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Endometriosis

By

James H. Liu

, MD, Case Western Reserve University School of Medicine

Last full review/revision Apr 2022| Content last modified Apr 2022
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In endometriosis, functioning endometrial cells are implanted in the pelvis outside the uterine cavity. Symptoms depend on location of the implants. The classic triad of symptoms is dysmenorrhea, dyspareunia, and infertility, but symptoms may also include 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 about

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

Etiology and Pathophysiology of Endometriosis

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 histologically 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, some endometriotic implants 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.

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 fertilization, sperm, and oocyte function

  • Nonreceptive endometrium (because of luteal phase dysfunction or other abnormalities)

Potential risk factors for endometriosis are

Potential protective factors seem to be

  • Multiple births

  • Prolonged lactation

  • Late menarche

  • Long-term use of low-dose oral contraceptives (continuous or cyclic)

  • Regular exercise (especially if begun before age 15, if done for > 4 hours/week, or both)

Etiology and pathophysiology reference

Symptoms and Signs of Endometriosis

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. Endometriosis tends to become inactive after menopause because estrogen and progesterone levels decrease.

Symptoms can vary depending on location of implants.

  • 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

  • Bladder: Dysuria, hematuria, suprapubic or pelvic pain (particularly during urination), urinary frequency, urge incontinence, or a combination

  • Large intestine: Pain during defecation, abdominal bloating, diarrhea or constipation, or rectal bleeding during menses

  • 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 of Endometriosis

  • Direct visualization, usually during pelvic laparoscopy

  • Sometimes biopsy

Diagnosis of endometriosis is suspected based on typical symptoms. Misdiagnosis as pelvic inflammatory disease, urinary tract infection, or irritable bowel syndrome is common. Negative cervical and/or urine cultures suggest the possibility of endometriosis.

The diagnosis of endometriosis must be confirmed by direct visualization, usually via pelvic laparoscopy but sometimes via laparotomy, vaginal examination, sigmoidoscopy, or cystoscopy. Biopsy is not required, but results confirm the diagnosis.

Macroscopic appearance (eg, clear, red, blue, brown, black) and size of implants vary during the menstrual cycle. However, typically, early lesions are clear or red (hemorrhagic). As the blood in the lesions oxidizes, they turn purple, then brown; they then turn to bluish or purplish brown spots that are > 5 mm and resemble powder burns.

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 do not reliably detect endometriosis; however, these tests sometimes show the extent of endometriosis and thus can be used after diagnosis to monitor the disorder and response to treatment. An ultrasound showing an ovarian cyst consistent with an endometrioma is highly suggestive of the diagnosis. The presence and size of ovarian endometriomas are part of the staging system for endometriosis (stage III: small endometriomas; stage IV: large endometriomas), and a decrease in endometrioma size can show response to treatment.

Because endometrial tissue has a unique MR signal, MRI is becoming increasingly useful for evaluating patients who may have endometriosis ( 1 Diagnosis reference In endometriosis, functioning endometrial cells are implanted in the pelvis outside the uterine cavity. Symptoms depend on location of the implants. The classic triad of symptoms is dysmenorrhea... read more ). T1- and T2-weighted MRI can detect some endometriotic lesions in the pelvis, particularly larger lesions. Hemorrhage in the fallopian tubes or in an ovarian cyst without an increase in blood flow suggests endometriosis. Multiple large areas of endometriosis located in the cul de sac indicate severe (stage IV) endometriosis.

No laboratory tests contribute to the diagnosis of endometriosis.

Pearls & Pitfalls

  • Consider endometriosis if patients have persistent cyclic pelvic pain, particularly if they also have dyspareunia or infertility.

Staging endometriosis 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

Table

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

Diagnosis reference

  • 1. Guerriero S, Saba L, Pascual MA, et al: Transvaginal ultrasound vs magnetic resonance imaging for diagnosing deep infiltrating endometriosis: systematic review and meta‐analysis. Ultrasound Obstet Gynecol 51 (5):586–595, 2018. doi: 10.1002/uog.18961

Treatment of Endometriosis

  • Nonsteroidal anti-inflammatory drugs (NSAIDs) for discomfort

  • Estrogen-progestin contraceptives

  • 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.

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

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

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, endometriosis can recur.

Drug therapy

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

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 and antagonists

  • Danazol

Table

GnRH agonists initially increase hypothalamic GnRH secretion, but continued use then temporarily decreases pituitary release of follicle-stimulating hormone (FSH), resulting in a decreased in estrogen production by the ovaries; however, treatment is limited to 6 months because long-term use may result in bone loss. If treatment lasts > 4 to 6 months, a progestin or a bisphosphonate may be used concurrently to minimize bone loss. If endometriosis recurs, women may need to be treated again.

The GnRH antagonist elagolix directly decreases GnRH secretion and thus suppresses pituitary release of FSH and estrogen production by the ovaries. It is available in 2 different doses; the higher dose is available to treat dyspareunia as well as other symptoms of endometriosis. Long-term use may result in bone loss. If treatment lasts > 6 months, a progestin may be used concurrently (as add-back therapy) to minimize bone loss.

The GnRH antagonist relugolix combined with estradiol 1 mg and norethindrone 0.5 mg is undergoing clinical trials for use as primary treatment for endometriosis; this combination minimizes hot flushes and bone loss; use is limited to 24 months because possible continued bone loss may be irreversible.

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 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 this tactic increases 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, colon 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). Also, concomitant continuous progestin therapy (eg, medroxyprogesterone acetate 2.5 mg orally once a 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 orally once a day, micronized progesterone 100 to 200 mg orally 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.

  • Reserve hysterectomy for women who have completed childbearing or who prefer a definitive procedure.

Drugs Mentioned In This Article

Drug Name Select Trade
No US brand name
ORILISSA
ORGOVYX
ESTRADERM, ESTROGEL, VIVELLE
AYGESTIN, CAMILA
PROVERA
CRINONE
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