Gerald Hurowitz, M.D.·Published 4 June 2009·12 min read
Key points
Although endometriosis has traditionally been blamed on retrograde menstruation and coelomic metaplasia, the latest research puts a new spotlight on stem cell dysfunction.
Traditional theories of what causes endometriosis include retrograde menstruation and coelomic metaplasia.
Initial treatment is often empirical, based on a clinical diagnosis.
Endometriosis is found in 20% to 50% of infertile women.
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.
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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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Endometriomas. For patients with endometriomas that are causing pain, sometimes surgery is the best first-line treatment. Laparoscopic excision of the endometrioma and the cyst wall appears to be superior to drainage and ablation of the endometrioma. Women who had undergone laparoscopic endometrioma excision had lower rates of endometrioma recurrence and reduced rates of postoperative dysmenorrhea, dyspareunia, and pelvic pain. Surgical excision of endometriomas should provide postoperative pain relief; however the long-term effects on fertility and ovarian reserve are less clear. Aggressive removal of endometriomas appears to reduce ovarian reserve and potentially future fertility. For women with a clear diagnosis of endometrioma who wish to have children, drugs are preferable to surgery.
Gonadotropin-releasing hormone agonists. GnRH agonists can be used in patients who have failed oral contraceptives or who decline surgery, or both. They work by inducing a menopausal state through down regulation of gonadotropin secretion and a resulting drop in estrogen production. But there's no good evidence that they provide greater pain relief than OCs plus NSAIDs.
Furthermore, the side effects of GnRH agonists include bone loss and vasomotor symptoms. To avoid these side effects when choosing GnRH agonists, be sure to prescribe them with add-back therapy consisting of 5 mg daily of norethindrone acetate, especially for patients who are treated for more than 6 months. The addition of add-back therapy does not diminish the efficacy of the GnRH agonists in reducing pain.
Alternative add-back approach. Also consider estrogen/progestin add-back therapy using low-dose conjugated equine estrogens (CEE) daily and a progestin in these patients. Keep in mind, however, that higher doses of estrogen add-back therapy, such as 1.25 mg daily of CEE daily, may not suppress pelvic pain symptoms as much.
Adding norethindrone. This medication—with or without estrogen add-back therapy—can reduce bone loss in women taking GnRH agonists, and this combination therapy can be continued for at least 12 months. Pain will usually return within 60 to 90 days of discontinuing GnRH agonists, though, with up to 75% of patients having recurrent symptoms. For women with clinically suspected endometriosis who fail OCs and NSAIDs, you can give a standard 6-month trial with GnRH agonists plus add-back with either 2.5 to 5 mg of norethindrone daily or 0.3 to 0.625 mg of CEE daily plus 2.5 to 5 mg of medroxyprogesterone acetate daily. There's almost never a reason to use a GnRH agonist alone in this setting.
Progestins alone. These can also be used to treat endometriosis, as they cause decidualization and atrophy of the endometrial cells and reduce ovarian production of estrogen. Norethindrone can be started at 5 mg per day or medroxyprogesterone acetate at 10 mg two or three times a day. However, effective pain control may require higher doses and some patients cannot tolerate the adverse side effects of progestins, such as bloating, depression, or weight gain.
Danazol. Although this medication isn't used as frequently as it used to be in the United States to treat endometriosis, it's still widely used in Europe and throughout the world. It is just as effective as GnRH agonists or progestins, but use waned in this country due to side effects like acne and hair growth. However, the androgenic effect might be a plus for patients who complain of decreased libido while taking other drugs that all reduce androgens.
Newer medical treatments. These include the levonorgestrel-releasing intrauterine device (LNG-IUD). This approach has been investigated in patients who have had an LNG-IUD placed postoperatively after surgery for endometriosis to inhibit the growth of endometriosis implants. In one randomized trial, an LNG-IUD reduced the postoperative recurrence of dysmenorrhea. Alternatively, progesterone given vaginally can be particularly helpful for patients with rectovaginal endometriosis.
Aromatase inhibitors (AIs). These are another novel treatment option for patients with endometriosis who fail first-line medical therapy. Endometriosis expresses the aromatase enzyme and can therefore make its own estrogen. Aromatase inhibitors work by blocking estrogen production in the endometriosis lesions as well as in the ovary and at peripheral sites. Since AIs also increase FSH with resultant ovarian stimulation, you'll only want to use them along with a progestin or GnRH agonist for treating endometriosis. When used in conjunction with a GnRH agonist, AIs significantly improved pain compared to GnRH agonists alone.
Progesterone antagonists. These hold promise in treating endometriosis. It's thought progesterone antagonists work by inhibiting endometriosis progression or by suppressing the production of endometrial prostaglandin. Mifepristone, when used in doses of 50 mg per day, can decrease pain symptoms and also cause a regression of endometriosis lesions.
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Endometriosis and fertility
Endometriosis is found in 20% to 50% of infertile women. We theorize that it affects fertility by impairing oocyte development and/or quality, sperm penetration or fer-tilization, tubal function, and implantation. Without treatment, spontaneous monthly fecundity rates are between 2% and 3%.
Forget hormonal therapies. But that said, do not attempt medical suppression of endometriosis in women who hope to conceive. Hormonal therapies, such as danazol, progestins, and GnRH agonists, are ineffective despite their suppressive effect on endometriosis implants. They prevent ovulation and only further delay fertility.15,16 Surgery for endometriosis-associated infertility can modestly increase the monthly fecundity rate to under 5%.
Refer early to fertility specialists. Ovulation induction using clomiphene, coupled with intrauterine insemination, increases monthly fecundity rates to 9% and gonadotropin-controlled ovarian hyperstimulation further raises monthly fecundity rates to about 15%. In vitro fertilization has the highest monthly success rates in patients with endometriosis-associated infertility, reaching pregnancy rates of 30% to 50% per cycle, depending on age. Clearly, patients with endometriosis-associated infertility can benefit from early referral for infertility treatment.
Future directions
Why do current medical and surgical procedures fail so often? And why do drugs fail to restore fertility? As we begin to understand more about the molecular and cellular defects in endometriosis, we have begun to explain these phenomena. The stem cell theory explains how endometriosis can be found remote from the peritoneal cavity, resist some treatments, and occasionally even occur after hysterectomy. Endometriosis has also found ways to avoid the normal hormonal restraints that we use to control it. By ex-pressing its own aromatase, endometriosis can make high local concentrations of estrogen and resist treatment with GnRH agonists. We have recently learned that in women with endometriosis, the progesterone response is blunted or undetectable, indicating a resistance to progesterone. Patients who fail conventional medical treatment likely have progesterone resistance. In the future, treatment options for endometriosis may need to target progesterone resistance.
Finally, we've recently shown that endometriosis induces epigenetic changes in the uterus that inhibit implantation. These changes involve DNA methylation and persist even after the endometriosis is removed. This finding helps to explain the continued infertility even after complete surgical resection of endometriosis. An understanding of the scientific basis of this enigmatic disease has and will continue to lead to novel and superior treatments for endometriosis.
Two important messages to keep in mind when treating patients with endometriosis: (1) recognize the treatment goal for each woman, whether it's pain management or preserving or restoring fertility; (2) impress upon her that endometriosis is a disease that can be chronic and incurable. Fortunately, a broad and expanding armamentarium is available to treat these women.
DR. KULP is Instructor, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT.
DR. TAYLOR is Professor of Obstetrics, Gynecology and Reproductive Sciences, and Director of Reproductive Endocrinology and Infertility at the Yale University School of Medicine. He is also Professor of Molecular, Cellular and Developmental Biology at Yale University and a recipient of eight National Institutes of Health research grants. Dr. Taylor is on the Speaker's Bureau at Wyeth.
By: Jennifer L. Kulp, MD, Hugh S. Taylor, MD Contemporary OB/GYN
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