Department of Obstetrics and Gynecology  ,   Chia-Yi Chang Gung Memorial Hospital       

  Etiology

 1. Retrograde menstruation: the most popular theory

 2. Metaplasia

 3. Lymphatic and vascular metaplasia: can helps to explain rare and remote sites of endometriosis ( as well as multiple lesions in the lung). 

 4. Iatrogenic dissemination:

 5. Immunologic defects: it is not yet established whether endometriosis is a related to

   immunologic problem.

 6.Genetic predisposition: the risk of endometriosis is seven times greater if a first-degree relative has been affected by endometriosis.

Pathology

1.  The majority of endometrial implants are located in the dependent portions of the female pelvic.
common sites: ovaries, pelvic peritoneum, ligaments of the uterus, sigmoid colon,               pelvic lymph nodes, appendix, cervix, vaginal fallopian tubes. 

2.  Gross pathologic changes of endometriosis exhibit wide variability in color, shape, size, and associated inflammatory and fibrotic changes. The color of the lesion varies widely and may be red, brown, black, white, or yellow or a pink, clear, or red vesicle. New lesions are small, sometimes blood filled cysts that are less than 1 cm in diameter. The older lesions have more intense scarring and are usually puckered or retracted from the surrounding tissue.

3.  The three cardinal histologic features of endometriosis are ectopic endometrial glands,

Ectopic endometrial stroma, and hemorrhagic into the adjacent tissue.   

Clinical diagnosis

Symptoms

1.  The classic symptoms of endometriosis are cyclic pelvic pain and infertility. The 

chronic pelvic pain usually presents as secondary dysmenorrhea and/or dyspareunia.

Approximately one third of patients with endometriosis are symptomatic.

2.  No correlation between the anatomic stage of the disease and the patient's perception of severity of pelvic pain.

3. Increased incidence of first trimester abortion.

4. Approximately 15% of women with endometriosis have coincidental anovulation.

5. Less common symptoms: cyclic abdominal pain, intermittent constipation, diarrhea,

dyschezia, catamenial hemothrax, bloody pleural fluid.

 Signs

1.  The most prominent pelvic finding of endometriosis is a fixed retroverted uterus with

scarring and tenderness posterior to the uterus.

2.  Ultrasound examination shows no specific pattern for pelvic endometriosis. Therefore

pelvic ultrasound may give additional and confirmatory information, but cannot be used for primary screening.

  Sonagraphy findings of endometrioma:

  echogenic homogenous cystic mass: most common

    Multiple lobular cystic mass

    Heterogenic cystic mass

    Cystic with local echogenic mass 

Natural History

1.  The rate of progression of the disease varies widely from one patient to another.

Serial pelvic examinations are a poor indicator of progression of the disease. The natural history of the disease is largely speculation.

2.  CA-125 levels are elevated in most patients with endometriosis and increase

  incrementally with advanced stages. However, assays for serum levels of CA-125

  have a low specificity, physicians may only be able to follow the course of persistent 

  or recurrent disease or predict the success of therapy by measuring serial CA-125 

  levels.

3.  Approximately 10% of teenagers who develop endometriosis have associated

  congenital outflow obstruction. 

Management

The appropriate treatment for endometriosis varies widely because of the spectrum of clinical symptoms and vast differences in extent of the disease from one patient to another. Therefore the treatment plan must be individualized. Choice of therapy depends on multiple variables, including the patient's age, her future reproductive plans, the location and extent of her disease, her symptoms, and associated pelvic pathology.

Medical Therapy

The primary goal of the hormone treatment of endometriosis is induction of amenorrhea.

To date no hormonal therapy has been able to produce long-lasting cures with ablation of all foci of endometriosis after discontinuation of hormonal management. 

Danazol

1. Danazol is a synthetic steroid derivative of ethisterone (17-à-ethinyltestosterone). The 

  half-life of this oral drug is between 4 and 5 hours. It is metabolized in the liver with

  cleavage of the isoxazol ring, women who take danazol for longer than 6 months should 

  have serum liver enzyme determinations.

2.The drug is mildly androgenic and anabolic. Many of danazol's side effects are directly

  related to these two properties. Danazol binds to androgen and progesterone receptors 

  and also binds to sex hormone- binding globulin. The latter effect results in a three-fold

  increase in endogenous free testosterone levels.

3.It can significantly decreases FSH and LH levels by a dose of 800 mg a day.

  Dosages of 800 mg daily produce amenorrhea and inhibition of ovulation within 4

  to 6 weeks after onset of therapy. The drug is started on the fifth day after the onset of 

  menses. The lower dosages of danazol are not as effective at producing amenorrhea  

  and anovulation.

4.  Side effects related to danazol therapy include menopausal hot flushes, atrophic

  vaginitis, emotional lability, weight gain averaging 8 to 10 pounds, fluid retention,

  migraine headaches, dizziness, fatigue, depression, oily skin, facial hair, and deepening 

  of voice, decreases HDL levels and elevates LDL levels.

5.  The uncorrected fertility rate following danazol therapy is approximately 40%, 5% to 

  30% of patients will have recurrence of symptoms within 2 years following therapy.    

  No significant differences between the efficacies of danazol and GnRHa.

GnRH Agonists

1.  GnRH agonists are 10 to 200 times more potent and have much longer half-lives than

  the natural hormone, induce protracted periods of downward regulation. These  

  agonists may be administered by intravenous, intramuscular, subcutaneous, intravaginal,

  or intranasal routes.

2.  GnRH agonists have no effect on sex hormone-binding globulin. Thus the androgenic

  side effects from danazol caused by the increase in free serum testosterone are not 

  observed, and no significant changes occur in total serum cholesterol, HDLs, or LDLs

  during therapeutic periods as long as 6 months. The side effects are primarily those 

  associated with estrogen deprivation, similar to menopause. The three most common

  symptoms are hot flushes, vaginal dryness, and insomnia. The decrease in bone density 

  is partly or completely reversible after discontinuing therapy.

3.  After 6 months of GnRH agonists therapy, ovarian function will return to normal in 6 to 12 weeks. Endometriomas and severe adhesive disease have not responded to hormonal therapy. The primary advantage of GnRH agonists over danazol is better patient compliance. 

Oral Contraceptives

1.  The present low-estrogen combination pills, specifically the ones with a relatively high progestin potency, are equally effective. The regimen is aimed to maintain their amenorrhea on a comparatively low dosage of steroids. It is important to emphasize to the patient the goal of continuous rather than intermittent oral contraceptive therapy.

2.  The many side effects of inducing amenorrhea with oral contraceptives include weight gain, breast tenderness, nausea, chloasma, an increase in appetite, irritability, depression, edema, hypertension, and vaginal discharge.

3.  The results of continuous oral contraceptive therapy include a decrease in symptomatology in approximately 80% of patients during therapy and an uncorrected pregnancy rate of about 30 % after therapy.

 Surgical Therapy

The choice between medical treatment to suppress endometriosis and surgical therapy to

remove it depends on the patient's age, symptoms, and reproductive desires.

1.  Laparoscopy is employed frequently for diagnostic reasons and can also be used therapeutically. Conservative surgery has as its goal the removal of all macroscopic,

  visible areas of endometriosis with preservation of ovarian function, adhesionlysis to 

  restore normal anatomy. Definitive surgical treatment is reserved for patients with far-

  advanced disease and for whom future fertility is not a consideration. Definitive surgery

  involves total hysterectomy, BSO, and the remove of all visible endometriosis.

2.  Classification system of endometriosis:

  AFS(American fertility society )system:

  This system reflects the extent of endometrial disease, but it is not based on the  

  correlation of pain or infertility .

 AFS classification of endometriosis               Additional  Endometriosis

Stage I (Minimal) 1-5      _________________________        ______________________________

Stage II (Mild)    6-15    _________________________        ______________________________

Stage III (Moderate) 40   _________________________        ______________________________

Stage IV (Severe)    >40 _________________________        ______________________________

Total:  _________________________

* If the fimbriate end of the fallopian tube is completely enclosed, change the point assignment to 16.

3.  The pregnancy rate after laparosopy treatment :

  Treatment of moderate disease has an approximate 60% pregnancy success rate,

  severe disease has pregnancy success rate of 35%. Surgical management of infertile 

  women with minimal to mild endometriosis is controversial .

Recurrence rate after treatment:

1.Operation: recurrence rate is about 5-20% per year a cumulative rate of 40% after 5 

   years

2.GnRHa: minimal disease: 37% (five years after therapy)

          Severe disease: 74% (five years after therapy)

3.Danazol: similar to GnRHa.