Endometriosis

Overview

Definition

Endometriosis is a condition in which endometrial glands and stroma implant outside of the uterus. These implants can be highly inflammatory but are generally not malignant.

Epidemiology

• Incidence in general female population: approximately 10%
  • Estimates vary widely based on the population studied.
  • Many cases are asymptomatic.
• Incidence in infertile patients: up to 50%
• Incidence in patients with pelvic pain: 70%–80%
• Average age at diagnosis: 27 years
• Cases are uncommon, but also possible in: 
  • Premenarcheal girls 
  • Postmenopausal women (2%–5% of cases)

Risk factors

• Prolonged endogenous estrogen exposure:
  • Nulliparity
  • Early age at menarche
  • Late menopause
  • Shorter menstrual cycles
• Heavy menstrual bleeding
• History of infertility
• History of obstructed outflow (e.g., Müllerian anomalies)
• Low body mass index (BMI)
• Family history of endometriosis

Pathophysiology

Contributing factors

• Genetic factors
• Abnormal endocrine signaling:
  • Estrogen stimulates endometrial proliferation.
  • Unlike normal endometrium, endometriosis implants express enzymes that: 
    • Convert androgens to estrogens
    • Inhibit estrogen deactivation
  • Results in ↑ estrogen stimulation within endometriosis implants compared with normal endometrium
• Altered immunity:
  • ↑ Inflammatory response
  • Thought to contribute to the implantation process
• Abnormalities in cell proliferation and apoptosis
• Obstruction of the reproductive outflow tract

Theories about the establishment of implants

• Retrograde menstruation (Sampson’s theory):
  • Menstrual efflux of endometrial cells into the peritoneal cavity through the fallopian tubes
  • Does not explain implants outside the abdominopelvic cavity or cases in premenstrual girls
• Coelomic metaplasia: 
  • Coelomic epithelium transforms into endometrium-like glands.
  • Coelomic epithelium normally becomes:
    • Endometrium
    • Ovary
    • Peritoneum
    • Pleura
• Vascular or lymphatic dissemination:
  • Similar mechanisms to how cancer spreads via the blood and lymph system
  • Explains cases of endometriosis lesions outside the abdominopelvic cavity

Sites of ectopic implantation

• Ovary (most common site)
• Pelvic peritoneum (2nd-most common)
• Uterine ligaments (broad, uterosacral)
• Within the uterine myometrium → adenomyosis
• Rectovaginal septum
• Fallopian tubes
• Colon, rectum, and appendix
• Bladder and ureters
• Prior surgical incision sites
• Distant organs (rare):
  • Lungs
  • Breast
  • Bones
  • Liver, gallbladder, pancreas, and spleen

Causes of pain

• Cyclic hormone fluctuations → bleeding from implants → ↑ production of inflammatory mediators
• Chronic inflammation → fibrin deposition → pelvic adhesions and scarring → distortion of peritoneal surfaces → pain
• Nerve sensitization near implants, potentially caused by:
  • Chronic inflammation
  • Estrogen acting as a neuromodulator
  • Direct neuronal invasion of endometrial implants
• The severity of pain is not directly related to the extent of disease.

Clinical Presentation

General considerations

• The location of implants determines the clinical presentation.
• Symptoms may be cyclic or chronic.
• Some patients are asymptomatic.
• Symptoms often improve during pregnancy.

Pelvic pain

• Presenting symptom in 80% of cases
• Severe dysmenorrhea
  • Dull or crampy pain
  • Cyclic, often beginning a few days before the onset of bleeding
• Noncyclic pain:
  • Pelvic or abdominal
  • May be focal or generalized
  • Dull, throbbing, sharp, or pressure
• Dyspareunia

Infertility

• Presenting symptom in 25% of cases
• Due to:
  • Pelvic adhesions in fallopian tubes
  • Inflammatory and/or hormonal milieu affecting folliculogenesis

Ovarian mass

• Presenting symptom in 20% of cases
• Called an endometrioma:
  • Benign ovarian cyst with endometrial tissue
  • Also called “chocolate cysts“

Less common symptoms

• Heavy or irregular menstrual bleeding
• Low back pain
• Fatigue
• Bladder symptoms:
  • Dysuria
  • Frequency
  • Hematuria
• Bowel symptoms:
  • Constipation
  • Diarrhea
  • Dyschezia (pain with defecation)
  • Hematochezia

Diagnosis

Definitive diagnosis can only be made on histologic examination of a surgical biopsy. The diagnosis is therefore often made clinically based on history and exam findings alone, unless imaging suggests an endometrioma.

Physical exam

Findings suggestive of endometriosis:

• Tenderness on vaginal exam
• Visible vaginal endometrial implants
• Palpable nodules in the posterior fornix or rectovaginal septum
• Adnexal mass
• “Frozen pelvis”:
  • Immobility of the cervix and/or uterus on bimanual exam
  • Due to adhesions and scarring

Laboratory

• Lab tests are not clinically useful.
• Test for gonorrhea and chlamydia if considering pelvic inflammatory disease (PID)
• Cancer angigen 125 (CA 125) may be ↑ in endometriosis
  • ↑ CA 125 is more commonly associated with ovarian carcinoma. 
  • Should be ordered in patients with an ovarian mass suspicious for cancer

Imaging

• Transvaginal ultrasound:
  • Endometrioma (chocolate cysts)
  • Nodules on the rectovaginal septum, abdominal wall, or bladder
  • Normal-size uterus (compared with an enlarged uterus with adenomyosis)
• Magnetic resonance imaging (MRI):
  • More sensitive than ultrasound for detection of localized disease
  • Not useful in cases of diffuse endometriosis

Laparoscopy

• The gold standard for diagnosis
• Implant appearance:
  • Lesions may be red, white, clear, or black-purple.
  • Powder-burn lesions: superficial implants with the appearance of sprinkled powder
• Biopsy is used for definitive histologic confirmation.
• Other findings:
  • Peritoneal defects or holes
  • Endometriomas
  • Pelvic adhesions

Management and Complications

General considerations

• Therapy can be initiated based on a clinical (rather than surgical) diagnosis.
• Requires a chronic management plan in order to ↓ repeated surgeries
• Goals of treatment:
  • Improve pain.
  • Suppress endometrial growth.
  • Treat infertility:
    • Standard treatment until patient is ready to conceive
    • Refer to a reproductive endocrinology specialist.

First-line medical management

• Non-steroidal anti-inflammatory drugs (NSAIDs)
• Hormonal contraceptives:
  • Primary initial treatment
  • Often given continuously (without placebo days) to completely suppress menstruation
  • Progestins suppress endometrial growth.
  • Options include:
    • Combined oral contraceptive pills (OCPs)
    • Progesterone-only contraceptive pills (POPs)
    • Contraceptive patch 
    • Contraceptive vaginal ring
    • Levonorgestrel-containing intrauterine devices (IUDs)
    • Etonogestrel contraceptive implant
    • Medroxyprogesterone acetate injections

Second-line medical management

The following are used in patients who cannot take or derive no benefit from 1st-line management:

• Gonadotropin-releasing hormone (GnRH) agonists and antagonists:
  • Suppress the hypothalamic-pituitary-ovarian (HPO) axis by eliminating the GnRH pulse
  • Results in ↓ estrogen → endometrial atrophy
  • Used to treat severe pain
  • Should only be used for 6–12 months in order to prevent osteoporosis
  • Options: 
    • Leuprolide (agonist)
    • Elagolix (antagonist)
• Androgens
  • Danazol
  • Effective at treating pain
  • Not commonly used due to androgenic side effects
• Neuropathic agents
  • To treat pain, especially when nerve sensitization is suspected
  • Options:
    • Tricyclic antidepressants (TCAs)
    • Serotonin-norepinephrine reuptake inhibitors (SNRIs)
    • Antiepileptic drugs (e.g., gabapentin)

Surgical management

The goal is to provide a definitive histologic diagnosis and resect any visible lesions to treat pain.

• Ovarian cystectomy for endometriomas
• Resection or ablation of the endometrial lesions
• Lysis of adhesions
• Hysterectomy with or without salpingo-oophorectomy:
  • Reserved for patients with moderate-to-severe pain
  • Definitive procedure
  • If ovaries remain → persistent estrogen production → stimulates any remaining implants → possible to have persistent pain
  • Supplemental hormone therapy may be considered if ovaries are removed.
• Nerve ablation or transection to treat pain refractory pain.

Complications

• Pregnancy implications:
  • ↑ Risk of preterm birth
  • Infertility
  • Ectopic pregnancy
• ↑ risk of clear cell epithelial ovarian cancer
• Intestinal obstruction from adhesions
• Possible ↑ risk of cardiovascular disease due to chronic systemic inflammation

Differential Diagnosis

• Adenomyosis: similar to endometriosis; however, endometrial implants are confined specifically to the uterine myometrium, resulting in painful and heavy menstrual bleeding. On ultrasound, the uterus is often enlarged and may show myometrial cysts or heterogeneity. Management involves suppression of the endometrium, usually with progestins, or definitive treatment with hysterectomy. Adenomyosis often coexists with endometriosis. 
• Leiomyoma (fibroids): benign fibrous tumors of myometrial origin. Leiomyomas are more common in Black women than Caucasian women, and typically present with heavy menstrual bleeding, dysmenorrhea, or pelvic pressure. Leiomyomas are typically easily identified on ultrasound. Management involves hormonal suppression with OCPs for smaller fibroids or if a woman wants to retain her uterus. Surgical resection is the definitive treatment.
• PID: an ascending infectious process involving the uterus, fallopian tubes, and ovaries. Pelvic inflammatory disease is closely linked with sexually transmitted diseases (especially Chlamydia trachomatis and Neisseria gonorrhoeae) and bacterial vaginosis. Unlike endometriosis, which is chronic, PID is an acute process and causes extreme tenderness on pelvic exam, and fever. Diagnosis involves identification of the causative organism. Treatment is with antibiotics.
• Hemorrhagic ovarian cyst: a functional cyst arising from a normal ovarian follicle that has bled into itself. These cysts are often painful, usually with more of an acute onset of pain. Hemorrhagic cysts can appear clinically indistinguishable from endometriomas. However, hemorrhagic cysts will resolve spontaneously (usually within 1–2 menstrual cycles) while endometriomas will not. Repeating pelvic ultrasound is important to confirm resolution.
• Interstitial cystitis/bladder pain syndrome: a noninfectious, inflammatory condition involving chronic bladder pain that can be severe. The cause is unknown. Pain is typically worse when the bladder is distended, with pain relief after voiding, and is unrelated to the menstrual cycle. Urinalysis is normal, and the diagnosis is one of exclusion. Treatment is complex and can include lifestyle modifications, medical therapy, and surgical procedures.
• Irritable bowel syndrome (IBS): a functional disorder of the gastrointestinal tract that typically presents with chronic abdominal pain and altered bowel habits. Endometriosis may present similarly if there is bowel involvement. In endometriosis, symptoms will often have a cyclic component to them. This is also a diagnosis of exclusion. Management for IBS involves dietary modification and symptom-control measures.