Endometriosis

Aka: Endometriosis

1. Epidemiology
   1. Age at diagnosis: 20-40 years (peak Incidence age 25 to 29)
   2. Prevalence: 10-15% of 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]
2. 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
3. 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. Vascular and lymphatic spread (Halban)
      1. Associated with abdominal surgery
      2. Would explain distant spread to organs such as lung
   3. Metaplasia (Meyer)
      1. Coelomic epithelium differentiates into endometrium
   4. Decreased Cellular Immunity (Dmowski)
4. Risk Factors: More days of menstrual flow
   1. Early Menarche
   2. Late Menopause
   3. Nulliparity
   4. Mullerian abnormalities
   5. Low Body Mass Index
   6. Mother or sister with Endometriosis (Odds Ratio 7.2)
   7. Menstrual flow 6 or more days (Odds Ratio 2.5)
   8. Menstrual Cycle <28 days (Odds Ratio 2.1)
   9. References
      1. Mounsey (2006) Am Fam Physician 74:594-602 [PubMed]
5. 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. Painful Defecation (Dyschezia)
   8. Premenstrual spotting
   9. Heavy Menstrual Bleeding
   10. Suprapubic Pain
   11. Dysuria
   12. Hematuria
   13. Constipation
6. Signs: Pelvic exam
   1. Tender, nodular uterosacral ligaments (pathognomonic for Endometriosis)
   2. Fixed uterine retroversion
7. 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
8. Diagnosis
   1. Precaution
      1. Endometriosis is a histologic diagnosis
      2. Presentations are often non-specific and associated with >10 years on average delay in formal diagnosis from symptom onset
   2. Laparoscopy
      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. References
         1. Stegmann (2008) Fertil Steril 89: 1632 [PubMed]
   3. Histology (confirms visual diagnosis)
      1. Hemosiderin-laden Macrophages
      2. Endometrial tissue (epithelium, glands, stroma) found in ectopic tissue samples
   4. Tests not recommended for diagnosis
      1. CA 125
      2. CA 19-9
      3. MRI Abdomen
9. Imaging
   1. Trasvaginal Ultrasound
      1. Identifies retroperitoneal and uterosacral lesions
      2. Identifies cystic endometriomas (89% sensitivity, 91% Specificity)
      3. Misses peritoneal lesions
10. Differential Diagnosis
    1. See Dysmenorrhea
    2. See Dyspareunia
    3. See Dysuria
    4. See Infertility
    5. See Pelvic Pain
    6. See Chronic Pelvic Pain
11. Management: First Line
    1. Precautions
       1. First-line management listed below are directed to primary care providers
          1. GnRH are the best studied and most effective agents for Endometriosis
          2. GnRH (with add-back therapy) should be considered first-line therapy for specialist initiation
       2. Laparoscopy recommended initially
          1. Confirmation of diagnosis
          2. Especially if fertility desired
    2. Analgesics
       1. NSAIDs
    3. Oral Contraceptives
       1. Use for at least 3-4 months
       2. Norethindrone Acetate containing OCP may be preferred for Osteoporosis Management
       3. 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. Provera 20-30 mg daily for 2 months
       2. Depo Provera every 3 months
          1. Higher Incidence of adverse effects including Osteoporosis and weight gain risk
       3. Levonorgestrel IUD (Mirena IUD)
    5. High Dose Progesterone (not recommended)
       1. Unclear efficacy and safety
       2. Recent study suggests no benefit over standard dose
       3. Protocol
          1. Start: Depo Provera 150 mg IM q2 weeks for 4 doses
          2. Next: Depo Provera 150 mg IM monthly for 4 months
          3. Last Provera 30-50 mg for 4-6 months
12. 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
          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
          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 BMD and decreases hot flash symptoms
             2. Norethindrone Acetate (Aygestin) 5 mg orally daily
    2. Gonadotropin-Releasing Hormone antagonist (GnRH antagonist)
       1. Elagolix (Orilissa)
          1. Oral tablet taken 150 mg once daily, or if Dyspareunia, 200 mg twice daily ($870/month in 2019)
          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)
          5. (2018) Presc Lett 25(10): 58 [PubMed]
          6. Ford (2019) Am Fam Physician 100(8): 503-4 [PubMed]
    3. Other hormonal agents
       1. Danazol (androgenic agent)
          1. Dose: 200-800 mg PO qd for 6 months
          2. Efficacy: Improvement in 55-93% of patients
          3. Adverse effects in up to 85% of patients
          4. Older, but effective agent
       2. Gestrinone (anti-Progestin agent)
          1. Dose: 2.5 mg PO bid for 6 months
       3. Norethindrone 2.5 mg PO and Premarin 0.625 mg PO qd
13. Management: Surgical
    1. 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
    2. Pain Management (unclear efficacy)
       1. Presacral neurectomy (midline pain)
       2. Laparoscopic uterosacral nerve ablation (LUNA)
    3. Refractory cases
       1. Hysterectomy with oophorectomy and lesion ablation
          1. Endometriosis may still recur in up to 10% of cases
14. 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
15. Resources
    1. Endometriosis Association
       1. http://www.endometriosisassn.org
16. References
    1. Jensen (2012) Mayo POIM Conferences, Rochester
    2. Bulun (2009) N Engl J Med 360(3): 268-79 [PubMed]
    3. Mounsey (2006) Am Fam Physician 74:594-601 [PubMed]
    4. Schrager (2012) Am Fam Physician 87(2): 107-13 [PubMed]
    5. Vercellini (2003) Fertil Steril 80:560-3 [PubMed]
    6. Winkel (2003) Obstet Gynecol 102:397-408 [PubMed]