How the points work: a randomised trial or a natural experiment counts 5, a large cohort or meta-analysis 4, a smaller cohort, case-control or primate study 3, ecological or animal work 2, mechanism, case series, history or review 1, a single case 0.5. Indirect evidence counts half. A theory is called strong above 15 points, moderate above 8, weak above 3.
1. Too many spills strong
Modern life quadrupled lifetime menstrual cycles (~100 → 400+) and each cycle seeds the pelvis; the clean-up capacity did not grow
What would prove it wrong: a large cohort finds no protective effect of pregnancy, breastfeeding or hormonal rest, or cycles-to-date does not predict diagnosis once age is held fixed
| For or against | Finding | Design | Source |
|---|---|---|---|
| for (5) | Placebo-controlled surgery trial: 80% improved after excision vs 32% after sham; and in women who had only the diagnostic look, disease PROGRESSED in 45% within 6–12 months, static in 33%, improved in 22% | rct | Abbott, Fertil Steril (2004) |
| for (4) | Nurses' Health Study II, 72,394 women: every extra 3 months of breastfeeding per pregnancy −8% risk; ≥36 months lifetime −40%; postpartum absence of periods explains a third to a half | cohort large | Farland, BMJ / Brigham (2017) |
| for (4) | Menstrual cycle length ≤27 days → OR 1.22 (1.05–1.43) for endometriosis; cycles ≥29 days → OR 0.68 (11 case-control studies pooled); heavy and prolonged flow are classic risk factors | meta | Wei, Medicine meta-analysis (2016) |
| for (4) | Recurrence after endometrioma surgery falls steeply with age: 43.3% at 20–29, 22.5% at 30–39, 10.2% at 40–45 (meta-analysis of 3,125 patients) | meta | Arch Gynecol Obstet meta-analysis (2020) |
| for (4) | Meta-analysis of 154 studies, 20,718 patients, 29 countries: pelvic lesions favour the LEFT side and thoracic/inguinal lesions the RIGHT, matching two anatomical recesses sheltered from peritoneal fluid flow (left hemipelvis behind the sigmoid; right upper abdomen under the diaphragm) | meta | Human Reproduction Open, anatomical recesses meta-analysis (2026) |
| for (4) | In adolescent girls investigated by laparoscopy, 62% (543/880) had visually confirmed endometriosis; 75% (237/314) among those with pelvic pain resistant to treatment. The review warns the figure may overestimate prevalence because of the quality of the included papers. | meta | systematic review, adolescent laparoscopy (2013) |
| for (3) | Captive baboons: 11% had endometriosis when caught <1 yr ago, 17% at 1–2 yrs, 32% after >2 yrs in captivity with no pregnancies; biopsy-proven 8% → 27% | primate | D'Hooghe, Acta Obstet Gynecol Scand (1996) |
| for (3) | Serial laparoscopies over 30 months show endometriosis in captive baboons is progressive | primate | D'Hooghe, Fertil Steril (1996) |
| for (3) | Spontaneous endometriosis occurs in baboons, rhesus and cynomolgus monkeys including wild-caught animals, and only in menstruating species | primate | rhesus macaque characterisation (2020) |
| for (2.5) | Post-surgical hormonal suppression: PRE-EMPT RCT (405 women) found long-acting progestogens and the combined pill both held ~40% pain improvement at 3 years, with fewer repeat surgeries on the long-acting arm | rct, indirect | PRE-EMPT, BMJ / HTA (2024) |
| for (2) | Dogon women of Mali: median 2 menstrual cycles per year, ~100 per lifetime, versus 400+ in industrialised countries | ecological | Strassmann, Behavioral Ecology (1996) |
| for (2) | Age at first period fell from ~16 in the mid-1800s West to ~12.5 by 2000 | ecological | J Pediatr Adolesc Gynecol (2016) |
| for (2) | Early-1800s American women had 7–8 live births; today under 2 | ecological | EH.net encyclopedia (2008) |
| for (2) | Prevalence rises with socioeconomic status in every racial group and is highest in high-income regions | ecological | disease mechanisms and health disparities review (2024) |
| for (2) | Indigenous African population: endometriosis in 0.9% of gynaecological specimens versus 2–10% prevalence in developed countries | ecological | African population study (2022) |
| for (1.5) | NSAIDs cut menstrual blood loss by about 30% (Cochrane), and women prescribed COX-2-selective painkillers had a lower endometriosis incidence than those on traditional NSAIDs (HR 0.77, 0.63–0.93) | cohort, indirect | Yonsei Med J cohort + Cochrane (2024) |
| for (1) | Retrograde menstruation occurs in over 90% of women but only ~10% develop the disease | review | Reprod BioMed Online review (2024) |
| for (1) | Adolescents with obstructed reproductive-tract anomalies: 46% had endometriosis at median age 13.5; lesions on the obstructed side in 97%; regression after repair variable | case series | obstructive anomalies series (2023) |
| for (1) | Menstrual effluent of patients carries a stem/progenitor survival program with inflammatory activation and matrix remodelling | mechanistic | menstrual effluent systematic review (2025) |
| for (1) | Spontaneous endometriosis is common in women, great apes and Old World monkeys, rare in New World monkeys; zoos contracept primates with the same progestins used in women, and the Species360 ZIMS database holds their medical records | ecological, indirect | Species360 ZIMS (2026) |
| for (1) | The spiny mouse (Acomys cahirinus) is the only menstruating rodent, discovered 2016: a cheap animal in which cycle count, chemicals, heat and bacteria could be tested against spontaneous disease | animal, indirect | Bellofiore, Front Reprod Health (2022) |
| for (1) | Peritoneal fluid circulates clockwise and pools at four anatomical sites (pouch of Douglas, right lower quadrant, left lower quadrant along the sigmoid, right paracolic gutter); these are the four commonest lesion sites; flow is slower and weaker on the left, where lesions predominate | mechanistic | Bricou/Chapron, Eur J Obstet Gynecol Reprod Biol (2008) |
| against (0.5) | Endometriosis in Mayer-Rokitansky-Küster-Hauser syndrome patients with no functional uterus | case report | MRKH case report (2015) |
2. Seeded before birth strong
Ectopic lining tissue is laid down in the womb in ~10% of female fetuses; what the mother and infant took in shapes it; adult estrogen lights the fuse
What would prove it wrong: prenatal and infant exposures show no association in a prospective cohort, or fetal ectopic tissue is shown not to persist to adulthood
| For or against | Finding | Design | Source |
|---|---|---|---|
| for (4) | Daughters exposed to DES in the womb: +80% endometriosis incidence (NHS II); 2020 meta-analysis RR 1.65 | cohort large | Missmer, Fertil Steril (2004) |
| for (4) | NutriNet-Santé, 25,251 women: maternal smoking during pregnancy → aOR 1.86 (1.33–2.61) for endometriosis/adenomyosis; low birth weight aOR 1.43; daycare attendance aOR 1.61 | cohort large | NutriNet-Santé, Sci Total Environ (2025) |
| for (4) | Meta-analysis of 11 studies: low birth weight (<2.5 kg) → pOR 1.26 (1.05–1.52); preterm birth → pOR 1.32 (1.01–1.72) for adult endometriosis | meta | Brønd, Acta Obstet Gynecol Scand (2023) |
| for (4) | 2020 meta-analysis of six studies (2,360 cases): prematurity, low birthweight, formula feeding and DES exposure in utero each raise adult endometriosis risk; DES logRR 0.65 (RR ~1.9) | meta | Gao, Reprod BioMed Online (2020) |
| for (4) | In adolescent girls investigated by laparoscopy, 62% (543/880) had visually confirmed endometriosis; 75% (237/314) among those with pelvic pain resistant to treatment. The review warns the figure may overestimate prevalence because of the quality of the included papers. | meta | systematic review, adolescent laparoscopy (2013) |
| for (3) | Regular soy-formula feeding in infancy: adjusted OR 2.4 (1.2–4.9); prematurity OR 1.7 | case control | Upson, Fertil Steril (2015) |
| for (1.5) | Soy-fed infant girls show estrogen-responsive epigenetic changes in vaginal cells | cohort, indirect | IFED study, Environ Health Perspect (2017) |
| for (1.5) | Prenatal paracetamol (acetaminophen/Tylenol) exposure: daughters had smaller ovaries, fewer follicles and smaller uteri in infancy (COPANA cohort, 2026); animal models show reduced ovarian reserve at human-relevant doses | cohort, indirect | COPANA, Hum Reprod Open (2026) |
| for (1) | Ectopic endometrium found in 9–11% of 101 female fetuses at autopsy | case series | Signorile, J Exp Clin Cancer Res (2012) |
| for (1) | Neonatal uterine bleeding (occult in most newborns, overt in ~5%) may seed the pelvis with stem cells before menarche | mechanistic | Brosens, Hum Reprod (2013) |
| for (1) | Two-thirds of women diagnosed with endometriosis in adulthood presented with symptoms before age 20 (1998 Endometriosis Association survey of 3,680 US members with surgically diagnosed disease, as summarised in a 2020 review) | review | review citing Sinaii 2002 / Endometriosis Association survey (2020) |
| for (0.5) | 38% of women with endometriosis started experiencing period pain before 15 years of age (American endometriosis registry, as cited by Endometriosis Australia) | case series, indirect | Endometriosis Australia adolescent page citing the American registry (2002) |
3. Partly a pain-wiring disease strong
Half of risk is inherited, and the genes overlap with migraine and chronic pain; some of what women suffer is nervous-system wiring, not lesion size
What would prove it wrong: pain-gene variants do not predict symptoms once lesion stage is held fixed
| For or against | Finding | Design | Source |
|---|---|---|---|
| for (4) | GWAS meta-analysis of 60,674 cases: 42 risk loci; heritability ~50%; genetic correlation with migraine, back pain, multisite chronic pain, asthma; pain-perception genes (NGF, BSN) | meta | Rahmioglu, Nature Genetics (2023) |
| for (4) | Nurses' Health Study II, 60,595 women: severe-chronic childhood physical and sexual abuse → 79% higher risk of laparoscopically confirmed endometriosis, dose-response by severity and type | cohort large | Harris, Hum Reprod (2018) |
| for (4) | Endometriosis polygenic risk interacts with comorbidities: the risk conferred by fibroids, heavy bleeding, IBS or asthma depends on genetic risk (UK and Estonian biobanks) | cohort large | HGG Advances (2025) |
| for (3) | Central sensitisation (a pain system that amplifies ordinary signals) is present in 41% of women with endometriosis in a 285-woman study, 52% in a 2026 cross-sectional study, up to 75% in tertiary centres | case control | JMIG cross-sectional, 285 women (2022) |
| for (3) | A first-degree relative with endometriosis carries OR 7.2 (2.1–24.3) for the disease | case control | Moen, Acta Obstet Gynecol Scand (1993) |
| for (2) | Endometriosis is systemic: glial activation across the central nervous system in a mouse model; psychiatric and pain comorbidity in patients | animal | J Neuroinflammation (2023) |
| for (1.5) | A 24-symptom self-report questionnaire predicts endometriosis in the general population with 94% accuracy (machine learning) | case control, indirect | Scientific Reports (2023) |
| for (1.5) | Ziwig Endotest (109 salivary microRNAs + AI): 97.4% sensitivity, 93.5% specificity claimed; reimbursed in France at ~€800 for 25,000 patients in 100 hospitals under scrutiny for independence of evidence | case control, indirect | Ziwig / French HAS pathway (2025) |
| for (1.5) | Women with endometriosis and lower vagally-mediated heart-rate variability (a nervous system stuck in alarm) report more intense pelvic pain and higher perceived stress | case control, indirect | vmHRV and pain study (2021) |
| for (1) | Interstitial cystitis / bladder pain syndrome co-occurs with endometriosis in 15–78% of series; the non-bladder-centric phenotype clusters with fibromyalgia, IBS, vulvodynia, migraine | case series | IC/BPS cohort review (2024) |
| for (1) | Endometriotic lesions grow their own nerve supply (neuroangiogenesis) and lesion nerve-fibre density correlates directly with pain severity | mechanistic | Annual Review of Physiology (2011) |
4. The clean-up crew fails strong
The immune cells that should clear stray tissue are sluggish and the uterus lining itself is inflamed and progesterone-resistant; the body's own defence is part of the disease
What would prove it wrong: restoring NK-cell function or blocking the inflammatory program in a trial does not reduce lesion formation, or immune differences turn out to be consequences rather than precedents of disease
| For or against | Finding | Design | Source |
|---|---|---|---|
| for (4) | Endometriosis polygenic risk interacts with comorbidities: the risk conferred by fibroids, heavy bleeding, IBS or asthma depends on genetic risk (UK and Estonian biobanks) | cohort large | HGG Advances (2025) |
| for (3) | Large case-control of 10 autoimmune diseases: higher odds of autoimmune conditions in women with endometriosis | case control | npj Women's Health (2025) |
| for (3) | Allergies in 61% of women with endometriosis vs 18% of the general population; asthma 12% vs 5%; higher rates of lupus, Sjögren's, RA, MS, fibromyalgia, chronic fatigue | case control | Sinaii, Hum Reprod (2002) |
| for (3) | Nickel allergy is a risk factor for endometriosis: 11-year population-based nested case-control, adjusted OR 2.47; 90% of GI-symptomatic patients tested nickel-sensitive and a low-nickel diet reduced pain in an uncontrolled pilot | case control | Taiwan NHI case-control (2015) |
| for (2) | AI target discovery found ITGB2; lifitegrast, an approved dry-eye drug, suppressed lesion growth in mice | animal | Liu / Insilico, Advanced Science (2024) |
| for (2) | Endometriosis raises later melanoma risk (RR 1.62) and is associated with red hair, nevi and sun-sensitive skin in French and US cohorts; no genetic correlation with pigment traits found | cohort large, indirect | Kvaskoff, E3N cohort (2009) |
| for (1.5) | Thyroid: autoimmune hypothyroidism associated with endometriosis; thyroid hormones change lesion size in mice; causality uncertain by Mendelian randomisation | case control, indirect | Peyneau, PNAS (2019) |
| for (1.5) | Swedish register: women with celiac disease had markedly higher endometriosis risk (11,000 patients); 75% of 207 women on a gluten-free diet reported less pain (uncontrolled) | case control, indirect | gluten-free diet evidence review (2024) |
| for (1) | Retrograde menstruation occurs in over 90% of women but only ~10% develop the disease | review | Reprod BioMed Online review (2024) |
| for (1) | Natural killer cells in the pelvis of patients show reduced cytotoxicity, immature phenotypes and immunosuppressive cytokines | mechanistic | NK dysfunction review (2025) |
| for (1) | Progesterone resistance in both lesions and the uterine lining of patients; inflammation and lost progesterone signalling reinforce each other | mechanistic | Int J Mol Sci review (2023) |
| for (1) | Heat-shock protein Hsp70 elevated in blood of biopsy-proven patients; small HSPs in pelvic fluid; Hsp60 provokes TNF-α from pelvic immune cells | mechanistic | Int J Mol Sci (2024) |
| for (1) | Single-cell atlas of 466,371 cells from 60 donors: the uterine lining of patients runs inflammation, adhesion and blood-vessel programs, macrophages pivotal; an 11-gene signature predicts disease (AUC 0.83) | mechanistic | Nature Communications (2026) |
5. The uterus injures itself strong
A self-perpetuating mechanical loop: uterine hyper-contraction → micro-injury at the lining–muscle border → local estrogen → more contraction; obstructed outflow forces the same thing
What would prove it wrong: girls with obstructed outflow do not get the disease more often, or blocking uterine peristalsis does not reduce new lesions
| For or against | Finding | Design | Source |
|---|---|---|---|
| for (4) | Cesarean delivery → 80% higher later endometriosis diagnosis (HR 1.8, 1.7–1.9) in Swedish registers; C-section after endometriosis surgery → 2.25x recurrence | cohort large | Swedish registers / recurrence cohort (2013) |
| for (3) | After hysterectomy for endometriosis, keeping the ovaries carried a six- to eight-fold higher chance of another operation (62% recurrence vs 10% with ovaries removed in one series) | cohort | Shakiba 2008 via Hum Reprod Update (2021) |
| for (2) | Ontario, 83,787 patients: 80% were operated on by low-volume surgeons (≤6 endometriosis cases a year); highest-volume surgeons had the lowest complication rate (5.5%) and lower re-operation (aHR 0.84) | cohort large, indirect | JMIG population cohort (2025) |
| for (1.5) | COX-2-selective painkillers associated with lower endometriosis incidence than traditional NSAIDs, especially at ages 20–44 | cohort, indirect | Yonsei Med J cohort (2024) |
| for (1.5) | Deep-learning multi-sequence MRI model detects endometriosis at human-reader level (AUROC 0.911, sensitivity 0.976, specificity 0.72); radiologists improve from 84% to 88% sensitivity with AI | case control, indirect | deep-learning MRI model (2025) |
| for (1) | Endometriotic lesions over-express aromatase and make their own estrogen; aromatase inhibitors treat the disease | mechanistic | Reprod Biol Endocrinol (2011) |
| for (1) | Adolescents with obstructed reproductive-tract anomalies: 46% had endometriosis at median age 13.5; lesions on the obstructed side in 97%; regression after repair variable | case series | obstructive anomalies series (2023) |
| for (1) | Tissue-injury-and-repair (TIAR) mechanism: hyperperistalsis injures the lining–muscle border, injury induces local estradiol, estradiol drives more peristalsis | mechanistic | Leyendecker, Arch Gynecol Obstet (2022) |
| for (1) | Progesterone resistance in both lesions and the uterine lining of patients; inflammation and lost progesterone signalling reinforce each other | mechanistic | Int J Mol Sci review (2023) |
| for (1) | Single-cell atlas of 466,371 cells from 60 donors: the uterine lining of patients runs inflammation, adhesion and blood-vessel programs, macrophages pivotal; an 11-gene signature predicts disease (AUC 0.83) | mechanistic | Nature Communications (2026) |
| for (0.5) | VEGF-driven blood-vessel growth is central to lesion establishment; 31 studies of anti-angiogenic agents (5 early human) show lesion regression signals; one bevacizumab case had complete resolution of refractory pain | review, indirect | network meta-analysis, anti-VEGF (2026) |
6. Something ingested strong
A medication or something eaten is causing it; true for estrogenic drugs (DES in the womb, estrogen therapy in men) and infant soy formula; no evidence for common non-hormonal drugs
What would prove it wrong: pharmacoepidemiology finds no drug class beyond hormonal ones with a replicated association after adjusting for indication
| For or against | Finding | Design | Source |
|---|---|---|---|
| for (4) | Daughters exposed to DES in the womb: +80% endometriosis incidence (NHS II); 2020 meta-analysis RR 1.65 | cohort large | Missmer, Fertil Steril (2004) |
| against (4) | Meta-analysis: current pill use lowers apparent risk, past use raises it; likely reverse causation (painful periods get the pill first) | meta | Vercellini, Hum Reprod Update (2011) |
| for (4) | Red meat >2 servings/day → 56% higher endometriosis risk in 81,908 nurses (95% CI 1.22–1.99); poultry, fish, eggs unrelated | cohort large | Yamamoto, Am J Obstet Gynecol (2018) |
| for (4) | 2020 meta-analysis of six studies (2,360 cases): prematurity, low birthweight, formula feeding and DES exposure in utero each raise adult endometriosis risk; DES logRR 0.65 (RR ~1.9) | meta | Gao, Reprod BioMed Online (2020) |
| for (3) | Regular soy-formula feeding in infancy: adjusted OR 2.4 (1.2–4.9); prematurity OR 1.7 | case control | Upson, Fertil Steril (2015) |
| for (3) | Nickel allergy is a risk factor for endometriosis: 11-year population-based nested case-control, adjusted OR 2.47; 90% of GI-symptomatic patients tested nickel-sensitive and a low-nickel diet reduced pain in an uncontrolled pilot | case control | Taiwan NHI case-control (2015) |
| for (1.5) | Prenatal paracetamol (acetaminophen/Tylenol) exposure: daughters had smaller ovaries, fewer follicles and smaller uteri in infancy (COPANA cohort, 2026); animal models show reduced ovarian reserve at human-relevant doses | cohort, indirect | COPANA, Hum Reprod Open (2026) |
| for (0.5) | Endometriosis in men on long-term estrogen therapy for prostate cancer (bladder, inguinal, paratesticular); symptoms resolve when estrogen stops | case report | Rei, Case Rep Obstet Gynecol (2018) |
7. An infection nobody looked for moderate
A mouth-and-gut bacterium (Fusobacterium) and gut-derived endotoxin in menstrual blood teach lining cells to scar and dig in; part of the disease may be treatable with antibiotics
What would prove it wrong: the Nagoya antibiotic trial shows no effect on lesions or symptoms, or the 64%-vs-7% finding fails to replicate in another population
| For or against | Finding | Design | Source |
|---|---|---|---|
| for (3) | Fusobacterium found in uterine tissue of 64% of endometriosis patients vs 7% of controls; in mice it converts fibroblasts to an invasive type and antibiotics prevent and shrink lesions | case control | Muraoka, Science Translational Medicine (2023) |
| for (3) | E. coli contamination of menstrual blood; endotoxin 4–6x higher in menstrual fluid of patients (285 vs 115 pg/mL) driving TLR4 inflammation | case control | Khan, Fertil Steril (2010) |
| for (2) | Gut bacteria are required for lesion growth in mice: broad-spectrum antibiotics shrank lesions ~5-fold, metronidazole alone did so, and faeces from diseased mice restored growth | animal | Chadchan, Hum Reprod (2019) |
| for (1.5) | Swedish register: women with celiac disease had markedly higher endometriosis risk (11,000 patients); 75% of 207 women on a gluten-free diet reported less pain (uncontrolled) | case control, indirect | gluten-free diet evidence review (2024) |
| for (0.5) | The same bacterium, F. nucleatum, drives colorectal cancer and ulcerative colitis via the mouth-to-gut axis | mechanistic, indirect | oral–gut axis review (2025) |
8. Heat inside the body moderate
A temperature or thermal-stress disturbance is involved; 1980s work found a distinctive basal-temperature signature, and heat-shock (cell stress) proteins are raised, but no evidence yet that heat causes the disease
What would prove it wrong: wearable night-time temperature in thousands of women shows no difference between those with and without the disease after matching cycle phase
| For or against | Finding | Design | Source |
|---|---|---|---|
| for (2.5) | Melatonin RCT: daily pain −39.8%, dysmenorrhea −38%; a 2025 triple-blind RCT (n=80) found large effects on pelvic pain and sleep | rct, indirect | Schwertner, Pain (2013) |
| for (2.5) | Cryotherapy (local cold) for primary dysmenorrhea: pain fell from 7.1 to 1.8 vs 5.9 to 5.4 with usual care in a 2026 RCT; heat is the traditional remedy and both relieve | rct, indirect | Pérez Domínguez, Ther Hypothermia Temp Manag (2026) |
| against (2) | Vitamin D: lower levels track with more pain, but a cross-climate comparison found nothing significant | meta, indirect | vitamin D meta-analysis (2024) |
| for (2) | Heat therapy for period pain: heating pads beat painkillers in 3 RCTs (SMD −0.72) and beat no treatment by 4 points on a 10-point scale; so both heat and cold relieve the pain | meta, indirect | Jo & Lee, Scientific Reports meta-analysis (2018) |
| for (1.5) | Thyroid: autoimmune hypothyroidism associated with endometriosis; thyroid hormones change lesion size in mice; causality uncertain by Mendelian randomisation | case control, indirect | Peyneau, PNAS (2019) |
| for (1) | 1980s basal-body-temperature studies: temperature above 97.8°F on the first three days of menses and a late-declining pattern associated with pelvic endometriosis; elevated or peaked follicular temperatures in 64.9% of patient cycles | case series | Acta Obstet Gynecol Scand / Fertil Steril (1985–88) (1988) |
| for (1) | Heat-shock protein Hsp70 elevated in blood of biopsy-proven patients; small HSPs in pelvic fluid; Hsp60 provokes TNF-α from pelvic immune cells | mechanistic | Int J Mol Sci (2024) |
| for (0.5) | Luteal-phase defects in 55% of 84 endometriosis patients | case series, indirect | Moeloek, Asia-Oceania J Obstet Gynaecol (1993) |
| for (0.5) | Percutaneous cryoablation of abdominal-wall endometriosis: pain 8/10 → 1/10, 80–100% complete response, 77% pain-free at 5 years, major complications <2%; HIFU heat ablation works for adenomyosis but not for small pelvic lesions | case series, indirect | systematic review, cryoablation (2024) |
| for (0.5) | Varicocele: pooled, stagnant venous blood around the testis raises its temperature 0.6–2.6°C and impairs sperm production; the temperature falls back to normal after the veins are repaired | review, indirect | Varicocele and testicular function, review (2015) |
9. Stress re-wires the system moderate
Chronic stress and early trauma change immune tone, pain wiring and hormone rhythm; the captive-baboon effect and the abuse dose-response point the same way
What would prove it wrong: stress biomarkers (cortisol rhythm, heart-rate variability) measured before diagnosis do not predict later disease once abuse history and cycle count are held fixed
| For or against | Finding | Design | Source |
|---|---|---|---|
| for (4) | Nurses' Health Study II, 60,595 women: severe-chronic childhood physical and sexual abuse → 79% higher risk of laparoscopically confirmed endometriosis, dose-response by severity and type | cohort large | Harris, Hum Reprod (2018) |
| for (3) | Hair cortisol, a three-month integrated record of stress hormone, is higher in women with endometriosis than in healthy controls, and correlates with chronic pain and lower quality of life | case control | hair cortisol study, Psychoneuroendocrinology (2018) |
| for (1.5) | Women with endometriosis and lower vagally-mediated heart-rate variability (a nervous system stuck in alarm) report more intense pelvic pain and higher perceived stress | case control, indirect | vmHRV and pain study (2021) |
| for (1) | Women perform 76% of the world's unpaid care work, 4 h 25 min a day against 1 h 23 min for men; 708 million women are outside the labour force because of care duties | ecological, indirect | ILO, Care Work and Care Jobs (2018) |
10. The estrogen leak moderate
Chemicals that mimic or boost estrogen (PFAS, persistent pesticides, dioxins, the weedkiller atrazine, pharmaceutical estrogens in water) feed a disease that runs on estrogen
What would prove it wrong: a replicated human study shows a chemical exposure more than doubling the odds (then it is more than an amplifier), or conversely well-measured exposures show no association at all
| For or against | Finding | Design | Source |
|---|---|---|---|
| for (4) | Meta-analysis: PFAS sulfonates OR 1.50 (1.12–2.00) and carboxylates OR 1.46 (1.12–1.90) for endometriosis | meta | Toxics meta-analysis (2026) |
| for (4) | Red meat >2 servings/day → 56% higher endometriosis risk in 81,908 nurses (95% CI 1.22–1.99); poultry, fish, eggs unrelated | cohort large | Yamamoto, Am J Obstet Gynecol (2018) |
| against (4) | Air pollution (PM2.5, PM10, roadway proximity) NOT associated with incident endometriosis in 84,060 nurses over 710,230 person-years | cohort large | Mahalingaiah, NHS II (2014) |
| against (3) | Spontaneous endometriosis occurs in baboons, rhesus and cynomolgus monkeys including wild-caught animals, and only in menstruating species | primate | rhesus macaque characterisation (2020) |
| for (3) | Organochlorine pesticides: β-HCH OR 1.7 (1.0–2.8), mirex OR 1.5; ovarian subtype OR 2.5 | case control | Upson, Environ Health Perspect (2013) |
| against (3) | Tampon use associated with LOWER endometriosis (11.6% tampon-only users among cases vs 20.9% controls), contradicting the idea that tampons cause it | case control | Meaddough, Yale (2002) |
| for (3) | After hysterectomy for endometriosis, keeping the ovaries carried a six- to eight-fold higher chance of another operation (62% recurrence vs 10% with ovaries removed in one series) | cohort | Shakiba 2008 via Hum Reprod Update (2021) |
| for (2.5) | The pill's estrogen at 5–6 ng/L collapsed a whole-lake fish population; the population recovered after dosing stopped | natural, indirect | Kidd, PNAS (2007) |
| against (2) | Global Burden of Disease 1990–2021: age-standardised incidence fell 1.07%; case counts rose only with population | ecological | GBD trend analysis, Frontiers in Medicine (2025) |
| for (2) | Rhesus monkeys fed dioxin for 4 years: 43% moderate-severe endometriosis at 5 ppt and 71% at 25 ppt, ten years later | animal | Rier, Fundam Appl Toxicol (1993) |
| for (2) | Belgium: among the world's highest endometriosis incidence and among Europe's highest dioxin exposure through food | ecological | Koninckx, Hum Reprod (1994) |
| against (1) | Symptom cluster described in Egyptian papyri ~1855 BCE and Hippocratic writings; 4,000-year record | historical | Nezhat, Fertil Steril (2012) |
| against (1) | Ten years on, the primate dioxin data were judged equivocal and human data scanty and conflicting | review | critical reappraisal (2004) |
| for (1) | Atrazine induces aromatase and feminises male frogs at 0.1 ppb, below the US drinking-water limit of 3 ppb | animal, indirect | Hayes, PNAS (2010) |
| for (1) | Endometriotic lesions over-express aromatase and make their own estrogen; aromatase inhibitors treat the disease | mechanistic | Reprod Biol Endocrinol (2011) |
| against (1) | Institute of Medicine: evidence inadequate to link Agent Orange (dioxin) exposure of veterans to endometriosis in their daughters | review | Veterans and Agent Orange, IOM (2014) |
| for (0.5) | Endometriosis in men on long-term estrogen therapy for prostate cancer (bladder, inguinal, paratesticular); symptoms resolve when estrogen stops | case report | Rei, Case Rep Obstet Gynecol (2018) |
| for (0.5) | Metals in tampons: lead in 100% of 60 products (mean 120 ppb, 24x the bottled-water limit), cadmium, arsenic; leaching into the body not yet shown | mechanistic, indirect | Shearston, Environment International (2024) |
| for (0.5) | Microplastics found in human endometrium (median 21 particles per 100 mg), more in endometrial polyps; microplastics drive stromal cell proliferation and collagen deposition in a 3D endometrial model | mechanistic, indirect | Reprod Toxicol / 3D model 2025 (2024) |
| for (0.5) | Hair relaxers used by up to 95% of Black US women carry phthalates and parabens; uterine cancer HR 2.55 with frequent use in one cohort but a 2025 systematic review found no consistent increase in hormone-sensitive cancers; endometriosis specifically unstudied | review, indirect | Hernandez, J Appl Toxicol (2025) |
11. The cells were already there moderate
Lining-type cells can arise in place from the pelvic lining or stem cells, or travel by blood and lymph; the disease occurs in women with no uterus and in men on estrogen
What would prove it wrong: lineage tracing shows every lesion derives from shed uterine lining
| For or against | Finding | Design | Source |
|---|---|---|---|
| for (4) | Cesarean delivery → 80% higher later endometriosis diagnosis (HR 1.8, 1.7–1.9) in Swedish registers; C-section after endometriosis surgery → 2.25x recurrence | cohort large | Swedish registers / recurrence cohort (2013) |
| for (1) | Cancer-driver mutations (ARID1A, PIK3CA, KRAS, PPP2R1A) in lesions of 79% of patients without cancer; KRAS in epithelium not stroma | mechanistic | Anglesio, NEJM (2017) |
| for (1) | Thoracic endometriosis (lung, diaphragm) and rare central-nervous-system lesions: the disease reaches sites no menstrual spill can | case series | thoracic endometriosis review (2026) |
| for (1) | Menstrual effluent of patients carries a stem/progenitor survival program with inflammatory activation and matrix remodelling | mechanistic | menstrual effluent systematic review (2025) |
| for (1) | Endometriotic cells reach pelvic sentinel lymph nodes in 11% of women with ovarian or peritoneal disease; lymphatic spread is frequent in rectosigmoid disease | case series | Fertil Steril prospective study (2011) |
| for (0.5) | Endometriosis in men on long-term estrogen therapy for prostate cancer (bladder, inguinal, paratesticular); symptoms resolve when estrogen stops | case report | Rei, Case Rep Obstet Gynecol (2018) |
| for (0.5) | Endometriosis in Mayer-Rokitansky-Küster-Hauser syndrome patients with no functional uterus | case report | MRKH case report (2015) |
12. Where fluid stalls, disease grows moderate
Lesions form where pelvic fluid pools and slows (behind the sigmoid colon, in the recesses), and stagnant veins and lymph travel with the disease; flow is protective
What would prove it wrong: lesion distribution does not follow the fluid-flow recess map once surgical access bias is removed, or venous congestion co-occurs no more than chance
| For or against | Finding | Design | Source |
|---|---|---|---|
| for (4) | Meta-analysis of 154 studies, 20,718 patients, 29 countries: pelvic lesions favour the LEFT side and thoracic/inguinal lesions the RIGHT, matching two anatomical recesses sheltered from peritoneal fluid flow (left hemipelvis behind the sigmoid; right upper abdomen under the diaphragm) | meta | Human Reproduction Open, anatomical recesses meta-analysis (2026) |
| for (1) | Peritoneal fluid circulates clockwise and pools at four anatomical sites (pouch of Douglas, right lower quadrant, left lower quadrant along the sigmoid, right paracolic gutter); these are the four commonest lesion sites; flow is slower and weaker on the left, where lesions predominate | mechanistic | Bricou/Chapron, Eur J Obstet Gynecol Reprod Biol (2008) |
| for (1) | Pelvic venous congestion (varicose pelvic veins) co-occurs with radiological signs of endometriosis in 61.5% of women with chronic pelvic pain on multiparametric MRI | case series | multiparametric MRI study (2025) |
| for (1) | Endometriotic cells reach pelvic sentinel lymph nodes in 11% of women with ovarian or peritoneal disease; lymphatic spread is frequent in rectosigmoid disease | case series | Fertil Steril prospective study (2011) |
| for (1) | Endometriotic lesions grow their own nerve supply (neuroangiogenesis) and lesion nerve-fibre density correlates directly with pain severity | mechanistic | Annual Review of Physiology (2011) |
| for (0.5) | VEGF-driven blood-vessel growth is central to lesion establishment; 31 studies of anti-angiogenic agents (5 early human) show lesion regression signals; one bevacizumab case had complete resolution of refractory pain | review, indirect | network meta-analysis, anti-VEGF (2026) |
| for (0.5) | Varicocele: pooled, stagnant venous blood around the testis raises its temperature 0.6–2.6°C and impairs sperm production; the temperature falls back to normal after the veins are repaired | review, indirect | Varicocele and testicular function, review (2015) |
13. Neglected because it is a women's disease weak
Research money follows the burdens the funders recognise; when funders and the profession were mostly men, diseases that only women get were under-recognised, and the pattern outlived the people who set it
What would prove it wrong: once research funding is normalised to disease burden, female-predominant diseases are funded at parity with male-predominant ones, or endometriosis's burden-to-funding ratio sits in the middle half of all diseases
| For or against | Finding | Design | Source |
|---|---|---|---|
| for (2) | Across NIH-funded diseases normalised to disability-adjusted life years, in nearly three quarters of single-sex-dominant diseases the funding pattern favours men; endometriosis, migraine, headache, anorexia and ME/CFS are among the most underfunded | ecological | Mirin, Journal of Women's Health (2021) |
| for (2) | NIH spent about $28 million on endometriosis in FY2024, roughly $4.30 per affected woman per year, against about $130 per patient for Crohn's disease and about $31 per woman for diabetes | ecological | npj Women's Health (2024) |
| for (1) | Conditions that disproportionately affect women (migraine, headache, endometriosis, anxiety) attract much less funding relative to their burden than conditions that disproportionately affect men (HIV/AIDS, substance misuse); Canada: 5.9% of 9,000 grants looked at female-specific outcomes | review | Nature, Smith, in a series of charts (2023) |
| for (0.5) | Women of childbearing potential were excluded from early-phase drug trials by FDA policy from 1977; inclusion of women in NIH research only became law with the NIH Revitalization Act of 1993 | historical, indirect | NIH Office of Research on Women's Health (1993) |
14. Salt in, water out: the sodium-potassium imbalance weak
Modern diets carry far more sodium and far less potassium and magnesium than the bodies we evolved in expect; water follows salt, so tissues run drier and stiffer, flow slows, and the pelvis pays
What would prove it wrong: women with endometriosis do not differ from matched controls in sodium-to-potassium intake or 24-hour urinary Na:K once diet quality is adjusted, or correcting the ratio changes nothing measurable about pain or lesion progression
| For or against | Finding | Design | Source |
|---|---|---|---|
| for (3) | In 156 Tehran women, higher dietary potassium was associated with lower odds of endometriosis (OR 0.32, 0.12–0.82, P-trend 0.01) and magnesium and phosphorus were also inversely associated; sodium intake did not differ between cases and controls | case control | Dietary micronutrients and endometriosis, case-control (2023) |
| for (0.5) | The Paleolithic diet delivered about 16 times more potassium than sodium; the average American diet contains about twice as much sodium as potassium, and most Americans get barely half the recommended potassium | review, indirect | Harvard Health, The importance of potassium (2019) |
| for (0.5) | Higher sodium-to-potassium ratio is associated with higher cardiovascular risk; potassium relaxes blood-vessel walls and lowers blood pressure | review, indirect | Harvard Health, Potassium lowers blood pressure (2017) |
| for (0.5) | Cochrane review of dietary supplements for period pain: magnesium reduced pain versus placebo in small trials, but there is no high-quality evidence for any supplement and safety evidence is lacking | review, indirect | Cochrane, dietary supplements for dysmenorrhoea (2016) |
| against (0.5) | Oestrogen lowers the threshold for vasopressin release and increases body water and sodium retention; the pill, pregnancy and the high-oestrogen phases of the cycle all retain water rather than shed it | mechanistic, indirect | Stachenfeld, Am J Physiol (1998) |
15. The record is already in the drawer: baby teeth as a time-stamped log of exposure before birth speculative
Baby teeth mineralise in weekly rings from about 20 weeks in the womb to roughly age one and lock in whatever chemistry the child was exposed to. If endometriosis is seeded before birth (H2/H8 developmental-origins line), the exposure fingerprint of women later diagnosed should differ from their sisters' and peers' — and millions of parents have kept those teeth.
What would prove it wrong: the tooth-exposure profiles of women with surgically confirmed endometriosis do not differ from unaffected sisters or matched peers on any prenatal window, or no lab can be found that has run deciduous-tooth exposure biography in any adult disease outside neurodevelopment
| For or against | Finding | Design | Source |
|---|
Facts any explanation has to survive
- Retrograde menstruation occurs in over 90% of women but only ~10% develop the disease Reprod BioMed Online review
- Spontaneous endometriosis occurs in baboons, rhesus and cynomolgus monkeys including wild-caught animals, and only in menstruating species rhesus macaque characterisation
- Endometriosis in Mayer-Rokitansky-Küster-Hauser syndrome patients with no functional uterus MRKH case report
- Nurses' Health Study II (116,430 women, 5,504 cases): morbidly obese women had 39% lower risk; waist-to-hip ratio <0.60 nearly 3x the rate Shah, Hum Reprod
- Tampon use associated with LOWER endometriosis (11.6% tampon-only users among cases vs 20.9% controls), contradicting the idea that tampons cause it Meaddough, Yale
- Older cohorts reported maternal smoking in pregnancy associated with LOWER endometriosis in some studies and no association in others; a 2025 narrative review calls the direction unsettled Smoking and endometriosis review, Tob Induc Dis
- COVID-19 vaccination shifted menstrual cycle length by under one day, resolving the next cycle, in Natural Cycles data across countries; no endometriosis association has been reported Edelman, BMJ Medicine / NIH
- Physical activity and endometriosis: 40–80% lower risk in case-control studies but only RR 0.89 (0.77–1.03) in the 102,197-woman Nurses' cohort; Mendelian randomisation points protective again Vitonis, Epidemiology (NHS II)
- Obstetrics and gynaecology has been majority-female since 2008 and is about 59% women today, heading for 66% within a decade Changes in the numbers of male and female obstetrician-gynecologists