Endometriosis

.Moustafa Kamel, M.D

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Endometriosis, defined as endometrial glands and stroma outside the uterine cavity and musculature, may be asymptomatic or may cause chronic pelvic pain or infertility in women. The most common sites are the ovaries, posterior cul-de-sac, broad and uterosacral ligaments, rectosigmoid colon, bladder, and distal ureter. Uncommon sites include the bowel, kidneys, lungs, and pleurae.

Section of endometriosis shows both well-developed glands and stroma in fibrofatty tissue. (Hematoxylin-eosin stain, original magnification x 20)

Theories of disease development

1. The classic theory, first suggested by John Sampson in 1921, is that retrograde flow of endometrial tissue through the fallopian tubes and into the abdominal cavity causes endometriosis. 2. A second hypothesis, Halban's theory of coelomic metaplasia, suggests that transformation of coelomic epithelia into endometrial-type glands results from unspecified stimuli. 3. A third theory suggests that remnant mllerian cells remain in the pelvic tissues during development, and these may be induced to differentiate into functioning endometrial glands and stroma. 4. Recent research has suggested involvement of the immune system in the pathogenesis of endometriosis. Women with this disorder appear to exhibit increased humoral immune responsiveness and macrophage activation while showing diminished cell-mediated immunity with decreased T-cell and natural killer cell responsiveness. 5. Some women may have a genetic predisposition to endometriosis. Studies have shown that first-degree relatives of women with this disease are more likely to develop it as well. The search for an endometriosis gene is currently underway. 6. Finally, iatrogenic deposition of endometrial tissue has been found in some cases following gynecologic procedures and cesarean sections.

The true etiology remains to be determined and, in fact, may be a combination of all of these occurrences.

 Prevalence:
1. Endometriosis is reported to affect 7% to 50% of menstruating women. Among infertile women, 25% to 35% have the disease. 2. Age: Pelvic endometriosis typically occurs in women aged 25-30 years. Extrapelvic manifestations of this disorder occur in woman aged 35-40 years. Women younger than 20 years with this disease often have anomalies of the reproductive system. Endometriomas and symptoms related to them regress significantly after menopause.

Risk factors
1. 2. 3. 4. 5. 6. 7. 8. 9. Family history of endometriosis Early age of menarche Short menstrual cycles (<27 d) Long duration of menstrual flow (>7 d) Heavy bleeding during menses Inverse relationship to parity Delayed childbearing Defects in the uterus or fallopian tubes Hypoxia and iron deficiency may contribute to the early onset of endometriosis

Evaluation
The most common symptom is dysmenorrhea, which may precede the onset of menstruation. In addition to pain, patients present with nonspecific symptoms of fatigue, generalized malaise, and sleep disturbances. Endometriosis should be suspected in any woman who has a history of infertility. Suspicion should increase with complaints of dysmenorrhea or dyspareunia. Other symptoms may include low back pain, rectal discomfort, and chronic, nonspecific pelvic pain. Because these symptoms are nonspecific for endometriosis, other causes should always be considered. Extra-abdominal manifestations can include cyclical hemoptysis and pneumothorax (catamenial). Symptoms usually improve during pregnancy and after menopause. They can recur postpartum or with postmenopausal hormone replacement therapy One third of women with endometriosis are asymptomatic, (endometrial implants are sometimes found incidentally during a surgical procedure).

Proposed Mediators and Mechanisms of Infertility

Anatomic distortion and tubal obstruction Anovulation, luteal phase defects, and hormonal abnormalities Galactorrhea or hyperprolactinemia Autoimmunity Peritoneal leukocytes and the peritoneal inflammatory response Peritoneal fluid prostaglandins Peritoneal fluid cytokines Embryo implantations defect and spontaneous abortion

Research to explain the subfertility has focused on peritoneal fluid leukocytes and their cytokine products. Studies have suggested that constituents in the peritoneal fluid inhibit sperm function, fertilization, embryonic development, and implantation. The clinical significance of .these findings has not been established

Possible causes of chronic pelvic pain

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. Endometriosis Adenomyosis (endometrial tissue within the myometrium) Dyspareunia Primary dysmenorrhea Mittelschmerz (pain with ovulation) Pelvic venous congestion Gastrointestinal disease (eg, irritable bowel disease, inflammatory bowel disease) Ovarian disease (eg, cysts, malignancy) Pelvic inflammatory disease Uterine prolapse Pregnancy (normal or abnormal) Psychosomatic disorders (secondary to stress) Referred pain


1. 2.

Physical examination Results of physical examination may be normal.

The most common finding is nonspecific pelvic tenderness. The hallmark finding on examination is the presence of tender nodular masses along thickened uterosacral ligaments, the posterior uterus, or the posterior cul-de-sac. Ovarian involvement may present with adnexal tenderness or masses, this sign occurs especially if endometriosis takes the form of blood-filled cysts known as endometriomas. Obliteration of the cul-de-sac in conjunction with fixed uterine retroversion implies extensive disease. Rupture of an ovarian endometrioma may present as an acute abdomen. Extensive involvement of the rectum and other areas of the GI tract may cause adhesions and obstruction.

3.

4. 5. 6.

Clinical Signs
Localized tenderness in the cul-de-sac or uterosacral ligament Palpable tender nodules in the cull-desac, uterosacral ligament, or rectovaginal septum Pain with uterine movement Tender, enlarged adnexal masses Fixation of adnexa or uterus in retroverted position

Laboratory evaluation Laboratory test have essentially no role in the diagnosis of endometriosis. Testing for the antigen CA-125, often used for follow-up monitoring of ovarian cancer, is not sensitive enough to screen for endometriosis. However, CA-125 levels do correlate somewhat with the degree of disease and response to treatment. Routine imaging studies are not recommended for diagnosis of endometriosis, ultrasonography may be part of an evaluation for chronic pelvic pain. magnetic resonance imaging (MRI) is helpful for diagnosing an endometrioma . MRI may be useful for identifying endometriosis hidden by adhesions and for monitoring response to medical therapy in patients with established disease .

 Laparoscopy with biopsy is considered the "gold standard" for diagnosis of endometriosis. The disease is staged on the basis of laparoscopic findings. Stages are based on a point system, from stage I (minimal disease, 1 to 5 points) to stage IV (severe disease, >40 points). Points are assigned according to the location, size and depth (superficial versus deep) of the endometriosis, and the presence of adhesions. However, staging does not correlate with degree of infertility or severity or number of symptoms.

Stages of Endometriosis

Puckered black lesions are typical of endometriosis and are among the easiest lesions for physicians to .see during laparoscopy

Diffuse endometriosis is seen in the cul-de-sac, a fluid-filled space between the uterus and rectum that is a common site of the disease

There is normally a space behind the uterus separating it from the bowel. Instead, the rectum (the white area surrounded by the yellow fatty area) is stuck to the back of the uterus.

A closer look shows brownish-red nodules typical of endometriosis

When endometriosis lesions coalesce together and create a blood-filled cyst, this is an

Endometrioma.

These are also called chocolate cysts, after the brownish colour of the contents

Upon opening a chocolate cyst, irregular brown areas are observed.

Complications
1. 2. 3. 4. Infertility/subfertility Chronic pelvic pain Adhesions Ruptured cysts

Treatment Options
Expectant Management Medical therapy Progestins Levonorgestrel-releasing intrauterine device Danazol GnRH analogues Aromatase inhibitors Surgical therapy (laparoscopy or laparotomy) Conservative: retains uterus and ovarian tissue Definitive: removal of uterus and possibly ovaries Combination therapy Preoperative medical therapy Postoperative medical therapy

Expectant Management Avoiding specific therapy is considered when patients have minimal or no symptoms and have suspected minimal or mild endometriosis. Medical Therapy Endometriotic implant growth is highly dependent on ovarian steroids. Medical therapy attempts to induce pseudopregnancy or menopause Surgical Management Surgery is indicated when the symptoms are severe,incapacitating, or acute and when the disease is advanced

Combination Medical and Surgical Therapy Medical therapy is used before surgery to decrease the size of endometriotic implants and thus reduce the extent of surgery. When complete removal of implants is not possible or advisable, postoperative medical therapy is used to treat residual disease.

Treatment
Current treatment strategies focus on a combination of surgical and medical therapies. Surgery is used to diagnose disease and decrease its bulk. Medical regimens are often initiated postoperatively for treatment of residual disease.

 Surgical management Surgery is the most common treatment method. It can be conservative for diagnosis, restoration of normal anatomic relationships, and destruction of as much disease as possible, or radical, involving hysterectomy and oophorectomy for total eradication of the disease.

 The success of surgery is related to the severity of disease. For minimal and mild endometriosis, studies have shown no improvement in fertility with surgery over expectant management. In fact, if initial surgery for treatment of moderate to severe disease fails to restore fertility, reoperation offers little benefit. In vitro fertilization (embryo transfer) is a more effective alternative, with a two fold to three fold increase in the pregnancy rate. Thus, surgical treatment is best used for patients who have pain refractory to pharmacologic therapy.

 Pharmacologic management Medical management has relied on alteration of the normal hormonal balance of the menstrual cycle by long-term inducement of anovulation, pseudopregnancy, or pseudomenopause.

Characteristics of medications commonly used in treatment of endometriosis

Clinical course
Even with the use of GnRH analogs or danazol, recurrence rates for endometriosis range from 37% to 74%, depending on the extent of disease. Several studies have shown that with hysterectomy alone (compared with hysterectomy and oophorectomy), risk of recurrent pain is increased by a factor of 6.1 and risk of reoperation by a factor of 8.1. It is thus prudent to tell patients that surgery will not necessarily cure their disease. The recurrence rate after conservative surgical treatment is reported to be less than 20%; however, further surgery to improve infertility has limited success Fortunately, the symptoms of endometriosis resolve as women reach menopause. Whether hormone replacement therapy after menopause is acceptable for these patients is still controversial.

Sample MCQs
Endometriosis.

Summary Points The pathogenesis of endometriosis is poorly understood, but emerging evidence supports the causative role of retrograde menstruation and implantation of endometrial tissue. Endometriosis is common in women with pelvic pain and/or infertility. Laparoscopy is the optimal technique to diagnose pelvic endometriosis. In most cases, surgical therapy at the time of initial diagnosis effectively relieves pain and may enhance fertility. Alternatively, medical therapy with progestins, progestinreleasing intrauterine devices, danazol, or GnRH analogues will ameliorate pelvic pain, but they do not enhance fertility. Endometriosis is a recurrent disease, and definitive treatment with removal of pelvic organs may be necessary

 1. A 34-year-old woman, gravida 0, has been trying to get pregnant for the last 3 years and has been unsuccessful. Her history is also significant for pelvic pain for several years and deep dyspareunia. On pelvic examination, you palpate a nodular, tender uterosacral ligament, a retroverted but normal-sized uterus, and a right adnexal mass. A recent pelvic ultrasound reveals a 6-cm right complex ovarian mass. Her CA-125 is elevated. What is the initial next step in management?
A. Expectant management B. GnRH agonist C. Diagnostic laparoscopy D. Laparoscopy with cystectomy E. Laparoscopy and right oophorectomy

The answer is D . The most likely diagnosis here is an endometrioma of the right ovary. Because this patient has been attempting to get pregnant, conservative surgery to remove the endometrioma while preserving ovarian tissue and to ablate any endometriotic implants may improve her chances. Expectant management is not appropriate because she is infertile, has a 6-cm ovarian mass, and has significant pelvic pain. Furthermore, other complex ovarian lesions, including ovarian cancers, cannot be ruled out without surgical evaluation. Simple diagnostic laparoscopy without any treatment is also not appropriate. Medical therapy with a GnRH agonist may treat her symptoms, but it will not treat the ovarian cyst or help her get pregnant. It is not necessary to remove what is most likely normal ovarian tissue. CA-125 can be elevated with endometriosis and does not indicate ovarian cancer.

 A 23-year-old woman, gravida 1, para 1, reports lower abdominal pain of 1 year's duration. She says that the pain is constant and dull and is worse around the time of her periods. She has no significant medical history and is taking birth control pills for contraception. You perform a laparoscopy and find several deep, typical endometriotic lesions over the bladder and on both uterosacral ligaments and adjacent to both ovaries. All visible lesions are ablated using the laser. What is the next best step in management? A. Oral contraceptive therapy B. GnRH agonist C. Aromatase inhibitor added to oral contraceptive therapy D. Total abdominal hysterectomy and bilateral salpingooophorectomy (TAH-BSO) E. Danazol

The answer is A. Endometriosis is diagnosed and surgically treated at the time of laparoscopy. Medical management of the endometriosis is indicated at this point to help control the disease. Oral contraceptive pills given continuously would be the best option. The patient had significant pain while on cyclic oral contraceptives prior to the surgery, but the surgery treated the disease and therefore the symptoms may be significantly improved. Also giving the contraceptive on a continuous schedule may improve pain symptoms seen with menses. GnRH agonists would be the next best option if the pain symptoms are not improved with continuous oral contraceptives. GnRH would not be the first medicine tried because of the hypoestrogenic side effects and risk of osteoporosis in this young woman. Danazol is effective for endometriosis, but because of its many androgenic side effects, it is not preferred over leuprolide. Aromatase inhibitors are still considered investigational at this point and would not be recommended. A TAH-BSO is too radical a procedure for this problem and at this point in this patient's life (she is young and still interested in childbearing).

 Which of the following patients is unlikely to have endometriosis?

A. A 19-year-old with cyclic pelvic pain and bicornuate uterus with a noncommunicating uterine horn B. A 28-year-old patient with cyclic pelvic pain and who has a mother and a sister with endometriosis C. A 25-year-old female with a history of dyspareunia, painful nodular masses in the rectovaginal septum, and a left adnexal mass D. A 28-year-old with menorrhagia and a 4-cm submucosal myoma E. A 32-year-old with infertility and dysmenorrhea and a fixed and retroverted uterus on physical examination

 The answer is D. Patients with a mullerian anomaly that blocks the progress of menses are at high risk of developing endometriosis. Likewise, patients who have a sibling with endometriosis are at increased risk of the disease (7% versus 1% for controls). The presence of dys-pareunia, rectovaginal nodularity, and an adnexal mass in a young woman is highly suggestive of endometriosis and an endometrioma. A complaint of infertility in a patient who has a fixed and retro-verted uterus, presumably from scarring, is also very suggestive of endometriosis. Myomas are generally benign proliferations of uterine smooth muscle tissue and are not thought to be associated with endometriosis.