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Endometriosis
Andrew G. Alexander, MD
Maegen Dupper, MD
Heidi S. Millard, MD
image BASICS
DESCRIPTION
  • Endometriosis is a common but potentially painful and debilitating estrogen-dependent gynecologic condition affecting women of predominately reproductive age (1)[A].
  • Symptoms and signs generally consists of pelvic pain and decreased fertility.
  • Due to estrogen-dependent implants of endometrial tissue found outside the uterus. Although endometriomas have been recorded in liver, bowel, umbilicus, lung, and other tissue, the most common pathologic sites are:
    • Peritoneum(bladder, cul-de-sac, pelvic walls, ligaments, and fallopian tubes)
    • Ovaries
    • Rectovaginal septum
  • Ectopic endometrial implants proliferate and slough with the menstrual cycle
  • Stage I (minimal) to IV (severe). Staging is useful in therapeutic planning but does not correlate with pain severity.
EPIDEMIOLOGY
Prevalence
  • Female only
  • Affects 11% of fertile women (2)
  • Found in 30-50% of infertile women
  • Found in 50-60% of women and adolescent women with pelvic pain
Pediatric Considerations
Endometriosis may begin with puberty as endometrial implants are dependent on ovarian hormones. This can lead to debilitating pelvic pain and severe dysmenorrhea associated with missed school, social, and family activities.
Pregnancy Considerations
The presence of endometriosis decreases fecundability from 15-20% per month to 2-10% per month. 25-50% of infertile women have endometriosis. However, pelvic endometriosis generally improves during pregnancy.
Geriatric Considerations
Although menopause often results in a resolution of symptoms, pelvic endometriosis may extend into menopause and is exacerbated by hormone replacement therapy (HRT).
ETIOLOGY AND PATHOPHYSIOLOGY
  • Not fully understood, several factors are believed to play a role, including immunologic changes and genetic predisposition in the presence of abnormal proliferating endometrial tissue implants causing chronic peritoneal inflammation.
  • Theories include:
    • Sampson theory: Retrograde menstruation results in peritoneal implantation and disease
    • Halban theory: Distant disease is probably caused by hematogenous/lymphatic dissemination or metaplastic transformation.
    • Coelomic metaplasia: Coelomic epithelium remains undifferentiated in the peritoneal cavity and differentiates to form functioning endometrium.
  • Endometrial-associated infertility is multifactorial:
    • Pelvic inflammation
    • Anatomic disruption of pelvic structures (involvement of the fallopian tube may cause isthmic tubal obstruction)
    • Proliferation and activation of peritoneal macrophages (may predispose to gamete phagocytosis)
    • Alteration in eutopic endometrium
Genetics
Odds ratio of symptomatic endometriosis with a first degree affected relative is 7.2. Those with affected first-degree relatives have a 26% chance of severe manifestations, versus 12% if no first degree affected relatives.
RISK FACTORS
  • Family history
  • Menstruation and ovulation
  • Delayed childbirth
GENERAL PREVENTION
  • Suppression of heavy menstruation and ovulation with oral contraceptives during adolescence may delay sequelae.
  • Some factors are considered protective:
    • Fruits, green vegetables, n-3 long-chain fatty acids
    • Aerobic exercise may decrease pelvic pain.
  • Early diagnosis and treatment might help prevent sequelae.
COMMONLY ASSOCIATED CONDITIONS
Associated with increased risks for cancer of the ovary, breast, endometrium; increased risk for cutaneous melanoma, non-Hodgkin lymphoma, autoimmune diseases, asthma, and cardiovascular disease
image DIAGNOSIS
  • History: dysmenorrhea (50-90% of cases) due to deep infiltrating endometrial implants
  • Dyspareunia due to lesions of the cul-de-sac, uterosacral ligaments, and posterior vaginal fornix
  • Dyschezia due to involvement of the rectosigmoid colon and rectovaginal regions
  • Chronic pelvic pain (≥6 months) that worsens with time and begins 1 to 2 days prior to menstrual cycles
  • Hematochezia
  • Cyclic nausea, abdominal distention
  • Infertility (late finding)
  • History of pelvic pain, infertility, and hysterectomy in first- or second-degree relative
PHYSICAL EXAM
  • Focal pain/tenderness on pelvic exam is associated with endometriosis in 66% of patients.
  • Pelvic mass may be present.
  • Immobile pelvic organs (frozen pelvis)
  • Rectovaginal exam revealing uterosacral nodules, beading, or tenderness
  • An exquisitely tender “barb” stabbing pain in the region of the uterosacral ligament is found in severe cases.
DIFFERENTIAL DIAGNOSIS
Differential diagnosis of pelvic pain includes all causes of acute abdomen and
  • Complications of intrauterine/ectopic pregnancy
  • Pelvic adhesions
  • Acute salpingitis/pelvic inflammatory disease
  • Ruptured ovarian cyst
  • Uterine leiomyomas
  • Adenomyosis
  • Irritable bowel syndrome
  • Inflammatory bowel disease
  • Pelvic malignancy
  • Cystitis
  • Depression
  • History of sexual abuse
  • Chronic pain syndrome
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • Labs are only useful to rule out other diagnoses; there are no useful labs to rule in endometriosis.
  • CA-125 levels are not recommended (3)[C] due to low sensitivity.
  • If history and physical exam reveal adnexal pain or tenderness with/without fullness on pelvic exam
    • Transvaginal ultrasound (US) and MRI are equally effective in detecting ovarian endometriomas: sensitivity, 80-90%; specificity, 60-98% for both
    • US is preferred (less costly).
    • Both modalities are poor in detecting peritoneal implants and adhesions.
Diagnostic Procedures/Other
Definitive diagnosis is made by the gross and microscopic characteristics of tissue visualized and biopsied during laparoscopy or laparotomy.
Test Interpretation
  • Laparoscopically visualized red and blue-black lesions described as “powder-burns,” adhesions, and “chocolate cysts” on the ovarian and peritoneal surfaces.
  • Histologically described endometrial glands and stroma on analysis of biopsied lesions
image TREATMENT
GENERAL MEASURES
Management is dependent on multiple factors:
  • Age and reproductive desires of the patient
  • The certainty of the diagnosis
  • The degree of degradation on quality of life due to pain and infertility
  • The threat to other organ systems: GI tract, bladder
MEDICATION
Medications are used to improve the patient's quality of life through symptom relief, and to prevent progression of the disease and its potential to cause organ dysfunction.
P.341

First Line
Women found to have endometriomas during incidental surgery or studies may not need any treatment. Others with minimal symptoms may find sufficient relief with NSAID medications. Increased exercise, especially aerobic, may help others.
  • NSAIDs initiated at the beginning or just before menses. Evidence is inconclusive on effectiveness (4)[B].
  • Cyclic combined oral contraceptive pills (OCPs) suppress ovulation.
Second Line
  • Low-dose OCPs or low-dose progestins with recommendations to switch from cyclic to continuous contraception for 3 to 6 months if symptoms persist or if there is chronic, noncyclic pelvic pain
    • Levonorgestrel intrauterine device (IUD) (Mirena) found to decrease recurrence of painful menstruation (although not FDA approved for this indication).
  • Medroxyprogesterone acetate 150 mg IM 3 months. Prolonged use may lead to loss of bone mineral density of uncertain clinical significance. Gonadotropin-releasing hormone (GnRH) agonists: Inhibit pituitary gonadotropin synthesis and induce a hypoestrogenic state.
  • Norethindrone acetate 5 mg PO once daily plus conjugated equine estrogen 0.625 mg PO once daily
Third Line
If symptoms and signs continue, physicians should be experienced in the use and side effects of gonadotropin-releasing hormone analogues prior to their use (symptoms return in as many as 70% of treated patients):
  • Leuprolide acetate (Depo-Lupron) 3.75 mg IM each month or 11.25 mg IM every 3 months (gluteal)
  • Nafarelin (Synarel) intranasal one spray (200 &mgr;g) in one nostril each morning and the other nostril each evening (start between days 2 and 4 of menstrual cycle)
  • Goserelin (Zoladex) implant 3.6 mg SC in upper abdominal wall every 28 days
  • Danazol: also effective, with side effects similar to GnRH analogs
  • Aromatase inhibitors (anastrozole and letrozole) prolong the remission induced by gonadotropin-releasing hormone medications.
ISSUES FOR REFERRAL
  • Refer early to a physician with expertise in medical and surgical treatment of endometriosis, especially if the patient desires to conceive in the future.
  • Indications for referral to a properly experienced gynecologist include the following:
    • Need for definitive diagnosis
    • Failure to respond to a conservative or first-line therapy
    • Chronic pelvic pain
    • Delayed fertility
ADDITIONAL THERAPIES
Regular exercise and counseling for pain-management strategies. Narcotics are contraindicated for chronic pain.
SURGERY/OTHER PROCEDURES
Surgery (laparoscopy or laparotomy) is both diagnostic and therapeutic (first line or when conservative measures fail):
  • Peritoneal endometriosis: laser ablation/excision/fulguration
  • Ovarian endometriosis (endometriomas) >3 to 4 cm: ablation, excision, drainage
  • Lysis of adhesions (LOA)
  • Hysterectomy with bilateral salpingo-oophorectomy for debilitating symptoms refractory to other medical or surgical treatments:
    • Relieves pain in 80-90%, but pain recurs in 10% within 1 to 2 years after surgery
    • Postoperative HRT should include estrogen and progestogen or progesterone
  • Interruption of nerve pathways: laparoscopic ablations and presacral neurectomy improve dysmenorrhea
  • Fertility procedures: Ablation or excision of lesions with LOA is recommended to treat infertility in stages I-II disease:
    • Spontaneous conception should be attempted for 1 year prior to assisted reproduction techniques.
    • Disease does not endanger in vitro fertilization (IVF) pregnancies.
COMPLEMENTARY & ALTERNATIVE MEDICINE
  • Osteopathic manipulative therapy found to improve quality of life (3)[C].
  • Postsurgical use of Chinese herbal medicine has been found to be effective.
  • Acupuncture may be more effective than Danazol to decrease pain, irregular menstruation, and perineal swelling (6)[B].
  • Osteopathic manipulation
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Routine gynecologic care
Patient Monitoring
Symptomatic and asymptomatic pelvic masses http://www.acog.org/
PROGNOSIS
  • Excellent, especially if diagnosis and treatment plans are initiated early in disease course
  • Poor for recovery of fertility if the disease has progressed to stage III/IV
  • Symptoms and signs improve after bilateral oophorectomy.
REFERENCES
1. Brown J, Farquhar C. Endometriosis: an overview of Cochrane Reviews. Cochrane Database Syst Rev. 2014;(3):CD009590.
2. Buck Louis GM, Hediger ML, Peterson CM, et al. Incidence of endometriosis by study population and diagnostic method: the ENDO study. Fertil Steril. 2011;96(2):360-365.
3. Daraï C, Deboute O, Zacharopoulou C, et al. Impact of osteopathic manipulative therapy on quality of life of patients with deep infiltrating endometriosis with colorectal involvement: results of a pilot study. Eur J Obstet Gynecol Reprod Biol. 2015;188:70-73.
4. Allen C, Hopewell S, Prentice A, et al. Nonsteroidal anti-inflammatory drugs for pain in women with endometriosis. Cochrane Database Syst Rev. 2009;(2):CD004753.
5. Giudice LC. Clinical practice. Endometriosis. N Engl J Med. 2010;362(25):2389-2398.
6. Zhu X, Hamilton KD, McNicol ED. Acupuncture for pain in endometriosis. Cochrane Database Syst Rev. 2011;(9):CD007864.
Additional Reading
&NA;
  • Davis L, Kennedy SS, Moore J, et al. Modern combined oral contraceptives for pain associated with endometriosis. Cochrane Database Syst Rev. 2007;(3):CD001019.
  • de Ziegler D, Borghese B, Chapron C. Endometriosis and infertility: pathophysiology and management. Lancet. 2010;376(9742):730-738.
  • Fujii S. MR Imaging of endometriosis. In: Harada T, ed. Endometriosis: Pathogenesis and Treatment. Tottori, Japan: Springer; 2014.
  • Hughes E, Brown J, Collins JJ, et al. Ovulation suppression for endometriosis. Cochrane Database Syst Rev. 2007;(3):CD000155.
  • Jacobson TZ, Duffy JM, Barlow D, et al. Laparoscopic surgery for pelvic pain associated with endometriosis. Cochrane Database Syst Rev. 2009;(4):CD001300.
  • Koga K, Yoshino O, Hirota Y, et al. Infertility treatment of endometriosis patients. In: Harada T, ed. Endometriosis: Pathogenesis and Treatment. Tottori, Japan: Springer; 2014.
  • Practice Committee of American Society for Reproductive Medicine. Treatment of pelvic pain associated with endometriosis. Fertil Steril. 2008;90(5 Suppl):S260-S269.
Codes
&NA;
ICD10
  • N80.9 Endometriosis, unspecified
  • N80.3 Endometriosis of pelvic peritoneum
  • N80.2 Endometriosis of fallopian tube
Clinical Pearls
&NA;
  • Severe dysmenorrhea and dyspareunia are never normal. Failure to respond to NSAIDs and/or OCPs warrants further investigation.
  • A rectovaginal exam can be useful in patients suspected of having endometriosis.