Endometriosis: Are stem cells to blame?

Although endometriosis has traditionally been blamed on retrograde menstruation and coelomic metaplasia, the latest research puts a new spotlight on stem cell dysfunction. Two experts outline this theory and discuss newer treatment options, including the levonorgestrel-releasing IUD, aromatase inhibitors, and progesterone antagonists.

Endometriosis is defined as endometrial glands and stroma that are located outside of the uterine cavity, right? Actually, researchers are chipping away at that traditional view, finding that in reality we’re likely looking at several diseases. New research has widened our understanding of the molecular and cellular basis of endometriosis and has shed light on a causative role for stem cells. In turn, this improved scientific understanding has led to novel treatments. Our goal here is to review the many current treatments for endometriosis and introduce the new stem cell theory, which explains a lot and promises to further expand treatment options.

Theories of pathogenesis: the old and the new
Traditional theories of what causes endometriosis include retrograde menstruation and coelomic metaplasia. The former theory holds that during menstruation, shed pieces of endometrium travel out of the fallo-pian tubes and implant on the pelvic peritoneum and organs. We know that women with müllerian anomalies that obstruct menstrual outflow are more likely to have endometriosis than those who do not have obstruction. This observation supports the theory that retrograde menstruation causes endometriosis.

Coelomic metaplasia. A second theory holds that coelomic metaplasia can also cause endometriosis when undifferentiated cells in the peritoneal cavity differentiate into endometrium. Some researchers theorize that certain women with endometriosis are genetically predisposed to the disease. Women with this predisposition would be more prone to peritoneal invasion of endometriosis implants after retrograde menstruation occurs. Furthermore, many investigators theorize that women with endometriosis have a dysfunctional immune response that causes the endometriosis lesions to persist and even grow. Finally, endometriosis lesions stimulate angiogenesis and produce their own estrogen, fueling their persistent invasion and growth.

Role of stem cells. Current research focuses on the stem cell theory of endometriosis, which suggests that mesenchymal stem cells derived from bone marrow can differentiate into endometrium and endometriosis. These stem cells can then be recruited to the endometrium, where they differentiate into both endometrial stromal and epithelial cells.

Supporting this theory is evidence from women who have undergone bone marrow transplants. The endometrium in these women contains a substantial number of donor-derived endometrial cells. Stem cells derived from bone marrow reside in the endometrium, and we believe retrograde menstruation of these stem cells or endogenous uterine stem cells can cause endometriotic implants.

We further know that bone-marrow-derived stem cells can also populate established endometriotic implants. Even in hysterectomized mice, endometriosis lesions contain bone marrow-derived endometrial cells, thereby eliminating the possible explanation that this exemplifies hematogenous or lymphatic dissemination. Bone marrow-derived stem cells add to the persistence and progression of endometriosis. The stem cell theory also explains the more unusual cases of endometriosis located outside the peritoneal cavity; it’s possible that endometriosis located at distance sites such as lung or brain arises from stem cells.

We believe there’s more than one source of endometriosis—that retrograde menstruation can lead to peritoneal endometriosis, while metaplasia can cause endometriomas. And that ectopic differentiation of stem cells can also cause the progression of endometriosis lesions and explain those at distant sites. Endometriosis likely involves many genes, wherein alterations in many different pathways cause its presence and persistence.

Medical and surgical treatment options

Initial treatment is often empirical, based on a clinical diagnosis. If the clinical impression is that of endometriosis without any adnexal masses palpated on bimanual exam, then medical treatment is indicated.

First-line medical treatment. This consists of oral contraceptives and nonsteroidal anti-inflammatory medications (NSAIDs). Continuous oral contraceptives are often preferable to cyclic therapy to control endo-metriosis-related dysmenorrhea.

Observational studies of women with endometriosis show NSAIDs will control mild pelvic pain, but there are no randomized controlled trials comparing NSAIDs to placebo. NSAIDs also do not keep endometriosis from progressing. If medications are controlling a woman’s symptoms, she can expect continued success by maintaining the regimen. But if she fails medical treatment, then surgery or second-line drugs are both reasonable options. Surgery is preferable if the diagnosis is unclear or if there are contraindications to medications. Second-line medical treatments for endometriosis are described below.

Role of laparoscopy. Both diagnosis and treatment of endometriosis can be done laparoscopically. And any endometriosis seen at the time of laparoscopy can be ablated with coagulation.

A study looking at patients with endometriosis who had diagnostic laparoscopy or laparoscopy with laser ablation of endometriosis initially showed that symptoms improved in both groups 3 months postoperatively. However, the placebo effect that was present at 3 months had dissipated by 6 months. After diagnostic laparoscopy, some 77% of patients had a recurrence of their pelvic pain, whereas pelvic pain recurred in only 37% of patients who’d undergone an operative laparoscopy. At 1 year, the recurrence rate of pelvic pain for patients in the operative group was 44%. This means that almost half of patients who undergo an operative laparoscopic procedure to ablate or remove visible endometriosis will have a recurrence within 1 year. After 6 years of follow-up, the recurrence rate of pelvic pain was 74%, with pain recurring in most patients within the first 1 or 2 years after the initial surgical procedure.

Resection vs. ablation. Resection of endometriosis provides better pain relief than simple ablation. In one study, patients who had their disease resected during their initial operative procedure had a recurrence rate of about 40% at 2 years, whereas those who’d had laser ablation of the disease had a significantly higher recurrence rate: roughly 77% at 2 years. Giving GnRH agonists postoperatively after an ablative surgical procedure reduced the recurrence rate at 2 years from 77% to approximately 30% in this retrospective study. Simple ablation with postoperative medical treatment appears to provide similar results to those achieved with extensive resection. Aggressive surgical resection of visible disease, along with postoperative GnRH analogue treatment might offer the best long-term results.

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