Endometriosis

INTRODUCTION — The normal tissue that lines the uterus and bleeds during the menstrual period is called the endometrium (show figure 1). Endometriosis is a noncancerous disorder in which tissue that is similar to the endometrium develops outside of the uterus. Typically this occurs in the pelvis, but it may occur in virtually any part of the body.

The most common locations for endometriosis are: the outer surface of the ovaries, peritoneum (the tissue that lines the abdomen) and peritoneal structures (the area behind the uterus and the various ligaments that hold the uterus in place), uterus, fallopian tubes, bowel, and bladder. Most women have endometriosis in more than one location.

RISK FACTORS — It is not known how many women are affected by endometriosis; the disease can only be diagnosed with a biopsy of lesions seen during surgery. Therefore, women who have no symptoms and never have surgery may not know that they are affected. Studies in small groups of women have shown that endometriosis is present in at least 5 percent of all women of reproductive age.

Endometriosis is rarely diagnosed before menarche (the first menstrual period of a woman's life) and new cases are seldom diagnosed after menopause (the last menstrual period of a woman's life). The growth and function of endometriosis depends upon stimulation from estrogen and progesterone, which are produced by the ovaries in women who menstruate. The condition is most common among women 25 to 29 years old and least common in women over age 44.

Risk factors for developing endometriosis include: No pregnancies resulting in the birth of an infant Endometriosis in a woman's mother (7 percent chance) Short menstrual cycles (<27>8 days) (2 percent chance) Partial or complete obstruction of normal menstrual flow (eg, from uterine abnormalities such as a tight cervical opening or vaginal septa [band of tissue] blocking the flow of menses) White or Asian race

Conditions that decrease the amount or frequency of menstrual bleeding lower the risk of endometriosis. Some examples are amenorrhea (absent menstrual periods), pregnancy, and prolonged use of birth control pills.

CAUSES — The cause of endometriosis is not known, but several theories have been suggested. Retrograde menstruation is a theory that menstrual blood and tissue flows backwards from the uterus, through the fallopian tubes and into the pelvis (show figure 1). This theory was proposed because women with a partial or complete obstruction of the uterus or cervix that prevents normal menstrual flow are more likely to have endometriosis. This is presumably because menstrual blood and tissue are more likely to flow backwards. Retrograde menstruation has been observed during surgery. The endometrial tissue shed during a menstrual period is able to grow when "planted" in the pelvis. Endometrial tissue from the uterus may be transported through blood and lymphatic vessels to sites elsewhere in the body, including the pelvis. Changes in the immune system allow endometrial tissue outside of the uterus to grow and develop. Coelomic metaplasia is the concept that the cells from lining of the abdomen and surface of the ovaries can change into endometrial tissue with certain stimuli, such as irritation from retrograde menstruation or infection.

SYMPTOMS AND SIGNS — For many women, severe pelvic pain is the main symptom of endometriosis. Pelvic pain usually occurs just before or during menses or during or after sex. Other symptoms may include pain during bowel movements, spotting before the menstrual period, frequent or heavy uterine bleeding, and pain during urination. Painful periods cause mild to severe discomfort (often cramps) in the lower abdomen; this may worsen over a period of years. Some women have constant pelvic soreness or pain in the lower back and legs that is aggravated during menses or intercourse. (See "Patient information: Chronic pelvic pain in women").

Pelvic pain is probably the result of bleeding from areas of endometriosis and release of substances that cause pain (eg, prostaglandins). Endometriosis implants respond to the hormonal changes that occur during the menstrual cycle, similar to the normal endometrium. Thus, at the end of the menstrual cycle, small amounts of endometrial tissue are shed and bleeding occurs (show figure 2).

Endometriomas are areas of endometriosis that are large enough to be considered a mass or tumor. They are usually filled with old blood that resembles chocolate syrup; thus, they are sometimes called chocolate cysts. Endometriomas may be seen as a mass on the ovary during a pelvic ultrasound, although only surgery can confirm that the mass is an endometrioma.

DIAGNOSIS — The diagnosis of endometriosis is one possibility for women who develop pelvic pain, problems with fertility, or have an abnormal pelvic examination or ultrasound. The disease may have no signs or symptoms and the intensity of the symptoms (eg, amount of pain and bleeding) does not always correlate with the severity or amount of endometriosis. For example, it is possible to have mild endometriosis with severe pelvic pain.

Pelvic examination — During a pelvic examination, a healthcare provider may feel thickening of, or nodules on, pelvic structures, an adnexal mass (a mass in the area of the ovary), or fixed or distorted pelvic organs, which suggests the presence of endometriosis. However, since these signs and symptoms are present in a variety of disorders, the diagnosis and stage (severity) of endometriosis can only be made with certainty by viewing the implants (small areas of endometriosis) during surgery, with either laparoscopy or laparotomy.

There are no blood tests or x-ray examinations that can make a definitive diagnosis, but a mildly elevated CA-125 blood level or growth near the ovaries on ultrasonography may suggest the disease.

Surgical evaluation — Laparoscopy and laparotomy are surgical procedures that are commonly used to diagnose and treat endometriosis. Both procedures are usually done in an operating room after the woman has received general anesthesia to induce sleep and prevent pain. After laparoscopy most women go home the same day. After laparotomy most women go home after spending one to three nights in the hospital.

At surgery, endometriosis appears as small (< 1/4 inch) blue, purple, or red implants. Scar tissue (adhesions) and/or an ovarian cyst may also be noted. A biopsy (removal of a small piece of tissue) can be done to confirm the diagnosis.

Staging — Surgery is also helpful for staging (determining the volume and location of disease) and treating the disorder. To stage the disease, the surgeon assigns points based upon size, depth, and location of implants (show figure 3). Endometriosis is classified as minimal (stage I, 1 to 5 points) if there are isolated superficial implants; mild (stage ll, 6 to 15 points) if there are several small, superficial implants and no more than a few small adhesions. Endometriosis is moderate (stage lll, 16 to 40 points) if the implants are superficial and deep with prominent adhesions. Endometriosis is severe (stage lV, over 40 points) when there are multiple superficial and deep implants with large endometriomas and prominent adhesions.

TREATMENT — There are several treatment options for women with endometriosis: No therapy Pain medication Birth control pills Other forms of hormonal therapy Surgery A combination of therapies

The treatment strategy depends upon whether the woman's major concern is pain, infertility, or a pelvic mass.

Women with minimal disease or who are near menopause and have no troubling symptoms may choose to have no treatment of endometriosis. Young women with minimal disease may consider taking birth control pills to protect against unplanned pregnancy and to prevent progression of disease. Near menopause, endometriosis may regress without treatment because the ovaries produce lower levels of estrogen, which decreases stimulation of the implants.

Endometriosis progresses slowly, over years, and resolves after menopause. Most women with endometriosis will get relief of pain from taking medication, after a pregnancy, or after menopause; some women will be helped only by surgery. Removal of the ovaries almost always provides excellent pain relief, making this an option for women who do not wish to have children.

Some women with endometriosis will have difficulty becoming pregnant, especially those who have severe disease and extensive adhesions. However, most women can achieve pregnancy after medical or surgical therapy or with fertility enhancing drugs or procedures (eg, in vitro fertilization). Rarely, endometriosis causes other problems such as blockage of the intestines or urinary tract or disease in the chest. ( See "Patient information: Evaluation of the infertile couple" and see "Patient information: Infertility treatment with clomiphene (Clomid® or Serophene®)").

Pelvic pain — When a laparoscopy is performed to diagnose endometriosis, endometrial implants and scar tissue are usually removed, which may relieve pain temporarily. However, the disease and pain tend to recur unless the uterus and ovaries are removed.

Recurrent or persistent pain after surgery is usually treated with medication. Studies have not determined the best medical therapy for treating pelvic pain, and no medical therapy has been proven to improve the chance of becoming pregnant in the future.

One advantages of medical therapy is that surgery can be avoided. Pelvic surgery has potential risks, some of which include damage to pelvic organs and formation of scar tissue. Another advantage is that medical therapy treats all implants, not just those seen during surgery. Disadvantages of medical therapy include the inability to treat existing adhesions or endometriomas. Medications may have side effects, including prevention of pregnancy (if drugs suppressing ovulation are used), and pain often recurs when medical therapy is stopped. Nonsteroidal antiinflammatory drugs — Nonsteroidal antiinflammatory drugs (NSAIDs, eg, ibuprofen, naproxen sodium) may be useful in relieving mild pain. NSAIDs inhibit prostaglandins, one of the main chemicals responsible for pain during menses. NSAIDs do not shrink or prevent the growth of implants, and pain often returns when medication is stopped.

The recommended dose of ibuprofen 400 to 600 mg by mouth every six hours, taken when pain starts or is expected. Other NSAIDs may also be used (show table 1).

Serious side effects from NSAIDs, although uncommon, include gastrointestinal pain and bleeding, kidney problems, and worsening high blood pressure. Oral contraceptive pills — Oral contraceptive pills (OCPs or birth control pills) contain both estrogen and progestin and cause the endometrial lining and endometriosis implants to shrink. There is no effect on scar tissue or endometriomas. OCPs are usually less effective than GnRH agonists and danazol (see below) for women with moderate or severe disease, but are a good choice for women with minimal or mild symptoms. OCPs prevent pregnancy and generally have tolerable side effects.

Birth control pills work by reducing the number of menstrual cycles and volume of bleeding. For most patients with only mild pain, this results in less painful periods and may also slow progression of endometriosis. The side effects of OCPs include nausea, breast tenderness, and decreased libido, although most side effects improve after being on the pill for several months. Serious side effects (eg, blood clots, stroke, heart attack) are rare in women who do not smoke and have no underlying blood vessel disease.

Continuous use of OCPs can be effective in relieving painful periods. Traditional birth control pill packs can be used in continuous dosing. In this regimen, the woman takes the first three weeks of a pill pack, then immediately starts a new pack (without a break); the last week of (placebo) pills is not used. This regimen can be continued for as long as desired.

Taking an oral contraceptive for an extended time results in fewer periods per year, although many women experience breakthrough bleeding when starting this regimen. Breakthrough bleeding is inconvenient, but does not indicate an increased risk of pill failure (unless pills are forgotten). Gonadotropin releasing hormone agonists — Gonadotropin releasing hormone (GnRH) agonists (eg, nafarelin, leuprolide, goserelin) work by turning off ovarian production of estrogen, thereby causing a temporary type of menopause. The lack of estrogen causes the endometriosis implants to shrink and reduces pain in over 80 percent of patients. The drugs may be given as a nasal spray, implant, or injection.

The full dose of a GnRH agonist is usually taken for up to six months; they are not usually taken for longer due to the risk of bone thinning. Side effects of GnRH agonists include headaches in 20 percent of women, especially in patients with a history of migraine, and the signs and symptoms of menopause: lack of menstrual bleeding, hot flashes, vaginal dryness, decreased libido, insomnia, and loss of bone density (on average a 2 to 7 percent loss). Bone strength recovers substantially after the drug is stopped.

Many of these side effects can be minimized by giving estrogen or a bone strengthening drug along with the GnRH agonist. Five years after completing GnRH agonist treatment, many women will again have pain (37 of women with mild disease and 74 percent of women with severe disease).

Alternate dosing regimens that use lower doses of the GnRH agonist for longer than five years may be considered for some women; this reduces the amount of bone density lost, and may allow the woman to have better, long-lasting relief of pain compared to other treatments. Monitoring of bone density is usually recommended while GnRH agonists are used. Danazol — Danazol is a medication that increases the level of androgens (male type hormone) and decreases the level of estrogen. This temporarily stops the menstrual period by inhibiting ovulation and ovarian production of estrogen and by shrinking the endometrium.

The medication is taken by mouth at a dose of 200 to 400 mg two to four times per day for 6 months or more. Eighty percent of patients will have good pain relief and shrinkage of implants. However, there is a high (75 percent) incidence of one or more side effects, but only a small percentage of patients discontinue the drug because of them.

Side effects may include weight gain, edema, decreased breast size, acne, oily skin, hirsutism (male pattern hair growth), deepening of the voice, headache, hot flashes, changes in libido, and mood changes. All of these changes are reversible, except for voice changes; however, return to normal may take many months.

Danazol should not be taken by women with certain types of liver, kidney, and heart disease because these disorders may worsen. Women who could become pregnant must use a nonhormonal form of birth control (eg, condoms) while taking danazol because of a serious risk of birth defects if danazol is taken during pregnancy. (See "Patient information: Barrier methods of birth control"). Progestins — Progestins (eg, medroxyprogesterone acetate (Depo Provera®) norethindrone acetate (Micronor®, NorQD®, Aygestin®) norgestrel acetate) may be recommended for women who do not get pain relief from or who cannot take a birth control pill (eg, smokers). These medications cause the endometrial lining and endometriosis implants to shrink, and usually cause the menstrual periods to temporarily stop. (See "Patient information: Long-term methods of birth control").

Side effects are common and include: bloating, weight gain, irregular uterine bleeding, and rarely, aggravation of depression. Women who use long-acting medroxyprogesterone acetate may not have a menstrual period for six to twelve months after stopping the treatment. Therefore, this drug may not be the best choice for women planning pregnancy in the near future. Surgery — Surgery is an option when medication has failed to improve pain or if there is severe disease (scarring, endometriomas, involvement of the bowel or bladder) that is unlikely to respond to medications alone. The goal of conservative surgery is to eliminate as many implants and adhesions as possible.

Pain relief is achieved in 80 to 90 percent of women, but the risk of recurrent pain within 10 years is 40 percent. Surgical therapy avoids the side effects of medication and can improve fertility, although there are some risks, including damage to pelvic organs, development of new adhesions, bleeding, and infection.

Definitive surgery consists of removal of the uterus (hysterectomy), ovaries, and endometrial implants to eliminate as much of the disease as possible and create a low estrogen state. It may be recommended for women who are not planning pregnancy if severe symptoms remain after trying other less invasive treatments. Low dose hormone replacement therapy (eg, estrogen pills or a patch) is usually given after surgery to prevent menopausal symptoms and other complications of a low estrogen level; this treatment usually does not cause the pain to return. (See "Patient information: Abdominal hysterectomy" and see "Patient information: Vaginal hysterectomy").

Pelvic mass — A pelvic mass in a woman with endometriosis may be an endometrioma, chocolate cyst, a combination of scarring and normal pelvic organs, or a mass unrelated to the disease. Surgery is the best way to make a definite diagnosis and remove the mass. Medical therapy is not effective.

Infertility — Endometriosis sometimes interferes with the ability to become pregnant. Reduced fertility may develop because of adhesions that develop between the ovaries and fallopian tubes or as a result of substances produced by endometriosis implants that impair normal ovulation, fertilization, and implantation. However, as many as 70 percent of women with minimal or mild endometriosis and infertility will conceive within three years without any therapy. If pregnancy occurs, endometriosis often regresses or resolves. Women with endometriosis who become pregnant have no increased risk of pregnancy complications.

The treatment of infertility caused by endometriosis includes a combination of observation, surgery, use of medications that enhance ovulation combined with intrauterine insemination, or in vitro fertilization (IVF). Medical treatments for endometriosis (eg, GnRH agonists) are of no benefit in improving fertility. (See "Patient information: Infertility treatment with clomiphene (Clomid® or Serophene®)").

The ideal infertility treatment for women with mild to moderate endometriosis is surgical removal (burning or cutting) of endometriosis implants. Women found to have severe endometriosis are best treated with IVF.

PREVENTION — There is no proven way to prevent endometriosis. Reducing the number of periods and amount of bleeding during the menstrual period may reduce the risk. Having one or more pregnancies or using hormonal contraception (eg, birth control pills) may be of benefit.

SUMMARY Endometriosis is a common condition in women. Its name is based on the endometrium, which is the tissue inside the uterus. During a woman's monthly period, the endometrium sheds and bleeds (show figure 1). With endometriosis, tissues that are similar to the endometrium grow outside the uterus. These growths also bleed during a woman's monthly period. The condition is not related to cancer. The cause of endometriosis is not known. Women whose mother, sister, or aunt had endometriosis have a higher chance of developing it. The most common symptom of endometriosis is pain. Pain may occur in the abdomen, lower back, or pelvis, and is usually worst before and during a woman's monthly period. Some women also have pain during sex. Surgery is needed to be certain of the diagnosis of endometriosis. Surgery is not always performed if endometriosis is likely and pain improves with medical treatment. There are many treatments for endometriosis. For most women, the first option is to use a medication to reduce pain and shrink the abnormal growths. Surgery may be the best choice for women with severe disease or pain that does not improve with medications. Endometriosis can cause difficulty becoming pregnant (infertility). If endometriosis is mild, surgery to remove the abnormal growths can treat infertility. Some women also need to use infertility medications or procedures to become pregnant (eg, in vitro fertilization or IVF).

WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.

This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. National Library of Medicine

(www.nlm.nih.gov/medlineplus/healthtopics.html)
The Hormone Foundation

(www.hormone.org)
The Endometriosis Association

(www.endo-online.org)


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