of conception in women who remained amenorrheic (2 out of 11; 18.2%) were significantly lower than those who continued to have menses (37 out of 74; 50%). At second look hysteroscopy, the conception rate in women who had reformation of intrauterine adhesions (2 out of 17; 11.8%) was significantly lower than that of women who had a normal cavity (26 out of 44; 59.1%). CONCLUSION(S): The outcome of hysteroscopic adhesiolysis for Asherman's syndrome is significantly affected by recurrence of intrauterine adhesions. Further research in Asherman's syndrome should be directed toward reduction of adhesion reformation with a view to improving outcome.