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    Endometriosis

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    Sep.25.2023

    Endometriosis

    Synopsis

    Key Points

    • Endometriosis is an inflammatory disease in which ectopic endometrial-like tissue forms lesions outside the uterus
    • Classified into 4 stages based on the presence, location, and severity of ectopic endometrial lesions: stage I (minimal) through stage IV (severe); this classification is based on extent of disease and does not correlate well with pain and quality of life
    • Primary manifestations include dysmenorrhea, dyspareunia, chronic pelvic pain, and infertility
    • Patient history and imaging findings (on ultrasonography and MRI) can suggest the diagnosis and are often sufficient, although definitive diagnosis is established only by laparoscopic identification of ectopic endometrial tissue
      • Laparoscopy is no longer considered the gold standard for diagnosing endometriosis r1
      • It is not routinely used for diagnosis due to invasiveness and risk of complications; typically performed to treat surgically r1r2r3
    • The primary goals of endometriosis symptom management are to improve pain and quality of life through a combination of medical, surgical, and complementary care
      • Long-term, multidisciplinary care has been suggested as a strategy for improved long term outcomes r4
    • Patients in whom endometriosis is suspected and who seek pain management but not fertility are commonly treated empirically with NSAIDs and combined contraceptives or progestogens; if these do not work adequately, second line medical treatments can be used
    • Patients who wish to remain fertile are referred to a gynecologist, who may choose medical therapies (second and third line agents), with laparoscopic exploration of the pelvis for those with inadequate response to medical therapy, or may apply an earlier surgical approach
    • Roughly half of females with endometriosis are infertile, and females with severe endometriosis experience significantly lower pregnancy rates compared with those with mild endometriosis r5
    • After 1 year of laparoscopically diagnosed endometriosis, 17% to 29% of lesions spontaneously resolve, 24% to 64% progress, and 9% to 59% remain stable;r6 after laparoscopic destruction of lesions, recurrence occurs in 10% to 55% within 1 yearr7

    Pitfalls

    • Hormonal therapies do not eliminate endometriosis, and symptoms may recur with discontinuation of treatment
    • Surgery also does not eliminate endometriosis, and pain may return after surgical management
    • It is important to remember that endometriosis is a chronic disease requiring long-term strategies r4

    Terminology

    Clinical Clarification

    • Endometriosis is a chronic, estrogen-dependent and inflammatory disease in which ectopic endometrial-like tissue forms lesions outside the uterus r1r6
    • Affects 2% to 10% of reproductive-age females worldwide and up to 50% of infertile females r1
    • Symptoms include painful ovulation, menstrual pain, heavy bleeding, pain during or after sex, chronic pelvic pain, fatigue, and infertility—all of which can affect physical, mental, and social well-being; not all patients experience symptoms r8

    Classification

    • Endometriosis can be classified by location, depth, and severity of ectopic endometrial lesions
      • Classified as superficial endometriosis, ovarian endometrioma, or deeply infiltrating endometriosis
        • Superficial endometriosis r2
          • Endometrial tissue resides within pelvic cavity: in peritoneum, in any pelvic organs, or in rectouterine pouch
        • Ovarian endometrioma r2
          • Endometrioma in which an ovarian cyst is lined with endometrial tissue
        • Deeply infiltrating endometriosis r2
          • Endometrial tissue that extends at least 5 mm into retroperitoneal space r9
          • May exist in several regions, including anterior and posterior pelvic compartment
          • Common endometriotic sites include:
            • Uterosacral ligament
            • Rectovaginal septum
            • Vagina
            • Rectouterine pouch (severe disease causes obliteration of pouch)
            • Vesicouterine pouch
            • Bowel
              • Rectosigmoid area
            • Surgical scar
        • Rare locations of endometriosis r2
          • Bladder
          • Ureters
          • Extrapelvic areas (atypical endometriosis), such as lungs
      • Classified by the American Society for Reproductive Medicine into stages 1 to 4 in a scoring system that indicates the presence, location, and severity of ectopic endometrial lesions r9r10
        • Extent of disease, and therefore the score, does not correlate well with pain and quality of life, which is the major therapeutic target
        • Endometriosis classification of the American Society for Reproductive Medicine.Data from American Society for Reproductive Medicine: Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 67:817, 1997.
          StageFindingsScores
          I: minimalSuperficial lesions in peritoneum and/or ovary; filmy adhesions are possible1-5
          II: mildStage I findings plus deep lesions may be detected in peritoneum6-15
          III: moderateStage I and II findings plus deep lesions may be detected in ovary, cul-de-sac may be partially obliterated, or filmy adhesions may be detected in fallopian tubes16-40
          IV: severeStage I, II, and III findings plus deep lesions and dense adhesions may be detected in several regions, as well as complete obliteration of cul-de-sacMore than 40

    Diagnosis

    Clinical Presentation

    History

    • Clinical manifestations range from asymptomatic to severe and may worsen over time r2c1
      • Dysmenorrhea r1c2
        • Pain may start before each menstrual period
      • Dyspareunia r1c3
        • Deep pain with intercourse, increased during menses
      • Chronic pelvic pain r1c4
        • Chronic pain defined as lasting for at least 6 months r6
        • Endometriosis is found in 70% to 90% of females with chronic pelvic pain r11
        • Pain can occur unpredictably and intermittently during entire menstrual cycle, or it may be continuous r6
        • Can be described as dull, throbbing, or sharp; characteristics may change r6c5c6c7
        • May be worsened by physical activity r6
      • Menorrhagia r1c8
      • Dysuria r12c9
      • Dyschezia, constipation, or hematochezia r5c10c11c12
        • May indicate ectopic endometrial tissue in perianal compartments (bowel involvement)
      • Infertility r2c13
        • Compared with fertile females, infertile females are 6 to 8 times more likely to have endometriosis r13
      • Family history c14
        • Some studies have suggested an increased risk for the development of endometriosis in first-degree relatives of patients with endometriosis r14

    Physical examination

    • Pelvic examination (rectal examination in adolescent and adult females who have not had intercourse) r6
      • Tenderness or focal pain on examination is correlated surgically with endometriosis in 66% of patients r6c15c16
      • Other significant findings that are consistent with endometriosis
        • Uterosacral ligament nodularity c17
        • Adnexal mass c18
        • Limited motion of ovaries or uterus c19c20
        • Painful induration, nodules, or both detected in rectovaginal wall or posterior vaginal fornix c21c22
      • Endometriosis is not ruled out by normal examination findings
    • Abdominal examination may be positive for lower abdominal masses or tenderness r1c23c24

    Causes and Risk Factors

    Causes

    • Causes are unknown but may include the following: r15c25
      • Attachment and implantation of endometrial glands and stroma outside the uterus within the peritoneum due to retrograde menstruation
      • Lymphatic or hematogenous spread or metaplastic transformation (possible cause of distant endometrial sites)
      • Inefficient lesion clearing due to an immune dysfunction

    Risk factors and/or associations

    Age
    • Characteristic of reproductive age r2
      • Peak incidence is in females aged 25 to 29 years and lowest is in females older than 44 years, although endometriosis may affect any female of reproductive age r16c26c27c28
        • Females frequently experience 6 to 12 years of symptoms before surgical diagnosis r2
    Genetics
    • Some studies have suggested an increased risk for the development of endometriosis in first-degree relatives of patients with endometriosis r14c29
    • Genetic risk factors identified include the following single nucleotide polymorphisms: r17
      • rs10965235 in the CDKN2BAS gene at locus 9p21.3 (OMIM %131200;r18 odds ratio, 1.44)
      • Intergenic single nucleotide polymorphism (rs12700667) at locus 7p15.2 (odds ratio, 1.22)
      • Allele A of rs7521902 at the 1p36.12 WNT4 locus (odds ratio, 1.18)
      • Allele C of rs10859871 at the 12q22 VEZT locus (odds ratio, 1.18)
      • Allele G of rs13394619 at the 2p25.1 GREB1 locus (odds ratio, 1.12)
    Other risk factors/associations
    • Several factors have associations with endometriosis, although the evidence tends to be weak
      • Menstrual outflow obstruction r6c30
      • In utero diethylstilbestrol exposure r6c31
      • Prolonged exposure to endogenous estrogen (eg, early menarche, late menopause) r6c32c33c34
      • Endocrine-disrupting chemical exposure r6
        • Exposure to agents in the environment that interfere with synthesis, secretion, transport, metabolism, binding action, or elimination of natural blood-borne hormones
        • Examples include polychlorinated biphenyls, polybrominated biphenyls, plastics, pesticides, and fungicides c35c36c37c38c39
      • Short menstrual cycles r6c40
      • Trans fats and red meat consumption r6c41c42
      • Low BMI r13c43
        • Average BMI of females with endometriosis: 21.3 ± 0.6 kg/m² r19
        • For each unit (kg/m²) increase in BMI, there is a decrease of approximately 12% to 14% in the likelihood of endometriosis diagnosis r19
    • Risk of endometriosis is lower for females who have had multiple pregnancies or with prolonged lifetime duration of lactation (more than 23 months) r20
    • Decreased risk of developing endometriosis is associated with diet containing fruits, green vegetables, and ω-3 long-chain fatty acids (found in fatty fish) r21c44c45

    Diagnostic Procedures

    Primary diagnostic tools

    • A clinical or presumptive diagnosis of endometriosis is based on combination of symptoms, signs, and imaging findings r22c46
      • Perform pelvic and abdominal examination for all patients in whom endometriosis is suspected on the basis of history r2r23c47
      • Abnormal pelvic examination findings (eg, tenderness, focal pain, palpable mass) correlate with laparoscopic endometriosis diagnosis in 70% to 90% of cases r2
        • However, more than 50% of females surgically diagnosed with endometriosis have normal pelvic examination findings r2
      • Obtain imaging (ultrasonography or MRI) for patients with suspected endometriosis; however, negative imaging finding does not exclude endometriosis, particularly superficial peritoneal disease r2
        • Ultrasonography is indicated for all patients in whom endometriosis is suspected; may include the following types: r2r23
          • Transabdominal and transvaginal scans (typically performed) r3
          • Transrectal scan is performed only in cases with focused rectal symptoms
        • MRI is indicated for those patients in whom ectopic endometrial tissue was not clearly detected via ultrasonography but clinical suspicion remains r2r23
          • Especially useful for evaluation of endometrial ovarian cyst and tubal endometriosis r24
          • Used less frequently than ultrasonography owing to higher cost
    • Laparoscopy for diagnosis and treatment is indicated for patients with clinical diagnosis of symptomatic endometriosisr22 and unsuccessful empirical medical treatment r1r2r23
      • Detection of ectopic endometrial tissue defines the diagnosis, with surgeons mainly relying on the visual appearance of endometrial implants r2
        • Biopsy of presumed endometrial implants is left to discretion of surgeon; histologic confirmation of endometriotic lesions is recommended. However, negative histology does not entirely exclude endometriosis r1c48
      • No longer considered the gold standard for diagnosing endometriosis r1
      • Not routinely used for diagnosis, owing to invasiveness and risk of complications; typically performed to treat surgically r1r2r3
    • Measurement of biomarkers in endometrial tissue, blood, menstrual or uterine fluids has no role in diagnosis of endometriosis r1

    Imaging

    • Ultrasonography c49c50c51c52
      • Obtain transabdominal and transvaginal ultrasonography for all patients with symptoms of endometriosis r1
        • Transvaginal mode is more sensitive than transabdominal mode for the detection of endometriomas; small pelvic implants may not be detected by transvaginal scan r25
          • Stage I and II endometriosis are often not visible on ultrasound examination
          • Stage IV disease is often visible on ultrasound examination, and stage III disease may be visible
      • Endometrioma
        • Form of endometriosis that is most frequently localized
        • Typically, an endometrioma is cystic and associated with the adnexa
          • Ultrasonographic finding of unilocular or multilocular cyst as homogeneous hypoechoic focal lesion within the ovary, with diffuse low-level internal echoes (ground-glass echogenicity) r25
            • Observed in up to 95% of patients with endometriomas r25
            • Color Doppler scan may assist in identification, given the poor vascularity r24
        • Endometrioma may also appear as a simple cyst (5.5% of endometriomas) or a solid mass (4.9% of endometriomas) r25
      • Other endometriosis
        • Transvaginal ultrasonography along with transabdominal ultrasonography can detect lesions within pelvic cavity: in peritoneum, in any pelvic organs, and in rectouterine pouch r2
        • Transvaginal ultrasonography also evaluates deeply infiltrating endometriosis r24
          • Able to assess uterosacral ligaments, rectovaginal septum, posterior fornix, rectum and rectosigmoid, and ureters
          • Findings include hypoechoic lesions and retroperitoneal thickening with irregular borders (linear and nodular), with Doppler demonstrating few vessels
          • Detection of kissing ovaries (ovaries joined behind rectouterine pouch) indicates severe endometriosis r25
      • Transvaginal ultrasonography with bowel preparation is accurate in identifying all sites of ovarian and deep endometriosis and is more accurate at detecting rectosigmoid endometriosis than diagnostic laparoscopy r26
    • MRI c53c54
      • Indicated when ectopic endometrial tissue was not clearly detected via ultrasonography and clinical suspicion remains high r23
        • Especially useful for evaluation of endometrial ovarian cyst in select cases (ie, if results of ultrasonographic evaluation are inconclusive or if malignant transformation is suspected) r5r24
          • Limited by distortion of view of pelvic structures from adhesions, endometrial implantation, and hyperperistalsis of bowel
        • Capable of evaluating for tubal endometriosis by detecting hematosalpinx

    Procedures

    Laparoscopy c55
    General explanation
    • Minimally invasive abdominal surgery using a camera with various probes to evaluate the pelvis and abdominal region r2
    Indication
    • May be indicated when endometriosis is suspected based on clinical signs but has not been demonstrated in preoperative investigations r23
    • Females with clinically diagnosed endometriosis who: r2
      • Do not respond to empiric therapy
      • Want to become pregnant
    Contraindications
    • Abdominal wall infection r2
    • Uncorrected coagulopathy r2
    • Tense, distended abdomen r2
    Complications
    • Injury to pelvic organs (2% risk) r2
    • Major blood vessel damage (1% risk) r27
    Interpretation of results
    • Primary types of endometriosis
      • Superficial endometriosis r2
        • Endometrial tissue within pelvic cavity, including within peritoneum, any pelvic organ, and rectouterine pouch
      • Ovarian endometriosis r2
        • Diagnosed if adnexal endometrioma is detected
      • Deeply infiltrating endometriosis r2
        • Diagnosed if deep endometriotic lesions are detected and extend more than 5 mm below peritoneum in pelvic/abdominal cavity
    • Rare types of endometriosis r2
      • Bladder endometriosis
      • Ureteral endometriosis
      • Extrapelvic/atypical endometriosis
    • Histologic evaluation of ectopic endometrial tissue can be performed to confirm diagnosis r1
      • Endometriosis diagnosis is confirmed if ectopic tissue is verified to be endometrial
      • Improves accuracy of diagnosis by 20% r28

    Differential Diagnosis

    Most common

    • Dysmenorrhea c56d1
      • Painful menstrual cramps, originating from the uterus
      • Usually, pain of 8 to 72 hours in duration before onset or during first few days of menstruation
      • In primary dysmenorrhea, abdominal and pelvic examination findings are usually normal; in secondary dysmenorrhea, examination may show uterine enlargement
      • Primary dysmenorrhea is a presumptive diagnosis based on clinical presentation r29
      • Differentiated by lack of ultrasonographic or other imaging findings suggesting endometriosis
    • Adenomyosis r30c57
      • Endometrial tissue within myometrium
      • As in endometriosis, symptoms may include noncyclic pelvic pain, dysmenorrhea, menorrhagia, dyspareunia, and infertility
      • More common in parous females, tending to occur in females aged 35 to 50 years
      • Findings on transvaginal ultrasonography include uterine enlargement; asymmetrical enlargement of the anterior or posterior myometrial wall; lack of contour abnormality or mass effects; heterogeneous, poorly circumscribed areas within the myometrium; hyperechoic islands or nodules; fingerlike projections or linear striations; indistinct endometrial stripe; and anechoic lacunae or cysts of varying sizes r30
      • Findings on MRI include a focal or diffuse thickened junctional zone due to uncoordinated proliferation of the inner myometrial cells causing junctional zone hyperplasia r30
      • Differentiated from endometriosis by findings on transvaginal ultrasonography or MRI
    • Ovarian cyst c58
      • 1 of several benign neoplasms including:
        • Hemorrhagic ovarian cyst (will regress within 6-8 weeks); hemorrhagic corpus luteum cyst is the most common
        • Mature cystic teratoma
      • As in endometriosis, symptoms may include noncyclic pelvic pain
      • Ultrasonographic characteristics indicating that a cyst is likely and is probably benign include round shape, thin walls, increased acoustic enhancement, anechoic fluid, and absence of septation or nodules r31
      • Differentiated from endometriosis by ultrasonography; if differentiation is not clear, obtain MRI scan
    • Cystadenoma r25c59
      • Type of benign serous or mucinous epithelial tumor of ovary
      • As in endometriosis, symptoms may include cyclic pelvic pain and dyspareunia
      • On ultrasound examination, serous cystadenomas appear as smooth, thin-walled, anechoic, fluid-filled structures; mucinous cystadenomas are thin walled and large and consist of internal thin-walled locules containing mucin, which appears as fluid with low-level echogenicity
      • Differentiated from endometriosis by findings on ultrasonography
    • Ovarian fibroma r25c60
      • Type of benign sex cord–gonadal stromal tumor
      • As in endometriosis, symptoms may include noncyclic pelvic pain
      • Differentiated from endometriosis by ultrasonographic findings (eg, solid mass); requires tissue biopsy for diagnosis
    • Subserosal leiomyoma r25c61d2
      • Uterine fibroid that grows on outer uterine wall
      • As in endometriosis, symptoms may include noncyclic pelvic pain and menorrhagia
      • Differentiated from endometriosis by ultrasonographic findings demonstrating fibroids
    • Epithelial ovarian cancer r32c62d3
      • As in endometriosis, symptoms may include noncyclic pelvic pain
      • Differentiated from endometriosis by ultrasonographic findings (eg, solid mass)
      • Diagnosed by histology of surgically acquired biopsy specimen
    • Pelvic inflammatory disease c63d4
      • Infection of fallopian tube commonly caused by Neisseria gonorrhoeae or Chlamydia trachomatis and resulting in a spectrum of clinical disease r33
      • As in endometriosis, symptoms may include noncyclic pelvic pain and dyspareunia, and pelvic examination may show uterine and adnexal tenderness
      • However, acute pelvic inflammatory disease is typically also accompanied by fever and chills, abnormal uterine bleeding, and abnormal vaginal discharge r33
      • Diagnosed by DNA probe for gonorrhea and chlamydia and by cultures of cervical discharge
      • Differentiated by history, physical examination, inflammatory markers, diagnostic imaging findings, and microbiologic testing r33
    • Ovarian torsion c64
      • Sudden, severe, unilateral pelvic pain (bilateral in some patients) that is usually sharp and stabbing, although sometimes crampy
      • Differentiated from endometriosis by ultrasonographic findings, particularly impaired blood flow to ovary as seen on Doppler scan

    Treatment

    Goals

    • Relieve pain and improve quality of life r6
      • It is important to note that this is the primary goal, rather than to eradicate or shrink burden of disease; can be achieved through a combination of medical, surgical, and complementary care
    • Preserve fertility r6

    Disposition

    Recommendations for specialist referral

    • Refer the following patients to a gynecologist:
      • Those with presumed endometriosis who want to become pregnant
      • Those whose endometriosis has not responded adequately to a 6-month trial of hormonal therapy of any type r3
      • Those for whom diagnosis cannot be established

    Treatment Options

    No cure for endometriosis yet exists; primary treatment is directed toward relief of painr22 and improvement in quality of life r2

    • Strategies to achieve these goals include medical therapies, surgery, and complementary therapies with a shared decision-making approach r1r4
    • Long-term multidisciplinary care has been suggested as a strategy for improved long-term outcomes r4

    Hormonal therapies do not eliminate endometriosis, and symptoms recur or worsen when treatment is discontinued

    Empiric therapy is generally administered without surgical diagnosis; plan is based on clinical diagnosis r22

    Although the supporting data for this are weak,r1 initial therapy of NSAIDs can be used for patients who present with pelvic pain that is likely due to endometriosis, especially dysmenorrhea r1r6

    If response to NSAIDs is inadequate and pregnancy is not desired, additional medical therapy includes the following: r1r11

    • Combined hormonal contraceptives (oral, vaginal ring, or transdermal); combined hormonal contraceptive pill may be used cyclically or continuously
      • Published guidelines typically recommend using a combined oral contraceptive pill as first line hormonal treatment for endometriosis; however, combined hormonal options may be less effective than progestin-dominant therapy r3
    • Progestogens, including medroxyprogesterone acetate, levonorgestrel-releasing intrauterine system, or an etonogestrel-releasing subdermal implant
      • Progestin-dominant therapy may be the most effective means of controlling symptoms and suppressing disease progression r3
    • GnRH (gonadotropin-releasing hormone) agonists (eg, leuprolide, Synarel [nafarelin acetate], goserelin) or GnRH antagonists (eg, elagolix, relugolix) may be prescribed as second line options if hormonal contraceptives or progestogens have been ineffective r34r35
      • To prevent bone loss and hypoestrogenic complications with these agents, administer hormonal add-back therapy using estrogen and progestogen combination r1
    • Aromatase inhibitors (eg letrozole) are an option for endometriosis-associated pain refractory to other medical or surgical treatment; these may be prescribed in combination with oral contraceptives, progestogens, GnRH agonists, or GnRH antagonists
      • May be prescribed in combination with oral contraceptives, progestogens, GnRH agonists, or GnRH antagonists
    • Danazol is no longer routinely recommended as a medical treatment for endometriosis-associated pain due to its severe adverse effects at higher doses r1
    • May choose further medical therapies (second and third line agents) for those with inadequate response to medical therapy or may opt for an earlier surgical approach

    If response to NSAIDs is inadequate and future pregnancy is desired, early referral to a gynecologist is recommended r11

    Surgical therapy

    • Laparoscopic removal of ectopic endometrial tissue r1
      • Reserved for patients with medically refractory pain that limits function or causes significant emotional distress
      • Removal of ectopic endometrial tissue may be achieved by excision, diathermy, or ablation/vaporization r1r36
      • For patients with ovarian endometrioma, ovarian cystectomy is preferred rather than drainage and coagulation r1r36
        • CO₂ laser vaporization is an alternative to cystectomy. Early postsurgical recurrence rates may be lower after cystectomy; however, recurrence rates are similar beyond the first year after surgery r1
      • Laparoscopic uterosacral nerve ablation offers no additional benefit over conventional laparoscopic surgery for endometriosis r1
      • Presacral neurotomy is helpful as an adjunct to conventional laparoscopic surgery for the treatment of endometriosis-associated midline pain; however, it requires a high level of expertise and has risk of significant adverse effects r1
      • Surgical removal of deep endometriosis nodule may reduce pain and improve quality of life but should be undertaken at centers of excellence. Colorectal involvement may require segmental bowel resection r1
    • Hysterectomy r1
      • Hysterectomy (with or without removal of the ovaries) including removal of all visible endometriosis lesions can be considered for females who do not wish to conceive and have failed to respond to more conservative treatments
      • Relieves pain in 80% to 90% of patients with pain resistant to drug therapy and other surgical treatments r6
      • 10% of patients experience pain recurrence within 1 to 2 years after surgery r6
      • Combined estrogen/progestogen is recommended for patients with endometriosis after surgical menopause until the age of natural menopause r1

    Adjunctive hormonal therapy after surgery

    • Postoperative adjunctive hormone therapy (for less than 6 months after surgery) may be considered to improve the immediate outcome of surgery for endometriosis-associated pain in females not desiring immediate pregnancy r1
    • Hormone treatment for secondary prevention of recurrence r1
      • Consider use of a levonorgestrel-releasing intrauterine system or a combined hormonal contraceptive for at least 18 to 24 months for the secondary prevention of endometriosis-associated dysmenorrhea
      • For patients who have undergone surgical treatment of ovarian endometrioma, offer long-term hormone treatment (eg, combined hormonal contraceptives) to prevent endometrioma and endometriosis-associated/related symptom recurrence
      • Consider long-term postoperative hormone treatment for patients with deep endometriosis

    Fertility-associated treatment options for infertile patients r6

    • Laparoscopic excision or ablation of endometriotic lesions and adhesions generally improves chances of natural pregnancy r1
    • Endometriosis Fertility Index can be used to identify patients that may benefit from assisted reproductive technologies after surgery
    • No specific protocol is recommended r1

    Drug therapy

    • NSAIDs r1c65
      • Ibuprofen c66
        • Ibuprofen Oral tablet; Adults: 400 mg PO every 4 to 6 hours as needed. Max: 3,200 mg/day.
      • Naproxen c67
        • Naproxen Oral tablet; Adults: 500 mg PO once, then 250 mg PO every 6 to 8 hours as needed. Max: 1,250 mg/day.
      • Mefenamic acid c68
        • Mefenamic Acid Oral capsule; Adults: 500 mg PO once at onset of menses, then 250 mg PO every 6 hours as needed for 2 to 3 days.
      • Celecoxib c69
        • Note: Celecoxib may pose a reproductive risk by delaying or preventing prostaglandin-mediated rupture of ovarian follicles, which has been associated with reversible infertility. Consider withdrawal of celecoxib for females who have difficulties conceiving or who are undergoing infertility evaluation r37
        • Celecoxib Oral capsule; Adults: 400 mg PO once initially, followed by an additional 200 mg PO once on day 1 if needed, then 200 mg PO twice daily as needed.
    • Cyclic oral contraceptives r6c70
      • Norgestimate–ethinyl estradiol c71
        • Inert Oral tablet, Norgestrel, Ethinyl Estradiol Oral tablet; Adult and Adolescent females: Follow dose as for routine contraception. Alternatively, the active tablets can be given continuously in selected patients.
      • Norethindrone–ethinyl estradiol c72
        • Ethinyl Estradiol, Norethindrone Oral tablet, Ethinyl Estradiol, Norethindrone Oral tablet, Inert Oral tablet; Adult and Adolescent females: 1 tablet PO once daily in the order indicated in the pack for 21 days, followed by a period of 7 days without drug. Phase 1 consists of 10 tablets, each containing 0.5 mg of norethindrone and 35 mcg of ethinyl estradiol. Phase 2 consists of 11 tablets, each containing 1 mg of norethindrone and 35 mcg of ethinyl estradiol.
    • Cyclic vaginal ring c73
      • Etonogestrel–ethinyl estradiol vaginal ring c74
        • Ethinyl Estradiol, Etonogestrel Vaginal insert; Adult and Adolescent females: Follow dosage as for routine contraception.
    • Continuous combined oral contraceptives r6c75
      • Norgestimate–ethinyl estradiol c76
        • Inert Oral tablet, Norgestimate, Ethinyl Estradiol Oral tablet; Adult and Adolescent females: Follow dose as for routine contraception for specific product; alternatively, the active tablets can be given continuously.
      • Levonorgestrel–ethinyl estradiol c77
        • Levonorgestrel, Ethinyl Estradiol Oral tablet; Adult and Adolescent females: Follow dose as for routine contraception for specific product; alternatively, the active tablets can be given continuously.
    • Progestins (progestogens) r1c78
      • Medroxyprogesterone acetate c79
        • Medroxyprogesterone Acetate Oral tablet; Adult and Adolescent females: 10 mg PO once daily for 10 days a month (e.g., from day 16 to 25 of the menstrual cycle) for 3 months. Endometriosis treatment guidelines recommend medroxyprogesterone as an option for reducing endometriosis-associated pain.
      • Levonorgestrel-releasing intrauterine system c80
        • Levonorgestrel Vaginal insert; Adult and adolescent females: Insert 1 IUD into the uterus as per instructions. IUD delivers 20 mcg/day. Provides efficacy for up to 5 years, then remove and replace. Wait 6 weeks postpartum or until uterine involution occurs before inserting. Per endometriosis guidelines, may consider a levonorgestrel-releasing IUD as 1 of the options to reduce endometriosis-associated pain.
    • Gonadotropin-releasing hormone agonists r1c81
      • Females at high risk for osteoporosis are not good candidates for the use of gonadotropin-releasing hormone agonists1,46 r1r38
      • Leuprolide c82
        • Leuprolide Acetate Suspension for injection [Endometriosis]; Adults: Initially, 3.75 mg IM once monthly OR 11.25 mg IM once every 3 months with or without norethindrone acetate 5 mg/day PO for 6 months. For recurrence of symptoms, leuprolide must be given with norethindrone acetate 5 mg/day PO for 6 months; the total duration of therapy with leuprolide plus norethindrone acetate should not exceed 12 months. Assess bone density before retreatment.
      • Nafarelin
        • Nafarelin Acetate Nasal spray, solution; Adult females: 400 mcg/day intranasally administered as 1 spray (200 mcg) into one nostril qAM and 1 spray into the other nostril qPM. Initiate treatment between days 2 and 4 of the menstrual cycle. If no response after 2 months, dose may increase to 800 mcg/day, as 1 spray in each nostril qAM and qPM. Duration of treatment is recommended not to exceed 6 months. Clinical guidelines/studies suggest hormonal add-back therapy (e.g., with estrogens and/or progestins) with nafarelin is an effective means of reducing the bone mineral loss that occurs with nafarelin therapy alone; such therapy does not compromise nafarelin efficacy and may relieve vasomotor symptomss and vaginal dryness associated with hypoestrogenism.
    • Gonadotropin-releasing hormone antagonists
      • Elagolix r34r39r40c83
        • Elagolix Oral tablet; Adult Females: Initiate at 150 mg PO once daily; Max duration: 24 months. WOMEN WITH CO-EXISTING DYSPAREUNIA: Consider 200 mg PO twice daily initially; Max duration at this dose: 6 months. Use the lowest effective dose. Limit the duration of use as recommended to reduce risk of bone loss.
      • Relugolix in combination with estradiol and norethindrone (Myfembree)
        • Relugolix, Estradiol, Norethindrone Acetate Oral tablet; Adults: 1 tablet (40 mg relugolix; 1 mg estradiol; 0.5 mg norethindrone) PO once daily for up to 24 months. LIMIT of USE: Limit use to 24 months due to the risk for bone loss, which may not be reversible.
    • Aromatase inhibitors r6c84
      • Letrozole c85
        • Letrozole Oral tablet; Adults: 5 mg PO once daily for up to 3 months, with or without other hormonal therapies, has been studied; guidelines recommend letrozole in combination with oral contraceptive pills, progestogens, gonadotropin-releasing hormone analogs or gonadotropin-releasing hormone antagonists for endometrioses-associated pain refractory to other medical or surgical treatment. r1r41

    Nondrug and supportive care

    Procedures
    Laparoscopic treatment of endometriosis c86
    General explanation
    • Minimally invasive abdominal surgery to remove ectopic endometrial tissue r1r6
    • Highly effective at reducing pain and improving fertility, but the recurrence rate is 40% to 50% at 5 years after surgery r2
    • Any of 3 methods of endometrial tissue removal may be chosen based on symptoms and disease severity r6
    • Superior pain relief when combining presacral neurectomy with lesion ablation
      • Denervation of uterus and part of bladder is accomplished by electrosurgical destruction of nerve bundle within interiliac triangle
    Indication
    • Excision (preferredr42) or drainage and ablation of ectopic endometrial tissue r6
      • First line therapy for patients with endometrioma larger than 3 cm in diameter and chronic pelvic pain, and for infertile patients
    • Fulguration, ablation, and excision of ectopic endometrial tissue r6
      • Second line therapy for patients with dysmenorrhea, dyspareunia, or chronic pelvic pain resistant to pharmaceutical therapy
      • First line therapy for patients with pelvic mass
    • Laparoscopic presacral neurectomy r6
      • Third line therapy for patients with dysmenorrhea, dyspareunia, and deep central abdominal pain poorly responsive to first or second line surgical therapies
    Contraindications
    • Presence of dense pelvic adhesions that: r28
      • Render accurate evaluation of pelvic pathosis impossible
      • Prevent safe access to abdominopelvic cavity
    Complications
    • Complications associated with laparoscopic removal of endometrial tissue include risk of 1 or more of the following: r6
      • Infection
      • Internal organ damage
      • Hemorrhage
      • New adhesion formation
    • Complications associated with laparoscopic presacral neurectomy include: r6
      • Hemorrhage of adjacent venous plexus
      • No pain during first-stage labor
      • Constipation
      • Urinary urgency
    Hysterectomy with or without bilateral salpingo-oophorectomy r1c87
    General explanation
    • Surgical removal of uterus, fallopian tubes, and both ovaries r6
    Indication
    • Fourth line therapy for noncyclic chronic pelvic pain resistant to all other therapies r6
    Contraindications
    • Desire to maintain fertility r1
    Complications
    • Persistent or recurrent pain r6
    • Bowel injury or bladder injury
    • Infection (greatest risk with vaginal hysterectomy) r43

    Comorbidities

    • Patients may have polycystic ovary syndrome, which can cause irregular cycles, as well as manifestations encountered in patients with endometriosis, such as menorrhagia and infertility c88c89c90d5
      • In addition to oral contraceptives, these patients may require statins to control high cholesterol, hormones to increase fertility, and metformin to prevent diabetes r44

    Special populations

    • Females who may be pregnant or those who are breastfeeding
      • Do not administer combined oral contraceptives r45
      • Do not start or continue progestin therapy
      • Stop administering gonadotropin-releasing hormone agonists

    Complications and Prognosis

    Complications

    • Infertility is a major complication of endometriosis c91
      • 30% to 50% of females with endometriosis are infertile r13
      • Females with severe endometriosis (stages III and IV) experience significantly lower pregnancy rates compared with females with mild endometriosis (stages I and II) r46
    • Among females who undergo treatment with assisted reproductive technologies, those with endometriosis have higher risk of the following (compared with those without endometriosis): r13
      • Preeclampsia r13c92
      • Antepartum bleeding or placental complications r13c93
      • Cesarean delivery r13c94

    Prognosis

    • After 1 year of laparoscopically diagnosed endometriosis: r6
      • 17% to 29% of endometrial lesions spontaneously resolve
      • 24% to 64% of endometrial lesions progress
      • 9% to 59% remain stable
    • After laparoscopic excision of endometriotic lesions, recurrence occurs in 10% to 55% within 1 year, with recurrence in approximately 10% of the remaining females each year r7
    • Pain response to laparoscopic removal of lesions at 6 months after surgery tends to be best with the initial surgery (83% with pain improvement) compared with subsequent surgery (53% after second procedure) r7
    • 0.6% to 1% of females with ovarian endometriosis develop ovarian cancer r32

    Screening and Prevention

    Screening c95

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