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 Ovarian endometriosis histology Ovarian chocolate cyst Peritoneal endometrioma 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 子宮內膜的變化 濾泡期 增殖期 黃體期 分泌期 卵巢的變化 子宮內膜的變化 月經 月經 排卵
什麼是子宮內膜異位？ • 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。
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 > Whites > Blacks
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
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
Transvaginal ultrasound: Chocolate cysts Laparoscopy: Endometriomas and adhesions
子宮內膜異位的成因 • 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 。
(Lancet, 2004) Retrograde menstruation/transplantation as the primary mechanism involved in the pathogenesis of endometriosis First described by John Sampson in 1927
Lines of evidence supporting Sampson’s 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
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
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.
Stem cell theory • The human endometrium is responsive to sex steroid hormones, undergoes extraordinary growth in a cyclic manner, and is shed and regenerated throughout a woman’s lifetime. • It has been proposed that the human endomtrium may contain a population of stem cells that is responsible for its remarkable regeneration ability (1, 2). Gargett et al. Endometrial stem cells. Curr Opin Obstet Gynecol 2007;19:377-83.
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, 17HSD type 1/type 2 .
(Lancet, 2004, modified) Immunobiology of endometriosis
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.
Mechanisms of pain • Actions of inflammatory cytokines in the peritoneal cavity: mild (early stage) disease or severe (advanced stage) disease • Direct and indirect effects of focal bleeding from endometriotic implants: mild disease or severe disease • 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 • (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 • 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 • 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 • A 19-nortestosterone derivative • Have androgenic, antiprogestinic and antiestrogenic actions • Doses: 2.5-10 mg biw • Side effects: similar to danazol, but less pronounced Testosterone Danazol Gestrinone (Clin. Gynecol. Endocrinol. Infertil., 2005)
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
蜜蕊娜是什麼？ • 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 Menstruation Ovulation Ovulation Days of cycle
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)
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 • 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)
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
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)
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 • 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