Connie E. Alford, MD, Clinical Fellow, Combined Federal Fellowship in Reproductive Endocrinology and Infertility, Program in Reproductive and Adult Endocrinology, National Institutes of Health, Bethesda, Maryland
Robert N. Taylor, MD, PhD, Leach/Hendee Professor and Vice Chair for Research, Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, Georgia,1639 Pierce Drive, 4217-WMB, Atlanta, Georgia 30322
Alan H. DeCherney, MD, Head, Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD

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DEFINITION

Endometriosis is a disease in which endometrial glands and stroma implant and grow in areas outside the uterus (Fig. 1). The most common place to find implants is in the peritoneal cavity (involving the ovary, cul-de-sac, uterosacral, broad and round ligaments, fallopian tubes, colon, and appendix), but endometriosis lesions have occasionally been found in the pleural cavity, liver, kidney, gluteal muscles, bladder, abdominal scars, and even in men (1).

Figure 1. Common locations of endometriosis within the pelvis and abdomen. (Reprinted by permission from the New England Journal of Medicine 2001. Olive DL, Pritts EA. Treatment of Endometriosis. Vol. 345:267).

There are three typical types of endometriotic lesions: 1) superficial peritoneal and ovarian implants, 2) endometriomas (ovarian cysts that are lined with endometrioid mucosa), and 3) deep infiltrating endometriosis (complex nodules comprised of endometriotic tissue, adipose tissue, and fibromuscular tissue) (2,3). The anatomical location and inflammatory response to these lesions are believed to account for the symptoms and signs associated with endometriosis.

ETIOLOGY

Classically, three theories exist to explain the etiology of endometriosis; 1) Sampson’s theory, 2) Meyer’s theory, and 3) Halban’s theory. The most often quoted theory, and to date the one supported by the most evidence, is Sampson’s theory of transplantation and implantation. This theory stemmed from observations made during surgeries in the 1920’s that many women shed endometrial debris through their fallopian tubes into the peritoneum during menstruation (4). Not only has viable endometrial tissue been found in the fallopian tubes and peritoneal fluid of women, but in humans and other animals, endometrial tissue will grow if placed ectopically. Further supporting this theory, endometriosis seems to occur most commonly in the gravitationally dependent parts of the pelvis (5). Finally, the incidence of endometriosis is significantly increased in patients with mullerian anomalies or genital tract obstructions, both which increase the likelihood of retrograde flow (6). One problem with this theory is that retrograde menstruation has been shown in 76-90% of menstruating women, a prevalence much higher than the prevalence of endometriosis (7,8). This discrepancy suggests that additional factors beyond the presence of ectopic tissue are needed to establish the disease, such as the amount of endometrial debris that reaches the peritoneal cavity, the immunocompetency of the woman to clear the debris, and the molecular abnormalities/properties inherent in the ectopic tissue.

Meyer’s theory (9) suggests that metaplasia of the coelomic epithelium is the origin of endometriosis. This theory is logical, as cells from both the peritoneum and endometrium are derived from a common embryological precursor: the coelomic cell. However, this has been a difficult theory to support scientifically. If this postulate were correct, one would expect much higher rates of pleural endometriosis than are observed.

Halban’s theory is one that suggests that distant lesions are established by the hematogenous or lymphogenous spread of viable endometrial cells. Although this metastatic theory explains rare endometriotic lesions in the brain or lung, it does not explain the gravitationally-dependent location of most foci of endometriosis.

Sampson’s transplantation and implantation theory is the most widely accepted, but most researchers agree that it grossly simplifies the disease process. Whilst retrograde menstruation can transplant tissue fragments into the peritoneal cavity, the cells themselves must escape apoptosis (10), adhere to the underlying peritoneum (11,12), degrade the underlying extracellular matrix (13), generate a new vascular supply (14), and evade the immune surveillance system (15) in order to survive.

Clear molecular differences exist between endometriotic lesions and eutopic endometrium. Secondary to the inflammation associated with endometriosis, there are increased levels of prostaglandins, chemokines, and cytokines, such as interleukin-1ß, intlerleukin-6, and tumor necrosis factor (TNF) which are thought to enhance the adhesion of endometriotic implants to the peritoneal surface. Proteolytic membrane metalloproteinases, also increased in endometriosis, promote implantation. Angiogenesis and apoptosis are also altered in endometriosis in favor of survival of the implant. Granulocytes, macrophages, and natural killer cells are attracted by the increased monocyte chemoattractant protein 1, interleukin-8, and RANTES (regulated upon activation normal T-cell expressed and secreted), present in endometriosis. These inflammatory mediators accumulate in endometriotic tissue by autoregulatory positive feedback loops. (16).

While steroidogenic factor 1 (SF1) is present in ectopic endometrial tissue, it is not found in the eutopic endometrium. SF1 is involved in estradiol synthesis. The increased amount of estradiol seen in the peritoneal fluid of patients with endometriosis increases local cyclo-oxygenase -2 (COX-2) activity, resulting in stimulation of prostaglandin E₂ formation, which upregulates aromatase activity, resulting in additional estradiol to perpetuate the symptoms and lesions present in endometriosis(16). There is elevated expression of both estrogen receptor α and estrogen receptor ß leading to a downregulation of progesterone receptors (2), ultimately causing the characteristic hormonal profile seen in endometriosis.

DEMOGRAPHY

Endometriosis is diagnosed in women aged 12-80 and the average age at diagnosis is approximately 28. Exposure to ovarian hormones appears to be essential with the vast majority of the cases found in women aged 20-50. Caucasians appear to be more likely to suffer from endometriosis than African Americans or Asians (17). There is also an increased prevalence in taller women and those with a lower BMI (18). Although with severe disease there seems to be a familial correlation, no clear mendalian genetic trait has been identified and most researchers believe it to be multifactorial. Risk factors for this disease include nulliparity, early menarche, and frequent or prolonged menses. Protective factors include pregnancy, menopausal status, multiparity, and periods of lactation (19).

PREVALENCE

The prevalence of endometriosis ranges from 2-50% of reproductive aged women. Unfortunately, this number is widely disparate depending on the study. In women with infertility, the prevalence ranges from 12-47%. This may be due to the fact that endometriosis plays a causative role in infertility, but it also may be due to a diagnostic selection bias, as women with infertility typically undergo laparoscopy as part of their clinical evaluation.

Between the years 1965 and 1984, endometriosis increased from 10-19% as the primary indication for hysterectomy in the USA. Interestingly, this happened during a time in which a trend towards more conservative therapies as treatment modalities for endometriosis occurred (20). This finding suggests a true increase in the incidence of the disease. Varying theories have been proposed to explain this increase, including a delay in childbearing, declining use of oral contraceptives, and exposure to environmental toxins such as dioxin as a causative agent (21). A recent study involving mice has demonstrated that bisphenol A (one of the highest volume chemicals produced worldwide) is able to elicit an endometriosis-like effect in mice who were prenatally exposed (22). These theories, while intriguing require further investigation.

SYMPTOMS

Pain

The most common symptom for women who have endometriosis is pelvic pain, although the pathophysiologic mechanisms are not well understood and many women with endometriosis may not have this complaint. The pain is most often cyclic, but may also be chronic in nature. The pain usually begins just before menses, continues throughout the duration of menstrual flow, and typically includes dysmenorrhea, dyspareunia, dysuria, or dyschezia. The pain may also be perceived in musculoskeletal regions, such as the flank, low back, or thighs. The heterogeneity of the disease process makes it difficult to ascertain the exact etiology of the pain.

Actively bleeding lesions can certainly cause discomfort. Pain may also be produced by the production of inflammatory mediators and neurologic stimulation. It is likely that different types of lesions cause pain through differing pathways. Early papular lesions contain higher levels of prostaglandins than older lesions. These prostaglandins may activate afferent neuronal pathways. Lesions deeply penetrating the peritoneum also have an increased propensity to cause pain, probably by direct irritation of pelvic nerves. Endometriomas may cause a mass-effect, which can result in the perception of pain. Adhesions and fibrosis cause pain by compromising the blood supply to certain neuronal plexi, or by placing small nerves on tension (23). In addition to the perturbation of nerve fibers by the lesions, recent studies have demonstrated that neuronal fibers are present in endometriotic lesions found on the ovaries. A nerve growth factor (a substance important for the maintenance of sensory nerves), S 100 (a neurotrophic factor), and PGP9.5 (an immunoreactive nerve fiber) have all been demonstrated in these lesions, which may contribute to the generation of pain (24). Other studies have shown that there is an increased amount of nerve fibers present in the endometrium in patients with endometriosis (25-28). The significance of these observations remains to be determined, but it has been suggested that the presence of nerve fibers in the endometrium may be used to diagnose endometriosis.

Macrophages in the peritoneal fluid in women suffering from endometriosis are increased in concentration and activity (29). As discussed previously, macrophages are part of an inflammatory cascade, which perpetuates the sensation of pain, as does the constant elevated production of prostaglandins.

Infertility

The next most common symptom is that of infertility. Women with moderate and severe endometriosis, particularly those in which the ovaries and oviducts are involved with adhesive disease, have decreased fertility rates. It is theorized that this stems from the mechanical obstruction between the ovary and oviduct, with subsequent failure of gamete transport into the tubal ampulla. Many women with moderate to severe endometriosis have undergone operative management for their disease and as a result, may have decreased amounts of functional ovarian tissue, and thereby suffer from decreased fecundity.

Interestingly, women with only minimal or mild disease may also have decreased fertility when compared to those without clinical evidence of endometriosis. It remains controversial whether endometriosis is the cause of this subfertility. Some studies report that even minimal stage disease is associated with decreased fecundity, while other studies report no effect on endometriosis and pregnancy outcome. (30,31). The monthly fecundity rate in normal couples is 15-20%, while the monthly fecundity rate in women with untreated endometriosis and infertility is 2-10% (32).

In addition to the anatomic causes of infertility mentioned above, there are two other major theories that may explain the decreased monthly fecundity rates seen in women with endometriosis: 1) inflammation and 2) a locally altered hormonal profile. The altered cellular immunity results in an increased amount of inflammatory mediators, such as activated macrophages, RANTES (regulated on activation, normal T-cell expressed and secreted), interleukins, and tumor necrosis factor in follicular fluid and in peritoneal fluid. This results in a locally hostile, cytotoxic environment, characterized by oxidative stress, that negatively impacts most aspects of reproduction by causing altered folliculogenesis, oocyte degradation, structural DNA damage, decreased spermatozoal integrity, decreased fertilization potential, embryo fragmentation, impaired tubal function, and decreased endometrial receptivity. The altered humoral immunity results in the presence of autoantibodies with the capability of binding to the endometrium and, possibly the oocyte, sperm, embryo, and tube. The presence of elevated levels of steroidogenic factor-1, estrogen, and estrogen receptors in endometriotic cells ultimately leads to a down regulation of local progesterone receptors, and thus, an altered reproductive hormonal profile. (2,16,33).

Altered folliculogenesis has been proposed as one of the contributing factors to infertility. Characteristics of in vitro fertilization cycles in women with endometriosis include a slower follicular growth rate and reduced follicle size. Changes in the cell-cycle kinetics of the granulosa cell that favor an increase in the amount of cells in the S phase and in cells undergoing apoptosis may play a role in this phenomenon. There is a decreased amount of vascular endothelial growth factor present in follicular fluid which is believed to be responsible for the decreased follicular health and vascularization seen in endometriosis.

Endometriosis has a multifactorial impact on the health and function of spermatozoa. The increased generation of reactive oxygen species seen in women with endometriosis results in the loss of spermatozoal membrane integrity and enzyme inactivation, thereby decreasing the potential for fertilization. Decreased sperm motility, mediated by glycoprotein-130 binding in sperm, is also a result of the negative impact endometriosis has on sperm function. The endosalpinx in women with endometriosis tends to bind spermatozoa more tightly, resulting in a decreased amount of available spermatozoa. A decreased ability of spermatozoa to bind to the zona pellucida is evident in patients with endometriosis, resulting in impaired fertilization. Taken together, it is clear that endometriosis has a negative impact on the spermatozoa. (16).

There are a few proposed mechanisms by which endometriosis impairs implantation. Explanations include the delayed histologic maturation or the biochemical alterations of the endometrium, both seen in endometriosis. In another mechanism, αvβ 3 integrin, an adhesion factor which is normally increased during the optimum implantation window, is decreased or absent in patients with endometriosis. (16). Evidence indicates that the eutopic endometrium of women who suffer from endometriosis is abnormal in its expression of implantation-associated proteins, e.g., complement protein (C3) (34), IL-6 (35), HOX A 10 and 11 (36), and b3 integrins (37). The zona pellucida of the embryo is compromised by the cytotoxic effects of the reactive oxidative species, which may also lead to impaired implantation. (16).

Other Symptoms and Associations

Other symptoms of endometriosis can include abnormal menstrual bleeding, diarrhea, constipation, and chronic fatigue. There are elevated rates of autoimmune diseases, including hypothyroidism, rheumatoid arthritis, lupus, Sjogren’s syndrome, and multiple sclerosis in patients with endometriosis. Reports of allergies, asthma, chronic fatigue syndrome, and fibromyalgia are also more common in women with endometriosis than in women in the general US population (38).

PHYSICAL EXAM FINDINGS

Unfortunately, due to the diffuse and often varying nature of endometriotic lesions, the physical examination is typically unrevealing. The findings are variable and of limited precision in either localization or diagnosis of endometriosis. However, tender nodules may be palpable along the uterosacral ligaments, rectovaginal septum, or within the cul-de-sac, especially if the examination is performed just before menses. The astute clinician can appreciate pain or induration in the vicinity of otherwise non-palpable lesions, most commonly in the cul-de-sac, along the uterosacral ligaments, or rectovaginal septum. The clinician may also appreciate uterine or adnexal fixation or a tender adnexal mass. Because much disease is found in the dependent areas of the pelvis, it is critical to perform a systematic rectovaginal examination. In that way, the practioner is assured of evaluating the cul-de-sac and uterosacral ligaments as well as the adnexa (39).

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of endometriosis includes pelvic inflammatory disease, tubo-ovarian abscess, ectopic pregnancy, irritable bowel syndrome, interstitial cystitis, adenomyosis, pelvic adhesions, uterine fibroids, chronic or acute endometritis, ovarian neoplasms, musculoskeletal disease, gastrointestinal neoplasms, appendicitis, and diverticular disease.

DIAGNOSTIC MODALITIES

Laparoscopy with visualization of lesions is considered the gold standard for the diagnosis of endometriosis. Dogma states that a biopsy of the lesion is the only way to truly confirm a disease diagnosis. For those surgeons trained in advanced laparoscopy, direct visual recognition of endometriosis also allows treatment to be instituted immediately. Laparoscopy is preferred over laparotomy as it provides visualization of the entire abdomen and pelvis at magnified views, has less morbidity than laparotomy, and carries a decreased risk of adhesion formation (40, 41). One of the major limitations of diagnostic laparoscopy for pelvic pain is the assumption that those lesions seen (or not seen) directly correlate with the symptoms of pain.

Attempts to develop noninvasive radiological imaging techniques as diagnostic tools for endometriosis have been compromised by lack of specificity. Computed tomography was used initially to diagnose endometriomas in the setting of adnexal masses. Unfortunately, not only was it difficult to distinguish between benign versus malignant masses, it was often impossible to distinguish adnexal structures and loops of bowel (27,28). Hence, this modality is of little value for this purpose.

With more recent technological advances, transvaginal ultrasonography has been employed to evaluate possible endometriomas. Transvaginal ultrasound may also identify other types of lesions with characteristics of endometriosis, such as hypoechogenic linear thickening or nodules/masses with irregular contours (3). The addition of cystoscopy, colonoscopy/sigmoidoscopy, renal ultrasound, intravenous pyelogram, or barium enema should be considered if there is cyclic bowel/bladder dysfunction or back pain to rule out ureteral, bladder, or rectal involvement of deep lesions or other malignancy. Because of the broad range of symptoms that are included in endometriosis, a multi-disciplinary approach is often required for diagnosis and management. (42-48).

At present, magnetic resonance imaging is the best imaging for identifying endometriosis, and can resolve implants as small as 3mm in size (49, 50). It also has been shown to differentiate benign from malignant lesions, with excellent sensitivity and specificity, and is the method of choice for preoperative evaluation of any adnexal mass (51,52). Because of the large disparity in cost of an MRI versus a transvaginal ultrasound, physicians may resort to using an MRI in cases of ultrasonographically indeterminate pelvic masses (3).

Much research has been devoted to discovering a serum marker that will allow diagnosis and monitoring of treatment, to no avail. Monoclonal antibodies raised against a high molecular weight ovarian cancer epithelial cell antigen, CA-125, have been used as a biochemical marker of endometriosis. Moderate and severe endometriosis is associated with elevated levels of CA-125 in the peripheral blood (53). Unfortunately, this marker is relatively non-specific, being increased in ovarian cancer and other gynecologic malignancies (fallopian tube carcinoma, germ cell tumors, adenocarcinoma of the cervix, sertoli-leydig cell tumors), benign gynecologic conditions (benign pelvic neoplasms, adenomyosis, pregnancy, pelvic inflammation), liver disease, colitis, colon cancer, diabetes, congestive heart failure, some autoimmune and rheumatologic disorders, ascites, breast cancer, lung cancer, and even during menstruation of women without any disease. Although it may help define progression of disease in individual patients, its diagnostic utility is limited.

Recent studies have reported that an increased in density of nerve fibers exists in the eutopic endometrium of patients with endometriosis. Although there are limitations to these studies, endometrial biopsies may prove to be useful in the diagnosis of endometriosis in the future, with a sensitivity that ranges from 95-98% and a specificity that ranges from 83-100%(25,26). However, the sample sizes were small (26), patients were included if they had either pain or infertility in one study (25) and their endometrium wasn’t compared with normal controls (25).

CLINICAL APPEARANCE

Grossly, peritoneal endometriosis can take on many visual appearances. Classically, it was taught that endometriosis implants were blue-black “powder-burns” or “mulberry lesions” of the peritoneum. In recent years, several stages of implant development have been appreciated, each with a corresponding appearance. Early, active lesions can appear as papular excrescences or vesicles, and can range in color from clear to pink, or bright red (54). About a third of these lesions are in phase with the eutopic endometrium, and have a tendency to spontaneously grow and regress, suggesting a fluctuation of proliferation in association with the cyclic hormone production during the menstrual cycle (55). Advanced, active lesions are associated with inflammation, fibrosis and hemorrhage, and take on a more classic appearance identifiable at surgery. These lesions can express a myriad of colors, from black to brown, purple, red, or green. These are due to the presence of heme degradation products as the foci undergo hemorrhage and fibrosis. Dormant and healed lesions take on either a white or calcified appearance, and represent remnants of glands embedded in fibrous tissue (54). The surface of peritoneum may also be puckered or contain windows (Allen-Masters windows).

A specific manifestation is the endometrioma or chocolate cyst. These ovarian cysts gained their moniker by the characteristic chocolate syrup appearance of their contents often seen at rupture. They arise after implantation of ectopic endometrial tissue and subsequent invasion into the normal ovarian cortex. The cell types present in these cysts include endometrial epithelium, both as glands and flattened cells, endometrial stroma, and hemosiderin-laden macrophages. In some cases, ciliated cells, similar to those of oviduct epithelium, have been observed (56).

Under scanning electron microscopy, microscopic lesions have been found in the normal appearing peritoneum of women with and without endometriosis (57). The clinical significance of these findings is presently unknown.

HISTOLOGY

Although the histopathologic finding of ectopic endometrial glands and stroma is the sine qua non for establishing the diagnosis of disease, only about 50-70% of presumed endometriosis specimens fulfill these criteria. Many specimens harbor fibrosis, chronic inflammation, and/or hemosiderin-laden macrophages. Most pathologists and clinicians accept these latter findings as highly suggestive of disease status. Eutopic endometrium and endometriotic implants are histologically similar, but as mentioned previously, they are functionally, biochemically, and hormonally different from each other.

CLASSIFICATION

The scheme most widely used to classify the extent of disease is the one derived from the American Society for Reproductive Medicine (ASRM), revised in 1996 (58)(Fig. 2 and 3). This scheme designates disease extent based upon the total 3-dimensional volume of endometriosis. Importance is placed upon the size, depth of invasion, bilaterality, ovarian involvement, extent of cul-de-sac involvement, as well as density of associated adhesions. From this system, point scores are assigned and tallied, with scores of 1-15 representing minimal or mild disease, 16-40 moderate, and >40 severe. It is important to note that this staging system was established to predict fertility outcomes and does not correlate with the more common symptom of pelvic pain. Unfortunately the classification system is not even good at predicting just which women will suffer from infertility, as infertility may occur even in women with mild endometriosis. Commonly, practitioners classify endometriosis as minimal (isolated small implants), mild (superficial implants <5cm total, only located on the ovaries and peritoneum, no adhesions), moderate (multiple superficial and invasive implants with or without adhesions), or severe (endometriomas); and the classification system by the American Society for Reproductive Medicine is sometimes reserved for use in studies, where standardization of the classification is important. Use of the ASRM classification system should be encouraged, however, because its greatest use is in documenting for those involved in the care of the patient the full extent and location of endometriotic lesions.

Figure 2. The American Fertility Society Revised Classification of Endometriosis. (Reprinted by permission from Fertil Steril 1985;43:351).

Figure 3. Examples and guidelines for use of the American Fertility Society Revised Classification of Endometriosis. (Reprinted by permission from Fertil Steril 1985;43:352).

TREATMENT

Treatment for endometriosis differs depending on which symptom is being targeted. Treatment is either aimed at pain reduction, fertility restoration, or evaluating a mass, such as in the case of an endometrioma. Unfortunately, there are very few options for treatment of the patient who, both desires fertility and has pelvic pain. Sometimes pregnancy itself will relieve the pain symptoms of endometriosis.

Pain

Pain is the most commonly reported symptom of endometriosis, an estrogen-dependent condition characterized by chronic peritoneal and pelvic inflammation. Since endometriosis is a chronic disease, it would be most beneficial to use agents that can be safely used long-term. Dysmenorrhea is one of the most common complaints in women with endometriosis, so many of the hormonal agents aim to cause amenorrhea. These treatments may also relieve deep dyspareunia, non-cyclic pelvic pain, and dyschezia. These hormonal agents may have an additional effect on reducing the nerve fiber density present in endometriotic lesions, which is believed to be one of the factors involved in the origin of the pain caused by endometriosis. (59). Oral contraceptives, progestins, danazol, gestrinone, medroxyprogesterone acetate, and GnRH agonists are all supported by clinical trials showing approximately equal benefit over placebo (Fig. 4). Their side-effect profiles and costs lead one agent to be preferred over another. However, once the agent is discontinued, the symptoms tend to recur.

A definitive diagnosis of endometriosis can only be made with surgery. If there is sufficient clinical suspicion of endometriosis, it is reasonable to try empiric therapy with a single agent or a combination of agents. Oftentimes, the pain will improve and surgery can be avoided.

The combined oral contraceptive pill has been used for the treatment of endometriosis associated pain for several years. The pill’s efficacy in reducing symptoms of pain is well-established. Their advantages include a mild side-effect profile, several combinations from which to choose, and the choice of cyclic or continuous administration. However, not all women are candidates for the use of combined oral contraceptives. The pill is FDA approved as a contraceptive, but is commonly used off-label for the treatment of endometriosis-associated pain.

There are many progestins (synthetic derivatives of progesterone) that have been used to treat endometriosis-associated pain. Examples include norethindrone (norethisterone), medroxyprogesterone, and levonorgestrel. There are several routes of administration. They do not contain estrogen; thus they are believed to be safer for use in women who have a contraindication to estrogen.

Norethindrone acetate is a progestin that is taken orally and is initiated at the dose of 5 mg/day and can be increased by increments of 2.5 mg to amenorrhea or a total dose of 20 mg/day. Side effects include break-through bleeding and breast tenderness. Favorable effects on bone-mineral density (short term) and lipid metabolism have been reported. (60). Norethindrone acetate is FDA approved for the treatment of endometriosis-associated pain.

Medroxyprogesterone, a 17-hydroxy derivative of progesterone, taken orally, has moderate androgenic activity and minor effects on the lipid profile. The dose may range from 15-50 mg/day. Side effects may include breakthrough bleeding and depression/anxiety. The intramuscular dose or subcutaneous dose of depot medroxyprogesterone acetate is 150 mg given every 3 months. There is concern about the decrease in bone mineral density with long-term use of medroxyprogesterone. However, studies have shown that after discontinuation of this medication, the bone mineral density profile improves and that it takes and average of 7 months for menses to return. The abnormal bleeding and lipid profiles are still concerns for long-term use. (60). Medroxyprogesterone is FDA approved for the treatment of endometriosis-associated pain.

The levonorgestrel releasing intrauterine device releases 20 µg/day and induces amenorrhea by causing the endometrium to become atrophic and inactive. It has been shown to improve dysmenorrhea, relieve deep dyspareunia and, as expected, reduce monthly blood loss. Reasons for discontinuation include irregular bleeding, pelvic pain, breast tenderness, and weight gain. There is a 5% expulsion rate and a 1.5% infection rate associated with use of the intrauterine device. Advantages of this system are that it doesn’t induce a systemic hypoestrogenic state, and it is effective, without any further medical intervention, for five years. It is currently being evaluated for postoperative use in women who undergo laparoscopy for endometriosis (60). It is not FDA approved for the treatment of endometriosis-associated pain, but it is approved for the treatment of heavy menstrual bleeding.

For the relief of pain caused by the deep infiltrative type of endometriosis, a combination of different types of agents may be of benefit. A study with continuous oral ethinyl estradiol 0.01 mg/day with cyproterone acetate 3 mg/day or only norethisterone 2.5 mg/day demonstrated that both regimens substantially decreased dysmenorrhea, non-cyclic pelvic pain, deep dyspareunia, and dyschezia, but both caused slight weight gain and undesirable changes in lipid profiles. The group treated by norethisterone reported slightly better symptom improvement but also registered additional androgenic side effects (60).

GnRH agonists have been shown to decrease dysmenorrhea, dyspareunia, and non-cyclic pelvic pain by creating a hypoestrogenic environment. Some agonists are given subcutaneously either once a month at a dose of 3.75 mg or once every three months at a dose of 11.25 mg. The side effects of GnRH agonists include a reduction in bone mineral density and, therefore are not recommended for periods longer than 6 months. Other side effects include hot flushes, emotional lability, vaginal dryness, insomnia, and loss of libido. “Add-back therapy” with a low dose estrogen/progestin combination has been introduced to prevent the loss of bone mineral density and control the other side effects resulting from the hypoestrogenic environment, while continuing to control the symptoms of endometriosis. (60). GnRH agonists are FDA approved for the treatment of endometriosis-associated pain.

GnRH antagonists are newer compounds and avoid the undesirable “flare” caused by the agonists. Unfortunately, they are not as well studied and must be administered subcutaneously at least once a week at a dose of 3 mg (60). GnRH antagonists are not FDA approved for the treatment of endometriosis-associated pain.

Danazol, an oral agent, induces an amenorrheic state by suppressing the hypothalamic-pituitary-ovarian axis, and is characterized by hyperandrogenemia and hypoestrogenemia. The hormonal cyclicity of the menstrual cycle is interrupted, thereby disrupting steroidogenesis and estrogen production from the ovary that lead to the undesirable painful symptoms in endometriosis. Its use is losing favor because of its undesirable side effects. Weight gain, fluid retention, breast atrophy, acne, oily skin, hot flushes, hirsutism, and unfavorable changes in the lipid profile are among the side effects of danazol. Alternative routes of delivery may result in a beneficial relief of symptoms, while significantly reducing the side effect profile. Studies have looked at a danazol-releasing intrauterine device, vaginal ring, or vaginal capsules, but these preparations are not available at this time (60). Danazol is FDA approved for the treatment of endometriosis-associated pain.

Gestrinone, an oral agent, is a 19-norsteroid derivative that was originally designed as an oral contraceptive. It has the ability to block follicular development and estradiol production and cause both agonist and antagonist effects when bound to progesterone receptors. Its ability to bind to androgen receptors is responsible for its undesirable side effects: an unfavorable lipid profile, weight gain, hirsutism, seborrhea, and acne. Like danazol, this medication is not frequently used (60). Gestrinone is FDA-approved for the treatment of endometriosis-associated pain.

Aromatase inhibitors have recently become part of the armamentarium against endometriosis-associated pain. Aromatase is the enzyme responsible for the conversion of androgens into estrogens, and is normally expressed in granulosa cells, skin fibroblasts, adipocytes, and syncytiotrophoblasts. Although, steroidogenic factor-1 is found in endometriotic tissue, it is not found in eutopic endometrium. Steroidogenic factor-1 activates aromatase gene transcription, thereby increasing the production of estrogen. Because endometriosis is estrogen-dependent and aromatase is responsible for estrogen production, aromatase inhibitors have therefore been employed to alleviate the painful symptoms caused by endometriosis. Combination therapy of an aromatase inhibitor with a progestin, oral contraceptive agent, or GnRH agonist is recommended in the treatment of endometriosis in pre-menopausal women because of their ovarian stimulatory properties in this population and to prevent pregnancy. Aromatase inhibitors have a tolerable side-effect profile and don’t reduce bone mineral density (60). Aromatase inhibitors are not FDA approved for the treatment of endometriosis-associated pain.

Historically, there has been a well-established role for prostaglandin inhibitors, such as ibuprofen, in the treatment of endometriosis-associated pain. Recently, a Cochrane Review evaluated non-steroidal anti-inflammatory use for the treatment of endometriosis (61). It discovered two studies that met their inclusion criteria. They found inconclusive evidence to show that non-steroidal anti-inflammatory agents are effective for the treatment of pain associated with endometriosis. Despite this review, prostaglandin inhibitors are relatively safe, have a tolerable side-effect profile, and can generally be taken on a long-term basis by most patients, so they remain part of the first-line therapy for the treatment of endometriosis-associated pain. However, their use is associated with undesirable and potentially severe gastrointestinal side-effects that may cause them not to be candidates for use in every patient. Motrin (ibuprofen), a commonly used prostaglandin inhibitor is FDA approved for the treatment of endometriosis-associated pain.

As previously mentioned, endometriosis is associated with a peritoneal and pelvic inflammatory cascade, and anti-inflammatory compounds may alleviate the pain associated with endometriosis. Since the cyclo-oxygenase-2 pathway is upregulated, COX-2 inhibitors may have a role in treatment, but their main role in treatment of this disease is not well established.

Other targeted approaches have included agents that enhance cell-mediated immunity, agents that counteract tumor necrosis factor-α (TNF-α), anti-angiogenic agents, metalloproteinase inhibitors, hypocholesterolemic agents, and selective progesterone modulators. A recent Cochrane Review examined the use of TNF-α inhibitors for the treatment of endometriosis-associated pain and found no benefit. (62). These agents are not FDA approved for the treatment of endometriosis-associated pain.

From the available evidence it is clear that medical treatment is effective for endometriosis-associated pelvic pain. In general, a non-steroidal anti-inflammatory agent alone or in combination with an oral contraceptive agent or a progestin derivative should be considered as first-line therapy. GnRH analogues with add-back therapy and possibly aromatase inhibitors (with oral contraceptive agents, progestins, or a GnRH analog in premenopausal patients), should be regarded as second-line agents. Danazol and gestrinone should be reserved for cases that have failed other medical treatments.

If a patient continues to have symptoms of pain, despite medical therapy, conservative surgery should be performed with resection or ablation of lesions and lysis of adhesions. The evidence shows that both ablation and resection of lesions are equally effective techniques. There is no evidence supporting the performance of a uterosacral nerve ablation; however, if there is significant midline pain, presacral neurectomy may be of benefit (63). It should be noted, that presacral neurectomy requires excellent surgical skills, as there is significant risk for damaging the neurovascular plexus or causing retroperitoneal bleeding sufficiently severe as to require transfusion or re-operation.

A debatable issue is the use of medical therapy, such as a GnRH agonist or medroxyprogesterone acetate, as a neoadjuvant or adjuvant to surgical management. Preoperative medical therapy may be helpful to decrease the pelvic vascularity and size of the endometriotic implants, reducing intraoperative blood loss and surgical resection required. However, by reducing the endometriotic load, the disease may be understaged, which may affect management. Postoperative medical therapy may eradicate the residual implants.

There are three randomized trials in the literature that evaluate the effects of post-operative medical treatment versus placebo (63). The first trial showed a significant benefit if medroxy progesterone acetate or danazol were used for 6 months after lesion ablation and if adhesiolysis were performed compared to placebo. The second two trials compared GnRH agonist with placebo for either 3 or 6 months following surgery. Although the women in the placebo arms showed no differences in pain scores over 3-6 months in each study, there was a reduced need for a second operative procedure within the following two years in women who received GnRH agonist for six months. It is important to understand, however, that diagnostic laparoscopy alone has an important effect on pain, as high as 50% in some studies. A benefit can last up to 6 months postoperatively. To further complicate this issue, a recent randomized trial compared postoperative medical treatment with either GnRH agonist or progestin for 6 months followed by second-look laparoscopy. Not only was the post-operative addition of GnRH agonist more effective than progestin at relieving dyspareunia, dysmenorrhea, and general pelvic pain, but at second look laparoscopy, the endometriosis scores were significantly lower in this group (64). Although the results are not conclusive at present, these small studies suggest an enhancement of surgical pain relief with the addition of medical therapy, particularly in the use of GnRH analogues. Currently, there are no randomized trials reporting a benefit of pre-operative medical therapy.

There have been no trials comparing medical and surgical treatment to subdue endometriosis-associated pain. The studies employing each treatment modality, though, have similar success rates. With this in mind, it is reasonable to conclude that the treatments are equally effective. With the development of newer medical therapies with better tolerated side-effect profiles, surgery may be avoided or delayed. Narcotics should never be considered for treatment of the chronic pain associated with endometriosis. Referral to a multidisciplinary pain center may be of value. In the absence of other factors, if the pain continues to be present after surgery, a diagnosis of adenomyosis should be considered.

Infertility

The treatment of infertility, in the absence of pain, may involve expectant management, surgery, ovulation induction/stimulation with intrauterine insemination, or assisted reproductive techniques, such as in vitro fertilization. Infertility clinics differ in their use of diagnostic laparoscopy in the evaluation of the etiology of infertility, at which time asymptomatic endometriosis may be diagnosed and excised or ablated. Physicians that do not perform diagnostic laparoscopy as part of their evaluation for infertility would argue that there are significant anesthetic and surgical risks afforded by laparoscopy, ovarian reserve may be compromised by the incidental removal/destruction of normal ovarian tissue, surgery is a cause of adhesions, and that the practice of restoring normal tubal anatomy has fallen out of favor as the success of in vitro fertilization continues to rise.

In women with stage I/II endometriosis, laparoscopic ablation of lesions may offer a small, but significant improvement in live birth rates. A Cochrane Review evaluated two trials in which women were randomized to operative laparoscopy or diagnostic laparoscopy (65). They found two randomized trials that addressed the question of whether laparoscopic surgery improved outcomes in patients with otherwise unexplained infertility (66, 67). When combining live birth rates and clinical on-going pregnancy rates after 20 weeks, the meta-analysis demonstrated an advantage of laparoscopic surgery when compared to diagnostic laparoscopy alone, with an odds-ratio (OR) of 1.64 (95% CI 1.05-2,57). However, the two studies had incompatible results which should be taken into account in this interpretation. One study (66) reported a large positive effect, while the other (67) reported a small negative effect. The number needed to treat, resulting from this analysis, was 12 laparoscopies for one additional pregnancy. The decision to perform surgery should therefore be balanced with the patient’s age, history, health status, wishes, and should be entered into with informed consent about the risks and possible benefits. Suppressive medical therapy (such as in the treatment for pain) should not accompany surgery or be involved in the treatment of infertility, as it does not improve fertility and may increase the time to pregnancy. Viable options for the medical treatment of endometriosis-related infertility are discussed.

Ovulation induction in women with stage I/II endometriosis confers a fertility benefit. The three randomized trials in the literature addressing this issue, employing either GnRH agonists with follicle-stimulating hormone and luteinizing hormone, clomiphene citrate/intrauterine insemination, or follicle-stimulating hormone/intrauterine insemination, all showed increased pregnancy rates relative to the control arm, where the patient did not receive treatment (63). Thus, both ovulation induction plus intrauterine insemination and assisted reproductive technology (ART) have a place in the treatment of women with endometriosis-associated infertility.

If the patient is under the age of 35, initial treatment options include expectant management or controlled ovarian stimulation with clomiphene citrate or gonadotropins combined with intrauterine insemination. In a woman over the age of 35, because of the age-associated decrease in fecundity, controlled ovarian stimulation combined with intrauterine insemination or in vitro fertilization are reasonable therapies.

In women with stage III/IV endometriosis, surgery is likely to be of benefit and is recommended by the ASRM Practice Committee, but there are no randomized controlled trials to document efficacy and some studies show a negative effect of surgery on pregnancy rates. (32,68).

Advanced staged disease is often associated with a complex surgical history which, combined with an extensive amount of disease, causes the operation to be difficult, sometimes requiring advanced laparoscopic techniques or laparotomy, and the risk of serious complications is increased. In situations when the initial surgery fails to restore fertility, in vitro fertilization, rather than another operation for infertility, is likely a better option. However, randomized controlled trials are lacking. If surgery is performed, then the subsequent treatment for infertility should be controlled ovarian stimulation with gonadotropins) and intrauterine insemination or in vitrofertilization, especially in women of advanced reproductive age(32). If the plan is to go directly to in vitro fertilization, surgery may not show a benefit, as the slight possible benefit afforded by the surgery is greatly overshadowed by the benefits of in vitro fertilization.

There has been some debate about the management of endometriomas in stage IV disease in the absence of pain. Should the endometriomas be removed prior to in vitro fertilization? A meta-analysis evaluated five studies that compared surgery versus no treatment for an endometrioma. (66). In this analysis, there were no differences in the pregnancy rates or responses to controlled ovarian stimulation in the two groups, favoring against surgical resection. There are no randomized controlled trials that evaluate this question. Surgery for endometriomas should be performed to relieve pain and to confirm the diagnosis in situations when it is in question.

Other Therapeutic Modalities

There have been many studies exploring complementary alternative medicine (CAM) for the treatment of symptoms associated with endometriosis. Although these approaches are not FDA or USDA approved for the treatment of endometriosis, they may offer relief by suppressing cytokines and inflammatory pathways, inhibiting cyclooxygenase-2 (COX-2) pathways, acting as antioxidants, and alleviating pain by other mechanisms (69). High frequency transcutaneous electrical nerve stimulation, acupuncture, vitamin B1, magnesium, reflexology, traditional Chinese medicine, herbal treatments, and homeopathy are examples of CAM that have been explored for use in endometriosis-associated pain. Even though the risks associated with some of these modalities appear minimal, the standards of evidence-based medicine on aspects of safety and efficacy have not been applied to most studies involving CAM. A promising note for CAM is that there is now a National Center for Complementary and Alternative Medicine (NCCAM) at the National Institutes of Health (NIH). Hopefully, this will allow for proper evidence-based evaluation, so that their safety and efficacy can be compared with the more traditional approaches (69). Another therapeutic modality that may be considered is patient self-help and support groups. Information can be found at www.endometriosis.org. (42).

CONCLUSION

Endometriosis is an enigmatic disease, the pathophysiology of which we are just beginning to understand. Symptomatic women with endometriosis, suffering from infertility or pain, are often difficult patients to treat because we have few treatment options to offer. The therapies themselves are imperfect, with none that permanently eradicate the disease. A multidisciplinary approach is often required for the diagnosis and management of this disease.

In deciding how to treat women with pelvic pain or infertility, we must consider the best available evidence to form our decisions. In women with pelvic pain and suspected endometriosis, first line treatment would be non-steroidal anti-inflammatory medications with/without oral contraceptives or progestins. Although the evidence is lacking, it makes theoretical sense to use continuous oral contraceptive therapy. If these conservative approaches fail, three alternative treatments would be empiric: GnRH agonist therapy with estrogen and progestin add-back therapy, aromatase inhibitors, or operative laparoscopy. The laparoscopy should certainly include lysis of adhesions and excision or ablation of the endometriosis. Surgery for pain may be followed by medical treatment with GnRH agonist and add-back therapy (Fig. 5). It is important to note that at no time are narcotics advocated for the treatment of endometriosis-associated pelvic pain except immediately pre-operatively or post-operatively. If the above measures fail, patients should be enrolled into a multi-disciplinary chronic pelvic pain treatment group. This should include physicians from many subspecialties, including psychiatry, anesthesiology, gynecology, and often gastroenterology and urology.

Figure 5. Treatment algorithm for pain associated with endometriosis.

In the treatment of infertility associated with endometriosis, the age, history, health status, physical exam, and wishes concerning her treatment should be weighed. There are certain situations where surgery may be indicated for the treatment of infertility associated with endometriosis. Controlled ovarian stimulation with intrauterine insemination and in vitrofertilization offer significantly higher pregnancy rates when compared to intracervical insemination (Fig. 6).

Figure 6. Treatment algorithm for infertility associated with endometriosis.