Definition and Path
Ophysiology
Endometriosis is a condition in which tissue resembling endometrial glands or stroma occurs outside the uterus. En-dometriosis lesions are most often found in the pelvis.
Endometriosis lesions are heterogeneous, ranging from 1 mm superficial peritoneal lesions to 4 cm deeply invasive lesions in the rectovaginal septum. Ovarian lesions of endometriosis can grow to 4 to 10 cm in size, necessitating surgical resection. En-dometriosis lesions undergo cycles of growth and bleeding in tandem with the menstrual cycle. Intraperitoneal bleeding from the lesions elicits an inflammatory response in the pelvis that is associated with pain and infertility.
Epidemiology
Many authorities believe that approximately 5% of women between 15 and 45 years of age have endometriosis.1 The precise incidence is difficult to determine because there is no inexpensive, highly reliable method for diagnosing endometriosis. The current gold standard for the diagnosis of endometriosis is surgical visualization of endometriosis lesions, usually by lap-aroscopy, and so (as with any disease that requires expensive and invasive procedures for diagnosis) a significant number of cases may be missed.2 Collection of definitive data would require selecting a random sample of women and performing lap-aroscopy on them to determine whether they have endometrio-sis; understandably, no such study has been done.
Endometriosis is rare before menarche and after menopause, when estrogen production is low. Most cases of endometriosis are diagnosed in women in their 20s who have never had a child. Full-term pregnancy and delivery appear to markedly reduce the risk of developing endometriosis. Multiple full-term pregnancies further reduce the risk. Long periods of amenor-rhea (for example, the amenorrhea of athletes) is associated with a reduced risk of endometriosis, as is aerobic exercise for more than 7 hours a week.
Pathogenesis
The pathogenesis of endometriosis lesions involves mechanical, hormonal, immunologic, and genetic factors. The prominence of particular factors may vary from case to case; indeed, it is possible that endometriosis comprises several different diseases with a common clinical outcome.
Mechanical factors
In women with a normal uterus, 99.9% of menstrual blood flow occurs in an antegrade direction—that is, from the en-dometrium through the cervix and into the vagina. Numerous clinical observations as well as experiments in laboratory animals indicate that anatomic changes, such as cervical stenosis, that hinder antegrade flow are associated with an increased risk of endometriosis. In women with cervical stenosis, the relative obstruction at the level of the cervix causes blood to flow from the uterus back through the fallopian tubes and into the peritoneal cavity. This retrograde menstrual flow contains blood, growth factors, and viable bits of endometrial tissue. The greater the amount of retrograde blood flow, the higher the risk of endometriosis. For example, about 80% of women with congenital cervical stenosis and a functioning endometrium will develop endometriosis. Epidemiologic studies suggest that more prolonged menstrual flow (> 8 days) and more frequent menses (cycle length < 27 days) are also associated with an increased risk of endometriosis.3
Hormonal factors
Steroid hormones control the growth and function of en-dometriosis lesions. Estradiol stimulates growth, and andro-gens cause atrophy of endometriosis lesions [see Table I]. High doses of progestins induce terminal differentiation in en-dometriosis lesions, a process called pseudodecidualization. Once endometriosis tissue undergoes pseudodecidualization, it can no longer grow. The reason pregnancy reduces the risk of endometriosis is probably that the extremely high progesterone levels that occur in pregnancy cause pseudodecidualization of endometriosis lesions.
Organochlorine chemicals (e.g., dioxin) can disrupt steroid metabolism; exposure to these pollutants has been proposed as a factor in the development of endometriosis. In animal models, dioxin has been found to increase the incidence and severity of endometriosis,4 possibly by interfering with the action of progesterone,5 but the effect in humans has yet to be confirmed.
Table 1 Effects of Different Steroids on Endometrium and Endometriosis Lesions
|
Steroid |
Effect on Endometrium |
Effect on Endometriosis Lesions |
|
Estrogen |
Growth |
Growth |
|
Androgen |
Atrophy |
Atrophy |
|
Progesterone at physiologic concentrations |
Differentiation and secretory changes |
No effect on lesions that have no progesterone receptors; differentiation and secretory changes in lesions with progesterone receptors |
|
Progesterone at high concentrations |
Decidualization |
Pseudodecidualization (a terminal differentiation step) |
Immunologic factors
Numerous studies indicate that in women with endometriosis, the pelvic peritoneal environment is immunologically abnormal, with increased concentrations of white blood cells, cy-tokines, and growth factors. Indeed, elevated levels of cy-tokines—specifically, tumor necrosis factor-a in peritoneal fluid and interleukin-6 in serum—have been proposed as a potential diagnostic marker for endometriosis.6 One group of researchers has found an increased incidence of autoimmune disease in women with endometriosis—a finding that supports the concept that immunologic abnormalities play a role in the development of endometriosis.7
Some authorities believe that in women with endometriosis, a primary immunologic abnormality prevents the clearance, from the peritoneal environment, of the endometrial tissue fragments deposited by retrograde menstruation.8 This postulated primary alteration in the immune response allegedly contributes to the development of endometriosis. Other authorities believe that the observed peritoneal immunologic changes are not a cause of endometriosis but a consequence of it: the en-dometriosis lesions produce a chronic pelvic inflammation, which leads to an increase of immune cells in the peritoneal fluid. Interestingly, factors secreted by these immune cells appear to promote angiogenesis and cause endometriosis lesions to grow. It is likely that there is cross-talk between the immune system and endometriosis lesions: endometriosis lesions cause inflammation, inducing immune cells to enter the peritoneal environment; in turn, immune cells secrete factors that can stimulate the growth of endometriosis lesions.
Genetic abnormalities
The risk of endometriosis is approximately doubled in first-degree relatives of women with endometriosis.9 The heritable aspects of endometriosis may involve alterations in the immune response that predispose women to ectopic transplantation and survival of endometrial tissue.
Ovarian endometriosis cysts (endometriomas) are monoclonal and appear to arise from a somatic mutation in a precursor cell, although those mutations have not been characterized.10 This finding suggests that a small number of genes play a central role in the pathogenesis of endometriosis.
Endometriosis and infertility
An association between endometriosis and infertility in women has long been noted,11 and many possible mechanisms for the infertility have been identified. Nevertheless, the hypothesis that endometriosis decreases fertility has not been definitively proved by consistent data from rigorous studies.
In advanced endometriosis, infertility can have an anatomic cause: adhesions interfere with the release of the ovum from the ovary and its uptake into the fallopian tube. Although women with early-stage endometriosis often have reduced fertility, a causal link between the endometriosis and the infertility is not clear.
Abnormalities in peritoneal, tubal, and endometrial function caused by endometriosis may inhibit fertility, especially in women with early-stage disease.11 Numerous investigators have reported peritoneal abnormalities in women with endometrio-sis, including an increased volume of peritoneal fluid12 and increased concentrations of activated macrophages,13 prostaglandin, interleukin-1, tumor necrosis factor, and proteases.14 Peritoneal fluid from women with advanced endometriosis appears to inhibit sperm function, thereby possibly reducing fertility.15
A few investigators have reported that women with endome-triosis may have increased levels of antiendometrial antibodies, which may impair endometrial function.16,17 Some women with early-stage endometriosis have luteal phase dysfunction,18 abnormal follicle growth,19 multiple premature luteinizing hormone surges,20 and luteinized unruptured follicle syndrome.
Intrauterine endometrium may be abnormal in women with endometriosis, which suggests the possibility of a so-called field defect in the mullerian tract. Significant suppression of P3 in-tegrin has been reported in the endometrium of women with early-stage endometriosis.21 This decrease in p3 integrin expression may be associated with an impaired interaction of the embryo with the endometrium. In addition, elevated levels of the mullerian antigen CA-125 have been found on endometrial biopsies taken during the luteal phase of the menstrual cycle from women with advanced endometriosis22 and in the menstrual discharge of women with endometriosis.23
Diagnosis
Although endometriosis is a common disorder, it remains remarkably difficult to diagnose. In one cohort study, women with endometriosis reported that, on average, 4 years elapsed between their first presentation with symptoms caused by en-dometriosis and their diagnosis.
Clinical presentation
Women with endometriosis typically present because of chronic pelvic pain or infertility. Other possible symptoms include secondary dysmenorrhea, dyspareunia, pain with bowel movements (dyschezia), and pelvic pain not associated with menses. The rare cases of diaphragmatic endometriosis have been associated with chest pain at the onset of menstruation.24
Physical examination
In most women with endometriosis, the physical examination is normal. However, certain findings on physical examination suggest the presence of endometriosis. These include tender, thickened, or nodular uterosacral ligaments and fixed ad-nexal masses. A retroverted, fixed uterus suggests involvement of the cul-de-sac with endometriosis.
The uterosacral ligaments connect the base of the uterus to the sacrum. Nodularity of the ligaments is evident on bimanual pelvic examination as pea-sized nodules palpable at 4 o’clock and 8 o’clock at the base of the cervix. These nodules most often are implants of endometriosis.
Two less common physical findings in endometriosis are cervical stenosis25 and lateral displacement of the cervix. Lateral displacement of the cervix occurs when one uterosacral ligament becomes severely involved with endometriosis, shortens as a result of scarring, and pulls the cervix to the side.26
Noninvasive laboratory tests
A complete blood count, urinalysis, and endocervical cultures for gonococci and Chlamydia should be performed to rule out infectious causes of pelvic pain in women. Results of all these tests will be normal in women with endometriosis. In most women with endometriosis, the pelvic sonogram is normal, but other conditions, such as uterine leiomyomas, will be evident on sonography. Although many conditions can cause adnexal masses, including dermoids (mature teratomas), serous and mucinous cysts, and hemorrhagic corpora lutea, en-dometriomas have classic characteristics on ultrasound, which aids in their diagnosis.
Surgical staging
The current gold standard for the diagnosis of endome-triosis is the surgical visualization of lesions, usually by lap-aroscopy. The normal peritoneal surface is smooth and glistening, like the inner surface of the oral mucosa. Classic endo-metriosis lesions are often black, purple, or red and measure 1 to 5 mm in diameter; they stud the surface of the peritoneum. Atypical endometriosis lesions are often translucent or yellow, and they may take the form of either flat plaques or vesicles.
Unfortunately, surgeons vary considerably in their ability to detect endometriosis lesions reliably. One study reported pathologic confirmation rates of visually diagnosed en-dometriosis at 42%, 65%, and 76% for three different surgeons.27
Endometriosis is staged surgically using the American Society of Reproductive Medicine staging system. This system divides the disease into four stages: stage I, minimal; stage II, mild; stage III, moderate; and stage IV, severe. As with detection, however, staging is not always performed consistently. Studies of intersurgeon and intrasurgeon variability in the staging of endometriosis report low reproducibility and a kappa coefficient in the range of 0.28.28
Histologic diagnosis
Biopsy and histologic analysis of lesions found on lap-aroscopy may enable more reliable diagnosis of endometriosis than does visual inspection alone. The criteria for histologic diagnosis of endometriosis include the presence of one of the following components: (1) both endometrial glands and stroma; (2) glandular epithelium with hemosiderin; or (3) endometrial stroma-like tissue with hemosiderin. One weakness of histolog-ic diagnosis for endometriosis is that diagnostic criteria vary among pathologists.29,30 Furthermore, no study has demonstrated high interobserver reproducibility in the histologic diagnosis of endometriosis.
Clinical diagnosis
An innovative approach to the diagnosis of endometriosis is to use a combination of history, physical examination, and noninvasive laboratory testing.31 This approach is called clinical diagnosis.
Differential diagnosis
Pelvic Pain
Chronic pelvic pain, defined as the presence of pain below the umbilicus for more than 6 months, is a common gynecologic problem. In one study of primary care practices that included 284,162 women 12 to 70 years of age, the reported prevalence of chronic pelvic pain was 3.8%.32 Along with endometriosis, other common gynecologic causes of chronic pelvic pain include chronic pelvic inflammatory disease, adenomyosis, and uterine leiomyomata. Nongynecologic diseases such as irritable bowel syndrome and fibromyalgia, as well as psychiatric diseases such as somatization, may also contribute to chronic pelvic pain. In populations in which the prevalence of sexually transmitted diseases is low, endometriosis is the most common cause of chronic pelvic pain. In three large studies, 70% to 80% of women with chronic pelvic pain had endometriosis as the cause.
Infertility
Endometriosis is considered to be responsible for 8% of all cases of infertility. The most common causes of infertility, accounting for about 75% of cases, are ovulatory disorders, tubal disease, and semen abnormalities. Miscellaneous factors, such as cervical or immunologic abnormalities and uterine synechi-ae, cause 2% of cases; 15% are unexplained.35-37
Treatment of Pelvic Pain
Interventions that reduce estradiol production are the most reliable way to cause atrophy of endometriosis lesions and are the most effective in treating pain symptoms. A variety of hormonal and surgical interventions are available for this purpose. Most authorities recommend a stepwise approach to the use of these interventions [see Table 2].
Table 2 Stepwise Treatment of Pelvic Pain
|
Step |
Description |
Recommendation |
|
1 |
Thorough history and physical examination |
Detailed history and physical examination forms for evaluating pelvic pain are available on the Internet at www.pelvicpain.org |
|
2 |
Noninvasive laboratory testing |
Pelvic ultrasound, complete blood count, urinalysis, endo-cervical cultures for gonococci and Chlamydia |
|
3 |
Empirical therapy |
Oral contraceptive plus nonsteroidal anti-inflammatory medication |
|
4 |
Surgical diagnostic procedure |
Laparoscopy to determine the cause of pain if empirical therapy does not result in sufficient relief of pain |
|
5 |
GnRH agonist therapy |
For regimens, see Table 3 |
|
6 |
GnRH agonist therapy plus steroid add-back |
Consider for reduction of GnRH agonist side effects; for regimens, see Table 4 |
|
7 |
Progestin-only treatment |
If GnRH agonists cannot be tolerated because of side effects; for regimens, see Table 5 |
GnRH—gonadotropin-releasing hormone
Hormonal treatment for relief of pain
Randomized clinical trials have demonstrated that combination estrogen-progestin oral contraceptives, gonadotropin-releasing hormone (GnRH) agonist analogues, danazol, and pro-gestins are all effective in relieving pelvic pain caused by en-dometriosis. GnRH agonist analogues are the most effective; combination estrogen-progestin oral contraceptives are the least expensive.
Combination Estrogen-Progestin Oral Contraceptives
Oral contraceptives are sometimes effective in the treatment of pelvic pain caused by endometriosis because progestins can block the growth of endometrium and endometriosis lesions. Although estrogen stimulates the growth of endometriosis lesions, modern oral contraceptives are progestin dominant and contain low doses of estrogen.
In the United States, almost all women with chronic pelvic pain are initially treated empirically with a combination of cyclic oral contraceptives and nonsteroidal anti-inflammatory drugs (NSAIDS), such as ibuprofen. In contrast, in some European countries, the standard practice is to perform laparoscopy on women with chronic pelvic pain to determine the cause of the pain before starting hormonal treatment. In one randomized study, women with endometriosis who had not previously undergone hormonal treatment were randomized to receive treatment with either low-dose cyclic oral contraceptives or a GnRH agonist analogue. Both groups experienced significant improvement in pelvic pain and dysmenorrhea. However, the group treated with GnRH agonists had better relief of dyspareunia.38
Oral contraceptives can be used in monthly cycles or long-cycle regimens. If a regimen of oral contraceptives taken in monthly cycles does not relieve the pain, many physicians will try a regimen of long-cycle oral contraceptives. In long-cycle regimens, the active pills are taken for 42 to 105 days in a row; no pills are taken for a period of 1 week between cycles.
If oral contraceptives and NSAIDs fail to relieve chronic pelvic pain, most physicians recommend laparoscopy to definitively determine whether endometriosis is present.
