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  1. 1. Benha University Hospital, Egypt Email:elnashar53@hotmail.com Aboubakr Elnashar
  2. 2. Define Ectopic (outside the uterus) endometrial glands & stroma. Aboubakr Elnashar
  3. 3. Prevalence •5% of women in the reproductive age group. •25% of infertile women. •50% of chronic pelvic pain. Aboubakr Elnashar
  4. 4. Age At Diagnosis < 19 6% 19 – 25 24% 26 –35 52% 36 –45 15% > 45 3% Aboubakr Elnashar
  5. 5. Pelvic  Uterine= Adenomyosis (50%).  Extrauterine: - Ovary 30% - Pelvic peritoneum 10%. - F. tube. - Vagina. -Bladder & rectum. - Pelvic colon. - Ligaments. Extra pelvic Umbilicus. Scars (Lap.). Lungs & pleura. Others. Sites Aboubakr Elnashar
  6. 6. Types I. Superficial peritoneal lesions Typically located on the pelvic organs or pelvic peritoneum. Classic bluish or blue-black “powder-burn” lesion resembles the endometrium and may be associated with hemosiderin deposits. Non-classic lesions: clear and red “flame-like” lesions or white lesions. Endometriosis can also be found in the base of a peritoneal defect called an “Allen-Masters” window. Aboubakr Elnashar
  7. 7. II. Endometrioma (Endometriotic Cyst) >90% are pseudocysts [formed by invagination of the ovarian cortex, which is sealed off by adhesions] (Brosens et al, 2003). • Characterized by: fibrosis retraction of the cortex, islands of glandular endometrial tissue organized blood clots. • The remainder of the cyst wall: Smooth lined by a thin endometrial-like tissue that consists of surface epithelium and highly microvascularized stroma. • There is no evidence that endometriotic tissue invades the ovarian stroma; however, large multilocular cysts frequently combine endometriomas with a hemorrhagic corpus luteum or lutein cyst. Aboubakr Elnashar
  8. 8. III. Deep endometriosis Define: Endometriosis infiltrating deeper than 5mm. It is very active Includes 1. Rectovaginal lesions 2. Infiltrative forms of bowel, ureters, bladder. It originates intraperitoneally rather than extraperitoneally. Aboubakr Elnashar
  9. 9. Pathogenesis: intraperitoneal seeding of regurgitated endometrial cells, which collect and implant in the most dependent portions of the peritoneal cavity and the anterior& posterior cul-de-sac, trigger an inflammatory process leading to adhesion of contiguous organs with creation of false peritoneal bottoms Treatment: Drugs induce temporary quiescence of active deep lesions Progestins should be considered as first-line medical treatment for temporary pain relief. Surgery is the final solution. Mirena Aboubakr Elnashar
  10. 10. Ovarian Endometriosis: Usually bilateral. Two forms: 1- Multiple spots on the surface of the ovary. 2- Endometriotic (Chocolate) cysts can reach the size of a fetal head, but is rarely larger. usually difficult to remove the cysts intact out of surrounding adhesions. Aboubakr Elnashar
  11. 11. Pathogenesis I- Endometrial implantation: Retrograde. Vascular & lymphatic. Mechanical. II- In situ development: Coelomic metaplasia. Induction. III- Immunological. IV- Composite. Aboubakr Elnashar
  12. 12. Donnez et al (2003) Red lesions= early endometriosis Black lesions= advanced endometriosis White lesions are believed to be - healed endometriosis or - quiescent or latent lesions. Aboubakr Elnashar
  13. 13. Pathogenesis Hypothesis (Donnez et al, 2003) - quiescent or latent lesions .Red lesions White lesions Black lesions White lesions Advanced endometriosis Early endometriosis Healed endometriosis Aboubakr Elnashar
  14. 14. Atypical (subtle) E: Incidence: More common than the classic dark blue-black lesions in adolescents. Common in age < 25 yr. Types: Red White Symptoms: like that characterize classic E. Aboubakr Elnashar
  15. 15. Significance: 1. Paraphysiological or self-limiting condition which exist in all reproductive women as a results of retrograde menstruation. 2. Biochemically & morphologically more active than the classic lesions {synthesize more PG F2} Treatment: E. does not itself demand treatment unless it is causing, or it is likely to cause symptomsAboubakr Elnashar
  16. 16. Aboubakr Elnashar
  17. 17. Aboubakr Elnashar
  18. 18. Aboubakr Elnashar
  19. 19. Risk factors (Odukoya & Cooke, 1996) I- Associated: First or second degree relation. Menstrual cycle < 27 days. Menstrual duration > 7 days. Genital outflow obstruction. II- Inconclusive: Obesity, Exercise, Age at menarche, uterine retroversion. III- Not associated: Age, Race, Social class, duration of marriage, ICUD, Miscarriage. Aboubakr Elnashar
  20. 20. Factors associated with a reduced risk {reduced estrogen levels} (ACOG, 1999) : Menstrual disorders Decreased body-fat content Smoking. Aboubakr Elnashar
  21. 21. Classification The revised American Fertility Society (rAFS) (1985)was produced to standardize the documentation of findings in patients who have pelvic pain & endometriosis. Staging Involves: 1. Location 2. Depth of Disease, 3. Extent of Adhesions. Aboubakr Elnashar
  22. 22. Aboubakr Elnashar
  23. 23. >3cm1-3cm< 1cmEndometriosis 421Superficial 642Deep 421R Superficial 20164Deep 421L Superficial 20164Deep Aboubakr Elnashar
  24. 24. COMPLETEPartialPOSTERIOR CULDESAC OBLTTERATION 404 > 2/3 Enclosure1/3-2/3 Enclosure < 1/3 Enclosure ADHESIONS 421R Filmy 1684Dense 421L Filmy 1684Dense 421R Filmy 168º4ºDense 421L Filmy 168º4ºDense Aboubakr Elnashar
  25. 25. Revised AFS (1985) • Stage I (minimal) 1 – 5. • Stage II (mild) 6 – 15. • Stage III (moderate) 16 – 40. • Stage IV (severe) > 40. Aboubakr Elnashar
  26. 26. ASRM classification (1996) The only difference between the 1985 rAFS classification & 1996 ASRM classification is that the latter includes information on the morphologic appearance of the disease. •Red: red, red-pink & clear lesions •White: white, yellow-brown, peritoneal defects, subovarian adhesion •Black: black & blue lesions. •Denote percent of total described as R ….%, W ….% and B ….%. Total should equal 100%. Aboubakr Elnashar
  27. 27. Atypical Typical Red Red yellow Clear White Defect White Black Blue Aboubakr Elnashar
  28. 28. Aboubakr Elnashar
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  30. 30. Aboubakr Elnashar
  31. 31. Aboubakr Elnashar
  32. 32. Aboubakr Elnashar
  33. 33. CLINICAL PICTURE Common symptoms: •Infertility. •Pain Pelvic pain. Dysmenorrhea (Crescendo=progressive) Dysparunia. Dyschasia. Dysuria Less common symptoms: Heamaturia, rectal pain, urgency, heamoptysis, coetaneous nodules, hyperprolactinaemia. Aboubakr Elnashar
  34. 34. Aboubakr Elnashar
  35. 35. Infertility: E should be suspected in infertile females. Suspicion is heightened when there are also dysmenorrhea & dysparunia. .Aboubakr Elnashar
  36. 36. Mechanism of infertility (Prentice, 2001) I- Advanced disease: Mechanical interference with ovulation, ovum pick up, Tubo-ovarian adhesion, Severe pelvic adhesions & Distorted tubal anatomy. Aboubakr Elnashar
  37. 37. II- Minimal & mild disease: 1. Coital problems: dysparunia. 2. Altered peritoneal environment: increase volume of peritoneal fluid, increase proportion of activated macrophages (phagocytosis of sperms, decreased sperm motility & embyotoxicty). 3. Altered foliccular maturation: lutenized unruptured follicle, anovulation, luteolysis caused by prostaglandin F2 No evidence that they are more common in E. Aboubakr Elnashar
  38. 38. Chronic Pain: The severity of pain is not correlated to the extent of E but to the site & the depth (Demco, 1998) Midline disease is more painful than lateral disease (Konickx, 1994) Aboubakr Elnashar
  39. 39.  Acute Abdominal Pain  {Rupture of an endometrioma, usually at menstruation}.  Differential Diagnosis: 1. Disturbed ectopic 2. PID 3. Acute appendicitis.  Careful analysis of past and present history suggests the diagnosis of endometriosis. Laparoscopy is usually needed to reach the diagnosis. Aboubakr Elnashar
  40. 40. Dyschasia Pain during defecation occurs when there is involvement of the rectovaginal septum It is particularly noticeable during menstruation. Aboubakr Elnashar
  41. 41. Dysmenorrhea  E should be considered in women who develop dysmenorrhea after years of pain-free cycles.  Pain 1. May be diffuse in the pelvis localized to one side or felt in the rectum. 2. Comes on gradually for few days before the period, but is more severe during menstruation (Crescendo). 3. Later on it may persist during most of the cycle. Aboubakr Elnashar
  42. 42. Deep-seated dyspareunia: Douglas pouch. Uterosacral ligament . Rectovaginal 'septum Fixed retroversion flexion. Aboubakr Elnashar
  43. 43. Aboubakr Elnashar
  44. 44. Sings: Pelvic tenderness, Nodules in the cul-de-sac, Adnexal mass, Uterine fixity, Nodules along the uterosacral ligament. Aboubakr Elnashar
  45. 45. Aboubakr Elnashar
  46. 46. Adolescent Endometriosis (Reese et al's 1996) %Symptoms 95Pelvic pain. 94Dysmenorrhea. 25Irregular menses. 29Deep dyspareunia 43Abdominal pain & nausea 3Constipation and diarrhea Aboubakr Elnashar
  47. 47. A history of E in the family should prompt further questioning & raise the index of suspicion (Attaran and Gidwani, 2003) Laparoscopic evaluation of the pelvis commonly reveals atypical, endometriotic lesions. Microlaparoscopic evaluation may be recommended in those cases (Nazhate et al 2000) Aboubakr Elnashar
  48. 48. Diagnosis Aboubakr Elnashar
  49. 49. Diagnosis is very difficult (Taylor ,2003):  Most women become accustomed to painful menstrual cycles at an early age.  Even with extensive E, it is possible to have minimal symptoms or none at all.  The presentation is so variable and there is considerable overlap with other conditions such as irritable bowel syndrome and pelvic inflammatory disease (RCOG 1999)  Physicians have few diagnostic-usually invasive- tools. Aboubakr Elnashar
  50. 50. Diagnosis is usually delayed: • It takes a average of 4 years from the time a woman has her first symptom, to the time she discusses it with her doctor. • It takes average of 9 years from the time she first experiences symptoms, until a diagnosis of E is finally made. Aboubakr Elnashar
  51. 51. Methods of diagnosis:  Invasive diagnosis I. Laparoscopy II. Microlaparoscopy.  Non invasive diagnosis. I. Therapeutic . II. Imaging: U/S, MRI III. Endometrial nerve fibers IV. CA 125 V. Other. Aboubakr Elnashar
  52. 52. Laparoscopy  Gold standard' diagnostic test  Advantages (RCOG Grade B evidence lll) 1. Excludes other conditions e.g. ovarian cancer 2. Treatment of E. Aboubakr Elnashar
  53. 53.  Disadvantages. 1. Requirement for surgery and anesthesia. 2. Risk of major complications (e.g. bowel perforation) Diagnostic laparoscopy: 0.06% operative laparoscopy: 1.3% in (Harkki-Siren et al, 1999) 3. Visual inspection might not prove to be E on histological analysis. not detect deep E. Aboubakr Elnashar
  54. 54. Technique: •2 port approach •Inspection of D pouch, us lig, pelvic side walls, anterior surface of the ovary (adhesions) To ensure complete evaluation, inspection of the pelvis in a clockwise or counterclockwise fashion. •Biopsy if there is doubt. It is not a routine Aboubakr Elnashar
  55. 55.  Findings:  Peritoneal Typical E: black-blue, powder-burn appearance. Diagnosis in most cases is simple, without the need for a biopsy. Atypical (Subtle = Non-pigmented) E: E lesions that lack the typical black-blue, powder-burn appearance Diagnosis: more difficult with standard laparoscopy Other laparoscopic procedures or biopsy may be necessary to confirm diagnosis (Martin,1999)  Endometrioma Aboubakr Elnashar
  56. 56. Atypical Typical Red Red yellow Clear White Defect White Black Blue Aboubakr Elnashar
  57. 57. Aboubakr Elnashar
  58. 58. 1-Near-contact: magnifies the peritoneal area (Redwin,1987) 2-Peritoneal blood painting: flowing erythrocytes outline surface irregularities (Redwin,1987) 3-Examined from different angles and at different degrees of illumination to see vesicles or whitish lesions. 4-Direct vision: Although the resolution of cameras has improved, it is still not comparable to that of direct vision (Nezhate et al, 2000) Aboubakr Elnashar
  59. 59. 5. Laparoscopic visualization through lactated Ringer or normal saline (Laufer,1997) . Vesicular lesions are no longer falsely interpreted as light reflection . 6. Bubble test: The posterior cul de sac is irrigated with short bursts of saline under controlled pressure. Development of dense soap like bubbles for at least 5 s indicates a positive test. {increased level of triglycerides in peritoneal fluid} (Amer A & Omar M., 2002) Aboubakr Elnashar
  60. 60. Accuracy Visual diagnosis of endometriosis is unreliable. 54–67% of suspected endometriotic lesions are confirmed histologically 18% of patients clinically suspected to have endometriosis have no evidence of endometriosis on pathology (Walter et al, 2001) a positive finding on laparoscopy will be incorrect in half of the cases (Wakes et al, 2004) Aboubakr Elnashar
  61. 61. In these circumstances, peritoneal lesions± inflammatory changes, hemangiomas, foreign body reaction, mesothelial hyperplasia hemosiderin deposits Biopsy of normal-appearing peritoneum has revealed endometriosis in 6% of women with no visible lesions and 25% of asymptomatic infertile women (Balasch et al, 1999). Aboubakr Elnashar
  62. 62. Directed biopsy (Brosen, 1994) •E in 90% of typical & 40% of atypical cases. •Endometrioma: The appearance most commonly associated with positive histology: irregular brown or red mottling on the surface of white capsule. •old hemorrhagic corpus luteum: uniform brown appearance Aboubakr Elnashar
  63. 63. Laparoscopic visualization of peritoneal lesions alone is of limited accuracy, and if a diagnostic laparoscopy is performed, confirmatory biopsies of peritoneal lesions, even atypical ones, will be of value (SOGC, 2010). The lesions most likely to be histologically confirmed as endometriosis are generally large mixed-color lesions in the culde sac or on the uterosacral ligaments (Stegmann et al, 2008) On histopathology, the diagnosis requires the presence of two or more of these histologic features: endometrial epithelium endometrial glands endometrial stroma hemosiderin-laden macrophages (ACOG, 1999) Aboubakr Elnashar
  64. 64. Is laparoscopy required before medical management of pelvic pain? (SOGC, 2010) not always necessary . {1. Management of the pain is required whether or not endometriosis is the cause. 2. All the management strategies for E are relatively general strategies to decrease inflammatory conditions in the pelvis} Aboubakr Elnashar
  65. 65. E can be strongly suspected severe dysmenorrhea unresponsive to NSAID with pelvic tenderness and nodularity on palpation of the uterosacral ligaments and rectovaginal septum, or US: endometrioma. : In these situations, laparoscopy for diagnosis is not necessary before medical treatment. Laparoscopy should be performed only if the surgeon is prepared to vaporize or excise lesions if endometriosis is discovered {surgical management provides long-term pain relief for up to 50%} (Abbott et al, 2003) Aboubakr Elnashar
  66. 66. • Less invasive II. Microlaparoscopy Out patient procedure Local anesthesia Pain mapping. For adolescent E. Aboubakr Elnashar
  67. 67. Non Invasive Diagnosis Aboubakr Elnashar
  68. 68. I. Diagnosis by therapeutic trials: 1. Pain suggestive of E + Woman not trying to conceive + No pelvic mass • Therapeutic trial of COCs (monthly or tricycling) or Progestogen without performing a diagnostic laparoscopy (RCOG 1999) Aboubakr Elnashar
  69. 69. 2. Chronic pelvic pain {Moderate to severe at least 6 m, unrelated to menstruation unrelieved by NSAI & antibiotics} + Clinically suspected E + • Clinical response to GnRha (Depot leuprolide acetate 3.75 mg monthly for 3 m) Can diagnose E (Ling, 1999). Aboubakr Elnashar
  70. 70. • GnRH agonist is an appropriate therapy of chronic pelvic pain, even in the absence of surgical confirmation of E, provided that a detailed initial evaluation fails to demonstrate some other cause of pelvic pain (ACOG Recommendations Grade (B) Aboubakr Elnashar
  71. 71. II. Imaging 1. Transvaginal ultrasound • first-line investigational tool for suspected E • help diagnose endometriomas, bladder lesions, and deep nodules such as those in the rectovaginal septum. • Findings: 1. Anechoic to echogenic cysts 2. Masses containing multiple septations & solid tissue (Morane &Older, 1996) 3. Cysts with low-level echoes: The commonest finding (95%) Aboubakr Elnashar
  72. 72. Cysts with low-level echoes (Patel et al, 1999) Endometrioma 95% Hemorrhagic cyst 50% Teratoma 18% Malignant neoplasm 12% Benign neoplasm 6% Aboubakr Elnashar
  73. 73. No Wall Nodularity Unilocular Adnexal mass with diffuse low-level internal echoes (Patel et al,1999) 6 w Follow- up US MRI or Doppler Wall Nodularity regional bright echo = Teratoma hyperechoic wall foci = Endometrioma No characteristic feature. Aboubakr Elnashar
  74. 74. Hyperechoic wall foci No neoplastic features Multilocular Adnexal mass with diffuse low-level internal echoes (Patel et al,1999) = Endometrioma No hyperechoic wall foci Neoplastic features MRI or Doppler Aboubakr Elnashar
  75. 75. 2. Transrectal ultrasound Detect rectal involvement in E depth of infiltration by E, lesions on the posterior bladder wall but it has not been shown to be superior to transvaginal ultrasound. Aboubakr Elnashar
  76. 76. 3. CT: has been replaced by MRI poor specificity high radiation dose An important role for the CT scan with contrast is to detect ureteral involvement and possible renal insufficiency. Aboubakr Elnashar
  77. 77.  MRI Indications: (Funt et al, 2002): 1. Indeterminate 2. Poorly visualized 3. Inadequately localized lesions Relies on: Detection of pigmented hgic lesions: signal characteristics vary according to the age of hge. Aboubakr Elnashar
  78. 78. MR And Endometriosis Advantages: 1. Greater sensitivity. Detect 75% of mild disease (Stratton et al, 2003). 2. Evaluation of deep lesions 3. superior to ultrasound in diagnosing rectosigmoid lesions and endometriosis of the bladder. Disadvantages: Not readily available Expensive. Aboubakr Elnashar
  79. 79. Aboubakr Elnashar
  80. 80. III. Endometrial nerve fibers Appropriate marker (Fatheima et al, 2011) an increased number of nerve fibers in the endometrium of women with endometriosis compared to women without endometriosis. These nerve fibers are reported to be primarily small unmyelinated sensory C fibers in the functional layer of endometrium, which are identified by their staining with PGP9.5, VIP, and substance P, but not with neurofilament. Aboubakr Elnashar
  81. 81. (A) Absence of nerve fibres in the functional layer of endometrium in adenomyosis but no endometriosis. (B) Small unmyelinated C nerve fibres (black arrows) in the functional layer of endometrium in a woman with peritoneal endometriosis (immunohistoclinical staining with protein gene product 9.5 and fast red chromogen.Aboubakr Elnashar
  82. 82. IV. Serum markers: • limited value as a screening test as well as a diagnostic test. • Useful marker for monitoring treatment • no individual serum marker has been found to specifically correlate with the symptoms of endometriosis, and many of them are present in other conditions. Aboubakr Elnashar
  83. 83. V. Other: 1. Cystoscopy (for bladder endometriosis) 2. sigmoidoscopy or colonoscopy (for transmural bowel lesions), 3. ultrasound-guided fine needle aspiration (FNA: for endometriosis in the rectosigmoid, rectovaginal septum, or in abdominal scars). 4. IVP, barium study Aboubakr Elnashar
  84. 84. D.D. 1. Ovarian cysts*. 2. Pelvic inflammatory disease . 3. Other causes of nodularity in Douglas pouch: tuberculous peritonitis metastases of ovarian cancer. 4. Causes of haematuria, bleeding per rectum and acute abdominal pain if the patient is presented by one of these symptoms. 5. Asymmetrical enlarged uterus. Aboubakr Elnashar
  85. 85. • Endometrioma Hyperechoic wall foci (in 35%) • Hemorrhagic cyst : Lacelike internal echoes (in 40%) • Teratoma Regional bright echoes ( in 97% ) *Cysts With Low-level Echoes + Characteristic Features Aboubakr Elnashar
  86. 86. *Endometrioma Vs Malignancy (Brown et al 1998) Suggestive of malignancy: 1. Mural thickening 2. Wall nodularity 3. Septations > 3 mm 4. Papillary projections The most significant predictor of malignancy: Solid component within an ovarian mass Aboubakr Elnashar
  87. 87. Aboubakr Elnashar
  88. 88. Medical treatment of endometriosis Prof Aboubakr Elnashar Benha university hospital elnashar53@hotmail.com Aboubakr Elnashar
  89. 89. Contents Lines of treatment and treatment strategy Non hormonal Hormonal New treatments Evidence based recommendations Aboubakr Elnashar
  90. 90. Depend on: 1. Age 2. Presenting symptoms 3. Reproductive status 4. Fertility demands 5. Stage 6. Previous response to treatment. Aboubakr Elnashar
  91. 91. Lines of treatment A- Symptomatic: PG inhibitors ART Psychotherapy. Aboubakr Elnashar
  92. 92. B- Hormone (Medical) suppression: Conventional New drugs C. Surgical: Conservative: Diathermy, laser vaporization, excision, Ov cystectomy, presacral neurectomy Radical: Hysterectomy & ovarian removal. Aboubakr Elnashar
  93. 93. Treatment strategy 1. Endometriosis & pain (RCOG,2000) : a. Medical: NSAID: may be effective. COC, progestagens, danazol & GnRHa: equal in relieve pain associated with E. Prescribe the safest & cheapest. b. Surgical: Effective for many women. Some women fail to respond {incomplete excision or post-operative disease recurrence}.Aboubakr Elnashar
  94. 94. (SOGC, 2010) Aboubakr Elnashar
  95. 95. 2. Endometriosis & infertility: Medical: No value. {results in 6 mo. of contraception which further delays pregnancy.} Minimal or mild E: Ovarian stimulation & IUI is more effective than either no treatment or IUI alone Surgical: Minimal or mild: Laparoscopy: destruction or ablation of the E implants & lysis of adhesions Moderate to Severe: Surgical treatment may improve fertility but RCTAboubakr Elnashar
  96. 96. Aboubakr Elnashar
  97. 97. I. Non hormonal NSAIDs Conventional: COC Progestagens, GnRHa Danazol New LNG-IUD GnRHan Aromatase inhibitors SERM Progesterone antagonist SPRM Angiogenesis inhibitors Immunomodulatory drugs. Medical treatment II. Hormonal Aboubakr Elnashar
  98. 98. I. NSAIDs  Useful in women trying to conceive  ibuprofen (Sapofen) naproxen (Naprosyn). Mefenamic acid (Ponstan) Start 2 d before menstruation Similar efficacy Gastric irritation. Aboubakr Elnashar
  99. 99.  Cyclooxygenase-2 (COX-2).  Celebrex  Vioxx Not more effective (than naproxen or ibuprofen) lower risk of gastric ulceration high cost (Mahutte & Arici, 2003) Aboubakr Elnashar
  100. 100. II. Hormonal Conventional Rationale: E. Implants: estrogen, progesterone & androgen receptors at a lower concentration than eutopic endometrium. Aboubakr Elnashar
  101. 101. Is laparoscopy required before medical management of pelvic pain? (SOGC, 2010) Not always necessary . {1. Management of the pain is required whether or not E is the cause. 2. All managements aim to decrease inflammatory conditions in the pelvis} Aboubakr Elnashar
  102. 102. E can be strongly suspected Severe dysmenorrhea unresponsive to NSAID+ on palpation of the uterosacral ligs and rectovaginal septum: tenderness and nodularity OR US: endometrioma. : In these situations, laparoscopy for diagnosis is not necessary before medical treatment. Aboubakr Elnashar
  103. 103. Laparoscopy should be performed only if the surgeon is prepared to  vaporize or excise lesions {: long-term pain relief for up to 50%} (Abbott et al, 2003) Aboubakr Elnashar
  104. 104. Diagnosis by therapeutic trials: 1. Pain suggestive of E + Woman not trying to conceive + No pelvic mass  COCs (monthly or tricycling) or Progestogen for 3 cycles (RCOG 1999) Clinical response can diagnose E Aboubakr Elnashar
  105. 105. 2. Chronic pelvic pain {Moderate to severe at least 6 m, unrelated to menstruation unrelieved by NSAI & antibiotics} + Clinically suspected E +  GnRha (monthly for 3 m) Clinical response can diagnose E (Ling, 1999). Aboubakr Elnashar
  106. 106. GnRHa An appropriate therapy of CPP, even in the absence of laparoscopic confirmation of E, provided that a detailed evaluation fails to demonstrate other cause (ACOG Recommendations Grade (B) Aboubakr Elnashar
  107. 107. Indications of medical treatment . Suspected endometriosis Confirmed endometriosis . 1. Dysmenorrhea, dysparunia & pelvic pain associated E. 2. Temporary relief of pain in women awaiting for IVF 3. After surgical treatment who need long-term management. Aboubakr Elnashar
  108. 108. Indications of long term medical therapy 1. Severe symptoms with little palpable findings 2. Recurrence after conservative surgery. Aboubakr Elnashar
  109. 109.  Results: 1. Volume of the disease: similar for all forms 2. Pain: equally effective 3. Subsequent pregnancy rates: similar for all forms 4. Recurrence rates: similar 5. Infertility: no improvement  The various agents: are comparable in terms of efficacy  Choice is determined by cost & side effects. Aboubakr Elnashar
  110. 110.  Aim: (A) Pseudopregnancy : 1. Combined contraceptive pills 2. Progestins {avoid oestrogen's side effects} (B) Pseudomenopause (induction of amenorrhoea) 1. Danazol. 2. Gn RH analogues. Aboubakr Elnashar
  111. 111. 1. Combined oral contraceptives Mechanism of action: pseudopregnancy Decidual transformation of both normal & ectopic endometrium followed by gradual necrosis & absorption of the decidual cells. Dose: Initially, a trial of continuous or cyclic for 3 months. With pain relief, continue for 6-18 months. Aboubakr Elnashar
  112. 112. Aboubakr Elnashar
  113. 113. Continuous administration: more beneficial in terms of pain relief. {preventing withdrawal bleeding prevent retrograde menstruation} Aboubakr Elnashar
  114. 114. Side effects: BTB: More common with continuous than with cyclic tt Treated with conjugated estrogen 1.25 mg or estradiol 2mg for 1 w. Other estrogen induced side effects: Nausea & vomiting weight gain DVT. Aboubakr Elnashar
  115. 115. Efficacy: OCP Vs GnRHa (Cochrane library, 2005). No significant difference in the relief of dyspareunia or non-menstrual pain With OCP: More Headaches and wt gain Less Hot flushes, insomnia & vaginal dryness Aboubakr Elnashar
  116. 116. OCP is first line therapy in the management of E. 1. Effective as GnRHa 2. With E: an increased risk of epithelial ovarian cancer: COCPs protect against this. 3. Can be taken indefinitely (SOGC, 2010) Aboubakr Elnashar
  117. 117. 2. PROGESTAGNES  Mechanism of action: decedualization & subsequent atrophy of the endometrial tissue. Suppression of the ovarian activity. Aboubakr Elnashar
  118. 118. Dose: Continuously: Progestagens given in the luteal phase are not effective DoseNamePreparation 30mg/dProveraMPA 150mg/1- 3 mo, IM.Depo proveraDMPA 10-20 mg/d.Primoult norNoreethisterone acetate 20 mg/dDuphastonDydrogestrone 2mg/dVisanneDienogest Aboubakr Elnashar
  119. 119. Side effects: Irregular bleeding: Common Treated with estrogen for 7d Wt gain Fluid retention, Depression. Adverse effect on lipoprotein High doses Aboubakr Elnashar
  120. 120. Efficacy: Norethindrone acetate effective in most patients for relieving dysmenorrhea and chronic pelvic pain. positive effect on calcium metabolism: relatively good maintenance of BMD. BTB: 50% Negative effects on serum levels of high-density lipoprotein cholesterol. Aboubakr Elnashar
  121. 121. MPA: like danazol can relieve the symptoms of E effective in the treatment of painful symptoms (Cochrane library, 2005). First choice for medical T.T. of E. {more cost effective & fewer side effects}. Aboubakr Elnashar
  122. 122. DMPA equivalent to leuprolide acetate in relieving pain. effective in relieving pelvic pain in up to 75% Very economical alternative Aboubakr Elnashar
  123. 123. loss of BMD but not as much as leuprolide acetate without addback. Long-term use:±detrimental to BMD. Prolonged delay in resumption of ovulation (6-12 mo) :not be given if pregnancy is aimed in the near future. BTB: may be prolonged, heavy, and difficult to correct {progestin effect can not be reversed quickly}. An ideal indication: residual E after hysterectomy with or without BSO when future conception and irregular uterine bleeding are not issues. Aboubakr Elnashar
  124. 124. Dienogest: Visanne selective 19-nortestosterone and progesterone activity. {strong progestational and moderate antigonadotrophic effects, but no androgenic, glucocorticoid or mineralocorticoid Activity}. Effective as GnRHa (triptorelin 3.75 mg/4w) Quality of life: slightly improved compared with leuprolide acetate Effective long-term treatment option  less hypoestrogenic side effects and little changes in BMD: advantages in safety and tolerability  Higher incidence of abnormal menstrual bleeding patterns Aboubakr Elnashar
  125. 125. Vercellini et al, 2011 For pain relief, OCs used continuously is a worthy option in women with peritoneal and ovarian lesions NETA appears to be the preferable compound in patients with rectovaginal disease. For prevention of endometrioma recurrence, OCs are extremely effective whether used continuously or cyclically, as the mechanism of action seems to be ovulation inhibition. Aboubakr Elnashar
  126. 126. 3. GNRH AGONISTS Produced by Modification of the native GnRH decapeptide at 6 & 10 positions Glp-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2 LHRH Glp-His-Trp-Ser-Tyr-Ser(But)-Leu-Arg-Pro-Azgly-NH2 Goserelin 100 times more potent than natural LHRH Aboubakr Elnashar
  127. 127. Mechanism: After initial agonistic action (flare response), down-regulation & desensitization of the pituitary: hypogonadotrophic, hypogonadal state. Aboubakr Elnashar
  128. 128. Indications GnRHa with HT addback should be considered as 2nd line treatment: No response to CHCs or progestins Recurrence of symptoms after initial improvement (SOGC, 2010) Aboubakr Elnashar
  129. 129. Types PriceEPcompanyDoseRouteNamePreparation 530Astrazenica3.6 mg/4w 11.8mg/12w SCZoladexGoserelin 605 266(7syr) FerringCR: 3.75mg, 0.1mg then 0.05 mg IM, SCDecapeptylTriptolerin 750 1550 540 Abbot3.75 mg/4w 11.25 mg/12 w 2.8 ml, 1 ml daily IM, SC IM, SC Lupron Lucrin Leuprorelin Sanofi0.5 mg then 0.2 mgNasal, SCsuperfactBuserelin Pfaizer0.2 mg bidnasalSynarelNafarelin Aboubakr Elnashar
  130. 130.  Site of injection: anterior abdominal wall • Best route of absorption and steady dissolution of depot • The trunk area is less sensitive than the thighs: negligible pain on injection Aboubakr Elnashar
  131. 131. Side effects: GnRHa alone: symptoms of estrogen deficiency hot flushes insomnia Loss of libido, vaginal dryness, emotional instability, depression, headache. loss of BMD, which is not always reversible. Aboubakr Elnashar
  132. 132. Add-back therapy: Aim: To prevent demineralization of bone & menopausal symptoms. When: •GnRha should not be given as a single agent for >6 ms. •GnRHa should not be used for any length of time in the absence of HT addback (SOGC, 2010). Aboubakr Elnashar
  133. 133. Rationale: There is a threshold serum estrogen concentration that is low enough that endometriosis is not stimulated but high enough that hypoestrogenic symptoms are prevented (Barbieri,1992). Addback GnRHa Oestradiol Endometriosis symptoms Menopausal symptoms This concentration is the same as that achieved with physiologic HT for menopausal women.Aboubakr Elnashar
  134. 134. •Estrogen-progestagen combination. Tibilone (livial): 2.5 mg/d. Bisphosphonates: Etidronate.  Aboubakr Elnashar
  135. 135. Efficacy: GnRHa: Pain relief 85-100% persisting for 6-12 months after cessation of tt. (Winkel et al,2005 ) GnRHa Vs other hormonal tt: No difference with respect to pain relief or reduction in E deposits (Cochrane library, 2005). Aboubakr Elnashar
  136. 136. 4. DANAZOL(Danocrine, Danol). isoxazzole derivative of 17 α ethinyltestosterone It is an oral “impeded” or weak androgen The golden age for danazol has passed: No more effective than the other medications Side effects Expensive Aboubakr Elnashar
  137. 137. Mechanism of action: Inhibition of pituitary Gnt. Inhibition of steriodogenesis in C. luteum. It is metabolized to at least 60 products. The multiple effects of these products is high-androgen, low-estrogen environment that does not support the growth of endometriosis & amenorrhea prevents new seeding from the uterus into peritoneal cavity. Aboubakr Elnashar
  138. 138. Side effects: Androgenic Wt gain fluid retention Fatigue decreased breast size acne, oily skin, growth of facial hair Hepatocellular damage {metabolized in liver} increased cholesterol & LDLP & decreased HDLP. Hypoestrogenic atrophic vaginitis hot flushes muscle cramps emotional liability. small study raised the concern of an increased risk of ovarian cancer The significant side effects limit its use (Cochrane Reviews 2003) Aboubakr Elnashar
  139. 139. Contraindications: Liver disease. Severe hypertension congestive heart failure impaired renal function. Dose: 200mg 4 times daily for 6 mo. < 800 mg daily is less effective. low-dose regimens or vaginal administration have been described. Aboubakr Elnashar
  140. 140. Efficacy: Recurrence in 1/3 of cases. Success is greatest in cases of peritoneal E. Endometriomas > 1cm are less likely to respond. Effective in treating symptoms and signs of E. Useful to relieve pain & prevent progress of the disease. Aboubakr Elnashar
  141. 141. New drugs An ideal treatment: Regression of the disease & symptoms No adverse hypoestrogenic effects Aboubakr Elnashar
  142. 142. DrugsGroup Mirena1. LNG-IUD Cetrorelix2. GnRHan Anastrazole (Arimidex), Letrozole (Femara) 3. Aromatase inhibitors Tamoxifen, Raloxifene4. SERM Mifepristone, Onopristone5. Progesterone antagonist Asoprisnil6. SPRM TNP470, Endostatin, Anginex, Rapamycin 7. Angiogenesis inhibitors Loxoribine, IFN- α 2 β, TNF- α inhibitors. 8. Immunomodulatory drugs. Matrix metalprotease, Doxycycline, 5- fluorouracil, Thiazolidinediones 9. Others Aboubakr Elnashar
  143. 143. 1. levonorgestrel (IUD): Mechanism of action: Unclear LNGIUD delivers significant amounts of LNG into the peritoneal fluid: clearing up the local effect on the endometriotic implants Aboubakr Elnashar
  144. 144. LNG-IUD T-shaped Release rate of LNG: 20 μg/24 h during 1st y slowly ↓ throughout the 5 y of use. : Endometrial atrophy Ovulation: usually not suppressed. Contraception Hypomenorrhea or amenorrhea Reduced dysmenorrhea Aboubakr Elnashar
  145. 145. LNG-IUD Treatment of choice for CPP-associated E in women who do not wish to conceive. 1. Effective for at least 5 ys 2. Can be reapplied every 5 ys. 3. No modifications in estrogen levels 4. In the long term it is a low-cost therapy 5. Fewer SE than other progestogenic agents. Aboubakr Elnashar
  146. 146. II. GnRH antagonists Aboubakr Elnashar
  147. 147. Mechanism of action: GnRHan immediately block GnRH effects competing with endogenous GnRH for pituitary binding sites suppress LH secretion in a dose-dependent manner. Aboubakr Elnashar
  148. 148. Studies: 3 mg of cetrorelix/w for 8 w  E2: suppressed to 50 pg/ml.  100%: symptom-free period during GnRH TT  50%: Regression  2nd look laparoscopy: Degree of E declined to a mild stage (Kupker et al, 2002). Aboubakr Elnashar
  149. 149. 3. Armoatase inhibitors Anastrazole (Arimidex): 1mg/d Letrozole (Femara): 2.5 mg/d Both are approved in USA for tt of breast cancer. Aboubakr Elnashar
  150. 150. Mechanism of action in endometriosis Estrogen is produced by 3 pathways 1. Hypothalamic-pituitary-ovarian pathway 2. Peripheral conversion 3. Locally within endometriosis.  GnRHa stops only 1st pathway  AI stop all 3 pathways •Decreasing aromatase in the brain: decrease LH& FSH: decrease estrogen •Suppress ovarian & peripheral (e.g. adipose tissue) estrogen production. Aboubakr Elnashar
  151. 151. Aboubakr Elnashar
  152. 152. AIs: 1. Should be combined with a progestin or COCs or GnRHa 2. Combinations of an AI with a progestin or COCs is more popular {cheaper, fewer side effects} 3. No severe SE 4. AIs should be offered with severe pain despite previous surgical& hormonal therapies. 4. Further research is required before recommending the routine use of these agents. Aboubakr Elnashar
  153. 153. Evidence based Recommendations Aboubakr Elnashar
  154. 154. 1. Combined hormonal contraceptives, ideally administered continuously, should be considered as 1st line agents. (I-A) 2. Administration of progestin alone orally,IM, or SC may also be considered as 1st line therapy. (I-A) 3. A GnRHa with HT addback, or the LNG-IUS, should be considered 2nd line therapeutic option. (I-A) Aboubakr Elnashar
  155. 155. 4. A GnRHa should be combined with HT addback therapy from commencement of therapy and may be considered for longer-term use (> 6 months). (I-A) 5. While awaiting resolution of symptoms from the directed medical or surgical treatments for endometriosis, NSAIDs can be tried. (III-A) Aboubakr Elnashar
  156. 156. 4. SERM: Raloxifene has Estrogen antagonist on the endometrium (attenuates the growth) Estrogen agonist on bone (preserve bone mineral), but Vasomotor symptoms limits its use Aboubakr Elnashar
  157. 157. 5. SPRM (asoprisnil): Mixed agonistic & antagonistic. It inhibits endometrial growth without producing systemic progestational effects Aboubakr Elnashar
  158. 158. 6. Pentoxifylline: Multi-site immunomodulating drug 7. Mifepristone: It has antiprogesterone & antiglucocorticoid actions. 8. Endostatin (Becker et al, 2005) angiogenesis inhibitor suppressed the growth of endometriotic in mice without any apparent negative effects on fertility or reproduction, Aboubakr Elnashar
  159. 159. Endometriosis & miscarriage RCT: miscarriage rate was in the normal range in women with E who were not treated. Implantation failure & early abortion: E does not result in a higher rate of early pregnancy loss. Endometriosis & ovulation The frequency of anovulation & luteal phase defects is similar in women with & without E. Aboubakr Elnashar
  160. 160. Endometriosis & IVF • The presence of E does not generally impair the results of IVF but it increases the risk of infection. • It is preferable not to cauterize ovarian endometrioma if IVF or ICSI is indicated for fear of destruction of ovarian tissues. Aboubakr Elnashar
  161. 161. SURGICAL Aboubakr Elnashar
  162. 162. A- Conservative: Aim : •Restore normal anatomical relationships •Excise or destroy as much of the E as possible •Prevent or delay recurrence Even 1/10 of an ovary can be enough to preserve function & fertility (Speroff, 1999). Aboubakr Elnashar
  163. 163. Routes: Laparoscopy or laparotomy Laparoscopy •Advantages: Better visualization Less tissue trauma & desiccation Smaller incision, speedier postoperative recovery. Postoperative adhesions & complications may be less than laparotomy Results are equivalent or better than laparotomy (Admson & Pasta, 1994) Aboubakr Elnashar
  164. 164. Disadvantages: In advanced E it may be extremely hazardous. For gynecologist without level III training laparotomy will be more appropriate. Strict adherence to microsurgical principles: Magnification Minimal tissue trauma Minimal exposed sutures Meticulous hemostasis Aboubakr Elnashar
  165. 165. Procedures: 1. Peritoneal implants: Ablation (with unipolar or bipolar electrosurgery or laser) or Excision by sharp dissection. Superiority of one method over another are not substantiated (Sperof & Fritz, 2005) 2. Adhesions: Excision is preferable to simple lysis because adhesions will frequently contain disease.Aboubakr Elnashar
  166. 166. 3. Ovarian endometrioma: Wedge resection, stripping, drainage with & without ablation of the internal cyst wall. The best is cystectomy or fenestration with ablation of the internal cyst wall (Sperof & Fritz, 2005) 1. Residual deep ovarian disease is less likely than after drainage alone 2. Reoperation rates are lower after drainage without ablation 3. Wedge resection is associated with marked postoperative adhesions 4. Fenestration & ablation may preserve more functional ovarian tissue Aboubakr Elnashar
  167. 167. 4. Dysmenorrhea & central pelvic pain: Presacral neurectomy (PSN) & Laparoscopic uterosacral nerve ablation (LUNA) PSN= interrupting the sympathetic innervations of the uterus at the level of the superior epigastric plexus. LUNA= transecting the mid-portion of ut sac lig. Risks: injury to the ureters or bowel bladder dysfunction. RCT These procedures add no significant benefit to conservative surgery (Daniell et al 1995). Aboubakr Elnashar
  168. 168. 5. Deeply infiltrating rectovaginal E: Extensive surgery By the most skilled & experienced surgeons. Often, a portion of the posterior vagina must be excised, & sometimes, a short segment of rectum must be resected, followed by anastomosisAboubakr Elnashar
  169. 169. Results of surgery: Pain Mild E: effectiveness is comparable to that of medical tt. Endometriomas or deeply infiltrating disease: Surgical tt offers better long term results. The combined surgical approach (of laparoscopic laser ablation, adhesiolysis and uterine nerve ablation) is beneficial for pelvic pain associated with minimal, mild and moderate endometriosis (Cochrane library, 2005) Aboubakr Elnashar
  170. 170. Infertility: Moderate to severe E: Surgical treatment improves fertility Minimal & mild: improvement to a modest extent Aboubakr Elnashar
  171. 171. Preoperative medical treatment: No proven value except in deep disease involving the cul-de sac or rectovaginal septum. Aboubakr Elnashar
  172. 172. Postoperative medical treatment: Infertility: It does not increase PR (Vercellini et al, 1998). The highest PR following conservative surgery occur in the first year & most doctors not use it. Pain: It delays recurrence (6 mo) of the disease & symptoms & warrants consideration in extensive or residual disease (Hrnestein, 1997) Aboubakr Elnashar
  173. 173. Recurrence of E after surgery E. tend to recur unless definitive surgery (TAH & BSO) is performed. Recurrence rate: 10-20% per year Reasons of recurrence: Microscopic E escaped detection Incomplete treatment, Reestablishment of primary disease. Aboubakr Elnashar
  174. 174. B- Radical: Indications: Failure of hormonal tt & conservative surgery is unnecessary or unsuccessful Hysterectomy& usually bilateral salpingo- oophrectomy. Aboubakr Elnashar
  175. 175. HRT after radical surgery •Estrogen & progestagen replacement therapy at usual doses can be started immediately after surgery with negliable risk of recurrence. Aboubakr Elnashar
  176. 176. Thank you Benha University Hospital, Egypt Email:elnashar53@hotmail.com Aboubakr Elnashar
  177. 177. Aboubakr Elnashar
  178. 178. Pharmacological therapy for endometriosis is inevitably a compromise. Not all women using progestins will be relieved from pain, not all will be satisfied with their treatment, not all will continue it and not all will avoid surgery. But at least two-thirds of them could substantially ameliorate their health-related quality of life, controlling the disease with marginal associated morbidity. This appears to be a major medical achievement, and as such should be regarded. Aboubakr Elnashar
  179. 179. Aboubakr Elnashar
  180. 180. Aboubakr Elnashar
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  182. 182. Aboubakr Elnashar