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    Endometriosis

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    Feb.11.2025

    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 and delay to definitive care; 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 r4r5
    • 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 r6
    • After 1 year of laparoscopically diagnosed endometriosis, 17% to 29% of lesions spontaneously resolve, r79% to 59% remain stable, and 24% to 64% progress; after laparoscopic destruction of lesions, recurrence occurs in 10% to 55% within 1 yearr8r7

    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
    • Adolescents may have unique presentation of endometriosis and are especially prone to delayed diagnosis
    • It is important to remember that endometriosis is a chronic disease requiring long-term strategies r5

    Terminology

    Clinical Clarification

    • Endometriosis is a chronic, estrogen-dependent, inflammatory disease in which ectopic endometrial-like tissue forms lesions outside the uterus r1r7
    • 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 r9

    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 r3
          • Endometrial tissue resides within pelvic cavity: in peritoneum, in any pelvic organs, or in rectouterine pouch
        • Ovarian endometrioma r3r10
          • Endometrioma in which an ovarian cyst is lined with endometrial tissue; also known as a "chocolate cyst"
        • Deeply infiltrating endometriosis r3
          • Endometrial tissue that extends at least 5 mm into retroperitoneal space r11
          • 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 r3
          • Bladder
          • Ureters
          • Extrapelvic areas (atypical endometriosis), such as lungs
      • Classified by the American Society for Reproductive Medicine into stages I to IV in a scoring system that indicates the presence, location, and severity of ectopic endometrial lesions r11r12
        • Extent of disease, and therefore the score, does not correlate well with pain and quality of life, which is the major therapeutic target

    Diagnosis

    Clinical Presentation

    History

    • Clinical manifestations range from asymptomatic to severe and may worsen over time r3c1
      • Dysmenorrhea (ie, cyclic pain) r1c2
        • Pain may start before each menstrual period
      • Dyspareunia r1c3
        • Deep pain with intercourse, increased during menses
      • Chronic pelvic pain (ie, noncyclic pain) r1c4
        • Chronic pain defined as lasting for at least 6 months r7
        • Endometriosis is found in 70% to 90% of females with chronic pelvic pain r13
        • Pain can occur unpredictably and intermittently during entire menstrual cycle or it may be continuous r7
        • Can be described as dull, throbbing, or sharp; characteristics may change r7c5c6c7
        • May be worsened by physical activity r7
      • Menorrhagia r1c8
      • Dysuria or hematuria, particularly if cyclic r10r14r15c9
      • Dyschezia, constipation, or hematochezia, particularly if cyclic r6r10c10c11c12
        • May indicate ectopic endometrial tissue in perianal compartments (bowel involvement)
      • Infertility r3c13
        • Compared with fertile females, infertile females are 6 to 8 times more likely to have endometriosis r16
      • End-organ damage
        • Deep endometriosis can cause end-organ damage (eg, kidney failure) from ureteric obstruction or bowel obstruction r14
      • Cyclic shortness of breath, chest pain, shoulder pain, or hemoptysis can occur in patients with thoracic extension of endometriosis r1r14
      • Family history c14
        • Some studies have suggested an increased risk for the development of endometriosis in first-degree relatives of patients with endometriosis r17

    Physical examination

    • Pelvic examination (rectal examination in adolescent and adult females who have not had intercourse) r7
      • Tenderness or focal pain on examination is correlated surgically with endometriosis in 66% of patients r7c15c16
      • 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: r18c25
      • Attachment and implantation of endometrial glands and stroma outside the uterus within the peritoneum due to retrograde menstruation r19
      • 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 r3
      • 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 r20c26c27c28
        • Females frequently experience 6 to 12 years of symptoms before surgical diagnosis r3
        • Most patients report that their symptoms started in adolescence and improve at menopause, although some patients continue to have pain after menopause r14
    Genetics
    • Some studies have suggested an increased risk for the development of endometriosis in first-degree relatives of patients with endometriosis r17c29
    • Genetic risk factors identified include the following single nucleotide polymorphisms: r21
      • rs10965235 in the CDKN2BAS gene at locus 9p21.3 (OMIM %131200;r22 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)
    • Activating mutations of the KRAS gene are the most commonly found genetic variant in endometriotic epithelial cells; this same mutation is found in nearly all epithelial cells in patients with adenomyosis r23
    • Variable expression of genes associated with pain and perception management (SRP14/BMF, GDAP1, MLLT10, BSN, and NGF) is associated with endometriosis r24
      • There are significant genetic correlations between endometriosis and pain conditions including migraine and multisite chronic pain r24
    Ethnicity/race
    • A systematic review found that Black women had a lower risk and Asian women had a higher risk of endometriosis than White women, although it is possible these estimates reflect a bias related to access to care r25
    Other risk factors/associations
    • Several factors have associations with endometriosis, although the evidence tends to be weak
      • Menstrual outflow obstruction r7c30
      • In utero diethylstilbestrol exposure r7c31
      • Prolonged exposure to endogenous estrogen r7r10r14c32c33c34
        • Early menarche (ie, at 12 years of age or younger) r10
        • Late menopause r10
      • Endocrine-disrupting chemical exposure r26
        • Exposure to agents in the environment that activate multiple intracellular signaling pathways associated with proinflammation, estrogen, progesterone, prostaglandins, cell survival, apoptosis, migration, invasion, and growth of endometriosis r26
        • Examples include polychlorinated biphenyls, dioxins, bisphenol A and its analogs, and phthalates r26c35c36c37c38c39
      • Short menstrual cycles r27c40
      • Trans fats and red meat consumption r7c41c42
      • Low BMI r16r27c43
        • Average BMI of females with endometriosis: 21.3 ± 0.6 kg/m² r28
        • For each unit (kg/m²) increase in BMI, there is a decrease of approximately 12% to 14% in the likelihood of endometriosis diagnosis r28
      • Müllerian anomalies r27
      • Risk of endometriosis is lower for females who have had multiple pregnancies or with prolonged lifetime duration of lactation (more than 23 months) r29
      • Women with endometriosis seem to consume a diet with fewer fruits, vegetables, dairy products, foods rich in vitamin D and ω-3 long-chain fatty acids (found in fatty fish); however, there is no robust evidence demonstrating a significant association r1r30r31c44c45
    • An association has been suggested between endometriosis and inflammatory conditions, including asthma and osteoarthritis r24

    Diagnostic Procedures

    Primary diagnostic tools

    • Laparoscopic visualization of endometriosis lesions with histopathologic confirmation was previously considered the gold standard for diagnosis; however, to reduce delays in starting treatment, most international guidelines now advocate a nonsurgical (clinical) diagnosis based on symptoms, findings on physical examination, and imaging r14r32r33r34c46
      • Perform pelvic and abdominal examination for all patients in whom endometriosis is suspected on the basis of history r3r35c47
        • Abnormal pelvic examination findings (eg, tenderness, focal pain, palpable mass) correlate with laparoscopic endometriosis diagnosis in 70% to 90% of cases r3
          • However, more than 50% of females surgically diagnosed with endometriosis have normal pelvic examination findings r3
      • Obtain imaging for patients with suspected endometriosis; however, negative imaging findings do not exclude endometriosis, particularly superficial peritoneal disease r1r3r36
        • Transvaginal ultrasonography (TV-US) is the first line imaging modality used to identify endometriosis due to its accessibility and cost efficacy r3r35r37
          • Transabdominal ultrasonography may also be performed depending on patient characteristics and preference r2
          • Transrectal scan is performed only in cases with focused rectal symptoms
          • Augmented sonographic techniques (eg, advanced ultrasonography) are emerging as methods for evaluating deep infiltrating endometriosis r37
            • Utility depends on the location of the lesions as well as the expertise of the sonographer r37
        • MRI is indicated for those patients in whom ectopic endometrial tissue was not clearly detected via ultrasonography, but clinical suspicion remains r3r35
          • Can be used as complementary modality to ultrasonography for preoperative planning as it allows for a larger field of view r37
          • Especially useful for evaluation of endometrial ovarian cyst and tubal endometriosis r38
          • Used less frequently than ultrasonography owing to higher cost
    • Laparoscopy for diagnosis and treatment is indicated for patients with clinical diagnosis of symptomatic endometriosisr34 and unsuccessful empiric medical treatment, or individuals who wish to become pregnant r1r3r35
      • No longer considered the gold standard for diagnosing endometriosis owing to invasiveness, risk of complications, and delay in treatment while waiting for procedure and results r1r2
      • Detection of ectopic endometrial tissue defines the diagnosis, with surgeons mainly relying on the visual appearance of endometrial implants r3
        • 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
      • Excision of endometrial implants, endometriomas, and adhesions is performed at the time of surgery
    • 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 as the first line imaging modality for all patients with symptoms of endometriosis r1
        • Transvaginal ultrasonography along with transabdominal ultrasonography can detect lesions within pelvic cavity: in peritoneum, in any pelvic organs, and in rectouterine pouch r3
        • Transvaginal mode is more sensitive than transabdominal mode for the detection of endometriomas; small pelvic implants may not be detected by transvaginal scan r39
          • Stages I and II endometriosis are often not visible on routine ultrasonography examination r40
          • Stage IV disease is often visible on ultrasonography examination, and stage III disease may be visible
      • Depending on availability, may start evaluation with a basic transvaginal ultrasonography examination, and if endometrioma or symptoms or signs of deep endometriosis are visualized, proceed to advanced transvaginal ultrasonography or pelvic MRI r14
        • The Society of Radiologists in Ultrasound Expert Consensus recommends performing augmented (advanced) pelvic ultrasonography in premenopausal or early postmenopausal individuals r40
      • Endometrioma on ultrasonography examination
        • Form of endometriosis that is most frequently localized
        • Endometriotic lesions typically appear hypoechoic on ultrasonography r37
          • 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) r39
              • Observed in up to 95% of patients with endometriomas r39
              • Color Doppler scan may assist in identification, given the poor vascularity r38
          • Endometrioma may also appear as a simple cyst (5.5% of endometriomas) or a solid mass (4.9% of endometriomas) r39
      • Additional techniques are employed in advanced transvaginal ultrasonography to reliably detect deep endometriosis, including: r3r14r40
        • Examination of the posterior compartment for endometriosis nodules r14r40
          • The most common site of endometriosis and therefore the area in which reporting physicians can add the most value to patient management r36
        • Examination of the anterior compartment for endometriosis nodules r14
        • Observation of the relative positioning of the uterus and ovaries r36r40
        • The uterine sliding sign maneuver between the uterus and sigmoid colon to assess the rectouterine pouch obliteration state r14r36r40
        • Other findings in deep infiltrating endometriosis include:
          • Fixed retroverted uterus r14
          • Nodularity in posterior vaginal fornix r14
          • Detection of kissing ovaries (ovaries joined behind rectouterine pouch), which indicates severe endometriosis r39
        • Direct and indirect observations of deep endometriosis should be assessed during the examination; results should be reported using four categories: r40
          • Incomplete (augmented pelvic US, or APU-0) r40
          • Normal (APU-1) r40
          • Equivocal (APU-2) r40
          • Positive (APU-3) with associated management r40
      • Transvaginal ultrasonography with bowel preparation is also accurate in identifying all sites of ovarian and deep endometriosis and is more accurate at detecting rectosigmoid endometriosis than diagnostic laparoscopy r41
      • Criteria for performing and reporting transvaginal ultrasonography for patients with suspected endometriosis have been published r42
    • MRI r1c53c54
      • Indicated when ectopic endometrial tissue was not clearly detected via ultrasonography and clinical suspicion remains high, or for patients who are suspected to have bladder, ureteral, or bowel disease r10r35
        • Similar sensitivity and specificity (more than 90%) for diagnosing deep endometriosis as advanced transvaginal ultrasonography, although accuracy is affected by the protocols used and the experience of the reader r3
        • 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) r6r38
          • 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
        • Standardized language for describing endometriosis on MRI should be employed r43
        • Classic findings include: r37
          • Deep infiltrating endometriosis: T2 hypointensity r37
          • Endometrioma: T2 hypointensity and T1 hyperintensity r37
          • Superficial peritoneal endometriosis: a small focus of T1 hyperintensity r37

    Procedures

    Laparoscopy c55
    General explanation
    • Minimally invasive abdominal surgery using a camera with various probes to evaluate the pelvis and abdominal region r3
    Indication
    • May be indicated when endometriosis is suspected based on clinical signs but has not been demonstrated in preoperative investigations r35
    • Females with clinically diagnosed endometriosis who: r3
      • Do not respond to empiric therapy
      • Want to become pregnant
    Contraindications
    • Abdominal wall infection r3
    • Uncorrected coagulopathy r3
    • Tense, distended abdomen r3
    Complications
    • Injury to pelvic organs (2% risk) r3
    • Major blood vessel damage (1% risk) r44
    Interpretation of results
    • Primary types of endometriosis
      • Superficial endometriosis r3
        • Endometrial tissue within pelvic cavity, including within peritoneum, any pelvic organ, and rectouterine pouch
      • Ovarian endometriosis r3
        • Diagnosed if adnexal endometrioma is detected
      • Deeply infiltrating endometriosis r3
        • Diagnosed if deep endometriotic lesions are detected and extend more than 5 mm below peritoneum in pelvic/abdominal cavity
    • Rare types of endometriosis r3
      • 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% r45
      • Laparoscopy that does not demonstrate visual or histologic disease is highly reliable for excluding endometriosis r46

    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 r47
      • Differentiated by lack of ultrasonographic or other imaging findings suggesting endometriosis
    • Adenomyosis r48c57
      • Endometrial tissue within myometrium
      • Evidence suggests a possible shared pathophysiology between endometriosis and adenomyosis r23
      • 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 r48
      • Findings on MRI include a focal or diffuse thickened junctional zone due to uncoordinated proliferation of the inner myometrial cells causing junctional zone hyperplasia r48
      • 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 r49
      • Differentiated from endometriosis by ultrasonography; if differentiation is not clear, obtain MRI scan
    • Cystadenoma r39c59
      • Type of benign serous or mucinous epithelial tumor of ovary
      • As in endometriosis, symptoms may include cyclic pelvic pain and dyspareunia
      • On ultrasonography 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 r39c60
      • 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 r39c61d2
      • 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 r50c62d3
      • 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 r51
      • 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 r51
      • 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 r51
    • 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 r7
      • 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 r7

    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 r2
      • Those for whom diagnosis cannot be established

    Treatment Options

    No cure for endometriosis yet exists; primary treatment is directed toward relief of painr34 and improvement in quality of life r3

    • Strategies to achieve these goals include medical therapies, surgery, and complementary therapies with a shared decision-making approach r1r5
    • Long-term multidisciplinary care has been suggested as a strategy for improved long-term outcomes r4r5

    Hormonal therapies do not eliminate endometriosis, improve fertility, diminish endometriomas, or treat complications of deep endometriosis; symptoms recur or worsen when treatment is discontinued

    Empiric therapy is generally administered without surgical diagnosis; plan is based on clinical diagnosis r34

    Evidence suggests that early treatment of endometriosis and associated pain may decrease the risk of development of chronic pain, which further supports the importance of early assessment and intervention r14

    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 r1r7

    • Use of NSAIDs may pose a reproductive risk by delaying or preventing prostaglandin-mediated rupture of ovarian follicles, which has been associated with reversible infertility r52
      • Consider withdrawal of NSAIDs for females who have difficulties conceiving or who are undergoing infertility evaluation

    If response to NSAIDs is inadequate and pregnancy is not desired, additional medical therapy includes the following: r1r13

    • Combined hormonal contraceptives (oral, vaginal ring, or transdermal) r10
      • Published guidelines typically recommend using a combined oral contraceptive pill as first line hormonal treatment for endometriosis r1
      • A continuous oral contraceptive regimen appears to be more effective at reducing pain than a cyclic oral contraceptive regimen r53r54
      • No method or preparation of combined hormonal contraceptive appears to be more effective than any other r10
    • Progestogens, including medroxyprogesterone acetate, levonorgestrel-releasing intrauterine system, or an etonogestrel-releasing subdermal implant
      • Primarily used for patients who are unable to tolerate combined hormonal contraceptive therapy r2
    • GnRH (gonadotropin-releasing hormone) agonists (eg, leuprolide, nafarelin, goserelin) or GnRH antagonists (eg, elagolix, relugolix) may be prescribed as second line options if hormonal contraceptives or progestogens have been ineffective r55r56r57
      • Females at high risk for osteoporosis are not good candidates for the use of gonadotropin-releasing hormone agonists r1r58
      • To prevent bone loss and hypoestrogenic complications with these agents, administer hormonal add-back therapy using estrogen and progestogen combination r1r57
      • Laparoscopy for diagnosis and treatment is frequently offered before initiation of these medications due to significant medication side-effects
    • 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
    • Danazol is no longer routinely recommended as a medical treatment for the general population in endometriosis-associated pain due to its severe adverse effects at higher doses r1
      • Exception is transgender patients with endometriosis, in whom androgenic side-effects may be desirable r59r60
    • May choose further medical therapies (second and third line agents) for those with inadequate response to initial medical therapy or may opt for an earlier surgical approach

    Surgical therapy

    • Laparoscopic removal of ectopic endometrial tissue r1
      • A minimally invasive approach with complete treatment of the disease is considered best practice by most international guidelines r14r32r33
      • Reserved for patients with medically refractory pain that limits function or causes significant emotional distress, or for those individuals trying to conceive
      • Removal of ectopic endometrial tissue may be achieved by excision, diathermy, or ablation/vaporization r1r61
      • For patients with ovarian endometrioma, surgery is required as medical therapy does not resolve endometriomas
        • 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
        • Ovarian cystectomy is preferred rather than drainage and coagulation surgery r1r61r62
        • Surgical removal can diminish ovarian reserve, so small endometriomas (5 cm or smaller) may not be removed r63
      • 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 nodules may reduce pain and improve quality of life but should be undertaken at centers of excellence r1
      • In patients for whom endometriosis has led to ureteric or bowel obstruction, surgery may be the only management option r14
        • Colorectal involvement may require segmental bowel resection r1
    • Hysterectomy r1
      • Hysterectomy, 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 r7
      • 10% of patients experience pain recurrence within 1 to 2 years after surgery r7
      • Combined estrogen/progestogen is recommended for patients with endometriosis after surgical menopause until the age of natural menopause r1
      • Removal of both ovaries causes premature surgical menopause with potential adverse effects on bone and heart health (as compliance with hormone replacement therapy is low) and provides only marginal additional benefit for pain over hysterectomy alone r14r64

    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

    Nociplastic pain

    • Some patients may not respond to medical or surgical management and can develop persistent pelvic pain; may reflect central sensitization or nociplastic pain, with accompanying chronic overlapping pain conditions r14
    • A multidisciplinary plan of care that follows chronic pelvic pain guidelines is most likely to lead to improved quality of life in these patients r14

    Pelvic floor muscle physiotherapy

    • In a randomized controlled trial studying the effects of pelvic floor muscle physiotherapy on urinary, bowel, and sexual functions in women with deep infiltrating endometriosis, it did not appear to affect urinary, bowel, or sexual functions r65

    Fertility-associated treatment options for infertile patients r7

    • Laparoscopic surgery for endometriosis elevates both spontaneous and assisted reproductive pregnancy rates above those achieved with expectant management alone r66
      • Resection or destruction of endometriosis implants reduces inflammation, which likely improves the multifactorial infertility related to endometriosis r66
    • Endometriosis Fertility Index can be used to identify patients who may benefit from assisted reproductive technologies after surgery r67r68
    • Hormonal therapy should not be offered postoperatively when fertility is a main priority r1r10
    • ESHRE guideline recommends intrauterine insemination with ovarian stimulation in women with stage I and stage II endometriosis r1
    • In vitro fertilization is recommended if: r1r10
      • Tubal function is compromised
      • Male factor infertililty is present
      • Other treatments have failed

    Drug therapy

    • NSAIDs c65
      • Celecoxib c66
        • Celecoxib Oral capsule; Adults: 400 mg PO once, then 200 mg PO every 12 hours as needed.
      • Ibuprofen c67
        • Ibuprofen Oral tablet; Adults: 800 mg PO once, then 400 to 800 mg PO every 8 hours as needed.
      • Mefenamic acid c68
        • Mefenamic Acid Oral capsule; Adults: 500 mg PO once, then 250 mg PO every 6 hours as needed.
      • Naproxen c69
        • Naproxen Oral tablet; Adults: 500 mg PO once, then 250 mg PO every 6 to 8 hours as needed. Max: 1,250 mg/day.
    • Oral combined hormonal contraceptives c70
      • Ethinyl estradiol–norethindrone c71
        • Ethinyl Estradiol, Norethindrone Oral tablet; Adolescents: 0.4 to 1 mg norethindrone; 0.035 mg ethinyl estradiol PO once daily for 21 days, followed by 7 days of inert, inactive tablets as for routine contraception. Omit 7 days of inert, inactive tablets for continuous therapy.
        • Ethinyl Estradiol, Norethindrone Oral tablet; Adults: 0.4 to 1 mg norethindrone; 0.035 mg ethinyl estradiol PO once daily for 21 days, followed by 7 days of inert, inactive tablets as for routine contraception. Omit 7 days of inert, inactive tablets for continuous therapy.
      • Levonorgestrel–ethinyl estradiol c72
        • Levonorgestrel, Ethinyl Estradiol Oral tablet; Adolescents: 0.05 to 0.15 mg levonorgestrel; 0.02 to 0.04 mg ethinyl estradiol PO once daily for 21 days, followed by 7 days of inert, inactive tablets as for routine contraception. Omit 7 days of inert, inactive tablets for continuous therapy.
        • Levonorgestrel, Ethinyl Estradiol Oral tablet; Adults: 0.05 to 0.15 mg levonorgestrel; 0.02 to 0.04 mg ethinyl estradiol PO once daily for 21 days, followed by 7 days of inert, inactive tablets as for routine contraception. Omit 7 days of inert, inactive tablets for continuous therapy.
      • Norgestimate–ethinyl estradiol c73
        • Inert Oral tablet, Norgestimate, Ethinyl Estradiol Oral tablet; Adolescents: 0.18 to 0.25 mg norgestimate; 0.025 to 0.035 mg ethinyl estradiol PO once daily for 21 days, followed by 7 days of inert, inactive tablets as for routine contraception. Omit 7 days of inert, inactive tablets for continuous therapy.
        • Inert Oral tablet, Norgestimate, Ethinyl Estradiol Oral tablet; Adults: 0.18 to 0.25 mg norgestimate; 0.025 to 0.035 mg ethinyl estradiol PO once daily for 21 days, followed by 7 days of inert, inactive tablets as for routine contraception. Omit 7 days of inert, inactive tablets for continuous therapy.
    • Vaginal combined hormonal contraceptive c74
      • Etonogestrel–ethinyl estradiol c75
        • Etonogestrel, Ethinyl Estradiol Vaginal insert; Adolescents: 11.7 mg etonogestrel; 2.7 mg ethinyl estradiol vaginally on or before Day 5 of menstrual cycle. Remove ring after 21 days, followed by 7 days of rest before inserting a new ring as for routine contraception.
        • Etonogestrel, Ethinyl Estradiol Vaginal insert; Adults: 11.7 mg etonogestrel; 2.7 mg ethinyl estradiol vaginally on or before Day 5 of menstrual cycle. Remove ring after 21 days, followed by 7 days of rest before inserting a new ring as for routine contraception.
    • Progestins c76
      • Levonorgestrel c77
        • Levonorgestrel Vaginal insert; Adolescents: 52 mg intrauterine device (IUD) inserted into the uterus. Remove and replace the IUD after 5 years; may need to replace earlier for pain control.
        • Levonorgestrel Vaginal insert; Adults: 52 mg intrauterine device (IUD) inserted into the uterus. Remove and replace the IUD after 5 years; may need to replace earlier for pain control.
      • Medroxyprogesterone acetate c78
        • Medroxyprogesterone Acetate Oral tablet; Adults: 10 to 50 mg/day PO.
      • Norethindrone acetate
        • Norethindrone Acetate Oral tablet; Adults: 5 mg PO once daily with leuprolide for 6 months. May repeat course for recurrence of symptoms; limit total duration of therapy to 12 months.
    • Gonadotropin-releasing hormone agonists c79
      • Leuprolide c80
        • Leuprolide Acetate Suspension for injection [Endometriosis]; Adults: 3.75 mg IM once monthly or 11.25 mg IM every 3 months with or without norethindrone acetate for 6 months. May repeat course with norethindrone acetate for recurrence of symptoms; limit total duration of therapy to 12 months.
      • Nafarelin
        • Nafarelin Acetate Nasal spray, solution; Adults: 200 mcg (1 spray) intranasally in 1 nostril twice daily, starting on Days 2 to 4 of menstrual cycle. If amenorrhea is not achieved after 2 months, increase the dose to 200 mcg (1 spray) intranasally in each nostril twice daily. Limit duration of therapy to 6 months.
    • Gonadotropin-releasing hormone antagonists
      • Elagolix c81
        • For endometriosis-associated pain
          • Elagolix Oral tablet; Adults: 150 mg PO once daily for up to 24 months.
        • For endometriosis-associated pain with co-existing dyspareunia
          • Elagolix Oral tablet; Adults: 200 mg PO twice daily for 6 months.
      • Relugolix in combination with estradiol and norethindrone acetate
        • Relugolix, Estradiol, Norethindrone Acetate Oral tablet; Adults: 40 mg relugolix; 1 mg estradiol; 0.5 mg norethindrone PO once daily for 24 months.
    • Aromatase inhibitors c82
      • Letrozole c83
        • Letrozole Oral tablet; Adults: 2.5 mg PO once daily for up to 6 months or 5 mg PO once daily for 3 months.
    • Androgenic hormone
      • Danazol
        • Danazol Oral capsule; Adults: 100 to 200 mg PO twice daily, initially. Adjust dose based on clinical response. Max: 800 mg/day. Continue treatment for 3 to 6 months; may extend treatment duration to 9 months if necessary and can reinstitute therapy if symptoms recur after discontinuing.

    Nondrug and supportive care

    Procedures
    Laparoscopic treatment of endometriosis c84
    General explanation
    • Minimally invasive abdominal surgery to remove ectopic endometrial tissue r1r7
    • Highly effective at reducing pain and improving fertility, but the recurrence rate is 40% to 50% at 5 years after surgery r3
    • Any of 3 methods of endometrial tissue removal may be chosen based on symptoms and disease severity r7
    • 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
    • Should be performed at a center of excellence for endometriosis surgery r1r10
    Indication
    • Pain despite medical therapy
    • Contraindications to or refusal of medical therapy
    • Exclusion of malignancy of adnexal mass
    • Obstruction of urinary tract or bowel
    • Excision (preferredr69) or drainage and ablation of ectopic endometrial tissue
      • First line therapy for patients with endometrioma larger than 3 cm in diameter and chronic pelvic pain, and for infertile patients r7
      • Reduces the risk of recurrence and pain and increases spontaneous pregnancy rates compared with ablation r62
    • Fulguration, ablation, and excision of ectopic endometrial tissue r7
      • 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 r7
      • 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: r45
      • 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: r7
      • Infection
      • Internal organ damage
      • Hemorrhage
      • New adhesion formation
    • Complications associated with laparoscopic presacral neurectomy include: r7
      • Hemorrhage of adjacent venous plexus
      • No pain during first-stage labor
      • Constipation
      • Urinary urgency
    Hysterectomy with or without bilateral salpingo-oophorectomy r1c85
    General explanation
    • Surgical removal of uterus, fallopian tubes, and both ovaries r7
    Indication
    • Fourth line therapy for noncyclic chronic pelvic pain resistant to all other therapies r7
    Contraindications
    • Desire to maintain fertility r1
    Complications
    • Persistent or recurrent pain r7
    • Bowel injury or bladder injury
    • Infection (greatest risk with vaginal hysterectomy) r70

    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 c86c87c88d5
      • In addition to oral contraceptives, these patients may require statins to control high cholesterol, hormones to increase fertility, and metformin to prevent diabetes r71

    Special populations

    • Adolescents
      • History
        • Two-thirds of adults with endometriosis reported that their first pelvic symptoms started before age 20 years r72
        • A younger age at onset of symptoms has been associated with a longer diagnostic delay r73
        • Adolescents most commonly present with r59
          • Heavy or irregular uterine bleeding
          • Dysmenorrhea (may start shortly after menarche)
          • Noncyclic pelvic pain
          • Nausea
        • Adolescents with endometriosis experience dyspareunia twice as often as their peers without endometriosis r59
        • Comorbid pain syndromes common in adolescents with endometriosis include r59
          • Irritable bowel syndrome
          • Chronic headaches
          • Chronic low back pain
          • Fibromyalgia
          • Chronic fatigue syndrome
      • Examination and imaging
        • Adolescents are less likely to consent to or be appropriate candidates for a pelvic examination r59
        • When obtaining a pelvic ultrasonogram, a transabdominal approach may need to be the initial choice to minimize discomfort r1r10r59
      • Treatment
        • As in treatment of adults, NSAIDs should be the initial therapy adolescents with endometriosis r74
        • After NSAIDs, combined hormonal contraceptive is the first line therapy r74
        • If a patient is not responding to medical management after 3 to 6 months of therapy, proceeding to laparoscopy is the primary approach for diagnosing and treating endometriosis r74
          • The appearance of endometriosis on laparoscopy in adolescents is unique; typically clear or red lesions that can be difficult to identify for gynecologists unfamiliar with endometriosis in adolescents r74
          • If an adolescent patient is undergoing a diagnostic laparoscopy for dysmenorrhea, chronic pain, or both, consider placing a levonorgestrel-releasing intrauterine system (LNG-IUS) at the time of laparoscopy to minimize the pain of insertion r74
          • Radical excisional surgery or peritoneal stripping have not demonstrated long-term benefit in the surgical management of endometriosis in adolescents and may result in adhesion formation r59
        • Gonadotropin-releasing hormone agonists should not be used empirically in adolescents without a definitive diagnosis of endometriosis and failure of first line hormonal management, as adolescence is a time of peak bone accrual r59r74
      • Symptoms of endometriosis may result in significant school absenteeism; resources including school counselors or social workers can promote accommodations to keep adolescents engaged in school r59
    • Transgender individuals
      • Transgender adolescents may experience dysmenorrhea and pelvic pain symptoms, and even be laparoscopically diagnosed with endometriosis, while on gender-affirming testosterone therapy r60
      • Danazol, a testosterone derivative, may be a more desirable treatment choice for transgender adolescents due to its potential androgenic side effects which may include weight gain, acne, deepening of the voice, and hirsutism r60r75
    • Females who may be pregnant or those who are breastfeeding
      • May have a higher risk of miscarriage and ectopic pregnancy r1r10
      • Pregnancy has a variable effect on endometriosis lesions, which may regress or grow r10
      • Medication management
        • Do not administer combined oral contraceptives r76
        • Do not start or continue progestin therapy
        • Stop administering gonadotropin-releasing hormone agonists
        • NSAIDs may be used in some cases, but in general avoid after 20 weeks gestation r77
    • Menopausal individuals
      • 2% to 5% of females will have endometriosis-related symptoms after menopause
      • Differential diagnosis should include malignancy in a postmenopausal patient presenting with pelvic pain
      • A systematic review suggested that people with endometriosis might experience reactivation of endometriosis when receiving hormone therapy to treat menopausal symptoms; there is also increased risk of malignant transformation of the lesions with estrogen-only preparations r78
        • Combined estrogen-progesterone formulations are therefore recommended in this population, including those who have had a hysterectomy r1

    Complications and Prognosis

    Complications

    • Infertility is a major complication of endometriosis c89
      • 30% to 50% of females with endometriosis are infertile r16
      • Females with severe endometriosis (stages III and IV) experience significantly lower pregnancy rates compared with females with mild endometriosis (stages I and II) r79
    • Among females who undergo treatment with assisted reproductive technologies, those with endometriosis have higher risk of the following (compared with those without endometriosis): r16
      • Preeclampsia r16c90
      • Antepartum bleeding or placental complications r16c91
      • Cesarean delivery r16c92

    Prognosis

    • After 1 year of laparoscopically diagnosed endometriosis: r7
      • 17% to 29% of endometrial lesions spontaneously resolve
      • 9% to 59% of endometrial lesions remain stable
      • 24% to 64% of endometrial lesions progress
    • 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 r8
    • 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) r8
    • 0.6% to 1% of females with ovarian endometriosis develop ovarian cancer r50

    Screening and Prevention

    Screening c93

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