Key points
- •
Endometriosis is a benign, usually progressive, and sometimes recurrent disease that invades locally and disseminates widely. Causes include retrograde menstruation, coelomic metaplasia, vascular metastasis, immunologic changes, iatrogenic dissemination, and a genetic predisposition.
- •
Endometriosis lesions produce estrogen locally and have increased secretion of prostaglandins and inflammatory cytokines, which can cause pain and contribute to infertility. There is also a relative resistance to progesterone in endometriosis lesions.
- •
There are several established treatments for endometriosis (such as oral contraceptives, gonadotropin-releasing hormone [GnRH] agonists, and danazol) and some novel therapies undergoing trials such as the use of oral antagonists, aromatase inhibitors, progesterone receptor modulators, and cytokine inhibitors. The recurrence rate after medical therapy is 5% to 15% in the first year and increases to 40% to 50% in 5 years.
- •
The recurrence rate after medical therapy is 5% to 15% in the first year and increases to 40% to 50% in 5 years.
- •
The incidence of endometriosis is 30% to 45% in women with infertility. There is probably some benefit to ablating endometriosis lesions when seen at laparoscopy. In patients with endometriosis, the success of in vitro fertilization–embryo transfer (IVF-ET) decreases only in women with severe disease.
- •
Endometriosis is a benign, usually progressive, and sometimes recurrent disease that invades locally and disseminates widely. Causes include retrograde menstruation, coelomic metaplasia, vascular metastasis, immunologic changes, iatrogenic dissemination, and genetic predisposition.
- •
Endometriosis lesions produce estrogen locally and have increased secretion of prostaglandins and inflammatory cytokines, which can cause pain and contribute to infertility. Endometriosis lesions also have a relative resistance to progesterone.
- •
There are several established treatments for endometriosis (such as oral contraceptives and gonadotropin-releasing hormone agonists and danazol) and some novel therapies undergoing trials, such as the use of oral antagonists, aromatase inhibitors, progesterone receptor modulators, and cytokine inhibitors. The recurrence rate after medical therapy is 5% to 15% in the first year, increasing to 40% to 50% in 5 years.
- •
The recurrence rate after medical therapy is 5% to 15% in the first year, increasing to 40% to 50% in 5 years.
- •
The incidence of endometriosis is 30% to 45% in women with infertility. There is probably some benefit to ablating endometriosis lesions when seen at laparoscopy. In patients with endometriosis, the success of IVF-ET decreases only in women with severe disease.
Endometriosis: Overview
Endometriosis is a benign but, in many women, progressive and aggressive disease, with a major impact on the quality of women’s lives and creating a significant economic burden of billions of dollars. 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 often stated that the incidence of endometriosis has been increasing, but this is likely secondary to an enlightened awareness of mild endometriosis as diagnosed by the increasing use of laparoscopy. Delay in making the diagnosis is common; 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 overall prevalence of endometriosis in reproductive-age women has been suggested to be as high as 11% ( ). 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 female patients. Active endometriosis may be found in approximately three-quarters of women with chronic pelvic pain and in 30% to 45% of women with subfertility . In subfertile women the diagnosis is not commonly made because diagnostic laparoscopy is rarely carried out. In a compilation of eight studies encompassing 162 patients with endometriosis, the natural course of endometriosis was reported to increase or progress in 31% of cases , to remain the same in 32%, and to regress in 38%.
The cause of endometriosis is uncertain and involves many mechanisms including retrograde menstruation, vascular dissemination, metaplasia, genetic predisposition, immunologic changes, and hormonal influences, as discussed later. In addition, there is increasing evidence that environmental factors may also play a role, including exposure to dioxin and other endocrine disruptors. Clinically it is most difficult to predict the natural course of endometriosis in any one individual.
The classic symptom of endometriosis is pelvic pain. However, in clinical practice the majority of cases are not “classic.” The diagnosis and treatment of infertility associated with endometriosis is discussed in Chapter 40 . Aberrant endometrial tissue grows under the cyclic influence of ovarian hormones and is particularly estrogen dependent; therefore the disease is most commonly found during the reproductive years. However, 5% of women with endometriosis are diagnosed after menopause. Postmenopausal endometriosis is usually stimulated by exogenous estrogen. Teenagers with endometriosis should be investigated for obstructive reproductive tract abnormalities that increase the amount of retrograde menstruation. Although previously thought to be rare in adolescents, endometriosis has been found in approximately half of teens with pelvic pain.
Endometriosis is a disease not only of great individual variability but also of contrasting pathophysiologic processes. There is an inverse relationship between the extent of pelvic endometriosis and the severity of pelvic pain . Women with extensive endometriosis may be asymptomatic, whereas other patients with minimal implants may have incapacitating chronic pelvic pain. However, as would be expected, women with deep infiltrating endometriosis (DIE), especially in retroperitoneal spaces, often experience severe episodes of pain. Pelvic lesions of endometriosis have been found to have positive immune staining for smooth muscle and nerve cells ( ). The clinical variability in responses among women with endometriosis may relate to differences in immunologic function and variations in cytokine production.
Etiology
Several theories have been posited to explain the pathogenesis of endometriosis, but no single theory adequately explains all the manifestations of the disease. Most important, there is only speculation as to why some women develop endometriosis and others do not. 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 (these in turn may depend on ethnic and genetic variability).
Retrograde menstruation
The most popular theory is that endometriosis results from retrograde menstruation. Sampson suggested that pelvic endometriosis was secondary to implantation of endometrial cells shed during menstruation ( ). It has been suggested that the shedding of endometrial-based adult stem cells and mesenchymal cells may explain this phenomenon ( ). These cells attach to the pelvic peritoneum and under hormonal influence grow as homologous grafts. Indeed, reflux of menstrual blood and viable endometrial cells in the pelvis of ovulating women has been documented. Endometriosis is discovered most often in areas immediately adjacent to the tubal ostia or in the dependent areas of the pelvis.
Endometriosis is commonly found in women with outflow obstruction of the genital tract. The attachment of the shed endometrial cells involves the expression of adhesion molecules and their receptors. This is thought to be an extremely rapid process as demonstrated in vitro. Figs. 19.1 and 19.2 depict the process of implants from retrograde menstruation and early invasion ( ; ).
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. The müllerian ducts and nearby mesenchymal tissue form the majority of the female reproductive tract. The müllerian duct is derived from the coelomic epithelium during fetal development. The metaplasia hypothesis postulates that the coelomic epithelium retains the ability for multipotential development. The decidual reaction of isolated areas of peritoneum during pregnancy is an example of this process. It is well known that the surface epithelium of the ovary can differentiate into several different histologic cell types. Endometriosis has been discovered in prepubertal girls, women with congenital absence of the uterus, and, rarely, in men. These examples support the coelomic metaplasia theory.
Metaplasia occurs after an “induction phenomenon” has stimulated the multipotential cell. The induction substance may be a combination of menstrual debris and the influence of estrogen and progesterone. It has been hypothesized that the histogenesis of endometriosis in peritoneal pockets of the posterior pelvis results from a congenital anomaly involving rudimentary duplication of the müllerian system ( ). The peritoneal pockets that they describe are found in the posterior pelvis, the posterior aspects of the broad ligament, and the cul-de-sac ( Fig. 19.3 ). Similarly, it has been postulated that metaplasia of the coelomic epithelium that invaginates into the ovarian cortex is the pathogenesis for the development of ovarian endometriosis ( ).
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, such as the spinal column and nose. Endometriosis has been observed in the pelvic lymph nodes of approximately 30% of women with the disease. Hematogenous dissemination of endometrium is the best theory to explain endometriosis of the forearm and thigh, as well as multiple lesions in the lung.
Iatrogenic dissemination
Endometriosis of the anterior abdominal wall is sometimes discovered in women after a cesarean delivery. The hypothesis is that endometrial glands and stroma are implanted during the procedure. The aberrant tissue is found subcutaneously at the abdominal incision. Rarely, iatrogenic endometriosis may be discovered in an episiotomy scar.
Immunologic changes
One of the most perplexing, unanswered questions concerning the pathophysiology of endometriosis is that some women with retrograde menstruation develop endometriosis, but most do not. Multiple investigations have suggested that changes in the immune system, especially altered function of immune-related cells, are directly related to the pathogenesis of endometriosis . Whether endometriosis is an autoimmune disease has been intensely debated for many years. Studies have demonstrated abnormalities in cell-mediated and humoral components of the immune system in both peripheral blood and peritoneal fluid. Box 19.1 depicts various cytokines and growth factors that have been implicated in the pathogenesis of endometriosis ( ).
Concentrations increased in endometriosis
Complement
Eotaxin
Glycodelin
IL-1
IL-6
IL-8
MCP-1
PDGF
RANTES
Soluble ICAM-1
TGF-β
VEGF
Concentrations unchanged in endometriosis
EGF
Basic FGF
Interferon-γ
IL-2
IL-4
IL-12
Concentrations decreased in endometriosis
IL-13
EGF, Epidermal growth factor; FGF, fibroblast growth factor; ICAM, intercellular adhesion molecule; IL, interleukin; MCP, membrane cofactor protein; PDGF, platelet-derived growth factor; RANTES, regulated on activation, normal T cell expressed and secreted; TGF, transforming growth factor; VEGF, vascular endothelial growth factor. References are from the original source.
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. 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. Conversely, women who develop endometriosis have more peritoneal macrophages that are larger. These hyperactive cells secrete multiple growth factors and cytokines that enhance the development of endometriosis. The attraction of leukocytes to specific areas is controlled by chemokines, which are chemotactic cytokines. Changes in the expression of integrins also may be an important local factor. 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. Also, peritoneal fluid of women with endometriosis has less influence of NK activity than is found in fertile women without endometriosis .
Another attractive theory is the finding of a protein similar to haptoglobin in endometriosis epithelial cells called endo-1. This chemoattractant protein–enhanced local production of interleukin-6 (IL-6) self-perpetuates lesion/cytokine interactions. Further compounding the proliferative activity of endometriosis lesions are angiogenic factors that are increased in lesions. Here the expression of basic fibroblast factor, IL-6, IL-8, platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF) are all increased (see Box 19.1 ).
Steroid interactions also enhance the progression of disease. Estrogen production is enhanced locally, and there is evidence for upregulation of aromatase activity , increased cyclooxygenase-2 (COX-2) expression, and dysregulation of 17β-dehydrogenase activity, where there is a deficiency in 17β-dehydrogenase II activity and possibly an enhancement of type II activity favoring local estradiol production ( ). Fig. 19.4 shows abnormalities of COX-2, aromatase, and 17β-hydroxysteroid dehydrogenase type 2 (HSD17B2) in disease-free women, and endometrium and ectopic lesions in women with endometriosis where high local concentrations of estrogen and prostaglandin E 2 predominate ( Fig. 19.5 ). Enhanced aromatase activity appears to be the result of overexpression of the orphan nuclear receptor steroidogenic factor-1 (SF-1) in lesions. The local production of estrogen through aromatase activity explains why progression of lesions may occur even with ovarian suppression. Further, there is evidence for progesterone “resistance” ( ) ( Fig. 19.6 ). This is occasioned by a dysregulation of the isoform B of the progesterone receptor in most endometriotic lesions, where levels may be undetectable. The latter propensity may be on a genetic basis, as discussed later.
Autoimmunity may well exist in women with endometriosis , and although the findings of abnormalities of the histocompatibility locus antigen system have not been consistent, there are reports of increased B and T cells and serum immunoglobulin (IgG, IgA, and IgM) autoantibodies in endometriosis. A survey from the U.S. Endometriosis Association has provided suggestive evidence of the higher prevalence of other autoimmune diseases . The association of all these immune processes in the symptoms and signs of endometriosis is depicted in Fig. 19.7 .
Genetic predisposition
Several studies have documented a familial predisposition to endometriosis with grouping of cases of endometriosis in mothers and their daughters. 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 ( ). One of 10 women with severe endometriosis will have a sister or mother with clinical manifestations of the disease. The genetic heritability of endometriosis has been estimated at 52% based on twin studies ( ). 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.
Endometriosis is clearly not a single-gene disease but rather polygenic, with various susceptibility factors discovered. Studies have identified deletions of genes, most specifically increased heterogenicity of chromosome 17 and aneuploidy, in women with endometriosis compared with controls ( ). Loci on 7p and 10q have also been found to increase the susceptibility for endometriosis. The expression of this genetic liability most likely depends on an interaction with environmental and epigenetic factors , with many factors being involved.
Epigenetic factors play a significant role and may be influenced by environmental factors ( ). The epigenetics involves hypomethylation of genes and may help explain, for example, the increased expression of SP1 leading to increased estrogen receptor (ER)β over ERα, which in turn leads to progesterone resistance in endometriosis.
Preliminary data suggest some bilateral ovarian endometrial cysts may arise independently from different clones. Although no consistent abnormality has been found in women with endometriosis, there are several candidate genes. Box 19.2 provides a partial list of genes and gene products aberrantly expressed in endometriosis.
Aromatase
Endometrial bleeding factor
Hepatocyte growth factor
17β-hydroxysteroid dehydrogenase
HOX A10
HOX A11
Leukemia inhibitory factor
Matrix metalloproteinases 3, 7, and 11
Tissue inhibitors of metalloproteinases
Progesterone-receptor isoforms
Complement 3
Glutathione peroxidase
Catalase
Thrombospondin 1
Vascular endothelial growth factor
Integrin α v β 3
Glycodelin
Several of these aberrantly expressed gene products, such as the matrix metalloproteinases (MMPs) and integrins, have important implications for endometrial lesion attachment and for implantation defects, which may exist in infertile women with endometriosis. Reflux of MMPs into the peritoneal cavity at menstruation may contribute to peritoneal attachment in susceptible women.
MicroRNAs have also been found to be involved (particularly the 9 and 34 families) and may be implicated in the pathogenesis as well. Also, the measurement of certain microRNAs has been suggested as a test for endometriosis, although there are no data to support this.
Certain ethnic groups have an increased risk of endometriosis. This is particularly striking in Asian women, in whom a ninefold increase has been suggested.
Pathology
The majority of endometrial implants are located in the dependent portions of the female pelvis ( Fig. 19.8 ). The ovaries are the most common site, being involved in two of three women with endometriosis. In most of these women the involvement is bilateral. The pelvic peritoneum over the uterus; the anterior and posterior cul-de-sac; and the uterosacral, round, and broad ligaments are also common sites where endometriosis develops. Pelvic lymph nodes have been found to be involved in up to 30% of cases.
The cervix, vagina, and vulva are other possible pelvic locations. Brosens has emphasized the importance of distinguishing between superficial and deep lesions of endometriosis ( ). Deep lesions, penetrations of greater than 5 mm, represent a more progressive form of the disease. Distinguishing superficial implant lesions on peritoneal surfaces, including the ovary, from deep endometriotic ovarian cysts and cul-de-sac nodules is important for therapy because the latter abnormalities may suggest different causes of the disease (e.g., metaplasia), which require a surgical approach.
Approximately 10% to 15% of women with advanced disease have lesions involving the rectosigmoid. Depending on the amount of associated scarring, endometriosis of the bowel may be difficult to differentiate grossly from a primary neoplasm of the large intestine. Endometriosis may be found in a wide variety of sites, including the umbilicus, areas of previous surgical incisions of the anterior abdominal wall or perineum, the bladder, ureter, kidney, lung, arms, legs, and even the male urinary tract ( Table 19.1 ).
| Common Sites | Rare Sites |
|---|---|
| Ovaries | Umbilicus |
| Pelvic peritoneum | Episiotomy scar |
| Ligaments of the uterus | Bladder |
| Sigmoid colon | Kidney |
| Appendix | Lungs |
| Pelvic lymph nodes | Arms |
| Cervix | Legs |
| Vagina | Nasal mucosa |
| Fallopian tubes | Spinal column |
Gross pathologic changes of endometriosis exhibit wide variability in color, shape, size, and associated inflammatory and fibrotic changes. The visual manifestations of endometriosis in the female pelvis are protean and have many appearances. Increased awareness and anticipation have focused on the subtle lesions of endometriosis. Clinicians closely inspect the pelvic peritoneum to identify abnormal areas and small, nonhemorrhagic lesions. More emphasis has been placed on biopsy confirmation of endometriosis because of increasing awareness of subtle lesions. The gross appearance of the implant depends on the site, activity, relationship to the day of the menstrual cycle, and chronicity of the area involved. The color of the lesion varies widely and may be red, brown, black, white, yellow, pink, clear, or a red vesicle. The predominant color depends on the blood supply and the amount of hemorrhage and fibrosis. The color also appears related to the size of the lesion, the degree of edema, and the amount of inspissated material ( Table 19.2 ). Fig. 19.9 depicts the spectrum of lesions with black and white lesions reflecting older lesions with inflammatory and fibrotic changes. Other peritoneal lesions that grossly appear similar to endometriosis, but on histologic examination are not, include necrotic areas of an ectopic pregnancy, fibrotic reactions to suture, hemangiomas, adrenal rest, Walthard rest, breast cancer, ovarian cancer, epithelial inclusions, residual carbon from laser surgery, peritoneal inflammation, psammoma bodies, peritoneal reactions to oil-based hysterosalpingogram dye, and splenosis.
| Symptom | No. of Patients | (%) |
|---|---|---|
| Pelvic pain | 111 | (85) |
| Rectal pain | 68 | (52) |
| Cyclic rectal bleeding | 24 | (18) |
| Diarrhea | 55 | (42) |
| Constipation | 53 | (41) |
| Diarrhea and constipation | 18 | (14) |
| Dyspareunia | 83 | (64) |
New lesions are small, bleblike implants that are less than 1 cm in diameter. Initially these areas are raised above the surrounding tissues. Red, blood-filled lesions have been shown, by histologic and biochemical studies, to be the most active phase of the disease ( Fig. 19.9 ). With time, the areas of endometriosis become larger and assume a light or dark brown color, and they may be described as “powder burn” areas or “chocolate cysts.” The older lesions are white, have more intense scarring, and are usually puckered or retracted from the surrounding tissue. White or mixed-colored lesions are more likely to provide histologic confirmation of endometriosis. Also, the progression from red to white lesions also seems to correlate with age.
The pattern of ovarian endometriosis is also variable. Individual areas range from 1 mm to large chocolate cysts greater than 8 cm in diameter ( Fig. 19.10 ). The associated adhesions may be filmy or dense, and larger cysts are usually densely adherent to the surrounding pelvic sidewalls or broad ligament.
The three cardinal histologic features of endometriosis are ectopic endometrial glands, ectopic endometrial stroma, and hemorrhage into the adjacent tissue ( Fig. 19.11 ). Previous hemorrhage can be discovered by identifying large macrophages filled with hemosiderin near the periphery of the lesion. In the majority of cases, the aberrant endometrial glands and stroma respond in cyclic fashion to estrogen and progesterone. These changes may or may not be in synchrony with the endometrial lining of the uterus. The ectopic endometrial stroma will undergo classic decidual changes similar to pregnancy when exposed to high physiologic or pharmacologic levels of progesterone.
In approximately 25% of cases of endometriosis, viable endometrial glands and stroma cannot be identified . 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 a presumptive diagnosis of endometriosis is made by visualizing the intense inflammatory reaction and the large macrophages filled with blood pigment.
The natural history of endometriosis has been discussed, and although clinicians usually think of endometriosis as a progressive disease, this is not always the case; it has been shown to be progressive only about one-third of the time. The pathophysiology of progression from subtle endometriosis to severe disease may be expected from the multiple mechanisms of potential disease acceleration discussed earlier, with immune function most likely involved.
Clinical diagnosis
Symptoms
It is important to reemphasize that endometriosis has many clinical presentations, with one in three women being asymptomatic . Most important, the disease has an extremely unpredictable course. The classic symptoms of endometriosis are cyclic pelvic pain and infertility. The chronic pelvic pain usually presents as secondary dysmenorrhea or dyspareunia (or both). Secondary dysmenorrhea usually begins 36 to 48 hours before the onset of menses. However, approximately one-third of patients with endometriosis are asymptomatic, with the disease being discovered incidentally during an abdominal operation or visualized at laparoscopy for an unrelated problem. Conversely, endometriosis is discovered in at least one of three women whose primary symptom is chronic pelvic pain .
Clinicians have appreciated the paradox that the extent of pelvic pain is often inversely related to the amount of endometriosis in the female pelvis. Women with large, fixed adnexal masses sometimes have minor symptoms, whereas other patients with only a few small foci with deep infiltration may experience moderate to severe chronic pain. The cyclic pelvic pain is related to the sequential swelling and the extravasation of blood and menstrual debris into the surrounding tissue. The chemical mediators of this intense sterile inflammation and pain are believed to be prostaglandins and cytokines. Infiltrative endometriosis, which involves extensive areas of the retroperitoneal space, often is associated with moderate to severe pelvic pain. Studies of pain mapping by laparoscopy under minimal sedation have found that pelvic pain arises from areas of normal peritoneum adjacent to areas of endometriosis.
Secondary dysmenorrhea is a common component of pain that varies from a dull ache to severe pelvic pain. It may be unilateral or bilateral and may radiate to the lower back, legs, and groin. Patients often complain of pelvic heaviness or a perception of their internal organs being swollen. Unlike primary dysmenorrhea, the pain may last for many days, including several days before and after the menstrual flow.
The dyspareunia associated with endometriosis is described as pain deep in the pelvis. The cause of this symptom seems to be immobility of the pelvic organs during coital activity or direct pressure on areas of endometriosis in the uterosacral ligaments or the cul-de-sac. Sometimes patients describe areas of point tenderness. The acute pain, experienced during deep penetration, may continue for several hours after intercourse.
Abnormal bleeding is a symptom noted by 15% to 20% of women with endometriosis . The most common complaints are premenstrual spotting and menorrhagia . Usually this abnormal bleeding is not associated with anovulation and may be related to abnormalities of the endometrium. On the other hand, patients with endometriosis often have ovulatory dysfunction. Approximately 15% of women with endometriosis have coincidental anovulation or luteal dysfunction.
An increased incidence of first-trimester abortion in women with untreated endometriosis has been reported, although this notion has been challenged and remains an unproven association. Less common, yet troublesome, are the symptoms resulting from endometriosis influencing the gastrointestinal and urinary tracts . Cyclic abdominal pain, intermittent constipation, diarrhea, dyschezia, urinary frequency, dysuria, and hematuria are all possible symptoms. Bowel obstruction and hydronephrosis may occur. One rare clinical manifestation of endometriosis is catamenial hemothorax , which is bloody pleural fluid occurring during menses. Massive ascites is a rare symptom of endometriosis. This is important because the disease process initially masquerades as ovarian carcinoma.
Clinical findings (physical examination)
The classic pelvic finding of endometriosis is a fixed retroverted uterus, with scarring and tenderness posterior to the uterus. The characteristic nodularity of the uterosacral ligaments and cul-de-sac may be palpated on rectovaginal examination in women with this distribution of the disease. Advanced cases have extensive scarring and narrowing of the posterior vaginal fornix. The ovaries may be enlarged and tender and are often fixed to the broad ligament or lateral pelvic sidewall. The adnexal enlargement is rarely symmetric, as one may expect in some benign pelvic conditions. Speculum examination may demonstrate small areas of endometriosis on the cervix or upper vagina. Lateral displacement or deviation of the cervix is visualized or palpated by digital examination of the vagina and cervix in approximately 15% of women with moderate or severe endometriosis. Carrying out a pelvic examination during the first or second day of menstrual flow may aid in the diagnosis because it is the time of maximum swelling and tenderness in the areas of endometriosis. The diagnosis can be confirmed in most cases by direct laparoscopic visualization of endometriosis with its associated scarring and adhesion formation. In many patients, endometriosis was discovered for the first time during an infertility investigation, although routine laparoscopy is no longer being carried out in the infertility investigation. Biopsy of selected implants confirms the diagnosis.
Imaging
Imaging can be a useful adjunct to the clinical presentation and physical examination for evaluation of endometriosis, especially with DIE.
Ultrasound examination shows no specific pattern to screen for pelvic endometriosis but may be helpful in differentiating solid from cystic lesions and may help distinguish an endometrioma from other adnexal abnormalities. Because the lesions are vascular, increased Doppler flow may be demonstrated in endometriosis ( Fig. 19.12 ). More recent studies have demonstrated a fair sensitivity from 49% to 91%, with high specificity (93% to 100%) when using transvaginal ultrasound (TVUS) to detect DIE, with the greatest sensitivity and specificity for detection of rectosigmoid lesions. Modified techniques such as rectal water contrast TVUS can increase the probability of detecting a DIE lesion and are now considered to be the more sensitive technique for the diagnosis of DIE .
Magnetic resonance imaging (MRI) provides the best overall diagnostic tool for endometriosis but is not always a practical modality for its diagnosis. With a detection ratio and specificity of around 78% for implants, MRI for endometriosis has a reported sensitivity and specificity of approximately 91% to 95%. There is a characteristic hyperintensity on T1-weighted images and a hypointensity on T2-weighted images ( ).
Endometrial biopsy
In part because the endometrium of women with endometriosis shows abnormal features such as enhanced aromatase expression and progesterone resistance, it has been suggested that an endometrial biopsy may aid in the outpatient diagnosis of endometriosis. One such candidate marker is B-cell lymphoma 6 (BCL6), which is only minimally expressed in the normal secretory endometrium of women without endometriosis; however, enhanced expression of BCL6 has been found in the eutopic endometrium of women with endometriosis . Using an immunochemical staining score for BCL6, the receive operating characteristic (ROC) curve showed a sensitivity of about 94% ( ). Although there is a commercially available test for this marker, it is still not universally accepted.
Diagnostic laparoscopy
Laparoscopy remains the gold standard for the diagnosis of endometriosis . When laparoscopy is undertaken to establish the diagnosis of endometriosis, it is important to describe systematically the extent of the pathology. The American Society for Reproductive Medicine (ASRM) developed a point-scoring system in 1996 designed primarily to record the extent of the disease in fertility patients ( ). The focus was intended to provide characterization of disease extent for fertility and not for pain assessment. Nevertheless, there are no data supporting this correlation of scoring with pregnancy rates. Another classification system, ENZIAN, is more recent and may be helpful for the classification of deep pelvic endometriosis ( ). In addition, the Endometriosis Fertility Index (EFI), a proposed scoring system by Adamson focused on the fertility potential of patients with endometriosis, has been shown in prospective evaluation to correlate with pregnancy rates ( ). For example, patients with a low score of 0.3 were shown to have a 3-year cumulative pregnancy rate of only 10% to 11%.
Figs. 19.13 and 19.14 illustrate ultrasound and MRI findings in retrocervical endometriosis and endometriosis infiltrating the bowel.
Although a benign disease, endometriosis exhibits characteristics of both malignancy and sterile inflammation. Therefore the common considerations in the differential diagnosis include chronic pelvic inflammatory disease, ovarian malignancy, degeneration of myomas, hemorrhage or torsion of ovarian cysts, adenomyosis, primary dysmenorrhea, and functional bowel disease.
Occasionally a large endometrioma of the ovary may rupture into the peritoneal cavity. This results in an acute surgical condition of the abdomen and brings into the differential diagnosis conditions such as ectopic pregnancy, appendicitis, diverticulitis, and a bleeding corpus luteum cyst.
Monitoring the course of disease: Are there markers?
Serial pelvic examinations are a poor indicator of progression of disease. Serum levels of CA-125 have been used as a marker for endometriosis. CA-125 levels are elevated in most patients with endometriosis and increases incrementally with advanced stages. However, assays for serum levels of CA-125 have a low specificity because they also increase with other pelvic conditions such as leiomyomas, acute pelvic inflammatory disease, and the first trimester of pregnancy. Similarly, serum CA-125 levels have a low sensitivity for the diagnosis of early or minimal endometriosis ( ).
Glycodelin, previously known as placental protein 14, has been shown to be elevated in endometriosis and is produced in endometriotic lesions. Levels also fall with removal of the disease. However, because of great variability in levels, glycodelin has not proved to be useful clinically. The most predictive markers appear to be IL-1, chemoattractant protein-1 and interferon gamma, with IL-1 being the most useful marker. There has been interest in proteomic analyses as well ( ).
Although it is generally thought that endometriosis improves during pregnancy, this is not always the case, and an increase in lesions has been documented, although primarily in the first trimester. Ovarian endometriomas, which may have a different pathogenetic origin from surface implants of endometriosis on the ovary, may persist during pregnancy, and they are at risk for rupture during pregnancy as well.
Endometriosis may be associated with ovarian cancer . Not only are lesions found at the time of diagnosis of ovarian cancer, but the risk of developing ovarian cancer may increase fourfold in women with endometriosis. Loss of heterozygosity and mutations in suppressor genes, such as P53 , may explain this association ( ). These findings warrant caution in the long-term follow-up of women who have extensive disease and ovarian endometriomas, particularly with large masses and those that increase in size.
The association of other cancers with endometriosis, although suggested, has not been substantiated. However, cervical endometriosis is a particular condition that can produce abnormalities in cervical cytologic test results.
Endometriosis is dependent on ovarian hormones to stimulate growth. With natural menopause, there is often a gradual relief of symptoms , and after surgical menopause, areas of endometriosis rapidly disappear. However, it is important to note that 5% of symptomatic cases of endometriosis present after menopause. The majority of cases in women in their late 50s or early 60s are related to the use of exogenous estrogen, which may stimulate existing lesions.
Treatment
The two primary short-term goals in treating endometriosis are the relief of pain and promotion of fertility. The primary long-term goal in the management of endometriosis is attempting to prevent progression or recurrence of the disease process, but there is a paucity of definitive, evidence-based literature to select the most appropriate method of treatment. A Cochrane review of evidence-based therapies lists a variety of agents that may be helpful but does not specify a clearly preferred agent. This is because there have been few prospective head-to-head comparisons and because the disease is heterogeneous, with vast differences in the spectrum of clinical symptoms and extent of disease from one woman to another. Therefore the treatment plan must be individualized . Choice of therapy, for women whose primary symptom is pelvic pain, depends on multiple variables, including the patient’s age, her future reproductive plans, the location and extent of her disease, the severity of her symptoms, and any associated pelvic pathologic conditions she may have. Although the gold standard for making a diagnosis is laparoscopy to establish the nature and extent of endometriosis, this is not always possible, particularly in a younger population. Imaging techniques may only be helpful if a mass is identified, and the suggestion of performing an endometrial biopsy may be too invasive for younger nulliparous woman. If other gynecologic conditions such as chronic pelvic inflammatory disease or neoplasia have been ruled out, empiric medical therapy for 3 months is a reasonable option . Various suppressive treatments (gonadotropin-releasing hormone [GnRH] analogs, oral contraceptives, progestins) and aromatase inhibitors and where they act in the pathophysiology of endometriosis may be found in Fig. 19.15 .
Treatment of endometriosis can be medical, surgical, or a combination of both. Most of the sex steroids, alone or in combination, have been tried in clinical studies to suppress the growth of endometriosis. Optimal regression secondary to medical treatment is observed in small endometriomas that are less than 1 to 2 cm in diameter. Response in larger areas of endometriosis may be minimal with medical therapy . A poor therapeutic result may be governed by the reduction of blood supply to the mass caused by surrounding scar tissue. Some data have suggested that with certain suppressive therapies, such as the use of dienogest, there is a decrease in nerve fiber density in endometriosis lesions.
Surgical therapy is divided into conservative and definitive operations. Conservative surgery involves the resection or destruction of endometrial implants, lysis of adhesions, and attempts to restore normal pelvic anatomy. Definitive surgery involves the removal of both ovaries, the uterus, and all visible ectopic foci of endometriosis. This type of surgery is analogous to cytoreductive surgery in ovarian carcinoma.
Medical therapy
Medical therapy is aimed at suppression of lesions and associated symptoms, particularly pain. This is best achieved by menstrual suppression, ideally without inducing hypoestrogenism. Unfortunately, once suppressive therapy is stopped, symptoms tend to recur at variable rates. The choice of medical therapy should be individualized, weighing in potential adverse effects, side effects, cost of therapy, and expected patient compliance. The clinical effectiveness, as measured by relief of symptoms and recurrence rates of current medical therapies, are largely similar. The recurrence rate after medical therapy is 5% to 15% in the first year and increases to 40% to 50% in 5 years ; obviously the chance of recurrence is directly related to the extent of initial disease.
In summary, medical therapy usually suppresses symptoms and prevents progression of endometriosis, but it does not provide a long-lasting cure of the disease. The recurrence rate in women who initially had minimal disease is approximately 35%, whereas in those women whose initial disease was severe the rate is approximately 75%. Although there are several medical therapies for endometriosis, the Food and Drug Administration (FDA) has approved only danazol , GnRH agonists, and elagolix, a GnRH antagonist . Other therapies include traditional oral contraceptives (OCs), novel progestogens such as gestrinone and dienogest, an oral GnRH antagonist, the levonorgestrel-releasing intrauterine system (IUS), the aromatase inhibitor letrozole, and certain selective progesterone receptor modulators.
Danazol
Although approved for use in the 1970s, clinicians rarely prescribe danazol (because of lack of familiarity, its side effect profile, and the availability of other agents) and most often select GnRH agonists, progestogens, or OCs. Danazol, an attenuated androgen that is active when given orally, is also prescribed for women with benign cystic mastitis, menorrhagia, and hereditary angioneurotic edema. Chemically it is a synthetic steroid that is the isoxazole derivative of ethisterone (17-α-ethinyltestosterone). Many years ago, oral androgens such as methyltestosterone were also used because they induce endometrial atrophy. Danazol produces a hypoestrogenic and hyperandrogenic effect on steroid-sensitive end organs. The drug is mildly androgenic and anabolic, leading to its side effect profile.
Danazol induces atrophic changes in the endometrium of the uterus and similar changes in endometrial implants. It has been suggested to also modulate immunologic function. Although doses of 400 to 800 mg of danazol have been prescribed, many clinicians reduce the total daily dosage of the drug to 200 mg, and even 100 mg, of danazol daily. Danazol is usually begun during menses (days 1 to 5). Because the relief of the symptoms is directly related to the incidence of amenorrhea, the lower dosages of danazol are not as effective. Side effects of the hormonal changes are encountered by 80%, and approximately 10% to 20% of women discontinue danazol because of side effects. There have been reports of deepening of the voice that did not resolve after discontinuation. Mild elevation in serum liver enzyme levels has been reported in women treated for endometriosis, and women who take danazol for longer than 6 months should have serum liver enzyme determinations. An androgenic effect on lipids occurs, with reduction in high-density lipoprotein (HDL) cholesterol and triglycerides and an increase in low-density lipoprotein (LDL) cholesterol.
The standard length of treatment with danazol is 6 to 9 months. Approximately three of four patients note significant improvement in their symptoms, and about 90% have objective improvement discovered at a second-look laparoscopy. The uncorrected fertility rate after danazol therapy is approximately 40%. Unfortunately, symptoms will recur in 15% to 30% of women within 2 years after therapy.
Several randomized, double-blind clinical studies have compared the therapeutic effectiveness of danazol with GnRH agonists. The results do not show significant differences between the efficacies of these two drugs.
Gonadotropin-releasing hormone agonists
Several GnRH agonists have been developed and approved for the treatment of endometriosis. Representative agonists are leuprolide acetate (Lupron, injectable), nafarelin acetate (Synarel, intranasal), and goserelin acetate (Zoladex, subcutaneous implant). The usual dose of leuprolide acetate is 3.75 mg intramuscularly once per month or an 11.25-mg depot injection every 3 months. Nafarelin acetate nasal spray is given in a dose of one spray (200 μg) in one nostril in the morning and one spray (200 μg) in the other nostril in the evening up to a maximum of 800 μg daily. Goserelin acetate is given in a dosage of 3.6 mg every 28 days in a biodegradable subcutaneous implant.
Studies have determined the dose-response curve of the GnRH agonists, establishing the optimal dose to produce sufficient downregulation and desensitization of the pituitary to produce extremely low levels of circulating estrogen and amenorrhea . Chronic use of GnRH agonists produces a “medical oophorectomy.” A dramatic reduction occurs in serum estrone, estradiol (E 2 ), testosterone, and androstenedione to levels similar to the hormonal levels in oophorectomized women. There are no significant changes in total serum cholesterol, HDL, or LDL levels during therapeutic periods as long as 6 months. Endometrial samples obtained after several months of chronic agonist therapy demonstrated either atrophic or an early proliferative endometrium.
The side effects associated with GnRH agonist therapy are primarily those associated with decreased estrogen, similar to menopause. The three most common symptoms are hot flushes, vaginal dryness, and insomnia. A decrease in bone mineral content has been demonstrated in the trabecular bone of the lumbar spine by quantitative computed tomography. This decrease in bone density is not seen in the compact bone of the distal radius. There is a decrease in measured bone mass of 2% to 7% during a 6-month course of agonist therapy. However, it has been established that the decrease in bone density associated with 6 months of therapy is completely recovered between 12 and 24 months.
The clinical response to agonist therapy depends on when the therapy is initiated as related to the menstrual cycle. If agonist therapy is begun during the follicular phase, an agonist phase results in an initial rapid rise in follicle-stimulating hormone (FSH) and E 2 for approximately 3 weeks. FSH levels fall to basal levels by the third to fourth week of therapy. E 2 levels rapidly decline after 21 days of therapy. The expected surge in luteinizing hormone (LH) does not occur, and serum progesterone levels do not become elevated. Amenorrhea is induced within 6 to 8 weeks. In contrast, when beginning agonist therapy during the luteal phase or if artificially manipulated by the concurrent administration of oral progestogen, serum E 2 levels are suppressed within 2 weeks. Amenorrhea is induced in 4 to 5 weeks. It is important to ensure that the patient is not pregnant when beginning GnRH agonist therapy during the luteal phase.
GnRH agonist therapy improves symptoms in 75% to 90% of patients with endometriosis , depending on the extent of the disease in the study group. Growth of endometriosis is arrested, diminished, or eliminated. The greatest therapeutic effects are seen when areas of endometriosis are less than 1 cm in diameter. Ovarian function usually returns to normal in 6 to 12 weeks after 6 months of GnRH agonist therapy . Large ovarian endometriomas and severe adhesive disease have not responded to hormonal therapy.
Many clinicians “add back” hormone replacement therapy with dosages similar to those used in menopausal therapy in combination with chronic GnRH agonist regimens. The clinical hypothesis is that the add-back medication will reduce or eliminate the vasomotor symptoms and vaginal atrophy and also diminish or overcome the demineralization of bone. Barbieri has suggested that there is a therapeutic window that he estimates is a circulating level of approximately 30 pg/mL of E 2 ( ). He postulated that this level of E 2 is enough to protect the body from substantial bone loss and is not high enough to interfere with the inhibition of growth of endometriosis ( Fig. 19.16 ). Multiple randomized trials have demonstrated that add-back therapy does not interfere with the effectiveness of agonists to relieve the pelvic pain from endometriosis. The majority of studies have also demonstrated no diminished therapeutic efficacy when add-back therapy is initiated simultaneously with the GnRH agonist. Some clinicians additionally give bisphosphonates and calcium with the low-dose progestins and estrogen, but bisphosphonates are not recommended in younger women who may wish to become pregnant. Add-back regimens not only reduce or eliminate adverse clinical and metabolic side effects associated with hypoestrogenism but also facilitate safe and effective prolongation of GnRH agonist therapy for up to 12 months. Additional agents that have been used for add-back therapy are tibolone and raloxifene.
