Endometriosis: Medical treatment of pelvic pain

INTRODUCTION — 

Endometriosis, a disease characterized by endometrial implants outside of the endometrial cavity, is a chronic inflammatory process that requires a continuous management during the reproductive period. Treatment goals include maximizing medical therapy to control symptoms and avoiding repeat surgical intervention. Despite extensive research, the optimal management of endometriosis and its related symptoms is unclear.

This topic will review medical options for treating pelvic pain caused by endometriosis. Surgical treatment options for endometriosis are presented separately. (See "Endometriosis: Surgical management of pelvic pain".)

Additional content related to the pathophysiology, clinical presentation, and diagnosis of endometriosis is available in other topics:

●(See "Endometriosis in adults: Pathogenesis, epidemiology, and clinical impact".)

●(See "Endometriosis: Clinical manifestations and diagnosis of rectovaginal or bowel disease".)

In this topic, when discussing study results, we will use the terms "woman/en" or "patient(s)" as they are used in the studies presented. We encourage the reader to consider the specific counseling and treatment needs of transgender and gender-expansive individuals.

PRETREATMENT CONSIDERATIONS

Importance of counseling and shared decision-making — As there are no data supporting one treatment or treatment combination over another, the treatment choice involves shared decision-making with the patient and is based upon symptom severity, patient preferences around drug exposure and dosing, medication side effects, treatment efficacy, contraceptive needs, costs, and availability [1]. Medical treatment options include nonsteroidal analgesics, hormonal contraceptives, gonadotropin-releasing hormone (GnRH) analogs (agonists and antagonists), and aromatase inhibitors (AIs).

The general advantages and disadvantages of medical treatment of endometriosis-related pelvic pain are listed in the table (table 1). Of note, medical interventions do not improve fertility or treat complications of deep endometriosis such as ureteral obstruction [1,2]. Patients with these problems generally proceed with therapy targeted at the specific problem. (See 'Treatment of special populations' below.)

Need to exclude other sources of symptoms — Prior to treatment, all patients should have a thorough history and examination. Other sources of pelvic pain are excluded, particularly for patients with sudden increase in pain symptoms on top of their baseline pain levels. (See "Chronic pelvic pain in adult females: Evaluation".)

Decision to proceed with surgery — The decision to proceed with surgery varies based on the severity and duration of the patient's symptoms, response to prior therapies, and history of prior surgery. Patients whose pain does not adequately respond to a trial of medical therapy are generally offered laparoscopy for diagnosis and treatment. Individuals with severely disabling symptoms may reasonably wish to proceed with a surgical evaluation sooner. (See "Endometriosis in adults: Clinical features, evaluation, and diagnosis", section on 'Indications, timing, and technique'.)

Excision of endometrial implants, endometriomas, and adhesions is performed at the time of surgery. Surgical intervention may be conservative (retain uterus and ovarian tissue) or definitive (removal of the uterus, and possibly the ovaries, in women who have completed childbearing). The decision is based on the patient's preferences, child-bearing plans, and age. After surgery, hormonal suppression (usually with continuous oral contraceptives [COCs]) is started to prevent recurrence of symptoms. (See "Endometriosis: Surgical management of pelvic pain".)

Patients with endometrioma — For patients who have an endometrioma as part of their disease presentation, treatment is influenced by the severity of the symptoms, as discussed above, as well as by the imaging characteristics of the endometrioma and patient's desire for future fertility. Patients with mild to moderate symptoms may benefit from a trial of hormonal treatment, as outlined above. Those with severe symptoms likely related to the endometrioma may prefer surgical removal. The clinical evaluation and treatment options for patients with ovarian endometriomas are reviewed in more detail separately. (See "Endometriosis: Management of ovarian endometriomas".)

Role of long-term management — We agree with the American Society for Reproductive Medicine (ASRM) Practice Committee statement that "endometriosis should be viewed as a chronic disease that requires a lifelong management plan with the goal of maximizing the use of medical treatment and avoiding repeated surgical procedures" [3]. Thus, we aim to manage the patient's pain with medical therapy and supportive therapies, such as pelvic floor physical therapy, for as long as possible and limit the number of surgical interventions. As with all management plans, the patient's preferences shape the final treatment plan.

INITIAL TRIAL OF NSAID PLUS HORMONAL TREATMENT

Approach — We prescribe nonsteroidal anti-inflammatory drugs (NSAIDs) (table 2) and hormonal treatment, typically with continuously dosed hormonal contraceptives (table 3), as first-line medications because these therapies are low-risk, have few side effects, and relieve symptoms for many patients [1,3,4]. Selection of estrogen-progestin or progestin-only therapy is mostly based on patient preferences around hormone content, administration route, dosing frequency, contraceptive efficacy, and adverse effects. Individuals who cannot use NSAIDs may use acetaminophen instead or use hormonal treatment alone.

While this approach is consistent with recommendations from major societies and is theoretically cost-effective [1,3,5], there are no data supporting the superiority of one NSAID or hormonal treatment over another. Additionally, treatment decisions are individualized and consider clinical presentation (eg, pain, infertility, mass), symptom severity and duration, disease extent and location, reproductive desires, patient age, medication side effects, surgical complication rates, and cost. Patients with severe symptoms who do not wish a trial of NSAID/hormonal treatment may reasonably proceed with an initial trial of gonadotropin-releasing hormone (GnRH) analog (agonist or antagonist) instead. (See 'Patients with persistent symptoms' below.).

NSAIDs — Multiple NSAIDs are available (table 2). One commonly used regimen is ibuprofen 400 mg orally every 4 to 6 hours, maximum dose of 2400 mg per 24 hours. Patients who cannot use NSAIDs are offered acetaminophen 650 mg orally every 4 to 6 hours, maximum dose of 3000 mg per 24 hours.

Individuals who desire pregnancy can use NSAIDs, although we avoid selective COX-2 inhibitors (celecoxib, rofecoxib, and valdecoxib) as some studies indicate these drugs can prevent or delay ovulation, although peripheral hormonal cyclicity is typically maintained [6-8].

NSAID mechanisms of action, dosing, and use are presented in related topics:

●(See "NSAIDs (including aspirin): Pharmacology and mechanism of action".)

●(See "NSAIDs: Therapeutic use and variability of response in adults".)

Combined estrogen-progestin contraceptives — Combined estrogen-progestin contraceptives (COCs; ie, oral pills, transdermal patches, or vaginal rings) are often the first-line treatment given their general availability and lower cost compared with long-acting methods (table 3) [1]. We prefer extended- or continuous-dosing regimens of these short-acting methods to reduce or avoid withdrawal bleeding. Supporting data and mechanisms of action are presented below. (See 'Hormonal contraceptives' below.)

Detailed descriptions of the combined estrogen-progestin formulations are available separately:  

●(See "Combined estrogen-progestin oral contraceptives: Patient selection, counseling, and use".)

●(See "Contraception: Transdermal contraceptive patches".)

●(See "Contraception: Hormonal contraceptive vaginal rings".)

Progestin-only treatment — Progestin-only options include contraceptives (oral progestin-only contraceptive pills, depot medroxyprogesterone acetate [DMPA] injections, etonogestrel implant, and levonorgestrel intrauterine devices [LNG IUDs]) and oral norethindrone acetate. DMPA, LNG IUDs, and etonogestrel implant also provide highly effective contraception. Oral norethindrone acetate is not considered a contraceptive but has oral dosing and a short half-life if the patient desires to stop the method. By contrast, norethindrone 0.35 mg is avoided for patients with endometriosis-related pain because it does not suppress ovulation and is not associated with a hypoestrogenic state [9]. As with other treatments, selection is based on patient preferences around hormone content, administration route, dosing frequency, contraceptive efficacy, and adverse effects.

Discussions of each method, including dosing and adverse effects, are presented separately.

●(See "Contraception: Progestin-only pills (POPs)".)

●(See "Depot medroxyprogesterone acetate (DMPA): Efficacy, side effects, metabolic impact, and benefits".)

●(See "Depot medroxyprogesterone acetate (DMPA): Formulations, patient selection and drug administration".)

●(See "Intrauterine contraception: Background and device types", section on 'Levonorgestrel IUDs'.)

●(See "Contraception: Etonogestrel implant".)

Assess response — Patients are typically reassessed three to four months after initiation of NSAID/hormonal treatment. Next steps are based on treatment response:

●Patients with adequate symptom improvement continue this approach until pregnancy is desired or the average age of menopause is reached.

●Patients with persistent severe symptoms are offered the next line of therapies. Patients who have not yet received surgical diagnosis and treatment generally do so at this point and then proceed with the next treatment options.

●Patients with partial improvement are given the choice of continuing NSAID/hormonal therapy, trying an alternate medication combination, or proceeding to the next step.

PATIENTS WITH PERSISTENT SYMPTOMS — 

Patients with inadequate response to initial NSAID/hormone treatment have the option of trying an alternate medication, as discussed above, or proceeding with a gonadotropin-releasing hormone (GnRH) analog (antagonist or agonist). While the decision for one approach below over the other is patient-dependent and involves discussion of medication dosing frequency and route, treatment duration, and adverse effects, among others, patients often prefer antagonists for oral dosing and reduced adverse effects.

●GnRH antagonists – GnRH antagonists include elagolix (commercial name Orilissa) and relugolix combination therapy (combination relugolix, estradiol, and norethindrone acetate, commercial name Myfembree) [10,11]. Advantages of GnRH antagonists over agonists include oral dosing, less impact on bone mineral density, and, for relugolix, that the add-back therapy is included in the same pill. Patients treated for up to 2 years had a mean bone mineral density loss of < 1 percent; bone density loss mostly occurred by 36 weeks and then remained stable [12]. For these reasons, GnRH antagonists are more commonly used than agonists for patients with persistent symptoms. Use, dosing, and efficacy data are presented below. (See 'GnRH antagonists' below.)

●GnRH agonists – GnRH agonists include nafarelin and leuprolide as well as goserelin and buserelin, where available. Similar to society recommendations, we start GnRH agonist and add-back therapy simultaneously [1,3]. This strategy limits bone loss, reduces vasomotor symptoms, and improves compliance without reducing efficacy [3,13-16]. Summary discussions of use, dosing, and efficacy data for these agents are presented below. (See 'GnRH agonists' below.)

Detailed discussions of GnRH agonist efficacy, adverse effects, and need for add-back therapy are presented in related content. (See "Endometriosis: Long-term treatment with gonadotropin-releasing hormone agonists".)

Symptoms are reassessed after three to four months of GnRH analog treatment (typically GnRH antagonist). Patients with adequate symptom improvement can continue the regimen until pregnancy is desired or menopause is achieved. Patients with refractory symptoms are offered a trial of the alternate therapy (ie, agonist treatment is switched to antagonist treatment, or vice versa). Patients are again reassessed for improvement after three to four months of treatment. Patients with adequate symptom control continue the regimen while those with refractory symptoms proceed as below. (See 'Patients with refractory symptoms' below.)

PATIENTS WITH REFRACTORY SYMPTOMS — 

Patients whose symptoms persist despite adequate trials of GnRH antagonists and/or agonists, and who are not proceeding with surgery, may be offered medical therapy with danazol or aromatase inhibitors. We counsel patients on the androgenic side effects of danazol and, for aromatase inhibitors (AIs), discussion of off-label use and need for add-back therapy. (See 'Danazol' below and 'Aromatase inhibitors' below.)

We offer neuropathic pain treatment to patients with persistent pain. Discussions of neuropathic pain and treatment options are reviewed separately. (See "Overview of pharmacologic management of chronic pain in adults", section on 'Pharmacologic therapy for neuropathic or nociplastic pain'.)

COMPLEMENTARY THERAPIES

●Pelvic floor physical therapy – Pelvic floor physical therapy is a common treatment for chronic pelvic pain in females and appears to reduce pain in adolescent and adult patients with endometriosis [17,18]. Pelvic muscle spasm may be one contributory mechanism for patients with endometriosis as a study reported increased pelvic muscle spasm in patients with deep endometriosis as seen on magnetic resonance imaging (MRI; n = 104) compared with those without endometriosis (n = 52) [19].

●Acupuncture – In a systematic review of acupuncture for treatment of endometriosis-related pain, only one randomized trial met the inclusion criteria [20]. In that trial (n = 67), auricular acupuncture was significantly more effective than Chinese herbal medicine for treating dysmenorrhea in women with endometriosis [21].

●Diet – There are no dietary recommendations for prevention or treatment of endometriosis. One study reported that a lower risk of developing endometriosis was associated with a high intake of green vegetables and fruit and an increased risk with intake of beef or other red meat or ham [22]. Risk of endometriosis was not associated with alcohol, coffee, fish, and milk. Several studies have addressed the correlation of diet and dysmenorrhea, but not exclusively in patients with endometriosis. (See "Dysmenorrhea in adult females: Treatment", section on 'Diet and vitamins'.)

SUPPORTING DATA FOR MEDICAL TREATMENT OPTIONS

Nonsteroidal anti-inflammatory drugs — Nonsteroidal anti-inflammatory drugs (NSAIDs) effectively treat primary dysmenorrhea (table 4) [23]. NSAIDs are be considered the first-line treatment for pelvic pain, including endometriosis-related pain. However, there are no high-quality data reporting NSAID efficacy in treating pain due to endometriosis, nor have NSAIDs been shown to be superior to other agents or to placebo [24]. Use of NSAIDs is based on their ready availability, low cost, acceptable side-effect profile, and trial data consistently demonstrating effective reduction of primary dysmenorrhea. (See "Dysmenorrhea in adult females: Treatment".)

While NSAIDs are commonly combined with a contraceptive hormonal therapy, women who desire conception can use NSAIDs alone. For women attempting conception, we avoid selective COX-2 inhibitors (celecoxib, rofecoxib, and valdecoxib) as some studies indicate these drugs can prevent or delay ovulation, although this may not delay peripheral hormonal cyclicity [6-8]. (See "Dysmenorrhea in adult females: Treatment", section on 'Nonsteroidal anti-inflammatory drugs'.)

Adverse events associated with NSAID use are presented separately. (See "Nonselective NSAIDs: Overview of adverse effects".)

Hormonal contraceptives — Hormonal contraceptives include combined estrogen-progestin products (COCs; eg, oral pill, transdermal patch, or vaginal ring) and progestin-only contraceptives (eg, oral pills, long-acting injections, implants, and intrauterine devices [IUDs]). As all of these options have demonstrated pain reduction, patient preferences become the basis for treatment selection [1].

Comparative data — Trials that directly compare hormonal treatment options with each other and placebo are generally lacking. In a trial of 405 patients undergoing conservative endometriosis surgery and randomly assigned postoperative treatment with either combined hormonal contraceptives or progestin-only contraceptives, both groups reported 40 percent reductions in pain scores at three years of follow-up when compared with their preoperative values [25]. Postoperative treatments included COCs (any type) or long-acting progestin-only methods (depot medroxyprogesterone acetate [DMPA] or levonorgestrel 52 mg intrauterine devices [LNG 52 mg IUDs]). This trial adds to the body of evidence supporting both estrogen-progestin and progestin-only contraceptives for reducing endometriosis-related pain symptoms,

Estrogen-progestin contraceptives — Combined estrogen-progestin treatments include COCs, transdermal patches, and vaginal rings (table 3) [1,26,27]. Combined contraceptives are commonly for first-line treatment because they can be used long term, are well-tolerated, are relatively inexpensive and easy to use, and provide contraception and additional benefits, including decreasing the risk of ovarian and endometrial cancers [28,29]. No method or drug combination has been demonstrated as superior to another.

●Supporting data – The body of evidence, including randomly assigned trials and a systematic review, supports using combined hormonal contraceptives for treating endometriosis-related pain symptoms [25,30-33]. By contrast, one meta-analysis limited to two trials concluded that the evidence was insufficient to make a judgment [34]. Study challenges include differing combinations and doses of medications, duration of follow-up, study size and design, and varying tools used to assess pain.

●Dosing – As no formulation has demonstrated superiority, we typically begin with a COC containing 20 mcg of ethinyl estradiol given in a continuous dose fashion (table 3). While both cyclic and continuous-dose hormonal regimens appear to be effective at reducing endometriosis-related pain [35,36], two systematic reviews (one with meta-analysis) reported that continuous COC regimens were more effective at reducing pain symptoms than cyclic COC regimens [28,37]. Additionally, one trial reported that the efficacy of COC treatment was equivalent to GnRH treatment (goserelin) at reducing pelvic pain, but the trial was limited by small sample size (57 women) and relatively short duration (12 months) [36]. (See "Contraception: Counseling and selection", section on 'The shared decision-making process' and "Hormonal contraception for menstrual suppression", section on 'Combined estrogen-progestin methods'.)

●Mechanism of action – Estrogen-progestin contraceptives are thought to suppress ovarian function and thereby reduce endometriosis disease activity and pain [38]. The purported therapeutic mechanism is progestin-induced decidualization and subsequent atrophy of endometrial tissue [39]. In addition, estrogen-progestin contraceptives may slow progression of disease, although evidence is conflicting [35,40].

●Advantages and side effects – In general, patients at increased risk of a thromboembolic event should avoid estrogen-containing drugs. Risks and side effects of estrogen-progestin contraceptives are presented separately. (See "Combined estrogen-progestin contraception: Side effects and health concerns".)

Progestins — Oral progestin-only treatments include norethindrone acetate 5 mg taken once daily, dienogest 2 mg once daily (available outside the United States), or gestrinone 2.5 mg orally twice weekly (a mixed progesterone agonist/antagonist available outside the United States). Long-acting options include DMPA (150 mg intramuscularly or 104 mg subcutaneously every three months), the etonogestrel implant, and the LNG 52 mg IUD. By contrast, norethindrone 0.35 mg is avoided for patients with endometriosis-related pain because it does not suppress ovulation and is not associated with a hypoestrogenic state [9]

●Supporting data – In a trial including 405 patients undergoing conservative surgery for endometriosis, three-year treatment with DMPA, levonorgestrel 52 mg IUD, or COCs all reduced pain scores by 40 percent compared with preoperative values [25,41].

●Formulations and dosing – Patients with endometriosis-related pain may select among daily oral pills, injectables, and long-acting options (etonogestrel implant or LNG 52 mg IUD). The choice of progestin depends upon the contraceptive needs of the patient, side-effect profile of the various drugs, and patient preferences around dosing route and schedule.

•Oral progestins – The oral progestins most commonly used to treat endometriosis-related pain include the 19-nortestosterone derivatives norethindrone acetate (5 mg dose) and dienogest, but there are others (table 3) [3].  

-Norethindrone acetate – A commonly used regimen of norethindrone acetate is 5 mg by mouth daily, but the dose can be increased to 15 mg daily depending on side effects including breakthrough bleeding [42]. Advantages of norethindrone include low cost, general availability, and reduction of endometrioma size [43]. (See "Endometriosis: Management of ovarian endometriomas".)

-Dienogest – Dienogest is prescribed as a 2 mg oral pill taken daily [44]. In our practice, we reserve dienogest for those who do not tolerate norethindrone acetate because the treatment outcomes appear to be similar [45], but norethindrone acetate is less expensive and dienogest has been associated with decreased bone mineral density [44]. In systematic reviews of progestin therapy for pain associated with endometriosis, dienogest was superior to placebo [46,47]. Dienogest has also been demonstrated to reduce ovarian endometrioma size [48,49].

Dienogest is also available in combination with estradiol valerate as part of a multiphasic oral contraceptive pill (commercial name Natazia), but this formulation is not for use in patients with contraindications to estrogen treatment [50].

-Gestrinone – Gestrinone (ie, ethylnorgestrienone, a synthetic steroid with mixed progesterone agonist/antagonist effects available in Europe) is an alternate treatment option. The dose is gestrinone 2.5 mg orally twice weekly. Because efficacy data specific to endometriosis-related pain are limited, we prefer the progestin therapies reviewed above. In a meta-analysis including two small studies, treatment with either gestrinone or danazol resulted in similar reductions in pain [46].

•Depot medroxyprogesterone acetate (DMPA) – DMPA can be given as 150 mg intramuscular injection every three months or as a 104 mg subcutaneous injection every three months [51,52].

-(See "Depot medroxyprogesterone acetate (DMPA): Formulations, patient selection and drug administration".)

-(See "Depot medroxyprogesterone acetate (DMPA): Efficacy, side effects, metabolic impact, and benefits".)

•Etonogestrel implant – In a systematic review including 335 patients with endometriosis-related pain from 11 studies, etonogestrel implant users reported improved visual analog scale (VAS) scores for cyclic pelvic pain, noncyclic pelvic pain, and dyspareunia compared with baseline [53]. Symptom improvements were similar to those reported for DMPA users. A different trial comparing etonogestrel implant use with levonorgestrel IUD use in 103 patients with endometriosis-related pain reported both treatments reduced pain as reported by VAS scores for dysmenorrhea and chronic pelvic pain [54]. [55] (See "Contraception: Etonogestrel implant".)

•Levonorgestrel 52 mg intrauterine device (LNG 52 mg IUD) – The LNG 52 mg IUD is generally viewed as an effective treatment for endometriosis-related pain, although conflicting data exist [1,56]. Small trials evaluating the LNG 52 mg IUD with other treatments concluded that there was limited but consistent evidence that postoperative LNG IUD use reduced the recurrence of dysmenorrhea in women with surgically confirmed endometriosis compared with expectant management [57,58], GnRH agonist [59], and DMPA [60]. Unlike long-term DMPA use, LNG 52 mg IUD treatment does not impact bone mineral density [61]. However, a 2021 review of two trials including 95 total patients could not determine if postoperative LNG IUD use reduced dysmenorrhea or improved quality of life for patients with symptomatic endometriosis because of lack of adequate blinding of study participants and personnel [56].

●Mechanisms of action – Progestins are synthetic progestogens that inhibit endometrial tissue growth by causing initial decidualization and then atrophy [3]. Additional proposed mechanisms of action include suppression of matrix metalloproteinases, a class of enzymes important in the growth and implantation of ectopic endometrium [39], and inhibition of angiogenesis [62].

●Advantages and side effects – Progestin-only treatments have several advantages compared with other medical therapies. Progestin-only treatment avoids the estrogen-related thromboembolic risk seen with estrogen-containing contraceptives. Compared with the GnRH analogs (antagonists or agonists), high-dose oral progestin treatment is not associated with bone loss and is less expensive. Compared with danazol, progestins are better tolerated, have no androgenic side effects, and have a less detrimental impact on lipids. (See 'GnRH antagonists' below and 'GnRH agonists' below and 'Danazol' below.)

Side effects of progestin treatment can include irregular uterine bleeding/spotting, amenorrhea (dienogest), weight gain, mood changes (eg, depression), and bone loss (specific to long-term use of DMPA). Additionally, long-term use of norethindrone acetate can lead to a significant reduction in high-density lipoprotein cholesterol and significant increases in low-density lipoprotein cholesterol and triglycerides; lipid levels are monitored in patients on long-term therapy [63].

•(See "Drugs that affect bone metabolism", section on 'Medroxyprogesterone acetate (monotherapy)'.)

•(See "Depot medroxyprogesterone acetate (DMPA): Efficacy, side effects, metabolic impact, and benefits", section on 'Reduction in bone mineral density'.)

GnRH antagonists — GnRH antagonists (eg, elagolix, relugolix) competitively bind to the receptor without triggering a response, rapidly suppressing pituitary gonadotropin hormone production and creating a hypoestrogenic state [64]. Pituitary suppression is nearly immediate, and the drug can be titrated (eg, the response increases with increasing dose). Unlike GnRH agonists, antagonist agents are dosed orally, effective immediately, do not cause an initial surge in luteinizing and follicle-stimulating hormone, and do not require 7 to 14 days for GnRH suppression [10,65,66].

●Dosing and adverse effects

•Elagolix – Elagolix is an oral tablet approved for treatment of moderate-to-severe endometriosis-related pain [10,67]. For this indication, elagolix is given alone (ie, without add-back). Data on combination elagolix with norethindrone for endometriosis symptoms are pending.

Elagolix is available in doses of 150 mg (taken once daily for up to 24 months) or 200 mg (taken twice daily for up to six months). We start with the lower dose and increase to the higher dose as needed for patients whose symptoms are not adequately controlled, such as those with deep dyspareunia. The medication is started within seven days of menses.

-Contraindications – Contraindications include pregnancy and hepatic dysfunction (Child-Pugh Class B).

-Adverse effects – These include hot flushes or night sweats as the drug is used without add-back estrogen and progestin.

•Relugolix combination therapy – Relugolix has been studied as a combination therapy (relugolix-estradiol-norethindrone [norethisterone acetate; 40 mg/1 mg/0.5 mg]) [11,65]. The relative therapeutic contribution of each drug (relugolix, estradiol, norethindrone) is unknown, nor is it known if relugolix combination therapy is superior to norethindrone alone.

-Contraindications – Because it may increase the risk of thromboembolism, it is contraindicated in patients with increased risk for or history of thromboembolic disorders [11].

-Adverse effects – Relugolix combination therapy has been associated with allergic reactions, including anaphylaxis, urticaria, and angioedema [66].  

●Pain reduction – For elagolix, patients reported decreased pain scores of approximately 40 percent with the lower dose regimen and nearly 80 percent for the higher dose [68,69]. For relugolix, patients reported clinically meaningful and sustained improvements in dysmenorrhea (85 percent) and nonmenstrual pelvic pain (76 percent) [12]. In the author's experience, about 60 percent of patients who did not respond to initial therapies will improve with GnRH antagonists.

●Hypoestrogenic symptoms and bone loss – GnRH antagonists induces a dose-dependent hypoestrogenic state to inhibit endometriotic cell proliferation. Both symptom relief and hypoestrogenic adverse effects, including vasomotor phenomena, vaginal atrophy, and bone loss, are dose-dependent. For elagolix, six-month mean changes from baseline in lumbar spine bone density were approximately -0.5, -2.6, and +0.5 percent in the low-dose, high-dose, and placebo trial groups, respectively [68,69]. In patients using relugolix combination therapy, initial bone loss was <1 percent and then remained stable over two years of therapy [12]. For comparison, six months of treatment with the GnRH agonist leuprolide (without add-back) reduces bone density by approximately 6 percent. (See "Endometriosis: Long-term treatment with gonadotropin-releasing hormone agonists", section on 'Side effects'.)

●Review of trial data

•Elagolix trial data – Two phase-three trials compared two different doses of the oral GnRH antagonist elagolix (150 mg once daily or 200 mg twice daily) with placebo in patients with endometriosis-related dysmenorrhea and noncyclic pelvic pain [68,69].

-Pain reduction – Patients in both elagolix groups reported significantly reduced symptoms and improved quality of life (Endometriosis Health Profile-30 questionnaire) at three months of treatment [68,69]; these reductions persisted at six months of follow-up [70]. In both trials, at three months, meaningful reductions in dysmenorrhea pain were reported by approximately 44 percent of the low-dose elagolix group, 74 percent of the high-dose elagolix group, and 21 percent of the placebo group. Nonmenstrual pelvic pain was decreased in 50, 56, and 36 percent of women in the low-dose, high-dose, and placebo groups, respectively. Hot flushes were the most common adverse event. However, the improvement in dysmenorrhea in the low-dose elagolix group was modest compared with previously published data on the GnRH agonist depot-leuprolide acetate. (See 'GnRH agonists' below.)

-Adverse events and side effects – While 72 percent or more of women in all three groups noted an adverse event, side effect-driven discontinuation rates of up to 10 percent were reported in both treatment and placebo groups. Patients in the treatment groups reported significantly more hot flushes (mostly mild to moderate), headache, and insomnia and had higher serum lipids levels (total cholesterol, low-density lipoprotein, high-density lipoprotein, and triglycerides) compared with women receiving placebo.

•Relugolix combination therapy data – In two phase-three trials and the follow-up extension study, patients treated with relugolix combination therapy (relugolix-estradiol-norethindrone [norethisterone acetate; 40 mg/1 mg/0.5 mg]) reported clinically meaningful reductions in dysmenorrhea and nonmenstrual pelvic pain compared with placebo [12,65]. Reductions in dysmenorrhea were reported at six, 12, and 24 months for patients taking combination therapy (percent responders: 75 percent at six months, 84.8 percent at 12 months, and 84.8 percent at 24 months compared with 27 to 30 percent for patients receiving placebo in the 12-week study) [12]. Reductions in nonmenstrual pelvic pain were 58 to 66 percent at six months, 73.6 percent at 12 months, and 75.8 percent at 24 months, compared with approximately 40 percent for patients receiving 12 weeks of placebo. At the end of the two-year study, 91 percent of patients were opioid-free and 75 percent were analgesic-free. Across the entire study period, commonly reported adverse effects were headache (52.7 percent), nasopharyngitis (22.7 percent), and hot flushes (14.8 percent).

GnRH agonists — GnRH agonists include nafarelin, leuprolide, buserelin, goserelin, and triptorelin.

●Efficacy and comparative data – In a trial comparing GnRH agonist treatment, laparoscopy, and combined medical/surgical treatment, all three groups reported an overall cure rate of ≥50 percent [71]. A meta-analysis of 41 trials including nearly 5000 women reported that GnRH agonists were more effective than placebo and as effective as other medical therapies (danazol, levonorgestrel, COC) for relieving pain [72]. The meta-analysis concluded that the evidence was limited regarding optimal dose and treatment duration and no route of administration appeared superior to others.

●Treatment regimens – Commonly used drug regimens with demonstrated efficacy for improving endometriosis-related symptoms include leuprolide acetate 3.75 mg intramuscular injection given monthly, leuprolide acetate 11.25 mg intramuscular injection given every three months, and intranasal nafarelin acetate 200 mcg given twice daily [73-75]. Medication selection is driven by availability and cost.

●Concomitant use of add-back therapy – To minimize the hypoestrogenic side effects of GnRH agonist treatment, we begin hormone add-back therapy at the same time as the GnRH agonist [1,3]. We prefer treatment with oral norethindrone acetate 5 mg daily but other regimens are reasonable. (See "Endometriosis: Long-term treatment with gonadotropin-releasing hormone agonists", section on 'GnRH with add-back therapy'.)

●Mechanisms of action – GnRH agonists bind to receptors in the pituitary gland. Because GnRH analogs have a longer half-life than native GnRH, the pituitary-ovarian axis is down-regulated and hypoestrogenism results [3]. Endometriosis-related pain is likely treated by the induction of amenorrhea and progressive endometrial atrophy [39]. The hypoestrogenic state is the main source of adverse effects, including hot flushes, vaginal dryness, decreased libido, mood swings, headache, and decreased bone density [76]. Negative effects can be reduced by add-back therapy, typically with oral norethindrone acetate or a combination of estrogen and progestin (ie, COC pill) [3]. When GnRH agonists are used with add-back therapy, side effects are often better tolerated compared with a progestin-only or danazol treatment. (See "Endometriosis: Long-term treatment with gonadotropin-releasing hormone agonists", section on 'Pharmacology of GnRH agonists' and "Endometriosis: Long-term treatment with gonadotropin-releasing hormone agonists", section on 'GnRH with add-back therapy'.)

●Side effects – Side effects from GnRH agonist use are mostly related to the resultant hypoestrogenism and include vasomotor symptoms, urogenital syndrome of menopause, and bone loss. Adverse effects of GnRH agonists are reviewed separately. (See "Endometriosis: Long-term treatment with gonadotropin-releasing hormone agonists", section on 'Side effects'.)

Danazol — While danazol is effective at treating endometriosis-related pain, it is not commonly used because of androgenic side effects.

●Supporting data – In a systematic review of five trials, all of which included women with surgically diagnosed endometriosis, six months of danazol treatment was more effective than placebo in relieving endometriosis-related pain [77]. In one of the included studies, the improvement in pain scores persisted at six months after discontinuation of therapy [78].

●Dosing – Danazol is typically given orally in divided doses ranging from 400 to 800 mg daily, generally for six months. Additionally, one systematic review reported symptom relief with vaginal dosing, particularly for women with rectovaginal endometriosis [79].

●Side effects – Reported adverse effects, including acne, muscle cramps, edema, weight gain (5 percent of body weight), spotting, hirsutism, and voice deepening were common and limited the use of danazol in the above studies [77,78,80].

●Mechanisms of action – Danazol is a derivative of 17 alpha-ethinyltestosterone [39]. It primarily inhibits the luteinizing hormone surge and steroidogenesis, and increases free testosterone levels. Its mechanisms of action include inhibition of pituitary gonadotropin secretion, direct inhibition of ovarian enzymes responsible for estrogen production, and inhibition of endometriotic implant growth.

Aromatase inhibitors — The author reserves aromatase inhibitor (AI) treatment for women with severe, refractory, endometriosis-related pain based on small trials and observational studies that have reported reductions in mean pain scores and lesion size with AI combination treatment [1,81-86]. AIs, such as anastrozole or letrozole, are used in combination with progestins, estrogen-progestin contraceptives, or GnRH analogs (agonists or antagonists) to minimize side effects and avoid ovarian stimulation by aromatase inhibitor monotherapy [1,87,88]. Patients are informed that treatment of endometriosis is an off-label use of these medications.

●Dosing – Typical treatments include oral anastrozole 1 mg once daily or oral letrozole 2.5 mg once daily. The AI is prescribed in combination with a GnRH analog, norethindrone acetate, or an oral estrogen-progestin contraceptive to suppress follicular development [89]. For women unable to use GnRH analogs or oral estrogen-progestin contraceptives, oral norethindrone acetate 5 mg per day is another option.

●Mechanisms of action – These agents appear to regulate local estrogen formation within the endometriotic lesions themselves, in addition to inhibiting estrogen production in the ovary, brain, and periphery (eg, adipose tissue) [81,90].

●Side effects – AI side effects include bone loss with prolonged use, hot flashes, sexual dysfunction, musculoskeletal pain, and ovarian follicular cyst development.

Side effects of AI treatment are presented in detail separately. (See "Managing the side effects of tamoxifen and aromatase inhibitors".)

TREATMENT OF SPECIAL POPULATIONS

Infertility — Women with infertility and pain caused by endometriosis are not candidates for hormone suppression therapies because hormonal suppression prevents pregnancy and does not improve fertility [2]. The treatment of infertility associated with endometriosis involves a combination of surgery and assisted reproduction technology. We offer nonsteroidal anti-inflammatory drugs (NSAIDs) to women with pain. A stepwise approach to treatment of infertility in women with endometriosis is presented separately. (See "Endometriosis: Treatment of infertility in females".)

Deep endometriosis — Deep infiltrating endometriosis is a term used to describe infiltrative forms of the disease that involve the uterosacral ligaments, rectovaginal septum, bowel, ureters, or bladder. The management of rectovaginal or bowel endometriosis is impacted by the presenting symptoms, location of lesions, and patient preference. At least one study supports expectant management of asymptomatic women with deep endometriosis [91]. For women with bothersome urinary or bowel symptoms (eg, urinary urgency or frequency, dyspareunia, dysmenorrhea, or dyschezia), medical therapy with hormonal suppression is appropriate [92,93]. Surgery is indicated for women with ureteral or bowel obstruction or women whose symptoms do not improve with medical management [5,94]. (See "Endometriosis of the bladder and ureter" and "Endometriosis: Clinical manifestations and diagnosis of rectovaginal or bowel disease".)

Lesions of nonreproductive organs — Endometriosis has been reported in the upper abdomen, diaphragm, abdominal wall (umbilicus, surgical scar), perineum (episiotomy or obstetric scar), and thorax [5]. Complications such as pneumothorax are treated as indicated; ovarian suppression can be added to limit disease progression or treat pain.

Typically, ovarian suppression with gonadotropin-releasing hormone (GnRH) analogs are the first-line agents because they are highly effective at suppressing ovarian hormone production and inhibiting the growth of endometrial tissue [95-105]. Obstruction of the ureter or bowel should be treated surgically; medical therapy is not effective [5]. (See "Clinical features, diagnostic approach, and treatment of adults with thoracic endometriosis" and "Endometriosis of the bladder and ureter", section on 'Ureteral endometriosis' and "Endometriosis: Treatment of rectovaginal and bowel disease", section on 'Treatment considerations'.)

Presumed endometriosis — Women with pain from presumed endometriosis can also benefit from the approach detailed above. It is reasonable to begin medical therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) and hormonal treatment without a definitive diagnosis because these treatments are low risk. However, surgically confirming the diagnosis is preferred before initiating medication with significant side effects, such as GnRH analogs [3]. (See "Endometriosis in adults: Clinical features, evaluation, and diagnosis", section on 'Presumptive clinical diagnosis'.)

MEDICATIONS TO AVOID — 

We avoid using misoprostol and selective estrogen receptor modulators (SERMs) for the treatment of endometriosis-related pain. While misoprostol has demonstrated efficacy for pain reduction, its associated side effects of dyspareunia and hot flushes make it less preferred compared with the treatments above [106]. We do not use SERMs based on limited data suggesting inadequate effect [107].  

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Endometriosis".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Endometriosis (The Basics)")

●Beyond the Basics topic (see "Patient education: Endometriosis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●General principles – Endometriosis is a chronic inflammatory disease that requires continuous management during the reproductive period. Treatment goals include maximizing medical therapy to control symptoms and avoiding repeat surgical intervention. Each treatment plan is individualized to include patient preferences and takes into account the clinical presentation, symptom severity, disease extent and location, reproductive desires, patient age, medication side effects, surgical complication rates, and cost. (See 'Pretreatment considerations' above.)

●Initial trial of NSAID and hormonal treatment – For patients with endometriosis-related pain, we suggest nonsteroidal anti-inflammatory drugs (NSAIDs) (table 4) and continuous hormonal contraceptives (table 3) rather than either agent alone (Grade 2C). Patients who wish to conceive can use the NSAID alone. (See 'Initial trial of NSAID plus hormonal treatment' above.)

These therapies have demonstrated efficacy and are low-risk, have few side effects, are low-cost, and are generally well-tolerated compared with other medical therapies. Patients who wish to conceive can use the NSAID alone.

●Assess response – Symptoms are reassessed after three to four months of treatment. (See 'Assess response' above.)

•Symptoms respond – Patients with adequate symptom improvement continue the hormonal therapy/NSAID regimen until pregnancy is desired or the average age of menopause is reached.

•Symptoms persist – Patients with persistent severe symptoms are offered the next line of therapies. Patients who have not yet received surgical diagnosis and treatment generally do so at this point and then proceed with the next treatment options.

●Patients with persistent symptoms – For patients with inadequate treatment response, we suggest a trial of a gonadotropin-releasing hormone (GnRH) analog rather than other drugs or surgical resection (Grade 2C). GnRH analogs include antagonists (eg, elagolix or relugolix combination therapy) and agonists (eg, nafarelin, leuprolide acetate, goserelin, and buserelin). Patients generally prefer antagonists because of the rapid onset of action and oral dosing. (See 'Patients with persistent symptoms' above.)

●Patients with refractory symptoms – Patients who continue to have refractory symptoms despite the above treatments and who are not proceeding with surgery may be offered medical therapy with danazol or aromatase inhibitors (AIs). Danazol use is limited by androgenic side effects and use of AIs for endometriosis is off-label. (See 'Patients with refractory symptoms' above.)

●Complementary therapies – Pelvic floor physical therapy may help reduce pelvic pain in patients with endometriosis-related pain. The impact of acupuncture is less clear. There are no dietary recommendations for the prevention or treatment of endometriosis. (See 'Complementary therapies' above.)

●Treatment of special populations – Patients with endometriosis-related pain who warrant additional consideration include those with infertility, deeply infiltrating endometriosis, and extra-pelvic lesions. (See 'Treatment of special populations' above.)