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Endometriosis is a gynecological condition in which cells from the lining of the uterus (endometrium) appear and flourish outside the uterine cavity, most commonly on the membrane which lines the abdominal cavity, the peritoneum. The uterine cavity is lined with endometrial cells, which are under the influence of female hormones. Endometrial cells in areas outside the uterus are also influenced by hormonal changes and respond in a way that is similar to the cells found inside the uterus. Symptoms of endometriosis are pain and infertility. The pain often is worse with the menstrual cycle and is the most common cause of secondary dysmenorrhea. Endometriosis was first identified by Baron Carl von Rokitansky in 1860.
Endometriosis is typically seen during the reproductive years; it has been estimated that endometriosis occurs in roughly 6–10% of women. Symptoms may depend on the site of active endometriosis. Its main but not universal symptom is pelvic pain in various manifestations. There is an established association between endometriosis and infertility. Endometriosis has a significant social and psychological impact.
There is no cure for endometriosis, but it can be treated in a variety of ways, including pain medication, hormonal treatments, and surgery.
A major symptom of endometriosis is recurring pelvic pain. The pain can range from mild to severe cramping or stabbing pain that occurs on both sides of the pelvis, in the lower back and rectal area, and even down the legs. The amount of pain a woman feels correlates poorly with the extent or stage (1 through 4) of endometriosis, with some women having little or no pain despite having extensive endometriosis or endometriosis with scarring, while other women may have severe pain even though they have only a few small areas of endometriosis. Symptoms of endometriosis-related pain may include:
Throbbing, gnawing, and dragging pain to the legs are reported more commonly by women with endometriosis. Compared with women with superficial endometriosis, those with deep disease appear to be more likely to report shooting rectal pain and a sense of their insides being pulled down. Individual pain areas and pain intensity appears to be unrelated to the surgical diagnosis, and the area of pain unrelated to area of endometriosis.
Endometriosis lesions react to hormonal stimulation and may "bleed" at the time of menstruation. The blood accumulates locally, causes swelling, and triggers inflammatory responses with the activation of cytokines. This process may cause pain. Pain can also occur from adhesions (internal scar tissue) binding internal organs to each other, causing organ dislocation. Fallopian tubes, ovaries, the uterus, the bowels, and the bladder can be bound together in ways that are painful on a daily basis, not just during menstrual periods.
Also, endometriotic lesions can develop their own nerve supply, thereby creating a direct and two-way interaction between lesions and the central nervous system, potentially producing a variety of individual differences in pain that can, in some women, become independent of the disease itself.
In addition to pain during menstruation, the pain of endometriosis can occur at other times of the month. There can be pain with ovulation, pain associated with adhesions, pain caused by inflammation in the pelvic cavity, pain during bowel movements and urination, during general bodily movement like exercise, pain from standing or walking, and pain with intercourse. But the most desperate pain is usually with menstruation and many women dread having their periods. Pain can also start a week before menses, during and even a week after menses, or it can be constant. The pain can be debilitating and the emotional stress can take a toll.
Current research has demonstrated an association between endometriosis and certain types of cancers, notably some types of ovarian cancer, non-Hodgkin's lymphoma and brain cancer. Despite similarities in their name and location, endometriosis bears no relationship to endometrial cancer.
Endometriosis often also coexists with leiomyoma or adenomyosis, but studies that look into similarities and differences between endometriosis and adenomyosis have conflicting results. A 1988 survey conducted in the US found significantly more hypothyroidism, fibromyalgia, chronic fatigue syndrome, autoimmune diseases, allergies and asthma in women with endometriosis compared to the general population.
Complications of endometriosis include internal scarring, adhesions, pelvic cysts, chocolate cyst of ovaries, ruptured cysts, and bowel and ureteral obstruction resulting from pelvic adhesions. Endometriosis-associated infertility can be related to scar formation and anatomical distortions due to the endometriosis.
Ovarian endometriosis may complicate pregnancy by decidualization, abscess and/or rupture.
Genetic predisposition plays a role in endometriosis. Daughters or sisters of patients with endometriosis are at higher risk of developing endometriosis themselves; low progesterone levels may be genetic, and may contribute to a hormone imbalance. There is an about 6-fold increased incidence in women with an affected first-degree relative.
It has been proposed that endometriosis results from a series of multiple hits within target genes, in a mechanism similar to the development of cancer. In this case, the initial mutation may be either somatic or heritable.
Individual genomic changes (found by genotyping) that have been associated with endometriosis include:
In addition, there are many findings of altered gene expression and epigenetics, but both of these can also be a secondary result of, for example, environmental factors and altered metabolism. Examples of altered gene expression include that of miRNAs.
Several studies have investigated the potential link between exposure to dioxins and endometriosis, but the evidence is equivocal and potential mechanisms are poorly understood. In the early 1990s, Sherry Rier and colleagues found that 79% of a group of monkeys developed endometriosis ten years after exposure to dioxin. The severity of endometriosis found in the monkeys was directly related to the amount of TCDD (2,3,7,8-Tetrachlorodibenzodioxin – the most toxic dioxin) to which they had been exposed . Monkeys that were fed dioxin in amounts as small as five parts per trillion developed endometriosis. In addition, the dioxin-exposed monkeys showed immune abnormalities similar to those observed in women with endometriosis. A similar follow up study in 2000 observed similar findings. In 1994, Drs. Frederick Yves Bois and Brenda Eskenazi wrote in the Environmental Health Perspectives journal titled Possible Risk of Endometriosis for Seveso, Italy Residents: An Assessment of Exposure to Dioxin stating that women who are sensitive to exposure may have a greater risk of having this condition. However, a 2004 review of studies of dioxin and endometriosis concluded that "the human data supporting the dioxin-endometriosis association are scanty and conflicting," and a 2009 follow-up review also found that there was "insufficient evidence at this moment" in support of a link between dioxin exposure and women developing endometriosis. A 2008 review by Rier, however, concluded that more work was needed, stating that "although preliminary work suggests a potential involvement of exposure to dioxins in the pathogenesis of endometriosis, much work remains to clearly define cause and effect and to understand the potential mechanism of toxicity."
Aging brings with it many effects that may reduce fertility. Depletion over time of ovarian follicles affects menstrual regularity. Endometriosis has more time to produce scarring of the ovary and tubes so they cannot move freely or it can even replace ovarian follicular tissue if ovarian endometriosis persists and grows. Leiomyomata (fibroids) can slowly grow and start causing endometrial bleeding that disrupts implantation sites or distorts the endometrial cavity which affects carrying a pregnancy in the very early stages. Abdominal adhesions from other intraabdominal surgery, or ruptured ovarian cysts can also affect tubal motility needed to sweep the ovary and gather an ovulated follicle (egg).
While the exact cause of endometriosis remains unknown, many theories have been presented to better understand and explain its development. These concepts do not necessarily exclude each other. The pathophysiology of endometriosis is likely to be multifactorial and to involve an interplay between several factors.
Broadly, the aspects of the pathophysiology can basically be classified as underlying predisposing factors, inflammation, metabolic changes, formation of ectopic endometrium, and generation of pain and other effects. It is not certain, however, to what degree predisposing factors lead to metabolic and inflammatory changes and so on, or if metabolic and inflammatory changes or formation of ectopic endometrium is the primary cause. Also, there are several theories within each category, but the uncertainty over what is a cause versus what is an effect when considered in relation to other aspects is as true for any individual entry in the pathophysiology of endometriosis. Inflammation is a central part of the aetiopathology and causes pain.
Also, pathogenic mechanisms appear to differ in the formation of distinct types of endometriotic lesion, such as peritoneal, ovarian and rectovaginal lesions.
The main theories for the formation of ectopic endometrium are retrograde menstruation, müllerianosis, coelomic metaplasia and transplantation, each further described below.
The theory of retrograde menstruation (also called the implantation theory or transplantation theory) is the most widely accepted theory for the formation of ectopic endometrium in endometriosis. It suggests that during a woman's menstrual flow, some of the endometrial debris exits the uterus through the fallopian tubes and attaches itself to the peritoneal surface (the lining of the abdominal cavity) where it can proceed to invade the tissue as endometriosis.
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While most women may have some retrograde menstrual flow, typically their immune system is able to clear the debris and prevent implantation and growth of cells from this occurrence. However, in some patients, endometrial tissue transplanted by retrograde menstruation may be able to implant and establish itself as endometriosis. Factors that might cause the tissue to grow in some women but not in others need to be studied, and some of the possible causes below may provide some explanation, e.g., hereditary factors, toxins, or a compromised immune system. It can be argued that the uninterrupted occurrence of regular menstruation month after month for decades is a modern phenomenon, as in the past women had more frequent menstrual rest due to pregnancy and lactation.
Retrograde menstruation alone is not able to explain all instances of endometriosis, and it needs additional factors such as genetic or immune differences to account for the fact that many women with retrograde menstruation do not have endometriosis. Research is focusing on the possibility that the immune system may not be able to cope with the cyclic onslaught of retrograde menstrual fluid. In this context there is interest in studying the relationship of endometriosis to autoimmune disease, allergic reactions, and the impact of toxins. It is still unclear what, if any, causal relationship exists between toxins, autoimmune disease, and endometriosis. There are immune system changes in women with endometriosis, such as an increase macrophage-derived secretion products, but it is unknown if these are contributing to the disorder or are reactions from it.
In addition, at least one study found that endometriotic lesions are biochemically very different from artificially transplanted ectopic tissue. The latter finding, however, can in turn be explained by that the cells that establish endometrial lesions are not of the main cell type in ordinary endometrium, but rather of a side population cell type, as supported by exhibitition of a side population phenotype upon staining with Hoechst dye and by flow cytometric analysis. Similarly, there are changes in for example the mesothelium of the peritoneum in women with endometriosis, such as loss of tight junctions, but it is unknown if these are causes or effects of the disorder.
In rare cases where imperforate hymen does not resolve itself prior to the first menstrual cycle and goes undetected, blood and endometrium are trapped within the uterus of the patient until such time as the problem is resolved by surgical incision. Many health care practitioners never encounter this defect, and due to the flu-like symptoms it is often misdiagnosed or overlooked until multiple menstrual cycles have passed. By the time a correct diagnosis has been made, endometrium and other fluids have filled the uterus and fallopian tubes with results similar to retrograde menstruation resulting in endometriosis. The initial stage of endometriosis may vary based on the time elapsed between onset and surgical procedure.
The theory of retrograde menstruation as a cause of endometriosis was first proposed by John A. Sampson.
Bowel endometriosis affects approximately 10% of women with endometriosis, and can cause severe pain with bowel movements.
Endometriosis may also present with skin lesions in cutaneous endometriosis.
Less commonly lesions can be found on the diaphragm. Diaphragmatic endometriosis is rare, almost always on the right hemidiaphragm, and may inflict cyclic pain of the right shoulder just before and during menses. Rarely, endometriosis can be extraperitoneal and is found in the lungs and CNS.
A health history and a physical examination can in many patients lead the physician to suspect endometriosis. Laparoscopy, a surgical procedure where a camera is used to look inside the abdominal cavity, is the gold standard in diagnosis as it permits lesion visualization, unless the lesion is visible externally, e.g. an endometriotic nodule in the vagina.
Use of pelvic ultrasound may identify large endometriotic cysts (such as endometrioma). However, endometriosis implants cannot be visualized with ultrasound technique.
The only way to diagnose endometriosis is by laparoscopy or other types of surgery with lesion biopsy. The diagnosis is based on the characteristic appearance of the disease, and should be corroborated by a biopsy. Surgery for diagnoses also allows for surgical treatment of endometriosis at the same time.
Although doctors can often feel the endometrial growths during a pelvic exam, and these symptoms may be signs of endometriosis, diagnosis cannot be confirmed by exam only. To the eye, lesions can appear dark blue, powder-burn black, red, white, yellow, brown or non-pigmented. Lesions vary in size. Some within the pelvis walls may not be visible, as normal-appearing peritoneum of infertile women reveals endometriosis on biopsy in 6–13% of cases. Early endometriosis typically occurs on the surfaces of organs in the pelvic and intra-abdominal areas. Health care providers may call areas of endometriosis by different names, such as implants, lesions, or nodules. Larger lesions may be seen within the ovaries as ovarian endometriomas or "chocolate cysts", "chocolate" because they contain a thick brownish fluid, mostly old blood.
Frequently during diagnostic laparoscopy no lesions are found in patients with chronic pelvic pain, a symptom common to other disorders. In order to avoid invasive diagnosis and potentially life-threatening complications of laparoscopy, the U.S. Food and Drug Administration (FDA) approved the use of intramuscular injection of Lupron (3.75 mg each month) as the effective diagnostic method. If the chronic pelvic pain was apparently reduced or relieved with Lupron, the diagnosis is established. Note that Lupron is not approved by FDA for the treatment of endometriosis due to its long term side effects (bone loss, menopausal symptoms, low estrogen state, etc.) Most gynecologists in USA will not give Lupron as the diagnostic method for more than three months. Indeed, this approach may delay diagnosis and surgery may in any case be necessary to excise lesions.
Surgically, endometriosis can be staged I–IV (Revised Classification of the American Society of Reproductive Medicine). The process is a complex point system that assesses lesions and adhesions in the pelvic organs, but it is important to note staging assesses physical disease only, not the level of pain or infertility. A patient with Stage I endometriosis may have little disease and severe pain, while a patient with Stage IV endometriosis may have severe disease and no pain or vice versa. In principle the various stages show these findings:
Endometrioma on the ovary of any significant size (Approx. 2 cm +) must be removed surgically because hormonal treatment alone will not remove the full endometrioma cyst, which can progress to acute pain from the rupturing of the cyst and internal bleeding. Endometrioma is sometimes misdiagnosed as ovarian cysts.
A systematic review in 2010 of essentially all proposed biomarkers for endometriosis in serum, plasma and urine came to the conclusion that none of them have been clearly shown to be of clinical use, although some appear to be promising. Another review in 2011 identified several putative biomarkers upon biopsy, including findings of small sensory nerve fibers or defectively expressed β3 integrin subunit.
The one biomarker that has been used in clinical practice over the last 20 years is CA-125. However, its performance in diagnosing endometriosis is low, even though it shows some promise in detecting more severe disease. CA-125 levels appear to fall during endometriosis treatment, but has not shown a correlation with disease response.
It has been postulated a future diagnostic tool for endometriosis will consist of a panel of several specific and sensitive biomarkers, including both substance concentrations and genetic predisposition.
Typical endometriotic lesions show histopathologic features similar to endometrium, namely endometrial stroma, endometrial epithelium, and glands that respond to hormonal stimuli. Older lesions may display no glands but hemosiderindeposits (see photomicrograph on right) as residual.
Immunohistochemistry has been found to be useful in diagnosing endometriosis as stromal cells have a peculiar surface antigen, CD10, thus allowing the pathologist go straight to a staining area and hence confirm the presence of stromal cells and sometimes glandular tissue is thus identified that was missed on routine H&E staining.
While there is no cure for endometriosis, there are two types of interventions; treatment of pain and treatment of endometriosis-associated infertility. In many women menopause (natural or surgical) will abate the process. In patients in the reproductive years, endometriosis is merely managed: the goal is to provide pain relief, to restrict progression of the process, and to restore or preserve fertility where needed. In younger women with unfulfilled reproductive potential, surgical treatment attempts to remove endometrial tissue and preserving the ovaries without damaging normal tissue.
In general, the diagnosis of endometriosis is confirmed during surgery, at which time ablative steps can be taken. Further steps depend on circumstances: patients without infertility can be managed with hormonal medication that suppress the natural cycle and pain medication, while infertile patients may be treated expectantly after surgery, with fertility medication, or with IVF. As to the surgical procedure, ablation (or fulguration) of endometriosis (burning and vaporizing the lesions with a pointy electric device) has shown high rate of short-term recurrence after the procedure. The best surgical procedure with much less rate of short-term recurrence is to excise (cut and remove) the lesions completely.
Conservative treatment consists of the excision (called cystectomy) of the endometrium, adhesions, resection of endometriomas, and restoration of normal pelvic anatomy as much as is possible. Laparoscopy, besides being used for diagnosis, can also be used to perform surgery. It's considered a "minimally invasive" surgery because the surgeon makes very small openings (incisions) at (or around) the belly button and lower portion of the belly. A thin telescope-like instrument (the laparoscope) is placed into one incision, which allows the doctor to look for endometriosis using a small camera attached to the laparoscope. Small instruments are inserted through the incisions to remove the endometriosis tissue and adhesions. Because the incisions are very small, there will only be small scars on the skin after the procedure, and all endometriosis can be removed, and patients recover from surgery quicker and have a lower risk of adhesions. 55% to 100% of women develop adhesions following pelvic surgery, which can result in infertility, chronic abdominal and pelvic pain, and difficult reoperative surgery. Trehan's temporary ovarian suspension, a technique in which the ovaries are suspended for a week after surgery may be used to reduce the incidence of adhesions after endometriosis surgery.
Conservative treatment involves excision of endometriosis whilst preserving the ovaries and uterus, very important for women wishing to conceive, but may increase the risk of recurrence.
Endometriosis recurrence following conservative surgery is estimated as 21.5% at 2 years and 40-50% at 5 years.
A hysterectomy (removal of the uterus) can be used to treat endometriosis in patients who do not wish to conceive, however this should only be done when combined with removal of the endometriosis by excision, as if endometriosis is not also removed at the time of hysterectomy, pain may still persist.
For patients with extreme pain, a presacral neurectomy may be very rarely performed where the nerves to the uterus are cut. However, this technique is almost never used due to the high incidence of associated complications including presacral haematoma and irreversible problems with urination and constipation.
Cochrane Menstrual Disorders and Subfertility Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, CINAHL, and PsycINFO. Reference lists of included trials were also searched and experts were contacted to identify additional trials. The updated review included four randomized control trials (RCT) involving 334 patients. - one RCT for evaluation of pain relief with pentoxifylline, and three RCTs for evaluation of improved clinical pregnancy rates with pentoxifylline. For the outcome of clinical pregnancy, a low level of heterogeneity was found among RCTs, demonstrated by I2 of 0% and Chi2 of 1.59. The results of the original review published in 2009 remain unchanged in the 2012 update. No relationship was found between reduction in pain and pentoxifylline use at any visit (one month: MD -0.36, 95% CI -2.08 to 1.36; two months: MD - 1.25, 95% CI -2.67 to 0.17; three months: MD -1.60, 95% CI - 3.32 to 0.12). There was no significant increase in the odds of clinical pregnancy in the pentoxifylline group as compared with the placebo group (OR 1.54, 95% CI 0.89 to 2.66) . This study concludes that there remains insufficient evidence to support the use of pentoxifylline for the management of premenopausal women with endometriosis for relief of pain symptoms or to improve fertility rates.  Current American Congress of Obstetricians and Gynecologists (ACOG) guidelines do not include immune-modulators, such as pentoxifylline, in standard treatment protocols.
The overall effectiveness of manual physical therapy to treat endometriosis has not yet been identified.
There is no evidence to support the notion that nutritional therapy is effective in the management of endometriosis. Research in Italy has suggests that removal of gluten from the diet can ease the pain of 75% of the women with endometriosis, however the study was flawed as it was not randomised and lacked a control group.
Efficacy studies show that both medicinal and surgical interventions produce roughly equivalent pain-relief benefits. Recurrence of pain was found to be 44 and 53 percent with medicinal and surgical interventions, respectively. Each approach has advantages and disadvantages. Manual therapy showed a decrease in pain for 84 percent of study participants, and a 93 percent improvement in sexual function.
The advantages of medicinal intervention are decreased initial cost, therapy can be modified as needed, and effective pain control. Its disadvantages are common adverse effects, unlikely improvement in fertility, and limitations on the length of time some can be used. Evidence on how effective medication is for relieving pain associated with endometriosis is limited.
The advantages of surgery are demonstrated efficacy for pain control, it is more effective for infertility than medicinal intervention, it provides a definitive diagnosis, and surgery can often be performed as a minimally invasive (laparoscopic) procedure to reduce morbidity and minimize the risk of post-operative adhesions. Efforts to develop effective strategies to reduce or prevent adhesions have been undertaken, but their formation remain a frequent side effect of abdominal surgery.
The advantages of physical therapy techniques are decreased cost, absence of major side-effects, it does not interfere with fertility, and near-universal increase of sexual function. Disadvantages are that there are no large or long-term studies of its use for treating pain or infertility related to endometriosis.
In case of infertility in a woman with endometriosis, surgery is more effective than medicinal intervention. For this purpose, surgery attempts to remove endometrial tissue and preserving the ovaries without damaging normal tissue. In addition, in-vitro fertilization (IVF) procedures are effective in improving fertility in many women with endometriosis.
Proper counseling of patients with endometriosis requires attention to several aspects of the disorder. Of primary importance is the initial operative staging of the disease to obtain adequate information on which to base future decisions about therapy. The patient's symptoms and desire for childbearing dictate appropriate therapy. Not all therapy works for all patients. Some patients have recurrences after surgery or pseudo-menopause. In most cases, treatment will give patients significant relief from pelvic pain and assist them in achieving pregnancy.
The underlying process that causes endometriosis may not cease after surgical or medical intervention. Studies have shown that endometriosis recurs at a rate of 20 to 40 percent within five years following conservative surgery, unless hysterectomy is performed or menopause reached. Monitoring of patients consists of periodic clinical examinations and sonography.
Vaginal childbirth decreases recurrence of endometriosis. In contrast, endometriosis recurrence rates have been shown to be higher in women who have not given birth vaginally, such as in Cesarean section.
Endometriosis can affect any female, from premenarche to postmenopause, regardless of race or ethnicity or whether or not they have had children. It is primarily a disease of the reproductive years. Its prevalence varies, but 6–10% is a reasonable number, more common in women with infertility and chronic pelvic pain (35–50%).
As an estrogen-dependent process, it can persist beyond menopause and persists in up to 40% of patients following hysterectomy.
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