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Endometriosis

By James H. Liu, MD, Arthur H. Bill Professor and Chair, Departments of Obstetrics and Gynecology and Reproductive Biology, UH Cleveland Medical Center, Case Western Reserve University

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In endometriosis, functioning endometrial tissue is implanted in the pelvis 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 direct visualization and sometimes 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 alone or hysterectomy plus bilateral salpingo-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, and, more rarely, the lung, pleura, and pericardium.

Bleeding from peritoneal implants is thought to initiate sterile inflammation, followed by fibrin deposition, adhesion formation, and, eventually, scarring, which distorts peritoneal surfaces of organs, leading to pain and distorted pelvic anatomy.

Reported prevalence varies but is probably about

  • 6 to 10% in all women

  • 25 to 50% in infertile women

  • 75 to 80% in women with chronic pelvic pain

Average age at diagnosis is 27, but endometriosis also occurs among adolescents.

Etiology and Pathophysiology

The most widely accepted hypothesis for the pathophysiology of endometriosis is that endometrial cells are transported from the uterine cavity during menstruation and subsequently become implanted at ectopic sites. Retrograde flow of menstrual tissue through the fallopian tubes is common and 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 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 and inflammation interfere with mechanisms of ovum pickup, oocyte fertilization, 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 luteal phase dysfunction or other abnormalities)

Potential risk factors for endometriosis are

  • Family history of 1st-degree relatives with endometriosis

  • Delayed childbearing or nulliparity

  • Early menarche

  • Late menopause

  • Shortened menstrual cycles (< 27 days) with menses that are heavy and prolonged (> 8 days)

  • Müllerian duct defects

  • Exposure to diethylstilbestrol in utero

Potential protective factors seem to be

  • Multiple births

  • Prolonged lactation

  • Late menarche

  • Use of low-dose oral contraceptives (continuous or cyclic)

  • 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 (dysmenorrhea) and during sexual intercourse (dyspareunia), is typical and can be progressive and chronic (lasting > 6 mo). Adnexal masses and infertility are also typical. Interstitial cystitis with suprapubic or pelvic pain, urinary frequency, and urge incontinence is common. 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 or pelvic pain (particularly during urination), urinary frequency, urge incontinence, 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 or tender 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

  • Direct visualization, usually during pelvic laparoscopy

  • Sometimes biopsy

Diagnosis of endometriosis is suspected based on typical symptoms but must be confirmed by direct visualization and sometimes biopsy, usually via pelvic laparoscopy but sometimes via laparotomy, vaginal examination, sigmoidoscopy, or cystoscopy. Biopsy is not required, but results may help with the diagnosis. 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, endometrial glands and stroma are usually present. Stromal elements in the absence of glandular elements indicate a rare variant of endometriosis called stromal endometriosis.

Imaging tests (eg, ultrasonography) 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 neither helpful nor specific in diagnosis or management. Testing for other infertility disorders may be indicated.

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

  • Presence of endometriomas and filmy or dense adhesions (see Table: 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

The endometriosis fertility index (EFI) has been developed to stage 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

  • The least-function score for both fallopian tubes, fimbria, and ovaries

  • 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 or without bilateral salpingo-oophorectomy if disease is severe and the patient has completed childbearing

Symptomatic medical treatment begins with analgesics (usually NSAIDs) and hormonal contraceptives. 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.

Conservative surgical treatment of endometriosis is excision or ablation of endometriotic implants and removal of pelvic adhesions during laparoscopy.

Drugs and conservative surgery are used mainly to control symptoms. In most patients, endometriosis recurs within 6 mo to 1 yr after drugs are stopped unless ovarian function is permanently and completely ablated. Endometriosis may also recur after conservative surgery.

Total abdominal hysterectomy with or without bilateral salpingo-oophorectomy is considered definitive treatment of endometriosis. It helps prevent complications and modify the course of disease as well as relieving symptoms; however, it can recur.

Drug therapy

Drugs that suppress ovarian function inhibit the growth and activity of endometriotic implants. The following are commonly used:

  • Continuous combination oral contraceptives

The following drugs are usually used only when women cannot take combination oral contraceptives or when treatment with combination oral contraceptives is ineffective:

  • Progestins

  • Gonadotropin-releasing hormone (GnRH) agonists

  • Danazol

Drugs Used to Treat Endometriosis

Drug

Dosage

Adverse Effects

Combination estrogen/progestin oral contraceptive

Ethinyl estradiol 20 mcg plus a progestin

Ethinyl estradiol 10 mcg plus a progestin

Continuous, prolonged use (1 tablet once/day for 3–4 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, mood changes

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)

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, 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, joint stiffness, headaches, weakness, myalgias, reduced libido

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, joint stiffness, vaginal dryness

*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 and reduce hot flushes during treatment.

GnRH =gonadotropin-releasing hormone.

GnRH agonists temporarily suppress estrogen production by the ovaries; 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 or a bisphosphonate may be used concurrently (as add-back therapy) to minimize bone loss. If endometriosis recurs, women may need to be treated again.

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

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

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 restoring pelvic anatomy and preserving fertility as much as possible. Superficial endometriotic implants can be ablated. Deep, extensive implants should be excised.

Specific indications for laparoscopic surgery and hysterectomy include

  • Moderate to severe pelvic pain that does not respond to drugs

  • Presence of endometriomas

  • Significant pelvic adhesions

  • Fallopian tube obstruction

  • A desire to maintain fertility

  • Pain during intercourse

Lesions are usually removed via a laparoscope; peritoneal or ovarian lesions can sometimes be electrocauterized, excised, or, uncommonly, 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.

Rectovaginal endometriosis,the most severe form of the disease, can be treated with the usual treatments for endometriosis; however, colonoscopic resection or surgery may be required to prevent obstruction of the colon.

Hysterectomy with or without ovarian conservation should usually be reserved for patients who have moderate to severe pelvic pain, who have completed childbearing, and who prefer a definitive procedure. Hysterectomy is done to remove adhesions or implants that adhere to the uterus or cul-de-sac. If women < 50 require hysterectomy with bilateral salpingo-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. If symptoms persist after salpingo-oophorectomy in women > 50, continuous progestin therapy alone (norethindrone acetate 2.5 to 5 mg, medroxyprogesterone acetate 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 and chronic pelvic pain, dysmenorrhea, dyspareunia, and infertility.

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

  • Confirm the diagnosis usually by laparoscopy; a biopsy is not mandatory but may aid in the diagnosis.

  • 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 restoring normal pelvic anatomy.

Resources In This Article

Drugs Mentioned In This Article

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