Endometriosis

Endometriosis is a common chronic disease in individuals of reproductive age characterized by growth of benign endometrial-like tissue outside the uterus. The exact etiology of endometriosis is unclear, but retrograde menstruation may be involved. Symptoms include dysmenorrhea, abnormal uterine bleeding, dyspareunia, chronic pelvic pain, and infertility. Endometriosis is difficult to diagnose, but initial imaging with transvaginal ultrasound or MRI may help identify lesions. Definitive diagnosis is based on laparoscopy but is not required to begin treatment. Initial medical treatment includes hormonal contraceptives and NSAIDs. Referral to gynecology is recommended in diagnostic uncertainty, adolescent patients, refractory disease, and/or patients desiring pregnancy. Advanced treatments include GnRH agonists, GnRH antagonists, and surgical therapies.

• Age of onset: 20–40 years
• Incidence: 2–10% of all female individuals
• Ethnicity: In the US, endometriosis is more common in white and Asian individuals than in black and Hispanic individuals.

Epidemiological data refers to the US, unless otherwise specified.

• The etiology of endometriosis is not yet fully understood; however, retrograde menstruation seems to play a major role in the pathogenesis of endometriosis.
• Other contributing factors include:
  • Coelomic metaplasia
  • Iatrogenic implantation
  • Hematogenic and lymphogenic dissemination of endometrial cells
  • Hereditary component
• Risk factors ^[1]
  • Nulliparity
  • Prolonged exposure to endogenous estrogen (early menarche, late menopause)
  • Short menstrual cycles (< 27 days)
  • Menorrhagia (> 1 week)
  • Family history

• In endometriosis, endometrial-like tissue grows outside of the uterus.
• Common locations of endometriotic lesions include:
  • Pelvic organs
    • Ovaries: most common site; often affected bilaterally
    • Rectouterine pouch
    • Fallopian tubes
    • Bladder
    • Cervix
  • Peritoneum
  • Extrapelvic organs (e.g., lung or diaphragm): less commonly affected
• Regardless of where the endometrial tissue is located, it reacts to the hormone cycle; in much the same way as the endometrium and proliferates under the influence of estrogen.
• Endometriotic lesions result in:
  • ↑ Production of inflammatory and pain mediators
  • Anatomical changes (e.g., pelvic adhesions) → infertility
  • Nerve dysfunction

Clinical features by anatomic location

Endometriosis is often asymptomatic and may be an incidental finding during surgery for other conditions.

Examination findings ^[1][3][6]

Pelvic examination may show the following:

• Adnexal masses and/or tenderness
• Indurated rectovaginal septum
• Lateral displacement of the cervix (due to uterosacral scarring) ^[7]

The clinical features of endometriosis are extremely varied; maintain a low threshold for obtaining diagnostic studies and starting treatment, particularly in patients with refractory primary dysmenorrhea. ^[3]

Approach ^[1][3][6]

• Rule out differential diagnoses of endometriosis; consider the following based on symptoms: ^[1]
  • CBC
  • Urinalysis
  • Screening for chlamydia and screening for gonorrhea
• Consider starting treatment while awaiting diagnostic studies. ^[6]
• Obtain initial imaging: transvaginal ultrasound (TVUS) or MRI
• Consider referral to obstetrics and gynecology for confirmatory laparoscopy.

CA-125 levels may be elevated in endometriosis. However, this finding is nonspecific and thus not recommended for diagnosis. ^[6][8]

Imaging ^[9]

• TVUS (with or without transabdominal ultrasound) is frequently used for the initial study. ; ^[6]
  • May show ovarian endometriomas (chocolate cysts)
  • May show signs of rectosigmoid endometriosis (e.g., loss of uterine sliding sign)
  • Depending on disease location and severity, examination findings may appear normal. ^[6][9]
• Obtain MRI pelvis with and without IV contrast if ultrasound findings are normal or equivocal and:
  • Surgery is being considered
  • Deep infiltrating endometriosis is suspected ^[1]

Normal findings from pelvic examination or imaging do not rule out endometriosis. ^[10]

Laparoscopy ^[1][3]

• Laparoscopic biopsy of endometriosis lesions is the only method for confirming endometriosis.
• Laparoscopy can be used for diagnosis and surgical treatment of endometriosis (if indicated).
• Diagnostic confirmation is not required to start treatment; use shared decision-making discussion to determine if laparoscopy is appropriate. ^[1][3]

Laparoscopic findings rarely correspond to symptom severity. ^[10]

Macroscopic findings

• Endometrium: endometrial lesions that present as yellow-brown (sometimes reddish-blue) blebs, islands, or pinpoint spots
• Ovaries
  • Gunshot lesions or powder-burn lesions
    • Black, yellow-brown, or bluish nodules or cystic structures
    • Seen on the serosal surfaces of the ovaries and peritoneum
  • Ovarian endometriomas or chocolate cysts; : cyst-like structures that contain blood, fluid, and menstrual debris
• Fallopian tubes: salpingitis isthmica nodosa
  • Nodular tube changes, resulting in:
    • ↑ Risk of sterility and ectopic pregnancy
    • ↓ Transmittance

Microscopic findings

• Normal endometrial glands
• Normal endometrial stroma
• Preponderance of hemosiderin laden macrophages due to cyclic hemorrhages into endometriomas

For more information, see:

• Differential diagnosis of dysmenorrhea and AUB
• Adenomyosis
• Uterine leiomyomas
• Infertility

The differential diagnoses listed here are not exhaustive.

Management of endometriosis is challenging and should be individualized based on the patient's symptoms, reproductive plans, and tolerance of risks and/or adverse effects. ^[6]

Approach ^[1][3][6]

• Identify and treat associated complications (e.g., anemia).
• Start chronic noncancer pain management as needed.
• Patients trying to get pregnant: Refer directly to gynecology.
• Patients not trying to get pregnant:
  • Start initial medical therapy for endometriosis.
  • Refer to gynecology for advanced treatment based on the following criteria:
    • Onset in adolescence ^[3]
    • Diagnostic uncertainty and/or further workup required
    • Endometrioma identified on imaging in a patient without confirmed endometriosis ^[1]
    • Refractory symptoms
    • Evidence of extrapelvic disease ^[1]
• Regularly reassess for changes in symptoms or reproductive life plan, and refer to gynecology as needed.

A presumed clinical diagnosis of endometriosis is sufficient to begin treatment. ^[6]

Initial medical therapy for endometriosis

• Hormonal contraceptives: Continue until pregnancy is desired or average age of menopause. ^[6]
  • Preferred: continuous combined hormonal contraceptives (CHCs), e.g., levonorgestrel/ethinyl estradiol (off-label) ^[11][12]
  • Alternative: treatment with progestins
    • Progestin-only pill (e.g., norethindrone acetate )
    • Subcutaneous depot medroxyprogesterone acetate
    • Levonorgestrel IUD (off-label)
• NSAIDs (e.g., naproxen): may be used in combination with hormonal contraceptives (for dosages, see “Oral analgesia”) ^[6][13]

Medical therapy reduces pain from endometriosis but does not improve fertility. ^[1]

Advanced treatment ^[1][3][6]

Refer patients to gynecology for advanced treatments.

Advanced medical treatments ^[1][3][6]

• Indications
  • Initial medical therapy (hormonal treatment and NSAIDs) is ineffective or not tolerated.
  • Extrapelvic disease ^[1]
• Options: The following medications inhibit the growth of endometrial tissue by suppressing estrogen.
  • GnRH agonists (e.g., goserelin) OR GnRH antagonists (e.g., elagolix)
    • Treatment duration 6–24 months ^[1][6]
    • May be combined with add-back hormonal contraceptives to mitigate hypoestrogenic effects
  • Danazol
  • Severe or refractory disease: aromatase inhibitors (e.g., anastrozole)

Management of infertility ^[1][6][8]

• Mild disease: Consider laparoscopy. ^[14]
• Moderate or severe disease: Consider IVF as first-line therapy. ^[1][6]

Surgical treatment of endometriosis ^[1][15]

• Laparoscopic excision and/or ablation of endometrial lesions may be considered in patients with: ^[1][6]
  • Disease refractory to medical management
  • Infertility with mild disease ^[6]
• Hysterectomy with or without bilateral salpingo-oophorectomy may be considered in patients with both of the following:
  • No desire for future pregnancy
  • Disease refractory to all treatments

Symptoms may persist or recur after laparoscopic treatments and/or hysterectomy. Consider medical therapy after surgery to reduce the risk of symptom recurrence. ^[1][6]

• Anemia
• Endometriosis in the uterotubal junction inhibits implantation of the zygote: ↑ risk of ectopic pregnancy ^[16]
• Endometriosis → fibrous adhesions → strictures and entrapment of organs
  • Intestines: constipation or diarrhea; in rare cases, intestinal obstruction, ileus, or intussusception may occur ^[17]
  • Ureter: urine retention
• Endometriosis is associated with a slightly elevated risk of ovarian cancer. ^[18]
• Infertility ^[6]

We list the most important complications. The selection is not exhaustive.