DEFINITION
The disease definition according to a specific consensus conference or to The Diseases Database based on the Unified Medical Language System (NLM)
Also the link to the corresponding Mesh term has to be created
EPIDEMIOLOGY
age, sex, seasonality, etc
SYMPTOMS
DIAGNOSIS
histopathology
radiology
NMR
laboratory tests
PATHOGENESIS
PATIENT RISK FACTORS
Vascular
Genetic
Acquired
Hormonal
Genetic
Acquired
TISSUE SPECIFIC RISK FACTORS
anatomical (due its structure)
vascular (due to the local circulation)
physiopathological (due to tissue function and activity)
Introduction
Endometriosis, the presence of endometriumlike glands and stroma outside the uterus, is a common, poorly understood, and extremely debilitating benign gynecological condition. The psychological impact of the severe pain experienced by the patient is compounded by the negative impact of the disease on fertility. The etiology and pathophysiology of endometriosis is not well understood because of the lack of a suitable animal model on which to study the anatomic correlates and natural history of disease.1 No cure exists for the disease, and treatment is directed toward medical suppression, surgical excision, and symptom alleviation.
figura 1 border=0 src="http://img98.imageshack.us/img98/4528/25255827189938811.jpg
Adenomyosis is the invasion of the myometrium by endometrial tissue.
Frequency
United States
Endometriosis occurs in 7-10% of women in the general population.2 It is an estrogen-dependent disease and, thus, usually affects reproductive-aged women. Endometriosis has a prevalence rate of 20-50% in infertile women3,4,5 and as high as 80% in women with chronic pelvic pain6 . Evidence of endometriosis was found during laparoscopy in 20-50% of asymptomatic women.7 Approximately 4 per 1000 women are hospitalized with endometriosis each year. A familial association exists, with a 10-fold increased incidence in women with an affected first-degree relative.8 Monozygotic twins are markedly concordant for endometriosis.9
Clinical
History
A significant number of women with endometriosis remain asymptomatic.
Cyclic pain: Cyclic pain is pain that accompanies bleeding at the time of menstruation. This could involve the bladder (hematuria), bowel (hematochezia and painful defecation), or, rarely, bleeding at uncommon sites such as the umbilicus, abdominal wall, or perineum.
Chronic pain: The most important point to remember is that the degree of visible endometriosis has no correlation with the degree of pain or other symptomatic impairment.10 However, pain does correlate with the depth of tissue infiltration.11,12 Midline disease is generally believed to be more painful than lateral disease.
Acute exacerbations: These are believed to be caused by chemical peritonitis due to leakage of old blood from an endometriotic cyst. Recently, with conscious laparoscopic pain mapping, painful lesions were found to involve peripheral spinal nerves rather than autonomic nerves.10
Dysmenorrhea: Secondary dysmenorrhea occurs twice as often in women with endometriosis as in controls.7 Pain frequently commences prior to menses. Endometriosis should be considered in a patient presenting with significant dysmenorrhea, and the patient should be started on empiric therapy.
Dyspareunia: Deep dyspareunia may be due to scarring of the uterosacral ligaments, nodularity of the rectovaginal septum, cul-de-sac obliteration, and/or uterine retroversion. All of these may also lead to chronic backache. These symptoms are exaggerated during menses. Women with deep infiltration of the uterosacral ligaments were shown to have the most severe impairment of sexual function.13
Physical
Pelvic examination: Tenderness upon examination is best detected at the time of menses. Nodularity of the uterosacral ligaments and the cul-de-sac may be found. The uterus may be fixed in retroversion, owing to adhesions. Occasionally, a bluish nodule may be seen in the vagina due to infiltration from the posterior vaginal wall.
Causes
Theories of causation include the following:
Retrograde menstruation
Sampson described this theory in his classic paper published in 1927. Retrograde flow of endometrial tissue through the fallopian tubes into the peritoneal cavity is believed to cause endometriosis.
Various animal experiments and clinical observations support this theory.14,15,16,17
Lymphatic and vascular spread
These pathways may explain the occurrence of endometriosis at distant, noncontiguous sites.
Ovarian endometriosis is also believed to be caused by lymphatic spread18 , although superficial ovarian endometriosis may also be due to implantation via retrograde menstruation.
Coelomic metaplasia
Transformation of coelomic epithelium into endometrial-type glands in response to as yet unknown stimuli could explain endometriosis in unusual sites.19
Coelomic metaplasia is also believed to explain the occurrence of endometriosis in women who have undergone total hysterectomy and are not taking estrogen replacement.20
Endometriosis may also occur in men on high-dose estrogen therapy.21
Immunogenetic defects
These are believed to increase the susceptibility of a woman to endometriosis. Humoral antibodies to endometrial tissue have also been found in sera of women with endometriosis.22
Recent work has focused on studying the differences between eutopic endometrium and endometriosis. In endometriosis, an aberrantly expressed factor SF-1 activates the expression of the enzyme aromatase, which converts C19 steroids to estrogens. Consequently, estrogen increases the synthesis of prostaglandin E2, which exerts a positive feedback effect, resulting in increased aromatase activity. Additionally, endometriotic tissue is deficient in the enzyme 17-beta hydroxy steroid dehydrogenase type 2, which converts E2 in eutopic endometrium to the less potent E1 under the direction of progestins. A recent study found a higher number of endometriomas, more bilateral disease, and a higher incidence of significant pain in women with aromatase positive disease.23 However, recent studies have shown increased cyclooxygenase-2 (COX-2) expression in the stromal cells24 and aberrant aromatase expression25 in eutopic endometrium of women with endometriosis.
While successful treatment has been described with the aromatase inhibitor anastrozole in women with severe postmenopausal endometriosis26 , more recent studies have also shown it to be effective in cases of severe endometriosis in premenopausal women27,28 . Additional data are needed before recommending this as primary treatment. See related Medscape CME Activity Aromatase Inhibitors May Relieve Endometriosis-Associated Pain: Review.
Anatomic spread
The ovary is the most common site for endometriosis. Spread to the ovary is believed to be lymphatic18 , although superficial implants may be due to retrograde menstrual flow because the ovaries are in a dependent part of the pelvis. Lesions can vary in size from spots to large endometriomas. The classic lesion is a chocolate cyst of the ovary that contains old blood that has undergone hemolysis.
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Once intracystic pressure rises, the cyst perforates, spilling its contents within the peritoneal cavity. This can cause the severe abdominal pain typically associated with endometriosis exacerbations. The inflammatory response causes adhesions that further increase the morbidity of the disease.
Uterine serosa can be affected. Vesicular lesions may provoke an inflammatory response and scarring that cause the bladder to adhere anteriorly. Posteriorly, the disease may cause obliteration of the cul-de-sac and form dense adhesions between the posterior vaginal wall or cervix and the anterior rectum. Severe dyspareunia, dyschezia, and alteration of bowel habits are the clinical sequelae of this common spread.
Deep peritoneal disease is caused by infiltration of the uterosacral ligaments and rectovaginal septum by endometriotic nodules. Tethering of the uterus can lead to fixed retroversion. Dyspareunia is an important feature.
Through contiguous spreading, endometriosis may invade the rectovaginal septum and the anterior rectal wall. It may also involve the upper rectum and sigmoid colon, infiltrating the muscularis.
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Cyclical rectal bleeding (hematochezia) is pathognomonic of endometriosis. However, transmural bowel involvement by endometriosis remains a rarity. The ileum, appendix, and cecum may also be involved, leading to intestinal obstruction. Cicatrization as a consequence of endometriosis may lead to symptoms of obstruction even in postmenopausal women.
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Although uncommon, interference in the genitourinary tract by endometriosis can affect the bladder, ureters, and kidneys by invasion, compression, or scarring. Medical therapy has less than satisfactory results, and surgical intervention is often required.
Uncommon sites include incisional scars, the umbilicus, and the thoracic cavity. Catamenial or cyclic pneumothorax can cause hemoptysis. Remember that ectopic endometrial tissue theoretically can undergo malignant transformation; histologic evaluation may be necessary.
Postmenopausal endometriosis may be encountered in women who are on estrogen replacement therapy (ERT). Occasionally, if ERT is administered after total abdominal hysterectomy, endometriosis can be stimulated in an ovarian remnant. Extrapelvic endometriosis is believed to be hormone-resistant when it occurs after surgical castration.20 Transplantation of endometrial implants during the original surgery is believed to explain this occurrence. Another possible explanation is coelomic metaplasia.
Differential Diagnoses
Pelvic Inflammatory Disease
Workup
Laboratory Studies
Serum cancer antigen 125 test: Serial measurements have a low sensitivity in detecting endometriosis29 , but the results are useful as prognosticators of treatment outcome30 . However, normal posttreatment values do not mean that endometriosis is absent.
Imaging Studies
Ultrasonography: Transvaginal sonography is a useful method of identifying the classic chocolate cyst of the ovary. The typical appearance is that of a cyst containing low-level homogenous internal echoes consistent with old blood.
MRI: The cost-effectiveness of this imaging modality for endometriosis has yet to be justified for use as a routine tool. However, MRI is helpful in detecting rectal involvement31 and has been shown to accurately detect rectovaginal endometriosis and cul-de-sac obliteration in more than 90% of cases when sonographic gel was inserted in the vagina and rectum32 .
Other Tests
Conscious pain mapping: Recently, conscious pain mapping (ie, with the patient awake) has been used to locate the specific areas that cause pain.10 Subsequently, the patient is placed under anesthesia and the deposits are ablated.
Procedures
Laparoscopy: Laparoscopy is considered the primary diagnostic modality for endometriosis. Endometriosis has been described as protean in appearance. The classic lesions are blue-black or have a powder-burned appearance. However, the lesions can be red, white, or nonpigmented. Peritoneal defects and adhesions are also indicative. Bear in mind that microscopic evidence of endometriosis may be found in normal-appearing peritoneum.
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Staging
The American Society for Reproductive Medicine classification is currently the most widely used staging system.33 Point scores are assigned based on the number of lesions and their bilaterality. Lesion size is also a scoring factor. This classification is a fairly accurate method of recording laparoscopic findings. However, high intraobserver and interobserver variability precludes its use in comparing the outcomes of therapeutic studies.34 Further, this staging system does not correlate well with pain and dyspareunia35 and fecundity rates cannot be predicted accurately.
Treatment
Medical Care
Endometriosis and subfertility
Peritubal and periovarian adhesions can interfere mechanically with ovum transport and contribute to subfertility. Peritoneal endometriosis has been postulated to contribute to subfertility by interfering with tubal motility, folliculogenesis, and corpus luteum function. Aromatase is believed to increase the prostaglandin E levels via increase in the COX-2 expression. Endometriosis may also cause subfertility by causing more sperm binding to the ampullary epithelium thereby affecting sperm-endosalpingeal interactions.36
Medical treatment of minimal or mild endometriosis has not been shown to increase pregnancy rates.37 Moderate-to-severe endometriosis should be treated surgically.38
Other options for achieving pregnancy include intrauterine insemination, superovulation, and in vitro fertilization. In a case-controlled study, pregnancy rates with intracytoplasmic sperm injection were not affected by the presence or extent of endometriosis.39 Further, other analyses have shown improvement in in vitro fertilization pregnancy rates with pretreatment of stage 3 and 4 endometriosis with gonadotropin-releasing hormone (GnRH) agonists.
Interval treatment
Some authorities believe that endometriosis should be suppressed prophylactically by continuous combined oral contraceptives, GnRH analogs, medroxyprogesterone, or danazol in order to cause regression of asymptomatic disease and enhance subsequent fertility.
Surgical ablation of asymptomatic endometriosis has also been shown to improve fecundity rates on a 3-year follow-up.38
Recurrent pregnancy loss: Based on results from controlled prospective studies, no evidence indicates that endometriosis is associated with recurrent pregnancy loss and no evidence indicates that medical or surgical treatment of endometriosis reduces the spontaneous abortion rate.40
Medical therapy: Combination oral contraceptive pills (COCPs), danazol, progestational agents, and GnRH analogs form the mainstay of medical therapy. All these therapies have similar clinical efficacy in terms of reduction in pain-related symptoms and duration of relief.
COCPs act by ovarian suppression and continuous progestin administration.
Initially, a trial of continuous or cyclic COCPs should be administered for 3 months. If pain is relieved, this treatment is continued for 6-12 months. Subsequent pregnancy rates upon discontinuation of the pill are 40-50%. This applies to a population unselected for stage and fertility status of the disease.
Although few choices are available among individual formulations, note that the long-term efficacy of multiphasic preparations remains unproven.
Continuous noncyclical administration of COCPs, omitting the placebo menstrual tablets, for 3-4 months helps avoid any menstruation and associated pain.
Women with endometriosis are at increased risk of epithelial ovarian cancer, and COCPs are believed to protect against this.41
All progestational agents act by decidualization and atrophy of the endometrium.
Medroxyprogesterone acetate has proven efficacy in pain suppression in both the oral and injectable depot preparations.42,43 Oral doses of 10-20 mg/d can be administered continuously. The time to resumption of ovulation is longer and variable with depot preparations. Adverse effects include weight gain, fluid retention, depression, and breakthrough bleeding.
Megestrol acetate has been used in doses of 40 mg with similarly good results.44
The levonorgestrel intrauterine system (LNG-IUS) has been shown to reduce endometriosis-associated pain.45
GnRH analogs produce a hypogonadotrophic-hypogonadic state by down-regulation of the pituitary gland. Currently, goserelin and leuprolide acetate are the commonly used agonists.
Once again, efficacy is limited to pain suppression and fertility rates may show no improvement.46 Winkel et al claim that GnRH therapy may lead to improvement in pain associated with endometriosis in 85-100% of women.47 Further, the pain relief is believed to persist for 6-12 months after cessation of treatment.
Treatment is usually restricted to monthly injections for 6 months.
Loss of trabecular bone density caused by GnRH is restored by 2 years after cessation of therapy.48 Other prominent adverse effects include hot flashes and vaginal dryness.
Much interest has been shown in whether add-back therapy should be instituted to prevent osteoporosis and hypoestrogenic symptoms. Hormone replacement therapy preparations, progestins, tibolone maleate, and bisphosphonates have all been shown to be effective.49,50,51,52 Add-back therapy has been shown to prevent loss in bone density and to relieve vasomotor symptoms without reducing the efficacy of GnRH regimens. GnRH agonists have been used for 12 months with norethindrone add-back therapy with good results.53
A clinical trial has shown that a 3-month empiric course of GnRH, based on a diagnostic algorithm without definitive laparoscopic diagnosis, is efficacious.54 However, long-term effects of GnRH analogs on bone density in this population remain unproven. Therefore, add-back therapy remains the standard of care while the patient is on GnRH treatment. Also, empiric treatment without a firm diagnosis could result in unnecessary treatment in patients with chronic pelvic pain, whose condition could be due to other causes. In Ling's study, 13% of subjects were shown to not have endometriosis.
GnRH therapy has also been proven to relieve the pain and bleeding associated with extrapelvic distant endometriosis.55
Danazol acts by inhibiting the midcycle follicle-stimulating hormone (FSH) and luteinizing hormone (LH) surges and preventing steroidogenesis in the corpus luteum. It is the most extensively studied agent for endometriosis.
Danazol has been shown to be as effective as any of the newer agents, but with a higher incidence of adverse effects.
Its androgenic manifestations include oily skin, acne, weight gain, deepening of the voice, and facial hirsutism. Hypoestrogenic features due to danazol include emotional lability, hot flashes, vaginal dryness, and reversible breast atrophy.
The recommended dose is 600-800 mg/d. However, smaller doses have been used with success.56,57 In a recently reported small study of 21 patients, vaginal danazol (200 mg/d) was successful in relieving endometriosis-associated pain.58
Because of the possibility of virilizing changes in a female fetus, additional barrier contraception must be used while on danazol therapy.
Surgical Care
Surgical care can be broadly classified as conservative when reproductive potential is retained, semiconservative when reproductive ability is eliminated but ovarian function is retained, and radical when the uterus and ovaries are removed. Age, desire for future childbearing, and deterioration of quality of life are the main considerations when deciding on the extent of surgery.
Conservative surgery
With conservative surgery, the aim is to destroy visible endometriotic implants and lyse peritubal and periovarian adhesions that are a source of pain and may interfere with ovum transport. The laparoscopic approach is the method of choice for treating endometriosis conservatively.59,60 Ablation can be performed with laser or electrodiathermy. Overall, the recurrence rate is 19% and is similar for all techniques.61 Laparoscopic ablative surgery with bipolar diathermy or laser for endometriomas was shown to be effective for relieving pelvic pain in 87% of patients.62 Ovarian endometriomas can be treated by drainage or cystectomy. Laparoscopic cystectomy was found to yield better pain relief and pregnancy rates than drainage.63,64 Medical therapy with GnRH agonists reduces the size of the cyst but does not influence pain relief.65
Tubal flushing with oil-soluble media has been shown to improve pregnancy rates in women with endometriosis-associated infertility.66
Presacral neurectomy is used to relieve severe dysmenorrhea. The nerve bundles are transected at the level of the third sacral vertebra, and the distal ends are ligated. Vascular injury to the middle sacral artery and vein is a potential complication, and some authors advocate prophylactic ligation. Also, constipation is a long-term adverse effect (94%) of this procedure and should be considered while deciding whether to perform this procedure.
Nodularity of the uterosacral ligaments may contribute to dyspareunia and low back pain. The transmission of neural pathways is via the Lee-Frankenhãuser plexus. Laparoscopic uterine nerve ablation (LUNA) is performed to interrupt the pain fibers. Potential complications of this procedure include uterine prolapse and pelvic denervation. A systematic review of trials of LUNA found no advantage in terms of pain relief when compared to placebo.67 However, when combined with laparoscopic ablation, LUNA significantly reduced pain attributed to endometriosis.68 In patients with subfertility, tissue ablation significantly increased the cumulative pregnancy rate.38 A recent Cochrane review failed to show any benefit from either LUNA or presacral neurectomy.69
For patients with mild disease, postoperative adjunctive hormonal treatment has been shown effective in reducing pain but has no impact on fertility. GnRH analogs, danazol, and medroxyprogesterone have all been found to be useful for this indication.70,71,72,73 However, for severe endometriosis, the efficacy of preoperative or postoperative hormonal treatment has not yet been established.
Semiconservative surgery
The indication for this type of surgery is mainly in women who have completed their childbearing, are too young to undergo surgical menopause, and are debilitated by the symptoms. Such surgery involves hysterectomy and cytoreduction of pelvic endometriosis. Ovarian endometriosis can be removed surgically because one tenth of functioning ovarian tissue is all that is needed for hormone production. Patients who undergo hysterectomy with ovarian conservation have a 6-fold higher rate of recurrence compared to women who undergo oophorectomy.74
Medical therapy in women who have completed childbearing is equally efficacious for symptom suppression.75,76,77
Radical surgery
This involves total hysterectomy with bilateral oophorectomy and cytoreduction of visible endometriosis. Adhesiolysis is performed to restore mobility and normal intrapelvic organ relationships.
Ureteric obstruction may warrant surgical release or excision of a damaged segment. Bowel obstruction may require a resection anastomosis or a wedge resection if the obstruction is confined to the anterior rectosigmoid.
Endometriosis may recur in 15% of women after extirpative surgery, irrespective of whether ERT is given postoperatively.78 ERT can be instituted safely immediately after surgery, especially in younger women who face the prospect of accelerated bone loss and vasomotor symptoms.78,79 No trials have reported the use of estrogen plus progestin therapy compared to estrogen therapy alone postoperatively. However, theoretically, the addition of a continuous progestin could decrease the regrowth of endometriosis.
Comparison of medical and surgical therapy: In women who wish to preserve their reproductive potential, the rates of recurrent pain symptoms are 44% with surgical management and 53% with medical management.68,76
Medication
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Oral contraceptives
COCPs act by ovarian suppression and continuous progestin administration. Initially, a trial of continuous or cyclic COCPs should be given for 3 mo. If pain is relieved, this treatment is continued for 6-12 mo. Subsequent pregnancy rates are 40-50% upon discontinuation of the contraceptive pill. Although individual formulations offer few variations, note that the long-term efficacy of multiphasic preparations remains unproven. In addition, continuous noncyclical administration of COCPs, omitting the placebo menstrual tablets, for 3-4 months helps avoid any menstruation and associated pain.
Follow-up
Prognosis
Endometriosis was found to resolve spontaneously in one third of women who were not actively treated.80
Patient Education
For current information on endometriosis, visit the National Institutes of Health (NIH) Web site at Endometriosis Research at NIH.
For excellent patient education resources, visit eMedicine's Pregnancy and Reproduction Center and Women's Health Center. Also, see eMedicine's patient education articles Birth Control Overview, Birth Control FAQs, Female Sexual Problems, and Endometriosis.
Lavoro eseguito da NIKA LULASH.