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ENDOMETRIOSIS Endometriosis is a benign but, in many women, a progressive and aggressive disease.

The wide spectrum of clinical problems that occur with endometriosis has frustrated gynecologists, fascinated pathologists, and burdened patients for years. Although endometriosis was first described in 1860, the classic studies by Sampson in the 1920s were the first to emphasize the clinical and pathologic correlations of endometriosis. Even today, many aspects of the disease remain enigmatic. By definition, endometriosis is the presence and growth of the glands and stroma of the lining of the uterus in an aberrant or heterotopic location. Adenomyosis is the growth of endometrial glands and stroma into the uterine myometrium to a depth of at least 2.5 mm from the basalis layer of the endometrium. Adenomyosis is sometimes termed internal endometriosis; however, this is a semantic misnomer because most likely they are separate diseases. It is usually stated that the incidence of endometriosis has been increasing since the 1980s. This “opinion” is secondary to an enlightened awareness of mild endometriosis as diagnosed by the increasing use of laparoscopy. Since the early 2000s, diagnostic delay, the average time to the first diagnosis of the disease, has decreased dramatically. However, it has been estimated to take an average time of 11.7 years in the United States and 8 years in the United Kingdom to make the diagnosis. Evers has advanced a provocative hypothesis that endometrial implants in the peritoneal cavity are a physiologic finding secondary to retrograde menstruation, and their presence does not confirm a disease process. The prevalence of pelvic endometriosis in the general female population has been suggested to be 6% to 10%. The age specific incidence or prevalence of endometriosis is not known and has only been estimated. Many patients are diagnosed incidentally during surgery performed for a variety of other indications. Conservative estimates find that endometriosis is present in 5% to 15% of laparotomies performed on reproductive-age females. The prevalence of active endometriosis is approximately 33% in women with chronic pelvic pain. The incidence of endometriosis is 30% to 45% in women with infertility. Over one year of observation, it has been found that 17% to 29% of lesions may resolve spontaneously, whereas 24% to 64% progress, and 9% to 59% do not change. The cause of endometriosis is uncertain and involves many mechanisms including retrograde menstruation, vascular dissemination, metaplasia, genetic

5% of women with endometriosis are diagnosed following menopause. However. The clinical variability in responses among women with endometriosis may relate to . and has symptoms of secondary dysmenorrhea and pelvic pain. and widely disseminating. immunologic changes. pelvic lesions of endometriosis have been found to have positive immunostaining for smooth muscle as well as nerve cells. and hormonal influences. the use of contraceptive steroids of various doses is usually beneficial for treatment. Although the growth of ectopic endometrium is stimulated by physiologic levels of estrogen. However. the disease is most commonly found during the reproductive years. it is most difficult to predict the natural course of endometriosis in any one individual. there is increasing evidence that environmental factors may also play a role. invasive. especially in retroperitoneal spaces. it is locally infiltrative. In addition. Aberrant endometrial tissue grows under the cyclic influence of ovarian hormones and is particularly estrogen dependent. Another contrast often noted is the inverse relationship between the extent of pelvic endometriosis and the severity of pelvic pain. Postmenopausal endometriosis is usually stimulated by exogenous estrogen. therefore. For example. Clinically. It is a benign disease. Endometriosis in teenagers should be investigated for obstructive reproductive tract abnormalities that increase the amount of retrograde menstruation. as discussed later. as would be expected. including exposure to dioxin and other endocrine disruptors. whereas other patients with minimal implants may have incapacitating chronic pelvic pain. However. The classic symptom of endometriosis is pelvic pain. endometriosis has been found in approximately half the cases.predisposition. Although previously thought to be rare in adolescents.” The diagnosis and treatment of infertility associated with endometriosis is discussed in Chapter 41 (Infertility). women with deep infiltrating endometriosis. in teens with pelvic pain. Recently. but it must be stressed that symptoms and signs may be extremely variable. Endometriosis is a disease not only of great individual variability but also of contrasting pathophysiologic processes. Women with extensive endometriosis may be asymptomatic. in clinical practice the majority of cases are not “classic. the clinician cannot know which woman with mild disease in her 20s will progress to severe disease at a later age. yet it has the characteristics of a malignancy—that is. is nulliparous and involuntarily infertile. The typical patient with endometriosis is in her mid-30s. often experience severe episodes of pain.

Metaplasia In contrast to the theory of seeding from retrograde menstruation is the theory that endometriosis arises from metaplasia of the coelomic epithelium or proliferation of embryonic rests. there is only speculation as to why some women develop endometriosis and others do not. no single theory adequately explains all the manifestations of the disease.differences in immunologic function and variations in cytokine production. reflux of menstrual blood and viable endometrial cells in the pelvis of ovulating women has been documented. Sampson suggested that pelvic endometriosis was secondary to implantation of endometrial cells shed during menstruation. The decidual reaction of isolated areas of peritoneum during pregnancy is an example of this process. The Mullerian duct is derived from the coelomic epithelium during fetal development. Retrograde Menstruation The most popular theory is that endometriosis results from retrograde menstruation. Most important. The attachment of the shed endometrial cells involves the expression of adhesion molecules and their receptors. Endometriosis is frequently found in women with outflow obstruction of the genital tract. The metaplasia hypothesis postulates that the coelomic epithelium retains the ability for multipotential development. . Endometriosis is discovered most frequently in areas immediately adjacent to the tubal ostia or in the dependent areas of the pelvis. This is thought to be an extremely rapid process as demonstrated in vitro. ETIOLOGY There are several theories to explain the pathogenesis of endometriosis. The Mullerian ducts and nearby mesenchymal tissue form the majority of the female reproductive tract. Figures 19-1 and 19-2 depict the process of implants from retrograde menstruation and early invasion. However. These cells attach to the pelvic peritoneum and under hormonal influence grow as homologous grafts. Indeed. One popular theory is that there is a complex interplay between a dose-response curve of the amount of retrograde menstruation and an individual woman’s immunologic response.

the posterior aspects of the broad ligament. These examples support the coelomic metaplasia theory. The hypothesis is that endometrial glands and stroma are implanted during the procedure. Similarly. unanswered questions concerning the pathophysiology of endometriosis is that some women with retrograde menstruation develop endometriosis.It is well known that the surface epithelium of the ovary can differentiate into several different histologic cell types. Metaplasia occurs after an “induction phenomenon” has stimulated the multipotential cell. and very rarely in men. and the cul-de-sac (Fig. Endometriosis has been discovered in prepubertal girls. Hematogenous dissemination of endometrium is the best theory to explain endometriosis of the forearm and thigh. as well as multiple lesions in the lung. The induction substance may be a combination of menstrual debris and the influence of estrogen and progesterone. Batt and Smith have hypothesized that the histogenesis of endometriosis in peritoneal pockets of the posterior pelvis results from a congenital anomaly involving rudimentary duplication of the Mu¨ llerian system. women with congenital absence of the uterus. Endometriosis has been observed in the pelvic lymph nodes of approximately 30% of women with the disease. such as the spinal column and nose. 193). Rarely. Nisolle and Donnez have postulated that metaplasia of the coelomic epithelium that invaginates into the ovarian cortex is the pathogenesis for the development of ovarian endometriosis. Iatrogenic Dissemination Endometriosis of the anterior abdominal wall is sometimes discovered in women after a cesarean delivery. Immunologic Changes One of the most perplexing. The aberrant tissue is found subcutaneously at the abdominal incision. . Lymphatic and Vascular Metastasis The theory of endometrium being transplanted via lymphatic channels and the vascular system helps to explain rare and remote sites of endometriosis. The peritoneal pockets that they describe are found in the posterior pelvis. iatrogenic endometriosis may be discovered in an episiotomy scar.

and there is evidence for upregulation of aromatase activity.but most do not. Whether endometriosis is an autoimmune disease has been intensely debated for many years. It has been hypothesized that women who do not develop endometriosis have monocytic-type macrophages in their peritoneal fluid that have a short life span and limited function. increased Cox-2 expression. peritoneal fluid of women with endometriosis has less influence of NK activity than is found in fertile women without endometriosis. platelet-derived growth factor (PDGF). Studies have demonstrated abnormalities in cellmediated and humoral components of the immune system in both peripheral blood and peritoneal fluid. This chemoattractant protein enhanced local production of interleukin-6 (IL-6) self-perpetuates lesion/cytokine interactions. Here the expression of basic fibroblast factor. and dysregulation of 17b-dehydrogenase activity. and vascular endothelial growth factor (VEGF) are all increased. Further compounding the proliferative activity of endometriosis lesions are angiogenic factors that are increased in lesions. Another attractive theory is the recent finding of a protein similar to haptoglobin in endometriosis epithelial cells called Endo 1. 19-4). Most likely the primary immunologic change involves an alteration in the function of the peritoneal macrophages so prevalent in the peritoneal fluid of patients with endometriosis. Changes in the expression of integrins also may be an important local factor. These hyperactive cells secrete multiple growth factors and cytokines that enhance the development of endometriosis. Estrogen production is enhanced locally. which are chemotactic cytokines (Fig. Following the theory of different macrophage populations in endometriosis is the finding that the destroying of normally extruded endometrial cells in endometriosis may be deficient. It has been shown that natural killer (NK) cells have decreased cytotoxicity against endometrial and hematopoietic cells in women with endometriosis. Conversely. where there is a . Also. The attraction of leukocytes to specific areas is controlled by chemokines. IL-8. Steroid interactions also enhance the progression of disease. women who develop endometriosis have more peritoneal macrophages that are larger. Multiple investigations have suggested that changes in the immune system. are directly related to the pathogenesis of endometriosis. IL-6. especially altered function of immune-related cells. Table 19-1 depicts various cytokines and growth factors that have been implicated in the pathogenesis of endometriosis.

and IgM) autoantibodies in endometriosis. there are reports of increased B and T cells.deficiency in 17b-dehydrogenase II activity and possibly an enhancement of type II activity favoring local estradiol production. Further. Women who have a family history of endometriosis are likely to develop the disease earlier in life and to have more advanced disease than women whose first-degree relatives are free of the disease. The local production of estrogen through aromatase activity explains why progression of lesions may occur even with ovarian suppression. An investigation by Simpson and coworkers demonstrated a sevenfold increase in the incidence of endometriosis in relatives of women with the disease compared with controls. in women with endometriosis . Recent studies have identified deletions of genes. and HSD 17b2 in disease free women. has been thought to be 7%. Genetic Predisposition Several studies have documented a familial predisposition to endometriosis with grouping of cases of endometriosis in mothers and their daughters. Autoimmunity may well exist in women with endometriosis. A survey of the U. and although the finding of abnormalities of the histocompatibility locus antigen (HLA) system have not been consistent.S. and endometrium and ectopic lesions in women with endometriosis where high local concentrations of estrogen and prostaglandin E2 predominate. and serum immunoglobulin (IgG. The latter propensity may be on a genetic basis. women with severe endometriosis. The association of all these immune processes in the symptoms and signs of endometriosis is depicted in Figure 19-7. most specifically increased heterogenicity of chromosome 17 and aneuploidy. there is evidence for progesterone “resistance” (Fig. This is occasioned by a dysregulation of the isoform B of the progesterone receptor in most endometriotic lesions where levels may be undetectable. One of 10 women with severe endometriosis will have a sister or mother with clinical manifestations of the disease. 19-6). Endometriosis Association has provided suggestive evidence of the higher prevalence of other autoimmune diseases. The incidence of endometriosis in first-degree relatives. IgA. Enhanced aromatase activity appears to be the result of overexpression of the orphan nuclear receptor steroidogenic factor-1 (SF-1) in lesions. Figure 19-5 shows abnormalities of Cox-2. aromatase. as discussed later on.

Although no consistent abnormality has been found in women with endometriosis. represent a more progressive form of the disease. Reflux of MMPs into the peritoneal cavity at menstruation may contribute to peritoneal attachment in susceptible women. being involved in two of three women with endometriosis. The expression of this genetic liability most likely depends on an interaction with environmental and epigenetic factors. the matrix metalloproteinases (MMPs) and integrins. including the ovary. Pelvic lymph nodes have been found to be involved in up to 30% of cases. Several of these aberrantly expressed gene products. Distinguishing superficial implant lesions on peritoneal surfaces. In most of these women the involvement is bilateral. Table 19-2 provides a list of genes and gene products aberrantly expressed in endometriosis. Loci on 9q and 10q have also been found to increase the susceptibility for endometriosis. there are several candidate genes. 19-8). metaplasia). Bulun and others have suggested that genetic predisposition. and the uterosacral. Deep lesions. The cervix. which may exist in infertile women with endometriosis. Preliminary data suggest some bilateral ovarian endometrial cysts may arise independently from different clones. which increase the risk of developing endometriosis. and broad ligaments are also common sites where endometriosis develops. penetrations of greater than 5 mm.compared with controls. for example. from deep endometriotic ovarian cysts and cul-de-sac modules is important for therapy (discussed later on) in that these latter abnormalities may suggest different causes of the disease (e. vagina. which require a surgical . Brosens has emphasized the importance of distinguishing between superficial and deep lesions of endometriosis. round. have important implications for endometrial lesion attachment and for implantation defects. The pelvic peritoneum over the uterus. or exposure to environmental factors (toxics). Pathology The majority of endometrial implants are located in the dependent portions of the female pelvis (Fig. the anterior and posterior cul-de-sac..g. The ovaries are the most common site. and vulva are other possible pelvic locations. Finally. may program fetal progenitor cells in an epigenetic way to overexpress SP1 and estrogen receptor b.

and associated inflammatory and fibrotic changes. by histologic and biochemical studies. but on histologic examination are not. More emphasis has been placed on biopsy confirmation of endometriosis because of increasing awareness of subtle lesions. endometriosis of the bowel may be difficult to differentiate grossly from a primary neoplasm of the large intestine. brown. including the umbilicus. arms. bleblike implants that are less than 1 cm in diameter. and splenosis. breast cancer. yellow. Walthard’s rest. ovarian cancer. peritoneal inflammation. ureter.approach. to be the most active phase of the disease (see Fig. clear. 19-9). areas of previous surgical incisions of theanterior abdominal wall or perineum. or a red vesicle. The predominant color depends on the blood supply and the amount of hemorrhage and fibrosis. size. Endometriosis may be found in a wide variety of sites. kidney. Other peritoneal lesions that grossly appear similar to endometriosis. the bladder. Red. degree of edema. non-hemorrhagic lesions. hemangiomas. Depending on the amount of associated scarring. Figure 19-9 depicts the spectrum of lesions with black and white lesions reflecting older lesions with inflammatory and fibrotic changes. Approximately 10% to 15% of women with advanced disease have lesions involving the rectosigmoid. The gross appearance of the implant depends on the site. blood-filled lesions have been shown. New lesions are small. Gross pathologic changes of endometriosis exhibit wide variability in color. psammoma bodies. The color also appears related to the size of the lesion. The visual manifestations of endometriosis in the female pelvis are protean and have many appearances. black. and chronicity of the area involved. peritoneal reactions to oil-based hysterosalpingogram dye. pink. Recently. epithelial inclusions. Increased awareness and anticipation have focused on the subtle lesions of endometriosis. Initially these areas are raised above the surrounding tissues. relationship to the day of the menstrual cycle. fibrotic reactions to suture. and even the male urinary tract (Table19-3). activity. residual carbon from laser surgery. include necrotic areas of an ectopic pregnancy. and the amount of inspissated material (Table 19-4). shape. white. The color of the lesion varies widely and may be red. adrenal rest. clinicians closely inspect the pelvic peritoneum to identify abnormal areas and small. With time the areas of endometriosis become larger and assume a light or dark brown color. legs. and they may be described as “powder burn” areas or . lung.

and hemorrhage into the adjacent tissue (Fig. The pattern of ovarian endometriosis is also variable. although it is likely that immune mechanisms are involved. Spontaneous regression or disappearance of active disease may occur and lesions may regress in approximately one quarter of cases. In the majority of cases. In approximately 25% of the cases of endometriosis. Also. The natural history of endometriosis is a subject of intense speculation. 19-10). Previous hemorrhage can be discovered by identifying large macrophages filled with hemosiderin near the periphery of the lesion.“chocolate cysts. have more intense scarring. The three cardinal histologic features of endometriosis are ectopic endometrial glands. These changes may or may not be in synchrony with the endometrial lining of the uterus. and are usually puckered or retracted from the surrounding tissue. ectopic endometrial stroma. Larger cysts are usually densely adherent to the surrounding pelvic sidewalls or broad ligament. viable endometrial glands and stroma cannot be identified. The ectopic endometrial stroma will undergo classic decidual changes similar to pregnancy when exposed to high physiologic or pharmacologic levels of progesterone. a presumptive diagnosis of endometriosis is made by visualizing the intense inflammatory reaction and the large macrophages filled with blood pigment. Individual areas range from 1 mm to large chocolate cysts greater than 8 cm in diameter (Fig. The associated adhesions may be filmy or dense. . but in reality is not known. The pathophysiology of progression from subtle endometriosis to severe disease may be expected from the multiple mechanisms of potential disease acceleration discussed earlier. White or mixed colored lesions are more likely to provide histologic confirmation of endometriosis. the progression from red to white lesions also seems to correlate with age. 19-11). Repetitive episodes of hemorrhage may lead to severe inflammatory changes and result in the glands and stroma undergoing necrobiosis secondary to pressure atrophy or lack of blood supply. In these cases. the aberrant endometrial glands and stroma respond in cyclic fashion to estrogen and progesterone.” The older lesions are white.