Endometriosis

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Endometriosis

• Presence of endometrial glands and stroma
  outside the uterus
• Ovaries, pelvic peritoneum, tubal serosa,
• gastrointestinal tract, urinary tract.
• Surgical scars
• Extra-abdominal sites.

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Prevalence

• 5 to 15 of women of childbearing age1
• 50 to 70 of women with chronic pelvic pain
• 20 to 40 of infertile women2
• 6 million women in North America3

1National Institute of Health, 91-2413 2 Mayo
Foundation for Medical Education and
Research 3American Family Physician, 1999, vol
60, p. 1753
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Epidemiology

• 5-10 of reproductive-age women
• 25-35 of patients with infertility
• Usually regresses following menopause and not
  usually found prior to menarche
• No differences among ethnic groups or
  socioeconomic status
• Genetic predisposition - 6-7 increased risk with
  history of first degree relative

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Prevalence

• 30,000 new cases diagnosed each year in Canada
  (300,000 in the U.S.)
• A 6 to 9 year period between the onset of
  symptoms and diagnosis of endometriosis1
• 40 recurrence within 2 to 5 years following
  laparoscopic procedure2

1International Journal of GynecologyObstetrics
74 S1 (2001) S25-30 2International Journal of
GynecologyObstetrics 74 S1 (2001) S15-20
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Theories on Pathogenesis

• Transplant of endometrial tissue via retrograde
  menstruation
• Coelemic metaplasia
• Lymphatic or vascular transport
• Altered cellular immunity/ autoimmune mechansisms

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Pathogenesis

• Retrograde flow supported by
• Endometrial cells in menstrual fluid are capable
  of implanting on peritoneal surfaces
• Endometriosis is most commonly seen in dependent
  portions of pelvis
• Endometriosis occurs in patients with uterine
  outlet obstruction

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Pathogenesis

• Coelemic metaplasia transformation of embryonic
  tissue
• Peritoneal mesothelium, mullerian epithelium, and
  germinal epithelium may be derived from a common
  embryonic tissue
• Endometriosis reported in
• Prepubertal girls
• Women who have never menstruated
• Men
• Unusual sites such as knee, thumb, eye

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Pathogenesis

• Lymphatic vascular metastasis
• May explain endometriosis in distant sites
  outside pelvis

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Pathogenesis

• Immune mechanisms supported by
• Not all women with seeding of menstrual debris
  into pelvis develop endometriosis
• Evidence for decreased cellular immunity
• Increased prevalence of humoral antibodies
  against endodmetrial tissue

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ENDOMETRIOSIS (Hypothesis)

• In patients affected, there is an intrinsic
  difference in the endometrium

• Remains viable (apoptosis)

• Adheres to mesothelial cells (integrins)

• Erodes extracellular matrix (MMPs)

• Prompts vascularization (VEGF)

• Circumvents immune system mechanisms (i. e.
  leucocytes)

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Endometriosis

• Many evidences that endometrium of
• patients with endometriosis is different
• Aromatase P450 expression
• ? Expression of MCP-1
• ? FGF
• ? Apoptosis in endometrium of patients with
• endometriosis
• Ref From the VIII World Congress on
  Endometriosis, San Diego, Ca. February 2002

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ENDOMETRIOSIS (Hypothesis)

• In patients affected, feedback control mechanisms
  alter the endometrium

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Signs Symptoms

• Chronic pelvic pain

• Dysmenorrhea

• Dyspareunia

• Infertility

• Abnormal uterine bleeding

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Presenting symptoms

• Dysmenorrhea (25-80 of patients with pelvic pain
  or dysmenorrhea have endometriosis)
• Dyspareunia
• Dyschezia
• History of infertility (30-40 of patients with
  endometriosis)
• Abnormal uterine bleeding
• Other GI complaints (50 of pts with severe
  endometriosis have GI involvement)
• Diarrhea, constipation, perimenstrual changes in
  bowel habits, rectal bleeding
• Urinary tract complaints hematuria, dysuria,
  urgency, frequency
• Low back pain

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Specifics on pain

• Pain related to endometrial implants enlarging in
  response to hormonal stimulation
• History of years of pain-free menses, gradual
  onset and progressively worsening dysmennorhea
• Severity does not predict degree of pain
• Diffuse or localized
• Constant or vary throughout menstrual cycle
• Relief from oral contraceptives or GnRH agonists

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Physical findings

• Perform good bimanual exam
• Diffuse abdominal or pelvic pain
• Uterosacral ligament tenderness and nodularity is
  very specific to endometriosis
• Pain/nodularity in cul-de-sac
• Obliteration of the cul-de-sac occurs with fixed
  uterine retroversion implying severe disease
• Adnexal tenderness and palpable enlargement of
  endometriomas (chocolate cysts)

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Laboratory Findings CA-125 Assay

• CA-125 is a glycoprotein expressed on the cell
  surface of some coelomic epithelium (including
  endometrial tissue)
• Elevated levels found in women with endometriosis
  
• Shouldnt be used for screening but may correlate
  with patients response to treatment
• Elevated in other benign conditions - early
  pregnancy, acute pelvic inflammatory disease,
  uterine fibroids, and menstruation

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Sites of endometriosis

• Can occur in almost every organ
• Most common Ovaries, anterior and posterior
  cul-de-sac, uterosacral ligaments, posterior
  uterus, posterior broad ligaments
• Less common GI tract rectosigmoidgtappendixgtsmal
  l bowel Urinary tract
• Uncommon lungs, CNS, extremities, skin, eye,
  nasal mucosa, episiotomy scars

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Diagnosis

• Rule out other causes of pelvic pain first (PID,
  fibroids, malignancy)
• Trial of OCPs or GnRH agonists to help delineate
  etiology of pain
• Ultrasound to evaluate for chocolate cysts
• Colonoscopy if suspect GI involvement
• IVP/Cystoscopy if suspect urinary tract
  involvement

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Diagnosis

• Medical history, pelvic exam
• Diagnostic laparoscopy
• 40 inconclusive1
• 15 false negatives

1International Journal of GynecologyObstetrics
74 S1(2001) S15-20
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Diagnosis

• Laparotomy or laparoscopy for definitive dx and
  staging
• Classic powder-burn appearance but may be red,
  black, brown, white or hypopigmented
• Biopsy needed to make dx must reveal
  endometrial stroma and glands
• Staging American Society of Reproducitve
  Medicine Staging System based on depth,
  location, size of implants, presence or absence
  of cul-de-sac obliteration and extent and quality
  of adhesions

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Treatment

• Medical management NSAIDs, hormonal agents
• All treatment options are suppressive rather than
  curative
• Very helpful for dysmenorrhea, chronic pelvic
  pain, but not very effective for infertility
• Pain relief, recurrence rates, pregnancy rates
  similar for all
• Surgery

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Laparoscopy

• BENEFITS
• Precision
• Surgical treatment
• Sole standard available

• DISADVANTAGES
• Risks
• Costs
• Delays
• False negatives (15)
• Invasive

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Course of the Disease

• Spontaneous Recovery
• Natural Healing
• Pregnancy
• Menopause
• Infiltration
• Local
• Remote
• Blood
• Lymphatic

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Treatment

• NSAIDs
• Inhibit prostaglandins produced by endometrial
  implants
• Fenamate class meclofenamate, mefenamic acid
  and indomethacin work best
• Begin 1 to 2 days before the onset menses and
  continue for the duration of menstrual cycle

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Treatment

• Oral contraceptives
• Causes decidualization of endometrial tissue
• Low dose monophasic combination
  estrogen-progestin pills
• Use continuously for 6 to 12 months

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Treatment

• Danazol
• 17 alpha-ethinyl testosterone derivative
• Eliminates midcycle surge of LH and FSH,
  decreasing estrogen and progesterone creates
  high androgen low estrogen state
• Up to 90 of of patients with minimal to moderate
  disease have improvement
• 400mg bid
• Side effects weight gain, fluid retention,
  acne, decreased breast size, hot flashes, muscle
  cramps, emotional lability, deepened voice
• Contraindicated in women with liver disease

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Treatment

• Progestins
• Suppress ovarian function and cause atrophy of
  endometrial implants
• Provera 10 to 30 mg/day
• Megace 40mg qd
• Depo-Provera 150mg IM q3 months
• Side effects Breakthrough bleeding, depression,
  nausea, bloating, breast tenderness

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Treatment

• GnRH agonists (Leuprolide, Goserelin)
• Suppress ovarian function and produce
  hypoestrogenic state
• Equal efficacy compared with Danazol but less
  androgenic side effects
• Given monthly (Leuprolide IM, Goserelin SC)
• Monitor estradiol levels (20-40pg/nl)
• Side effects decreases bone density (can add
  low dose estrogen/progesterone or bisphosphonate)

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Surgical Treatment

• Laparoscopy
• Laparotomy
• Conservative vs Radical Treatment

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Treatment

• Surgery
• Try expectant management for mild disease first
• Minimal to mild disease can be removed by laser
  or electrocautery
• Surgery indicated for severe adhesive disease or
  endometriomas gt 2cm
• Severe disease removal of implants/adhesions
  if fertility not desired consider
  hysterectomy/oopherectomy
• Pre-sacral neurectomy has been used to treat
  severe dysmenorrhea

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Treatment (of associated infertility)

• Minimal disease - Pregnancy rate without
  treatment after 5 years is 90
• If severe disease is suspected proceed to
  laparoscopy
• If time is a factor (woman over 35 yrs old) -
  proceed with treatment
• Medical therapy is of limited value

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Endometriosis (Pelvic Pain)Medical Treatment

• BENEFITS
• Avoid Trauma and adhesion formation
• Treat microscopic endometriosis
• May improve surgical outcomes

• RISKS
• Side effects
• High recurrence rates
• Not effective for treatment of endometriomas or
  adhesions (infertility)

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Endometriosis (Pelvic Pain)Efficiency of medical
treatment
Canadian Consesus on Endometriosis SOGC Journal
0599
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Endometriosis (Infertility)Stages 1 - 2

• Monthly Fertility without treatment 3
• Pregnancy rate after 3 years 30-70
• Treatment efficiency ?(Relative Risks)
• Laparoscopy monthly fertility ?4.7 vs 2.4 1
• C.Clomiphere ?1.9 2
• C.C. I.U.I. ?3 3
• F.S.H. I.U.I. ?5 4
• I.V.F. ?10 5

1 Marcoux 1997 2 Samson 1993 3 Deaton 1990 4
Fedele 1992 5 Barbieri 2001
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Endometriosis (Infertility)Stages 3 - 4

• LSC Surgery Laparotomy
• Pregnancy rate after 3 years 40 70
• Vs ? 5 if expectative
• Repeat Surgery no increase of fertility vs
  I.V.F.
• In vitro Fertilization
• Implantation rate similar to non-endometriosis
  patients
• Pre-IVF surgical treatment of endometriomas ?
  outcome

Canadian Consensus Journal SOGC 1999
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Recurrences

• May recur with medical therapy or surgical
  therapy
• GnRH agonists or Danazol-Minimal disease 37,
  severe disease 74
• Surgery 40 after 5 years
• 56 of all patients after 7 years