Endometriosis

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Endometriosis

• Hsin-Yang Li, M.D., Ph.D.
• OB/GYN Dept.,
• Taipei Veterans General Hospital

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Endometriosis presence of endometrial glands
and stroma outside of the normal location
Ovarian endometrioma
Ovarian chocolate cyst
Ovarian endometriosis histology
Peritoneal endometrioma
Adenomyosis
Lung endometriosis
(BMJ, 2003 Med. Inform., 2006 BMJ, 2001
Respirology, 2006)
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Epidemiology

• Prevalence
• 4 in asymptomatic women having sterilization
• 5-20 in women with pelvic pain
• 20-40 among infertile women,
• 3-10 of the general female population
• Most commonly diagnosed in women of reproductive
  age. Mean age at time of diagnosis 25-30 years
  old
• Risk factors early menarche, short menstrual
  cycle, alcohol, caffeine
• Protection factors term pregnancy, regular
  exercise, smoking
• Asians gt Whites gt Blacks

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Clinical features

• Symptoms and signs dysmenorrhea, intermenstrual
  pain, dyspareunia, and infertility
• There is no relationship between stage, site, or
  morphological characteristics and the degree of
  pain
• Pelvic pain diffuse, dull, and deep, may radiate
  to the back, may be associated with nausea,
  diarrhea and rectal pressure
• Dysmenorrhea begins before menses and persists
  throughout menses
• Intermenstrual pain 1/2 to 2/3 of patients
• Dyspareunia disease involving the cul-de-sac and
  rectovaginal septum

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Diagnosis of endometriosis

• Clinical diagnosis history and physical
  examination (rectovaginal septum lesion, fixed
  adnexal mass, tenderness/nodularity of U-S lig.)
  ? poor predictive value
• CA125 elevated in endometriosis (also elevated
  in menstruation, early pregnancy, PID, and
  myomas) low sensitivity predicts the success of
  surgical but not medical treatment
• Transvaginal ultrasound/ MRI ovarian
  endometrioma/chocolate cyst
• Surgical diagnosis laparoscopy with histologic
  examination ? gold standard

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Transvaginal ultrasound Chocolate cysts
Laparoscopy Endometriomas and adhesions
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Theories on the pathogenesis of endometriosis

• Retrograde menstruation/transplantation
• Coelomic metaplasia
• Metastasis
• Genetic basis
• Immunologic basis

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Retrograde menstruation/transplantation as the
primary mechanism involved in the pathogenesis
of endometriosis
First described by John Sampson in 1927
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Lines of evidence supporting Sampsons theory of
retrograde menstruation

• Laparoscopy during menses peritoneal blood can
  be found in 75-90 of women with patent tubes
• Peritoneal endometrial cells recovered during
  menses can attach to and penetrate the peritoneum
• Incidence of endometriosis is increased in women
  with early menarche, short cycle, menorrhagia or
  obstructing Mullerian anomalies
• Commonly found in dependent sites ovaries,
  cul-de-sac, U-S lig., post. uterus, post. broad
  lig.
• Endometriosis can be induced in baboons by
  ligation of the cervix

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Coelomic metaplasia theory

• Metaplastic change in the coelomic epithelium
  (peritoneum and pleura) spontaneous or induced
• Supporting evidences
• Endometriosis has been found in premenarcheal
  girls
• Pleural and pulmonary endometriosis
• Endometriosis in men treated with high doses of
  estrogen
• In vitro, ovarian surface epithelium can be
  induced by estradiol to form endometrial glands

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Metastasis theory

• Hematogenous or lymphatic spread
• Unusual sites of endometriosis brain, colon

(BMJ,2003)
A 35 year-old female complained of severe
abdominal pain and constipation as well as bloody
stool during menses. Colonoscopy showed a
fungating mass, which turned out to be a
endometriotic lesion.
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The genetic basis

• Genetic predisposition 6-7 times more prevalent
  among first-degree relatives of affected women
  than in the general population
• Oxford endometriosis gene study
• Resistance to apoptosis Bcl-2/bax family
• Attachment to peritoneum integrins
• Invasion of peritoneum MMP
• High estrogen environment that stimulates growth
  of endometriosis aromatase, 17?HSD type 1/type 2

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Immunobiology of endometriosis
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The immunologic basis

• A wide range of immunologic abnormalities have
  been described in women of endometriosis
• The peritoneal fluid of affected women contains
  increased numbers of immune cells. However,
  instead of acting to efficiently remove refluxed
  endometrial cells, these immune cells appear to
  promote the disease by secreting a variety of
  cytokines and growth factors that stimulate
  endometriotic attachment, invasion,
  proliferation, and neovascularization.

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Mechanisms of pain

• (1) Actions of inflammatory cytokines in the
  peritoneal cavity mild (early stage) disease or
  severe (advanced stage) disease
• (2) Direct and indirect effects of focal bleeding
  from endometriotic implants mild disease or
  severe disease
• (3) Irritation and direct infiltration of nerves
  in the pelvic floor severe disease
• There is no relationship between stage, site, or
  morphological characteristics and the degree of
  pain
• Hormonal modulation pain threshold and tolerance
  are lowest just prior to and during menses

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Mechanisms of infertility

• (1) Distorted adnexal anatomy that inhibit ovum
  capture and transport severe disease
• (2) Interference with oocyte/sperm survival,
  fertilization, and embryogenesis mild or severe
  disease
• (3) Reduced endometrial receptivity mild or
  severe disease
• Endometriosis decreases fertility to an extent
  that roughly correlates with the severity of
  disease
• IVF success rates lower in endometriosis lower
  in severe disease than in mild disease

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Treatment

• Medical effective for pain, which tends to recur
  after cessation of treatment. Equal
  effectiveness among different approved
  medications. Not beneficial for improving
  fertility.
• Surgical equally effective as medical treatment
  for pain, which also tends to recur. Surgical
  treatment improves fertility to some extent.
  Higher pregnancy rates are observed in the first
  year after conservative surgery.

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• Danazol
• The first drug ever approved for the treatment
• of endometriosis in th U.S.
• 2. Orally administered isoxazol derivative of
  17?-ethinyl testosterone
• 3. Mechanisms inhibit steroidogenic enzymes and
  LH surge ?
• low estrogen and anovulation ? no retrograde
  menstruation
• free testosterone ? low estrogen ? inhibit
  endometriotic growth
• 4. Doses 600-800 mg daily
• 5. Side effects weight gain, fluid retention,
  decreased breast size,
• acne, atrophic vaginitis, irreversible deepening
  voice, poor lipid
• profile

Testosterone
Danazol
(Clin. Gynecol. Endocrinol. Infertil., 2005)
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• 
  Gestrinone
• A 19-nortestosterone derivative
• Has androgenic, antiprogestinic and
  antiestrogenic actions
• Doses 2.5-10 mg biw
• Side effects similar to danazol, but less
  pronounced

Gestrinone
Testosterone
Danazol
(Clin. Gynecol. Endocrinol. Infertil., 2005)
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Progestins

• Medroxyprogesterone acetate (provera) 20-100 mg
  daily or norethindrone acetate (primolut-nor) 40
  mg daily
• Mechanisms atrophy of endometrial tissue and
  inhibition of ovulation (higher doses)
• Side effects breakthrough bleeding (may be
  treated by conjugated estrogen 1.25 mg qd or
  estradiol 2 mg qd for a week), weight gain, fluid
  retention, breast tenderness, depression, and
  poor lipid profile

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Oral contraceptives

• Continuous treatment is preferred to induce an
  amenorrhea state
• Mechanisms atrophy of endometrial tissue,
  absence of retrograde menstruation (high estrogen
  and high progesterone state ? pseudopregnancy)

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Gonadotropin-releasing hormone agonists (GnRH-a)

• Modifications
• Position 6 ? enzymatic degradation
• Position 10 ? potency
• Position 6 and 10 ? receptor affinity

(Textbook of ART, 2004)
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Pituitary desensitization by continuous GnRH-a
administration

• Adequate pituitary suppression is achieved after
  7-10 days of GnRH-a administration
• Clinical application prevention of premature LH
  surge in COH, endometriosis,
• uterine myoma, breast cancer, prostate cancer

(Coccia ME., et. al., 2004)
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GnRH-a in the treatment of endometriosis

• Mechanisms hypogonadotropic hypogonadism ?
  deprives endometriosis of estrogen support
  absence of retrograde menstruation
• Administration im, sc, or nasal spray (depot
  form may be administered once per month)
• Side effects hot flush, vaginal dryness,
  decreased libido, mood swings, skin dryness,
  decreased bone density (significant after 6
  months of treatment, 1 per month)
• Add back conjugated estrogen 0.625 mg qd and
  medroxyprogesterone acetate 2.5 mg qd

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Surgical treatment

• Objectives restore normal anatomy, excise or
  destroy all visible lesions as possible, prevent
  or delay recurrence
• Operate in the follicular phase instead of in the
  luteal phase
• Excision of peritoneal implants and ovarian
  endometriomas
• Excision of adhesion bands
• Dissection and excision of nodular lesion in the
  rectovaginal septum
• Women with advanced disease who have completed
  childbearing hysterectomy BSO ? low-dose
  estrogen-progestin is recommended postoperatively
  (estrogen only will induce adenocarcinoma from
  residual endometriosis)

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Ovarian endometrioma excision is better
than drainage and ablation as regards to
recurrence and pregnancy rates. (Hum. Reprod.,
2005)
(Surgical management of endometriosis, 2004)
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Excision of adhesion bands
(Surgical management of endometriosis, 2004)
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Perioperative treatments

• Preoperative medical treatment no evidence
  showing that it improves pain control or
  infertility, except in cases with deep
  rectovaginal endometriosis
• Postoperative medical treatment not indicated
  for those who wish immediate pregnancy. May have
  value for those who do not wish to be pregnant in
  the near future, since it will decrease
  recurrence rates.
• Postoperative suggestions for infertile couples
• mild disease ? observe for 6 months, then IUI or
  IVF
• severe disease with tubal obstruction ? IVF