Endometriosis: The Estrogen-Inflammation-Immune Triad
Endometriosis is endometrial-like tissue growing outside the uterus — on the peritoneum, ovaries, bowel, bladder, uterosacral ligaments, diaphragm, and in rare cases, the lungs or brain. It affects approximately 10% of reproductive-age women, which translates to roughly 190 million people worldwide.
Endometriosis: The Estrogen-Inflammation-Immune Triad
A Disease That Hides in Plain Sight
Endometriosis is endometrial-like tissue growing outside the uterus — on the peritoneum, ovaries, bowel, bladder, uterosacral ligaments, diaphragm, and in rare cases, the lungs or brain. It affects approximately 10% of reproductive-age women, which translates to roughly 190 million people worldwide. The average time from symptom onset to diagnosis is 7-10 years. A decade of suffering misattributed to “bad periods” or, worse, dismissed as psychological.
This delay is not merely unfortunate. It is a systemic failure. Every year of untreated disease means deeper infiltration, more adhesion formation, more organ damage, and more central sensitization of pain pathways that become increasingly difficult to reverse.
Not Just Estrogen: The Three-Headed Driver
The conventional view reduces endometriosis to an estrogen-dependent condition. This is incomplete. Endometriosis is driven by three interconnected mechanisms, and addressing only one guarantees treatment failure.
Estrogen Dominance
Endometrial implants are not merely estrogen-responsive — they are estrogen-producing. Ectopic endometrial tissue expresses aromatase, the enzyme that converts androgens to estrogen. This creates a local estrogen factory independent of ovarian production. Even after surgical menopause, endo implants can generate their own estrogen supply.
Additionally, most women with endometriosis show impaired estrogen detoxification — preferential metabolism down the 4-OH and 16-OH pathways (proliferative, DNA-damaging) rather than the protective 2-OH pathway. DUTCH testing reveals this pattern clearly.
Immune Dysregulation
Natural killer (NK) cells are supposed to identify and destroy ectopic tissue. In endometriosis, NK cell cytotoxicity is reduced. The immune system sees the implants but cannot clear them. Simultaneously, macrophages in the peritoneal fluid are activated but dysfunctional — they secrete inflammatory cytokines (TNF-alpha, IL-1, IL-6, IL-8) and growth factors (VEGF) that promote implant survival and angiogenesis rather than destruction.
This is not an immune deficiency. It is an immune misdirection — inflammation without resolution.
Chronic Inflammation
NF-kB is constitutively activated in endometrial implants, driving a self-perpetuating inflammatory cascade. Prostaglandins (particularly PGE2) are elevated, produced by COX-2 overexpression in endo tissue. Oxidative stress damages surrounding tissue. The inflammation feeds the estrogen production (inflammatory cytokines upregulate aromatase), and the estrogen feeds the inflammation. A vicious spiral.
Why Only 10%? The Retrograde Menstruation Question
Sampson’s 1927 retrograde menstruation theory — that endometrial cells flow backward through the fallopian tubes during menstruation and implant on pelvic structures — remains the most cited explanation. But it has a fatal flaw: 90% of menstruating women have retrograde flow, yet only 10% develop endometriosis.
What determines who? The emerging understanding points to:
- Immune surveillance failure: Genetically determined NK cell dysfunction
- Epigenetics: Altered DNA methylation and histone modification in endo tissue
- Environmental toxins: Dioxins and dioxin-like compounds. The landmark 1993 Rier study exposed Rhesus monkeys to TCDD (dioxin) and found dose-dependent development of endometriosis. Dioxins are endocrine disruptors that alter immune function and estrogen metabolism.
- Stem cell theory: Endo may arise from endometrial stem cells that spread via lymphatic/vascular routes or from metaplasia of peritoneal mesothelium
- Neonatal uterine bleeding: Endo may begin in utero — neonatal vaginal bleeding occurs in up to 5% of female newborns, potentially seeding ectopic tissue before the first menstrual period
Symptoms: The Pattern Recognition
- Severe dysmenorrhea: Pain out of proportion to what is considered “normal.” Pain that does not respond to NSAIDs. Pain that begins days before menses and extends days after.
- Deep dyspareunia: Pain with deep penetration, often positional, particularly with posterior endo implants on uterosacral ligaments.
- Chronic pelvic pain: Not only menstrual. Can be daily.
- Dyschezia: Painful bowel movements, especially during menses — a hallmark of bowel endo or cul-de-sac involvement.
- Painful urination: Bladder endo.
- Endo belly: Severe bloating and distension, often cyclical. Mimics IBS.
- Infertility: 30-50% of infertile women have endometriosis. Mechanisms include tubal damage, altered peritoneal environment toxic to sperm and embryos, impaired implantation, and ovarian reserve reduction from endometriomas.
- Fatigue: Profound, often debilitating. Driven by chronic inflammation and immune activation.
- Heavy menstrual bleeding: Particularly with adenomyosis (endo within the uterine muscle wall — the “sister condition”).
Diagnosis
Gold standard: Laparoscopy with histological biopsy of excised lesions. Visual inspection alone misses atypical lesions (clear, white, brown, red — not just the classic “powder-burn” black lesions).
MRI: Can detect deep infiltrating endometriosis (DIE) and endometriomas (chocolate cysts). Limited for superficial peritoneal disease.
Transvaginal ultrasound: Detects endometriomas and some DIE. Misses most peritoneal disease.
CA-125: Elevated in some cases but not reliable — also elevated in fibroids, PID, ovarian cancer, and even during menses. Not a screening tool.
Emerging: Research into salivary microRNA panels (Zizioli 2023, Endotest) for non-invasive diagnosis.
The IFM Protocol: Medical, Surgical, and Functional
Estrogen Metabolism Optimization
The goal is to reduce estrogen load, shift metabolism toward protective pathways, and block aromatase activity in endo tissue.
- DIM (Diindolylmethane): 200mg/day. Derived from cruciferous vegetable metabolism. Shifts estrogen metabolism toward the protective 2-OH pathway and away from proliferative 4-OH and 16-OH pathways. DUTCH testing before and after to verify shift.
- Calcium d-glucarate: 500mg 2x/day. Inhibits beta-glucuronidase, the bacterial enzyme that deconjugates estrogen in the gut, allowing it to be reabsorbed (enterohepatic recirculation). If beta-glucuronidase is high on GI-MAP, this is essential.
- Sulforaphane: From broccoli sprout extract or fresh sprouts (30-60mg sulforaphane equivalent). Activates Nrf2 (master antioxidant pathway), supports Phase II detoxification, and modulates estrogen metabolism.
- Fiber: 35-50g/day. Binds conjugated estrogen in the gut for fecal excretion. Ground flaxseed, vegetables, legumes (if tolerated).
- Ground flaxseed: 2 tablespoons daily. Lignans are weak phytoestrogens that competitively block stronger estrogens at the receptor. Also reduces aromatase activity. Secoisolariciresinol diglucoside (SDG) is the key lignan.
- Xenoestrogen reduction: Eliminate plastics (BPA, BPS), pesticides (eat organic — the Dirty Dozen at minimum), parabens, phthalates (fragrance in personal care products). Switch to glass/stainless steel food storage. Filter drinking water (reverse osmosis or high-quality carbon block).
- Body composition: Adipose tissue contains aromatase. Excess body fat means excess peripheral estrogen production. Metabolically healthy body composition supports hormonal balance.
Anti-Inflammatory Arsenal
- Omega-3 fatty acids: 3-4g/day EPA+DHA, EPA-dominant formulation. Inhibits COX-2 and prostaglandin E2 production. The Hopeman 2023 systematic review confirmed anti-inflammatory benefits in endometriosis. Omega-3s also produce resolvins and protectins that actively resolve inflammation.
- Curcumin: 1000-2000mg/day (liposomal or phytosome form for absorption). Inhibits NF-kB, reduces endo lesion growth and angiogenesis in multiple animal models. Downregulates MMP-9 (matrix metalloproteinase involved in tissue invasion).
- Resveratrol: 200-400mg/day. Anti-aromatase, anti-angiogenic — inhibits new blood vessel growth to endo implants. Also activates SIRT1, supporting cellular repair.
- NAC (N-Acetyl Cysteine): 600mg 3x/day. The De Leo 2013 Italian study is remarkable: NAC reduced endometrioma cyst size, with 24% of treated women achieving complete cyst resolution versus 1% in the control group. Some patients cancelled planned surgery. NAC is a glutathione precursor (master antioxidant) and modulates NF-kB.
- Quercetin: 500mg 2x/day. Mast cell stabilizer, anti-inflammatory, and directly inhibits endometrial cell proliferation and adhesion in vitro. Pairs synergistically with curcumin.
- Pycnogenol: 30-60mg/day. French maritime pine bark extract. Kohama 2007 study showed 33% symptom reduction versus baseline. Antioxidant, anti-inflammatory, and reduces menstrual pain.
- Green tea (EGCG): 400-800mg EGCG/day. Anti-angiogenic — starves endo implants of blood supply. Reduces lesion growth in animal models. Also modulates estrogen metabolism.
Immune Modulation
- Vitamin D: 5000-10,000 IU/day, target serum level 60-80 ng/mL. Immunomodulatory — enhances NK cell function, reduces inflammatory cytokines, anti-proliferative against endo tissue. Most endo patients are deficient.
- Low-Dose Naltrexone (LDN): 1.5-4.5mg at bedtime. Upregulates endogenous opioids and modulates microglial activation. Reduces pain, modulates immune function. Emerging evidence in endo.
- Vitamin A (retinol): 5000-10,000 IU/day. Essential for NK cell function and mucosal immunity.
- Zinc: 30mg/day. Immune cell differentiation, anti-inflammatory, antioxidant.
- Medicinal mushrooms: Reishi (Ganoderma lucidum) 1-2g and Turkey Tail (Trametes versicolor) 1-2g daily. Beta-glucans modulate NK cell activity and macrophage function. Immunomodulatory rather than immunostimulatory.
Gut Health: The Estrobolome Connection
The estrobolome is the collection of gut bacteria capable of metabolizing estrogen via the enzyme beta-glucuronidase. When gut dysbiosis increases beta-glucuronidase activity, conjugated (deactivated) estrogen is deconjugated and reabsorbed into circulation — increasing total estrogen load.
High beta-glucuronidase on GI-MAP is a direct contributor to estrogen dominance. Treatment: calcium d-glucarate (inhibits the enzyme), Lactobacillus species probiotics (particularly L. acidophilus and L. rhamnosus — reduce beta-glucuronidase activity), gut healing via the 5R protocol (Remove, Replace, Reinoculate, Repair, Rebalance), and SIBO treatment if present — a common overlap condition in endo patients.
Pain Management
- Palmitoylethanolamide (PEA): 600-1200mg/day. An endocannabinoid system modulator that is anti-inflammatory, analgesic, and neuroprotective. Multiple RCTs support its use in chronic pelvic pain. No drug interactions. Safe long-term.
- Magnesium glycinate: 400-600mg/day. Muscle relaxant, reduces menstrual cramping, calms nervous system.
- CBD oil: Anti-inflammatory and analgesic through the endocannabinoid system. Emerging research in endometriosis-related pain. Start low (10-25mg), titrate up.
- Castor oil packs: Applied over the pelvis, 3-4 times per week (NOT during active menses). Increases circulation, supports lymphatic drainage, reduces inflammation. Use organic cold-pressed castor oil on flannel, covered with heat.
- Pelvic floor physical therapy: Muscle guarding, myofascial trigger points, and hypertonic pelvic floor are common secondary issues in endo. The pelvis braces against chronic pain. A skilled pelvic floor PT can release these patterns. Essential component of comprehensive treatment.
- Acupuncture: Meta-analyses support its use in dysmenorrhea and chronic pelvic pain. Modulates pain pathways, reduces inflammation, regulates autonomic nervous system.
Diet
Anti-inflammatory Mediterranean base with specific modifications:
- Eliminate dairy: A1 casein (in most conventional cow’s milk) is inflammatory and may influence prostaglandin production. A2 dairy or goat/sheep dairy may be tolerated.
- Reduce red meat: Rich in arachidonic acid, the precursor to inflammatory prostaglandins. Especially grain-fed conventional meat.
- Reduce alcohol: Increases aromatase activity (more estrogen production) and depletes B vitamins needed for estrogen detoxification.
- Gluten-free trial: Controversial but a significant subset of endo patients report marked improvement. Marziali 2012 reported 75% of endo patients had significant pain reduction on gluten-free diet after 12 months. Worth a 3-month trial.
- Increase: Cruciferous vegetables (DIM precursors), omega-3 rich fish (wild salmon, sardines, mackerel), turmeric, ginger, berries (polyphenols), green tea, ground flaxseed.
Surgical Considerations
Excision surgery is superior to ablation. Ablation burns the surface of endo lesions. Excision removes the lesion at its root, including deep infiltrating disease. The distinction matters enormously for outcomes and recurrence rates.
Not all surgeons are equal. Seek a specialist endometriosis excision surgeon — typically a fellowship-trained minimally invasive gynecologic surgeon (MIGS) or a recognized endo center of excellence. A general OB/GYN performing ablation at routine laparoscopy is not equivalent.
Post-surgical functional medicine is critical to prevent recurrence. Surgery removes existing disease but does not address the underlying drivers — estrogen dominance, immune dysregulation, inflammation, and environmental exposures. Without addressing root causes, recurrence rates are high.
Hormonal Suppression: The Conventional Bridge
- GnRH agonists (Lupron, Zoladex): Create medical menopause. Effective for pain but significant side effects — hot flashes, bone loss, mood changes, cognitive effects. Add-back therapy (low-dose estrogen/progesterone) mitigates some side effects. Time-limited use.
- Dienogest (Visanne): Progesterone derivative, suppresses endo without full menopausal side effects. Better tolerated long-term.
- Progesterone-only options: Norethindrone, Mirena IUD (local progesterone delivery to uterus), natural progesterone (less evidence for endo suppression).
- Combined oral contraceptives: Continuous use (skip placebo week) reduces menstrual-triggered inflammation.
The functional medicine approach prefers to address root causes rather than rely on hormonal suppression, but hormonal therapy can serve as a bridge — reducing symptoms and disease activity while the underlying protocol takes effect.
The Bigger Picture
Endometriosis is not simply a gynecological condition. It is a systemic inflammatory, immune-mediated, hormonally-driven disease with genetic and environmental contributors. Treating it requires thinking beyond the pelvis — to the gut (estrobolome), the liver (estrogen detoxification), the immune system (NK cell function), the environment (xenoestrogens), and the nervous system (central sensitization of pain).
The women who fare best are those whose care team addresses all three heads of the triad simultaneously: estrogen, inflammation, and immunity. Cut off one head, and the other two sustain the disease. Address all three, support the body’s own capacity for resolution, and the trajectory changes.