Endometriosis

Endometriosis

Definition of Endometriosis

Endometriosis 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 membrane which lines the abdominal cavity. The uterine cavity is lined with endometrial cells, which are under the influence of female hormones. 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 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. Endometriosis is a common finding in women with infertility.

There is no cure for endometriosis, but it can be treated in a variety of ways, including pain medication, hormonal treatments, and surgery.

Cause of Endometriosis

The exact cause of endometriosis is unknown, but there are several theories about what causes it. 

Retrograde Menstruation

 In retrograde menstruation, menstrual blood containing endometrial cells flows back through the fallopian tubes and into the pelvic cavity instead of leaving the body as a period. This tissue then embeds itself onto the organs of the pelvis and grows.

It is thought that retrograde menstruation happens in most women, but many are able to clear the tissue naturally without it becoming a problem. It is possible that this is how endometriosis occurs in some women.

Retrograde menstruation is the most likely explanation for endometriosis. However, why the condition can occur in women who have had a hysterectomy cannot be explained.

Genetics

Endometriosis is rare in women of African-Caribbean origin, and is more common in Asian women than in white (Caucasian) women. This suggests that genes may play a part.

Endometrial cells transport

Endometriosis cells are believed to get into the bloodstream or lymphatic system. How, in very rare cases, the cells are found in remote places such as the eyes or brain can be explained by this theory.

Immune Dysfunction

It’s possible that a problem with the immune system may make the body unable to recognize and destroy endometrial tissue that’s growing outside the uterus. This may be a result of the endometriosis, rather than the cause of the disease.

Surgical scar implantation

After a surgery, such as a hysterectomy or C-section, endometrial cells may attach to a surgical incision.

Metaplasia

Metaplasia is the process of one type of cell changing into another to adapt to its environment. The cells lining the abdominal and pelvic cavities come from embryonic cells. When one or more small areas of the abdominal lining change into endometrial tissue, endometriosis can develop.

Signs and Symptoms of Endometriosis

Pelvic Pain

A major symptom of endometriosis is recurring pelvic pain. The pain can range from 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 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
• 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.

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.

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 endometriotic 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.

Other

Other symptoms include constipation and 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.

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, as well as autoimmune disorders. A 1988 survey conducted in the US found significantly more hypothyroidism, fibromyalgia, chronic fatigue syndrome, autoimmune diseases, allergies and asthmain women with endometriosis compared to the general population.

Complications

Complications of endometriosis include internal scarring, adhesions, pelvic cysts, chocolate cyst of ovaries, ruptured cysts, and bowel and ureteral obstruction resulting from pelvic adhesions. 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. Peritonitis from bowel perforation can occur.

Ovarian endometriosis may complicate pregnancy by decidualization, abscess and/or rupture.

Pleural implantations are associated with recurrent right pneumothoraces at times of menses, termed catamenial pneumothorax.

Risk Factors for Endometriosis

Environmental Toxins

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-tetrachlorodibenzo-p-dioxin – 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. 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 in 2009, another literature review by the same author 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.”

Genetics

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:

• Changes in chromosome 10 at region 10q26.
  
• Changes in the 7p15.2 region.
  

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.

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).

Incidences of endometriosis have occurred in postmenopausal women, an in less common cases, girls may have endometriosis symptoms before they even reach menarche.

Diagnosis of Endometriosis

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. However, in the United States most insurance plans will not cover surgical diagnosis unless the patient has already attempted to become pregnant and failed.

Use of imaging tests may identify endometriotic cysts or larger endometriotic areas. It also may identify free fluid often within the Recto-uterine pouch. 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.

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 without performing a laparoscopic procedure. 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.

Often the symptoms of ovarian cancer are identical to those of endometriosis.

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. For example, internal hernias are difficult to identify in women, and misdiagnosis with endometriosis is very common. One cause of misdiagnosis is that when the woman lies down flat on an examination table, all of the medical signs of the hernia disappear, but the woman typically has tenderness and other symptoms associated with endometriosis in a pelvic exam. The hernia can typically only be detected when symptoms are present, so diagnosis requires positioning the woman’s body in a way that provokes symptoms.

Staging

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.

Markers

An area of research is the search for endometriosis markers.

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 biomarkers, including both substance concentrations and genetic predisposition.

Histopathology

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 as residual.

Prevention from Endometriosis

Limited evidence indicates that the use of combined oral contraceptives is associated with a reduced risk of endometriosis

Treatment of Endometriosis

While there is no cure for endometriosis, 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. The da Vinci robotic surgery is the best choice to perform the excision of endometriosis, compared to the traditional laparoscopy. Severe complications and adjacent vital organ injuries have been widely reported with the laparoscopy.

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 Progestins: Progesterone counteracts estrogen and inhibits the growth of the endometrium. Such therapy can reduce or eliminate menstruation in a controlled and reversible fashion. Progestins 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. Recently Seasonale was FDA approved to reduce periods to 4 per year. Other OCPs have however been used like this off label for years. Continuous hormonal contraception consists of the use of combined oral contraceptive pills without the use of placebo pills, or the use of NuvaRing 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 cause hirsutism 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 downregulation, inducing a profound hypoestrogenism 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.Aromatase inhibitors are medications that block the formation of estrogen and have become of interest for researchers who are treating endometriosis.
  
  • 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-dose injections (11.25mg); or a 6 month course of monthly injections, each with the dosage of 3.75mg. Note that the symptoms will mostly come back after completing the Lupron courses. Long-term use of Lupron (over 5-6 months) is associated with severe side effects, and should not be offered to the patients. Thus, Lupron is not considered a treatment option for endometriosis. Instead, it is widely used in the United States as the non-invasive method for the diagnosis of 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.
• Opioids: 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.
• Following laparoscopic surgery women who were given Chinese herbs were reported to have comparable benefits to women with conventional drug treatments, though the journal article that reviewed this study also noted that “the two trials included in this review are of poor methodological quality so these findings must be interpreted cautiously. Better quality randomised controlled trials are needed to investigate a possible role for CHM [Chinese Herbal Medicine] in the treatment of endometriosis.”,
  
• Pentoxifylline, an immunomodulating agent, has been theorized to improve pain as well as improve pregnancy rates in women with endometriosis. Upon systematic review, The Cochrane Collaboration examined three randomized controlled trials (RCT) in which pregnancy rates were examined and one RCT in which pain improvement was studied. The Systematic Review included 334 participants. Upon systematic review of 3 Randomized control trials, there is no statistically significance difference in clinical pregnancy rates between women treated with pentoxifylline and those not treated with pentoxifylline (OR 1.54, 95% CI: 0.89-2.66). Upon review of reduction in pain, a decrease in pain was found with pentoxifylline treatment, however it was not statistically significant (OR -1.6 95% CI: -3.32-0.12). The Cochrane Review ultimately concludes that there is too little evidence to support the use of pentoxifylline in the management of endometriosis with regards to improved fertility or reduction in pain.^[ Current American Congress of Obstetricians and Gynecologists (ACOG) guidelines do not include immune-modulators, such as pentoxifylline, in standard treatment protocols.
  
• Angiogenesis inhibitors lack in clinical evidence of efficacy in endometriosis therapy. Under experimental in vitro and in vivo conditions, compounds that have been shown to exert anti-angiogenic effects on endometriotic lesions include growth factor inhibitors, endogenous angiogenesis inhibitors, fumagillin analogues, statins, cyclo-oxygenase-2 inhibitors, phytochemical compounds, immunomodulators, dopamine agonists, peroxisome proliferator-activated receptor agonists, progestins, danazol and gonadotropin-releasing hormone agonists.
  

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. Laparoscopy, besides being used for diagnosis, can also be an option for 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 tissue and adhesions. Because the incisions are very small, there will only be small scars on the skin after the procedure.

Semi-conservative therapy preserves a healthy appearing ovary, but also increases the risk of recurrence.

For patients with extreme pain, a presacral neurectomy may be indicated where the nerves to the uterus are cut. However, strong clinical evidence showed that presacral neurectomy is more effective in pain relief if the pelvic pain is midline concentrated, and not as effective if the pain extends to the left and right lower quadrants of the abdomen. This is because the nerves to be transected in the procedure are innervating the central or the midline region in the female pelvis. Furthermore, women who had presacral neurectomy have higher prevalence of chronic constipation not responding well to medication treatment because of the potential injury to the parasympathetic nerve in the vicinity during the procedure.

After surgical treatment of deeply infiltrating endometriosis with colorectal involvement, the endometriosis recurrence rate is estimated to be 10% (ranging between 5 and 25%).

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. Each approach has advantages and disadvantages.

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.

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.

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.