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Endometriosis is a noncancerous disorder in which functioning endometrial tissue is implanted outside the uterine cavity. Symptoms depend on location of the implants and may include dysmenorrhea, dyspareunia, infertility, dysuria, and pain during defecation. Diagnosis is by biopsy, usually via laparoscopy. Treatments include anti-inflammatory drugs, drugs to suppress ovarian function and endometrial tissue growth, surgical ablation and excision of endometriotic implants, and, if disease is severe and no childbearing is planned, hysterectomy plus oophorectomy.

Endometriosis is usually confined to the peritoneal or serosal surfaces of pelvic organs, commonly the ovaries, broad ligaments, posterior cul-de-sac, and uterosacral ligaments. Less common sites include the serosal surfaces of the small and large intestines, ureters, bladder, vagina, cervix, surgical scars, pleura, and pericardium. Bleeding from peritoneal implants is thought to initiate inflammation, followed by fibrin deposition, adhesion formation, and, eventually, scarring, which distorts peritoneal surfaces of organs and pelvic anatomy.

Etiology and Pathophysiology

The most widely accepted hypothesis is that endometrial cells are transported from the uterine cavity and subsequently become implanted at ectopic sites. Retrograde flow of menstrual tissue through the fallopian tubes could transport endometrial cells intra-abdominally; the lymphatic or circulatory system could transport endometrial cells to distant sites (eg, the pleural cavity). Another hypothesis is coelomic metaplasia: Coelomic epithelium is transformed into endometrium-like glands.

Microscopically, endometriotic implants consist of glands and stroma identical to intrauterine endometrium. These tissues contain estrogen and progesterone receptors and thus usually grow, differentiate, and bleed in response to changes in hormone levels during the menstrual cycle.

Incidence of endometriosis is increased in first-degree relatives of women with endometriosis, suggesting that heredity is a factor. Incidence is also increased in women who delay childbearing, who have shortened menstrual cycles (< 27 days) with menses that are abnormally long (> 8 days), or who have müllerian duct anomalies.

Reported incidence varies but is probably about 10 to 15% in actively menstruating women aged 25 to 44. Average age at diagnosis is 27, but endometriosis also occurs among adolescents. About 25 to 50% of infertile women have endometriosis. In patients with severe endometriosis and distorted pelvic anatomy, incidence of infertility is high because mechanisms of ovum pickup and tubal transport are impaired. Some patients with minimal endometriosis and normal pelvic anatomy are also infertile; reasons for impaired fertility include the following:

• Increased incidence of luteinized unruptured ovarian follicle syndrome (trapped oocyte)
• Increased peritoneal prostaglandin production or peritoneal macrophage activity (resulting in oocyte phagocytosis)
• Nonreceptive endometrium (because of luteal phase dysfunction or other abnormalities)

Potential protective factors seem to be multiple pregnancies, use of low-dose oral contraceptives (continuous or cyclic), and regular exercise (especially if begun before age 15, if done for > 7 h/wk, or both).

Symptoms and Signs

Pelvic pain, pelvic mass, alteration of menses, and infertility are typical. Some women with extensive endometriosis are asymptomatic; some with minimal disease have incapacitating pain. Dyspareunia and midline pelvic pain before or during menses may develop. Such dysmenorrhea is an important diagnostic clue, particularly if it begins after several years of pain-free menses.

Symptoms can vary depending on location of implants.

• Large intestine: Pain during defecation, abdominal bloating, or rectal bleeding during menses
• Bladder: Dysuria, hematuria, suprapubic pain (particularly during urination), or a combination
• Ovaries: Formation of an endometrioma (a 2- to 10-cm cystic mass localized to an ovary), which occasionally ruptures or leaks, causing acute abdominal pain and peritoneal signs
• Adnexal structures: Formation of adnexal adhesions, resulting in a pelvic mass
• Extrapelvic structures: Vague abdominal pain (sometimes)

Pelvic examination may be normal, or findings may include a retroverted and fixed uterus, enlarged ovaries, fixed ovarian masses, thickened rectovaginal septum, induration of the cul-de-sac, and nodules on the uterosacral ligament. Rarely, lesions can be seen on the vulva or cervix or in the vagina, umbilicus, or surgical scars.

Diagnosis

• Biopsy—usually laparoscopic
• Imaging tests—nondiagnostic but sometimes used to follow progression

Diagnosis is suspected based on typical symptoms but must be confirmed by biopsy, usually via pelvic laparoscopy but sometimes via laparotomy, vaginal examination, sigmoidoscopy, or cystoscopy. Macroscopic appearance (eg, clear, red, brown, black) and size of implants vary during the menstrual cycle. However, typically, areas of endometriosis on the pelvic peritoneum are punctate red, blue, or purplish brown spots that are > 5 mm, often called powder burn lesions. Microscopically, both endometrial glands and stroma must be present to diagnose endometriosis.

Imaging procedures (eg, ultrasonography, barium enema, IV urography, CT, MRI) are not specific or adequate for diagnosis. However, if they are done to rule out other disorders, they sometimes show the extent of endometriosis. They can also be used to monitor the disorder once it is diagnosed. Investigational serum markers for endometriosis (eg, serum cancer antigen 125 level > 35 units/mL, antiendometrial antibody) may help monitor the disorder but require further refinement before being used routinely. Testing for other infertility disorders may be indicated (see Infertility).

Staging the disorder helps physicians formulate a treatment plan and evaluate response to therapy. According to the American Society for Reproductive Medicine, endometriosis may be classified as stage I (minimal), II (mild), III (moderate), or IV (severe), based on number, location, and depth of implants and presence of filmy or dense adhesions (see Table 1: Endometriosis: Stages of Endometriosis).

Table 1
Stages of Endometriosis Stage Disease Description I Minimal A few superficial implants II Mild More and slightly deeper implants III Moderate Many deep implants, small endometriomas on one or both ovaries, and some filmy adhesions IV Severe Many deep implants, large endometriomas on one or both ovaries, and many dense adhesions, sometimes with the rectum adhering to the back of the uterus

Another staging system is based primarily on the presence and severity of pelvic pain. However, because intraobserver and interobserver variability is high in the staging systems, a more reliable method of staging is being sought.

Treatment

• NSAIDs for discomfort
• Drugs to suppress ovarian function
• Conservative surgical resection/ablation of endometriotic tissue
• Conservative surgery plus drugs
• Total abdominal hysterectomy with bilateral salpingo-oophorectomy if disease is severe and patient has completed childbearing

Symptomatic treatment begins with NSAIDs. More definitive treatment must be individualized based on the patient's age, symptoms, and desire to preserve fertility and on the extent of the disorder.

Drugs and conservative surgery are symptomatic treatments; in most patients, endometriosis recurs after treatment is stopped unless ovarian function is permanently and completely ablated.

Drugs that suppress ovarian function inhibit the growth and activity of endometriotic implants. These drugs include continuous oral contraceptives (commonly used), gonadotropin-releasing hormone (GnRH) agonists, and danazol Some Trade Names
DANOCRINE
Click for Drug Monograph
(see Table 2: Endometriosis: Drugs Used to Treat Endometriosis).

Table 2
Drugs Used to Treat Endometriosis Drug Dosage Adverse Effects Combination estrogen/progestin oral contraceptive Ethinyl estradiol Some Trade Names ESTRADERM ESTROGEL VIVELLE Click for Drug Monograph 30–35 μg plus a progestin Continuous use (1 tablet once/day for 4-6 mo, then stop until menses) or cyclic use (as directed for contraception, usually not taken for several days to 1 wk each mo) Abdominal swelling, breast tenderness, increased appetite, edema, nausea, breakthrough bleeding, deep vein thrombosis, MI, stroke, peripheral vascular disease Progestins Medroxyprogesterone Some Trade Names PROVERA Click for Drug Monograph acetate 20–30 mg po once/day for 6 mo, followed by 100 mg IM q 2 wk for 2 mo, then 200 mg IM monthly for 4 mo Breakthrough bleeding, emotional lability, depression, atrophic vaginitis, MI, stroke, peripheral vascular disease Androgen Danazol Some Trade Names DANOCRINE Click for Drug Monograph 100–400 mg po bid for 3–6 mo Weight gain, acne, lowering of voice, hirsutism, hot flushes, atrophic vaginitis, edema, muscle cramps, breakthrough bleeding, decreased breast size, emotional lability, liver dysfunction, carpal tunnel syndrome, adverse effects on lipid levels GnRH agonists* Leuprolide Some Trade Names LUPRON Click for Drug Monograph Leuprolide Some Trade Names LUPRON Click for Drug Monograph depot 1 mg sc once/day 3.75 mg IM q 28 days or 11.25 mg IM q 3 mo Hot flushes, atrophic vaginitis, bone demineralization, emotional lability Nafarelin Some Trade Names SYNAREL Click for Drug Monograph 200–400 μg intranasally bid   *Treatment is limited to < 6 mo. GnRH = gonadotropin-releasing hormone.

GnRH agonists temporarily suppress estrogen production; however, treatment is limited to ≤ 6 mo because long-term use may result in bone loss. If treatment lasts > 4 to 6 mo, add-back therapy, usually a low-dose oral contraceptive taken daily, can be given. Danazol Some Trade Names
DANOCRINE
Click for Drug Monograph
, a synthetic androgen and an antigonadotropin, inhibits ovulation. However, its androgenic adverse effects limit its use. Cyclic or continuous oral contraceptives given after danazol Some Trade Names
DANOCRINE
Click for Drug Monograph
or GnRH agonists may slow disease progression and are warranted for women who wish to delay childbearing. After drug treatment, fertility rates range from 40 to 60%. Whether treating minimal or mild endometriosis improves fertility rates is unclear because the fertility rate among untreated women is unknown.

Most women with moderate to severe endometriosis are treated most effectively by ablating or excising as many implants as possible while preserving fertility. Specific indications for surgery include presence of endometriomas, significant pelvic adhesions, fallopian tube obstruction, incapacitating pelvic pain, and a desire to preserve fertility. Microsurgical techniques are used to prevent adhesions if women desire to preserve fertility. Laparoscopy can sometimes be used to remove lesions; peritoneal or ovarian lesions can sometimes be electrocauterized, excised, or vaporized with a laser. After this treatment, fertility rates are 40 to 70% and are inversely proportional to severity of the endometriosis. If resection is incomplete, use of oral contraceptives or GnRH agonists may increase fertility rates. Laparoscopic resection of the uterosacral ligaments with electrocautery or a laser may reduce midline pelvic pain. Some patients require presacral neurectomy.

Hysterectomy should usually be reserved for patients who have intractable pelvic pain and who have completed childbearing. If women < 50 require hysterectomy with oophorectomy, supplemental estrogen should be considered. Continuous progestin (eg, medroxyprogesterone Some Trade Names
PROVERA
Click for Drug Monograph
acetate 2.5 > mg po once/day) should be given with estrogen because, if estrogen is given alone, residual tissue may grow. Hormone replacement can be started postoperatively or, if a substantial amount of endometriotic tissue remains, may be delayed for 4 to 6 mo; during this interval, progestins to suppress the remaining endometriotic tissue may be necessary.

Last full review/revision May 2007 by Alan H. DeCherney, MD

Content last modified May 2007