Endometriosis

Sun-Wei GuoShanghai OB/GYN Hospital

Fudan University Shanghai College of Medicine

Learning objectives

• To know – Definition of endometriosis– Its signs and symptoms– Some notable features of endometriosis– Its diagnosis– Epidemiology– Its treatedment

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

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

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

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

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

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)

Extraperitoneal endometriosis

• Lung, brain, nose, eyelid,…• Very rarely, in men with prostate cancer after

receiving estrogen therapy

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

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Laparoscopic photographs

Ovarian endometrioma: chocolate cyst

Ovarian endometrioma: “kissing ovaries”

Peritoneal endometriosis

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?

http://upload.wikimedia.org/wikipedia/commons/6/68/Scheme_female_reproductive_system-en.svg

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

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

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

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

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

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

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

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

Differential diagnosis

• Ovarian malignancy• Adenomyosis• Pelvic Inflammatory Disease (PID)

Treatment goals

• To alleviate pains• To delay recurrence as long as possible• To help patients get pregnant

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

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

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)

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

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

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

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

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

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

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

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

Other medical treatment

• Traditional Chinese medicine– A recent review indicates that evidence is not

there due to poor quality

• Mifepristone (RU486)– Inadequate evidence

Treatment on the horizon

• GnRH antagonists– Removes the “flare-up”– More precise control

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

“He who knows endometriosis knows gynecology”