Endometriosis for the generalist

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Endometriosis is the presence of endometrial-like glands and stroma outside the uterus. It is a common cause of abdomino-pelvic pain, adnexal mass, and infertility in reproductive-age women. Endometriosis affects an estimated 10% to 20% of reproductive-age women and up to 70% to 90% of patients with chronic pelvic pain.^1-3 Several theories exist regarding the pathogenesis of endometriosis, with the most widely accepted being Sampson’s retrograde menstruation.^4,5 However, all theories have gaps, thus the exact pathophysiology of endometriosis remains enigmatic. 

Although hormonal management and surgery offer symptomatic relief, a cure for endometriosis continues to be elusive. Maneuvering through obstetric care, annual gynecologic visits, and the myriad of problem visits in a busy generalist practice is already challenging, and undertaking a thorough evaluation and management of endometriosis often leads to frustration to both patient and provider.

Initial evaluation
Ob/gyns should be prepared to have a lasting relationship with women with endometriosis because the condition is chronic and has no known cure. It is important to bear in mind that most patients have been dealing with pain for years prior to diagnosis, with a mean time of 7 to 11 years delay in diagnosis of endometriosis.⁶ The common 15- to 20-minute allotted time for a new patient consult will be wholly inadequate for an initial evaluation. To expect to review the pages of outside records that patients often have, obtain a comprehensive history, perform a detailed exam, and initiate an assessment/plan in this limited time is a set-up for patient and physician dissatisfaction.

Some changes to practice and communication go a long way. If possible, schedule all new pelvic pain or endometriosis consults for 30 minutes. When patients are scheduling their appointments, they should be asked to send any records over for review prior to the consult. This allows for focusing on the visit rather than scanning rapidly through pages of records during the allotted time. 

It is important to acknowledge the patient’s symptoms and the fact that they may have been present for a long time, while noting that it is unlikely that a solution will be available at the first consult. If outside medical records are available and have been reviewed, let the patient know that you have thoroughly reviewed them and are familiar with the location of her pain, aggravating factors, and prior medical and or surgical management. This allows for a focused and guided history that optimizes the consult time. 

If a detailed history of a patient’s symptoms is not available via outside records, then ask her about cyclic/noncyclic pain, pain with urination, pain with bowel movements, presence and site of pain with intercourse, bloating, fatigue, and disruptions in quality of life. Questions should also be asked to discern other potential causes of pelvic pain, including non-endometriosis gynecologic pain, gastrointestinal, urinary tract, musculoskeletal, psychological, and neurologic. Follow this with a detailed abdominal and pelvic exam. The pelvic exam should include a Q-tip evaluation of the vulva, single-digit vaginal exam to assess levator ani, obturator internus, piriformis, bladder, urethra, vaginal fornices, and uterosacral ligaments. A bimanual exam should then be performed, followed by a rectovaginal exam. Sometimes due to time constraints or inexperience with pelvic pain-centered exam, the pelvic exam portion of a patient’s note is normal and reads like a standard template. While this may, in fact, be the case, pertinent negatives of the exam components described above should be included. 

Imaging
Imaging of the pelvis can be used to rule out other causes of abdomino-pelvic pain, elaborate abnormal findings on exam, or to assess for endometriotic involvement of structures not palpated during the exam. The two common imaging modalities used in endometriosis imaging are pelvic ultrasound and magnetic resonance imaging (MRI). Pelvic ultrasound is the initial modality of choice because of its wide availability, relatively low cost, and utility for simultaneous assessment of pelvic structures and virtual diagnosis of most ovarian endometriomas.⁷

When pelvic exam or ultrasonography suggest advanced disease, i.e. deep infiltrating endometriosis (rectovaginal or uterosacral nodularity), some experts choose to order a pelvic MRI. This is done to determine the extent of deep infiltrating endometriosis and assess for rectovaginal nodules and bowel wall, bladder or ureteral involvement. Transvaginal ultrasound and pelvic MRI have been compared for their ability to identify deep infiltrating endometriosis, with both performing similarly. For MRI detection of rectosigmoid endometriosis, sensitivity was 85% (95% CI, 0.78-0.90) and specificity was 95% (95% CI, 0.83-0.99), while for transvaginal ultrasound, sensitivity was 85% (95% CI, 0.68-0.94), and specificity was 96% (95% CI, 0.85-0.99).⁸ For MRI detection of rectovaginal endometriosis, sensitivity was 66% (95% CI, 0.51-0.79) and specificity was 97% (95% CI, 0.89-0.99), while for transvaginal ultrasound, sensitivity was 59% (95% CI, 0.26-0.86) and specificity was 97% (95% CI, 0.94-0.99). For MRI detection of uterosacral ligament endometriosis, sensitivity was 70% (95% CI, 0.55-0.82) and specificity was 93% (95% CI, 0.87-0.97), while for transvaginal ultrasound, sensitivity was 67% (95% CI, 0.55-0.77) and specificity was 86% (95% CI, 0.73-0.93).⁸ It is important to note that while transvaginal ultrasound offers the advantage of dynamic imaging with pain- or tenderness-guided scanning, it is operator-dependent with expert guided transvaginal ultrasound performing better than routine scans.⁹ MRI has the advantage of imaging the abdomen and pelvis, assessing for endometriosis in less common sites (small bowel, appendix, abdominal wall), and has a reproducible protocol. Despite this performance, definitive diagnosis of endometriosis is surgical, preferably with laparoscopy. Presumptive diagnosis can be made without laparoscopy when typical symptoms are present, and patients can be started on medical management. 

Management
By the time most patients see a gynecologist for pelvic pain that later will be diagnosed with endometriosis, they have usually been on the first-line agent for pelvic pain, namely a nonsteroidal anti-inflammatory drug (NSAIDs). It is important to evaluate for and rule out other causes of pelvic pain before starting other therapies for a presumptive diagnosis of endometriosis. 

Endometriotic implants express hormone receptors, explaining the plausibility of hormonal suppression. There are several hormonal formulations available for managing endometriosis-related pain, including oral contraceptives (OCs), progestins, danazol, gonadotropin-releasing hormone (GnRH) agonists, GnRH antagonists, and aromatase inhibitors (AIs). It may be easier to divide these into first- (OCs and progestins), second-(danazol, GnRH agonists, and GnRH antagonists), and third-line agents (AI). A detailed patient history should identify comorbidities that may preclude use of certain classes of hormones in some women, such as migraines with aura, thrombosis, hypertension, and smoking status. 

Given the invasiveness of diagnostic laparoscopy, patients are often given a trial on NSAIDs and first-line agents for several months before surgery is considered. It is also reasonable to continue patients on these drugs after surgery. Although a variety of combined OC formulations are available and data support improvement in endometriosis pain,¹⁰ they do not support a benefit of one agent over another. 

Treatment can be started with a 20-µg ethinyl estradiol formulation, with titration up to a 35-µg pill as necessary. While patients are often initiated on cyclic use of combined OCs, they can be used in a continuous fashion. Both schedules have been shown to decrease pain, with an edge towards continuous use.^11,12 Available progestins include oral formulations such as the progestin-only pill (norethindrone 35 µg), norethindrone acetate 5 mg; depot medroxyprogesterone acetate, and the levonorgestrel intrauterine system. All of these have shown improvement in patient pain^13-17 and the limiting factors will often be patient preference, cost, and tolerability or side effect profile. Norethindrone acetate can be titrated to 10 or even 15 mg daily, but caution should be exercised if it is used for extended periods as it can adversely affect lipid levels. Side effects most often reported with progestins include weight gain, bloating, irregular bleeding, and mood changes. Depo provera carries risk of bone loss, but less than for GnRH agonists.¹⁴

Second-line agents can be used if a patient’s endometriosis fails to respond to a trial of first line agents or for postoperative medical suppression. GnRH agonists such as  Leuprolide acetate for depot suspension (monthly or 3-monthly), the most common second-line agent, or daily intranasal nafarelin have been shown to decrease endometriosis-related pain and can be offered to patients.^18-20 There is often some hesitancy in using these agents, given their significant side effect profile. Leuprolide acetate can be administered for 6 months without add-back or up to 12 months with add-back therapy, with daily oral norethindrone acetate 5 mg being the most commonly used add-back. The add-back limits the adverse effects on bone density and lessens vasomotor symptoms. Both leuprolide and continuous OCs achieve similar pain decreases in women with endometriosis, however, continuous OCs are considerably cheaper.¹⁹

The US Food and Drug Administration approved Elagolix, the first GnRH antagonist, in August 2018 after it demonstrated improvement in dysmenorrhea and non-menstrual pelvic pain in women with surgically diagnosed endometriosis.²¹ Two doses are available: 150 mg daily for 24 months and 200 mg twice daily for 6 months. Dyspareunia was improved on the higher dose. This agent adds to the armamentarium of medical therapy for endometriosis, but it is still quite new in clinical practice and there remain some insurance and prior authorization barriers. 

Danazol is an oral agent with high androgenic activity and related side effects including weight gain, decreased breast size, acne, hirsutism, deepening voice, and abnormal liver function tests.²² It is rarely used in practice nowadays, given the side effect profile and availability of other options. 

AIso, the third-line group of agents, are considered experimental and usage is typically in consultation with providers experienced or specializing in medical management of endometriosis. Certain factors have been associated with diagnosis of laparoscopy- confirmed endometriosis and are thus possibly amenable to lifestyle modifications. Missmer et al noted a higher incidence of laparoscopically-confirmed endometriosis in women with increased consumption of transfat and low intake of omega 3 fatty acids.²³ Risk of endometriosis was lower in women who consumed foods rich in thiamine, folate, vitamin C, and vitamin E, but that was not the case with consumption of those supplements alone.²⁴ Consumption of fresh fruits and green vegetables was also associated with a lower risk of endometriosis, while intake of red meat was associated with a higher risk.²⁵

Surgery 
The appropriate time to offer surgery will vary based on patient presentation, namely persistent pain, fertility evaluation, or abnormal imaging findings. Diagnostic laparoscopy should be offered to a patient with a presumptive diagnosis of endometriosis who has persistent pain despite 6 months of NSAIDs and first-line hormonal agents. Naturally, if large symptomatic endometriomas or deep infiltrating endometriosis are noted, surgery is also recommended. 

In the setting of a normal clinical exam and unremarkable imaging, it is important to discuss the possibilities of negative laparoscopy and also minimal-to-no change in pain following surgery. In the setting of significant deep infiltrating endometriosis, usually of the rectosigmoid or rectovaginal septum, it is equally important to have a preoperative discussion with the patient about the extent of surgery and excision as well as the associated surgical morbidity. This shared decision-making might reveal how aggressive a patient wants her procedure to be, a particularly important point, as the disease occurs in mostly otherwise healthy women. The notion of a bowel resection might be comprehensible for postmenopausal ovarian cancer, but not necessarily for a benign condition like endometriosis in a young patient, despite its significant impact on quality of life. That being said, the goal of surgery should be to offer a diagnosis and to address all endometriosis present. 

The most widely used staging system for endometriosis is the revised ASRM classification.²⁶ Visually, endometriosis has been described with various appearances, from vesicular, clear, red, blue, brown, powder burn, fibrotic, to Allen-Masters peritoneal defect. While many providers rely solely on visual diagnosis before proceeding to destroy endometriotic lesions, it is important to note that correct visual diagnosis of endometriosis, especially stage I disease, can be as low as 50%.²⁷

The gold standard for diagnosis should be histology, not visual. It is advisable to perform an exam under anesthesia as relaxation of the pelvis allows for a detailed exam that is often more accurate than in the clinic setting. Another tip in refining and improving exams performed in the clinic is to repeat one after laparoscopic visualization of lesions. For example, if a uterosacral nodule is noted on laparoscopy, perform a digital vaginal and rectovaginal exam under laparoscopic view. This offers unique real-time feedback about where the pelvic hand needs to be for a correct uterosacral examination. The same is true for rectovaginal nodules. It is important to know how high or low nodules are from the anal verge and  the relation of nodules to the pouch of Douglas, posterior cervix, and lower pelvic sidewall. Unfortunately, pneumoperitoneum will prevent adequate bimanual examination of the adnexa while under laparoscopic vision. Performing these exams habitually will lead to improved accuracy in exams performed in the office. 

For superficial peritoneal lesions encountered during laparoscopy, either excision or ablation of endometriosis can be performed as studies suggest that pain outcomes are similar.^28,29 In patients who have had prior laparoscopy with pathology-confirmed endometriosis, if superficial peritoneal lesions are found during future surgery, they can be ablated, but that again is surgeon preference. Ovarian endometriomas should be excised and not drained due to an 80% to 100% recurrence risk.^30,31

With the combination of a detailed clinical exam and imaging, it is possible to identify most cases of advanced stage endometriosis. When this is suggested by the evaluation in a symptomatic patient, the procedure should be performed by a surgeon experienced in surgical management of these complicated cases. This avoids an incomplete resection followed by referral for repeat surgical procedure. Finally, there is ample evidence that a hormonal regimen should be commenced following surgery in women who do not actively desire fertility.^{11,15,19,32,33} A continued partnership with the patient should be fostered, as the typical course is often one of trials of various hormonal formulations over time. Gynecologists are at the forefront of the care for women with endometriosis.  An understanding of the evaluation and comprehensive management of the condition therefore is mandatory to improve quality of life for patients.

Disclosures:

The author reports no potential conflicts of interest in regard to this article.

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