Endometriosis: Comprehensive Overview
Definition and Pathophysiology
Endometriosis is a chronic, estrogen-dependent inflammatory disease characterized by endometrial-like tissue located outside the uterine cavity, associated with inflammation and fibrosis, affecting approximately 10% of women of reproductive age worldwide. 1, 2
The disease should be understood as a systemic condition rather than merely a pelvic disorder, with multifactorial etiology including genetic predisposition, possible epigenetic modifications, and environmental exposure effects 3, 4
The tissue exhibits estrogen-dependence and progesterone resistance, creating a hormonal imbalance that perpetuates disease activity 3, 5
Endometriosis has proliferative characteristics with chronic inflammatory features that extend beyond the pelvis, affecting metabolism in liver and adipose tissue, causing systemic inflammation, and altering gene expression in the brain that leads to pain sensitization and mood disorders 3, 4
Deep infiltrating endometriosis (DIE) is specifically defined as lesions extending deeper than 5 mm beneath the peritoneal surface or involving/distorting the bowel, bladder, ureter, or vagina 1, 3, 6
The disease originates from eutopic endometrial tissue that reaches the abdominal cavity primarily via retrograde menstruation through the uterine tubes, with DNA evidence supporting this mechanism 7
Epidemiology
Endometriosis affects approximately 10% of women of reproductive age globally, representing an estimated 176 million women worldwide 1, 3, 6, 2
The disease impacts 9 million women in the United States alone 2
Approximately 50% of patients with endometriosis experience infertility, making it a major cause of reproductive dysfunction 1, 3, 6
The annual economic burden is estimated at $69.4 billion in the United States, comparable to other major chronic diseases such as type 2 diabetes, Crohn's disease, and rheumatoid arthritis 1, 6
Clinical Presentation
Pelvic pain is the most common symptom, reported by 90% of patients with endometriosis, though clinical presentation ranges from asymptomatic to severe symptoms that significantly interfere with daily activities. 1, 2
Pain Manifestations
Dysmenorrhea (painful menstruation) is the hallmark symptom 1, 8, 6, 2
Deep dyspareunia (painful intercourse) occurs frequently 1, 8, 6, 2
Sacral backache with menses represents the third classic pain pattern 8, 6
Dyschezia (painful bowel movements) indicates possible bowel involvement 1, 6
Dysuria (painful urination) suggests bladder or urinary tract involvement 1, 3, 6
Chronic non-menstrual pelvic pain lasting at least six months outside the menstrual cycle indicates possible endometriosis etiology 8
Important Clinical Correlations
The depth of endometriosis lesions correlates with pain severity, but pain has little relationship to the type of lesions seen at laparoscopy 8
Symptom severity does not correlate with anatomical extent of disease—the r-ASRM staging system shows very poor correlation with pain and quality of life 3, 6
Infertility is reported by 26% of patients and represents a major clinical concern 2
Menorrhagia (heavy menstrual bleeding) may occur depending on lesion location 1, 6
Systemic Manifestations
The disease is associated with hypercholesterolemia, hypertension, and increased cardiovascular disease risk 8
Patients have a 16-34% increased risk of stroke 8
Endometriosis can rarely persist or recur in postmenopausal individuals not receiving hormone therapy, suggesting maintenance by mechanisms beyond estrogen dependence 8
Diagnostic Approach
Expanded-protocol transvaginal ultrasound (TVUS) performed by clinicians trained in endometriosis imaging is the first-line diagnostic modality for identifying and mapping deep infiltrating lesions. 1, 6
Imaging Modalities
Transvaginal Ultrasound (First-Line)
Expanded protocol TVUS includes evaluation of the uterosacral ligaments, anterior rectosigmoid wall, appendix, and diaphragm—structures not part of standard female pelvic ultrasound 1
Dynamic sliding maneuvers to evaluate organ mobility are performed during the examination 1
Bowel preparation or enema is typically performed before imaging for optimal detection and characterization of bowel lesions 1
Competency requires performance of at least 40 examinations, indicating a significant learning curve 1, 6
Some protocols include 3-D ultrasound imaging and saline contrast sonovaginography 1
MRI (Alternative/Complementary)
MRI serves as an alternative imaging modality when ultrasound is incomplete or indeterminate 6
For adenomyosis (a related condition), MRI provides sensitivity of approximately 78% and specificity of approximately 93% 6
MRI can distinguish adenomyosis from uterine leiomyomas when ultrasound findings are inconclusive 6
Diagnostic Limitations and Pitfalls
Normal physical examination and imaging do not exclude the diagnosis of endometriosis 2
Diagnosis is often delayed by 5 to 12 years after onset of symptoms, with most women consulting 3 or more clinicians prior to diagnosis 2
Serum CA-125 measurement has limited diagnostic utility, particularly for minimal or mild disease 6
Histologic confirmation of endometrial lesions remains the gold standard for definitive diagnosis, especially for atypical-appearing lesions 6
Historically, diagnosis required diagnostic laparoscopy with histologic inspection, but preoperative imaging is now supported because it is associated with decreased morbidity and mortality and reduces the need for repeat surgeries 1
Classification Systems
The American Society for Reproductive Medicine recommends using a "classification toolbox" that combines the revised ASRM (r-ASRM) surgical staging, the Enzian system for deep infiltrating disease, and the Endometriosis Fertility Index (EFI) when fertility outcomes are a clinical priority. 3, 6
r-ASRM Classification
The r-ASRM classification assigns points for extent and density of adhesions affecting the ovaries and fallopian tubes, peritoneal implant size/location, and ovarian endometrioma size 3
Stage IV is defined as total score >40 3
Critical limitation: r-ASRM shows very poor correlation with pain severity, quality of life, fertility outcomes, and treatment response 1, 3, 6
The system inadequately describes deep infiltrating endometriosis involving bowel, bladder, ureter, or vagina 1, 3, 6
Anatomical extent does not predict surgical difficulty or outcomes—the stage IV label should not be interpreted as indicating more severe pain or higher infertility risk 3
The r-ASRM system remains prevalent because of historical longevity and extensive citation in medical literature 3
Enzian Classification
The Enzian system should be applied alongside r-ASRM when deep infiltrating endometriosis is present to provide comprehensive operative description 1, 3, 6
The system maps deep infiltrating lesions across compartments: A (vagina/rectovaginal septum), B (uterosacral ligaments/parametria), C (rectum), and additional sites including bladder (FB), ureters (FU), and other intestinal locations (FI) 3
Criteria for use: any deep infiltrating lesions extending >5 mm beneath the peritoneum or involving bowel, bladder, ureter, or vaginal structures 3
Limitation: The Enzian system has limited correlation with symptom severity and infertility, offering modest prognostic value for clinical outcomes 3
Endometriosis Fertility Index (EFI)
The EFI is a validated prognostic instrument for postoperative fertility 3, 6
It incorporates key clinical variables that influence pregnancy likelihood independently of the presence of endometriosis 3
The EFI is specifically designed for predicting fertility outcomes following surgical staging 1, 6
Management
First-Line Medical Therapy
Hormonal medications—including combined oral contraceptives and progestin-only options—are first-line treatment and should be offered to all symptomatic premenopausal women who do not currently desire pregnancy. 8, 2
Hormonal Treatment Options
Combined oral contraceptives, progestins, and GnRH agonists all lead to clinically significant pain reduction compared with placebo, with mean differences ranging between 13.15 and 17.6 points on a 0-100 visual analog scale, with little difference in effectiveness among options 2
Oral norethindrone 0.35 mg daily or depot medroxyprogesterone acetate are effective alternatives to combined oral contraceptives, with similar efficacy but without estrogen-related stroke risk 8
Progestin therapy reduces menstrual blood loss while managing endometriosis symptoms 8
NSAIDs provide additional pain relief and can be used in combination with hormonal therapies 6
Treatment Limitations
11% to 19% of individuals have no pain reduction with hormonal medications 2
25% to 34% experience recurrent pelvic pain within 12 months of discontinuing hormonal treatment 2
Progestins and oral contraceptives are unsuccessful in approximately one-third of symptomatic women globally, probably due to progesterone resistance 4
Medical therapies reduce lesion size and alleviate pain but do not eradicate endometriotic implants 6
Second-Line Medical Therapy
GnRH agonists for at least 3 months provide significant pain relief and are appropriate for chronic pelvic pain, even without surgical confirmation of endometriosis. 8, 6
GnRH agonist therapy for ≥3 months or danazol therapy for ≥6 months provides comparable pain relief 6
Add-back therapy with low-dose estrogen/progestin must be implemented when using GnRH agonists long-term to mitigate bone mineral loss without diminishing analgesic efficacy 8, 6
Oral GnRH antagonists constitute an effective and tolerable therapeutic alternative when first-line medications fail, with fewer side effects than other therapies 4
Third-Line Medical Therapy
- Aromatase inhibitors represent third-line treatment options 2
Surgical Management
Surgical excision of endometriotic lesions by an experienced specialist is considered the definitive treatment and should be considered if first-line hormonal therapies are ineffective or contraindicated. 1, 8, 2
Surgical Indications
Surgery is indicated when empiric medical therapy is ineffective, immediate diagnosis is necessary, or the patient desires pregnancy 8
Laparoscopic removal of lesions is the standard surgical approach 2
Surgical Outcomes and Limitations
Surgery provides significant pain reduction during the first six months 8
Up to 44% of women experience symptom recurrence within one year after surgical excision 8, 6
Approximately 25% of patients who undergo hysterectomy for endometriosis experience recurrent pelvic pain 2
10% of hysterectomy patients undergo additional surgery (such as lysis of adhesions) to treat pain 2
Preoperative imaging is associated with decreased morbidity and mortality and reduces the need for repeat surgeries by reducing incomplete surgeries 1
Hysterectomy Considerations
- Hysterectomy with surgical removal of lesions may be considered when initial medical treatments and surgical removal of lesions are ineffective 2
Fertility Management
Current evidence does not demonstrate that either medical or surgical treatment improves subsequent fertility outcomes 6
Infertility is often managed using in vitro fertilization, which improves embryo quality and alters endometrial development 7
Cardiovascular Risk Management
Screening for a history of endometriosis is reasonable to inform stroke risk assessment, and vascular risk factor evaluation and modification are reasonable to reduce stroke risk in individuals with endometriosis. 8
Patients should be evaluated for hypercholesterolemia, hypertension, and cardiovascular disease risk factors 8
The 16-34% increased stroke risk warrants systematic cardiovascular risk assessment 8
Common Pitfalls to Avoid
Do not assume symptom severity correlates with anatomical extent of disease—r-ASRM staging has very poor correlation with pain and quality of life 3, 6
Do not overlook deep infiltrating disease when using standard classification systems—supplement r-ASRM with Enzian classification when DIE is suspected 3, 6
Do not rely on normal physical examination or imaging to exclude endometriosis—the diagnosis can still be present 2
Do not use serum CA-125 as a primary diagnostic tool—it has limited utility, especially for minimal or mild disease 6
Do not assume surgical treatment will prevent recurrence—up to 44% experience symptoms within one year 8, 6
Do not expect medical or surgical treatment to improve fertility outcomes—current evidence does not support this expectation 6