Endometriosis

Chapter 26. ENDOMETRIOSIS



Sept. 9, 1997. 1st year resident S. M. CHOI M.D.



  • Definition : presence of endometrial tissue (glands and stroma) outside the uterus
  • Frequent site : pelvic viscera and peritoneum
  • Occur in 7% of reproductive age women
  • Associated with pelvic pain and infertility

Etiology


  • Endometriosis : an estrogen-dependent disease



  1. Ectopic transplantation of endometrial tissue



    • Endometriosis caused by the seeding or implantation of endometrial cells by
      transtubal regurgitation during menstruation


  • Coelomic metaplasia



    • Transformation (metaplasia) of coelomic epithelium into endometrial tissue


  • Induction theory



    • Extension of the coelomic metaplasia theory
    • Endogenous (undefined) biochemical factor can induce undifferentiated peritoneal
      cells to develop into endometrial tissue



    1. Genetic factor



      • Risk of endometriosis is seven times greater if a first-degree relative has been
        affected by endometriosis
      • Multifactorial inheritance



    2. Immunologic factor



      • Immune system may be altered in women with endometriosis, and the disease may
        develop as a result of reduced immunologic clearance of viable endometrial cells
        from the pelvic cavity


      • Decreased cell mediated cytotoxicity, NK cell activity is lower in endometriosis patients


      • Higher basal activation status of peritoneal macrophage in women with
        endometriosis : may impair fertility by reducing sperm motility, increasing sperm
        phagocytosis, or interfering with fertilization by increased secretion of cytokines such as a-TNF


      • a-TNF may also facilitate the pelvic implantation of ectopic endometrium
        : may promote the growth of endometrial cells by secretion of growth and
        angiogenetic factors such as EGF, MDGF, fibronectin, adhesion molecules such as
        integrins.


  • Prevalence

    • Predominantly found in women of reproductive age
    • Great variation in the reported prevalence
    • Vary with the diagnostic methods used
    • Minimal or mild endometriosis may be more thoroughly noted in a symptomatic
      patient
    • Experience of the surgeon is important because there is a wide variation in the
      appearance of subtle endometriosis implants, cysts, and adhesions


  • Diagnosis

    1. Clinical presentation



      ·Subfertility, dysmenorrhea, dyspareunia, chronic pelvic pain, asymptomatic



      1. Pain : bilateral



        • Mechanism : local peritoneal inflammation, deep infiltration with tissue damage,
          adhesion formation, fibrotic thickening and collection of shed menstrual blood in
          endometriotic implants, resulting in painful traction with the physiologic movement
          of tissue


      2. Subfertility



        • When endometriosis is moderate or severe, involving the ovaries and causing
          adhesions that block tubo-ovarian motility and ovum pickup, it is associated with
          subfertility


        • Although numerous mechanisms (ovulatory dysfunction, luteal insufficiency,
          luteinized unruptured follicle syndrome, recurrent abortion, altered immunity, and
          intraperitoneal inflammation) have been proposed, the association between fertility
          and minimal or mild endometriosis remains controversial


        • Spontaneous abortion : in uncontrolled, retrospective studies, endometriosis has been
          associated with an increased rate of spontaneous abortion - up to 40% compared
          with a normal spontaneous abortion rate of 15-25%. The association of
          endometriosis and spontaneous abortion is difficult to assess adequately because of
          the lack of prospective studies with well - defined control groups.


      3. Endocrinologic abnormalities



        • Associated with anovulation, abnormal follicular development, luteal insufficiency,
          premenstrual spotting, and galactorrhea and hyperprolactinemia


      4. Extrapelvic endometriosis



        • Should be suspected when symptoms of pain or a palpable mass occur outside the
          pelvis in a cyclic pattern
        • Intestinal tract - abdominal and back pain, abdominal distension, cyclic rectal
          bleeding, constipation, obstruction
        • Ureteral involvement - cyclic pain, dysuria, hematuria
        • Pulmonary endometriosis - pneumothorax,hemothorax,hemoptysis during menses
        • Umbilical endometriosis - palpable mass and cyclic pain in the umbilical area




    2. Clinical examination



      • In many women with endometriosis, no abnormality is detected during the clinical
        examination
      • Vulva, vagina, and cervix should be inspected
      • Uterosacral or cul de sac nodularity, painful swelling of the rectovaginal septum,
        and unilateral ovarian enlargement.
      • Uterus often in fixed retroversion and the mobility of the ovaries and fallopian
        tubes reduced
      • Diagnosis of endometriosis should always be confirmed by biopsy of suspicious
        lesions that are obtained laparoscopically
      • Ultrasound, CT, MRI can be used to provide additional and confirmatory
        information


    3. CA 125



      • Marker found on derivatives of the coelomic epithelium, and common to most
        nonmucinous epithelial ovarian carcinoma
      • High specificity (80%) , low level sensitivity (20 -50 %)
      • Sensitivity of 66% was found when CA125 was determined during the both the
        follicular phase and the menstrual phase in each patient and when the ratio of
        menstrual versus follicular values (>1.5) was used instead of one CA125
      • Serial CA125 determinations may be useful to predict the recurrence of
        endometriosis after therapy


    4. Laparoscopic findings



      • Inspection and palpation with a blunt probe of the bowel, bladder, uterus, tubes,
        ovaries, cul-de-sac, and broad ligament
      • Typical lesion : powder-burn, gunshot lesion, black, dark-brown, or bluish nodules
        or small cysts containing old hemorrhage surrounded by a variable degree of
        fibrosis
      • Subtle lesion : red implants (petechial, vesicular, polypoid, hemorrhagic, red flame-
        like), serous or clear vesicles, white plaques or scarring, yellow-brown peritoneal
        discoloration of the peritoneum, and subovarian adhesion.
      • Histologic confirmation of the laparoscopic impression is essential for the diagnosis
        of endometriosis, not only for subtle lesions but also for typical lesions reported to
        be histologically negative in 24% of cases
      • Ovarian endometriosis



        . Superficial endometriosis



        . Ovarian endometriotic cysts


        - contain a thick, viscous dark brown fluid (chocolate fluid)

        - because this fluid may also be found in other conditions, such as a hemorrhagic
        corpus luteum cysts or neoplastic cysts, biopsy and preferably removal of the
        ovarian cyst for histologic confirmation are necessary.


    5. Histological confirmation



      ·Microscopically, endometriotic implants consist of endometrial glands and stroma
      with or without hemosiderin-laden macrophages



      1. Stromal endometriosis,


        ·Containing endometrial stroma with hemosiderin-laden macrophages or hemorrhages
        may represent a very early event in the pathogenesis of endometriosis.


      2. Different type of lesions may have different degrees of proliferative or secretory
        glandular activity


    6. Classifications




      • AFS system based on appearance, size, and depth of peritoneal and ovarian implants
        , presence, extent, and type of adnexal adhesions, degree of cul-de-sac obliteration.


      • This system reflects the extent of endometriotic disease, but it is not based on the
        correlation of pain or infertility and it has considerable intraobserver and
        interobserver variability.


    7. Spontaneous evolution



      • Endometriosis appears to be a progressive disease


      • Subtle lesions and typical implants may represent younger and older types of
        endometriosis, respectively


      • Incidence, overall pelvic area involved, and volume of subtle lesions decreased with
        age, but in typical lesions these parameters and the depth of infiltration increased
        with age


      • Remodeling of endometriotic lesions (transition between typical and subtle types) has
        been reported to occur in women and in baboons, indicating that endometriosis is a
        dynamic condition


      • Characteristics of endometriosis are variable during pregnancy, and lesions tend to
        enlarge during the first trimester but regress thereafter establishment of a
        'pseudopregnant state' with exogenously administered estrogen and progestins was
        based on the belief that symptomatic improvement may result from decidualization of
        endometrial implants during pregnancy.



  • Treatment


    ·Unfortunately, elimination of the endometriotic implants by surgical or medical
    treatment often provides only temporarily relief. Therefore, the goal should be to
    eliminate the endometriotic lesions and, more importantly, to treat the sequelae (pain
    and subfertility) often associated with this disease

    1. Surgical treatment



      • Laparoscopy can be used in most women, and this technique decreases cost,
        morbidity, and the possibility of recurrence of adhesions postoperatively.

      • CO2 laser appear to be the preferred method <- minimal thermal damage


      • Goal of surgery is to excise or coagulate all visible endometriotic lesions associated
        adhesions and to restore normal anatomy.


      • In patients with severe endometriosis, surgical treatment be preceded by a 3 month
        course of medical treatment to reduce vascularization and nodular size are
        recommended


      • Postop. hormone replacement with estrogen is required after bilateral oophorectomy,
        and there is a negligible risk of renewed growth of residual endometriosis to reduce
        this risk, hormonal replacement therapy should be withheld until 3months after
        surgery.


      • Result of surgical treatment



        . Pain : laser laparoscopy may be effective for the treatment of mild to severe
        endometriosis pain, minimal endometriosis, laser treatment may limit progression of
        disease


        . Subfertility : success of surgery in relieving infertility is directly related to the
        severity of endometriosis. Preop. medical treatment may be useful to reduce the
        extents of endometriosis in patients with advanced disease. Postop. medical
        treatment is rarely indicated because it prevents pregnancy, and higher pregnancy
        rates occur during the first 6 to 12 months after conservative surgery.


    2. Medical treatment


      ·Estrogen is known to stimulate the growth of endometriosis, hormonal therapy has
      been designed to suppress estrogen synthesis, thereby inducing atrophy ectopic
      endometrial implants or interrupting the cycle of stimulation and bleeding.



      1. Oral contraceptives



        • Low dose monophasic combination contraceptives (one pill per day for 6 to 12
          months) was originally used to induce 'pseudopregnancy' caused by the resultant
          amenorrhea and decidualization of endometrial tissue. Unfortunately, there is no
          convincing evidence that medical therapy with oral contraceptives offers definitive
          therapy. Instead, endometrial implants survive the induced atrophy with reactivation
          in most patients following termination of treatment.

          Any low dose combination oral contraceptive pill containing 30-35mcg ethinyl
          estradiol used continuously can be effective in the management of endometriosis
          objective of the treatment is induction of amenorrhea, which should be continued
          for 6 to 12 months


        • First year recurrence rate : 17 -18%, annual recurrence rate : 5-10%

          Posttreatment pregnancy rate up to 50%


      2. Progestins



        • Antiendometriotic effect by causing initial decidualization of endometrial tissue
          followed by atrophy.


        • MPA starting at a dose of 30mg/day and increasing the dose based on the clinical
          response and bleeding patterns


        • 150mg IM every 3months also effective for the treatment of pain but is not
          indicated in infertile women because it induce profound amenorrhea and
          anovulation, and a varying length of times is required for ovulation to resume
          after discontinuation of therapy


        • Side effect - nausea, weigt gain, fluid retension, breakthrough bleeding due to
          hypoestrogenemia


      3. Gestrinone



        • 19-nortestosterone derivative with androgenic antiprogestagenic, antiestrogenic,
          antigonadotropic properties
        • Long half life (28hours) given orally
        • Standard dose 2.5mg twice a week
        • Side effect- nausea, muscle cramps, and androgenic effect such as weight gain,
          acne, seborrhea, and oily hair/skin
        • Pregnancy contraindicated while taking gestrinone


      4. Danazol



        • Suppression of GnRH or gonadotropin secretion
        • Direct inhibition of steroidogenesis
        • Increased metabolic clearance of estradiol and progesterone
        • Direct antagonistic interaction with endometrial androgen and progesterone
          receptors
        • Immunologic attenuation of potentially adverse reproductive effect --> high
          androgen, low estrogen environment
        • Dose - absence of menstruation is a better indicator of response than drug dose
          start with 400mg daily (200mg twice a day) and increase the dose to achieve
          amenorrhea and relieve symptoms
        • Side effect - weight gain, fluid retention, acne, oily skin, hirsuitism, hot
          flashes, atrophic vaginitis, reduced breast size, reduced libido, fatigue, nausea, muscle
          cramps, emotional instability
        • Contraindication - liver disease, hypertension, congestive heart failure, impaired renal
          function, pregnancy


      5. GnRH



        • Cause a loss of pituitary receptors and downregulation of GnRH activity, resulting
          in low FSH and LH level -- induced and reversible state of pseudomenopause
        • Leuprolide, buserelin, nafarelin, histrelin, goserelin, deslorelin, tryptorelin
        • Must be administered IM, SC ,or by intranasal absorption
        • Best therapeutic effect - estradiol dose of 20 -40 pg/ml
        • Side effect - hot flashes, vaginal dryness, reduced libido, osteoporosis (add-back
          regimen)




  • Recurrence

    • Recurrence rate approximately 5-20% per year, reaching a cumulative rate of 40%
      after 5years

  • Assisted reproductive technology

    • Infertility in patients with minimal to mild endometriosis can be treated by
      nonspecific cycle fecundity enhancement, including controlled ovarian hyperstimulation
      with intrauterine insemination, gamete intrafallopian transfer, and in vitro fertilization.

  • Prevention of infertility

    • Incidental finding of minimal to mild endometriosis in a young woman without
      immediate interest in pregnancy


    • Mild disease can be treated by surgical removal of implants at the time of diagnosis,
      followed by administration of cyclic low-dose combination oral contraceptives to
      prevent recurrence


    • More advanced disease can be treated medically for 6 months , followed by cyclic or
      continuous oral contraceptives to prevent progression of disease.