NORD gratefully acknowledges Lisa Chang and Rhea Kerawala, MSGDA Candidates, NORD Editorial Interns from the Keck Graduate Institute School of Pharmacy and Health Sciences, and Derick Han, PhD, Associate Professor of Biopharmaceutical Sciences for assistance in the preparation of this report.
Asherman's syndrome is a rare, acquired, gynecological disorder of the uterus. It is characterized by the bonding of scar tissue that lines the walls of the uterus, which decreases the volume of the uterine cavity. The bonding of uterine scar tissue (intrauterine adhesions or synechiae) may occur as a result of surgical scraping or cleaning of tissue from the uterine wall (dilatation and curettage [D and C]), infections of the endometrium (e.g., genital tuberculosis), or other factors. Asherman's syndrome can be severe (greater than 75% of the front and back walls of the uterus can fuse together) to moderate and mild, where only smaller portions of the uterine wall fuses together. Patients can experience a range of symptoms depending on the severity of the disease, including reduced menstrual flow, increased cramping and abdominal pain, eventual stoppage of menstrual cycles (amenorrhea), and, in some women, infertility. Current treatment options include hysteroscopic surgery as well as preventive (Foley catheter) and restorative therapies (hormone treatment). Newer options like stem cell treatments are also currently being explored to treat severe cases of Asherman’s syndrome.
Most patients with Asherman’s syndrome experience menstrual blood flow that is sparse (hypomenorrhea) or absent (amenorrhea) along with increased cramping and abdominal pain. Some patients may experience interrupted menstrual blood flow with substantial pain, while others may not have any abnormal changes to their menstrual cycle or experience any pain. Recurrent miscarriages and/or infertility may also be signs of Asherman’s syndrome. In more severe cases, adhesion of uterine scar tissue can also lead to either a partial or full blockage of the uterus or cervical canal that can cause retrograde menstruation (menstruation blood that flows backwards into the fallopian tubes instead of being expelled from the body).
Asherman’s syndrome is most commonly caused by trauma to the uterus through surgical scraping or cleaning of the uterine wall (dilatation and curettage, also known as D & C). D & C is generally performed to clear the uterine lining following a miscarriage or abortion or to treat certain uterine conditions such as heavy bleeding. D & C after a miscarriage is one of the highest risk factors for Asherman’s syndrome. The scraping of the uterine lining following this procedure can lead to scar tissue that can adhere, leading to Asherman’s syndrome. Other types of surgery to the uterus such as removal of fibroids or polyps or surgical repair of structural defects in the uterus can cause scar tissue formation which is also a risk factor for Asherman’s syndrome. Factors that trigger inflammation in the uterus known as endometriosis and sporadic inflammation of the uterus have been linked to Asherman’s syndrome. Infection and inflammation of the uterus caused by bacteria (genital tuberculosis) and parasites such as blood flukes are also risk factors for Asherman’s syndrome.
Since Asherman’s syndrome involves changes in the uterus, it is limited to the female population. While exact statistics on the prevalence of this condition are not known, the highest frequency of this condition has been reported in Israel, Greece, and South America. Overall, occurrence of Asherman’s syndrome does not seem to be related to any factor associated with geographic location. Genetic predisposition in patients to Asherman’s syndrome has not been identified. Women who have suffered miscarriages or underwent D & C in the first month postpartum have a higher risk for the condition.
Asherman’s syndrome is usually diagnosed through imaging the size and shape of the uterus. The gold standard for diagnosis is a scope and camera tool called a hysteroscope that is inserted into the uterus to display a real-time view of the uterine cavity. Unfortunately, hyperscopes are not readily available in most gynecologist offices. Consequently, Asherman syndrome may be underdiagnosed since it cannot be effectively detected by routine examinations or by more standard diagnostic scans such as ultrasound. Another common diagnostic method for Asherman’s syndrome is hysterosalpingography which involves the injection of a contrasting fluid into the uterus in order for an X-ray image to be generated. Hysterosalpingography allows for the imaging of the uterine cavity shape which may be abnormal in the presence of intrauterine adhesions. Other common imaging tools such as ultrasound and magnetic resonance imaging (MRI]) cannot usually detect Asherman’s syndrome and remain supplementary diagnostic tools.
Therapies for Asherman’s syndrome focus on restoring the uterus to its original size and shape. The therapies can be divided into three primary approaches: treatment – hysteroscopic surgery, re-adhesion prevention, and uterus restoration therapies. Mild cases of Asherman’s syndrome may only require surgical treatment, while more severe cases may require all three approaches. Most cases of Asherman’s syndrome can be cured with treatment.
Treatment
The most common treatment for Asherman’s syndrome is hysteroscopic surgery (hysteroscopes plus scissors or other cutting instruments) to cut the adhesions of the uterine wall. The hysteroscope allows the doctor a magnified and the direct view of the uterus for precise cutting of the uterine adhesions. Most hysteroscopic surgery can be done in an outpatient setting. The treatment of the severe cases of Asherman’s syndrome can be more challenging, as the cavity may be completely blocked or too narrow to allow the insertion of the hysteroscope inside the cervix.
Re-Adhesion Prevention
Several procedures have been developed to prevent re-adhesion of the uterine wall following hysteroscopic surgery, since the scar tissue may re-adhere. The Foley catheter was one of first devices developed to separate the uterine walls to prevent the recurrent adhesions. A Foley catheter can be inserted in the uterine cavity for 5 to 7 days with a bag for removing drainage from the uterus. Another method to prevent adhesions from reoccurring is a uterine balloon stent made from silicon and shaped to fill the uterine cavity. Finally, application of certain chemicals such as hyaluronic acid has been shown to help prevent uterine re-adhesion. Although the mechanism is not completely understood, it is believed that hyaluronic acid acts as a temporary barrier to prevent re-adhesion and may also promote tissue repair.
Uterus Restoration Therapy
Hormone therapy such as estrogen supplements have been proposed to help enhance tissue repair and restore the lining of the uterus. While some studies have suggested that estrogen therapy may enhance repair and growth of cells in the uterine wall, more clinical studies are being performed to confirm the value of estrogen therapy for treatment of Asherman’s syndrome. Antibiotics are also often prescribed following hysteroscopic surgery. While antibiotics do not directly prevent re-adhesion, they help prevent infections and inflammation that may damage the uterus and trigger re-adhesion of the uterine walls.
Clinical trials of stem cell therapy are ongoing to determine if this therapy can help rebuild the uterine wall particularly following severe cases of Asherman’s syndrome. Stem cells are basic cells (undifferentiated) that can be programmed to become almost any cell in the body including cells that line the uterus. Stem cell therapies are focusing primarily on rebuilding the endometrial lining that has become damaged from adhesions and surgery. Early clinical trials have demonstrated that stem cell therapy is safe and may be effective in helping regeneration the uterine walls as well as helping resumption of menstruation and improving fertility. Clinical trials of stem therapy for Asherman’s syndrome are currently ongoing.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/news-patient-recruitment/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
REVIEW ARTICLES
Doroftei B, Dabuleanu A M, Ilie OD, Maftei R, Anton E, Simionescu G, Matei T, and Armeanu T. Mini-Review of the new therapeutic possibilities in Asherman syndrome-where are we after one hundred and twenty-six years? Diagnostics (Basel, Switzerland) 2020; 10(9), 706. https://doi.org/10.3390/diagnostics10090706
Conforti A, Alviggi C, Mollo A, De Placido G, and Magos A. The management of Asherman syndrome: a review of literature. Reproductive Biology and Endocrinology,2013; 11, 118. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3880005/pdf/1477-7827-11-118.pdf
March CM. Asherman’s syndrome. Seminars in Reproductive Medicine. 2011; 29(2), 83–94. https://doi.org/10.1055/s-0031-1272470
JOURNAL ARTICLES
Carugno J, Laganà A and Vitale SG. Use of 3D ultrasound in the hysteroscopic management of Asherman syndrome. Annals of Translational Medicine. 2020; 8(14),847. https://doi.org/10.21037/atm.2020.04.18
Gibson M ES, Fleming N, Zuijdwijk C and Dumont T. Where Have the Periods Gone? The Evaluation and Management of Functional Hypothalamic Amenorrhea. Journal of Clinical Research in Pediatric Endocrinology 2020; 12(Suppl 1), 18–27. https://doi.org/10.4274/jcrpe.galenos.2019.2019.S0178
Han Q and Du Y. Advances in the Application of Biomimetic Endometrium Interfaces for Uterine Bioengineering in Female Infertility. Frontiers in Bioengineering and Biotechnology 2020; 8, 153. https://doi.org/10.3389/fbioe.2020.00153
Vancaillie T, Chan K, Liu J, Deans R and Howard E. Asherman syndrome: Audit of a single‐operator cohort of 423 cases. Aust N Z J Obstet Gynaecol. 2020; 60: 574-578.
https://doi.org/10.1111/ajo.13182
Amin TN, Saridogan E and Jurkovic D. Ultrasound and intrauterine adhesions: a novel structured approach to diagnosis and management. Ultrasound Obstet Gynecol. 2015; 46: 131-139. https://doi.org/10.1002/uog.14927
Tsui KH, Lin LT, Cheng JT, Teng SW, Wang PH. Comprehensive treatment for infertile women with severe Asherman syndrome. Taiwanese Journal of Obstetrics and Gynecology 2014; 53(3): 372-375.
https://doi.org/10.1016/j.tjog.2014.04.022.
Burney RO and Giudice C. Pathogenesis and pathophysiology of endometriosis. Fertility and Sterility 2012; 98(3), 511–519. https://doi.org/10.1016/j.fertnstert.2012.06.029
Conforti A, Alviggi C, Mollo A, De Placido G and Magos A. The management of Asherman syndrome: a review of literature. Reproductive Biology and Endocrinology. 2013; RB&E, 11, 118. https://doi.org/10.1186/1477-7827-11-118
Bauer ST and Bonanno C. Abnormal placentation. Seminars in Perinatology2009; 33(2), 88–96. https://doi.org/10.1053/j.semperi.2008.12.003
Livsey R. Hysterosalpingography. Australasian Radiology 2001; 45(1), 98–99. https://doi-org.ccl.idm.oclc.org/10.1046/j.1440-1673.2001.00893.x
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