Endometriosis

Endometriosis

1. What every clinician should know

Background and Clinical Presentation

Endometriosis is the presence of endometrial stroma and glands outside the uterus. While endometrial implants are most commonly found in the pelvis, distant implants have been reported. The most common site of endometriosis is the ovaries, followed by the anterior and posterior cul de sac, posterior broad ligaments, uterosacral ligaments, uterus, fallopian tubes, sigmoid colon/appendix, and round ligaments.

The most common presenting complaint is pain, which may be cyclic or constant as a result of chronic inflammation. Pain may be localized, diffuse or referred. Other symptoms include chronic pelvic pain, dysmenorrhea, deep dyspareunia, abnormal uterine bleeding, chronic fatigue, low back pain, presence of a pelvic mass, and infertility. Not all patients with endometriosis are symptomatic. No correlation between severity of symptoms and severity of disease has been established.

Prevalence

The prevalence of endometriosis is estimated to be 10% of reproductive age women, 30% of women with infertility and 50% of adolescents undergoing laparoscopy for pelvic pain.

Pathogenesis

The most widely accepted hypothesis of pathogenesis is Sampson’s theory of retrograde menstruation, according to which shed endometrial tissue is refluxed through the fallopian tubes to attach and proliferate in the pelvis. This is supported by an increased incidence of endometriosis in women with uterine outflow obstruction and has also been demonstrated in animal models where eutopic endometrial tissue placed in the peritoneal cavity leads to development of endometriosis. However, retrograde menstruation has been demonstrated in women with and without endometriosis, suggesting other factors mediate the development of the disorder.

Altered immunity is another pathogenetic theory, according to which host immune defenses fail to clear endometrial tissue from extrauterine locations. This theory is supported by findings of increased peritoneal fluid leukocytes, cytokines, and growth factors in patients with endometriosis. Women with endometriosis may suffer from a higher rate of other autoimmune and inflammatory disorders. One survey found higher rates of autoimmune inflammatory diseases, hypothyroidism, fibromyalgia, chronic fatigue syndrome, allergies and asthma in women with endometriosis compared to women in the general population.

Genetic Basis

The genetic basis of endometriosis is complex and multifactorial in nature. There is some evidence for a genetic predisposition to endometriosis, with a higher probability of endometriosis seen in first degree relatives of those with the disorder, as well as a high concordance rate in twins. Several genetic polymorphisms have been shown to be associated with endometriosis; however, at this time there is no clinical role for genetic testing in the diagnosis of endometriosis.

2. Diagnosis and differential diagnosis

Evaluation of the Patient with Suspected Endometriosis

In patients with suspected endometriosis, a thorough history and review of systems should be performed. Associated symptoms may help guide the practitioner’s diagnostic strategy, as many disorders have overlapping symptomatology. Pelvic pain questionnaires, such as the Short Form McGill Pain Questionnaire, may be helpful in determining response to treatment but have not been shown to be helpful in differentiating endometriosis from other disorders.

Physical Exam

Physical exam findings are variable and depend on the size and location of the implants. Often patients have no physical findings; however, the most common sign of endometriosis is tenderness on palpation of the posterior vaginal fornix. Other findings may include tenderness, nodularity or thickening in the posterior cul de sac and uterosacral ligaments, pain with uterine manipulation, adnexal tenderness or enlargement, and a fixed adnexa or fixed, retroverted uterus.

Role of Diagnostic Imaging

The ease of use and cost-effectiveness of transvaginal ultrasound make it the first choice in initial evaluation of suspected endometrioid cysts of the ovaries, also known as endometriomas. More than 50% of histologically confirmed endometriomas have a classic ultrasound appearance of diffuse, low-amplitude internal echoes, enhanced sound transmission and a visible, uniform wall that may contain bright echoes. Nonclassical endometriomas may have a heterogeneous component as well as a thickened wall or apparent septations, representing compressed ovarian tissue. Endometriomas are typically vascular, with Doppler flow sometimes mimicking an ovarian neoplasm.

MRI is a second-line imaging modality that has been found to be 77% sensitive and 78% specific in identification of endometrial implants, and 91% sensitivity and 95% specific in identification of endometriomas. Endometriomas characteristically have a homogeneous hyperintensity on T1-weighted images and relative hypointensity on T2-weighted images, but may also have a complex appearance due to the presence of blood or debris. Intravenous contrast may be useful in differentiating endometriomas from other neoplasms. MRI may be useful preoperatively in patients with known or suspected deep infiltrating rectovaginal implants in determination of the most appropriate surgical strategy. However, routine use of MRI is not recommended for the diagnosis of endometriosis.

Laboratory Evaluation

Serum CA-125 levels are often elevated in women with endometriosis, with values correlating somewhat with stage of endometriosis. Levels over 100 have been associated with the presence of extensive adhesions or ruptured endometrioma. Routine testing of CA-125 is not recommended in patients with known or suspected endometriosis.

Pelvic Laparoscopy

The gold standard for the diagnosis of endometriosis is direct visualization and biopsy of endometriotic implants via laparoscopy with histopathologic confirmation of endometrial glands and stroma. However, these features are seen in only 70% of clinically suspected cases. Endometriotic lesions are variable in appearance, including classic blue-black “powder burn lesions”, white opacification, translucent blebs, raised flame-like patches or reddish/reddish blue irregularly shaped islands. Often these lesions are seen in the background of scarred peritoneal surfaces or peritoneal defects. Ovarian implants may be either superficial or deep, cystic lesions known as chocolate cysts or endometriomas. Careful inspection should be performed of the entire pelvis and abdomen including the rectovaginal space and appendix. (See subsection on “Prophylactic Appendectomy” under “Pain-Surgical Management” below.)

Staging of endometriosis should be performed according to the American Society of Reproductive Medicine Revised Classification of Endometriosis as part of the patient’s medical record. When endometriosis is noted, excision or ablation of endometrial implants should be performed (Figure 1). (Also see section on “Pain-Surgical Therapy” below.)

Figure 1.n

Differential Diagnosis

There is a wide overlap in symptoms between patients with endometriosis and other conditions. These may include pelvic inflammatory disease, irritable bowel syndrome, interstitial cystitis, adenomyosis, ovarian neoplasms, pelvic adhesions, diverticular disease, musculoskeletal pain and colon cancer. In patients with significant bladder or bowel symptoms, referral to a specialist for evaluation should be performed prior to initiation of medical or surgical therapy.

3. Management

Therapy should be individualized according to the severity of symptoms, extent and location of disease, desire for fertility, age of the patient and possible side effects of medical and surgical therapy. Most patients seek treatment for one of three reasons: pain, infertility or a pelvic mass. As the goals of therapy differ, they will be discussed separately.

Pain

For patients with pain as their primary symptom, treatment options include expectant management, analgesia, hormonal medical therapy, surgery (either conservative or definitive) or combined medical and surgical therapy. It is preferable to excise or ablate implants at the time of diagnostic laparoscopy to avoid progression of lesions. For conservative surgery, the goal should be to decrease the volume of endometrioid implants to slow progression of the disease and improve response to medical therapy.

Expectant Management

Expectant management may be considered in an asymptomatic patient. The patient should be counseled on the progressive nature of the disease and possible worsening of symptoms in the future. Perimenopausal patients can often be managed expectantly, as decreased estrogen levels after menopause usually suppress the disease.

Medical Therapy

Medical therapy in patients with mild or moderate pain is a safe and effective approach prior to surgical diagnosis. We recommend a stepwise approach:

• Nonsteroidal inflammatory medications (NSAIDs): Many patients will note significant relief of symptoms with NSAIDs. These may be used alone or in conjunction with other medications.

• Oral contraceptives: Most studies have shown a decrease in both endometriosis symptoms and progression of disease with continuous combined oral contraceptives.

• Progestins: Norethindrone acetate taken daily is FDA approved for pelvic pain secondary to endometriosis. Alternatively, a levonorgestrel-releasing intrauterine system (Lng-IUS), is highly effective in reducing pain.

• GnRH agonists: GnRH agonists have been shown to decrease pain for up to 2 years after discontinuation of therapy. The FDA has approved their use for up to 12 months, but several studies have shown that they may be administered up to 10 years without significant bone loss when given in conjunction with progestin or combined low dose estrogen (0.625 mg daily) and progestin. We recommend initiating treatment with GnRH agonists with norethindrone acetate (5mg). Patients who cannot tolerate high dose progestin addback, low dose conjugated estrogen (0.625 mg) combined with medroxyprogesterone acetate (5mg) may be effective. Due to the estrogen-dependent nature of endometriosis, estrogen only addback is not recommended. Patients receiving GnRH agonists longer than 1 year should have yearly bone mineral density testing.

(See Table I. Medical Therapy for Endometriosis)

Table 1.n

Other Medical Therapies

Danazol has been used in the treatment of endometriosis-related pain with good success; however, hyperandrogenic side effects including possible permanent voice deepening limit its use. There is limited evidence that rectal dosing may reduce these side effects.

Aromatase inhibitors are known to decrease estrogen, in theory decreasing endometriotic implant progression; however, there are few studies to date reviewing their efficacy and safety for this indication. At this time, further randomized, controlled trials are needed prior to their routine clinical use.

Surgical Therapy

For patients with severe pelvic pain, or who have failed medical therapy, conservative surgical therapy is appropriate. All visible endometriotic lesions should be excised or ablated as this has been shown to reduce pain. The decision whether to excise or ablate depends on the location of the lesion and the level of surgical expertise. For implants overlying structures which undergo thermal damage, such as the ureter, excision is recommended. There is no evidence that one method of ablation is better than another, i.e. laser, monopolar, bipolar. After conservative surgery, we recommend initiation of medical therapy to prevent disease progression and to reduce the need for repeat surgical procedures.

Endometriomas should have the cyst wall completely resected rather than simple drainage to avoid cyst recurrence and need for reoperation.

Presacral neurectomy is a procedure in which the sympathetic innervation to the uterus is interrupted at the level of the superior hypogastric plexus. It has been found to be effective in decreasing midline dysmenorrhea but has not been effective in decreasing other symptoms. This procedure has a significant risk of bleeding from the adjacent venous plexus and should be reserved for surgeons experienced in this technique only for the indication of midline dysmenorrhea.

Laparoscopic Uterosacral Nerve Ablation (LUNA) is a procedure in which the efferent nerves in the uterosacral ligaments are disrupted to decrease pain and dysmenorrhea. LUNA has not been found to be more effective than conservative surgery in decreasing dysmenorrhea and is not recommended alone or in combination with conservative surgery.

Definitive surgical therapy is an option for patients with debilitating symptoms secondary to endometriosis who have failed conservative therapies and have completed childbearing. As endometriosis is an estrogen-dependent condition, hysterectomy with bilateral salpingectomy is recommended with debulking of endometriotic implants at the time of surgery. Hysterectomy without bilateral salpingectomy has been found to be less effective, with higher recurrence and reoperation rates.

Hormone replacement to manage menopausal symptoms after definitive surgery should be used with caution as estrogen may cause activation of endometriosis. Combined estrogen and progestin therapy is preferred as it has been shown to have a lower risk of recurrent disease than unopposed estrogen. Definitive surgery should be undertaken only after careful consideration, as bilateral oophorectomy in younger patients leads to increased risk for cardiac disease, worsening lipid profiles, and decreased bone mineral density.

In cases of known or suspected severe disease, we recommend preoperative consultation with a surgeon skilled at surgically correcting colorectal and/or severe adhesive disease.

Prophylactic Appendectomy

At the present time there is no consensus in whether patients with chronic pelvic pain should undergo prophylactic appendectomy. In patients with chronic pain, it may be beneficial in eliminating appendicitis from the differential diagnosis during acute pain exacerbations. Appendectomy should be performed for visible endometrial appendiceal implants.

Preoperative Medical Therapy

Preoperative hormonal suppression to reduce the size of endometrioid implants has not been shown to reduce the amount of surgical dissection, decrease operative time, improve postoperative pain relief, improve pregnancy rates or decrease recurrence rates.

Postoperative Medical Therapy

Postoperative hormonal suppression with combined oral contraceptive pills, progestins, levonorgestrel releasing intrauterine device and GnRH agonists is controversial. While the above methods have been been shown in individual studies to increase pain free intervals and decrease recurrence rates, systematic reviews have not shown improvement in pain or recurrence rates.

Infertility

Medical Therapy

While medical therapy for endometriosis is helpful in alleviating painful symptoms of the disease, it has not been shown to be effective in increasing fecundity. Several randomized controlled trials studying the effect of Danazol, gonadotropin releasing hormone agonists and antagonists, progestins, and combined estrogen-progestin therapy have not shown any improvement in infertility associated with stage I or II endometriosis versus expectant management.

Surgical Therapy

In women with stage I or II endometriosis, laparoscopic ablation or resection of endometriosis is associated with a small increase in live birth rates compared to no treatment. There is no evidence that ablation versus excision affects outcomes.

In women with stage III or IV endometriosis without other infertility issues, conservative surgical treatment (utilizing either laparoscopy or laparotomy) has been found to significantly increase pregnancy rates compared to no treatment.

Combination Medical and Surgical Therapy

Use of preoperative or postoperative GnRH agonists have not been found to enhance fertility and are not recommended as they may further delay fertility treatment.

In patients with Stage I or II endometriosis and infertility, superovulation combined with intrauterine insemination has been shown in multiple studies to increase cycle fecundity. In patients with more severe disease, in vitro fertilization (IVF) has been shown to increase pregnancy rates. Several studies have shown that pretreatment with GnRH agonists for 6 months prior to IVF increases the number of oocytes retrieved, embryos transferred and pregnancies. However, pre-IVF use of GnRH agonists is not widely accepted at this time.

Treatment of infertile women with endometriosis is difficult due to the small number of randomized controlled trials and conflicting results. The patient’s age, duration of infertility and presence of pain should guide therapy.

• Infertile women with known or suspected stage I or II endometriosis younger than age 35 may be treated with clomiphene/IUI, gonadotropin/IUI or IVF prior to performing laparoscopy.

• Patients age 35 and over should be treated more aggressively due to the combined effect of age and endometriosis.

• In patients with stage III or IV endometriosis, laparoscopy or laparotomy is recommended. In patients with prior infertility surgeries, IVF may be the best option.

Pelvic Mass

Surgery is the preferred treatment for or symptomatic endometriomas as medical therapy does not result in regression. This allows confirmation of diagnosis, exclusion of malignancy and may eliminate the need for emergency surgery due to rupture or torsion. It should be noted that even with careful resection of an endometrioma, ovarian reserve may be diminished post-operatively.

4. Complications

Patients with endometriosis may experience a multitude of complications such as pain and infertility. Painful symptoms decrease quality of life, resulting in missed work, increased medical costs and psychosocial distress. Endometriosis is the third most common reason for hysterectomy in the US.

Patients with a diagnosis of endometriosis have a 7.4-fold increase in ovarian cancer. Endometriosis is identified in 17% of ovarian cancers. However, most ovarian cancers associated with endometriosis are found in postmenopausal patients taking unopposed estrogen, which may allow progression of endometrial implants.

Endometriosis may be found in areas remote from the peritoneum, leading to misdiagnosis or concern for neoplasm. For example, cervical endometriosis may be misclassified as high grade intraepithelial lesion or atypical glandular cells on cervical cytology screening.

Treatment complications include adverse medication side effects, multiple surgeries, infertility or early surgical menopause (due to decreased ovarian reserve). In severe cases, patients may require colonic resection to remove deeply infiltrating endometriotic implants. As a result of adhesive and infiltrative disease, surgery may be especially challenging, with a higher risk of surgical complications such as bowel, bladder or ureteral injury.

5. Prognosis and outcome

Even when surgery is performed by an experienced surgeon, 6-51% of women with endometriosis will have recurrence within 5 years. Factors predictive of recurrence include: younger age at first laparoscopy, stage III or IV disease, high pre-operative pain score and becoming pregnant after surgery. Patients with a younger age at menarche and more severe dysmenorrhea are at higher risk for pain recurrence.

Because endometriosis is an estrogen-dependent disease, symptoms tend to regress after menopause.

6. What is the evidence for specific management and treatment recommendations

Droz, J, Howard, FM. “Use of the Short-Form McGill Pain Questionnaire as a diagnostic tool in women with chronic pelvic pain.”. J Minim Invasive Gynecol. vol. 18. 2011 Mar-Apr. pp. 211-7.

Kinkel, K, Frei, KA, Balleyguier, C, Chapron, C. “Diagnosis of endometriosis with imaging: a review”. Eur Radiol. vol. 16. 2006. pp. 285-98. Good reference for treatment of pelvic pain.

Cheng, YM, Wang, ST, Chou, CY. “Serum CA-125 in preoperative patients at high risk for endometriosis”. Obstet Gynecol. vol. 99. 2002. pp. 375CA-125 levels may be elevated in patients with endometriosis.

Gustofson, RL, Kim, N, Liu, S, Stratton, P. “Endometriosis and the appendix: a case series and comprehensive review of the literature”. Fertil Steril. vol. 86. 2006. pp. 298

“The Practice Committee of the American Society for Reproductive Medicine. Endometriosis and Infertility”. Fertil Ster. vol. 86. 2006. pp. S156-60.

Benaglia, L, Somigliana, E, Vighi, V. “Rate of severe ovarian damange following surgery for endometriomas”. Human Reprod. vol. 25. 2010. pp. 678

Allen, C, Hopewell, S, Prentice, A. “Non-steroidal anti-inflammatory drugs for pain in women with endometriosis”. Cochrane Database of Systematic Reviews. 2005. pp. CD004753

Somigliana, E, Vigano’, P, Parazzini, F, Stoppelli, S, Giambattista, E, Vercellini, P. “Association between endometriosis and cancer: a comprehensive review and a critical analysis of clinical and epidemiological evidence”. Gynecol Onc. vol. 101. 2006. pp. 331-41.

Coccia, ME. “Long-term followup after laparoscopic treatment for endometriosis: multivariate analysis of predictive factors for recurrence of endometrioitic lesions and pain”. Eur J Obstet Gynecol. 2011.

Sallam, HN, Garcia-Velasco, JA, Dias, S, Arici, A. “Long-term pituitary down-regulation before in vitro fertilization (IVF) for women with endometriosis”. Cochrane Database of Systematic Reviews. 2006. pp. CD004635

Bedaiwy, MA, Casper, RF. “Treatment with leuprolide acetate and hormonal add-back for up to 10 years in stage IV endometriosis patients with chronic pelvic pain”. Fertil Steril.. vol. 86. 2006. pp. 220

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