II. Definitions
- Endometriosis
- Ectopic, functional endometrial tissue (glands and stroma) implanted outside the Uterus, and especially on the surface of pelvic organs
- Estrogen-dependent lesions associated with local inflammation at implant sites, resulting in Chronic Pain and Infertility
III. Epidemiology
- Age at diagnosis: 20-40 years (peak Prevalence age 25 to 35 years old)
-
Prevalence: 10-15% of women (2 to 11% for asymptomatic women)
- Prevalence in women with Pelvic Pain: 82%
- Prevalence in women with Infertility: 21%
- Eskenazi (1997) Obstet Gynecol Clin North Am 24:235 [PubMed]
IV. Pathophysiology: Ectopic Endometrial Tissue implant Sites
V. Pathophysiology: Theories of Etiology
- Implantation during Menstruation (Sampson)
- Most accepted theory
- Endometrial cells spread via tube to peritoneum
- Retrograde flow
- Retrograde flow likely occurs in most women but at higher volumes in those with Endometriosis
- Implantation more likely in the presence of the plasminogen activator inhibitor gene
- Other theories
- Vascular and lymphatic spread (Halban)
- Associated with abdominal surgery
- Would explain distant spread to organs such as lung
- Metaplasia (Meyer)
- Coelomic epithelium differentiates into endometrium
- Decreased Cellular Immunity (Dmowski)
- Vascular and lymphatic spread (Halban)
- Superimposed Factors
- Estrogen Effects
- Promotes Endometriosis implantation and proliferation, and stimulates inflammatory factors
- Neurogenesis
- Increased nerve growth factors, with increased Sensory Nerves (esp. sympathetic fibers) in regions of Endometriosis
- Estrogen Effects
VI. Risk Factors
- Factors resulting in more days of menstrual flow
- Early Menarche
- Late Menopause
- Nulliparity
- Menstrual flow 6 or more days (Odds Ratio 2.5)
- Menstrual Cycle <28 days (Odds Ratio 2.1)
-
Family History
- Mother or sister with Endometriosis (Odds Ratio 7.2)
- Twin studies with 50% heritability of Endometriosis
- Other factors
- Mullerian abnormalities
- Low Body Mass Index
- Low birth weight
- Prematurity
- Diethylstilbesterol (DES) In-Utero Exposure
- References
VII. Symptoms
- Asymptomatic in 25-30% of women with Endometriosis
- Chronic Pelvic Pain (70%, Odds Ration 5.2)
-
Dysmenorrhea (71%, Odds Ratio 8.1)
- Cyclic
- Progressively increasing in severity
- Affects bilateral lower Abdomen
- Associated with sense of rectal pressure
- Refractory to anti-Prostaglandins
- Dyspareunia (44%, Odds Ration 6.8)
- Infertility (15-20%, Odds Ratio 8.2)
- Ovarian Cysts (Odds Ratio 7.3)
- Premenstrual spotting
- Heavy Menstrual Bleeding (51%)
- Cyclical, painful gastrointestinal symptoms or urinary symptoms (e.g. Hematuria, Dysuria) correlating with menstrual periods
- Painful Defecation (Dyschezia) or Constipation
- Suprapubic Pain
VIII. Signs: Pelvic exam
- Precautions
- A normal pelvic exam does not exclude Endometriosis
- Tender, nodular uterosacral ligaments or cul-de-sac (pathognomonic for Endometriosis)
- Adnexal or tubo-Ovarian Mass
- Induration of the rectovaginal septum
- Fixed uterine retroversion
IX. Types: Presentations
- Endometrial implantation
- Ectopic tissue lies superficially on peritoneum
- Endometriomas (Chocolate cysts)
- Endometrial lined Ovarian Cysts
- Endometriotic Nodules
- Solid, complex mix of endometrium with fibromuscular and fatty tissue
- Localized between vagina and Rectum
X. Imaging
-
Transvaginal Ultrasound (TVUS)
- Noninvasive study with high Test Sensitivity and Test Specificity for deep pelvic Endometriosis
- Identifies retroperitoneal and uterosacral lesions (85% Specificity)
- Identifies cystic endometriomas (89% sensitivity, 91% Specificity)
- Misses peritoneal lesions
- Bladder site tenderness technique has Test Sensitivity and Test Specificity >97%
- Noventa (2015) Fertil Steril 104(2): 366-83 [PubMed]
- MRI Pelvis (with or without MRI Abdomen)
- Indicated in cases of deep infiltrating Endometriosis of the bowel, Bladder or ureter
XI. Diagnosis
- Precautions
- Although Endometriosis is formally a histologic diagnosis, clinical diagnosis may be made by careful history and exam
- Presentations are often non-specific and associated with 4 to 10 years on average delay in formal diagnosis from symptom onset
- Clinical diagnosis is sufficient to initiate empiric treatment (without surgery or tissue diagnosis)
- Transvaginal Ultrasound (TVUS) may also be sufficient for definitive diagnosis
- Laparoscopy with biopsy (gold standard)
- Red, Brown or blue-black nodular implants
- Powder-burn spots
- Multiple, tiny, puckered hemorrhagic foci
- Ectopic tissue findings predictive factors for Endometriosis
- Implants >10 mm wide or >5 mm deep
- Implants with mixed coloration
- Implants in cul-de-sac, ovarian fossa, or utero-sacral ligaments
- Histology (confirms visual diagnosis)
- Hemosiderin-laden Macrophages
- Endometrial tissue (epithelium, glands, stroma) found in ectopic tissue samples
- References
- Tests not recommended for diagnosis
XII. Differential Diagnosis
- See Dysmenorrhea
- See Dyspareunia (e.g. Cervicitis or Vaginitis, Vulvodynia, Vaginal Atrophy)
- See Dysuria (e.g. Urinary Tract Infection, Interstitial Cystitis)
- See Infertility
- See Pelvic Pain
- See Chronic Pelvic Pain
- See Adnexal Mass (e.g. Ovarian Cyst)
- See Anorectal Pain or Dyschezia (e.g. Anal Fissure, Pelvic Floor Disorders)
- See Abdominal Wall Pain Causes (e.g. nerve entrapment)
- Functional Constipation
- Irritable Bowel Syndrome
- Pelvic Congestion Syndrome
- Sexually Transmitted Infection or Pelvic Inflammatory Disease
XIII. Management: First Line
- Precautions
- Endometriosis is a chronic disease requiring ongoing suppression of Estrogen, tissue proliferation and inflammation
- First-line management listed below are directed to primary care providers
- Laparoscopy is no longer required before initiating management
- Clinical diagnosis is sufficient after excluding other significant causes (e.g. infection)
- Laparoscopy may be considered for confirmation of diagnosis (especially if fertility desired)
- Transvaginal Ultrasound may be considered for definitive diagnosis in women not desiring pregnancy
-
Analgesics
- NSAIDs
- Effective in Primary Dysmenorrhea, but efficacy in Endometriosis is unclear
- Brown (2017) Cochrane Database Syst Rev (1):CD004753 [PubMed]
- NSAIDs
-
Oral Contraceptives (preferred)
- Use for at least 3-4 months
- If effective, may be continued until pregnancy desired or menopausal age
- Transdermal patches and vaginal rings are alternatives to Oral Contraceptives
- Norethindrone Acetate containing OCP may be preferred for Osteoporosis Management
- Norethindrone 2.5 mg orally and Premarin 0.625 mg orally daily may be considered in Perimenopause state
- Desogestrel OCPs (moderate Progestin, low Estrogen)
- Desogen (monophasic, 30 mcg Ethinyl Estradiol)
- Ortho-Cept (monophasic, 30 mcg Ethinyl Estradiol)
- Mircette (monophasic with 20 mcg Ethinyl Estradiol)
- Cyclessa (triphasic with 25 mcg Ethinyl Estradiol)
-
Progesterone
- Indicated if Estrogen products are contraindicated or not tolerated
- Provera 20-30 mg daily for 2 months
- Levonorgestrel IUD (Mirena IUD)
-
Depo Provera 150 mg every 3 months
- Higher Incidence of adverse effects including Osteoporosis and weight gain risk
- High dose protocol not found to offer benefit and not recommended (e.g. 150 mg IM every 2 weeks for 4 doses)
- Adjunctive and Complimentary Measures
- Regular Exercise
- Anti-inflammatory diet
- Diet high in fruits and vegetables, with whole grains, lean Protein and healthy fats
- Acupuncture
XIV. Management: Second Line
-
Gonadotropin-Releasing Hormone Agonist (GnRH Agonist)
- Efficacy
- GnRH are the best studied and most effective agents for Endometriosis
- Up to 100% improvement for 6-12 months post-therapy
- Mechanism
- Initially stimulates LH and FSH release (results in initial Endometriosis symptom flare)
- After 7 days, LH and FSH are depleted
- Ultimately results in pituitary GnRH receptor down-regulation
- Agents: Used for 6 months as initial course (longer courses are not recommended due to adverse effects)
- Leuprolide (Lupron)
- Dose: 3.75 mg injected every 4 weeks
- Goserelin (Zoladex)
- Implanted 3.6 mg SubQ for 6 months or
- Nafarelin (Synarel)
- Dose: 200 mcg intranasal twice daily for 6 month
- Buserelin
- Decapeptyl
- Leuprolide (Lupron)
- Adverse effects (most women are Hypoestrogenic at 8 weeks)
- Risk of Osteoporosis
- Initial Endometriosis symptom flare
- Use add-back therapy for most patients
- Maintains Bone Mineral Density and decreases hot flash symptoms
- Norethindrone Acetate (Aygestin) 5 mg orally daily (or low dose combined Estrogen and Progesterone product)
- Efficacy
-
Gonadotropin-Releasing Hormone Antagonist (GnRH Antagonist)
- Mechanism
- Inhibits gonadotropin release via initial competitive binding of GnRH receptors (and later their down regulation)
- Results in hypoestrogenic state
- Effective in Dysmenorrhea and non-menstrual Pelvic Pain
- Adverse Effects
- Fewer adverse effects than GnRH Agonists
- Adverse effects include Menopause effects (Osteoporosis, Hot Flashes), Headaches, Insomnia
- Not associated with Endometriosis symptom flare (unlike GnRH Agonists)
- Decreases efficacy of hormonal contraceptives (non-Hormonal Contraception is recommended)
- Preparations
- Elagolix (Orilissa)
- Oral tablet 150 mg once daily for up to 24 months
- If Dyspareunia, 200 mg orally twice daily for up to 6 months
- Relugolix 40 mg with Estradiol 1 mg and Norethindrone 0.5 mg (Myfembree)
- One tablet daily for up to 24 months
- Linzagolix
- Pending clinical trials in 2022
- Elagolix (Orilissa)
- References
- Mechanism
- Other hormonal agents
- Danazol
- Androgenic agent that increases Free Testosterone and lowers gonadotropins and Estrogens
- Dose: 200-800 mg orally daily for 6 months (also available as vaginal preparation)
- Efficacy: Improvement in 55-93% of patients
- Adverse effects in up to 85% of patients (related to androgen activity)
- Older, but effective agent
- Aromatase Inhibitors
- Aromatase Inhibitors block androgen conversion to Estrogens
- May be considered for off-label use in severe Endometriosis
- May be combined with a GnRH Agonist or combined Oral Contraceptive
- Avoid prolonged use due to bone loss, Ovarian Follicular Cysts
- Preparations
- Letrozole (Femara) orally daily
- Anastrozole (Arimidex) orally daily
- References
- Danazol
XV. Management: Surgical
- Surgical Indications
- Empiric therapy ineffective or not tolerated (e.g. failure of three medication trials)
- Adnexal Mass
- Infertility management (younger women with adequate ovarian reserve)
- Laparoscopy for diagnosis and treatment
- Laser or electrocautery of implanted endometrium
- Ablate as much extopic endometrial tissue as possible for maximal pain relief
- Pain Management (unclear efficacy)
- Presacral neurectomy (midline pain)
- Laparoscopic uterosacral nerve ablation (LUNA)
- Refractory cases
- Hysterectomy with oophorectomy and lesion ablation
- Endometriosis may still recur in up to 10% of cases
- Pain often persists in those who have high levels of centralized pain prior to Hysterectomy
- As-Sanie (2021) Am J Obstet Gynecol 225(5): 568.e1-e11 [PubMed]
- Hysterectomy with oophorectomy and lesion ablation
XVI. Complications
- Infertility (50-60%)
- Catamenial Pneumothorax
- Minimal to no risk of malignancy
- However has been associated with clear cell and endometrioid Ovarian Cancer
XVII. Resources
- Endometriosis Association
XVIII. References
- Jensen (2012) Mayo POIM Conferences, Rochester
- (2010) Obstet Gynecol 116(1): 223-36
- Bulun (2009) N Engl J Med 360(3): 268-79 [PubMed]
- Edi (2022) Am Fam Physician 106(4): 397-404 [PubMed]
- Mounsey (2006) Am Fam Physician 74:594-601 [PubMed]
- Schrager (2012) Am Fam Physician 87(2): 107-13 [PubMed]
- Vercellini (2003) Fertil Steril 80:560-3 [PubMed]
- Winkel (2003) Obstet Gynecol 102:397-408 [PubMed]