Endometriosis Pathogenesis and Management

Endometriosis has been described over 300 years ago [1-3]. It is a major cause of pain and infertility in 35-50% of women and chronic pelvic pain in 6-10% of women. It is a major cause of hospitalization and hysterectomy, with annual cost of 1.8 billion dollars in 2009 in Alberta and Quebec, Canada [4], 1.5 billion dollars in Germany, and 20 billion dollars in the United States [5]. Endometriosis is an estrogen dependent condition. On the other hand, this disease leads to defective response of Eutopic endometrium to progesterone and therefore implantation is difficult to occur thus leading to infertility or pregnancy loss. In addition, nerve fibers have been demonstrated in Eutopic endometrium of patients with endometriosis [6].


Introduction
Endometriosis has been described over 300 years ago [1][2][3]. It is a major cause of pain and infertility in 35-50% of women and chronic pelvic pain in 6-10% of women. It is a major cause of hospitalization and hysterectomy, with annual cost of 1. 8

billion dollars in 2009
in Alberta and Quebec, Canada [4], 1.5 billion dollars in Germany, and 20 billion dollars in the United States [5]. Endometriosis is an estrogen dependent condition. On the other hand, this disease leads to defective response of Eutopic endometrium to progesterone and therefore implantation is difficult to occur thus leading to infertility or pregnancy loss. In addition, nerve fibers have been demonstrated in Eutopic endometrium of patients with endometriosis [6].
Infertility due to pelvic endometriosis may be caused by several factors. Ovulatory dysfunction may result from the high concentrations of prostoglandins and cytokines in the peritoneal fluid in these patients [7]. Prostaglandins also may lead to tubal dysfunction that will interfere with the pickup of the oocyte from the ovary, and also the motion of the sperm towards the oocyte with the result of failure of fertilization to take place. Furthermore, the endometrium of these patients has been shown to have aromatase that leads to high estradiol concentration and that might lead to defective response to progesterone, and the end result will be failure of implantation [8].

Historical Aspects of Endometriosis
The first reference to endometriosis associated symptoms are found in the Ebers Papyrus (Tebas, Egypt, 500 BC) in which treatment for painful disorder of menstruation is described. In the 18th Century, scientists from England, Germany, Holland, and Scotland described endometriosis in autopsy studies [9]. Rokitansky (mid part of 19th Century-1885), suggested the presence of endometrial glands and stroma in ovarian and uterine neoplasia [10]. Cullen (1919) [11]: Was the first scientist to demonstrate histologically endometrial structures in the peritoneum of patients and called this process as adenomyoma of the peritoneum or adenomysis externa.
Russel [12]: Published a report in 1899 of an ovaries containing uterine mucosa. Sampson (1927) [13]: The first to describe the menstrual reflux theory for the development of endometriosis. He also described the various types of the disease including chocolate cysts, and deep infiltrating disease in the pelvis. i. or-Secondary involvement of functional ovarian cyst.

Pathogenesis of Endometriosis -Criteria of Eutopic Endometrium as Precursor for Endometriosis
ii. or -Metaplasia of Coelomic epithelium on the ovary.

Diagnosis of Endometriosis
Usually patients present with history of severe dysmenorrhea, pelvic pain, and dysparunia. If there is a bowel involvement, patient then will have constipation, diarrhea, and rectal bleeding.
If there is bladder involvement, the patient will have hematuria.
The pelvic examination will demonstrate pelvic pain, thickened This system has been used in Australia and New Zealand [18].
The next step in the diagnosis is laparoscopy [19]. This helps to define the disease and its location according to its morphologic criteria which includes vesicular forms, dark pigmented areas, or chocolate cysts in the ovaries. The vesicular form and pigmented areas can be treated with laser or using electro cautery to ablate the disease. In cases of chocolate cysts, the endometrioma is surgically excised followed by reconstruction of the ovary.

Medical Treatment of Endometriosis
Medical treatment of endometriosis is applied to early stages of the disease or recurrence after surgical medical treatment. Usually the treatment is for a period of six months. Various medications are used including birth control pills, Danazol, Medroxyprogesterone and GnRH agonist or antagonist [20].

Birth Control Pills
Use of steroidal oral contraceptives in patients with endometriosis alleviates severe dysmenorrhea in these patients.
There are no data to support any effect on the reduction of the size of the lesions.

Danazol
This is a synthetic steroid derivative of 17 alpha-ethinyl testosterone. It inhibits the secretion of FSH and LH, and leads to inhibition of ovarian function. The end result is pseudomenopause, and hypoestrogen status. This leads to suppression of endometriosis and its regression in about 80% of the patients. Following discontinuation of the treatment, the pregnancy rate is about 70%.
The recurrence rate after 24 months follow up was reported to be 29%.

Gonadotropin Releasing Hormone Agonist
Its administration leads to suppression of gonadotropins through inhibition of GnRH receptors in pituitary. This will lead to hypoestrogenism and the end result is suppression of endometriosis. This also leads to reduction in dysmenorrhea.

The use of gonadotropin releasing hormone antagonist
All the studies show that the use of GnRH antagonist for pain related to endometriosis, have shown marked improvement.
The medication is well tolerated. It is also an oral medication.
Laproscopic studies showed regression of endometriosis.

Antiangiogenic Factors
In a study to evaluate cabergoline effect on endometrioma, as compared to control groups given GnRH agonist 3.75mg

Surgical Management
This is usually done by laparoscopy and or laparotomy. The lesions are either excised, or fulgrated using bipolar cautery; or vaporized using laser [22]. Recently a study in experimental animals showed the beneficial effect of platelet rich plasma, and fibrin sealant on bowel wound healing after shaving endometriosis lesions experimentally induced. The results showed that these agents are safe and associated with improved tissue healing after shaving endometriosis from colon wall.

Intestinal Endometriosis
This is the most common extrapelvic location of endometriosis.
It commonly affects the rectosigmoid part of the bowel. It could be superficial disease, but sometimes it affects the whole thickness of the bowel wall. The symptoms will vary according to the degree of bowel involvement. The patient will complain of pelvic pain, or abdominal pain. In addition, the symptoms may be diarrhea, constipation, and/or rectal bleeding. Radiological studies including CT scan, MRI of the abdomen will show the location of the lesion.
In addition, Barium enema and Colonoscopy will be confirmatory.
Small intestines may be affected with endometriosis, but it is usually less common. The treatment of bowel endometriosis is surgical excision, and bowel anastomosis. The incidence of bowel endometriosis is 12% in women with endometriosis.