Endometriosis

Endometriosis (from Greek
- endon, "within", and - m tra, "womb") is a gynecological medical condition in which cells from the lining of the uterus (endometrium) appear and flourish outside the uterine cavity, most commonly on the ovaries. The uterine cavity is lined by endometrial cells, which are under the influence of female hormones. These endometrial-like cells in areas outside the uterus (endometriosis) are influenced by hormonal changes and respond in a way that is similar to the cells found inside the uterus. Symptoms often worsen with the menstrual cycle. Endometriosis is typically seen during the reproductive years; it has been estimated that endometriosis occurs in roughly 5 10% of women. Symptoms may depend on the site of active endometriosis. Its main but not universal symptom is pelvic pain in various manifestations. Endometriosis is a common finding in women with infertility. SIGNS & SYMPTOMS 1.)Pelvic pain A major symptom of endometriosis is recurring pelvic pain. The pain can be mild to severe cramping 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, on the other hand, other women may have severe pain even though they have only a few small areas of endometriosis. Symptoms of endometriosis-related pain may include:  Dysmenorrhea painful, sometimes disabling cramps during menses; pain may get worse over time (progressive pain), also lower back pains linked to the pelvis  Chronic pelvic pain typically accompanied by lower back pain or abdominal pain  Dyspareunia painful sex, or painful intercourse.  Dysuria urinary urgency, frequency, and sometimes painful voiding. 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. 2.) Fertility Many women with infertility may have endometriosis. As endometriosis can lead to anatomical distortions and adhesions (the fibrous bands that form between tissues and organs following recovery from an injury), the causality may be easy to understand; however, the link between infertility and endometriosis remains enigmatic when the extent of endometriosis is limited. It has been suggested that endometriosis lesions release factors which are detrimental to gametes or embryos, or, alternatively, endometriosis may more likely develop in women who fail to conceive for other reasons and thus be a secondary phenomenon; for this reason it is preferable to speak of endometriosis-associated infertility in such cases. In some cases it can take a woman with endometriosis 7 10 years to conceive her first child, to most couples this can be stressful and daunting. Other Other symptoms may be present, including:
 

Constipation Chronic fatigue

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. There is no known cure for endometriosis. Endometriosis bears no relationship to endometrial cancer. Current research has demonstrated an association between endometriosis and certain types of cancers, notably ovarian cancer, non-Hodgkin's lymphoma and brain cancer. Endometriosis often also coexists with leiomyoma or adenomyosis, as well as autoimmune disorders. 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

Endoscopic image of a ruptured chocolate cyst in left ovary. Complications of endometriosis include:
     

Internal scarring Adhesions Pelvic cysts Chocolate cyst of ovaries Ruptured cyst Bowel obstruction

Infertility can be related to scar formation and anatomical distortions due to the endometriosis; however, endometriosis may also interfere in more subtle ways: cytokines and other chemical agents may be released that interfere with reproduction. Other complications of endometriosis include bowel and ureteral obstruction resulting from pelvic adhesions. Also, peritonitis from bowel perforation can occur. Ovarian endometriosis may complicate pregnancy by decasualization, abscess and/or rupture. It is the most common adnexal mass detected during pregnancy, being present in

0.52% of deliveries as studied in the period 2002 to 2007. Still, ovarian endometriosis during pregnancy can be safely observed conservatively. Pleural implantations are associated with recurrent right pneumothoraxes at times of menses, termed cat menial pneumothorax.

RISK FACTORS Genetics Genetic predisposition plays a role in endometriosis. It is well recognized that daughters or sisters of patients with endometriosis are at higher risk of developing endometriosis themselves. One study found that in female siblings of patients with endometriosis the relative risk of endometriosis is 5.7:1 versus a control population. Environmental There is a growing suspicion that environmental factors may cause endometriosis, specifically some plastics and cooking with certain types of plastic containers with microwave ovens. Dioxin exposure has been found a very likely cause of endometriosis in one well known study by The Endometriosis association that found that 79% of monkeys developed Endometriosis after receiving doses of dioxin. Other sources suggest that pesticides and hormones in our food cause a hormone imbalance. y Tobacco smoking: The risk of endometriosis has been reported to be reduced in smokers. Smoking causes decreased estrogens with increased breakthrough bleeding and shortened luteal phases. Smokers have an earlier than normal (by about 1.5 3 years) menopause which suggests that there is some toxic effect of smoking on the follicles directly. Aging: 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). Endometriosis in postmenopausal women does occur and has been described as an aggressive form of this disease characterized by complete progesterone resistance and extraordinarily high levels of aromatase expression. In less common cases, girls may have endometriosis symptoms before they even reach menarche.

Pathophysiology 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 interplay between several factors. Broadly, the aspects of the pathophysiology can basically be classified as underlying predisposing factors, 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 changes and so on, or if metabolic 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.[16] Also, pathogenic mechanisms appear to differ in the formation of distinct types of endometriosis lesion, such as peritoneal, ovarian and rectovaginal lesions. Metabolic changes

Endoscopic image of endometriosis lesions at the peritoneum of the pelvic wall. Endometriosis correlates with abnormal amounts of multiple substances, possibly indicating a causative link in its pathogenesis, although correlation does not imply causation: y Endometrial cells in women with endometriosis demonstrate increased adherence to peritoneal cells and increased expression of splice variants of CD44, a cell-surface protein involved in cell adhesions. The matrix metalloproteinase MMP-1 and MMP-2 are also increased, and appear to be major factors involved in the invasion of endometrium into the peritoneum and in vascularization of endometriosis.

Endometriosis patients also have elevated levels of vascular endothelial growth factor A (VEGF-A), soluble vascular endothelial growth factor receptors-1 and -2 (sVEGFR-1 and -2) and angiopoietin-2 (Ang-2). IL-4 may induce angiogenesis in endometriosis by inducing expression of exotoxin. Increased oxidative stress is also implicated in the pathophysiology of endometriosis, as well as 8-iso-PGF2 and ox sterols, being potential causative links in this oxidative stress.

Endometriosis is a condition that is estrogen-dependent and thus seen primarily during the reproductive years. In experimental models, estrogen is necessary to induce or maintain endometriosis. Medical therapy is often aimed at lowering estrogen levels to control the disease. Additionally, the current research into aromatase, an estrogen-synthesizing enzyme, has provided evidence as to why and how the disease persists after menopause and hysterectomy. Formation of ectopic endometrium The main theories for the formation of ectopic endometrium are retrograde menstruation, mllerianosis, coelomic metaplasia and transplantation, each further described below. Retrograde menstruation The theory of retrograde menstruation 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. 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. 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. y y y hereditary factors toxins acompromised immune system.

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. It is still unclear what, if any, causal relationship exists between toxins, autoimmune disease, and endometriosis

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. John A. Sampson- was proposed the theory of menstruation as a cause of endometriosis. Other theories of endometrial formation y Mllerianosis: A competing theory states that cells with the potential to become endometrial are laid down in tracts during embryonic development and organogenesis. These tracts follow the female reproductive (Mullerian) tract as it migrates caudally (downward) at 8 10 weeks of embryonic life. Primitive endometrial cells become dislocated from the migrating uterus and act like seeds or stem cells. This theory is supported by foetal autopsy. Coelomic metaplasia: This theory is based on the fact that coelomic epithelium is the common ancestor of endometrial and peritoneal cells and hypothesizes that later metaplasia (transformation) from one type of cell to the other is possible, perhaps triggered by inflammation. This theory is further supported by laboratory observation of this transformation. Transplantation: It is accepted that in specific patients endometriosis can spread directly. Thus endometriosis has been found in abdominal incisional scars after surgery for endometriosis. It can also grow invasively into different tissue layers, i.e., from the cul-de-sac into the vagina. On rare occasions endometriosis may be transplanted by blood or by the lymphatic system into peripheral organs such as the lungs and brain.

Generation of pain The way endometriosis causes pain is the subject of much research. Because many women with endometriosis feel pain during or around their periods and may spill further menstrual flow into the pelvis with each menstruation, some researchers are trying to reduce menstrual events in patients with 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. It is thought that 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, endometriosis 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. Localization Most endometriosis is found on these structures in the pelvic cavity:         Ovaries (the most common site) Fallopian tubes The back of the uterus and the posterior cul-de-sac The front of the uterus and the anterior cul-de-sac Uterine ligaments such as the broad or round ligament of the uterus Pelvic and back wall Intestines, most commonly the recto sigmoid Urinary bladder and ureters

Bowel- endometriosis affects approximately 10% of women with endometriosis, and can cause severe pain with bowel movements.   Endometriosis may spread to the cervix and vagina or to sites of a surgical abdominal incision. Endometriosis may also present with skin lesions in cutaneous endometriosis.

Diagnosis

Endometriosis, abdominal wall

Micrograph showing endometriosis (right) and ovarian stroma (left). H&E stain. A health history and a physical examination can in many patients lead the physician to suspect endometriosis. Surgery is the gold standard in diagnosis. Use of imaging tests may identify endometriotic cysts or larger endometriotic areas. It also may identify free fluid often within the cul-de-sac. The two most common imaging tests are ultrasound and magnetic resonance imaging (MRI). Normal results on these tests do not eliminate the possibility of endometriosis. Areas of endometriosis are often too small to be seen by these tests.

Endoscopic image of endometriotic lesions in the Pouch of Douglas and on the right sacrouterine ligament. The only way to diagnose endometriosis is by:   Laparoscopy 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 without performing a laparoscopic procedure. To the eye, lesions can appear dark blue, powderburn black, red, white, yellow, brown or non-pigmented. Lesions vary in size. Some within the pelvis walls may not be visible to the eye, 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. Often the symptoms of ovarian cancer are identical to those of endometriosis. If a misdiagnosis of endometriosis occurs due to failure to confirm diagnosis through laparoscopy, early diagnosis of ovarian cancer, which is crucial for successful treatment, may have been missed. If surgery is not performed, then a diagnosis of exclusion process is used. This means that all of the other plausible causes of pelvic pain are ruled out. Staging

Possible locations of endometriosis 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: Stage I (Minimal) Findings restricted to only superficial lesions and possibly a few filmy adhesions Stage II (Mild) In addition, some deep lesions are present in the cul-de-sac Stage III (Moderate) As above, plus presence of endometriomas on the ovary and more adhesions. Stage IV (Severe) As above, plus large endometriomas, extensive adhesions.

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.

Prevention Use of combined oral contraceptives is associated with a reduced risk of endometriosis, apparently giving a relative risk of endometriosis of 0.63 during active use, yet with limited quality of evidence according to a systematic review.

Management While there is no cure for endometriosis, in many peoplemenopause (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. Sonography is a method to monitor recurrence of endometriomas during treatments. Treatments for endometriosis in women who do not wish to become pregnant include: HORMONAL MEDICATION
*Progesterone or Progestin s: Progesterone counteracts estrogen and inhibits the growth

of the endometrium. Such therapy can reduce or eliminate menstruation in a controlled and reversible fashion. Progestin s are chemical variants of natural progesterone. *Avoiding products with xenoestrogens, which have a similar effect to naturally produced estrogen and can increase growth of the endometrium. *Hormone contraception therapy: Oral contraceptives reduce the menstrual pain associated with endometriosis. They may function by reducing or eliminating menstrual flow and providing estrogen support. Typically, it is a long-term approach. Continuous hormonal contraception consists of the use of combined oral contraceptive pills without

the use of placebo pills, or the use of Nuva Ring or the contraceptive patch without the break week. This eliminates monthly bleeding episodes.
*Danazol (Danocrine) and gestrinone are suppressive steroids with some androgenic

activity. Both agents inhibit the growth of endometriosis but their use remains limited as they may causehirsutism and voice changes.
*Gonadotropin Releasing Hormone (GnRH) agonist: These agents work by increasing

the levels of GnRH. Consistent stimulation of the GnRH receptors results in down regulation, inducing a profound hypo estrogenism by decreasing FSH and LH levels. While effective in some patients, they induce unpleasant menopausal symptoms, and over time may lead to osteoporosis. To counteract such side effects some estrogen may have to be given back (add-back therapy). These drugs can only be used for six months at a time.
*Lupron depo shot is a GnRH agonist and is used to lower the hormone levels in the

woman's body to prevent or reduce growth of endometriosis. The injection is given in 2 different doses: a 3 month course of monthly injections, each with the dosage of (11.25 mg); or a 6 month course of monthly injections, each with the dosage of (3.75 mg).
*Aromatase inhibitors are medications that block the formation of estrogen and have

become of interest for researchers who are treating endometriosis. Other medication NSAIDs: Anti-inflammatory. They are commonly used in conjunction with other therapy. For more severe cases narcotic prescription drugs may be used. NSAID injections can be helpful for severe pain or if stomach pain prevents oral NSAID use. MST: Morphine sulphate tablets and other opioid painkillers work by mimicking the action of naturally occurring pain-reducing chemicals called "endorphins". There are different long acting and short acting medications that can be used alone or in combination to provide appropriate pain control. Pentoxifylline, an immuno-modulatory agent SURGERY Procedures are classified as:   conservative when reproductive organs are retained, semi-conservative when ovarian function is allowed to continue,

Conservative therapy consists of the excision (called cystectomy) of the endometrium, adhesions, resection of endometriomas, and restoration of normal pelvic anatomy as much as is possible. There are combinations as well, notably one consisting of

cystectomy followed by ablative surgery (removal of endometrium) using a CO2 laser to vaporize the remaining 10 20% of the endometrioma wall close to the hilus. Semi-conservative therapy preserves a healthy appearing ovary, but also increases the risk of recurrence. Comparison of medicinal and surgical interventions 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. However, each approach has its own advantages and disadvantages. Advantages of medicinal interventions Decrease initial cost Empirical therapy (i.e. can be easily modified as needed) Effective for pain control Disadvantages of medicinal interventions Adverse effects are common Not likely to improve fertility Some can only be used for limited periods of time Advantages of surgery 1. Has significant efficacy for pain control. 2. Has increased efficacy over medicinal intervention for infertility treatment 3. Combined with biopsy, it is the only way to achieve a definitive diagnosis 4. Can often be carried out as a minimally invasive (laparoscopic) procedure to reduce morbidity and minimize the risk of post-operative adhesions. Treatment of infertility While roughly similar to medicinal interventions in treating pain, the efficacy of surgery is especially significant in treating infertility. One study has shown that surgical treatment of endometriosis approximately doubles the fecundity (pregnancy rate). The use of medical suppression after surgery for minimal/mild endometriosis has not shown benefits for patients with infertility. Use of fertility medication that stimulates ovulation (clomiphene citrate, gonadotropins) combined with intrauterine insemination (IUI) enhances fertility in these patients. In-vitro fertilization (IVF) procedures are effective in improving fertility in many women with endometriosis. IVF makes it possible to combine sperm and eggs in a laboratory and then place the resulting embryos into the woman's uterus. The decision when to apply IVF in endometriosis-associated infertility takes into account the age of the patient, the severity of the endometriosis, the presence of other infertility factors, and the results and duration of past treatments.

Other treatments


One theory above suggests that endometriosis is an auto-immune condition and if the immune system is compromised with a food intolerance, then removing that food from the diet can, in some people, have an effect. Various dietary recommendations are made in popular media. Eating foods high in indole-3-carbinol, such as cruciferous vegetables appears to be helpful in balancing hormones and managing pain. Physical therapy for pain management in endometriosis has been investigated in a pilot study suggesting possible benefit. Physical exertion such as lifting, prolonged standing or running does exacerbate pelvic pain. Use of heating pads on the lower back area, may provide some temporary relief. Laboratory studies indicate that heparin may alleviate endometriosis-associated fibrosis. Prognosis 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. It is important for patients to be continually in contact with their physician and keep an open dialog throughout treatment. This is a disease without a cure but with the proper communication, a woman with endometriosis can attempt to live a normal, functioning life. Using cystectomy and ablative surgery, pregnancy rates are approximately 40%. Recurrence The underlying process that causes endometriosis may not cease after surgical or medical intervention. The most recent 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. Also, the CA 125 serum antigen levels have been used to follow patients with endometriosis. With combined cystectomy and ablative surgery, one study showed recurrence of a small endometrioma in only one case among fifty-two women (2%) at a mean follow-up of 8.3 months. 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.

EPIDEMIOLOGY 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. Estimates about its prevalence vary, but 5 10% is a reasonable number, more common in women with infertility (20 50%) and women with chronic pelvic pain (about 80%). As an estrogen-dependent process, it can persist beyond menopause and persists in up to 40% of patients following hysterectomy. In some cases, it may also begin beyond menopause and it has also been described in men taking high-dose estrogen therapy.