Transcript Endometriosis_YM I

Endometriosis
陳怡仁, M.D
OB/GYN Dept.,
Taipei Veterans General Hospital
Endometriosis: presence of
endometrial glands and stroma outside of the normal location
Ovarian endometrioma
Peritoneal endometrioma
Ovarian endometriosis histology Ovarian chocolate cyst
Adenomyosis
Lung endometriosis
(BMJ, 2003; Med. Inform., 2006; BMJ, 2001; Respirology, 2006)
內分泌與月經之關係
卵
巢
的
變
化
濾
泡
期
黃
體
期
子
宮
內
膜
的
變
化
增
殖
期
分子
泌宮
期內
膜
卵
巢
的
變
化
的
變
化
月經
排卵
月經
什麼是子宮內膜異位？
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子宮內膜組織生長在子宮腔以外的任何部位而引起的病變。
異位的子宮內膜組織呈現與月經周期相似的變化，
刺激周圍的組織充血、發炎、沾黏。
異位的內膜組織，在每次的月經週期一樣會剝離，剝離下
來的內膜無法順著陰道排出體外，就在體內不斷的累積。
長在卵巢就稱之為「巧克力囊腫」，長在子宮的稱之為
「子宮肌腺瘤」，長在骨盆腔就會造成「沾黏」。
偶爾長在距腹腔較遠的地方，如肺部或鼻腔
子宮內膜異位症」是良性的疾病，不是癌症。
Chocolate Cyst of Ovary
Epidemiology
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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 > Whites > Blacks
Clinical features
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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
Diagnosis of endometriosis
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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
Transvaginal ultrasound:
Chocolate cysts
Laparoscopy:
Endometriomas and adhesions
子宮內膜異位的成因
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經血逆流學說： 76%~90%婦女有經血逆流現象。這些經
血懸浮一些子宮內膜細胞，隨機種植在卵巢及腹腔上。
免疫障礙：大多婦女都有經血逆流現象，但為什麼不是每
個婦女都罹患此疾？
雌激素及月經的影響：子宮內膜異位症一般只發生在有月
經的婦女，尤其是初經早、月經周期少於27天、月經出血
多於七天、未生育過的婦女。懷孕或長時期服食避孕丸者，
則患此疾病機會較低。
遺傳因素：不少報告顯示有些患者的母親及姐妹都有此
症。
良性轉移學說：子宮內膜位症亦可發生在距子宮甚遠的器
官（如：肺、腦），可能因為這些器官的細胞發生良性變
化，變成子宮內膜細胞 。
Retrograde menstruation/transplantation as the primary
mechanism involved in the pathogenesis of endometriosis
First described by John Sampson in 1927
(Lancet, 2004)
Lines of evidence supporting Sampson’s
theory of retrograde menstruation
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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
Coelomic metaplasia theory
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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
Metastasis theory
Hematogenous or lymphatic spread
 Unusual sites of endometriosis: brain,
colon
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(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.
The genetic basis
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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
Immunobiology of endometriosis
(Lancet, 2004, modified)
The immunologic basis
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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.
Mechanisms of pain
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(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
Mechanisms of infertility
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(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
子宮內膜異位診斷方法
1.腹腔鏡與病理切片:確實診斷的好方式
可見骨盆腔有顆粒、小塊或大囊腫，暗紅或黑色的血塊沈
積之病灶 。 必須做病理切片來確定。
2.超音波：
超音波檢查下可以見到大型的囊腫。
3.Serum CA 125：
子宮
內膜異位的女性通常血液內的CA 125蛋白會比較高
（>35IU/ml）
子宮內膜異位Stage 1~4的CA 125濃度分別為19、40、77、
182 .
但CA 125並不是一個確實診斷的好方式
4.內診：若病人有嚴重經痛，再加上有婦產科的醫師內診發
現子宮薦韌帶有結節，可將診斷度提高到94%。
Treatment
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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.
Danazol
1. 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)
Gestrinone
1. A 19-nortestosterone derivative
2. Have androgenic, antiprogestinic and antiestrogenic actions
3. Doses: 2.5-10 mg biw
4. Side effects: similar to danazol, but less pronounced
Testosterone
Danazol
(Clin. Gynecol. Endocrinol. Infertil., 2005)
Gestrinone
Progestins
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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
蜜蕊娜是什麼？
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T型設計之子宮內投
藥系統 ；在置入子宮
之後，含荷爾蒙的圓
柱體將可徐徐釋出黃
體素
（levonorgestrel），
而達到避孕及治療經
血過多的效果。
Endometrial effects
with LNG IUS
Ovulation
Menstruation
Ovulation
Days of cycle
31
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)
Pituitary desensitization by continuous GnRH-a administration
1. Adequate pituitary suppression is achieved after 7-10 days of GnRH-a administration
2. Clinical application: prevention of premature LH surge in COH, endometriosis,
uterine myoma, breast cancer, prostate cancer
(Coccia ME., et. al., 2004)
GnRH-a in the treatment of
endometriosis
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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
Surgical treatment
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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 estrogenprogestin is recommended postoperatively (estrogen
only will induce adenocarcinoma from residual
endometriosis)
Ovarian endometrioma:
excision is better than
drainage and ablation
as regards to recurrence
and pregnancy rates.
(Hum. Reprod., 2005)
(Surgical management
of endometriosis, 2004)
Excision of adhesion bands
(Surgical management
of endometriosis, 2004)
Perioperative treatments
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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