Definition and epidemiology
Endometriosis is defined by the presence of endometrial-like glands and stroma outside the uterine cavity. The ectopic tissue responds to hormonal changes during the menstrual cycle, leading to inflammation, scarring, and adhesion formation.
Epidemiology:
- Affects approximately 10% of women of reproductive age worldwide
- Prevalence rises to 25-50% among infertile women
- Found in up to 70-90% of women with chronic pelvic pain
- Peak incidence occurs between ages 25-35 years
- Symptoms typically begin within years of menarche but diagnosis is often delayed by 7-10 years
- More common in nulliparous women and those with family history
- Rare after menopause unless exogenous estrogen is used
Endometriosis is classified by the American Society for Reproductive Medicine (ASRM) into stages I-IV based on extent and depth of implants, but staging correlates poorly with symptom severity.
- Endometriosis is the most common cause of secondary dysmenorrhea in reproductive-age women.
- Laparoscopy with biopsy is required for definitive diagnosis; imaging alone cannot confirm endometriosis.
- Classic triad: dysmenorrhea, dyspareunia, and dyschezia (painful defecation during menses).
- Medical therapy suppresses symptoms but does not improve fertility; surgical treatment is needed for infertility.
- Endometriomas have a ground-glass appearance on ultrasound and chocolate-colored fluid at surgery.
- Combined hormonal contraceptives used continuously are first-line medical therapy for pain control.
- CA-125 is neither sensitive nor specific and should not be used for diagnosis.
- GnRH agonists require add-back therapy with low-dose estrogen-progestin for use beyond 6 months to prevent bone loss.
Etiology and risk factors
The exact etiology remains incompletely understood, but several theories explain the pathogenesis:
Retrograde menstruation theory (Sampson): Menstrual blood containing endometrial cells flows backward through the fallopian tubes into the peritoneal cavity. While retrograde menstruation occurs in up to 90% of women, only some develop endometriosis, suggesting additional factors are necessary.
Coelomic metaplasia theory: Peritoneal cells transform into endometrial-like cells through metaplastic change, possibly stimulated by inflammation or hormones.
Vascular/lymphatic dissemination: Endometrial cells spread through blood or lymphatic vessels, explaining rare distant sites like lungs or brain.
Immune dysfunction: Impaired cell-mediated immunity and altered peritoneal macrophage function may fail to clear ectopic endometrial cells.
Risk factors:
- Early menarche (before age 11)
- Short menstrual cycles (less than 27 days)
- Heavy or prolonged menstrual flow
- Nulliparity or delayed childbearing
- First-degree relative with endometriosis (7-fold increased risk)
- Müllerian anomalies causing outflow obstruction
- Low body mass index
- Tall stature
Protective factors:
- Multiparity
- Prolonged lactation
- Later menarche
- Regular exercise
- Combined hormonal contraceptive use
Pathophysiology
Endometriotic lesions contain glands and stroma histologically similar to eutopic endometrium but with important differences. These lesions are estrogen-dependent and progesterone-resistant.
Key pathophysiologic mechanisms:
Hormonal responsiveness: Ectopic tissue expresses estrogen receptors and responds to cyclic hormonal changes. Aromatase expression in lesions allows local estrogen production, creating a positive feedback loop. Progesterone resistance develops through altered progesterone receptor expression.
Inflammation: Endometriotic lesions recruit inflammatory cells and produce cytokines (IL-1, IL-6, TNF-α) and prostaglandins, creating a chronic inflammatory microenvironment. This inflammation causes pain and adhesion formation.
Angiogenesis: Vascular endothelial growth factor (VEGF) promotes new blood vessel formation, allowing lesions to establish blood supply and grow.
Neurogenesis: Nerve fibers proliferate within and around lesions, contributing to chronic pain through peripheral and central sensitization.
Adhesion formation: Chronic inflammation leads to fibrosis and adhesions between pelvic organs, causing anatomic distortion.
Common sites of implantation:
- Ovaries (most common, often bilateral)
- Posterior cul-de-sac and uterosacral ligaments
- Anterior cul-de-sac and bladder peritoneum
- Pelvic sidewalls
- Bowel serosa (rectosigmoid most common)
- Less commonly: bladder, ureters, surgical scars, diaphragm, pleura, pericardium
Endometriomas are ovarian cysts lined with endometrial tissue containing old hemorrhagic fluid, giving them a characteristic chocolate-colored appearance. Deep infiltrating endometriosis (DIE) extends more than 5 mm beneath the peritoneum and carries higher morbidity.
Clinical features
Endometriosis presents with variable symptoms, and severity does not correlate with extent of disease. Some women with extensive disease are asymptomatic, while others with minimal disease have severe symptoms.
Classic symptom triad:
- Dysmenorrhea: Progressive, severe menstrual pain often beginning before menstruation and lasting throughout the period; typically worse than primary dysmenorrhea and may not respond to NSAIDs
- Dyspareunia: Deep pelvic pain with intercourse, especially with deep penetration
- Dyschezia: Painful bowel movements, particularly during menstruation
Other common symptoms:
- Chronic pelvic pain (may be non-cyclic)
- Infertility (often the presenting complaint in asymptomatic women)
- Dysuria or urinary frequency
- Cyclic hematuria (bladder involvement)
- Cyclic hemoptysis or pneumothorax (thoracic endometriosis)
- Chronic fatigue
- Painful defecation
- Diarrhea or constipation
Physical examination findings:
- Normal examination does not exclude endometriosis
- Fixed, retroverted uterus
- Nodularity or tenderness along the uterosacral ligaments
- Adnexal masses (endometriomas)
- Tenderness in the posterior fornix or cul-de-sac
- Visible lesions on vulva or cervix (rare)
- Palpable nodules in surgical scars (previous cesarean or laparotomy)
Examination is ideally performed during menstruation when lesions are most tender and prominent.
Atypical presentations:
- Catamenial pneumothorax (recurrent pneumothorax with menses)
- Cyclic sciatica
- Bowel obstruction
- Ureteral obstruction with hydronephrosis
- Abdominal wall mass in surgical scar
Diagnosis
Clinical diagnosis can be presumptive based on history and examination, but definitive diagnosis requires histologic confirmation via laparoscopy with biopsy.
Imaging:
Transvaginal ultrasound is the first-line imaging modality:
- Identifies endometriomas (ground-glass appearance with homogeneous low-level echoes)
- Assesses ovarian and deep infiltrating disease
- Cannot detect superficial peritoneal implants
MRI pelvis is superior for:
- Deep infiltrating endometriosis
- Bladder and bowel involvement
- Presurgical mapping
- T1-weighted images show hyperintense signal in endometriomas
- T2-weighted images show shading sign
Laboratory tests:
CA-125 may be elevated but is neither sensitive nor specific. It is not recommended for diagnosis but may be used to monitor disease activity after diagnosis.
No reliable serum biomarker exists for diagnosis.
Laparoscopy with biopsy remains the gold standard:
- Allows direct visualization of lesions
- Enables biopsy for histologic confirmation
- Permits staging using ASRM classification
- Offers opportunity for simultaneous treatment
Lesion appearance:
- Powder-burn or gunshot lesions (black/blue-black)
- Red flame-like lesions
- White plaques or scarring
- Clear vesicles
- Peritoneal windows (defects)
Histology shows endometrial glands and stroma, hemosiderin-laden macrophages, and fibrosis.
Empiric treatment trial without laparoscopy is increasingly accepted in young women with typical symptoms, especially when surgery is not immediately desired. Response to hormonal suppression supports the diagnosis but does not confirm it.
Differential diagnosis
Endometriosis mimics many conditions causing pelvic pain:
Gynecologic causes:
- Primary dysmenorrhea: Pain begins with menstruation, responds well to NSAIDs, no anatomic pathology
- Adenomyosis: Diffusely enlarged, tender uterus; heavy menstrual bleeding more prominent
- Pelvic inflammatory disease: Acute onset, fever, cervical motion tenderness, elevated inflammatory markers
- Ovarian cysts: Usually unilateral, may cause acute pain if rupture or torsion occurs
- Leiomyomas (fibroids): Enlarged irregular uterus, heavy bleeding, bulk symptoms
- Ovarian cancer: Older age, progressive symptoms, elevated CA-125, complex adnexal mass
Gastrointestinal causes:
- Irritable bowel syndrome: Altered bowel habits, bloating, no cyclic pattern typically
- Inflammatory bowel disease: Systemic symptoms, diarrhea with blood/mucus, colonoscopy findings
- Appendicitis: Right lower quadrant pain, fever, leukocytosis (consider when symptoms lateralize)
Urologic causes:
- Interstitial cystitis: Urinary frequency, urgency, nocturia, bladder pain relieved by voiding
- Urinary tract infection: Acute dysuria, frequency, positive urine culture
Musculoskeletal causes:
- Pelvic floor dysfunction: Pain with prolonged sitting, specific trigger points
- Hip pathology: Pain radiating to groin, limited range of motion
Other:
- Chronic pelvic pain syndrome: Diagnosis of exclusion, multifactorial
Key distinguishing features of endometriosis:
- Cyclic pattern of symptoms
- Progressive worsening over time
- Association with infertility
- Specific examination findings (nodularity, adnexal masses)
- Imaging findings suggestive of endometriomas or DIE
Management
Treatment is individualized based on symptoms, desire for fertility, disease extent, and prior treatment response. Goals include pain relief, fertility preservation, and preventing progression.
Medical management
First-line therapy for pain:
NSAIDs: Reduce prostaglandin production and inflammation. Use scheduled dosing during menstruation.
Combined hormonal contraceptives (CHC): Pills, patch, or ring used continuously (skip placebo weeks) or cyclically. Suppress ovulation and create decidualization of endometrial tissue. Effective for pain control in up to 80% of women.
Progestins:
- Norethindrone acetate, medroxyprogesterone acetate, dienogest
- Create amenorrhea and decidualization
- Can be used long-term
- Dienogest is specifically approved for endometriosis in some countries
Second-line therapy:
GnRH agonists (leuprolide, goserelin):
- Create medical menopause through pituitary downregulation
- Highly effective but limited to 6 months without add-back therapy due to bone loss
- Add-back therapy with low-dose estrogen-progestin reduces side effects and allows extended use
GnRH antagonists (elagolix):
- Dose-dependent suppression of estrogen without initial flare
- Fewer hot flashes than agonists at lower doses
- Duration limited by bone density concerns
Aromatase inhibitors (letrozole):
- Used off-label, typically combined with progestins or CHC
- Reduces local estrogen production in lesions
Levonorgestrel intrauterine system (LNG-IUS):
- Local progestin effect
- Effective for pain, particularly in adenomyosis coexistence
- Does not prevent extrauterine lesion progression
Surgical management
Indications:
- Failed medical management
- Desire for fertility
- Endometriomas larger than 4 cm
- Severe DIE with organ involvement
- Diagnostic uncertainty
Conservative surgery:
- Laparoscopic excision or ablation of visible lesions
- Cystectomy for endometriomas (preferred over drainage alone)
- Adhesiolysis
- Nerve ablation for central pain (presacral neurectomy, uterosacral nerve ablation)
- Improves pain and fertility outcomes
- Recurrence rate approximately 20-40% at 5 years
Definitive surgery:
- Total hysterectomy with bilateral salpingo-oophorectomy
- Reserved for women who have completed childbearing with severe symptoms
- Removes hormonal stimulus but does not guarantee cure if extrauterine disease persists
- Consider excision of remaining endometriotic lesions
Postoperative medical therapy with CHC or progestins reduces recurrence risk.
Fertility management
Endometriosis-associated infertility requires specialized treatment:
Mild endometriosis (Stage I-II):
- Surgical ablation/excision may improve spontaneous pregnancy rates
- Ovulation induction with intrauterine insemination (IUI)
- In vitro fertilization (IVF) if conservative measures fail
Moderate-severe endometriosis (Stage III-IV):
- Surgical treatment improves fertility but may not restore normal fecundity
- IVF often first-line after surgery
- GnRH agonist for 3-6 months before IVF may improve outcomes
Endometriomas:
- Surgical excision if larger than 4 cm before IVF
- Smaller cysts may be observed if not interfering with ovarian access
Medical therapy does not improve fertility and delays conception.
Multidisciplinary approach
Chronic pain may benefit from:
- Pelvic floor physical therapy
- Psychological support or cognitive behavioral therapy
- Pain management specialist referral
- Nutritional counseling
Complications and prognosis
Infertility:
- Affects 30-50% of women with endometriosis
- Mechanisms include anatomic distortion, inflammation, impaired oocyte quality, and altered tubal motility
- Severity of disease does not always correlate with fertility impairment
Chronic pelvic pain:
- May persist despite treatment
- Central sensitization can occur, making pain difficult to treat
- Psychological comorbidities (depression, anxiety) common
Adhesions:
- Cause bowel, bladder, or ureteral obstruction
- Create fixed pelvic anatomy
- Complicate future surgeries
Ovarian endometriomas:
- Risk of rupture causing acute pain and peritonitis
- Rarely undergo malignant transformation (less than 1%)
- May reduce ovarian reserve if large or requiring repeated surgery
Deep infiltrating endometriosis complications:
- Bowel: Obstruction, perforation, cyclic rectal bleeding
- Urinary tract: Ureteral obstruction with hydronephrosis, bladder involvement with hematuria
- Nerve involvement: Sciatica if sciatic nerve affected
Malignant transformation:
- Small increased risk of clear cell and endometrioid ovarian carcinomas
- Absolute risk remains low (less than 1%)
- Endometrioma-associated cancer typically diagnosed during cystectomy
Pregnancy complications:
- Slightly increased risk of miscarriage, preterm birth, placenta previa, preeclampsia
- Risk is modest and most pregnancies are successful
Prognosis:
Endometriosis is a chronic condition with variable natural history. Medical and surgical treatments effectively control symptoms in most women but cure is uncommon. Approximately 20-40% experience symptom recurrence within 5 years after surgery. Pregnancy and menopause typically improve or resolve symptoms due to hormonal changes, though postmenopausal hormone therapy may reactivate disease.
Quality of life is significantly impacted, with effects on work productivity, relationships, and mental health. Early diagnosis and multidisciplinary management optimize outcomes. Spontaneous improvement occurs in approximately 30% of women with mild disease, but progression is more common without treatment.
Long-term surveillance focuses on symptom control, fertility preservation when desired, and monitoring for rare complications like malignant transformation or organ dysfunction from deep disease.
ENDOMETRIOSIS symptoms: Dysmenorrhea, Dyspareunia, Dyschezia (the 3 D's)
Practice questions
1. A 28-year-old nulliparous woman presents with a 3-year history of severe pelvic pain that begins 2 days before menstruation and persists throughout her period. She also reports pain with deep intercourse and painful bowel movements during her periods. She has been trying to conceive for 18 months without success. Pelvic examination reveals a fixed, retroverted uterus and nodular tenderness along the uterosacral ligaments. Transvaginal ultrasound shows a 4 cm left ovarian cyst with homogeneous low-level echoes. What is the most appropriate next step in management?
2. A 32-year-old woman with laparoscopically confirmed stage II endometriosis presents for management. She has completed childbearing and desires definitive treatment for severe dysmenorrhea that has not responded to NSAIDs or combined oral contraceptives over the past 2 years. She reports missing work 3-4 days per month due to pain. Physical examination shows a normal-sized uterus and mild adnexal tenderness. What is the most appropriate management?
3. A 24-year-old woman presents with cyclic right-sided chest pain and shortness of breath that occurs with her menstrual periods for the past 6 months. She has a history of pelvic endometriosis diagnosed 2 years ago, currently managed with continuous combined oral contraceptives. Chest X-ray obtained during symptoms shows a small right-sided pneumothorax. After chest tube placement and resolution, what is the most likely diagnosis?
Frequently asked questions
What causes endometriosis?
The exact cause is unknown, but retrograde menstruation is the leading theory. Menstrual blood containing endometrial cells flows backward through fallopian tubes into the pelvis, where cells implant and grow. However, most women have retrograde menstruation but only some develop endometriosis, suggesting immune dysfunction, genetic factors, and hormonal influences also play roles. Risk factors include early menarche, short cycles, nulliparity, and family history.
What are the first symptoms of endometriosis?
The earliest symptom is typically progressively worsening menstrual cramps (dysmenorrhea) that begin in adolescence or early adulthood. Unlike normal period pain, endometriosis pain often starts before menstruation, lasts throughout the period, and does not respond well to over-the-counter pain relievers. Many women also experience pain with intercourse (dyspareunia) or painful bowel movements during their period. Some women have no symptoms and are only diagnosed when evaluated for infertility.
How is endometriosis diagnosed?
Definitive diagnosis requires laparoscopy (keyhole surgery) with biopsy to see and sample endometrial tissue outside the uterus. However, doctors can make a presumptive diagnosis based on symptoms and physical examination findings like nodular tenderness behind the uterus. Ultrasound or MRI can detect ovarian endometriomas (chocolate cysts) and deep disease, but cannot identify superficial implants. Many women are now treated based on symptoms alone without surgery, especially if they respond to hormonal therapy.
Is endometriosis curable?
Endometriosis is a chronic condition without a definitive cure. Medical treatments like hormonal contraceptives effectively control symptoms but do not eliminate the disease. Surgery to remove endometrial tissue can significantly improve pain and fertility but recurrence occurs in 20-40% of women within 5 years. Definitive surgery with hysterectomy and removal of both ovaries is the closest to a cure but is reserved for women who have completed childbearing. Symptoms typically improve naturally after menopause.
Endometriosis vs adenomyosis — what is the difference?
Endometriosis is endometrial-like tissue growing outside the uterus, most commonly on pelvic organs, while adenomyosis is endometrial tissue growing into the muscular wall of the uterus itself. Both cause pelvic pain and heavy periods, but adenomyosis typically presents with a diffusely enlarged, tender uterus and heavier menstrual bleeding, whereas endometriosis causes more dyspareunia and infertility. Adenomyosis is diagnosed by MRI or ultrasound; endometriosis requires laparoscopy. The two conditions can coexist in the same patient.
Key drugs
Related conditions and differentials
Sources and further reading
StatPearls (NCBI Bookshelf)MedlinePlusWHO ICD-10: N80
Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.