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Endometriosis

by Esther Eisenberg, MD

In endometriosis, 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. Severity of symptoms is not related to disease stage. 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 fallopian tubes, 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.

Reported prevalence varies but is probably about 6 to 10% in all women, 25 to 50% in infertile women, and 75 to 80% in women with chronic pelvic pain. Average age at diagnosis is 27, but endometriosis also occurs among adolescents. Incidence is increased in women who have 1st-degree relatives with endometriosis, who delay childbearing, who have shortened menstrual cycles (< 27 days) with menses that are heavy and prolonged abnormally long (> 8 days), or who have müllerian duct defects.

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; also, these tissues can produce estrogen and prostaglandins. Implants may become self-sustaining or regress, as may occur during pregnancy (probably because of progesterone levels are high). Ultimately, the implants cause inflammation and increase the number of activated macrophages and the production of proinflammatory cytokines.

The increased incidence in 1st-degree relatives of women with endometriosis suggests that heredity is a factor.

In patients with severe endometriosis and distorted pelvic anatomy, the infertility rate is high, possibly because the distorted anatomy interferes with mechanisms of ovum pickup and tubal transport. Some patients with minimal endometriosis and normal pelvic anatomy are also infertile; reasons for impaired fertility are unclear but may include the following:

  • Increased incidence of luteinized unruptured ovarian follicle syndrome (trapped oocyte)

  • Increased peritoneal prostaglandin production or peritoneal macrophage activity that may affect sperm and oocyte function

  • Nonreceptive endometrium (because of progesterone resistance, 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 > 4 h/wk, or both).

Symptoms and Signs

Cyclic midline pelvic pain, specifically pain preceding or during menses and during sexual intercourse, is typical and can be progressive. Adnexal masses and infertility are also typical. Intermenstrual bleeding is possible. Some women with extensive endometriosis are asymptomatic; some with minimal disease have incapacitating pain. Dysmenorrhea is an important diagnostic clue, particularly if it begins after several years of relatively pain-free menses. Symptoms often lessen or resolve during pregnancy.

Symptoms can vary depending on location of implants.

  • Large intestine: Pain during defecation, abdominal bloating, diarrhea or constipation, 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 or pain

  • 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, nodules on the uterosacral ligament, and/or adnexal masses. Rarely, lesions can be seen on the vulva or cervix or in the vagina, umbilicus, or surgical scars.

Diagnosis

  • Biopsy, usually laparoscopic

  • Sometimes imaging tests (to follow progression) but not for diagnosis

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 tests (eg, ultrasonography, barium enema, IV urography, CT, MRI) are not specific or adequate for diagnosis. However, they sometimes show the extent of endometriosis and thus can be used to monitor the disorder once it is diagnosed. The serum cancer antigen 125 level may be elevated, but obtaining this level is usually not helpful in diagnosis or management. 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 endometriomas and filmy or dense adhesions (see Stages of Endometriosis).

Stages of Endometriosis

Stage

Classification

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

A new staging system called the endometriosis fertility index (EFI) has been developed for women with endometriosis-associated infertility; this system can help predict pregnancy rates after various treatments. Factors used to score the EFI include the woman's age, the number of years she has been infertile, history or absence of prior pregnancies, and the least-function score for both fallopian tubes, fimbria, and ovaries, as well as the American Society for Reproductive Medicine endometriosis (lesion and total) scores.

Treatment

  • NSAIDs for discomfort

  • Drugs to suppress ovarian function

  • Conservative surgical resection or ablation of endometriotic tissue, with or without 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 within 6 mo to 1 yr after treatment is stopped unless ovarian function is permanently and completely ablated.

Drug therapy

Drugs that suppress ovarian function inhibit the growth and activity of endometriotic implants. These drugs include continuous oral contraceptives (commonly used), progestins, gonadotropin-releasing hormone (GnRH) agonists, and danazol (see Drugs Used to Treat Endometriosis).

Drugs Used to Treat Endometriosis

Drug

Dosage

Adverse Effects

Combination estrogen/progestin oral contraceptive

Ethinyl estradiol 20 mcg plus a progestin

Continuous, prolonged use (1 tablet once/day for 4–6 cycles, then stopped for 4 days) 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 venous thrombosis, MI, stroke, peripheral vascular disease

Progestins

Levonorgestrel-releasing intrauterine device (IUD)

About 20 mcg/day, decreasing progressively over 5 yr to 10 mcg (delivered by IUD)

Irregular uterine bleeding, sometimes amenorrhea (developing over time), weight gain

Medroxyprogesterone 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, weight gain

Norethindrone acetate

2.5–5 mg po at bedtime

Irregular uterine bleeding, emotional lability, depression, weight gain

Androgen

Danazol

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

1 mg sc once/day

Hot flushes, atrophic vaginitis, bone demineralization, emotional lability, headaches, weakness, myalgias

Leuprolide depot

3.75 mg IM q 28 days

or

11.25 mg IM q 3 mo

Same as for sc.

Nafarelin

200–400 mcg intranasally bid

Hot flushes, atrophic vaginitis, bone demineralization, emotional lability, headaches, acne, decreased libido, vaginal dryness, leukopenia

*Treatment is limited to 6 mo.

Leuprolide is often given with a progestin such as norethindrone acetate (2.5–5 mg po once/day) to prevent bone loss during treatment.

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, a progestin may be used concurrently (as add-back therapy) to minimize bone loss.

Danazol , a synthetic androgen and an antigonadotropin, inhibits ovulation. However, its androgenic adverse effects limit its use.

Cyclic or continuous oral contraceptives given after danazol or GnRH agonists may slow disease progression and are warranted for women who wish to delay childbearing.

An aromatase inhibitor plus a combination contraceptive can be considered if none of these drugs is effective; such treatment is sometimes successful.

Drug treatment does not change fertility rates in women with minimal or mild endometriosis.


Surgery

Most women with moderate to severe endometriosis are treated most effectively by ablating or excising as many implants as possible while maintaining pelvic anatomy and preserving fertility as much as possible. Specific indications for surgery include

  • Presence of endometriomas

  • Significant pelvic adhesions

  • Fallopian tube obstruction

  • Incapacitating pelvic pain

  • A desire to preserve fertility

Lesions are usually removed via a laparoscope; peritoneal or ovarian lesions can sometimes be electrocauterized, excised, or vaporized with a laser. Endometriomas should be removed because removal prevents recurrence more effectively than drainage. After this treatment, fertility rates are inversely proportional to the severity of endometriosis. If resection is incomplete, GnRH agonists are sometimes given during the perioperative period, but whether these drugs increase fertility rates is unclear. Laparoscopic resection of the uterosacral ligaments with electrocautery or a laser may reduce midline pelvic pain. If women have deep rectovaginal endometriosis, continuous progestin therapy is the most effective treatment.

Hysterectomy should usually be reserved for patients who have intractable pelvic pain and who have completed childbearing. Hysterectomy is done in addition to oophorectomy to remove adhesions or implants that adhere to the uterus or cul-de-sac. If women < 50 require hysterectomy with oophorectomy, supplemental estrogen should be considered (eg, to prevent menopausal symptoms). However, concomitant continuous progestin therapy (eg, medroxyprogesterone acetate 2.5 mg po once/day) is often recommended because if estrogen is given alone, residual tissue may grow, resulting in recurrence rates of up to 40%. If symptoms persist after oophorectomy in women > 50, continuous progestin therapy alone (medroxyprogesterone acetate 2.5 mg po once/day, micronized progesterone 100 to 200 mg po at bedtime) can be tried.


Key Points

  • Endometriosis is a common cause of cyclic pelvic pain, dysmenorrhea, and infertility.

  • The stage of endometriosis does not correlate with severity of symptoms.

  • Confirm the diagnosis usually by laparoscopic biopsy.

  • Treat pain (eg, with NSAIDs) and, depending on patient fertility goals, usually use drugs that suppress ovarian function to inhibit the growth and activity of endometriotic implants.

  • For moderate to severe endometriosis, consider ablating or excising as many implants as possible while preserving fertility.

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • CRINONE
  • SYNAREL
  • MIRENA, PLAN B
  • PROVERA
  • LUPRON
  • No US brand name
  • ESTRADERM, ESTROGEL, VIVELLE
  • AYGESTIN, CAMILA

* This is a professional Version *