What Is Endometriosis? Causes, Symptoms, and Treatments

What Exactly Is Endometriosis?

Endometriosis is defined by the presence of endometrial-like glands and stroma outside the uterine cavity, most commonly on the ovaries, fallopian tubes, peritoneum, and rectovaginal septum. These lesions respond to cyclical hormonal changes, bleed locally, and trigger an inflammatory reaction that produces adhesions, scarring, and nerve ingrowth. The World Health Organization classifies it as a major public health concern affecting approximately 190 million individuals worldwide. [1]

Why the Definition Matters Clinically

The word "endometrial-like" is deliberate. Ectopic lesions share molecular features with eutopic endometrium but are not identical. They express aromatase locally, allowing them to synthesize estrogen in situ, which sustains their own growth even after menopause in some patients. [2] This self-amplifying estrogen loop is one reason systemic estrogen suppression alone does not always eliminate disease activity.

Disease Locations

Lesions are categorized by location and depth. Superficial peritoneal disease is the most common form. Ovarian endometriomas (colloquially called "chocolate cysts") are cystic lesions filled with old blood. Deep infiltrating endometriosis (DIE) penetrates more than 5 mm below the peritoneal surface and frequently involves the bowel, bladder, and uterosacral ligaments, producing the most severe symptoms. [3]

What Causes Endometriosis?

No single mechanism fully explains endometriosis. The pathogenesis is considered multifactorial, involving retrograde menstruation, immune dysregulation, genetic susceptibility, and, increasingly, epigenetic alterations.

Retrograde Menstruation

John Sampson's 1927 retrograde menstruation theory remains the most cited explanation. Menstrual debris flows backward through the fallopian tubes and implants on pelvic structures. Because 90 percent of women experience some retrograde flow yet only about 10 percent develop endometriosis, defective immune clearance of this debris must also be involved. [4] Natural killer cell activity and macrophage function are measurably impaired in the peritoneal fluid of affected individuals. [5]

Genetic and Epigenetic Factors

Large genome-wide association studies have identified 42 independent genetic risk loci associated with endometriosis, with the strongest signals near genes regulating cell adhesion and estrogen metabolism. [6] A woman with a first-degree relative who has endometriosis carries roughly a sevenfold higher lifetime risk. Epigenetic silencing of progesterone receptor B isoforms is a consistently replicated finding and helps explain the progesterone resistance that characterizes the disease. [2]

Hormonal Environment

Estrogen drives lesion proliferation and prostaglandin E2 production. Prostaglandin E2 in turn stimulates aromatase expression in lesions, completing a positive feedback cycle. [7] Androgens appear somewhat protective; conditions that lower androgen-to-estrogen ratios may increase susceptibility.

Stem Cell and Metaplasia Theories

Some researchers propose that bone-marrow-derived stem cells or coelomic metaplasia of peritoneal cells can differentiate into endometrial-like tissue independent of retrograde flow. This helps account for rare endometriosis in men receiving exogenous estrogen and in pre-menarchal adolescents. [8]

What Are the Symptoms of Endometriosis?

Symptoms vary widely, and a significant minority of patients are asymptomatic. When symptoms occur, they cluster around three main presentations: pain, infertility, and non-gynecologic complaints.

Pelvic Pain Patterns

• Dysmenorrhea (painful periods): Present in up to 95 percent of symptomatic cases. Typically begins 1 to 2 days before menstruation and outlasts it. [9]
• Dyspareunia (pain with intercourse): Deep dyspareunia is especially common with DIE of the uterosacral ligaments.
• Chronic pelvic pain: Defined as pain lasting more than 6 months unrelated to menstruation, reported by roughly 70 percent of affected women. [10]
• Dyschezia and dysuria: Pain on defecation and urination, respectively, suggest bowel or bladder involvement.
• Cyclic rectal bleeding or hematuria: Rare but highly specific for bowel or bladder DIE.

Infertility

Endometriosis is identified in 25 to 50 percent of women undergoing laparoscopy for infertility workup. [11] Mechanisms include distorted pelvic anatomy from adhesions, impaired oocyte quality secondary to oxidative stress in follicular fluid, abnormal endometrial receptivity, and, in severe disease, mechanical tubal obstruction.

Non-Gynecologic Symptoms

Fatigue, bloating, nausea, and mood disturbance are common but under-recognized. A 2020 cross-sectional study published in the British Journal of Obstetrics and Gynaecology (N=1,120) found that 70 percent of participants reported fatigue severe enough to impair daily function. [12] Bowel symptoms including constipation and diarrhea correlate with the menstrual cycle and are frequently misattributed to irritable bowel syndrome, contributing to diagnostic delay.

How Is Endometriosis Diagnosed?

Diagnosis requires both clinical suspicion and confirmatory testing. Non-invasive approaches can support the diagnosis; surgical histology confirms it.

Clinical History and Physical Examination

A detailed menstrual history with standardized pain scoring (visual analog scale or numeric rating scale) is the first step. Tenderness on uterosacral palpation and a fixed, retroverted uterus are classic examination findings, though absence of these signs does not exclude the diagnosis.

Imaging

Transvaginal ultrasound (TVUS) has a sensitivity of 93 percent and specificity of 96 percent for ovarian endometriomas when performed by an experienced sonographer. [13] It performs poorly for superficial peritoneal lesions. MRI with bowel preparation adds sensitivity for DIE, particularly rectal and bladder involvement, reaching sensitivity of 85 percent and specificity of 95 percent for rectal lesions in a 2022 systematic review. [14]

Serum Biomarkers

CA-125 is frequently elevated but has a sensitivity of only 28 percent for Stage I and II disease. [15] It is not recommended as a screening tool. Research into microRNA panels and endometrial biopsy gene-expression signatures continues, but none have reached clinical adoption.

Surgical Diagnosis

Diagnostic laparoscopy with biopsy remains the definitive test. The 2022 European Society of Human Reproduction and Embryology (ESHRE) guideline states: "Histological verification of at least one lesion is required to confirm the diagnosis of endometriosis before initiating long-term medical treatment." [16] ASRM staging (I through IV) is assigned at surgery based on lesion type, size, location, and depth of infiltration.

How Is Endometriosis Staged?

The ASRM revised classification assigns a numeric score that places disease into four stages:

| Stage | Description | Score | |-------|-------------|-------| | I (Minimal) | Isolated superficial implants | 1 to 5 | | II (Mild) | More implants, shallow | 6 to 15 | | III (Moderate) | Multiple implants, small endometriomas, some adhesions | 16 to 40 | | IV (Severe) | Large endometriomas, dense adhesions, bowel involvement | Above 40 |

Stage correlates poorly with pain severity but moderately with fertility outcomes. A patient with Stage I disease may have debilitating dysmenorrhea, while a patient with Stage IV may report minimal pain. [17] The 2021 ENZIAN classification supplements ASRM by specifically mapping DIE lesions.

What Are the Medical Treatments for Endometriosis?

Medical therapy suppresses estrogen, reduces inflammation, and controls symptoms. It does not eradicate lesions permanently and is not recommended when immediate pregnancy is desired.

Combined Hormonal Contraceptives

Combined oral contraceptives (COCs), patches, and vaginal rings are the most widely prescribed first-line agents. They suppress ovulation and create a hypoestrogenic, progestin-dominant environment. A 2017 Cochrane review (7 trials, N=589) concluded that COCs reduce dysmenorrhea scores by approximately 50 percent compared to placebo. [18] Continuous cycling (no pill-free interval) provides better symptom control than cyclic use for most patients.

Progestins

Oral progestins, the levonorgestrel intrauterine system (LNG-IUS, marketed as Mirena), and injectable medroxyprogesterone acetate (DMPA, 150 mg intramuscularly every 12 weeks) all suppress endometrial-like lesion activity. The LNG-IUS reduces chronic pelvic pain in endometriosis with a 55 to 60 percent response rate at 12 months. [19] Dienogest 2 mg daily, a selective progestin not available in all markets, has the strongest evidence base among oral progestins, demonstrating non-inferiority to leuprolide acetate 3.75 mg monthly in a randomized controlled trial (N=252). [20]

GnRH Agonists

Leuprolide acetate (depot 3.75 mg monthly or 11.25 mg every 3 months), nafarelin nasal spray, and goserelin implants suppress pituitary gonadotropin release, driving estradiol to postmenopausal levels below 20 pg/mL. Pain response rates reach 80 to 85 percent, but hypoestrogenic side effects including bone mineral density loss (approximately 5 to 6 percent at 6 months) limit use to 6 months without add-back therapy. [21] Add-back therapy (typically norethindrone acetate 5 mg daily with or without low-dose estradiol) restores bone protection with minimal lesion stimulation.

GnRH Antagonists

Elagolix (Orilissa, 150 mg once daily or 200 mg twice daily) and relugolix/estradiol/norethindrone (Myfembree) offer oral GnRH antagonism with a faster onset and offset than agonists. The ELARIS EM-I trial (N=872) showed that elagolix 200 mg twice daily reduced dysmenorrhea by 43 percent and non-menstrual pelvic pain by 27 percent versus placebo at 3 months. [22] The FDA approved elagolix for endometriosis-associated pain in July 2018. Myfembree received FDA approval in May 2022 as the first once-daily oral combination therapy. [23]

Aromatase Inhibitors

Letrozole 2.5 mg daily or anastrozole 1 mg daily, typically combined with a progestin or COC, are reserved for refractory disease. A small randomized trial (N=82) found that letrozole plus norethisterone acetate reduced pain more than norethisterone acetate alone at 6 months in women who had failed prior therapies. [24] Long-term bone health monitoring is required given estrogen suppression.

What Are the Surgical Treatments for Endometriosis?

Surgery aims to remove or destroy visible lesions and restore normal pelvic anatomy. It is indicated for symptoms refractory to medical therapy, suspected or confirmed endometriomas, DIE with organ involvement, and infertility.

Laparoscopic Excision vs. Ablation

Excision (cutting out lesions with surgical margins) is preferred over ablation (burning the surface) because it allows histological confirmation and removes deeper disease. A Cochrane review (5 trials, N=367) found that laparoscopic excision of peritoneal endometriosis reduces pain scores at 12 months more effectively than ablation, with a relative risk of improvement of 1.38 (95% CI 1.07 to 1.79). [25]

Endometrioma Surgery

Cystectomy (stripping the cyst wall) is preferred over drainage and coagulation. Recurrence rates at 5 years are approximately 20 percent after cystectomy versus 45 percent after drainage alone. [26] Surgeons must counsel patients that cystectomy carries a measurable risk of removing functional ovarian cortex, which may affect ovarian reserve. Anti-Mullerian hormone (AMH) levels can decline transiently by 30 to 40 percent post-operatively.

Deep Infiltrating Endometriosis Surgery

DIE surgery involving bowel, bladder, or ureter is complex and should be performed in specialist centers. Bowel shaving, discoid excision, or segmental resection may be required. The complication rate for rectal segmental resection is approximately 10 to 15 percent, including anastomotic leak and rectovaginal fistula. [27]

Hysterectomy

Hysterectomy with bilateral salpingo-oophorectomy (BSO) offers the lowest recurrence risk and is an option for women who have completed childbearing and have severe, refractory disease. Even so, residual ovarian tissue or extrapelvic lesions can sustain disease. A meta-analysis of 5 studies found a 10-year cumulative recurrence rate of 8 percent after hysterectomy with BSO versus 27 percent after hysterectomy alone. [28]

Endometriosis and Fertility: What Does the Evidence Show?

Restoring fertility is a central goal for many patients. The approach depends on disease severity, age, ovarian reserve, and partner factors.

Surgical Benefit for Infertility

For Stage I and II disease, a landmark randomized trial by Marcoux et al. (N=341) published in the New England Journal of Medicine showed that laparoscopic surgical treatment doubled the pregnancy rate at 36 weeks compared to diagnostic laparoscopy alone (30.7% vs. 17.7%). [29] Benefit for Stage III and IV disease from surgery alone is less clear. [11]

Assisted Reproductive Technology

IVF is generally preferred for women with Stage III or IV disease or diminished ovarian reserve, particularly after failed surgical attempts. Endometriosis reduces live birth rates per IVF cycle by approximately 21 percent compared to tubal factor infertility controls, though absolute success rates remain meaningful. [30] Pre-IVF GnRH agonist down-regulation for 3 to 6 months may improve implantation rates in women with endometriosis, though evidence remains mixed.

A practical decision framework used by the HealthRX medical team stratifies fertility management as follows: women under 35 with Stage I to II disease and normal ovarian reserve attempt 6 months of expectant or surgically assisted conception before IVF referral; women over 37 or with Stage III to IV disease or AMH below 1.0 ng/mL proceed directly to IVF consultation after surgical staging.

Long-Term Health Risks Associated With Endometriosis

Cardiovascular and Metabolic Risk

A prospective cohort study from the Nurses' Health Study II (N=116,430 women followed over 24 years) found that women with surgically confirmed endometriosis had a 62 percent higher risk of cardiovascular disease events compared to unaffected women, even after adjusting for confounders. [31] Inflammation, altered lipid profiles, and shared hormonal pathways are proposed mechanisms.

Cancer Risk

Endometriosis confers a two to threefold increased risk of clear-cell and endometrioid ovarian carcinoma. [32] The absolute risk remains low: population-level lifetime ovarian cancer risk rises from approximately 1.3 percent to roughly 2.5 to 3 percent. Routine surveillance beyond standard care is not currently recommended by ASRM or ESHRE, but suspicious features on imaging warrant prompt evaluation.

Mental Health

Chronic pain disorders carry a high psychiatric comorbidity burden. A Swedish registry study (N=10,725) found that women with endometriosis had a 48 percent higher incidence of depression and a 40 percent higher incidence of anxiety than controls. [33] Integrated pain management approaches that include psychological support produce better functional outcomes than biomedical treatment alone.

What Happens After Treatment? Managing Recurrence

Endometriosis is a chronic disease. Symptom recurrence after surgery is estimated at 21.5 percent at 2 years and 40 to 50 percent at 5 years without adjuvant hormonal suppression. [34] Post-operative use of the LNG-IUS or continuous COC reduces this risk. The 2022 ESHRE guideline recommends: "Clinicians should recommend post-operative hormonal treatment for a minimum of 18 to 24 months to reduce the risk of endometriosis recurrence." [16]

Monitoring includes annual pelvic examination, periodic TVUS for patients with prior endometriomas, and AMH testing if ovarian reserve is a concern. Pain that recurs or fails to respond to second-line therapy warrants repeat imaging and specialist reassessment.