Endometriosis

1. Endometriosis Sun-Wei Guo Shanghai OB/GYN Hospital Fudan University Shanghai College of Medicine

2. Learning objectives • To know • Definition of endometriosis • Its signs and symptoms • Some notable features of endometriosis • Its diagnosis • Epidemiology • Its treatedment

3. Definition of endometriosis • “endo”: inside • E.g. endoscopy, endocrinology, • “metra”: womb, uterus • A gynecological condition in which endometrial cells appear and grow outside the uterine cavity • Endometrial cells: Both stromal and epithelial cells • If appeared in the myometrium, it’s called adenomyosis (once called “endometriosis in interna”) • Lesions: ectopic endometrium, endometriotic lesion, (ectopic) endometrial implant

4. Signs and Symptoms • Recurring pelvic pain (rarely, pain in other body parts) • Chronic pelvic pain • Dysmenorrhea (painful menstruation) • Dyspareunia (painful sex) • Dysuria (painful voiding) • Infertility • Menstrual disturbances

5. Some notable characteristics • Estrogen-dependence • Invasiveness • Like tumors, endometriotic cells are invasive • Adhesion • Tough to treat, let alone cure • Quite common • ~ ¼ gynecological surgeries are endometriosis-related • A debilitating disease • Loss of productivity • Reduction in life quality • Emotional and relationtional burden • Quite expensive to treat • $2800/yr for Tx, then $1000/yr for loss of productivity • In China, ~15000 Yuan for surgery+medication+hospitalization

6. Epidemiology: prevalence • Incidence • Unknown • Mostly women of reproductive age • Prevalence • 1-22%, depending on screening method and the population; • precise number unknown • Often 10% is used • ~26.1% in women with infertility • 17.7% in women with pelvic pain • 5.7% in women undergoing sterilization

7. Epidemiology: risk factors • Consistently identified (“incessant menstruation”) • Earlier age of menarche • Shorter menstrual cycle • Lower parity • Controversial • Dioxin exposure • Heavier menses • Alcohol consumption • Red hair • Protective factors • Regular exercise • Smoking

8. Subtypes of endometriosis • Depending mostly on location • Ovarian endometriosis (ovarian endometriomas) • Unilateral or bilateral • Mostly < 5 cm in size • Peritoneal endometriosis • Deep infiltrating endometriosis (DIE) • Rectovaginal • Ovarian endometriomas is the most common (40-80%, depending on hospital)

11. Extraperitoneal endometriosis • Lung, brain, nose, eyelid,… • Very rarely, in men with prostate cancer after receiving estrogen therapy

12. Pathogenesis • Formal description by Von Rokitansky (1860) • Largely unknown (“An enigma”) • Many theories, yet none proven • Retrograde menstruation • Coelomic metaplasia (peritoneum and endometrium are both derived from the coelomic cells) • Müllerianosis • Neoclassic theories • Dioxin exposure • Prenatal exposure • Genetic predisposition • Immune deficiency

13. Laparoscopic photographs Ovarian endometrioma: chocolate cyst Ovarian endometrioma: “kissing ovaries” Peritoneal endometriosis

15. The most popular theory • John A. Sampson’s retrograde menstruation theory • Viable menstrual debris is regurgitated into the pelvic cavity through the fallopian tubes, attatches itself to ectopic sites, invades the tissue and grows • Evidence • Human experimentation (innoculation of menstrual debris did cause endometriosis) • Uterine dysperistalsis and hyperperistalsis in endometriosis • Animal experiment (in baboons) • Anatomic anomaly (closure of cervical os and endometriosis) • Yet retrograde menstruation occurs in >95% of women with patent fallopian tubes; why not all of them develop endometriosis?

18. Diagnosis • Gold standard: • Direct visualizationof endometriotic lesions • usu. by laparoscopy or laparotomy • Imaging: • Ultrasonography • MRI • CT • Signs and symptoms • Secondary dysmenorrhea • Dyspareunia • Infertility • Gynecological examination • Histological confirmation • The presence of both • endometrial stroma and • epithelium • Blood biochemistry

19. Laparoscopy/laparotomy • Pros: • “Gold standard” • Can also remove lesions • Cons • Invasive procedure • Has its own risk of morbility and, rarely, mortality • Costly • Still difficult to detect microscopic and/or subperitoneal lesions • Accuracy depends on the skill levels of surgeons

20. Staging of endometriosis • The revised American Fertility Society (rAFS) scoring system is the most widely used (1995) • Could be used for determining treatment modalities • A score is assigned to lesions based on • Location • Number of lesions • Size • Infiltration depth • Presence of adhesion • 0—140 • rAFS stage: • I: 1-5 • II: 6-15 • III: 16-40 • IV: >40 • Problems • It does not correlate with either the severity of pain or infertility • It has no predictive value in prognosis

21. Serum markers • Over 200 different serum biomarkers have been proposed, yet none stands the test of time • The most used: CA125 > 30 U/ml • CA125 level can be elevated in moderate/severe cases • Pros • Non-invasive • Cheap • Fast • Cons • Low sensitivity/specificity

22. Symptomology • Pains • Secondary dysmenorrhea • Dyspareunia • Progressive • Infertility • Other factors ruled out • Difficulty in conceiving • Problems in implantation • Cyclic pains/bleedings (or bloody cough) • Caution: the signs and symptoms are not specific

23. Gynecological examination • Pelvic exam • Appearance (for cutaneous lesions) • Test for uterus size • Palpation of any nodules or tenderness on or near the posterior wall of the uterus (Douglas pouch, cul de sac) • Palpation of adnexal mass • Limited value

24. Radiologic imaging • Pros • Non-invasive • Cheaper than surgery • Cons • Lacks sufficient sensitivity and specificity • Somewhat expensive • Lower availability • MRI • Performed after day 8 of the cycle • Anti-peristaltic i.m. • T1 or T2-weighted images, before/after taking contrast • Good for peritoneal and ovarian endometriosis • CT • Only good for endometriosis in the lung

25. Ultrasound • Excellent for ovarian endometriomas • “Chocolate cyst” is filled with old blood, giving a typical ground-glass appearance with low-level echoes • Not good for other types of endometriosis

26. Differential diagnosis • Ovarian malignancy • Adenomyosis • Pelvic Inflammatory Disease (PID)

27. Treatment goals • To alleviate pains • To delay recurrence as long as possible • To help patients get pregnant

28. Treatment options • Thoughts before deciding the treatment • Symptoms • Pain or infertility or both • Patient characteristics • Age • Severity of disease • Severity of pain • Prior treatment history • Reproductive needs • Other wishes

29. Some rough guidelines • First-line medical treatment: patients with mild symptoms or adolascent girls • Medical treatment: Patients with endometriosis who wish to get pregnant • Fertility-preserving surgery: Young patients with severe endometriosis who wishes to have children • Ovary-preserving surgery+medication: young patients with severe endometriosis who does not wish to have children • Radical surgery: Older patients with severe endometriosis who do not wish to have children

30. Treatment options • Surgery • Laparoscopy or laparotomy • Radical or conservative • Non-surgical treatment (medication) • First-line medication • Progestins • Gonadotropin-releasing hormone (GnRH) agonists • Danazol (androgenic) • Oral contraceptives • Controlled ovarian hyperstimulation (fertility treatment)

31. Surgery • Indications • Medical treatment ineffective • Size of the adnexal mass > 5 cm • Wishing to get pregnant • Purposes • Accurate diagnosis • Removal of endometriotic lesions as much as possible • Removal of adhesion and restoration of normal anatomy

32. Surgery: Pros and cons • Pros • Proven efficacy • Cons • Invasive • Costly • Certain risks • Due to high recurrence risk (~50% 5 yrs), 2nd surgery may be needed • Increases the risk of damaging ovaries, and the risk of premature ovarian failure

33. Medical treatment: Expectant treatment • Use NSAIDs • Asprin • Other analgesics such as ibuproten • Selective COX-2 inhibitors • Little impact, if any, on endometriotic lesions • Follow-up

34. Medical treatment • Principles (for current treatment modalities) • To suppress ovarian estrogen production (GnRH-a and danazol) necessary for the development and maintenance of ectopic endometrium • To induce a pseudo-pregnency (progestins and OC), which suppresses ovulation and estrogen production • With reduced estrogen production, endometriotic lesions may shrink in size or may be eliminated • All are short-term; recurrence after termination • All have various side-effects • ~10% simply do not respond to pregestin therapy

35. Progestin treatment • Based on a serendipitous finding that pregnancy relieves the sysmptoms of endometriosis • Mechanism of action (MOA) • Suppresses ovulation • Suppress the growth of endometriotic lesions • Reduce inflammation • Progestins • Oral • Norethisterone acetate • Cyproterone acetate • Dienogest • Intramuscular route • Medroxiprogesterone acetate • Intrauterine route • Levonorgestrel-releasing IUD • Side-effects • Spotting, hot-flashes, breakthrough bleeding

36. GnRH agonists treatment • MOA • Negative feedback control of ovarian estrogen production • Method of administration • Injection • Side-effects • Hot-flashes • loss of libido • vaginal dryness, • decreased bone density • Quite expensive

37. Danazol treatment • Danazol is a modified androgen • 2.5-3.5% of activity of methyl testosterone • MOA • Antagonizes estrogen at the tissue level • Blocks estrogen receptor sites • Suppresses ovulation (and thus estrogen production) • Alters pulsatile GnRH release patterns • Side-effects: weight gain, acne, hirsutism, … • Decreased use after GnRHa introduction

38. Treatment with oral contractives • MOA • Suppresses ovulation • Induces a psudopregnancy state • Not approved by the USFDA yet • Often used as an “empirical” treatment (w/o a firm Dx) • Pros • Low cost • Easy • Addition to contraception • Cons • Not good for women who wish to get pregnant

39. Other medical treatment • Traditional Chinese medicine • A recent review indicates that evidence is not there due to poor quality • Mifepristone (RU486) • Inadequate evidence

40. Treatment on the horizon • GnRH antagonists • Removes the “flare-up” • More precise control

41. Take home messages • Endometriosis is a very complex disease • It involves hormones, immunology, neuroscience, molecular biology, genetics, epigenetics, and clinical research • Pathogenesis largely unknown • Treatment not very satisfactory • Can be an exciting research area

42. “He who knows endometriosis knows gynecology”