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: Imaging: Signs and symptoms
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 Infertility
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 CT Pros Cons MRI Non-invasive Cheaper than surgery
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 Non-surgical treatment (medication)
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 Purposes 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 Cons Proven efficacy 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 MOA Danazol is a modified androgen
% 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”