ENDOMETRIOSIS, PART 1

Pathophysiology, diagnosis, and surgical management of endometriosis: A chronic disease

Clinical Fellow, Department of Obstetrics and Gynecology, University Hospitals Case Medical Center, Case Western Reserve University, School of Medicine, Cleveland, Ohio

Chair, Department of Obstetrics and Gynecology, University Hospitals Case Medical Center, Case Western Reserve University, School of Medicine, Cleveland, Ohio

Endometriosis is defined as the presence and growth of the endometrial glands and stroma in a heterotopic location away from the normal endometrium.¹ These ectopic endometrial implants are usually located within the pelvis but can be found elsewhere in the body and are often associated with pain and an increased risk of infertility. It is estimated that more than 10 million women have endometriosis.

Although 9 decades have passed since it was first described by Sampson, endometriosis is still a puzzling disorder because of its diverse clinical presentations and controversial etiologic origins. Once endometriosis is diagnosed in a reproductive-aged woman, it should be considered a chronic disease with multiple recurrent episodes of pain, infertility, and longer symptom-free intervals. The estimated annual cost for treatment of endometriosis is more than $20 billion.

The exact etiology of endometriosis is unknown. However, many theories have been proposed to explain the multiple clinical presentations of the disease.^1,2 Sampson’s retrograde menstruation theory is probably the most accepted explanation for the disease. This theory is supported experimentally by animal studies and also by clinical observations during laparoscopy that have noted common sites of involvement around the ovaries and within the pouch of Douglas.³

Pelvic endometriosis is the most common anatomic location for the disease. The left hemipelvis and ovary are more frequently affected than the right, which may be explained by the left-sided presence of the sigmoid colon, decreasing peritoneal fluid movement. The clinical significance of this lateralization is unknown. Ovarian involvement is often associated with a cystic collection of endometriosis known as an endometrioma or “chocolate cyst.”⁴ The pelvic peritoneum, posterior cul-desac, uterovesical pouch, and the uterosacral, round, and broad ligaments are also common pelvic sites for endometriosis. Pelvic lymph nodes are involved in up to one-third of cases. Occasionally, the cervix, vagina, and vulva are involved.⁵

While the genital tract is the most commonly involved system, the gastrointestinal tract is the most frequent extragenital site of endometriosis.⁶ The urinary tract is the third most commonly involved system, affecting 10% of women with endometriosis. Small superficial endometriotic spots are found most commonly in the bladder followed by the ureter.^7,8 Ovarian endometriomas vary considerably in size, from 1 mm to large chocolate cysts that can be greater than 8 cm in diameter.⁹

Chronic pelvic pain and infertility are the most common symptoms of endometriosis. Chronic pelvic pain can take the form of cyclic pain, noncyclic pain, secondary dysmenorrhea, and/ or dyspareunia. The pain usually begins before the onset of menstruation, increases with the flow of menses (“crescendo dysmenorrhea”), and is relieved gradually toward the end of menstruation. Dyspareunia is often deep and mostly results from the immobility of the pelvic organs due to adhesions.¹⁰ At present, laparoscopy is the gold standard for diagnosing endometriosis. In addition, staging of endometriosis (stage I, minimal; II, mild; III, moderate; IV, severe) can be quantified according to the American Society for Reproductive Medicine (ASRM) classification.¹¹

Tissue diagnosis of endometriosis is advisable when the diagnosis is unclear, as visual confirmation of the disease is often erroneous, especially for white lesions.¹² In a study by Mettler et al, the correct visual diagnosis was obtained in 100% of the red lesions, 92% of the pigmented lesions, and only 31% of the white lesions.¹²

Pelvic imaging via ultrasonography is not specific for endometriosis. The typical ultrasonographic characteristics of an endometrioma include a “ground glass” appearance, fluid levels, and the “kissing ovary” sign (which is correlated with ovaries fixed to adjacent structures). Despite its ability to delineate tissues, magnetic resonance imaging (MRI) has not been shown to be superior to transvaginal ultrasonography and should be reserved for exceptional cases. Serum levels of cancer antigen 125 (CA-125) are often elevated in patients with endometriosis and are stage dependent.¹³ However, use of the CA-125 test as a diagnostic tool for endometriosis in clinical practice is disappointing because it lacks sensitivity and specificity.

Endometriosis has several unique biological properties. It behaves as a chronic and recurrent disease because of microscopic implants that continue to be active after surgical treatment. Many patients have quiescent disease with rare episodes of pain, while others have frequent, recurrent pain. These differing symptom patterns are often not correlated with lesion size or extent of disease. Current approaches for managing endometriosis are symptom oriented, aimed mainly at treating chronic pelvic pain and infertility. Management protocols may also be targeted at slowing disease progression or preventing recurrence. Medical, surgical, or a combined approach can be chosen (TABLE 1). In addition, assisted reproductive techniques (ART) are frequently used to treat endometriosis-associated infertility.

Treatment strategies for women with endometriosis vary according to the patient’s age, treatment goals, parity, extent of the disease, and menopausal status. For young patients with mild disease not desiring children, it is advisable to use medical suppression to control symptoms and minimize surgical intervention. For women with severe disease who desire fertility, surgery followed by ART is a reasonable option. Lastly, the management of surgically menopausal patients with symptomatic endometriosis requires a different approach, in which off-label use of new medical therapies, such as aromatase inhibitors, may be considered.

The following discussion reviews the various surgical approaches for the treatment of endometriosis, including conservative procedures, definitive interventions, and adjunct surgical treatments. Medical treatment for endometriosis and the use of ART for endometriosis-related infertility are discussed in “Long-term management of endometriosis: Medical therapy and treatment of infertility,” in this issue.

Treatment options for endometriosis

In the majority of patients, surgical intervention is usually an initial step in the diagnosis and treatment of endometriosis. In general, local excision of endometriosis is associated with good short-term outcomes but, on long-term follow-up, has a high reoperative rate.^14,15 In contrast, hysterectomy with conservation of the ovary is associated with a low reoperation rate.¹⁵ Indications for surgical management are shown in TABLE 2.

Indications for surgical management of endometriosis

Conservative surgery

The major objectives of conservative surgery are to ablate or excise all visible endometriotic lesions, preserve the uterus and ovarian tissue, and restore normal pelvic anatomy. A minimally invasive approach is associated with a shorter hospital stay and decreased recovery time. Laparotomy may be necessary for advanced disease with extensive adhesions or involvement of uterine arteries, ureter, bladder, and bowel.¹⁶ Recently, robotically assisted laparoscopic surgical series have been reported. In conservative operations, implants are either ablated (vaporized or coagulated) or excised, endometriomas are removed, and adhesions are lysed. Appendectomy may be performed concurrently if indicated. Laparoscopy has been shown to be as effective as laparotomy in the treatment of ovarian endometriomas. There are no studies demonstrating that one surgical energy modality (electrosurgical, laser, ultrasonic, or robotic) is superior to another. Multiple small studies have found that the pregnancy rate after excision of lesions was not significantly different from the rate following an electrocoagulation ablation for removal of endometriosis lesions.

For ovarian endometriomas greater than 3 cm in diameter, a systematic review concluded that excision of the cyst wall is better than drainage and cauterization of the cyst wall for relief of dysmenorrhea, dyspareunia, and nonmenstrual pelvic pain.¹⁷ The authors also concluded that fertility-related outcomes were improved with excision of endometriomas. The concern in terms of fertility is that excessive resection of ovarian tissue can compromise fertility.

Pain outcome

The effectiveness of surgical treatment of endometriosis was best shown in two small, prospective randomized controlled trials. In the first trial, Sutton and colleagues found that laser laparoscopy resulted in significant pain relief 6 months postoperatively compared with expectant management.¹⁴ They concluded that operative laparoscopy is an effective treatment for alleviating pain symptoms in women with stages I, II, and III endometriosis, although less benefit was observed for minimal disease. The majority of patients whose pain was initially relieved by surgery remained pain-free 1 year later.¹⁴ These findings were substantiated by another well-designed prospective randomized trial in which laparoscopic excision of implants led to symptomatic improvement in 80% of patients at 6 months compared with 32% of controls.¹⁸

Fertility outcome

Randomized trials to assess surgical treatment and fertility are limited. A trial in Canada of 341 patients randomized to either diagnostic laparoscopy only or laparoscopy with lesion ablation showed significant improvement in the time to pregnancy with surgical treatment.¹⁹ The number of laparoscopies needed to achieve an extra pregnancy was 9 (95% confidence interval [CI], 5-33). A second, smaller randomized trial conducted in Italy did not show differences between surgery and expectant management.²⁰ A meta-analysis of these two randomized clinical trials showed a clear beneficial effect on fertility.²¹ Unfortunately, no randomized trials have been performed to evaluate the subsequent fertility of patients with advanced endometriosis. However, it is generally believed that fertility is improved after surgery.

Definitive surgical interventions

The only definitive treatment for endometriosis is total abdominal hysterectomy with bilateral salpingo-oophorectomy with removal of all visible endometriosis. This is usually performed in women with advanced disease who have completed childbearing or in women with intractable pain unresponsive to more conservative treatments.²² Preservation of ovaries can be associated with a recurrence rate of 30%, with increased risk of a second operation either to remove the ovaries or to treat recurrent endometriosis. In a retrospective study with 7 years of follow-up, local excision of endometriosis was associated with good short-term outcomes, but long-term follow-up demonstrated a high reoperation rate.¹⁵ Hysterectomy was associated with a low reoperation rate. Removal of the ovaries did not significantly improve the surgery-free interval. Removal of both ovaries may be necessary in perimenopausal patients or when the ovaries are extensively damaged by the disease. Hormone therapy should be discussed with the patient when the ovaries are removed.²³ Most clinicians will consider use of combined estrogen and progestin therapy. The possible beneficial effect of progestins should be balanced against the risk of breast cancer and the risk of recurrent disease.²⁴

Adjunct surgical interventions

Presacral neurectomy and laparoscopic uterosacral nerve ablation (LUNA) have been performed for intractable endometriosis-associated chronic pelvic pain. These surgical therapies target midline pain and may have little impact on pain arising from other areas of the pelvis. A recent Cochrane review showed that there is insufficient evidence to recommend the use of LUNA in the management of dysmenorrhea, regardless of the cause.²⁵ Both procedures have fallen out of favor. A randomized trial in the United Kingdom showed that among women with chronic pelvic pain, LUNA did not result in improvements in pain, dysmenorrhea, dyspareunia, or quality of life compared with laparoscopy without pelvic denervation.²⁶

Medical and surgical therapies are often combined to treat advanced endometriosis. However, the advantages of either preoperative or postoperative medical therapy are debated. It is postulated that preoperative medical therapy facilitates the subsequent operative procedure. A Cochrane review found that hormonal suppression prior to surgery decreases the size of endometriotic implants, thereby reducing the extent of surgery required.²⁷

Postoperative medical suppressive therapy has been shown to be effective in decreasing endometriosis recurrence. This is especially the case if it is used for long periods of time.²⁸ Typically, however, postoperative medical therapy is used for a short period (6 months). Symptom recurrence is not usually seen while patients are receiving medical therapy. In a Cochrane review of post-surgical hormonal suppression compared with surgery alone, postoperative medical treatment decreased recurrence rates, but no benefit was observed for the outcomes of pain or pregnancy rates.²⁷

When comparing different postoperative treatment options, another Cochrane review showed that postoperative placement of a levonorgestrel-releasing intrauterine device (LNG-IUD) resulted in a greater reduction in recurrence of dysmenorrhea than administration of a gonadotropin-releasing hormone (GnRH) agonist,²⁹ although this has not been a widely adopted treatment.

For most women, symptom relief is the key treatment objective when managing endometriosis. While a large number of medical therapies are available, surgery may be warranted for patients who fail medical treatment, develop acute complications, or experience significant medication side effects. Conservative or definitive surgical interventions can be considered based on the patient’s age, extent of the disease, reproductive goals, treatment risks, side effects, and cost considerations. Current evidence is insufficient, however, to recommend adjunct surgical procedures involving presacral neurectomy or LUNA. Postoperative medical therapy is advised following incomplete removal of endometriotic implants to increase the duration of pain relief and delay symptom recurrence.

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