Endometriosis

Aka: Endometriosis

1. See Also
   1. Dysmenorrhea
   2. Chronic Pelvic Pain
2. Definitions
   1. Endometriosis
      1. Ectopic, functional endometrial tissue (glands and stroma) implanted outside the Uterus, and especially on the surface of pelvic organs
      2. Estrogen-dependent lesions associated with local inflammation at implant sites, resulting in Chronic Pain and Infertility
3. Epidemiology
   1. Age at diagnosis: 20-40 years (peak Prevalence age 25 to 35 years old)
   2. Prevalence: 10-15% of women (2 to 11% for asymptomatic women)
      1. Prevalence in women with Pelvic Pain: 82%
      2. Prevalence in women with Infertility: 21%
      3. Eskenazi (1997) Obstet Gynecol Clin North Am 24:235 [PubMed]
4. Pathophysiology: Ectopic Endometrial Tissue implant Sites
   1. Ovary (50%)
   2. Uterosacral ligaments
   3. Rectovaginal septum
   4. Sigmoid colon
   5. Serosal surface of
      1. Uterus or fallopian Tubes
      2. Cervix, Vagina or vulva
      3. Bladder
   6. Distant intrapelvic or low Abdominal Sites
      1. Appendix or Ileum
      2. Abdominal scars
      3. Umbilicus
      4. Ureter
   7. Distant extrapelvic sites (rare)
      1. Diaphragm, Pleura, or Lungs
      2. Spleen
      3. Gallbladder
      4. Kidney
5. Pathophysiology: Theories of Etiology
   1. Implantation during Menstruation (Sampson)
      1. Most accepted theory
      2. Endometrial cells spread via tube to peritoneum
      3. Retrograde flow
         1. Retrograde flow likely occurs in most women but at higher volumes in those with Endometriosis
         2. Implantation more likely in the presence of the plasminogen activator inhibitor gene
   2. Other theories
      1. Vascular and lymphatic spread (Halban)
         1. Associated with abdominal surgery
         2. Would explain distant spread to organs such as lung
      2. Metaplasia (Meyer)
         1. Coelomic epithelium differentiates into endometrium
      3. Decreased Cellular Immunity (Dmowski)
   3. Superimposed Factors
      1. Estrogen Effects
         1. Promotes Endometriosis implantation and proliferation, and stimulates inflammatory factors
      2. Neurogenesis
         1. Increased nerve growth factors, with increased Sensory Nerves (esp. sympathetic fibers) in regions of Endometriosis
6. Risk Factors
   1. Factors resulting in more days of menstrual flow
      1. Early Menarche
      2. Late Menopause
      3. Nulliparity
      4. Menstrual flow 6 or more days (Odds Ratio 2.5)
      5. Menstrual Cycle <28 days (Odds Ratio 2.1)
   2. Family History
      1. Mother or sister with Endometriosis (Odds Ratio 7.2)
      2. Twin studies with 50% heritability of Endometriosis
   3. Other factors
      1. Mullerian abnormalities
      2. Low Body Mass Index
      3. Low birth weight
      4. Prematurity
      5. Diethylstilbesterol (DES) In-Utero Exposure
   4. References
      1. Mounsey (2006) Am Fam Physician 74:594-602 [PubMed]
7. Symptoms
   1. Asymptomatic in 25-30% of women with Endometriosis
   2. Chronic Pelvic Pain (70%, Odds Ration 5.2)
   3. Dysmenorrhea (71%, Odds Ratio 8.1)
      1. Cyclic
      2. Progressively increasing in severity
      3. Affects bilateral lower Abdomen
      4. Associated with sense of rectal pressure
      5. Refractory to anti-Prostaglandins
   4. Dyspareunia (44%, Odds Ration 6.8)
   5. Infertility (15-20%, Odds Ratio 8.2)
   6. Ovarian Cysts (Odds Ratio 7.3)
   7. Premenstrual spotting
   8. Heavy Menstrual Bleeding (51%)
   9. Cyclical, painful gastrointestinal symptoms or urinary symptoms (e.g. Hematuria, Dysuria) correlating with menstrual periods
   10. Painful Defecation (Dyschezia) or Constipation
   11. Suprapubic Pain
8. Signs: Pelvic exam
   1. Precautions
      1. A normal pelvic exam does not exclude Endometriosis
   2. Tender, nodular uterosacral ligaments or cul-de-sac (pathognomonic for Endometriosis)
   3. Adnexal or tubo-Ovarian Mass
   4. Induration of the rectovaginal septum
   5. Fixed uterine retroversion
9. Types: Presentations
   1. Endometrial implantation
      1. Ectopic tissue lies superficially on peritoneum
   2. Endometriomas (chocolate cysts)
      1. Edometrial lined Ovarian Cysts
   3. Endometriotic Nodules
      1. Solid, complex mix of endometrium with fibromuscular and fatty tissue
      2. Localized between vagina and Rectum
10. Imaging
    1. Transvaginal Ultrasound (TVUS)
       1. Noninvasive study with high Test Sensitivity and Test Specificity for deep pelvic Endometriosis
       2. Identifies retroperitoneal and uterosacral lesions (85% Specificity)
       3. Identifies cystic endometriomas (89% sensitivity, 91% Specificity)
       4. Misses peritoneal lesions
       5. Bladder site tenderness technique has Test Sensitivity and Test Specificity >97%
       6. Noventa (2015) Fertil Steril 104(2): 366-83 [PubMed]
    2. MRI Pelvis (with or without MRI Abdomen)
       1. Indicated in cases of deep infiltrating Endometriosis of the bowel, Bladder or ureter
11. Diagnosis
    1. Precautions
       1. Although Endometriosis is formally a histologic diagnosis, clinical diagnosis may be made by careful history and exam
       2. Presentations are often non-specific and associated with 4 to 10 years on average delay in formal diagnosis from symptom onset
       3. Clinical diagnosis is sufficient to initiate empiric treatment (without surgery or tissue diagnosis)
       4. Transvaginal Ultrasound (TVUS) may also be sufficient for definitive diagnosis
    2. Laparoscopy with biopsy (gold standard)
       1. Red, Brown or blue-black nodular implants
       2. Powder-burn spots
          1. Multiple, tiny, puckered hemorrhagic foci
       3. Ectopic tissue findings predictive factors for Endometriosis
          1. Implants >10 mm wide or >5 mm deep
          2. Implants with mixed coloration
          3. Implants in cul-de-sac, ovarian fossa, or utero-sacral ligaments
       4. Histology (confirms visual diagnosis)
          1. Hemosiderin-laden Macrophages
          2. Endometrial tissue (epithelium, glands, stroma) found in ectopic tissue samples
       5. References
          1. Stegmann (2008) Fertil Steril 89: 1632 [PubMed]
    3. Tests not recommended for diagnosis
       1. CA 125
       2. CA 19-9
12. Differential Diagnosis
    1. See Dysmenorrhea
    2. See Dyspareunia (e.g. Cervicitis or Vaginitis, Vulvodynia, Vaginal Atrophy)
    3. See Dysuria (e.g. Urinary Tract Infection, Interstitial Cystitis)
    4. See Infertility
    5. See Pelvic Pain
    6. See Chronic Pelvic Pain
    7. See Adnexal Mass (e.g. Ovarian Cyst)
    8. See Anorectal Pain or Dyschezia (e.g. Anal Fissure, Pelvic Floor Disorders)
    9. See Abdominal Wall Pain Causes (e.g. nerve entrapment)
    10. Functional Constipation
    11. Irritable Bowel Syndrome
    12. Pelvic Congestion Syndrome
    13. Sexually Transmitted Infection or Pelvic Inflammatory Disease
13. Management: First Line
    1. Precautions
       1. Endometriosis is a chronic disease requiring ongoing suppression of Estrogen, tissue proliferation and inflammation
       2. First-line management listed below are directed to primary care providers
          1. However, second-line therapies (esp. GnRH) are most effective and typically managed by gynecologic specialists
          2. GnRH are the best studied and most effective agents for Endometriosis
          3. GnRH (with add-back therapy) should be considered first-line therapy for specialist initiation
       3. Laparoscopy is no longer required before initiating management
          1. Clinical diagnosis is sufficient after excluding other significant causes (e.g. infection)
          2. Laparoscopy may be considered for confirmation of diagnosis (especially if fertility desired)
          3. Transvaginal Ultrasound may be considered for definitive diagnosis in women not desiring pregnancy
    2. Analgesics
       1. NSAIDs
          1. Effective in Primary Dysmenorrhea, but efficacy in Endometriosis is unclear
          2. Brown (2017) Cochrane Database Syst Rev (1):CD004753 [PubMed]
    3. Oral Contraceptives (preferred)
       1. Use for at least 3-4 months
       2. If effective, may be continued until pregnancy desired or menopausal age
       3. Transdermal patches and vaginal rings are alternatives to Oral Contraceptives
       4. Norethindrone Acetate containing OCP may be preferred for Osteoporosis Management
          1. Norethindrone 2.5 mg orally and Premarin 0.625 mg orally daily may be considered in Perimenopause state
       5. Desogestrel OCPs (moderate Progestin, low Estrogen)
          1. Desogen (monophasic, 30 mcg Ethinyl Estradiol)
          2. Ortho-Cept (monophasic, 30 mcg Ethinyl Estradiol)
          3. Mircette (monophasic with 20 mcg Ethinyl Estradiol)
          4. Cyclessa (triphasic with 25 mcg Ethinyl Estradiol)
    4. Progesterone
       1. Indicated if Estrogen products are contraindicated or not tolerated
       2. Provera 20-30 mg daily for 2 months
       3. Levonorgestrel IUD (Mirena IUD)
       4. Depo Provera 150 mg every 3 months
          1. Higher Incidence of adverse effects including Osteoporosis and weight gain risk
          2. High dose protocol not found to offer benefit and not recommended (e.g. 150 mg IM every 2 weeks for 4 doses)
    5. Adjunctive and Complimentary Measures
       1. Acupuncture
          1. Mira (2018) Int J Gynaecol Obstet 143(1): 2-9 [PubMed]
14. Management: Second Line
    1. Gonadotropin-releasing Hormone Agonist (GnRH agonist)
       1. Efficacy
          1. GnRH are the best studied and most effective agents for Endometriosis
          2. Up to 100% improvement for 6-12 months post-therapy
       2. Mechanism
          1. Initially stimulates LH and FSH release (results in initial Endometriosis symptom flare)
          2. After 7 days, LH and FSH are depleted
          3. Ultimately results in pituitary GnRH receptor down-regulation
       3. Agents: Used for 6 months as initial course (longer courses are not recommended due to adverse effects)
          1. Leuprolide (Lupron)
             1. Dose: 3.75 mg injected every 4 weeks
          2. Goserelin (Zoladex)
             1. Implanted 3.6 mg SubQ for 6 months or
          3. Nafarelin (Synarel)
             1. Dose: 200 mcg intranasal twice daily for 6 month
          4. Buserelin
          5. Decapeptyl
       4. Adverse effects (most women are Hypoestrogenic at 8 weeks)
          1. Risk of Osteoporosis
          2. Initial Endometriosis symptom flare
          3. Use add-back therapy for most patients
             1. Maintains Bone Mineral Density and decreases hot flash symptoms
             2. Norethindrone Acetate (Aygestin) 5 mg orally daily (or low dose combined Estrogen and Progesterone product)
    2. Gonadotropin-Releasing hormone Antagonist (GnRH Antagonist)
       1. Mechanism
          1. Inhibits gonadotropin release via initial competitive binding of GnRH receptors (and later their down regulation)
          2. Results in hypoestrogenic state
          3. Effective in Dysmenorrhea and non-menstrual Pelvic Pain
       2. Adverse Effects
          1. Fewer adverse effects than GnRH agonists
          2. Adverse effects include Menopause effects (Osteoporosis, Hot Flashes), Headaches, Insomnia
          3. Not associated with Endometriosis symptom flare (unlike GnRH agonists)
          4. Decreases efficacy of hormonal contraceptives (non-Hormonal Contraception is recommended)
       3. Preparations
          1. Elagolix (Orilissa)
             1. Oral tablet 150 mg once daily for up to 24 months
             2. If Dyspareunia, 200 mg orally twice daily for up to 6 months
          2. Relugolix 40 mg with Estradiol 1 mg and Norethindrone 0.5 mg (Myfembree)
             1. One tablet daily for up to 24 months
          3. Linzagolix
             1. Pending clinical trials in 2022
       4. References
          1. (2018) Presc Lett 25(10): 58 [PubMed]
          2. Ford (2019) Am Fam Physician 100(8): 503-4 [PubMed]
    3. Other hormonal agents
       1. Danazol
          1. Androgenic agent that increases Free Testosterone and lowers gonadotropins and Estrogens
          2. Dose: 200-800 mg orally daily for 6 months (also available as vaginal preparation)
          3. Efficacy: Improvement in 55-93% of patients
          4. Adverse effects in up to 85% of patients (related to androgen activity)
          5. Older, but effective agent
       2. Aromatase Inhibitors
          1. Aromatase Inhibitors block androgen conversion to Estrogens
          2. May be considered for off-label use in severe Endometriosis
             1. May be combined with a GnRH agonist or combined Oral Contraceptive
             2. Avoid prolonged use due to bone loss, Ovarian Follicular Cysts
          3. Preparations
             1. Letrozole (Femara) orally daily
             2. Anastrozole (Arimidex) orally daily
          4. References
             1. Patwardhan (2008) BJOG 115(7): 818-22 [PubMed]
15. Management: Surgical
    1. Surgical Indications
       1. Empiric therapy ineffective or not tolerated (e.g. failure of three medication trials)
       2. Adnexal Mass
       3. Infertility management (younger women with adequate ovarian reserve)
    2. Laparoscopy for diagnosis and treatment
       1. Laser or electrocautery of implanted endometrium
       2. Ablate as much extopic endometrial tissue as possible for maximal pain relief
    3. Pain Management (unclear efficacy)
       1. Presacral neurectomy (midline pain)
       2. Laparoscopic uterosacral nerve ablation (LUNA)
    4. Refractory cases
       1. Hysterectomy with oophorectomy and lesion ablation
          1. Endometriosis may still recur in up to 10% of cases
          2. Pain often persists in those who have high levels of centralized pain prior to Hysterectomy
          3. As-Sanie (2021) Am J Obstet Gynecol 225(5): 568.e1-e11 [PubMed]
16. Complications
    1. Infertility (50-60%)
    2. Catamenial Pneumothorax
    3. Minimal to no risk of malignancy
       1. However has been associated with clear cell and endometrioid Ovarian Cancer
17. Resources
    1. Endometriosis Association
       1. http://www.endometriosisassn.org
18. References
    1. Jensen (2012) Mayo POIM Conferences, Rochester
    2. (2010) Obstet Gynecol 116(1): 223-36
    3. Bulun (2009) N Engl J Med 360(3): 268-79 [PubMed]
    4. Edi (2022) Am Fam Physician 106(4): 397-404 [PubMed]
    5. Mounsey (2006) Am Fam Physician 74:594-601 [PubMed]
    6. Schrager (2012) Am Fam Physician 87(2): 107-13 [PubMed]
    7. Vercellini (2003) Fertil Steril 80:560-3 [PubMed]
    8. Winkel (2003) Obstet Gynecol 102:397-408 [PubMed]