Endometriosis - Women Health Information Page

What is endometriosis?

Endometriosis is a condition in which endometrial tissue, which is normally found only in the lining (the endometrium) of the uterus (womb), grows outside the uterus. The misplaced endometrial tissue most commonly sticks to the ovaries and the ligaments that support the uterus. Less often, it adheres to the outer surfaces of the small and large bowel, the ureters (the tubes that convey the urine from the kidneys to the bladder), the bladder or the vagina. Rarely, endometrial tissue is found in surgical scars on the abdomen, in the lining of the chest cavity or in the lungs themselves.

The misplaced endometrial tissue responds to cyclical hormonal changes in just the same way as normal endometrial tissue does. Therefore, during a menstrual period, it may bleed. This internal bleeding tends to cause irritation and pain, often with cramps. With time, scar tissue develops and this can form �adhesions� which are fibrous bands that bind together structures that are normally separate from each other. By pulling against and distorting internal organs, adhesions can interfere with their normal function.

What causes endometriosis and who is at risk?

It is estimated that about 10 to 15 per cent of women have endometriosis. Exactly what causes endometriosis is unknown. Possibly, during menstruation, small pieces of endometrial tissue shed from the uterus wall pass backwards along the fallopian tubes towards the ovaries and into the abdominal cavity, instead of flowing out of the body via the vagina as normal.

The condition tends to run in families. It is more common in Caucasians than in other ethnic groups and is sometimes associated with having an abnormal uterus.

What are the common symptoms and complications of endometriosis?

The most common symptom of endometriosis is menstrual pain (dysmenorrhoea). Often, a woman will not start to have menstrual pain from her endometriosis until she has already had it for several years. The severity of the pain can vary greatly: some women with extensive endometriosis have no symptoms, whereas others with minimal disease have incapacitating pain. The pain may not be confined to menstruation. Pain can be experienced during sexual intercourse (dyspareunia). Another common symptom of endometriosis is infertility. Less commonly, endometrial tissue and adhesions attached to the bowel or bladder may cause abdominal swelling, pain during bowel movements, bleeding from the rectum (back passage) during menstruation, bowel obstruction, or pain during urination. Occasionally, blood collects in a mass of endometrial tissue, which can leak or rupture causing sudden, abdominal pain.

How do doctors recognise endometriosis?

To make the diagnosis, a �laparoscopy� is almost always necessary. For this procedure, a general anaesthetic is given and a fibre-optic viewing tube (a laparoscope) is inserted into the abdomen via a small incision just below the navel. In this way the doctor can inspect the inside of the abdominal cavity for patches of endometrial tissue. Sometimes, to confirm the diagnosis, a small piece of tissue (a biopsy) is removed through the laparoscope and sent to the laboratory for microscopic examination. Other procedures, such as ultrasound scans, barium enema with X-rays and computerised tomography (CT scanning) may be used to find out the extent of the disease inside the abdomen.

What is the treatment for endometriosis?

Self- care action plan

When the principal symptom is lower abdominal pain, stress may make the pain worse. Therefore, some form of relaxation therapy, such as yoga or the Alexander technique, may be helpful. Choice of treatment of the condition with medicines and / or surgery will depend on age, symptoms and pregnancy plans as well as the extent of the disease. All these factors should be discussed with your doctor.

Medicines

Drugs (such as danazol or buserelin) that suppress the activity of the ovaries slow the growth of the misplaced endometrial tissue. There is a variety of such medicines, each having different advantages and disadvantages. You and your doctor should discuss the options. If drug treatment is withdrawn, the disease usually returns. Medicines may be used in combination with surgery.

Surgery

If you have moderate to severe disease, surgery may be necessary. As much of the misplaced endometrial tissue as possible will be removed, while preserving your ability to have children. Often this procedure can be done during laparoscopy rather than afterwards as a major abdominal operation. However, surgical removal is only a temporary measure as the endometriosis tends to grow back.

Only surgical removal of both ovaries can prevent endometriosis from recurring. This operation, which includes removal of the uterus, is only carried out in women with severe pain unrelieved by medicines, and who do not want another pregnancy.

Afterwards, hormone replacement therapy with oestrogen is necessary because the removal of the ovaries results in the same effect as the menopause. This treatment may be started immediately after the surgery or, if a lot of endometrial tissue still remains in the abdominal cavity, after a delay of four to six months. This delay allows the endometrial tissue to disappear. Otherwise it would be stimulated to proliferate by the replacement oestrogen.

What is the outcome of endometriosis?

Endometriosis spontaneously subsides after the menopause as the ovaries become less active. Before the menopause, only surgical removal of both ovaries can prevent endometriosis from recurring. However, symptoms may improve considerably or even disappear after drug treatment with or without surgical removal of the misplaced endometrial tissue. Treating women who have moderate to severe disease results in pregnancy rates ranging from 40 to 60 per cent. It is not clear if treating women with mild disease improves their fertility.

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Treatment and Research Related to Endometriosis

Up to 20% of American women of childbearing age may have endometriosis, a condition which can cause severe pain or infertility. Endometrium is the tissue that lines the inside of the uterus. In women of childbearing age who are not pregnant, endometrium normally is shed each month as menstrual flow. Endometriosis is characterized by tissue that looks and acts like endometrium, but is located outside the uterus, usually in the abdominal cavity. This misplaced tissue reacts to the menstrual cycle the same way normal endometrium does. It breaks apart and begins to bleed at the end of each menstrual cycle. However, there is no place for blood to go. As a result, tissue around the area of endometriosis may become swollen and inflamed, producing scar tissue and lesions. Endometriosis is usually relieved by menopause, although estrogen-replacement therapy may cause the tissue to grow back.

Treatments for Endometriosis

There is no absolute cure, since endometriosis can reoccur after treatment. However, treatment may alleviate symptoms and improve fertility. The course of treatment is largely dictated by whether the patient wants to reduce pain, become pregnant or both. For pain control, medications are the first line of treatment. These include a wide variety of non-steroidal anti-inflammatory drugs (NSAIDS), such as ibuprofen and naproxen. A weak synthetic male hormone (Danazol, which is a type of progesterone), medroxy progesterone acetate (Provera) and birth control pills are other options. They stop the ovaries from functioning so that menstruation does not occur.

Injections of a drug like Lupron, known as gonadotropin releasing hormone agonist therapy, may be necessary. This brings on "medical menopause," ending the production of estrogen and progesterone, the hormones that fuel endometriosis. If medication does not alleviate pain, surgery to remove the endometrial material and, possibly, the reproductive organs may be necessary.

Surgery is usually necessary to improve fertility in patients with endometriosis. Attempts will be made to remove endometriotic tissue, restore pelvic anatomy and improve fallopian tube function. Fertility medications are often prescribed. For patients who are trying to control pain and become pregnant, surgery along with anti-inflammatories and fertility medications may be prescribed.

Because ultrasound and magnetic resonance imaging (MRI) results are not diagnostic, surgery is required to confirm endometriosis. A laparoscope, in the form of a narrow tube, is inserted through a small incision in the abdomen. This allows the physician to view areas of endometriosis. Advanced laparoscopic surgery, involving additional small incisions for other instruments, can remove or destroy endometriotic tissue. Sometimes a laser is used in this case.

Open surgery, which involves a larger abdominal incision, is commonly associated with treating very difficult cases of endometriosis in concert with removing the uterus or ovaries. Improvements in laparoscopic instruments and surgical knowledge allow many of these difficult cases to be performed, including removal of reproductive organs, by laparoscopy. Patients who have laparoscopic surgery can usually return to work within 72 hours, but they may be off the job two to four weeks with open surgery.

Current Research

The majority of endometriosis research going on around the world is seeking the cause of the disease so that effective therapies can be developed.

At the Medical College of Wisconsin, researchers are trying to determine the genetic origin of endometriosis. Researchers question if endometriosis begins as a result of menstruation or if it is entirely independent and develops like a tumor because of a gene abnormality. As part of the study, tissue samples from endometriosis are being compared to normal endometrial tissue in the uterus.

Other researchers are examining the mechanism by which the disease causes pain or infertility. While not yet proven, endometriosis is believed to occur when endometrium backs up into the fallopian tubes and on into the abdomen, causing inflammation.

It appears that sometimes endometriosis can produce chemicals that influence the release of eggs from the ovaries and the fallopian tubes' ability to pick up the eggs. Fertilization and implantation can also be affected by endometriosis. The influence of these chemicals is under study, as is the role of "selective estrogen receptor modulators" in the treatment of endometriosis. Endometriosis is believed to worsen under the influence of estrogen. If these receptor sites could be blocked on the cellular level, a cure for endometriosis might be possible.

Phototherapy, which has been used to destroy brain tumors and other abnormal cells, may hold promise for treating endometriosis. This method involves injecting a light-sensitive chemical agent, such as a dye. When activated by a specific wavelength of light, the agent kills the abnormal cells. This treatment for endometriosis, unfortunately, is still years in the future.

Estil Y. Strawn, Jr., MD

Keywords: Women's Health, uterus, Provera, progesterone, phototherapy, ovaries, menstruation, menstrual cycle, medroxy progesterone acetate, medical menopause, Lupron, laparoscopic surgery, laparoscope, HRT, hormone replacement therapy, Gonadotropin, fallopian tubes, estrogen replacement therapy, estrogen, ERT, endometrium, Danazol, laparoscopy, infertility, endometriosis

ENDROMETRIOSIS

Endometriosis: Conquering the Silent Invader

"When we had sex on our wedding night, instead of having an ultimate experience with my husband, sex was so painful I ended up in tears," Marilyn P. wrote to her Witsendo friends. "I thought something was wrong with me . . .that I was frigid or something.

"When I went to the doctor, I told him I'd always had some pain with my periods but that my cramps were getting worse.

"He did a pelvic exam and I screamed when he touched my left ovary. After doing an ultrasound examination, he told me that my left ovary was swollen to twice its normal size. He also felt small bumps behind my uterus. He recommended doing a laparoscopy to find out what was going on.

"That's when I got the news: endometriosis at the ripe old age of twenty-three, and that I had probably had endometriosis as a teenager! What a way to start married life."  

What is it?  

Endometriosis is described as the presence of endometrial tissue in locations outside the endometrial (uterine) cavity. Endometriosis is commonly found in the cul-de-sac (behind the uterus), the rectovaginal septum (the tissue between the rectum and vagina), on the surface of the rectum, the fallopian tubes and ovaries, the uterosacral ligaments, the bladder, and the pelvic side wall. Generally endometriosis in the rectovaginal septum is more likely to deeply invade the underlying structures.

Is endometriosis a genetic disease?

Studies have shown that sisters have a six times increased risk compared to their husband's sisters. Other studies show up to an eight times increased risk when compared to other women. Affected sisters are more likely to have severe disease than other. Although these studies suggest a genetic basis, presently, the mode of inheritance is unknown. The OXEGENE Study is enrolling family members with endometriosis to try and identify the genetic basis of this disease.

How common is it?

At the time of tubal ligation 2-5% of women will have endometriosis, while between 25-50% of infertile women have been reported to have endometriosis. Endometriosis affects 5 million U.S. women, approximately 6-7% of all females, 30-40% of whom are infertile.

What are the causes?

No one theory seems to explain all cases. Several theories, however, have been postulated:

The endometrial tissue migrates from the uterus through the tubes into the pelvis. (This doesn't explain how women with their tubes tied develop the disease or why it remains after hysterectomy.) An abnormality in the immune system allows normally shed endometrial cells to attach and grow. The disease is caused by a genetic birth defect as evidenced by the tendency for it to run in families. Patients with an affected mother or siblings are more likely (61 percent) to have severe endometriosis than those without affected relatives (23 percent). Tissue in the abdominal cavity changes into endometrial tissue as a result of repeated inflammation (sheer speculation at this point). The endometrial tissue spreads from the uterus to the abdominal cavity through the lymphatic system or bloodstream. Commonly during the menstrual period, cells can be found in the fluid behind the uterus. The most widely held theory, retrograde menstruation, states that endometriosis occurs when endometrial fragments attach to nearby pelvic structures and grow. Other theories include tissue transplantation, induction of changes in peritoneal lining cells, spread through uterine veins, and direct extension through the lymphatic system.

As endometrial cells are frequently seen in peritoneal fluid in all women at the time of menses, one would expect endometriosis to develop in everyone. Obviously this is not appear the case. Unfortunately, we don't really know why. Is the immune system the cause? Immunological changes have been demonstrated in women with endometriosis, however, it is uncertain whether these immunologic findings are responsible for the endometriosis or are a result of the inflammation caused by endometriosis.  

How Does Endometriosis Cause Fertility Problems?  

In cases where there is obvious disruption of the normal anatomy, endometriosis is a known cause of fertility problems. In fact 30-40% of patients with endometriosis are infertile. This is two to three times the rate of infertility in the general population.

In patients with endometriosis, the monthly fecundity (chance of getting pregnant) decreases by 12-36%. However, the long term cumulative pregnancy rates are normal in patients with minimal endometriosis and normal anatomy. Studies provide contradicting information, but the bulk of research at this time indicates that pregnancy rates are not improved by treating minimal endometriosis.

Under the influence of cycling female hormones, each month the displaced endometrial tissue grows and sheds blood at the time of menses. Instead of flowing harmlessly outside the body, however, the excrement wreaks havoc in the abdominal cavity.

The resulting chronic tissue inflammation leads to the formation of adhesions and scars, which surround and entrap delicate reproductive organs. The adhesions can be so extensive that they literally freeze the tubes, ovaries, and uterus into place (stages III and IV). The eggs themselves are trapped in the heavy shrouds of scar tissue surrounding the ovaries, and infertility results. As the disease spreads, the older endometrial cells burn out, leaving dead scar tissue in their wake.  

Even mild forms of the disease (stages I and II) may interfere with fertility. It is hypothesized that the prostaglandins (hormones) secreted by the active, young endometrial implants or other chemicals secreted by white blood cells may interfere with the reproductive organs by causing muscular contractions or spasms. The tube may be unable to pick up the egg, and the stimulated uterus may reject implantation. In addition, sperm motility may be adversely affected along with the ability of the sperm to penetrate into the egg. Although the mechanisms are not fully understood, endometriosis may also result in anovulation (17 percent), cause a luteal phase defect interfering with implantation, or cause a luteinized unruptured follicle.

Some researchers suggest that the woman's body may form antibodies against the misplaced endometrial tissue. The same antibodies may attack the uterine lining and cause the high spontaneous-abortion rate: up to three times the normal rate. (Fortunately, removing the endometriosis with medication or with surgery will reduce this risk to normal.)

The normal tissue surrounding the endometriosis implant becomes puckered and ischemic (suffering from lack of oxygen), causing pain similar to that from a heart attack. Attacked over a prolonged period, the fallopian tubes may become inflamed and swell shut. Blocked by adhesions, the tubes can no longer provide safe passage for egg, sperm, and embryo. Ectopic pregnancies become a real danger: up to sixteen times more likely than the normal population (16 percent vs. 1 percent). Let's evaluate the specific factors that may contribute to infertility in patients with endometriosis.

Hormonal parameters:
Compared to a normal cycle, the follicular phase may be shorter in patients with endometriosis, the estradiol may be lower, and a blunted LH surge may be seen. Progesterone levels and luteal phase endometrial biopsies, however, are normal. There is a tendency towards greater number of follicles which are smaller at the time of the LH surge in patients with endometriosis. However, this data does not prove that endometriosis is the cause of infertility. Women with subtle ovulatory dysfunction are more likely to have infertility and it may be that infertility or an abnormal hormone profile increases the likelihood of endometriosis.

Luteinized unruptured follicle syndrome:
In women with severe pelvic adhesions where the ovary is encased, luteinized unruptured follicle (LUF) may be noted. This is believed to occur when, despite normal hormonal parameters (LH surge), the egg is not released from the ovary. Endometriosis is found in 63% of those patients reported to have LUF. LUF is seen in 35% of patients with endometriosis versus 11% of patients without endometriosis. However, the detection of follicular rupture by ultrasound and laparoscopy is very subjective and the diagnosis of this condition is complicated. Therefore, studies that look at endometriosis and LUF must be held suspect.

IVF and experimental models:
Studies in rabbits have shown that surgical induction of endometriosis leads to a decrease in fertility from 75% to 25%. This may be due to anovulation associated with endometrial implants. Studies have evaluated immune modification in the rabbit model to attempt to restore fertility.

We know that during in vitro fertilization endometriosis patients have normal hormonal profiles. There is a tendency towards fewer oocytes and it appears that oocytes derived from ovaries with endometriomas may have a lower fertilization rate and implantation rate.

In order to understand whether this effect is due to the embryo or the uterine environment we can look at donor embryo studies. Dr. Simon found decreased donor oocyte implantation rates when the oocytes were from women with endometriosis. In his study, endometriosis in the recipient had no effect on implantation while other studies have found conflicting results.

On the other hand, Dr. Bruce Lessey performed endometrial biopsy surface at the time of implantation and found lower levels of vitronectin (an adhesion molecule on the endometrial surface) in women with unexplained and endometriosis related infertility. Treatment with Lupron and ovulation induction appeared to restore this implantation marker and fertility.

Peritoneal Effects:
The effect of endometriosis on the peritoneal environment may adversely affect fertility. There is an increased volume of peritoneal fluid, and peritoneal macrophages (scavenger white blood cells), are increased both in number and activity. Cytokines (white blood cell chemical messengers) such as IL-1, IL-2, IL-6, TNF-alpha, Interferon, C3, C4 are all increased. These may adversely affect sperm oocyte interaction, sperm mobility and survival, and oocye pick up. In addition, serum samples obtained from women with endometriosis were found to be embryotoxic in mouse embryo cultures 78% of the time versus 20% in women without endometriosis.

Immune System:
The immune system is affected by endometriosis and may adversely affect fertility. Patients with endometriosis may show decreased nature killer cell function, and decreased reactivity to transplanted endometrial tissue. In addition, complement, an immune component that breaks apart abnormal cells, is elevated in patients with endometriosis.

What Are the Symptoms of Endometriosis?

Nearly one-third of the women having endometriosis have no symptoms other than infertility. The others have varying degrees of symptoms, depending on the stage of the disease. Oddly enough, the early stages or milder forms are frequently more painful than the later stages. We believe this is because the young endometrial tissue liberates spasm-causing prostaglandins, whereas the older endometrial tissue simply burns out and turns into inactive scar tissue. The most common symptoms associated with endometriosis are pain and infertility, however, premenstrual spotting, urinary urgency, rectal bleeding, painful urination, bloody cough, and skin nodules may also be noted. Endometriosis may frequently mimic other disorders such as pelvic adhesions, dysmenorrhea (menstrual cramps), irritable bowel syndrome, colitis, and ulcer disease. Careful evaluation is necessary to ensure accurate diagnosis. Diarrhea or rectal bleeding and tenesmus (sense of rectal fullness) at the time of menses are particularly telling symptoms.

The below table gives a profile of the endometriosis patient and tells where the implants, which can be found anywhere in the body, are most frequently located.
 

Profile of the Endometriosis Patient (Most common age: 20-35)

Profile of Endometriosis Incidence (%)
No symptoms 33
Infertility 70
Dyspareunia (painful periods) 28-66
Hypermenorrhea (heavy periods) 12-74
Spontaneous abortion Up to 50
Weight lower than normal Up to 50
Weight higher than normal 13
Deep dyspareunia (pain during intercourse) 12-33
Sacral backache (accentuated during menses) 25-31
Pelvic adhesions 24-50
Tender or nodular uterosacral ligaments 34
Uterus tipped anteriorly 20
Anovulation 17
Irregular periods 12
Rectal pain 4
Pregnancy rate (without treatment)
    Mild cases  31-75
    Moderate and severe  Very low
Other symptoms
    Inguinal/thigh pain; leg cramps
    Intermenstrual bleeding
    Spontaneous abortion (habitual)
    Premenstrual spotting

Location of Endometrial Implants

Site Incidence (%)
Ovaries 61-78
Posterior cul-de-sac (behind uterus) 14-34
Uterine surface 17-55
Intramural sigmoid and rectum 3-4
Cervix, vagina, vulva Very low
 

Emotional Side Effects May Be Experienced

Depression
Decreased sex drive because of association with painful sex
Doubts about sexuality
Heightened guilt about sex
Poor self-image

Diagnosing Endometriosis

Any complaint related to menses suggests endometriosis. Endometriosis associated with the classic symptoms of painful menstrual periods and/or painful sexual intercourse is relatively easy to diagnose. However, when the symptoms are less suggestive-unexplained infertility, irregular periods, or spotting, for example-identifying the disease may be more difficult. Occasionally while doing the pelvic examination I can feel the telltale beading on the outside of the reproductive organs. The only definitive diagnostic procedure for endometriosis, however, is a direct look inside the abdominal cavity and a biopsy of the tissue.

Diagnostic Laparoscopy

Since laparoscopy requires general anesthesia, I try to rule out all other male and female fertility factors before performing it. Depending on the woman's age, history, and findings from the workup, however, I may choose a more aggressive diagnostic approach for a particular couple. If the woman is in her thirties and if she complains of pelvic pain or has unexplained infertility, I'm likely to perform a laparoscopy sooner.

Viewed through the laparoscope, the endometrial lesions look like raised shaggy brown or blue-black areas ranging from 2 to 10 cm (1 to 4 inches) in diameter. If the disease has been present for a prolonged period of time, the tissue adjacent to the implants will pucker and burned-out areas will show fibrotic scars. Advanced endometriosis (stage III or IV) may invade, pucker, and erode the walls of affected organs, and adhesions may be so dense that they "freeze" the pelvic organs into distorted positions.

Dr. Redwine has described the progressive nature of endometriosis lesions. They are first seen as clear vesicles, then become red, and then progress to black lesions over a period of 7-10 years. Dr. Karnaky described water blister lesions becoming blue dome cysts over a period of 4-10 years. The clear lesions are seen are at an average age of 21.5 while black scarred lesions are seen at a mean age of 31.9. This progression from clear to red to black lesions with age confirms the progressive nature of this disease if left untreated. Disease will progress in 47-64% of women without therapy and approximately 20% of women with therapy.

While performing the laparoscopy, I'll force a colored dye through the cervix, uterus, and tubes to demonstrate tubal patency. Many times, the dye will flow through only one tube (preferential flow) because that tube provides the least resistance to the colored liquid. Although this does not mean that the other tube is blocked, it does not rule out that possibility, either.

There is poor correlation between the degree of pain or infertility and the severity of disease. Early lesions which are clear or red are metabolically more active than older, dark, fibrotic lesions. This metabolic activity may be responsible for the associated infertility, immune abnormalities, urinary urgency, pelvic pain or diarrhea.

ENDOMETRIOSIS

Endometriosis is an enigmatic disease affecting about 7% of reproductive-aged women -approximately 5 million Americans. Although they may suffer significant symptoms ranging from pelvic pain to infertility, most of these women do not know that they have endometriosis,. Physicians' understanding of (1) the clinical presentation of endometriosis, (2) its proper diagnosis and staging, and (3) the management of its sequele have improved dramatically over the past few years. The result has been better, more cost-effective patient care.

Definition
Endometriosis is the presence of endometrial tissue (normally found only on the inside of the uterus) in locations outside the uterus. This tissue reacts to estrogen and progesterone. The usual location is in the pelvis (on the ovaries, fallopian tubes, uterus, or bladder), but endometriosis has also been found in sites outside the pelvis (including omentum, small intestine, appendix, anterior abdominal wall, surgical scars, diaphragm, lung, urinary tract, and musculoskeletal and neural systems). This endometrial tissue reacts to hormonal changes during the menstrual cycle, just as endometrial tissue lining the inside of the uterus reacts during the normal ovulatory cycle.

Prevalence and Incidence
The prevalence and incidence of endometriosis depends on the population of women being studied, ranging from 1 to 50%. It has been reported to occur in 10 - 15% of women undergoing diagnostic laparoscopy, 2 - 5% of women undergoing tubal sterilization, 30 -40% of infertile women having laparoscopy, and 14 - 53% of women with pelvic pain.

Pathophysiology
There are several theories that attempt to explain how endometriosis develops. The most popular theory describes retrograde menstruation through the fallopian tubes, with subsequent implantation and growth of endometrial cells contained in the menstrual blood. Other theories involve metaplasia (normal tissue in the abdominal cavity spontaneously changing to endometriosis), direct implantation of endometrial cells into the abdomen during surgery, and spread of endometrial cells from the inside of the uterus to other locations via blood vessels or lymphatics. Each of these may contribute to endometriosis in different patients. Altered immunity may also play a role.

Numerous factors seem to affect whether a woman will have this condition, the severity of the disease in any particular woman, her symptoms, and her response to treatment. These include:

genetics (an affected sister or mother doubles the risk)
hormonal status (higher estrogen levels and prolonged heavy menses increases risk)
lifestyle (low body weight and cigarette smoking reduce risk by decreasing estrogen levels)
contraceptive use (oral contraceptives possibly reduces progression of disease)
obstetric history (pregnancy and lactation reduce risk)
anatomic factors (cervical stenosis increases risk)
treatment history (prior medical or surgical treatment reduces risk)
race (caucasions are at higher risk than african-americans)
and possibly exposure to environmental toxins, especially those which are estrogenic
Endometriosis is thought to cause infertility by distorting anatomy, creating hormonal abnormalities, altering the pelvic biochemical enviornment, influencing the immune system, interfering with sperm function, and (possibly) altering the process of embryo implantation.

Clinical Presentation
Endometriosis primarily presents with pelvic pain (about 80% of patients). About 20% of patients presenting with endometriosis are also infertile, and 5% present with a "tumor" of endometriosis in one or both ovaries (these are called endometriomas). Anywhere from 1 to 40% of patients with endometriosis will have no symptoms. Endometriosis may occur anytime after puberty, including adolescence.

The extent of a patient's pain often does not correlate with severity of her endometriosis. Pain may occur as a result any or all of the following:

endometrial implants secreting irritating factors (e.g., histamine)
scar tissue (adhesions)
leaking endometriomas
compression of other abdominal structures (e.g., bowel, ureter)
compression of endometriotic nodules deep in the pelvis
invasion of the urinary tract (bladder or ureters)
invasion of the gastrointestinal tract (small bowel or colon)
Even in patients with minimal and mild disease (AFS stage I or II), endometriosis is probably associated with infertility. A cause-effect relationship most certainly exists for moderate and severe disease (AFS stage III or IV). These patients usually have adhesions, deep invasive lesions, and endometriomas. Endometriosis may also be associated with structural abnormalies and damage to the fallopian tubes. Studies overall do not, however, support an association between endometriosis and increased spontaneous abortion rates.

Endometriosis lesions occur throughout the pelvis. They tend to be more frequently in the posterior cul-de-sac and the ovary, and less frequently on the fallopian tubes. Endometriosis is almost certainly a progressive disease, but the rate of progression and nature of lesions varies from patient to patient.

Adhesions develop as a result of the inflammatory process caused by long standing endometriosis, with more extensive and dense adhesions developing over time. The worst adhesions in the most advanced cases usually involve the uterus, ovaries, and lower colon (near the rectum). Laparoscopic surgical treatment of these cases is always preferable, but demands skill, extensive experience, and patience on the part of the operating surgeon.

The Cause of Infertility: Endometriosis

Endometriosis can be defined as a nonmalignant disorder in which functioning endometrial tissue is present outside the uterus. The incidence of this disease ranges from 10-15% in women between the ages of 25 and 44 who are actively menstruating, but it also occurs in teenagers. It is estimated that 25-50% of infertile women have this disease. The incidence is higher in first degree relatives of women with endometriosis, which suggests that heredity may play a role. In addition, there is also a higher prevalence of the disease in women who delay childbearing or who are of Asian descent.

In women affected with endometriosis, endometrial tissue builds up in areas outside of the uterus - these areas are known as "ectopic implants". Ectopic implants may be found on the outside of the uterus, inside and outside the ovaries, fallopian tubes, bowel, urinary tract, or anywhere in the abdomen. Ectopic tissue responds to hormonal stimulation, just like the endometrium in the uterus. Unlike the normal tissue inside the uterus however, ectopic tissue has no place to shed in response to a decline in estrogen and progesterone, so the debris and blood accumulate locally (in various parts of the abdomen), instead of exiting the body as menstrual flow. This ectopic tissue accumulation, growth, and eventual death leads to inflammation, scarring and adhesions that ultimately cause the symptoms and complications of endometriosis.

Causes and Symptoms

The cause of endometriosis is unknown, however there are several theories.

• The first theory is known as retrograde menstruation, or the movement of sloughed endometrial tissue back through the fallopian tubes and into the abdominal cavity. This tissue can then attach itself to various internal organs or tissues outside of the uterus. Retrograde menstruation can occur in women with and without endometriosis, but it is thought that women with the disease have a deficiency in their immune system which is unable to destroy the ectopic implant. This leads to the second theory:
• Immune system dysfunction. It is believed that certain women may develop endometriosis due to deficiencies in their immune system - the main system in the body that fights infection and other foreign "invaders". In women without endometriosis, the immune system destroys any ectopic implants that may develop. However, in women with endometriosis, there is an altered immune response and the body is unable to destroy the growth of the implants. Furthermore, some scientists believe that endometriosis is an autoimmune disorder. This means that the body makes antibodies to endometrial cells. These antibodies may destroy the healthy endometrium found in the uterus, but are ineffective in destroying ectopic implants.

Most likely, both of these theories play a role in the cause of endometriosis.

Symptoms
Symptoms of endometriosis typically occur in a cyclic fashion with menstrual periods. The most commonly reported symptoms are:

• Pelvic pain and cramping before and during periods
• Pain during intercourse
• Inability to conceive
• Fatigue
• Painful urination during periods
• Gastrointestinal symptoms such as diarrhea, constipation, and nausea

There are other medical conditions that have similar symptoms and should be considered prior to making a diagnosis of endometriosis. Conditions that may cause generalized pelvic pain include:

• Pelvic inflammatory disease (PID)
• Pelvic adhesions
• Neoplasms (cancers), both benign or malignant
• Ovarian torsion
• Sexual or physical abuse
• Other causes that are not gynecologic in nature

Endometriosis may place patients at a higher risk for developing endometriomas. These are ovarian cysts that are composed of endometrial cells that grow and bleed during menstruation. Sometimes they are called chocolate cysts, because they appear chocolate in color. Endometriomas may be painful, especially during active bleeding and/or ovulation.

How does endometriosis contribute to infertility?

Endometriosis is believed to be the cause of infertility in approximately 30% of all infertile women. The cause of infertility is believed to result from the scarring and adhesions that form in the reproductive tract as a result of inflammation. Scar tissue and adhesions may reduce fertility by either obstructing or distorting the shape of the fallopian tubes, which in turn impedes the passage of sperm to the egg. In the event that sperm do reach the egg, they may encounter a hostile environment unfavorable to fertilization. Finally, scarring from endometriosis may obstruct the fallopian tubes so that if an egg is fertilized, it may be unable to travel to the uterus for implantation.

Testing, Diagnosis, and Treatment

One of two techniques may be used to confirm the diagnosis of endometriosis. Both procedures involve visualization of the pelvic cavity in order to confirm the presence or absence of ectopic implants. The first procedure is known as laparoscopy. A laparoscopy involves making a small incision (usually near the belly button) and inserting a small wire with a light on the end of it. The second technique is a laparotomy. This is a more invasive procedure that requires general anesthesia. An incision is carefully made in the abdomen in order to view a large pelvic area. If there are any suspected ectopic implants, they are biopsied in order to determine the presence of endometrial cells.

Treatment
The goals of treatment may include relieving/reducing pain symptoms, shrinking or slowing endometrial growths, preserving or restoring fertility, and preventing /delaying recurrence of the disease. These can be accomplished by using pain medication, hormonal therapy, surgical procedures, and alternative treatment.

The medications that are used to treat pain as well as inflammation are known as nonsteroidal anti-inflammatory drugs (NSAIDs). These agents (examples include Aleve�, Advil�, Naprosyn�, etc.) work by inhibiting the production of certain chemicals in the body that are responsible for producing pain and inflammation. However, these medications do not alter the course of the disease in any way other than by relieving pain. As a result, they are most commonly used in women with mild disease or in women who do not want to use more potent drugs. If a decision is made to stop taking these drugs, symptoms are more than likely to return.

Hormonal therapy is used in women who choose more aggressive medical intervention. Hormonal therapy is used to suppress elevated levels of estrogen, which maintains growth of the ectopic implants as well as the endometrial tissue in the uterus. There are two main classes of medications used to accomplish this: the gonadotropin-releasing hormone (GnRH) agonists and the androgen derivatives.

The GnRH agonists include leuprolide (Lupron�), goserelin (Zoladex�), and nafarelin (Synarel�). They work by reducing the production and release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the brain, which in turn reduces estrogen secretion from the ovaries. Treatment with these agents typically lasts for 6 months. A GnRH agonist may be used prior to surgery to shrink ectopic implants, or following surgery to eliminate any remaining implants.

The second class of medications used to treat endometriosis is the androgen derivative, danocrine (Danazol�). It works by slowing down the release of LH and FSH from the brain. This in turn, causes the ovaries to "rest" since they are not being hormonally stimulated. The result is an artificial menopause, where the woman is not producing estrogen, a primary hormone necessary for the growth and proliferation of ectopic implants. Besides inducing atrophy of implants, danocrine also provides pain relief. Unfortunately, this medication has many side effects (refer to graph below). Duration of treatment with danocrine ranges from 6 to 9 months.

An alternative to GnRH agonists and danocrine are oral contraceptive pills (OCPs) and progestins. OCPs suppress LH and FSH production, which reduces estrogen levels and makes the ectopic endometrial tissue thin and compact. OCPs can be taken continuously without stopping treatment or cyclically, with a week of placebo pills (no drug) between treatment cycles. Treatment with OCPs typically lasts 6 to 12 months. Progestins such as medroxyprogesterone acetate-depot (Depo-provera�) and medroxyprogesterone (Provera�) act in much the same way as the OCPs. Depo-provera is given as an injection once every 3 months whereas Provera is taken in the tablet form daily.

The surgeries that are used to diagnose the disease are also used for treatment. The goal of surgery is to remove any ectopic endometrial lesions and/or adhesions. Laser laparoscopy is used to remove endometrial tissue and blockages from the body that are sparse and less dense. Laser laparotomy is used to remove dense or larger sites of endometrial tissue. Pregnancy rates following surgery and medication therapy vary considerably depending on the severity and location of adhesions. Speak with your healthcare provider regarding the treatment that is most appropriate for you.

Medications Used to Treat Endometriosis

Medication	Dose/Duration/Administration	Side Effects
Leuprolide (Lupron�)	3.75 - 11.25 mg IM every month for 6 months	Depression, pain, hot flashes, weight gain, nausea and vomiting
Gosarelin (Zoladex�)	3.6 mg SQ injection into upper abdominal wall every 28 days	Hot flashes, decrease in libido, and rash
Nafarelin (Synarel�)	1 spray (200 mcg) in 1 nostril in the AM and the other nostril in the PM for 6 months	Headache, mood swings, acne, hot flashes, decrease in libido and breast size and nasal irritation
Danocrine (Danazol�)	200-800 mg twice daily for 6-9 months	Oily skin, acne, abnormal hair growth, breakthrough bleeding, weight gain, voice deepening
Oral Contraceptive Pills	1 pill per day (continuous or cyclic)	Headache, nausea, hypertension
Medroxyprogesterone acetate (Depo-provera�)	100 mg IM every 2 weeks for 2 months, then 200 mg IM every month for 4 months or 150 mg IM every 3 months	Breakthrough bleeding, spotting, weight gain
Medroxyprogesterone (Provera�)	5-20 mg orally every day	Similar to Depo-provera

Summary

Endometriosis is a common condition that can exert a significant physical and emotional toll on patients. One of the most common complications associated with the disease is a high prevalence of infertility due to numerous lesions and adhesions from ectopic sites. Unfortunately, there is still no cure, but progress is being made in identifying the causes of the disease. The most promising chance for finding a cure or effective treatment lies with future research on the role of the immune system in the development and progression of endometriosis.