Office Management of Endometriosis
Jennifer F. Knudtson
Robert S. Schenken
Endometriosis is the presence of endometrial glands and stroma outside the uterine cavity and musculature. These ectopic endometrial implants can occur anywhere in the body but are usually found in the pelvis. Endometriosis has a wide spectrum of symptoms. Women usually present with pelvic pain, with severity of the pain ranging from minimal to debilitating, dyspareunia, and infertility. They may present with a pelvic mass. Endometriosis is a chronic, estrogen-dependent disorder that can have a profound impact on a woman’s life affecting her physical, emotional, and social well-being.
The actual prevalence in the population is unknown, but it is estimated to be about 6 to 10% of reproductive age women in all ethnic and social groups.1 The prevalence of pelvic endometriosis is 1% in women undergoing major surgery for all gynecologic indications and 30 to 60% in women undergoing diagnostic laparoscopy for pelvic pain.2, 3, 4 Approximately two-thirds of teenagers undergoing laparoscopy for pelvic pain not responsive to treatment have endometriosis.5 One-third of women undergoing laparoscopy for infertility are found to have endometriosis.6 In the United States in 2002, the direct treatment cost of endometriosis was around $18.8 billion, and combination of direct and indirect cost was $22 billion.7
PATHOGENESIS
Multiple theories have been proposed to explain the histogenesis of endometriosis.6 No one theory can explain the pathogenesis completely, and it is possible that more than one source or pathway leads to the development of endometriosis. The most widely accepted theory is retrograde menstruation or implantation theory, also known as Sampson theory, where endometrial fragments shed during menstruation are transported retrograde through the fallopian tubes and then implant in the pelvis. The direct transplant theory explains the development of endometriosis in a scar after cesarean section, vaginal repair, or other pelvic surgery. The coelomic metaplasia theory is derived from the embryologic basis that all pelvic organs develop from the spontaneous or induced metaplastic change in mesothelial cells that line the coelomic (peritoneal) cavity. It proposes that the lining of the abdominal cavity contains undifferentiated cells with the ability to differentiate into endometrial cells. Evidence also indicates that endometriosis can spread outside the pelvis through vascular and lymphatic channels.
Anatomy, altered immunity, and genetics influence the development of endometriosis. Anatomic differences in the pelvis, which increase reflux through the fallopian tubes, increase the chance of endometriosis. For example, endometriosis has a higher incidence in females with müllerian anomalies, which result in outflow tract obstruction.8 However, women with endometriosis do not have a higher incidence of retrograde menstruation compared to women without endometriosis. Although almost all women have retrograde menstruation, not all women develop the disease. The development of endometriosis may depend on alterations in the immune response that recognizes and eliminates refluxed endometrial fragments as well as increased ability of the ectopic endometrial cells to adhere and invade into the peritoneal cavity or other surfaces.9,10 Endometriotic implants are associated with an increased production of cytokines, prostaglandins, and growth factors, which lead to increased proliferation of ectopic implants, enhanced local angiogenesis, and the attraction of leukocytes to the sites of inflammation.11 Genetics may also play a role in the development of endometriosis. The first-degree relatives of women with endometriosis have a 7% likelihood of developing or having the disease compared to a 1% likelihood in unrelated women.12 Numerous studies have looked for specific genes that predispose to the development of endometriosis, but the exact genetic cause is unclear.13
The stem cell theory of endometriosis centers on the idea that mesenchymal stem cells that are derived from bone marrow can differentiate into endometrium and endometriosis.14 There is evidence that in women who have undergone bone marrow transplants, the endometrium in these women contains a substantial number of donor-derived endometrial cells.14 It is possible that stem cells that are derived from the bone marrow (even in women who have not been given a bone marrow transplant) reside in the endometrium and may reflux during retrograde menstruation and cause
endometriotic implants just as endogenous endometrial cells may. Further evidence demonstrates that endometriotic implants are populated by bone marrow-derived stem cells. This stem cell theory would also explain cases of endometriosis at sites outside the peritoneal cavity; endometriosis at distant sites may arise from stem cells.
endometriotic implants just as endogenous endometrial cells may. Further evidence demonstrates that endometriotic implants are populated by bone marrow-derived stem cells. This stem cell theory would also explain cases of endometriosis at sites outside the peritoneal cavity; endometriosis at distant sites may arise from stem cells.
Women with endometriosis also have an increased risk of malignancy and autoimmune diseases. One study of women discharged from the hospital with a diagnosis of endometriosis suggested an increased risk of developing breast, ovarian, and hematopoietic cancers in the future.15 Rarely, adenocarcinoma may also develop from endometriotic implants.16 Endometriosis and ovarian cancer share certain risk factors such as early menarche (before age 11 years), shorter cycle lengths (less than 27 days), and lower parity.17 Studies show that the relative risk of ovarian cancer appears to be increased in women with a long history of endometriosis, although the magnitude of the increased risk is not clear.18,19 The risk of ovarian cancer appears to be highest for women with endometriosis and primary infertility, although this risk may be reduced with the use of oral contraceptive pills.20,21 Screening women with endometriosis for ovarian cancer is not recommended however because the incidence is low, and importantly, there is no effective screening test. There is also no evidence that removing sites of endometriosis will decrease the risk of ovarian cancer.
Autoimmune diseases such as rheumatoid arthritis and systemic lupus along with hypothyroidism, fibromyalgia, chronic fatigue syndrome, and asthma are also more common in patients with endometriosis.22
PATHOLOGY
Endometriosis is most commonly found in the ovaries, followed by the anterior and posterior cul de sac, posterior broad ligaments, uterosacral ligaments, uterus, fallopian tubes, and round ligaments. Both ovaries are involved in about 33% of cases. The left side of the pelvis and left ovary are more frequently affected than the right, possibly because the presence of the sigmoid colon decreases peritoneal fluid movement. Gastrointestinal involvement is the most frequent extragenital site of endometriosis, occurs in 5% of cases, and most commonly affects the sigmoid colon.23 The urinary tract is the third most commonly involved system with superficial endometriotic lesions found in the bladder, followed by the ureter. Other less common sites include the cervix, vagina, cecum, ileum, umbilicus, and inguinal canals. Rare cases have found endometrial implants in the lung, diaphragm, breast, pancreas, liver, gallbladder, kidney, urethra, vertebrate, bone, nervous system, and extremities.6
Microscopically, endometriosis has the characteristics of the uterine endometrium including glands and stroma. The endometriotic lesions also contain fibrosis, hemosiderin-laden macrophages, and blood. The lesions can be superficial or invasive into the ovary or retroperitoneum.
The visual appearance and size of endometrial lesions is extremely variable. Lesions can appear as the bluish black “powder burn” lesions due to the hemosiderin deposits and as whitish opacifications, translucent blebs, raised flame-like patches, or reddish/reddish blue irregularly shaped islands. These lesions are often seen with peritoneal surfaces that appear scarred (see Figs. 10.1, 10.2, 10.3 through 10.4 for pictures of endometriosis).
Ovarian implants can present superficially or as cystlike structures called endometriomas. Endometriomas, often referred to as chocolate cysts, contain blood, fluid, and endometrial fragments. They are frequently densely adherent to nearby structures.
 FIGURE 10.1 Typical and subtle endometriotic lesions on peritoneum. A: Typical black-puckered lesions with hypervascularization and orange polypoid vesicles. B: Red polypoid lesions with hypervascularization. (Photographs kindly donated by Dr. Christel Meuleman, Leuven University Fertility Center, Leuven University Hospitals, Leuven, Belgium. From Berek JS, ed. Berek & Novak’s Gynecology. 14th ed. Philadelphia: Lippincott Williams & Wilkins; 2007.) |
 FIGURE 10.2 Ovarian endometriosis. A: Superficial ovarian endometriosis. B: Superficial ovarian endometriosis and endometrioma laparoscopic image prior to adhesiolysis. (Photographs kindly donated by Dr. Christel Meuleman, Leuven University Fertility Center, Leuven University Hospitals, Leuven, Belgium. From Berek JS, ed. Berek & Novak’s Gynecology. 14th ed. Philadelphia: Lippincott Williams & Wilkins; 2007.) |
DIAGNOSIS
The diagnosis of endometriosis is most often made in reproductive age women. It is rarely found in prepubertal girls and only occasionally diagnosed after menopause. Clinical manifestations of endometriosis include pelvic pain, infertility, and adnexal masses. The most common symptom is pain. Pelvic pain symptoms usually include secondary dysmenorrhea, which typically begins before onset of menses, and dyspareunia, which is increased with deep penetration and prior to menses. Women may also experience noncyclic pelvic pain, abdominal cramps, low back pain, and abnormal menstrual bleeding. Another presenting complaint is infertility. If there is bowel involvement, endometriosis may present as dyschezia, constipation or diarrhea, rectal bleeding, and bloating. If the bladder is involved, there may be dysuria or hematuria. It is important to appreciate that the stage of endometriosis does not correlate with the severity of symptoms. The location and depth of implantation of the ectopic endometrium may play a role in symptomatology. Pain with defecation during menses and severe dyspareunia are the most predictable symptoms of deeply infiltrating endometriosis.24
 FIGURE 10.3 A: Laparoscopic image of uterus and right ovary with dark endometrioma. B: Ovarian endometriotic cystectomy. (From Berek JS. Berek & Novak’s Gynecology. 14th ed. Philadelphia: Lippincott Williams & Wilkins; 2007.) |
When considering the diagnosis of endometriosis for pelvic pain, other causes of pelvic pain need to be investigated. Adenomyosis, leiomyomata, pelvic inflammatory disease, ovarian or tubal masses, pelvic floor dysfunction, and pelvic adhesions are reproductive conditions that may also cause chronic pelvic pain. Common nongynecologic etiologies of pelvic pain are gastrointestinal, musculoskeletal, neurologic, psychological, or urinary system disorders. Patients may also present with irritable bowel syndrome, inflammatory bowel disease, or interstitial cystitis (see Table 10.1 for symptoms of endometriosis).
Although the average age at diagnosis is 28 years, up to 67% of adult women with endometriosis note that their symptoms started before the age of 20 years.25 Among adolescents, 47% of those with chronic pelvic pain that
have laparoscopy are found to have endometriosis, and among adolescents with chronic pelvic pain that do not respond to oral contraceptives or NSAIDs who undergo laparoscopy, endometriosis is found in 50 to 70% of cases. Adolescents with endometriosis often have both acyclic and cyclic pain. The least common pain presentation among adolescents is isolated cyclic pain, which is in contrast to adults with endometriosis who commonly have cyclical pain.
have laparoscopy are found to have endometriosis, and among adolescents with chronic pelvic pain that do not respond to oral contraceptives or NSAIDs who undergo laparoscopy, endometriosis is found in 50 to 70% of cases. Adolescents with endometriosis often have both acyclic and cyclic pain. The least common pain presentation among adolescents is isolated cyclic pain, which is in contrast to adults with endometriosis who commonly have cyclical pain.
 FIGURE 10.4 Laparoscopic excision of deep endometriosis from the cul de sac. A: Extensive endometriosis with deep nodule at the right uterosacral ligament masked by adhesions. B: Deep nodule is still present in dense adhesion between rectum and uterosacral ligaments. (Photographs kindly donated by Dr. Christel Meuleman, Leuven University Fertility Center, Leuven University Hospitals, Leuven, Belgium. From Berek JS. Berek & Novak’s Gynecology. 14th ed. Philadelphia: Lippincott Williams & Wilkins; 2007.) |
Endometriosis is sometimes difficult to diagnose based on clinical manifestations alone, but physical findings are variable and depend on the location and size of the implants. Frequently, there are no abnormal findings on physical examination. The most common findings are tenderness in the posterior cul de sac or nodularity on palpation of the uterosacral ligaments, although this latter finding is rarely found in adolescents. There may be thickening of the uterosacral ligaments, pain with uterine movement, or tender nodules in the posterior cul de sac or rectovaginal septum. Other findings include ovarian cysts, a nonmobile uterus secondary to adhesions, or an obliterated cul de sac.
TABLE 10.1 Symptoms of Endometriosis | |||||||||||||||||||||||||||||||||
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The gold standard to diagnosis of endometriosis is laparoscopy, which allows for direct visualization of the implants. It is best to avoid laparoscopy during or within 3 months of hormonal treatment because this may lead to underdiagnosis of the disease. Prominent pelvic vessels may suggest pelvic congestion syndrome, which some argue is a cause of chronic pelvic pain but is not a sign of endometriosis. In 2 to 4% of women with endometriosis, the appendix may be involved so this should be visualized during laparoscopy. A negative laparoscopy is highly reliable for excluding endometriosis, although it may miss occult microscopic implants, but visual diagnosis alone is associated with a high rate of error in diagnosis.26 Biopsy of suspicious areas are suggested, particularly when the appearance of the implants is atypical.
There are no blood tests or imaging studies to make the definitive diagnosis. Imaging studies, such as ultrasonography or magnetic resonance imaging, may be useful when an adnexal mass is present for a presumptive diagnosis of an endometrioma. Transvaginal sonography may be helpful in detecting deeply infiltrating endometriosis of the rectum or rectovaginal septum, and water contrast in the rectum may help determine if the lesions are infiltrating the bowel.27,28 CA-125, a cell surface antigen used for monitoring epithelial ovarian
cancer, is elevated in endometriosis and has been found to have a diagnostic specificity greater than 90% and sensitivity of 50%.29 In one series of 685 women undergoing surgery for endometriosis, the mean serum CA-125 levels in stage I, II, III, and IV disease were 19, 40, 77, and 182 IU/mL, respectively.30 Levels greater than 100 IU/mL were usually associated with extensive adhesions or a ruptured endometrioma. Other conditions that increase CA-125 levels are pelvic inflammatory disease, leiomyomas, pregnancy, cirrhosis, and appendicitis (see Table 10.2 for a listing of conditions associated with elevated levels of CA-125).
cancer, is elevated in endometriosis and has been found to have a diagnostic specificity greater than 90% and sensitivity of 50%.29 In one series of 685 women undergoing surgery for endometriosis, the mean serum CA-125 levels in stage I, II, III, and IV disease were 19, 40, 77, and 182 IU/mL, respectively.30 Levels greater than 100 IU/mL were usually associated with extensive adhesions or a ruptured endometrioma. Other conditions that increase CA-125 levels are pelvic inflammatory disease, leiomyomas, pregnancy, cirrhosis, and appendicitis (see Table 10.2 for a listing of conditions associated with elevated levels of CA-125).
The American Society for Reproductive Medicine classification system for endometriosis was first introduced in 1979 to correlate pain and infertility with disease severity. It was then revised in 1985 and again in 1996, and despite its limitations, it is the most widely accepted staging system. The system assigns points for the size and location of the lesions and any associated adhesions. It does not correlate well with pain, dyspareunia, or infertility. Its primary value lies in providing a uniform record of operative findings and quantification of disease, thus allowing for a comparison between various therapies.
TABLE 10.2 Conditions Associated With Elevated Serum CA-125 | ||||||||||
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The staging is performed surgically where all the lesions can be visualized. The total score determines the disease category of minimal (I), mild (II), moderate (III), or severe (IV). There is some evidence that endometriotic lesions are innervated and that pain may be related to nerve density in the lesions which, in turn, seems to correlate with the histologic type of lesion, depth of invasion, and proximity of nerves to the lesions31 (see Fig. 10.5 for the revised American Society for Reproductive Medicine classification of endometriosis).32
TREATMENT
The treatment of endometriosis depends on the severity of symptoms, extent of disease, location of disease, age of patient, and desire for future fertility. There are multiple treatments from medical to surgical to homeopathic. Despite extensive research, the optimal management of endometriosis remains controversial. Therapy is aimed at treating the patient’s symptoms, and treatment plans are individualized. The discussions of therapies that follow will focus on the management of endometriosis-related pain, infertility, and endometriomas, respectively. Regardless of the reason(s) for treatment, the side effects of medications, complication rates of surgery, and the costs of interventions of possible treatments are important management considerations.
Treatment of Pelvic Pain
There are many theories of the etiology for the pelvic pain including different nerve irritations, inflammatory reactions, or bleeding within the implants.33 Most studies have found increased proinflammatory cytokines and growth factors in endometriosis that are closely related to pain sensation, which may explain why even minimal endometriosis may cause severe pain. There is some evidence that the peripheral nerve fibers supplying endometriotic implants may sensitize spinal segmental neurons and eventually, the central nervous system as well. This would result in an exaggerated central nervous system response to pain, even if lesions were ablated.34,35 Multiple treatments are available for endometriosis-associated pelvic pain, and the multidimensional symptomatology of this disease warrants a multidisciplinary approach to treatment. Treatment regimens for pain usually begin with trials of medical treatments when the clinical suspicion for endometriosis is high and no pelvic mass is appreciated. Medical therapy for endometriosis aims to control pain and suppress estrogen production based on the premise that a hypoestrogenic environment will inhibit endometrial growth and promote regression of the disease. The main disadvantage to this approach is that symptoms usually recur once treatment is stopped. Overall, the available hormonal therapies used appear to have similar effectiveness in treating chronic pelvic pain. For some patients, surgery is the initial step in the diagnosis and treatment
of endometriosis. Additional surgery may be indicated in women with known severe disease who desire fertility, and assisted reproductive techniques may follow surgery. No studies have directly compared surgical versus medical treatment for endometriosis (see Table 10.3 for a list of treatment options for endometriosis).
of endometriosis. Additional surgery may be indicated in women with known severe disease who desire fertility, and assisted reproductive techniques may follow surgery. No studies have directly compared surgical versus medical treatment for endometriosis (see Table 10.3 for a list of treatment options for endometriosis).
 FIGURE 10.5 Revised American Society for Reproductive Medicine classification. (From Schenken R, Guzick D. Revised endometriosis classification: 1996. Fertil Steril. 1997;67:815-816.) |
Expectant Management
Although endometriosis is a chronic disease with a propensity for relapse, a woman with minimal or mild endometriosis can be managed expectantly if she is asymptomatic. These patients are usually diagnosed incidentally during a surgery for another reason. Although the natural course of endometriosis is not well known, long-term studies would indicate that expectant management will be associated with disease progression in 29 to 44% of patients, disease regression in 22 to 29% of women, and no change in 33 to 42% of women with this disease.36,37 Overall then, it would appear that the distribution of change is roughly divided into thirds among these possibilities. For women not currently interested
in pregnancy, starting a combination oral contraceptive may be beneficial regardless of symptoms to prevent further progression of disease.
in pregnancy, starting a combination oral contraceptive may be beneficial regardless of symptoms to prevent further progression of disease.
TABLE 10.3 Treatment Options for Endometriosis-Associated Pain | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Medical Therapy
Most of the medical therapies used to treat endometriosis are aimed at the key components of the disease process: retrograde menstruation, estrogen dependence, progesterone resistance, inflammation, and angiogenesis. NSAIDs are used to target inflammation (see Table 10.4 for medical therapy options for dysmenorrhea). Endometrial implants contain estrogen, androgen and progestin receptors, and hormonal treatments such as contraceptive steroids, progestogens, and antiprogestogens, GnRH agonists and danazol target these receptors and their ligands.38 Although many of these therapies effect a decrease in estrogen, it is important to note that shutting down the ovary alone will not eliminate estrogen production; other sources include adipose tissue, in the ectopic and eutopic endometrium in women with endometriosis, certain areas of the brain, and even the dorsal root ganglia help contribute to the production of estrogen.
Women presenting with pelvic pain and the suspected diagnosis of endometriosis can be started on empiric medical treatment prior to diagnosis by laparoscopy after other gynecologic sources of pain have been excluded.39 Although 80 to 90% of patients will improve with medical therapy, these interventions do not enhance fertility or treat endometriomas. If infertility or a pelvic mass is involved, a trial of medical therapy is not recommended (see Table 10.5 for drugs used in the treatment of endometriosis-associated pain).
TABLE 10.4 Medical Therapy Options and Dosages for Dysmenorrhea | |||||||||||||||||||||||||||||||||||||||
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Analgesics
Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in treating primary dysmenorrhea. By blocking cyclooxygenase (COX)-1 and COX-2 enzymes, they inhibit prostaglandin production and thus decrease the pain of dysmenorrhea. NSAIDs do not keep endometriosis from progressing. No large, randomized controlled trials have evaluated the use of NSAID analgesics for endometriosis. The Cochrane Review reports there is limited evidence to show that NSAIDs are effective, and no evidence shows one NSAID to be more effective than another.40 Common side effects are gastrointestinal symptoms. NSAIDs are affordable, available, and tolerable. A 3-month trial of NSAIDs in women with minimal or mild disease is a reasonable approach.
Combined Estrogen and Progesterone
Hormonal treatment of endometriosis is aimed at inducing amenorrhea or diminished menstruation, creating a relatively hypoestrogenic environment to inhibit endometrial growth and promote disease progression. Unfortunately, symptoms often recur once therapy is stopped. Combination contraceptives initially induce decidualization in eutopic and ectopic endometrium, followed later by atrophy and may help delay progression of disease.41
Combination oral contraceptive pills (OCPs) are used in women with no current interest in fertility and who have minimal to mild disease. There are few randomized
controlled trials on OCPs for endometriosis. All, including the Cochrane Review, have found OCPs to be more effective than placebo and as effective as GnRH analogues and danazol.42, 43, 44 Low-dose OCPs have also been shown to decrease endometriosis pain symptoms.43 Side effects from OCPs include nausea, breast tenderness, and irregular vaginal bleeding. Contraindications should be reviewed prior to prescribing especially any history of thromboembolic events. There is no conclusive evidence that one OCP formulation is better than another.
controlled trials on OCPs for endometriosis. All, including the Cochrane Review, have found OCPs to be more effective than placebo and as effective as GnRH analogues and danazol.42, 43, 44 Low-dose OCPs have also been shown to decrease endometriosis pain symptoms.43 Side effects from OCPs include nausea, breast tenderness, and irregular vaginal bleeding. Contraindications should be reviewed prior to prescribing especially any history of thromboembolic events. There is no conclusive evidence that one OCP formulation is better than another.
TABLE 10.5 Drugs Used for the Treatment of Endometriosis | ||||||||||||||||||||||||||||||||||||||||||||||||
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Continuous OCPs are a reasonable option to either start with or to use when cyclic OCPs do not control their pain.45 Typically, a continuous OCP regimen is 12 weeks (four packs) of active pills continuously then one hormone-free week. When on continuous OCPs, patients may experience increased breakthrough bleeding that may be corrected by adding estrogen supplement or returning to a cyclic regimen. OCPs are commonly combined with NSAID treatment. Other combined hormonal treatments include the NuvaRing and the Ortho Evra patch, which both provide pain relief.46 If after 3 to 6 months of combined hormonal treatment there is no relief, another treatment modality should be pursued.
Progestins
Endometriotic lesions may be resistant to decidualization and atrophy. Progestins have anti-inflammatory, antiangiogenic, and immunomodulatory effects and can be effective in controlling the underlying processes of pain in endometriosis. They decrease pituitary gonadotropins, induce anovulation, and thus create a relatively hypoestrogenic environment. When they are used at appropriate doses, they yield partial or complete pain relief in more than 80% of women with endometriosis.47,48 Their efficacy in eliminating implants and recurrence is not well known, although one study found that about half of symptomatic patients experience a recurrence upon discontinuation.48 Overall, they have a good tolerability profile and are affordable. Side effects include irregular bleeding, nausea, weight gain, breast tenderness, depression, and fluid retention. Breakthrough bleeding may occur and can be treated with micronized estradiol (2 mg daily) or conjugated estrogen (1.25 mg daily) for 7 to 14 days. There are multiple options for progestin treatment including oral agents, intramuscular injections, an intrauterine device, and subdermal implants (see Table 10.6 for a listing of progestins used in the treatment of endometriosis-associated pain).
Depot medroxyprogesterone acetate (DMPA or Depo-Provera) is an intramuscular or subcutaneous progestin given every 3 months in doses of 104 to 150 mg to prevent pregnancy. The subcutaneous injection has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of endometriosis. In randomized trials, it is as effective as leuprolide and danazol in reducing dysmenorrhea, pelvic pain, pelvic tenderness, and dyspareunia.47,48 Breakthrough bleeding, weight gain, mood changes, depression, irritability, and amenorrhea are common side effects of DMPA. This may be managed with a 10- to 14-day course of low-dose estrogen.
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