Endometriosis

• Retrograde Menstruation and Stem Cell Dysfunction: The primary mechanism involves reflux of menstrual endometrium through patent fallopian tubes into the peritoneal cavity (occurs in ~90% of menstruating women). However, normal clearance mechanisms fail in susceptible individuals due to reduced peritoneal natural killer (NK) cell activity, impaired macrophage function, and defective apoptosis of ectopic endometrial cells. Bone marrow-derived stem cells abnormally home to ectopic lesions and transdifferentiate into endometrial-like tissue, establishing self-perpetuating foci. Increased expression of stem cell factor (SCF) and its receptor (c-KIT) in endometriosis tissue promotes this pathologic neovascularization and lesion establishment.

• Estrogen Biosynthesis and Local Production: Ectopic endometrial tissue exhibits dramatically increased local estrogen synthesis independent of ovarian production through multiple mechanisms. Aberrant expression of aromatase (CYP19A1) in stromal fibroblasts and immune cells converts androstenedione to estrone and androstenediol to estradiol locally within lesions. Simultaneously, endometriosis tissue demonstrates reduced expression of 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2), the enzyme responsible for inactivating estradiol to estrone. Aberrant prostaglandin synthesis via upregulated cyclooxygenase-2 (COX-2) stimulates aromatase expression through cAMP/protein kinase A signaling, creating a self-amplifying estrogen production loop. These alterations result in local estradiol concentrations 10-fold higher than in eutopic endometrium, driving proliferation of ectopic lesions while rendering them responsive to lower systemic estrogen levels. This explains efficacy of aromatase inhibitors and the disease's dependence on estrogen despite normal serum hormone levels.

• Progesterone Resistance: A cardinal feature of endometriotic lesions is their functional progesterone resistance despite normal or elevated progesterone receptor expression. This resistance occurs through multiple mechanisms: (1) selective loss of progesterone receptor B isoform relative to receptor A, altering the normal 1:1 ratio that mediates optimal decidualization; (2) impaired recruitment of coactivator proteins and altered histone acetylation at progesterone response elements; (3) increased expression of progesterone receptor isoforms that lack DNA-binding capacity; and (4) enhanced Wnt/β-catenin signaling that antagonizes progesterone action. Consequently, endometrial epithelial cells fail to undergo normal progesterone-induced differentiation and instead proliferate. This explains the reduced efficacy of progestin-only contraceptives in some endometriosis patients and provides rationale for combining therapies with different mechanisms (e.g., combined oral contraceptives plus GnRH agonists).

• Chronic Inflammation and Altered Immune Tolerance: The peritoneal fluid of women with endometriosis contains dramatically elevated concentrations of pro-inflammatory cytokines (IL-6, IL-8, TNF-α, MCP-1) and growth factors (VEGF, FGF, TGF-β) that exceed levels in non-affected women 10-100 fold. Macrophage infiltration into lesions is enhanced, with M1 (pro-inflammatory) macrophages predominating in early lesions and shifting toward M2 (anti-inflammatory, pro-fibrotic) phenotype in established lesions, contributing to progression. Natural killer cell dysfunction manifests as reduced killing capacity, decreased CD56+ cell numbers, and impaired interferon-gamma production, allowing ectopic endometrial cell survival and proliferation. B and T cell abnormalities include elevated autoreactive B cells, reduced regulatory T cells (Tregs), and altered Th1/Th2 balance favoring Th2 responses. T cell exhaustion markers are paradoxically elevated despite relatively low T cell infiltration. This immune tolerance to ectopic endometrium parallels mechanisms of tumor immune evasion and may contribute to the small but real increased risk of ovarian cancer (particularly clear cell and endometrioid subtypes) associated with long-standing endometriosis.

• Angiogenesis and Lymphangiogenesis: Endometriosis requires and actively promotes new blood vessel formation through hypoxia-inducible factor-1α (HIF-1α)-mediated upregulation of vascular endothelial growth factor (VEGF). This increased angiogenesis is paradoxically inefficient, resulting in functionally abnormal, leaky vessels with poor pericyte coverage that contribute to continued bleeding and inflammation. Lymphangiogenesis also occurs with elevated expression of lymphatic endothelial growth factors, facilitating immune cell infiltration. Enhanced neovascularization combined with aberrant lymphatic drainage creates a self-perpetuating cycle of lesion vascularization and immunological recruitment.

• Neuroangiogenesis and Neuropathic Pain: Endometriotic lesions exhibit abnormally dense innervation by sensory nerve fibers (substance P, CGRP-expressing neurons) and sympathetic nerve terminals, with nerve density correlating with pain severity. Nerve fiber infiltration is mediated by increased NGF and neurotrophin expression by lesional macrophages and endothelial cells. Aberrant β3-adrenergic signaling impairs sympathetic nerve-mediated suppression of inflammation, and loss of normal neuropeptidergic feedback allows unchecked neurogenic inflammation. These mechanisms explain the often-severe and sometimes intractable pelvic pain and the potential efficacy of treatments targeting pain pathways independently of hormonal effects.

• Epigenetic Modifications: Endometrial cells in endometriosis patients demonstrate altered DNA methylation patterns, including hypomethylation of the aromatase gene promoter (increasing aromatase expression), altered HOXA10 methylation (impairing endometrial receptivity), and dysregulation of numerous growth and differentiation genes. Histone modifications and microRNA dysregulation further alter gene expression without changing DNA sequences. These epigenetic changes are thought to be both causes and consequences of the endometriotic microenvironment and may explain why endometriosis can recur and progress despite surgical removal of visible lesions.

• Retrograde Menstruation (Sampson Theory): The leading mechanistic explanation involves reflux of viable endometrial cells and menstrual blood through patent fallopian tubes into the peritoneal cavity during menstruation. This occurs in the majority of menstruating women but only progresses to clinical endometriosis in those with impaired peritoneal clearance mechanisms. Higher retrograde menstrual flow (associated with uterine myometrial contractions) increases inoculum of ectopic cells. Factors increasing retrograde flow include early menarche, short menstrual cycles, heavy menstrual bleeding, and obstructing lesions (fibroids, cervical stenosis). This explains why endometriosis is rare in women with complete müllerian agenesis (no menstruation) despite having peritoneal cavities.

• Genetic and Familial Susceptibility: Family history is a significant risk factor; relatives of affected women have 5-10 fold increased prevalence. Twin studies demonstrate heritability estimates of 50%, indicating substantial genetic contribution. Somatic mutations in endometriotic lesions (particularly KRAS, PIK3CA, and PTEN) suggest clonal origin from single or limited endometrial precursor cells. Germline polymorphisms in genes encoding estrogen metabolism (CYP19, estrogen receptors), progesterone signaling, and immune function (HLA loci, IL-6, IL-10) are associated with increased risk. GWAS studies have identified multiple common variants of small individual effect distributed across numerous loci affecting immune, metabolic, and reproductive pathways.

• Menstrual/Reproductive Factors: Early age at menarche (<12 years) increases endometriosis risk through prolonged exposure to menstrual retrograde flow. Shorter menstrual cycles (<27 days) and longer duration of menstruation (>7 days) increase retrograde flow and lesion implantation opportunity. Nulliparity is a consistent risk factor, likely because pregnancy and lactation suppress ovulation and menstruation for extended periods. Conversely, each pregnancy reduces endometriosis risk, with protective effects strongest for early pregnancies. Conversely, infertility status itself increases risk, though causality is bidirectional (endometriosis impairs fertility, but infertility increases probability of diagnosis through investigation).

• Environmental Exposures: Dioxin and related environmental contaminants are implicated through animal models and observational human studies suggesting associations between dioxin exposure and endometriosis prevalence. Dioxins suppress immune function and enhance aromatase expression, plausibly increasing susceptibility. Polychlorinated biphenyls (PCBs) and other persistent organic pollutants demonstrate similar biologic plausibility. Evidence for other environmental factors remains controversial; claims regarding endometrial ablation effects, talc exposure, or specific dietary components lack conclusive supporting evidence.

• Adenomyosis as Related Condition: Adenomyosis (myometrial invasion of basalis layer endometrium) and endometriosis may represent manifestations of shared underlying pathophysiology affecting endometrial cells. Adenomyosis frequently coexists with peritoneal endometriosis and increases pain severity and infertility impact. Both conditions show similar molecular abnormalities (aberrant estrogen synthesis, progesterone resistance, inflammation), suggesting they may be variants of a common "endometrial disorder" spectrum rather than distinct diseases.

• Reduced Protective Factors: Factors that reduce menstrual flow and ovulatory frequency protect against endometriosis. Obesity appears paradoxically protective despite higher estrogen levels, possibly through alterations in immune tolerance. Regular exercise reduces endometriosis risk. These observations support the retrograde menstruation mechanism as contributory, though not exclusively causal.

• Dysmenorrhea (Painful Menses): The most common symptom, occurring in 60-80% of symptomatic women. Pain characteristically begins several days before menses and peaks during menstruation, though endometriosis-associated dysmenorrhea often persists after flow cessation (secondary dysmenorrhea), distinguishing it from primary dysmenorrhea due to excessive prostaglandin production in eutopic endometrium. The pain typically worsens progressively over years (in contrast to primary dysmenorrhea which may improve with age). Pathophysiology involves lesional hemorrhage, inflammatory cytokine release, heightened prostaglandin production, and neurogenic inflammation. Pain may be unilateral (suggesting ovarian involvement) or diffuse (suggesting peritoneal disease). Dysmenorrhea severity is one of the strongest predictors of deep infiltrating endometriosis, particularly when accompanied by other pain symptoms.

• Chronic Pelvic Pain (Non-menstrual): Occurs in 20-30% of women with endometriosis and often represents the most limiting symptom. Pain may be constant or episodic and occurs independent of menses, reflecting the chronic inflammatory state within lesions and peritoneal cavity. Neuropathic pain components may predominate, causing sharp, shooting, or burning sensations that respond poorly to NSAIDs. Pain severity correlates with neuronal infiltration density rather than lesion burden, suggesting mechanisms beyond simple tissue damage. Patients with non-menstrual pain report greater impact on activities of daily living and sexual function.

• Dyspareunia (Painful Intercourse): Reported by 25-40% of women with endometriosis, classified as superficial (introital pain on penetration) when anterior lesions are present or deep (pain with deep penetration) when posterior compartment or uteroligamentous involvement occurs. Superficial dyspareunia results from lesions in the bladder, urethra, or anterior peritoneum; deep dyspareunia from rectosigmoid involvement, uteroligamentous thickening, or adhesions restricting organ mobility. Sexual dysfunction extends beyond pain to include reduced frequency (due to pain anticipation), diminished arousal, and reduced satisfaction, significantly impacting quality of life and relationship functioning.

• Infertility: Endometriosis reduces fertility through multiple mechanisms: (1) mechanical obstruction of fallopian tubes by adhesions or lesions; (2) impaired oocyte quality through oxidative stress and altered growth factor signaling in the follicular microenvironment; (3) reduced endometrial receptivity due to altered gene expression and progesterone resistance; (4) impaired embryo implantation and increased early pregnancy loss; and (5) altered sperm-oocyte interaction through inflammatory cytokines and altered complement activation. Women with endometriosis have approximately 50% normal fecundity compared to fertile controls. Infertility may be the presenting complaint in asymptomatic or minimally symptomatic women discovered during fertility evaluation. Subfertility in endometriosis does not correlate with disease stage—women with minimal endometriosis experience comparable fertility reduction as those with severe disease.

• Dyschezia (Painful Defecation): Occurs in 20-30% of women with endometriosis, particularly in those with bowel involvement. Pain characteristically occurs during or after defecation and may be accompanied by blood in stool (hematochezia). The symptom is most suggestive of rectosigmoid endometriosis, where lesions infiltrate muscularis propria and submucosa. Severity worsens during menses as lesions bleed. May be accompanied by diarrhea or constipation depending on inflammatory load and fibrosis. This symptom carries significant prognostic value for deep infiltrating disease and warrants colorectal evaluation.

• Dysuria (Painful Urination): Reported by 10-15% of women when bladder or ureteral endometriosis occurs. May be accompanied by urinary frequency and urgency. Hematuria or hematuresis occurs when lesions erode into bladder mucosa. Ureteric involvement may cause flank pain (simulating nephrolithiasis) or hydronephrosis if significant stenosis develops. This symptom is less common than GI involvement but carries high specificity for endometriosis diagnosis when present.

• Physical Examination Findings: Palpable findings are neither sensitive nor specific but may include: (1) Uterosacral nodularity—induration or nodules palpable on rectovaginal exam, highly suggestive of deep infiltrating disease when present; (2) Restricted uterine mobility—fixed retroversion of uterus suggesting extensive pelvic adhesions; (3) Tender adnexal masses—ovarian endometriomas palpable as smooth, mobile masses typically tender to palpation; (4) Bluish vaginal nodules—occasionally visible on speculum exam when vaginal involvement occurs (rare). Many women with endometriosis have entirely normal physical exams, particularly in early disease or peritoneal-predominant disease. Palpable findings are more common in advanced/deep infiltrating disease and correlate better with symptom severity than laparoscopic lesion appearance.

• Important Clinical Variants: Asymptomatic endometriosis discovered incidentally at surgery or imaging occurs in 20-30% of women with disease, highlighting the discordance between pathology and symptoms. Adolescent endometriosis presents with severe dysmenorrhea unresponsive to NSAIDs in teenagers (often presumed to have primary dysmenorrhea initially

Initial evaluation

• History and pelvic/rectovaginal examination: cyclic pain pattern plus uterosacral nodularity or a fixed, retroverted uterus raises suspicion for deep infiltrating disease. A normal exam does not exclude endometriosis.
• Transvaginal ultrasound (first-line imaging): the initial test in a woman with pelvic pain or an adnexal mass. An endometrioma ("chocolate cyst") appears as a unilocular or paucilocular cyst with homogeneous low-level "ground-glass" internal echoes, no internal vascularity, and no solid papillary projections. Solid vascular components should redirect the workup toward malignancy.
• MRI: reserved for mapping deep infiltrating disease (rectovaginal septum, bowel, bladder, ureter) before surgery. Endometriomas are classically T1-hyperintense and T2-hypointense ("T2 shading") from chronic hemorrhage.
• CA-125: often modestly elevated in moderate-to-severe disease but nonspecific (elevated in fibroids, PID, pregnancy, ovarian cancer). ACOG does not endorse it for diagnosis or screening — a classic distractor.

Confirmatory testing

• Laparoscopy with histologic confirmation remains the gold standard. Visualized lesions include powder-burn/gunshot blue-black implants, red "flame" vesicular lesions, white fibrotic scarring, and peritoneal windows (Allen–Masters defects).
• Histology requires at least two of: endometrial glands, endometrial stroma, hemosiderin-laden macrophages.
• Importantly, ACOG and ASRM accept empiric medical therapy without laparoscopy in a patient with a compatible history once other causes are excluded; failure to respond prompts surgical evaluation. Laparoscopy purely to establish a diagnosis is no longer required.

Staging

• Revised ASRM (rASRM) classification, stages I–IV (minimal, mild, moderate, severe), scored intraoperatively by lesion size/depth, adhesion density, and cul-de-sac obliteration. Stage correlates poorly with pain but does predict surgical complexity.
• Endometriosis Fertility Index (EFI) is used post-operatively to counsel on spontaneous conception probability; the #ENZIAN system supplements rASRM for deep infiltrating disease.

First-line (ACOG)

• NSAIDs: naproxen or ibuprofen inhibit COX-mediated prostaglandin synthesis, targeting the prostaglandin excess that drives dysmenorrhea. Start with menses onset or just before.
• Combined hormonal contraceptives: any low-dose estrogen–progestin pill, patch, or ring, used continuously to induce amenorrhea and decidualize then atrophy ectopic implants. Continuous dosing is preferred over cyclic for pain control.
• Progestins: norethindrone acetate (FDA-approved for endometriosis), depot medroxyprogesterone acetate, or the levonorgestrel-releasing IUD. Useful when estrogen is contraindicated (migraine with aura, prior VTE, smoker ≥35).

Second-line escalation

• GnRH agonists: leuprolide produces pituitary downregulation and hypoestrogenism. Must be paired with add-back therapy (norethindrone acetate ± low-dose estrogen) to limit bone mineral density loss and vasomotor symptoms.
• GnRH antagonists: oral elagolix (and relugolix combination therapy) suppress gonadotropins without a flare; approved for moderate-to-severe endometriosis pain.
• Aromatase inhibitors: letrozole, combined with ovarian suppression, for refractory disease — rational given lesional aromatase overexpression.
• Danazol is effective but largely abandoned for androgenic effects (hirsutism, voice deepening) and is teratogenic.

Surgical management

• Laparoscopic excision or ablation of implants and adhesiolysis for pain refractory to medical therapy; ovarian cystectomy (excision of the cyst wall) is superior to drainage/fenestration for endometrioma recurrence, though it costs ovarian reserve.
• Hysterectomy with bilateral salpingo-oophorectomy plus excision of all visible disease is definitive but not curative and is reserved for women with completed childbearing.

Contraindicated / avoid

• Hormonal suppression does not improve fertility and delays conception — in the infertile patient, ASRM directs management toward surgery for selected disease or IVF, not medical suppression.
• Estrogen-containing methods in women with standard combined-contraceptive contraindications.
• Prolonged unopposed GnRH agonist therapy without add-back, particularly in adolescents accruing peak bone mass.

Disease-related

• Endometrioma rupture (emergency): spillage of hemosiderin-rich fluid causes chemical peritonitis — sudden severe unilateral pelvic pain, rebound, guarding, free fluid on ultrasound. Mimics ruptured ectopic; always check hCG.
• Ovarian torsion (emergency): an enlarged endometrioma acts as a lead point; presents with acute pain, nausea, and absent or diminished ovarian Doppler flow. Requires urgent laparoscopic detorsion.
• Adhesive disease and bowel obstruction (emergency when complete): repeated bleeding and fibrosis produce dense adhesions; rectosigmoid infiltration can cause stricture with obstipation, distension, and air–fluid levels.
• Ureteral obstruction and hydronephrosis: deep infiltrating disease along the uterosacral ligaments encases the ureter. Often silent, with insidious loss of renal function — a reason to image the urinary tract in deep disease.
• Infertility: from tubal distortion, oxidative follicular damage, and progesterone-resistant, poorly receptive endometrium.
• Thoracic endometriosis: catamenial pneumothorax or hemoptysis, characteristically right-sided, recurring with menses.
• Malignant transformation: a small absolute increase in clear cell and endometrioid ovarian carcinoma. Signal findings are a growing endometrioma with solid vascular mural nodules, especially postmenopausally.
• Central sensitization, chronic pain, and depression from sustained neuroangiogenesis and nociceptive input.

Treatment-related

• GnRH agonist/antagonist hypoestrogenism: vasomotor symptoms, vaginal atrophy, and bone mineral density loss — the reason add-back therapy is standard.
• Danazol: androgenic hirsutism, acne, irreversible voice deepening, dyslipidemia; teratogenic (virilization of a female fetus).
• Ovarian cystectomy: inadvertent removal of normal cortex lowers anti-Müllerian hormone and antral follicle count — critical counseling point before surgery in women desiring fertility.
• Operative injury: ureteral, bladder, and rectal injury during excision of deep disease; delayed presentation with urinoma, fistula, or peritonitis.
• Surgical menopause after bilateral oophorectomy, with accelerated bone and cardiovascular risk; residual disease can reactivate on unopposed estrogen therapy.

• Classic triad buzzwords: cyclic dysmenorrhea, dyspareunia, dyschezia plus infertility in a woman in her late 20s to 30s. Add uterosacral nodularity on rectovaginal exam and a fixed, retroverted uterus and the answer is endometriosis.
• Symptom severity does not correlate with rASRM stage. A stage I patient can be crippled by pain; a stage IV patient can be asymptomatic. Examiners test this discordance directly.
• Best next step in a classic stem is empiric therapy, not laparoscopy. ACOG endorses NSAIDs plus continuous combined hormonal contraceptives before surgical diagnosis; laparoscopy is reserved for treatment failure. Laparoscopy with histology is still the gold standard for confirmation — know the distinction between "gold standard" and "next best step."
• CA-125 is the trap. It rises in endometriosis but is neither sensitive nor specific and is never the diagnostic test of choice.
• Imaging signatures: endometrioma = unilocular cyst with homogeneous low-level "ground-glass" echoes and no internal vascularity on transvaginal ultrasound; MRI shows T2 shading. Solid vascular nodules → think clear cell or endometrioid ovarian carcinoma.
• The association most tested: long-standing endometriosis and clear cell / endometrioid ovarian carcinoma.
• Fertility pearl: hormonal suppression treats pain but does not treat infertility — it prevents conception. In the woman trying to conceive, the answer is surgical excision in selected cases or IVF, per ASRM.
• GnRH agonist pearl: always pair leuprolide with add-back norethindrone acetate to protect bone; expect an initial flare before downregulation.
• Distractors to separate: adenomyosis = diffusely enlarged, globular, boggy tender uterus with heavy bleeding and MRI junctional-zone thickening; primary dysmenorrhea = onset within 1–2 years of menarche, pain limited to the first days of flow, resolves with NSAIDs/OCPs; PID = fever, cervical motion tenderness, purulent discharge.