Robert S. Schenken
INTRODUCTION
Endometriosis is defined by the presence of endometrial glands and stroma outside the endometrial cavity and uterine musculature. The pelvis is the most common site of endometriosis, but endometriotic implants may occur nearly anywhere in the body. Although there are numerous theories to explain why women develop endometriosis, no one theory has been proven conclusively. Endometriosis is a common gynecologic problem in reproductive-age women who have pelvic pain, dyspareunia, or infertility. The management of endometriosis is controversial, but randomized clinical studies have substantiated some therapeutic approaches.
Pathogenesis
Several theories have been proposed to explain the histogenesis of endometriosis. The implantation theory proposes that endometrial tissue desquamated during menstruation passes through the fallopian tubes, where it gains access to and implants on pelvic structures. The incidence of retrograde menstruation is similar in women with and without endometriosis. Thus, the development of endometriosis could depend on the quantity of endometrial tissue reaching the peritoneal cavity, specific factors enhancing attachment of endometrial cells to the peritoneum and ovary, or the capacity of a woman's immune system to remove the refluxed menstrual debris.
The direct transplantation theory is the probable explanation for endometriosis that develops in episiotomy, cesarean section, and other scars following surgery. Endometriosis in locations outside the pelvis likely develops from dissemination of endometrial cells or tissue through lymphatic channels or blood vessels. The coelomic metaplasia theory proposes that the coelomic (peritoneal) cavity contains undifferentiated cells or cells capable of dedifferentiating into endometrial tissue. This theory is based on embryologic studies demonstrating that all pelvic organs, including the endometrium, are derived from the cells lining the coelomic cavity. The induction theory, an extension of the coelomic metaplasia theory, postulates that the refluxed endometrial debris releases a product that activates undifferentiated peritoneal cells to undergo metaplasia. There is no conclusive proof that peritoneum can undergo spontaneous or induced metaplasia.
Anatomic alternations of the pelvis that increase tubal reflux of menstrual endometrium increase a woman's chance of developing endometriosis. The incidence of endometriosis is increased in young women with genital tract obstructions that prevent expulsion of menses into the vagina and increase the likelihood of tubal reflux. Other studies have suggested that deficient cellular immunity results in an inability to recognize the presence of endometrial tissue in abnormal locations. Decreased natural killer cell activity resulting in decreased cytotoxicity to autologous endometrium has been reported in women with endometriosis. The presence of increased concentrations of leukocytes and their cytokine products in peritoneal fluid of women with endometriosis may play a role in the initiation and growth of the ectopic implants. The immune system clearly has an important, albeit unclear, role in the pathogenesis of endometriosis.
The possibility of a familial tendency for endometriosis has been recognized for several decades. If a patient has endometriosis, a first-degree female relative has a 7% likelihood of being affected similarly.
Epidemiology
The true prevalence of endometriosis in the general population is unknown. Estimates of its prevalence are based on visualization of the pelvic organs. Pelvic endometriosis is present in approximately 1% of women undergoing major surgery for all gynecologic indications, 6% to 43% of women undergoing sterilization, 12% to 32% when laparoscopy is performed to determine the cause of pelvic pain in reproductive-age women, and 21% to 48% of women undergoing laparoscopy for infertility. Endometriosis is found in 50% of teenagers undergoing laparoscopy for evaluation of chronic pelvic pain or dysmenorrhea.
The influence of age, socioeconomic status, and race on the prevalence of endometriosis remains controversial. The age at time of diagnosis is commonly 25 to 35 years, and endometriosis rarely is diagnosed in postmenopausal women. Many believe that endometriosis is more common in women of upper economic classes because they delay pregnancy, which is postulated to increase the risk of developing endometriosis. It is unknown whether this reflects a true increased incidence or results from greater access to medical care. Evidence indicates that blacks have a prevalence of endometriosis similar to that in whites when controlled for socioeconomic status.
Pathology
The most common sites of endometriosis, in decreasing order of frequency, are the ovaries, anterior and posterior cul-de-sac, posterior broad ligaments, uterosacral ligaments, uterus, fallopian tubes, sigmoid colon, appendix, and round ligaments. Other sites less commonly involved include the vagina, cervix, and rectovaginal septum. These latter lesions usually result from extension and invasion of posterior cul-de-sac implants. Uncommon locations include the inguinal canal, abdominal or perineal scars, ureters, urinary bladder, umbilicus, kidney, lung, liver, diaphragm, vertebrae, and extremities.
Macroscopic Appearance
Endometriotic implants have a variety of appearances. Superficial lesions on the ovarian or peritoneal surface are commonly reddish maculae or nodules similar in consistency to normal endometrium. These implants vary from 1 millimeter to several centimeters in size. Collection of hemosiderin results in yellow-brown or black discoloration (“powder-brown” lesions). Nonpigmented disease appears as whitish opacified peritoneum, translucent blebs, or pinkish polyploid implants. Scarring with retraction of adjacent peritoneum and peritoneal pockets may occur.
Endometriosis also may appear as a deeply infiltrative disease. Tumorlike masses form from invasion, and diffuse fibrosis usually develops in the posterior cul-de-sac, pelvic sidewall, or posterior broad ligament and ovary and may extend deep into the retroperitoneal space, occasionally constricting the ureter. Lesions in the cul-de-sac may invade the rectovaginal septum. The rectosigmoid and small bowel may become adherent to these areas. Endometriotic foci on the ovarian surface may develop a fibrous enclosure and manifest cyst formation as a result of accumulation of fluid and blood. These endometriotic cysts (endometriomas) vary from several millimeters to over 10 centimeters in size. Bleeding with menses gives the cyst a dark red or bluish hemorrhagic color. The degradation of blood pigment over time results in thick, tarry contents, hence the term chocolate cysts. Occasionally, the content changes to a yellow straw color or clear fluid. Filmy or dense fibroid adhesions from these cysts to the pelvic sidewall and fallopian tubes are common and may obscure visualization of the cyst.
Microscopic Appearance
Endometriosis is histomorphologically similar to eutopic endometrium. The four major components of endometriotic implants are endometrial glands, endometrial stroma, fibrosis, and hemorrhage. The relative amount of each component is highly variable and dependent, in part, on the age and location of the lesions. Identifying the endometrial elements in individual implants requires an adequate tissue specimen, proper orientation, and often serial sections of the specimen.
The endometrial glands in ectopic implants lack uniform size and shape. The glands may show normal cyclic change with mitotic figures and pseudostratification in response to estrogen, or vacuoles and intraluminal secretion in response to progesterone. The response to endogenous and exogenous hormones is inconsistent. This may imply differences in steroid hormone receptor content and function or a loss of the normal gland-stromal interaction. When glands are responsive, the epithelium becomes attenuated, and hemorrhage ensues at the time of menstruation.
The stromal cell morphologies of ectopic and eutopic endometrium are similar. Small arterioles, similar to the spiral arterioles of normal endometrium, usually are present in implants. Interstitial hemorrhage with accumulation of blood products and hemosiderin-laden macrophages is a frequent finding.
Fibrosis may occur in older endometriotic implants. This is very common in the lining of endometriomas, where the only histologic finding may be fibroblast proliferation and hemosiderin pigment deposition.
Symptoms
The common signs and symptoms of endometriosis are pelvic pain, dysmenorrhea, dyspareunia, abnormal uterine bleeding, and infertility. The type and severity of symptoms are dependent on the extent of disease, the location, and the organs involved. Even limited amounts of disease may cause significant symptomatology.
Endometriosis is present in approximately one third of patients with chronic pelvic pain. The pain may be described as crampy, dull, or sharp and usually increases around menses. The discomfort may be unilateral or bilateral, and many patients complain of rectal pressure or low backache. Acute abdominal pain may result from hemorrhage secondary to a ruptured endometrioma.
Dysmenorrhea is a more frequent complaint than dyspareunia. There is some correlation between the extent of disease and the severity of pain. The morphologic appearance of an endometriotic implant appears to be unrelated to pain symptomatology. Dyspareunia is more common in women with invasive endometriotic nodules in the cul-de-sac, uterosacral ligaments, rectovaginal septum, and vagina.
Abnormal uterine bleeding occurs in up to one third of women with endometriosis with symptoms of oligomenorrhea, polymenorrhea, and midcycle or premenstrual spotting. The abnormal bleeding likely results from conditions associated with endometriosis: oligoanovulatory, luteinized unruptured follicles, luteal phase defects, and other pathology such as uterine fibroids.
Endometriosis involving the gastrointestinal or urinary tracts and extrapelvic sites causes symptoms characteristic of the location of disease. Bladder involvement is associated with frequency and urgency. Invasion of the mucosa results in hematuria. Ureteral and rare cases of renal endometriosis occasionally cause flank pain or gross hematuria. Symptoms suggestive of gastrointestinal involvement include, in decreasing order of frequency, diarrhea, rectal bleeding, constipation, and dyschezia. All symptoms usually are exacerbated catamenially.
There are numerous case reports of extrapelvic endometriosis. Pulmonary endometriosis causes catamenial hemoptysis and dyspnea. Cutaneous lesions are associated with catamenial bleeding, tenderness, and swelling.
It is estimated that 25% to 50% of infertile women have endometriosis, and 30% to 50% of women with endometriosis are infertile. Although the association of endometriosis and infertility is well recognized, the pathophysiologic mechanisms are poorly understood. Endometriomas and endometriosis with adhesions distort pelvic anatomy and impair tubal ovum pickup, which is an acceptable explanation for infertility. In less severe cases, there are several theories to explain the observed subfecundity (Table 40.1).
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TABLE 40.1. Proposed mediators and mechanisms of infertility |
Research to explain the subfertility has focused on peritoneal fluid leukocytes and their cytokine products. Studies have suggested that constituents in the peritoneal fluid inhibit sperm function, fertilization, embryonic development, and implantation. The clinical significance of these findings has not been established.
Diagnosis
Endometriosis usually is diagnosed during the third and fourth decades of life. It has not been found in prepubertal girls and rarely is diagnosed in postmenopausal women unless they are taking replacement hormones. Endometriosis should be suspected in any woman having the classic symptoms of pelvic pain, dysmenorrhea, dyspareunia, abnormal menstrual bleeding, and infertility. These symptoms are present in other gynecologic disorders. No one constellation of signs or symptoms is pathognomonic of endometriosis. Many women with endometriosis are completely asymptomatic, and endometriosis should be considered in all reproductive-age women with infertility or an adnexal mass.
Physical findings in women with endometriosis are variable and dependent on the location and severity of disease (Table 40.2). Frequently there are no obvious findings on pelvic examination. When findings are present, the most common is tenderness when palpating the posterior fornix. Nodules of endometriosis on the uterosacral ligaments, enlarged ovaries as a result of endometriotic cysts, and a uterus fixed in the cul-de-sac by adhesions may be detected during a pelvic examination. Uterosacral implants are best palpated during a rectovaginal examination. On the other hand, some patients with these clinical findings turn out not to have endometriosis.
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TABLE 40.2. Clinical signs |
The optimal way to diagnose endometriosis is by direct visualization of the site of suspected involvement. Because endometriosis is located primarily in the pelvis, laparoscopy is the preferred technique to make an accurate diagnosis. A double-puncture technique is necessary to view adequately all structures that may contain implants. Peritoneal fluid should be aspirated to see the entire cul-de-sac. Adhesions should be lysed to view the entire surface of the ovaries and the fossa ovarica. These sites are commonly involved with endometriosis when the ovary is adherent to the pelvic sidewall. Suspected endometriomas should be aspirated and resected to confirm the diagnosis. Biopsy and histologic study of any suspicious areas are helpful when the diagnosis is questionable, but often the visual diagnosis by the surgeon is more accurate than histologic sections of small peritoneal biopsies.
Transvaginal ultrasonography can be used to identify ovarian endometriomas, but it is of little utility to diagnose peritoneal implants. The use of other radiologic studies and blood tests to diagnose endometriosis rarely is required. Radioimmunoassay for the tumor marker CA-125 has been used, but the test is not sufficiently sensitive or specific, and patients having conditions other than endometriosis may have positive results.
Classification
A number of classifications have been developed for staging endometriosis. The most widely used system was introduced by the American Society for Reproductive Medicine (ASRM) in 1979 and revised in 1985 and in 1997. This system assigns a point score for the size and location of endometriotic implants and associated adhesions. The new ASRM endometriosis classification for infertility includes the morphologic appearance of the implant. There is a form published by the ASRM to assist in the management of endometriosis in the presence of pelvic pain.
Endometriosis is classified as minimal, mild, moderate, and severe. Mild disease is characterized by superficial implants less than 5 square centimeters in aggregate scattered on the peritoneum and ovaries. Minimal or no adhesions are present. Moderate forms are characterized by multiple implants, both superficial and invasive. Peritubal and periovarian adhesions may be evident. Severe forms are characterized by multiple superficial and deep implants, including large ovarian endometriomas. Filmy and dense adhesions are usually present. However, no staging system has been validated to correlate with the symptoms of pain or infertility.
Treatment
The treatment of endometriosis is dependent on (a) the severity of symptoms, (b) the extent of disease, (c) the location of disease, (d) the patient's desire for pregnancy, and (e) the age of the patient. Treatment options are presented in Table 40.3.
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TABLE 40.3. Treatment options |
Expectant Management
Avoiding specific therapy is considered when patients have minimal or no symptoms and have suspected minimal or mild endometriosis. Patients in this category may benefit from cyclic oral contraceptives to retard progression of the disease and protect against unwanted pregnancy. Minor pain may be controlled by nonsteroidal antiinflammatory drugs and/or analgesics. Infertile women having suspected limited disease may be observed without treatment. One study suggests that surgical treatment of mild endometriosis results in higher pregnancy rates than expectant management. Another study with fewer subjects failed to confirm the benefit of laparoscopic surgery for infertile women with endometriosis. If pregnancy occurs, regression or complete resolution of the disease is common. Perimenopausal women may be managed expectantly even when the disease is advanced, because endometriotic implants usually regress in the absence of ovarian hormone production after menopause.
Medical Therapy
Endometriotic implant growth is highly dependent on ovarian steroids. Medical therapy attempts to “induce” pseudopregnancy or menopause, the two physiologic states believed to inhibit or delay progression of endometriosis by interrupting cyclic ovarian hormone production. Progestins alone or in combination with estrogen hormonally mimic pregnancy. Danazol and gonadotropin-releasing hormone (GnRH) analogs induce a state of pseudomenopause. Medical therapy has the following advantages over surgery: (a) avoidance of the surgical risks of damaging pelvic organs and causing postoperative adhesions, and (b) treatment of implants that are not visible at surgery. Disadvantages of medical therapy are the associated side effects, high recurrence rates following discontinuation of treatment, lack of an effect on endometrioma and adhesions, and inability to conceive because of medically induced anovulation. Medical therapy never has been shown to enhance fertility (Fig. 40.1). Thus, it is not appropriate for women with advanced stages of endometriosis and adhesions causing symptoms or women desiring pregnancy. The medications used most commonly to treat endometriosis are continuous oral contraceptives, progestins, including oral contraceptives, danazol, and GnRH analogs. They should be considered after a definitive diagnosis of endometriosis has been made by direct visualization of the implants.
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FIG. 40.1. Meta-analysis of studies comparing medical treatment with no treatment. |
Progestins inhibit endometriotic tissue growth by a direct effect on the implants, causing initial decidualization and eventual pseudodecidual necrosis or atrophy (progestins). Progestins also inhibit pituitary gonadotropin secretion and ovarian hormone production. Treatment may consist of medroxyprogesterone acetate (10 mg 3 times a day) or norethindrone acetate (5 mg daily for 2 weeks), then increase by 2.5 milligrams per day every 2 weeks until a daily dose of 15 milligrams is reached. Depot-medroxyprogesterone may also be given as an injection (100 to 150 mg monthly). Treatment usually is continued for at least 6 months. Side effects include irregular menstrual bleeding, nausea, breast tenderness, fluid retention, and depression. The effectiveness of continuous oral contraceptives or progestins in eliminating implants and the risk of recurrent endometriosis following treatment are not precisely known. Over 80% of women have partial or complete pain relief. Low-dose cyclic oral contraceptives are effective in relieving dysmenorrhea in women with endometriosis, but they are less likely to relieve dyspareunia. Pregnancy rates in patients with less severe stages of disease are equivalent to those following expectant management.
Danazol is the isoxazole derivative of 17α-ethinyltestosterone. Danazol has the following three mechanisms of action: (a) inhibition of pituitary gonadotropin secretion, (b) direct inhibition of endometriotic implant growth, and (c) direct inhibition of steroidogenic enzymes. Danazol is given orally in divided doses, from 400 to 800 milligrams daily, generally for 6 months. Most women taking danazol have side effects, but only a small percentage of patients discontinue the drug because of unwanted effects. Side effects, in decreasing order of frequency, include weight gain, muscle cramps, decreased breast size, acne, hirsutism, oily skin, decreased high-density lipoprotein levels, increased liver enzyme levels, hot flashes, mood changes, and depression. Danazol decreases the size of implants, especially in treating mild or moderate stages of disease. Endometriomas and adhesions do not respond well to danazol treatment. More than 80% of patients experience relief or improvement of pain symptoms within 2 months of treatment. Pregnancy rates following treatment approximate 40% and are independent of the disease severity. However, danazol is no more effective than expectant management for treating infertility.
The GnRH analogs profoundly suppress ovarian estrogen production by inhibiting pituitary gonadotropin secretion. These medications are administered by nasal spray or depot injections. The usual dosage is 400 to 800 milligrams daily for nasal nafarelin, 3.6 milligrams for monthly subcutaneous goserelin, and 3.75 milligrams for monthly intramuscular leuprolide. Side effects of the hypoestrogenemia are common and include hot flashes, vaginal dryness, decreased libido, insomnia, breast tenderness, depression, headaches, and transient menstruation. In addition, GnRH analog treatment for the recommended 6-month period decreases bone density and total body calcium, but most of the bone loss is reversible. Hypoestrogenic side effects and bone loss may be prevented by “add-back” therapy with high-dose norethindrone (10 mg daily) or the daily combination of low-dose norethindrone (2.5 mg), sodium etidronate (400 mg), and calcium carbonate (500 mg) (Table 40.4). The GnRH analogs effectively reduce the size of endometriotic implants, even with add-back therapy. Recurrence rates over 5 years range from 37% for patients with mild disease to 74% for severe disease. The GnRH analogs are as affective as other medical therapy in relieving pain symptoms, but they do not enhance fertility.
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TABLE 40.4. Endometriosis “add-back” therapy |
Surgical Management
Surgery for endometriosis is considered conservative when the uterus and as much ovarian tissue as possible are preserved. Definitive surgery involves hysterectomy with or without removal of the fallopian tubes and ovaries.
Surgery is indicated when the symptoms are severe, incapacitating, or acute and when the disease is advanced. Surgery is preferred over medical therapy for advanced stages of disease with anatomic distortion of the pelvic organs, endometriotic cysts, or obstruction of the bowel or urinary tract. Women who are older than 35 years, infertile, or symptomatic following expectant or medical management should be treated surgically.
Laparoscopy is the preferred approach to perform conservative surgery. Treatment of endometriosis is possible during the initial laparoscopy, used to diagnose the condition. This offers the advantage of ablating the implants and adhesions, while avoiding possible progression of disease or symptoms and the expense and side effects of medical therapy. Disadvantages include possible damage to bowel and bladder, infection, and mechanical trauma that may result in adhesion formation.
Conservative surgery involves excision, fulguration, or laser ablation of endometriotic implants and removal of associated adhesions. The goal is to restore normal pelvic anatomy. Laparoscopic treatment offers advantages over laparotomy, including shorter hospitalization, anesthesia, and recuperation times. Laparotomy is advisable to deal with extensive adhesions or invasive endometriosis located near structures such as the uterine arteries, ureter, bladder, and bowel. Ancillary procedures include presacral neurectomy or uterosacral transection for interruption of sensory nerves innervating the pelvis to relieve midline pelvic pain. The Cochrane Review of three trials involving destruction of pelvic nerve pathways concluded that there is insufficient evidence to recommend these procedures. Uterine suspension may be performed to avoid adhesion formation from the cul-de-sac to the posterior surface of the uterus, tubes, and ovaries.
Surgery effectively removes pathology and restores normal anatomy in most cases. The disease recurrence risk is estimated to be as much as 40% with 10 years of follow-up. Pain relief is achieved in 80% to 90% of patients. Presacral neurectomy provides additional pain relief, but its benefit is not lasting, and bladder dysfunction occasionally occurs after the procedure. The chance for pregnancy following surgery is related to the stage of disease and presence of other infertility factors. Approximate pregnancy rates after surgery in patients with mild, moderate, and severe endometriosis are, respectively, 60%, 50%, and 40%. Surgery is preferred over expectant or medical management for infertile women with endometriosis (Fig. 40.2).
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FIG. 40.2. Meta-analysis of studies comparing surgical treatment (operative laparoscopy or laparotomy) with nonsurgical treatment (medical treatment or no treatment). |
Definitive surgery for treatment of endometriosis is indicated when significant disease is present and pregnancy is not desired, when incapacitating symptoms persist following medical therapy or conservative surgery, and when coexisting pelvic pathology requires hysterectomy. The decision to perform hysterectomy is dependent primarily on the patient's interest in maintaining childbearing potential and the severity of her symptoms. The ovaries may be conserved in younger women to avoid the need for estrogen replacement therapy. Removal of both ovaries is appropriate when the ovaries are damaged extensively by endometriosis or when menopause is approaching. Endometriosis may recur even with castration, presumably from microscopic foci of disease not visible at surgery. Menopausal hormonal replacement is indicated when the ovaries are removed, even when surgery has not removed all endometriotic implants. The chance for symptomatic recurrence in these cases is small except when endometriosis involves the bowel.
Combination Medical and Surgical Therapy
Medical therapy is used before surgery to decrease the size of endometriotic implants and thus reduce the extent of surgery. When complete removal of implants is not possible or advisable, postoperative medical therapy is used to treat residual disease. Progestin, danazol, or GnRH analogs may be used in conjunction with conservative or definitive surgery. Preoperative medical therapy may decrease the amount of surgical dissection required to remove implants, but it does not prolong pain relief, increase pregnancy rates, or decrease recurrence rates. Postoperative treatment with GnRH analogs will delay somewhat the recurrence of pelvic pain, but there is no evidence to support its use in infertile patients.
SUMMARY POINTS
· The histogenesis of endometriosis is poorly understood, but emerging evidence supports the causative role of retrograde menstruation and implantation of endometrial tissue.
· Endometriosis is common in women with pelvic pain or infertility.
· Laparoscopy is the optimal technique to diagnose pelvic endometriosis.
· In most cases, surgical therapy at the time of initial diagnosis effectively relieves pain and may enhance fertility.
· Alternatively, medical therapy with progestins, danazol, or GnRH analogs will ameliorate pelvic pain, but they do not enhance fertility.
· Endometriosis is a recurrent disease, and definitive treatment with removal of pelvic organs may be necessary.
SUGGESTED READINGS
Pathogenesis
Dmowski WP, Gebel HM, Braun DP. The role of cell-mediated immunity in pathogenesis of endometriosis. Acta Obstet Gynecol Scand Suppl 1994;159:7.
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Oosterlynck DJ, Cornillie FJ, Waer M, et al. Women with endometriosis show a defect in natural killer activity resulting in a decreased cytotoxicity to autologous endometrium. Fertil Steril 1991;56:45.
Schenken RS. Pathogenesis. In: Schenken RS, ed. Endometriosis: contemporary concepts in clinical management. Philadelphia: JB Lippincott, 1989:1.
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Epidemiology
Chatman DL, Ward AB. Endometriosis in adolescents. J Reprod Med 1982;27:156.
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Pathology
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Diagnosis
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