Tuesday, September 22, 2009

Future research:How stem cells may one day improve Asherman's syndrome treatment

Currently the gold standard for treatment of Asherman’s syndrome is surgery to remove/cut adhesions (hysteroscopic adhesiolysis or synechiolysis) and hormonal therapy to regenerate any residual endometrium. One of the challenges in treating Asherman’s syndrome is the propensity of intrauterine adhesions to reform again during the healing process. To try to overcome this, some doctors place a saline-filled stent (Foley or Cook) or an IUD in the uterus after surgery in order to keep the walls of the uterus and cervix apart during the healing process. If there is little endometrium regrowth adhesions will continue forming again in the same areas. Hormone therapy (2-4mg/day estrogen for up to 2 months followed by progestin (P) to induce a withdrawal bleed) is also used in addition to surgery to prevent adhesions from reforming by promoting regrowth of endometrium. It is also thought that it generally improves the thickness and quality of endometrium- some patients end up with thin endometrium or fibrosis (scar tissue with no viable endometrium) after instrumental trauma from surgery precipitating Asherman’s syndrome (usually a D&C). Adhesion reformation following corrective surgery correlates with the severity of adhesions. According to one study adhesion reformation occurs in 50% of severe cases and 21.6% of moderate cases (1). Sometimes multiple surgeries are needed to correct uterine architecture.

The problem is that if one does not have enough endometrium because it has been scraped away, either adhesions or fibrosis will continue to be a problem no matter how many surgeries are undertaken or how much hormonal stimulation is given.

As you can see from a previous post, the live birth rates after corrective surgery are not very high for moderate to severe cases. To understand why this treatment is not effective in all patients one needs to understand the physiology of the endometrium and adhesion formation. The outermost layer of the uterus is lined by the endometrium which sits above the muscle layer, the myometrium. The endometrium itself is comprised of two layers. The functional layer is outermost and is shed on a monthly basis during menstruation. The underlying basal layer is necessary to produce the functional layer each month. If permanent damage is incurred to the basal layer, the functional layer will not be able to regenerate. Without the regeneration of endometrium the bare myometrium underlying the endometrium will begin to stick to other areas devoid of endometrium as soon as the injury occurs. Adhesion formation is the normal physiogical response to injury whether this is in the uterus or elsewhere in the abdominal cavity. Adhesion formation begins immediately after scar formation from instrumental injury and will be complete by 8 weeks. Any area where injured tissue can come into contact with other injured tissue, adhesions form. Adhesions are a serious health problem related to surgery, not just in the uterus but also in the abdomen and intestines. However abdominal or intestinal surgery does not have alternatives whereas uterine evacuation does. In other words, D&C is not the only available method for effectively emptying the uterus after miscarriage or delivery, however staggeringly, it remains standard care for the former in many advanced countries.

So the problem comes down to endometrial regeneration (or the lack of it). Some tissue in the body is able to regenerate. For example, cells in the the gut and bone marrow regularly divide to repair damaged or worn out tissue. In other tissues such as the heart and brain, cells are only stimulated to divide under special circumstances. Endometrium is another such tissue. Tissue regeneration is due to the activity of stem cells which have special properties. Initially it was thought that only embryonic stem cells had the capacity to differentiate. More recently the existence of adult stem cells was discovered. Adult stem cells are undifferentiated cells usually found in little islands or "niches" in tissues and organs. They are generally thought to have a more limited ability to differentiate than embryonic stem cells which can develop into any type of cell in the body. Adult stem cells, on the other hand, are already partially committed to certain cell lineages. Adult stem cells are thought to play a role in tissue maintenance and reparation in the tissues they are found.

Recently the existence of endometrial adult stem cells was reported in the scientific literature (2). However, if all of the basal and stem cells have been removed from a large part of the uterus, it is impossible to resolve the problem of recurrent adhesion formation and/or fibrosis. Sadly, current therapy can only remove bands of scar tissue and promote endometrial regeneration in areas where there is some remaining basal cells or even perhaps stem cells. Put simply, current treatment will not be successful if the patient does not have enough residual endometrium to regenerate. In theory, the identification of endometrial stem cells in the junction between the endometrium and myometrium opens the possibility of future therapy for damaged endometrium. Stem cells can be introduced either from a donor, or better yet, from the same patient whose stem cells have proliferated in a culture medium. Once inside the right tissue and with the appropriate stimulation, they will be able to differentiate into basal endometrial cells and fill in any 'bald' patches of endometrium. Adhesion formation or sclerosis should no longer be a problem. The advantage of using the patients own cells is that it will avoid immune rejection. The use of adult stem cells also avoids any obstacles from those citing ethical problems in using embryonic stem cells. Note that I have greatly simplified the process in the scenario above.

Stem cell research, both adult and embryonic, are still in their infancy. Most stem cell researchers are focusing on regeneration of heart tissue or other major organs as an alternative to organ transplantation. The problem is that there is little if any research on endometrial regeneration and in particular for the treatment of Asherman’s syndrome. In the past basic research was carried out to improve endometrial growth in animals where AS was artificially produced. This type of research no longer seems to exist. Instead, there is research on uterus transplantation which is much more complex and difficult to achieve. As long as endometrial research remains stalled there is little hope that treatment will continue to progress much beyond what has been attained today- which leaves much to be desired if treatment is regarded as the primary solution to the problem of Asherman’s syndrome.


1. Valle RF, Sciarra JJ. Intrauterine adhesions: hysteroscopic diagnosis, classification, treatment, and reproductive outcome. Am J Obstet Gynecol. 1988 Jun;158(6 Pt 1):1459-70.

2. Gargett BE, Chan RW. Endometrial stem/progenitor cells and proliferative disorders of the endometrium. Minerva Ginecol. 2006 Dec;58(6):511-26.

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