Endometriosis: Treatment of pelvic pain

INTRODUCTION — Endometriosis, which is characterized by endometrial implants outside of the endometrial cavity, is a chronic disease that requires a lifelong management plan. Despite extensive research, the optimal management of endometriosis and its related symptoms is unclear. This topic will review medical and surgical options for treating pelvic pain caused by endometriosis.

Other topics related to endometriosis are discussed separately:

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

●(See "Endometriosis: Surgical management of pelvic pain".)

●(See "Endometriosis: Long-term treatment with gonadotropin-releasing hormone agonists".)

●(See "Endometriosis: Management of ovarian endometriomas".)

●(See "Endometriosis of the bladder and ureter".)

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

●(See "Clinical features, diagnostic approach, and treatment of adults with thoracic endometriosis".)

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 diverse individuals.

GENERAL PRINCIPLES — Treatment decisions are individualized and consider clinical presentation (eg, pain, infertility, mass), symptom severity, disease extent and location, reproductive desires, patient age, medication side effects, surgical complication rates, and cost. We agree with the American Society for Reproductive Medicine 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" [1].

Prior to treatment, all women should have a thorough history and examination. Other sources of pelvic pain are eliminated. (See "Chronic pelvic pain in adult females: Evaluation".)

OUR APPROACH — Our treatment plan is based on the severity of the patient's endometriosis-related pain. As noted above, other causes of pelvic pain are excluded. We aim to manage the patient's pain with medical therapy for as long as possible and thus limit the number of surgical interventions.

For women with mild to moderate pain (eg, pain symptoms that do not cause regular absence from school or work) and no ultrasound evidence of an endometrioma, we prescribe nonsteroidal anti-inflammatory drugs (NSAIDs) (table 1) and continuous hormonal contraceptives (table 2) as the first line of treatment because these therapies are low-risk, have few side effects, and provide relief of symptoms for many women. Women 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 [2-4]. Management of women with an endometrioma is presented separately. (See 'Endometrioma' below and "Endometriosis: Management of ovarian endometriomas".)

While this approach is supported by recommendations from major societies and has theoretical cost efficacy [1,5,6], there are no data supporting superiority of one NSAID or hormonal contraceptive over another. Selection is based on patient preference, availability, and cost.

●In women without medical contraindications, we prefer combined estrogen-progestin contraceptives (pill, patch, or vaginal ring) combined with an NSAID. (See 'Estrogen-progestin contraceptives' below.)

●For women who cannot or choose not to use estrogen therapy, we prescribe progestin-only contraceptive pills (ie, norethindrone 0.35 mg taken once daily) with an NSAID. (See 'Progestins' below.)

We reassess the woman's symptoms after three to four months of combined treatment. Women with adequate symptom improvement are continued on the hormonal therapy/NSAID regimen until pregnancy is desired or the average age of menopause is reached. Women whose symptoms do not improve continue NSAID treatment and are offered a different hormonal combination (eg, other estrogen-progestin contraceptive (table 2), oral norethindrone acetate 5 mg taken once daily, gestrinone 2.5 mg orally twice weekly [not available in the United States]) or depot medroxyprogesterone acetate 150 mg intramuscularly every three months. Drug selection is based on patient preference, availability, and cost. If the alternative hormonal treatment resolves symptoms, then this regimen is continued until pregnancy is desired or the patient reaches the average age of menopause. While we believe this approach of hormonal suppression and NSAID therapy is the preferred first-line treatment for women with mild to moderate symptoms, it is important to note that initial treatment with a gonadotropin-releasing hormone (GnRH) analog is a reasonable alternative used by some experts (see 'Gonadotropin-releasing hormone (GnRH) analogs' below). In one clinical trial, raloxifene, a selective estrogen receptor modulator (SERM), did not effectively treat pelvic pain associated with endometriosis [7]; we do not use SERMs to treat pelvic pain.

Women with more severe symptoms (eg, regularly missing school or work because of pain) or symptoms that do not respond to the above therapies are offered a trial of a GnRH analog or laparoscopy for diagnosis and treatment (if they have not already done so). Similar to society recommendations, we start GnRH agonist and add-back therapy simultaneously [1,6]. This strategy limits bone loss, improves vasomotor symptoms, and improves compliance without reducing efficacy [1,8-11].

We reserve treatment with aromatase inhibitors for women who continue to have refractory symptoms despite GnRH analog treatment because there are fewer data on long-term use of these agents for endometriosis treatment. (See 'Agonists' below and "Endometriosis: Long-term treatment with gonadotropin-releasing hormone agonists", section on 'GnRH with add-back therapy' and 'Aromatase inhibitors' below.)

Women whose pain does not respond to the above medical treatment are offered laparoscopy for diagnosis and treatment. 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), depending on the woman's child-bearing plans and age. After surgery, hormonal suppression (usually with continuous oral contraceptives) is started to prevent recurrence of symptoms. (See 'Surgical treatment options' below and "Endometriosis: Surgical management of pelvic pain", section on 'Postoperative care'.)

MEDICAL TREATMENT OPTIONS — Medical treatment options include nonsteroidal analgesics, hormonal contraceptives, gonadotropin-releasing hormone (GnRH) analogs, and aromatase inhibitors (AI). 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, medication side effects, treatment efficacy, contraceptive needs, costs, and availability [6]. (See 'Our approach' above.)

The general advantages and disadvantages of medical treatment of endometriosis-related pelvic pain are listed in the table (table 3). Of note, medical interventions do not improve fertility, diminish endometriomas, or treat complications of deep endometriosis such as ureteral obstruction [6,12]. Women with these problems proceed with therapy targeted at the specific problem. (See 'Treatment of special populations' below.)

Nonsteroidal anti-inflammatory drugs — Nonsteroidal anti-inflammatory drugs (NSAIDs) effectively treat primary dysmenorrhea (table 1) [13]. 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 [14]. 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 [2-4]. (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".)

Estrogen-progestin contraceptives — Combined (estrogen and progestin) contraceptives are the first-line treatment for most women with endometriosis-related pain 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 [15,16]. While data from randomly assigned trials support estrogen-progestin therapy to reduce pain [17-19], one meta-analysis of two trials of combined oral contraceptive pills concluded that the evidence was insufficient to make a judgment [20]. Study challenges include differing combinations and doses of medications, duration of follow-up, study size and design, and varying tools used to assess pain. Combined estrogen-progestin treatments include combined oral contraceptive pills (COCs), transdermal patches, and vaginal rings (table 2) [6,21,22].

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 2). While both cyclic and continuous-dose hormonal regimens appear to be effective at reducing endometriosis-related pain [23,24], two systematic reviews (one with meta-analysis) reported that continuous COC regimens were more effective at reducing pain symptoms than cyclic COC regimens [15,25]. 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) [24]. (See "Contraception: Counseling and selection", section on 'The shared decision-making process' and "Hormonal contraception for menstrual suppression", section on 'Combined estrogen-progestin methods'.)

Estrogen-progestin contraceptives are thought to suppress ovarian function and thereby reduce endometriosis disease activity and pain [26]. The purported therapeutic mechanism is decidualization and subsequent atrophy of endometrial tissue [27]. In addition, estrogen-progestin contraceptives may slow progression of disease, although evidence is conflicting [23,28].

Risks and side effects of estrogen-progestin contraceptives are presented separately. (See "Combined estrogen-progestin contraception: Side effects and health concerns".)

Progestins — For women with endometriosis-related pain who are unable to take or prefer to avoid combined estrogen-progestin contraceptives, progestin-only therapy is another treatment option. The progestins most commonly used for the treatment of endometriosis-related pain include the 19-nortestosterone derivatives norethindrone acetate (5 mg dose) and dienogest or medroxyprogesterone acetate (MPA) [1].

●Norethindrone acetate – A commonly used regimen of norethindrone acetate is 5 mg by mouth daily, but the dose can be increased to 2.5 to 15 mg daily depending on side effects including breakthrough bleeding [29].

●MPA and dienogest – In systematic reviews of progestin therapy for pain associated with endometriosis, MPA and dienogest were superior to placebo [30,31].

•Depot MPA can be given as 150 mg intramuscular injection every three months or as a 104 mg subcutaneous injection every three months [32].

•Dienogest can be prescribed as a 2 mg oral pill taken daily or combined with estradiol valerate as part of a multiphasic oral contraceptive pill (commercial name Natazia, only formulation available in United States, and cannot be used in women with contraindications to estrogen treatment) [33]. In our practice, we reserve dienogest for women who do not tolerate norethindrone acetate because the treatment outcomes appear to be similar [34], but norethindrone acetate is less expensive.

Progestins (synthetic progestogens) inhibit endometrial tissue growth by causing initial decidualization and then atrophy [1]. Additional proposed mechanisms of action include suppression of matrix metalloproteinases, a class of enzymes important in the growth and implantation of ectopic endometrium [27], and inhibition of angiogenesis [35]. The choice of progestin depends upon the contraceptive needs of the patient, side-effect profile of the various drugs, and patient preference. (See "Contraception: Progestin-only pills (POPs)" and "Depot medroxyprogesterone acetate (DMPA): Formulations, patient selection and drug administration".)

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, 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 '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 depot MPA). 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 [36]. (See "Drugs that affect bone metabolism", section on 'Medroxyprogesterone acetate' and "Depot medroxyprogesterone acetate (DMPA): Efficacy, side effects, metabolic impact, and benefits", section on 'Reduction in bone mineral density'.)

Alternate progestin treatment options — Alternate progestin treatment options for the treatment of endometriosis-related pain include ethylnorgestrienone (ie, gestrinone, a synthetic steroid with mixed progesterone agonist/antagonist effects available in Europe), the etonogestrel implant, and the levonorgestrel intrauterine device. Because data regarding these agents for the treatment of endometriosis-related pain are limited, we prefer progestin therapies reviewed above.

●Ethylnorgestrienone (ie, gestrinone) – In a meta-analysis including two small studies, treatment with either gestrinone or danazol resulted in similar reductions in pain [30].

●Etonogestrel implant – An observational study of five women and a trial of 41 women reported that the implant was effective for decreasing the intensity of endometriosis-related pain (dyspareunia, dysmenorrhea, nonmenstrual pelvic pain) [37,38]. In the trial, the average decrease in pain was similar in the implant and depot MPA users (68 versus 53 percent, respectively) [37].

●Levonorgestrel intrauterine device (LNG IUD) – A review of three trials of the LNG IUD concluded that there was limited but consistent evidence that postoperative LNG IUD use reduced the recurrence of dysmenorrhea in women with surgically confirmed endometriosis [39-41]. For both methods, irregular menstrual bleeding and amenorrhea were common side effects, but no treatment affected bone mineral density or lipid levels [42,43].

Gonadotropin-releasing hormone (GnRH) analogs — GnRH analogs include agonist and antagonist drugs.

Agonists — GnRH agonists include nafarelin, leuprolide, buserelin, goserelin, and triptorelin. 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 [44]. The meta-analysis concluded that the evidence was limited regarding optimal dose and treatment duration and no route of administration appeared superior to others. In a trial comparing GnRH agonists treatment, laparoscopy, and combined medical/surgical treatment, all three groups reported an overall cure rate of ≥50 percent [45].

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 [46-48]. Medication selection is driven by availability and cost.

To minimize the hypoestrogenic side effects of GnRH agonist treatment, we begin add-back therapy at the same time as the GnRH agonist [1,6]. 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' and 'Our approach' above.)

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 [1]. Endometriosis-related pain is likely treated by the induction of amenorrhea and progressive endometrial atrophy [27]. The hypoestrogenic state is the main source of adverse effects, including hot flushes, vaginal dryness, decreased libido, mood swings, headache, and decreased bone density [49]. Negative effects can be reduced by add-back therapy, typically with oral norethindrone acetate or a combination of estrogen and progestin (ie, COC pill) [1]. 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'.)

Adverse effects of GnRH agonists are reviewed separately. (See "Endometriosis: Long-term treatment with gonadotropin-releasing hormone agonists", section on 'Side effects'.)

Antagonists — GnRH antagonists (eg, elagolix, relugolix) suppress pituitary gonadotropin hormone production and create a hypoestrogenic state [50]. They are a treatment option for patients with endometriosis-related pain who do not respond to NSAIDs, estrogen-progestin contraceptives, or progestins, and they are easier to dose than GnRH agonists (oral versus intramuscular).

●Comparison with GnRH agonists – Unlike GnRH agonists, antagonist agents are effective immediately, do not cause an initial surge in luteinizing hormone and follicle stimulating hormone, and do not require 7 to 14 days for GnRH suppression. The antagonists elagolix and relugolix are available in oral form [51,52].

●Impact of hypoestrogenism – The GnRH antagonist induces a dose-dependent hypoestrogenic state to inhibit endometriotic cell proliferation. Symptom relief and adverse events such as vasomotor phenomena, vaginal atrophy, and bone loss are also dose-dependent.

●Dosing and adverse effects

•Elagolix – Elagolix is an oral tablet approved for treatment of moderate-to-severe endometriosis-related pain [51,53]. Elagolix is given alone (ie, without add-back) when used for this indication. Patients who use elagolix to treat fibroid-related heavy menstrual bleeding take elagolix in combination with add-back estrogen and progestin; this is discussed in detail separately. (See "Uterine fibroids (leiomyomas): Treatment overview", section on 'GnRH analogs'.)

-Dosing – It 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. The higher dose may be required for patients with dyspareunia as part of their symptomatology. 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 – Relugolix has been studied as a combination therapy (relugolix-estradiol-norethindrone [norethisterone acetate; 40 mg/1 mg/0.5 mg]) or as monotherapy (40 mg dose for 12 weeks) followed by combination therapy for 12 weeks [52,54,55]. The relative therapeutic contribution of each medication (relugolix, estradiol, norethindrone) is unknown.

-Limitations of efficacy data – Direct comparison studies of relugolix combination therapy versus norethindrone are needed to understand the contribution of each medicine to the clinical effect and assess if combination relugolix therapy has benefits above treatment with norethindrone alone.

-Adverse effects – Relugolix combination therapy has been associated with allergic reactions, including anaphylaxis, urticaria, and angioedema [56].

●Supporting data

•Elagolix phase-three 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 [57,58].

-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 [57,58]; these reductions persisted at six months of followup [59]. 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 'Agonists' above.)

-Impact on bone mineral density – At six months, 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 groups, respectively.

-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 phase-three trial data – Two phase-three, multicenter trials, performed across five continents, compared placebo with relugolix combination therapy (relugolix-estradiol-norethindrone [norethisterone acetate; 40 mg/1 mg/0.5 mg]) or delayed relugolix combination therapy (relugolix monotherapy, 40 mg dose for 12 weeks, followed by combination therapy for 12 weeks) in individuals with moderate-to-severe endometriosis-related pain [52]. Across the two trials, compared with the placebo group, more patients receiving relugolix reported reductions in dysmenorrhea (75 percent versus 27 to 30 percent) and less nonmenstrual pelvic pain (58 to 66 percent versus 40 to 43 percent) at six months of follow-up. The most common adverse events were headache, nasopharyngitis, and hot flushes. While both treatment groups experienced reductions in bone mineral density compared with placebo, the reductions were less than 1 percent and not considered clinically significant. Both relugolix treatments were also associated with reduced opioid use. Delayed therapy was associated with similar pain reductions but also with more hot flashes and greater loss of bone mineral density. Data comparing relugolix with established treatments for endometriosis-related pain are lacking.

Danazol — While danazol is effective at treating endometriosis-related pain, it is not commonly used because of androgenic side effects. 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 [60]. In one of the included studies, the improvement in pain scores persisted at six months after discontinuation of therapy [61]. However, side 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 [60-62]. When prescribed, 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 danazol, particularly for women with rectovaginal endometriosis [63].

Danazol is a derivative of 17 alpha-ethinyltestosterone [27]. 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 AI treatment for women with severe, refractory, endometriosis-related pain [64,65]. AIs are often used in combination with progestins [66]. Patients are informed that treatment of endometriosis is an off-label use of these medications. Typical treatments include oral anastrozole 1 mg once daily or oral letrozole 2.5 mg once daily. 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) [64,67].

The limited supporting data for this approach include the following:

●A systematic review of eight studies concluded that AI treatment, with or without progestin, COC, or GnRH agonist, significantly reduced pain compared with GnRH agonist alone [68]. Study limitations included only one randomized trial and the combination of AI with various agents. The included trial randomly assigned patients with severe endometriosis to six months of postoperative goserelin plus anastrozole or goserelin alone [69]. While patients receiving combination therapy reported longer time to symptom recurrence, quality-of-life and bone mass outcomes were similar between groups.

●In a nonrandomized trial including 82 women with rectovaginal endometriosis and pain, the combination of letrozole and norethindrone acetate was more effective in reducing pain and deep dyspareunia than norethindrone acetate alone, but combined treatment was associated with a higher incidence of adverse effects and cost [70]. Additionally, combination therapy did not improve patient satisfaction or reduce recurrence of pain compared with norethindrone alone.

●A trial that randomly assigned a total of 35 patients with rectovaginal endometriosis to either letrozole plus norethisterone acetate or letrozole plus triptorelin reported a similar reduction in pain symptoms during treatment [71]. Endometriotic nodules showed a greater reduction in the group receiving letrozole and triptorelin GnRH, but this group also experienced arthralgias, decreased libido, hot flashes, and depression. A statistically significant decrease in bone density was also seen in the triptorelin group.

Disadvantages of AIs include bone loss with prolonged use and ovarian follicular cyst development. The AI is prescribed in combination with a GnRH analog or an oral estrogen-progestin contraceptive to suppress follicular development [72]. For women unable to use GnRH analogs or oral estrogen-progestin contraceptives, oral norethindrone acetate 5 mg per day is another option.

Side effects of AI treatment are presented separately. (See "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer", section on 'Side effects'.)

Neuropathic pain treatments — We offer neuropathic pain treatment to women who continue to have pain despite the medical treatment options for endometriosis-related pain listed above. Treatment of neuropathic pain is reviewed separately. (See "Pharmacologic management of chronic non-cancer pain in adults", section on 'Pharmacologic therapy for neuropathic pain, or nociplastic or centralized pain'.)

SURGICAL TREATMENT OPTIONS — Because of surgery-associated risks, recovery, and upfront cost, medical therapy is typically tried first. Surgical resection of endometriosis or nerve transection procedures are offered to women who do not respond to medical therapy or who have recurrent pain symptoms. Surgical resection provides a histologic diagnosis as well as reduces pain [1,6]. Disadvantages of surgery include risk of injury (especially the bowel and bladder), possible reduction of ovarian reserve if ovarian surgery is performed (eg, ovarian cyst excision), and adhesion formation, in addition to common surgical risks.

Surgical treatment of endometriosis as well as pre- and postoperative management are reviewed in detail separately. (See "Endometriosis: Surgical management of pelvic pain".)

Surgical resection of endometriosis — Surgical resection provides a histologic diagnosis and reduces pain by destroying the endometriotic implants [1,6]. Surgical resection can be conservative (treatment of endometriosis lesions by ablation or resection), definitive (hysterectomy, with or without oophorectomy, in addition to resection of endometriosis), or radical (removal of all visible implants at time of surgery). At least one questionnaire study has reported reduced dyspareunia and improved quality of life with radical resection [73]. Choice of surgical treatment is reviewed in detail separately. (See "Endometriosis: Surgical management of pelvic pain".)

Nerve transection — Nerve transection procedures, including laparoscopic uterosacral nerve ablation (LUNA) and presacral neurectomy (PSN), have been used to treat pelvic pain caused by endometriosis. Limited data suggest that LUNA is not effective [6,74]. PSN may be effective for the treatment of midline pain associated with menses, but the success of the procedure depends, in part, on the experience of the surgeon, and long-term efficacy has not been demonstrated [1,6]. Nerve transection procedures are discussed in detail elsewhere. (See "Chronic pelvic pain in adult females: Treatment", section on 'When to perform additional surgical procedures aimed to reduce pain'.)

TREATMENT OF SPECIAL POPULATIONS

Infertility — Women with infertility and pain caused by endometriosis are not candidates for the hormone suppression therapies because hormonal suppression prevents pregnancy and does not improve fertility [12]. The treatment of infertility associated with endometriosis involves a combination of surgery and assisted reproduction technology. We offer nonsteroidal anti-inflammatory drugs 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".)

Endometrioma — The goals of endometrioma treatment are to relieve symptoms (eg, pain or mass), exclude malignancy, improve subfertility, and preserve ovarian function. Medical therapy does not resolve endometriomas [1,75,76]. Symptomatic or expanding endometriomas are removed laparoscopically. However, surgical removal can diminish ovarian reserve [77,78]. To protect ovarian reserve, asymptomatic and small (≤5 cm) endometriomas can be left in place. Management of ovarian endometriomas is reviewed in more detail separately. (See "Endometriosis: Management of ovarian endometriomas".)

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 [79]. For women with bothersome urinary or bowel symptoms (eg, urinary urgency or frequency, dyspareunia, dysmenorrhea, or dyschezia), medical therapy with hormonal suppression is appropriate [80,81]. Surgery is indicated for women with ureteral or bowel obstruction or women whose symptoms do not improve with medical management [5,82]. (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 [83-93]. 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 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 [1]. (See "Endometriosis in adults: Pathogenesis, epidemiology, and clinical impact" and 'Our approach' above.)

COMPLEMENTARY THERAPIES

Acupuncture — In a systematic review of acupuncture for treatment of endometriosis-related pain, only one randomized trial met the inclusion criteria [94]. In that trial (n = 67), auricular acupuncture was significantly more effective than Chinese herbal medicine for treating dysmenorrhea in women with endometriosis [95].

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 [96]. 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'.)

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 disease that requires a lifelong management plan that maximizes medical treatment and avoids repeat surgical intervention. Each treatment plan 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 'General principles' above.)

●Symptom-based approach – Our approach to treating endometriosis-related pain treatment is based on the severity of symptoms. Other causes of pelvic pain are excluded prior to treatment. (See 'Our approach' above.)

•Mild to moderate pain –For patients with mild to moderate pain, we suggest nonsteroidal anti-inflammatory drugs (NSAIDs) (table 1) and continuous hormonal contraceptives (table 2) rather than either agent alone (Grade 2C). These therapies 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. (See 'Nonsteroidal anti-inflammatory drugs' above and 'Estrogen-progestin contraceptives' above.)

•Adequate response to initial treatment – Patients with adequate symptom improvement continue the hormonal therapy/NSAID regimen until pregnancy is desired or the average age of menopause is reached. Those whose symptoms do not improve continue NSAID treatment and are offered an alternate hormonal combination (eg, change to a different estrogen-progestin contraceptive (table 2) or norethindrone acetate). (See 'Our approach' above.)

•More severe or refractory symptoms – For patients with more severe symptoms (eg, regularly missing school or work because of pain) or whose symptoms are not adequately controlled with the above treatments, we suggest a trial of a gonadotropin-releasing hormone (GnRH) analog rather than other drugs or surgical resection (Grade 2C). GnRH analogs include agonists (eg, leuprolide acetate) or antagonists (eg, elagolix). GnRH analog treatment has demonstrated efficacy without the negative impact on ovarian reserve as with surgery. When used without add-back hormone therapy, adverse effects include menopause-like symptoms and reduced bone density. (See 'Gonadotropin-releasing hormone (GnRH) analogs' above.)

•Continued refractory symptoms – Patients who continue to have refractory symptoms despite GnRH analog treatment are offered medical therapy with an aromatase inhibitor. (See 'Aromatase inhibitors' above.)

•Role of laparoscopy – Patients whose pain does not respond to the above treatments are offered laparoscopy for confirmation of the diagnosis and surgical resection. (See 'Our approach' above and 'Surgical resection of endometriosis' above.)

●Infertility – Patients with endometriosis-associated infertility are treated with a combination of expectant management, surgery, and assisted reproduction techniques. Medical therapy is ineffective. (See 'Infertility' above.)

●Endometrioma – For patients with symptomatic or expanding endometriomas, laparoscopic excision is performed to treat the associated pain, confirm the diagnosis, exclude malignancy, and prevent complications, such as cyst rupture or ovarian torsion requiring emergency surgery. For women with asymptomatic or small (≤5 cm) endometriomas, the lesions are left in place because surgical excision can decrease ovarian reserve. Medical therapy does not treat endometriomas. (See 'Endometrioma' above.)

●Urinary or bowel symptoms – For patients with bothersome urinary or bowel symptoms (eg, urinary urgency/frequency, dyspareunia, dysmenorrhea, or dyschezia) suggestive of deep endometriosis, medical therapy with hormonal suppression is appropriate. Surgery is indicated for women with ureteral or bowel obstruction or women whose symptoms do not improve with medical management. (See 'Deep endometriosis' above.)

●Endometriosis beyond the pelvis – For patients with symptomatic endometriosis of extra-pelvic organs, we prefer ovarian suppression with GnRH analogs because they are highly effective at suppressing ovarian hormone production and inhibiting the growth of endometrial tissue. (See 'Lesions of nonreproductive organs' above.)

●Empiric therapy for pain – For patients with pain from presumed endometriosis, we begin empiric medical therapy with NSAIDs and hormonal suppression because these treatments are low-risk. However, we prefer to confirm endometriosis with laparoscopy before initiating medication with significant side effects. (See 'Presumed endometriosis' above.)