endometriosis presentation.....ppt .pptx

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1. ENDOMETRIOSIS P resenter: Dr.M.Sai Sanjusha 2 nd year PG Moderators: Dr. Gayathri Sri Sri Madam(Professor) Dr. Bhavani Madam( Assistant professor) Dr. Sameera Madam (Senior Resident)

2. LEARNING OBJECTIVES Introduction Pathophysiology Risk Factors and Protective Factors Clinical Presentation Diagnosis Management Recent Advances

3. INTRODUCTION Endometriosis is defined as the presence of endometrial glands and stroma outside the uterus First described by Karl von Rokitansky. Father of modern endometriosis is Dr. John Sampson The most frequent sites of implantation are the pelvic viscera and the peritoneum . Although rare, it can also be found in the pericardium, pleura, lung, and even the brain . Endometriosis varies in appearance from a few minimal lesions to deep infiltrating nodules and massive ovarian endometriotic cysts with extensive adhesions involving bowel, bladder, and ureter resulting in significant distortion of the pelvic anatomy.

4. EPIDEMIOLOGY Prevalence Endometriosis is found predominantly in women of reproductive age, most commonly between the ages of 30 and 40 years. But endometriosis also reported in adolescents and in postmenopausal women receiving hormonal replacement therapy. Seen in 10 % among women of reproductive age. Seen in 50% among women of unexplained infertility. It is 20% in those with chronic pelvic pain.

5. RISK FACTORS OF ENDOMETRIOSIS Endometriosis In First-degree Relative*(the Risk Of Endometriosis Is Seven times Greater If A First-degree Relative Is affected Early Age At Menarche Shorter Menstrual Cycle Length Nulliparity Müllerian Anomalies with outflow obstruction( favor retrograde menstruation) Diethylstilbestrol (DES) Exposure Polymorphism of K- RAS gene

6. PROTECTIVE FACTORS OF ENDOMETRIOSIS Multiparity Lactation Tobacco exposure Increased body mass index Increased waist-to-hip ratio Diets high in vegetables and fruits.

7. PATHOPHYSIOLOGY The definitive cause of endometriosis remains unknown, but several theories are proposed. Retrograde Menstruation (Sampson’s theory) Coelomic Metaplasia (Myer and Ivanoff’s theory) Vascular/Lymphatic dissemination theory ( Halban’s theory) Induction theory Mullerian remnants Direct implantation

8. PATHOPHYSIOLOGY 1.Retrograde menstruation - By Sampson Refluxed endometrial fragments invade the peritoneal mesothelium. Interestingly, >90 % of women experience retrograde menstruation but only a few develop endometriosis Does not explain pleural and peritoneal endometriosis and endometriosis at other distant sites.

9. PATHOPHYSIOLOGY

10. PATHOPHYSIOLOGY 2.Hematogenous or Lymphatic spread: By Halban The eutopic endometrium of affected women has greater lymphatic vessel density leading to embolisation of menstrual fragments through lymphatic and vascular channels. 3. Coelomic Metaplasia Theory: By Meyer and Iwanoff This theory states that spontaneousmetaplastic change occurs in mesothelial cells derived from the coelomic epithelium. Thus explains pleural and pulmonary endometriosis.

11. PATHOPHYSIOLOGY 4.Induction Theory The induction theory is an extension of the coelomic metaplasia theory. Endogenous (undefined) biochemical factor(stimulus) is responsible for transformation of undifferentiated peritoneal cells to endometrial glands and stroma. 5. Mullerian remnants Remnants that are left along their embryonic path undergo abnormal differentiation leading to endometriosis. 6.Direct implantation of endometrial cells explains the presence of endometriosis in abdominal scars, Cesarean scars and episiotomy scars.

12. PATHOPHYSIOLOGY However, recent clinical and experimental evidences have demonstrated migration and differentiation of Bone-marrow derived stem cells into endometrial cells. This explains the presence of endometriosis in brain and other distant sites. The ectopic endometrial tissue is further capable of attracting bone marrow-derived stem cells.

13. PATHOPHYSIOLOGY

14. IMMUNOLOGY OF ENDOMETRIOSIS

15. SITES OF ENDOMETRIOSIS

16. OVARY The most common site Involved in 30 to 40 % of cases. Mostly bilateral. It appears as - “Burnt match head spots” on surface of ovary “Tarry cysts” surrounded by adhesions known as “Chocolate cysts”

17. CHOCOLATE CYSTS Ectopic endometrium responds to ovarian hormones-shows cyclical change  No outlet for this menstrual discharge  Blood and debris collect within to form cyst  With each cycle , it gradually increases in size. The blood gradually becomes dark coloured giving rise to tarry or chocolate cyst. As the size increases the endometrial lining is destroyed Large tarry cysts are lined by granulation tissue or by pseudoxanthoma cells( rich in hemosiderin). Not all tarry cysts are endometriotic . Rupture of endometriotic cysts scatter their contents leading to development of further areas of endometriosis. Source-Jeffcoate’s 9e

18. PELVIC PERITONEUM - including the uterovesical pouch and the Pouch of Douglas The peritoneum of the pouch of Douglas is the second most common site. The lesions on the pelvic peritoneum are manifested more by puckering and thickening of peritoneum and by adhesions. Often occlude the utero-rectal space, fixing the uterus in retroversion . OUTER COAT OF UTERUS Endometriosis of the ovary, pelvic peritoneum and associated ligaments, when adherent to the uterus, often invades its outer coat. The penetration is superficial and of little significance: it does not constitute adenomyosis.

19. INTESTINES Rectum, colon, ileum, caecum and appendix are possible sites. It causes stricture formation and adhesions leading to intestinal obstruction. VAGINA AND VULVA Posterior fornix is the most common site for vaginal endometriosis. The lesion appears as multiple small blue-domed cysts in the vagina.

20. CLINICAL FEATURES The five “Ds”: Dysmenorrhoea (secondary progressive) Disorders of menstruation Dyspareunia Dyschezia (cyclical) Dull ache of abdomen

21. Dysmenorrhea (50%) The classical symptom is dysmenorrhea which is progressive. The pain comes on gradually for a few days before the period, reaching a maximum towards the end of menstruation and persists for a few days after the period has ended. Mechanism of pain Direct and Indirect effects of focal bleeding from endometriotic implants Inflammatory cytokines in endometrial cavity Irritation/infiltration of pelvic nerves

22. Infertility The adhesions, distorted anatomy and altered tubal motility result in impaired ovum pick-up Altered immune response leads to phagocytosis of sperms. Hormonal dysfunction may lead to anovulation Dyspareunia Seen when pouch of Douglas and rectovaginal septum are affected; when there is an associated retroversion. Dyschezia Seen in cases where rectum is involved and is more noticeable at the time of menstruation when the lesion is larger and more tender.

23. MECHANISM OF INFERTILITY Infertility may be due to distorted anatomy, inflammation, and aberrant endometrial gene expression Distorted anatomy---------- inhibits or prevents ovum release and capture after ovulation, premature depletion of ovarian follicular pool Chronic inflammation------impaired folliculogenesis,fertilization and implantation, damage to oocytes and sperms, toxic effects on embryo Progesterone resistance--------no decidualization--decreased endometrial receptivity.

24. Abdominal pain Can be acute or chronic Acute: A sudden , severe pain associated with symptoms and signs of acute abdomen is seen when a cyst ruptures. It is often confused with appendicitis. It mostly occurs at the time of menstruation. Chronic: Chronic aching pain often referred to groins, thighs, hips occurs due to cysts and adhesions.

25. Chronic pelvic pain : Peritoneal fluid in endometriosis contains prostaglandins leading to pain Nerve entrapment also leads to pain. Extragynaecological manifestations: Headaches, Arthralgias, Myalgia, Eczema, Hypothyroidism, Chronic fatigue syndrome, Fibromyalgia, Vaginal candidiasis, Non menstrual pelvic pain. Urological symptoms such as increase in frequency, dysuria, hematuria can be seen due to the involvement of bladder or ureter.

26. DIAGNOSIS

27. DIAGNOSIS PHYSICAL EXAMINATION: The vulva, vagina and cervix should be inspected first with a speculum to rule out any deposits. 1. Tenderness on vaginal examination 2. Nodules in the posterior fornix (cobblestone like) – uterosacral ligaments involved. Speculum examination may reveal bluish / blackish puckered spots in posterior fornix. 3. Adnexal masses 4. Immobility or lateral placement of the cervix or uterus.

28. IMAGING Transvaginal ultrasonography Magnetic Resonance Imaging Transvaginal ultrasonography Can detect ovarian endometriomas but not pelvic adhesions or superficial peritoneal foci Endometriomas appear as cystic structures with diffuse low-level internal echoes surrounded by a crisp echogenic capsule. Also, occasionally with internal septations or thickened nodular walls

29. MRI Superior to TVS in differentiating endometriomas from other cystic ovarian masses. Identifies 30-40% of peritoneal implants. Differentiates acute hemorrhage from degenerated blood products. Endometriomas exhibit homogeneous high signal intensity on T1-weighted image and a hypointense “shading” on T2-weighted imaging. Acute hemorrhage has low signal intensity on both T1 and T2-weighted images.

30. SURGICAL DIAGNOSIS Laparoscopy is the gold standard technique for visualizing pelvis and establishing definitive diagnosis. During diagnostic laparoscopy, complete inspection of the bowel, bladder, uterus, tubes, ovaries, cul de-sac and broad ligament in a clockwise or counter clockwise fashion with a blunt probe should be done.

31. SURGICAL DIAGNOSIS Appearance of lesions on laparoscopy: Classic peritoneal implant appears as blue-black “powder-burn” lesion with surrounding fibrosis due to hemosiderin deposits from entrapped blood. Atypical inactive white and opaque lesions Active proliferating Red and flame-like lesions. Vesicular lesions

32. SUPERFICIAL ENDOMETRIOSIS In superficial endometriosis – also known as Sampson's syndrome – superficial plaques are scattered across the peritoneum, ovaries and uterine ligaments. These patients tend to have minor symptoms and usually also less structural changes in the pelvis. In laparoscopy, these implants may be seen as superficial powder-burn or gunshot lesions.

33. DEEP PELVIC ENDOMETRIOSIS In deep pelvic endometriosis - also called Cullen's syndrome - there is subperitoneal infiltration of endometrial deposits. The symptoms are more severe and related to the localization and depth of invasion. MRI is of use for the diagnosis of deep infiltrating endometriotic lesions and for the assessment of disease extension.

34. In the uterus - The torus uterinus ( where the uterosacral ligaments attach) and posterior fornix are common locations of endometriosis. Clinically these patients often present with dyspareunia.

35. Typical black-puckered lesions with hypervascularization and orange polypoid vesicles. Red polypoid lesions with hypervascularization

36. Superficial ovarian endometriosis.

37. Laparoscopic image of uterus and right ovary with dark endometrioma . Ovarian endometriotic cystectomy

38. Extensive endometriosis with deep nodule at the right uterosacral ligament, masked by adhesions Cul-de-sac after resection of deep nodule with CO2 laser.

39. NON-INVASIVE DIAGNOSIS Non-Invasive Biomarkers: CA-125, HE4(Human epididymis protein 4), miRNA (research ongoing). AI in Detection: Machine learning for early diagnosis. AI model called IMAGENDO that combines data from transvaginal ultrasound and MRI findings to provide real-time assessment of inferred diagnosis

40. DIFFERENTIAL DIAGNOSIS Chronic pelvic inflammatory disease. Uterine leiomyomas Malignant disease of the ovary or metastases on the pelvic peritoneum Carcinoma of the cervix and vagina Carcinoma of rectum and colon ,diverticulitis All causes of an acute abdomen, in the case of rupture of a tarry cyst

41. STAGING OF ENDOMETRIOSIS Revised American Society for Reproductive Medicine Scoring system ENZIAN classification Endometriosis Fertility Index(EFI)

42. STAGING OF ENDOMETRIOSIS Endometriosis is surgically staged according to the revised American Society for Reproductive Medicine scoring system ( rASRM ) based on: Morphology Size Depth of ovarian and peritoneal implantation Degree of cul-de-sac obliteration Presence, extent, and type of adnexal adhesions

43. STAGING OF ENDOMETRIOSIS Stage I– Minimal disease: Isolated implants and no significant adhesions. Stage II– Mild endometriosis: Superficial implants that are less than 5 cm in aggregate and are scattered on the peritoneum and ovaries. No adhesions are present. Stage III– Moderate disease: Multiple implants, both superficial and deeply invasive, including endometriomas>1cm. Peritubal and periovarian adhesions may be evident. Stage IV– Severe disease: Multiple superficial and deep implants, including large ovarian endometriomas. Filmy and dense adhesions are usually present

44. STAGING OF ENDOMETRIOSIS ENZIAN classification for deep infiltrating lesions

45. STAGING OF ENDOMETRIOSIS Endometriosis Fertility Index to predict cumulative pregnancy rates 3 years after surgery. Score ranges from 0-10 Score 0-poorest prognosis Score 10-best prognosis

46. TREATMENT

47. TREATMENT GOAL : Atrophy of ectopic endometrium and lessen the disease-associated inflammation. Expectant Management For those with mild symptoms For asymptomatic women diagnosed incidentally . At second-look laparoscopy after 1 year, 29 percent of women had disease regression, 42 percent remained unchanged, and 29 percent had disease progression.

48. MEDICAL MANAGEMENT Nonsteroidal Anti-inflammatory Drugs Both cyclooxygenase (COX)-1 and COX-2 enzymes promote synthesis of prostaglandins Specifically, ectopic endometriotic tissue expresses COX-2 at greater levels than eutopic endometrium. Due to the cardiovascular risks with long-term use of selective COX-2 inhibitors, these medications are used at the lowest possible dose.

49. Combined oral contraceptives Mainstay for the initial treatment of endometriosis-related pain. Inhibit gonadotropin release , decrease menstrual flow . Can be used conventionally in a cyclic regimen or may be used continuously. Monophasic COCs are preferred. Low-dose COCs (containing  20 μg ethinyl estradiol) may lead to higher rates of breakthrough bleeding.

50. In long-cycle regimens, active pills are usually taken for atleast 90 days continuously followed by a 7-day pill-free interval , to help prevent breakthrough bleeding.

51. Progestins Progestins antagonize the estrogenic effects on the endometrium. They cause initial decidualization and subsequent endometrial atrophy. Available as : Oral progestins, depot preparations and drug eluting intra uterine devices. Can also inhibit gonadotropin secretion and ovulation in high doses.

52. Etonorgestrel subdermal implant Medroxyprogesterone acetate 30-100mg PO 150mg IM every 3 months Norethindrone acetate 5-15mg PO Megestrol acetate 40mg PO LNG-IUCD Dienogest Fourth-generation progestin Increases the number of progesterone receptors.

53. Side effects Nausea Weight gain Fluid retention Breast tenderness Irregular bleeding Depression Breakthrough bleeding-treated with short courses of supplemental conjugated estrogens 1.25mg or estradiol 2mg daily for 7-10 days Bone-mineral depletion-reversed after discontinuing therapy Decreased HDL

54. GnRH Agonists Continuous, non pulsatile GnRH administration results in pituitary desensitization . Subsequent loss of ovarian sex steroid hormone production. Creates a pseudo-menopausal state during treatment GnRH agonists are inactive if taken orally. Can potentially decrease the size of endometriomas

55. Leuprolide 500mg sc daily 3.75mg IM monthly Goserelin 3.6mg sc monthly Buserelin 300mcg IN daily 200mcg sc daily Nafarelin 200mcg IN daily Triptorelin 3.75 mg IM monthly

56. Side effects Initial flare effect-minimised by starting the therapy one week prior to menses Hot flashes Decreased libido Vaginal dryness Depression, irritability, fatigue, headache, changes in skin texture Bone mineral depletion

57. Add-Back Therapy The goal of add-back therapy is to supply sufficient estrogen to minimize bone-mineral depletion. Available drugs: Norethindrone acetate 5mg Conjugated estrogen 0.625mg Medroxyprogesterone acetate 2.5mg

58. GnRH Antagonists Elagolix , relugolix and linzagolix MOA: competitively bind to the GnRH receptors and inhibit them. They have a short hal - life, therefore, they allow rapid reversibility. E LAGOLIX : The molecule was first approved by USFDA (2018). Allows rapid and reversible onset and offset , thus providing flexibility in modulating the hypothalamus–pituitary–gonadal axis. Elagolix 200 mg twice daily demonstrated exclusive efficacy in reducing dyspareunia score. Elagolix 150 mg and 200 mg twice daily for 6 months improved dysmenorrhea and non-menstrual pelvic pain in women suffering from moderate to severe pain associated with endometriosis

59. Danazol Dosage:400-800mg daily Inhibits midcycle LH surge and creates chronic anovulatory state leading to low estrogen levels Increases free testosterone levels. Median time to recurrence after discontinuation of therapy is 6 months

60. Side effects Weight gain, fluid retention, fatigue, decreased breast size, acne, oily skin, hirsutism, atrophic vaginitis, hot flushes, muscle cramps, emotional lability Crosses the placenta, a known teratogen. Decrease in HDL, Increased levels of LDL and cholesterol. Rarely liver damage and arterial thrombosis

61. Aromatase Inhibitors ANASTROZOLE (ARIMIDEX) and LETROZOLE Endometriotic tissue produces estrogen locally. Aromatase inhibitors block aromatase action and estradiol production in both the ovary and extraovarian sites. A serious concern is ovarian cyst formation . Therefore, always combine with progestins , COCs , or GnRH agonist to help blunt this significant side effect

62. Progesterone-Receptor Modulators Selective progesterone-receptor modulators (SPRMs) may activate or inactive progesterone receptors . Of SPRMs, ulipristal acetate is available in the United States for emergency contraception as single-dose. Of progesterone antagonists, mifepristone ( Mifeprex ) is currently FDA-approved solely for early pregnancy termination. Reduces both pelvic pain and the extent of endometriosis.

63. Selective Estrogen-Receptor Modulators Bazedoxifene (BZA) is a third-generation selective estrogen receptor modulator (SERM)

64. Gestrinone Gestrinone is a synthetic trienic 19-norsteroid. It is an antiprogestational agent prescribed for endometriosis. It has antiprogestational , antiestrogenic, and androgenic effects. During 6 months of treatment, gestrinone was not associated with the BMD decline commonly seen with GnRH agonist use and was more effective in persistently decreasing moderate to severe pelvic pain. One of the side effects of gestrinone appears to be lowering high-density lipoprotein (HDL) levels. Side-effects include weight gain, reduced breast size, muscle cramps Gestrinone can be administered as 2.5-mg oral twice weekly dose .

65. SURGICAL MANAGEMENT Minimally Invasive Techniques • Robotic-assisted laparoscopy. • CO₂ laser excision. Fluorescence-Guided Surgery Near-infrared fluorescence for lesion detection. Adhesion Prevention Hyaluronic acid-based barriers

66. Fluorescence-Guided Surgery NIR-ICG involves using a dye (indocyanine green or ICG) that fluoresces under near-infrared light, allowing for enhanced visualization of tissues during surgery. Improved lesion detection More precise surgery Understanding the disease Nerve-sparing surgery Limitations ICG is a non-specific dye, meaning it can highlight other tissues as well as endometriosis lesions .

67. TREATMENT OF ENDOMETRIOSIS-ASSOCIATED INFERTILITY

68. TREATMENT OF ENDOMETRIOSIS-ASSOCIATED INFERTILITY

69. EMERGING THERAPIES Stem Cell Therapy: Regenerative medicine for endometrial repair. MicroRNA-Based Therapeutics : Regulating inflammation and lesion growth. Immunotherapy: Immune checkpoint inhibitors under investigation. HIFU: High-intensity focused ultrasound (HIFU) technology is being explored as a non-invasive method for targeting and destroying abnormal tissues associated with endometriosis. 

70. STEM CELL THERAPY Stem cells possess unique properties, including self-renewal and differentiation capabilities, making them ideal candidates for regenerative medicine applications. By harnessing the regenerative potential of stem cells, researchers aim to repair damaged tissues and restore normal physiological function in patients with endometriosis. Stem cell therapy exerts its therapeutic effects through multiple mechanisms, including immunomodulation, anti-inflammatory activity, promotion of angiogenesis and tissue repair. These complex interactions contribute to the alleviation of symptoms and the restoration of tissue homeostasis in endometriosis. Types of stem cells used in treatment of endometriosis: Mesenchymal Stem Cells (MSCs) Induced Pluripotent Stem Cells ( iPSCs ) Endometrial Stem Cells ( EnSCs )

71. Advances in Pain Management Neuromodulation Techniques: • Transcranial magnetic stimulation (TMS). • Spinal cord stimulation. Cannabinoid-Based Therapies: • Potential anti-inflammatory and analgesic properties.

72. Integrative & Lifestyle Approaches Dietary Modifications: Anti-inflammatory diet (Mediterranean diet). Gut Microbiome & Probiotics: Potential role in symptom control. Mind-Body Interventions: Yoga, acupuncture, cognitive behavioural therapy (CBT).

73. RECURRENCE RATE Overall recurrence rate is 2 to 20% per year. It can be due to incomplete surgery or development of new lesions. Postoperative hormonal therapy should be continued to prevent recurrence. An exception to postsurgical hormonal therapy is if the woman wants to conceive immediately following surgery.

74. REFERENCES Berek & Novak’s Gynecology , SIXTEENTH EDITION JEFFCOATES PRINCIPLES OF GYNECOLOGY 7 TH EDITION American Society for Reproductive Medicine| ASRM 4.Speroff’s Clinical Gynecologic Endocrinology and Infertility

75. THANK YOU