Managing Endometriosis: Research and Recommendations

"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this 12-part journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

Endometriosis is a complex disease with manifestations well beyond the pelvic cavity. Extrapelvic manifestations are very probably underreported and therefore undertreated, noted Cara R. King, DO, a gynecologic surgeon in Madison, Wisconsin, and associated with the Cleveland Clinic.

Even totally negative imaging will not rule out the presence of endometriosis, and even a very small amount of lesions can sometimes cause more pain than widespread adhesions.

Treatment varies with the patient's degree of pain and individual priorities. "Most of our medical therapies are hormone-based, but if a patient is trying to get pregnant, then obviously we can't use hormone therapy," King said.

First-line therapy consists of progestin-based therapy (including combined oral contraceptives) as well as non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and naproxen. "But if the clinical exam and imaging indicate deep nodules or large endometriomas in the pelvic cavity, we may be pushed to go right to surgery," she explained.

If patients are on hormone suppressive therapy for 3 or 4 months with no improvement, "then it's time to switch gears," King said.

As for surgery, this is a highly complex procedure and needs special training, she explained. "And there's a lot of controversy as to whether to use ablation or excision of lesions."

Laparoscopic ablation is performed with energy sources such as lasers and electrocautery. "But ablation just burns the surface of the lesions and leaves the rest in place. And you can't burn the lesions that are on top of another organ," King noted.

Nor can ablation remove endometriotic tissue for histological identification under the microscope, and if left unremoved, tissue can continue to cause harm. Her typical gold standard, she said, is complete excision, which she said she has found can significantly relieve pain.

The European Society of Human Reproduction and Embryology (ESHRE) issued an updated guideline in Feb. 2022 on more than 100 recommendations on best practices on caring for women with endometriosis, including for relief of painful symptoms.

Regarding ablation versus excision of endometriosis, the guideline states that a 2017 systematic review and meta-analysis found three randomized clinical trials (RCTs) that compared the two approaches. One trial was not included in the meta-analysis because of incomplete data but showed that excision and ablation "equally improved pelvic pain associated with mild endometriosis."

The other two RCTs showed that laparoscopic excision was "significantly superior" to ablation in reducing symptoms of Endometriosis Health Profile-30 core pain score, dyschezia, and chronic pelvic pain. There was also a nonsignificant trend in reduction of dysmenorrhea and dyspareunia scores after excision compared with ablation. As the ESHRE guideline noted, subsequent 5-year follow-up of one of the trials showed that excision was better than ablation in treating deep dyspareunia.

Also as noted in the ESHRE guideline, a 2021 systematic review and meta-analysis aimed to update the literature on the surgical management of "minimal to mild" endometriosis, and concluded that there were no significant differences between the excision and ablation groups in improving pain measured with specific parameters.

When surgery is performed, clinicians may consider excision instead of ablation of endometriosis to reduce endometriosis-associated pain, the ESHRE recommendation concluded.

Christine Metz, PhD, of Northwell Health's Feinstein Institutes for Medical Research in Manhasset, New York, noted that no clinical trials have compared these two approaches in patients with a wide range of disease from surface lesions to deep-infiltrating lesions to determine whether excision surgery versus ablation surgery is optimal.

"Many endometriosis lesions grow into tissues like an iceberg where only the top of the iceberg or lesion is visible, so excision surgery is more effective because it scoops the lesions out of the tissues compared to ablation, which may only remove the top of the iceberg, leaving the bottom iceberg intact," she explained.

King noted that endometriosis can also lead to changes in nerve pathways resulting in hypersensitivity to pain and recurrent pain in the bladder and bowel and spasms in the pelvic muscle. "This hyperalgesia has a continuing impact on nerve generators – they make more nerve tissue and the volume is turned up."

How does surgery stack up against medical therapy? A German study compared medical versus surgical versus combined medical-surgical therapies for recurrence of symptoms, pain, and lesions in 450 endometriosis patients. "Patients who received combined treatment had the best outcome," Metz said. "It is important to note that this is influenced by the success of the surgery and the location and stage/type of the lesions."

As noted in the ESHRE guideline, a 2020 Cochrane review assessed the data for pain and disease recurrence in the short-term (i.e., 12 months or less), looking at gonadotropin-releasing hormone (GnRH) agonists, danazol, letrozole, oral contraceptives, and progestogens, and concluded that compared with use of surgery alone, postsurgical medical therapy may decrease pain recurrence at 12 months or less.

Regarding disease recurrence, there may be a decrease in favor of postsurgical medical therapy compared with no therapy, the review found. (Postoperative levonorgestrel-releasing intrauterine system (LNG-IUS) was not included as an intervention in the review.)

The ESHRE guidelines also pointed to a randomized controlled trial of 55 patients with endometriosis and moderate-to-severe dysmenorrhea randomized after surgery to LNG-IUS or expectant management. At 12 months, those in the LNG-IUS group had significantly lower median scores for dysmenorrhea and noncyclical pelvic pain, greater reduction in dysmenorrhea visual analogue scale (VAS) score (-81.0 vs -50.0 mm) and pelvic pain VAS score (-48.5 vs -22.0 mm). The reduction in dyspareunia VAS was comparable between the groups. Two patients in the LNG-IUS group (7.4%) and nine in the expectant management group (39.1%) had recurrent dysmenorrhea within the first postoperative year.

The American College of Obstetricians and Gynecologists (ACOG) concurs that surgery has its limitations. While surgery is associated with a significant reduction in pain during the first 6 months, as many as 44% of women have a recurrence of symptoms within a year. Moreover, there are no data on whether surgery influences long-term therapy and no data to indicate whether medical or surgical therapy results in better fertility outcomes.

In some cases where medical therapies have been unsuccessful, full hysterectomy-salpingo-oophorectomy may be warranted, said King. "But since a patient may continue to have pain even then, the endometriosis will still have to be addressed."

"We need more research into better medical treatments, especially nonhormonal options for women who want to get pregnant," she said. "Most of the current focus is on earlier treatment. There are some studies looking at immunomodulators and biologics."

In the meantime, physicians have an array of therapeutic choices, but studies of medical treatments are few, and evidence for their effectiveness varies in strength and quality.

Medical Management

According to the ACOG practice management guidelines for endometriosis, evidence suggests that pain can be managed with NSAIDs, oral contraceptives, progestins, the androgen danazol and GnRH analogues such as leuprorelin (Lupron) and triptorelin (Decapeptyl). Treatment with GnRH agonists initially stimulates the release of gonadotropins but ultimately release is suppressed through receptor downregulation and desensitization. The menstrual cycle is thereby interrupted, resulting in a hypoestrogenic state, endometrial atrophy, and amenorrhea.

More recently, GnRH antagonists such as elagolix have become available. These are better tolerated than the analogues and may be introduced earlier into treatment. They also downregulate the hypothalamic-pituitary-gonadal axis, suppressing ovulation and reducing estrogen levels. They generally are better tolerated with fewer side effects than the agonists, and some doctors may introduce them into treatment earlier, especially if progestin-based therapy is failing.

Aromatase inhibitors targeting the enzyme that converts androgens to estrogen are another option. These agents include letrozole (Femara) and anastrozole (Arimidex).

While NSAIDs and GnRH analogues have been shown to reduce the size of lesions, there is no evidence that such treatment prior to pregnancy improves fertility outcomes, except in the case of in vitro fertilization.

Postoperative Medical Therapy

Hormone therapy with estrogen can be used after hysterectomy and bilateral salpingo-oophorectomy. But endometriosis typically recurs in as many as 15% of women even if they do not receive postoperative estrogen therapy.

However, hormone therapy may stimulate the growth of residual ovarian or endometrial tissue after total hysterectomy and bilateral salpingo-oophorectomy, and there is also the potential for estrogen-induced malignant transformation in residual endometriosis. While this concern has led some physicians to routinely recommend adding a progestin to estrogen therapy, this is based on expert opinion and should be continued for at least a year following definitive surgery for endometriosis to minimize the risk of recurrences.

Non-Medical Approaches

For some women with endometriosis, exercise, improved sleep and rest habits or psychologically based mind-body approaches such as biofeedback, relaxation, yoga, meditation, and cognitive behavioral therapy can ease the chronic pain, fatigue, stress, anxiety, and depressive symptoms of endometriosis.

On the dietary front, omega-3 fatty acids (cold-water fatty fish, avocados, walnuts) have been found to decrease pain scores in some studies. Eliminating the consumption of specifically pro-inflammatory foods such as gluten, fatty meats, caffeine, alcohol, sugary drinks, and processed foods can also mitigate symptoms in some individuals.

A diet low in FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) of the type used to ease irritable bowel syndrome has shown benefit in some studies.

The ESHRE guidelines recommend that clinicians discuss non-medical strategies, including nutrition, with women with endometriosis to address quality of life and psychological well-being. Still, no recommendations can be made for any specific non-medical intervention to reduce pain or improve quality-of-life measures "as the potential benefits and harms are unclear," the document states.

However, "more studies are emerging," the document continues, and "it seems evident that women are searching for alternative ways of managing and coping without or alongside surgical and pharmacological interventions ... This highlights the importance of giving the woman the opportunity to gain information about nonmedical strategies in specialist pain management services with the expertise in managing complex abdomino-pelvic pain, and the potential benefits of local support groups."

Read previous installments of this series:

Part 1: Endometriosis: Understanding the Pathogenesis and Pathophysiology

Part 2: Diagnosing Endometriosis