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Endometriosis

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Synopsis
Terminology
Diagnosis
Treatment
Complications and Prognosis
Screening and Prevention

Feb.02.2023

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)
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
Patients in whom endometriosis is suspected who seek pain management but not fertility are generally treated empirically with NSAIDs, as well as combined contraceptives or progestogens, without having a confirmed surgical diagnosis
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 women with endometriosis are infertile, and women with severe endometriosis experience significantly lower pregnancy rates compared with those with mild endometriosis ^r1
After 1 year of laparoscopically diagnosed endometriosis, 17% to 29% of lesions spontaneously resolve, 24% to 64% progress, and 9% to 59% remain stable;^r2 after laparoscopic destruction of lesions, recurrence occurs in 10% to 55% within 1 year^r3

Pitfalls

Hormonal therapies do not eliminate endometriosis, and symptoms recur or worsen with discontinuation of treatment

Terminology

Clinical Clarification

Endometriosis is an inflammatory disease in which ectopic endometrial-like tissue forms lesions outside the uterus ^r4
Affects 2% to 10% of reproductive-age females worldwide and up to 50% of infertile females ^r4
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 ^r5

Classification

Endometriosis is classified by location, depth, and severity of ectopic endometrial lesions

Classified as pelvic endometriosis, ovarian endometrioma, or deeply infiltrating endometriosis
- Pelvic endometriosis ^r6
  - Endometrial tissue resides within pelvic cavity: in peritoneum, in any pelvic organs, or in rectouterine pouch
- Ovarian endometrioma ^r6
  - Endometrioma in which an ovarian cyst is lined with endometrial tissue
- Deeply infiltrating endometriosis ^r6
  - Endometrial tissue that extends at least 5 mm into retroperitoneal space ^r7
  - 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 ^r6
  - Bladder
  - Ureters
  - Extrapelvic areas (atypical endometriosis)

Classified by the American Society for Reproductive Medicine into 4 stages by a scoring system that indicates the presence, location, and severity of ectopic endometrial lesions ^r7^r8

Stage I: minimal
- Characterized by superficial lesions in peritoneum, ovary, or both; filmy adhesions are possible
- Scores 1 to 5
Stage II: mild
- In addition to stage I findings, deep lesions may be detected in peritoneum
- Scores 6 to 15
Stage III: moderate
- In addition to stage I and II findings, deep lesions may be detected in ovary, cul-de-sac may be partially obliterated, or filmy adhesions may be detected in fallopian tubes
- Scores 16 to 40
Stage IV: severe
- In addition to stage I, II, and III findings, deep lesions and dense adhesions may be detected in several regions, as well as complete obliteration of cul-de-sac
- Scores higher than 40
Most commonly used surgical scoring system; it is useful in providing uniform recording of operative findings and possibly for comparing results from different therapies ^r9
- However, there are limitations to its use
  - Correlates poorly with symptoms of pain and dyspareunia or infertility
  - Pregnancy after treatment is not predicted well
  - Does not provide sufficient information to be useful for deep endometriosis; other systems classifying and documenting the extent of the deep endometriosis have been developed (eg, ENZIAN classification) ^r10

Endometriosis classification of the American Society for Reproductive Medicine.
Stage	Findings	Scores
I: minimal	Superficial lesions in peritoneum and/or ovary; filmy adhesions are possible	1-5
II: mild	Stage I findings plus deep lesions may be detected in peritoneum	6-15
III: moderate	Stage 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 tubes	16-40
IV: severe	Stage 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-sac	More than 40

Diagnosis

Clinical Presentation

History

Clinical manifestations range from asymptomatic to severe and may worsen over time ^r6^c1
- Dysmenorrhea ^r4^c2
  - Pain may start before each menstrual period
- Dyspareunia ^r4^c3
  - Deep pain with intercourse, increased during menses
- Chronic pelvic pain ^r4^c4
  - Chronic pain defined as lasting for at least 6 months ^r2
  - 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 ^r2
  - Can be described as dull, throbbing, or sharp; characteristics may change ^r2^c5^c6^c7
  - May be worsened by physical activity ^r2
- Menorrhagia ^r4^c8
- Dysuria ^r12^c9
- Dyschezia, constipation, or hematochezia ^r1^c10^c11^c12
  - May indicate ectopic endometrial tissue in perianal compartments (bowel involvement)
- Infertility ^r6^c13
  - 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 endometriosis patients ^r14

Physical examination

Pelvic examination (rectal examination in adolescent and adult females who have not had intercourse) ^r2
- Tenderness or focal pain on examination is correlated surgically with endometriosis in 66% of patients ^r2^c15^c16
- Other significant findings that are consistent with endometriosis
  - Uterosacral ligament nodularity ^c17
  - Adnexal mass ^c18
  - Limited motion of ovaries or uterus ^c19^c20
  - Painful induration, nodules, or both detected in rectovaginal wall or posterior vaginal fornix ^c21^c22
- Endometriosis is not ruled out by normal examination findings
Abdominal examination may be positive for lower abdominal masses or tenderness ^r4^c23^c24

Causes and Risk Factors

Causes

Causes are unknown but may include the following: ^r9^c25
- 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 ^r6
- 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 ^r15^c26^c27^c28
  - Females frequently experience 6 to 12 years of symptoms before surgical diagnosis ^r6

Genetics

Some studies have suggested an increased risk for the development of endometriosis in first-degree relatives of endometriosis patients ^r14^c29
Genetic risk factors identified include the following single nucleotide polymorphisms: ^r16
- rs10965235 in the CDKN2BAS gene at locus 9p21.3 (OMIM %131200;^r17 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 ^r2^c30
- In utero diethylstilbestrol exposure ^r2^c31
- Prolonged exposure to endogenous estrogen (eg, early menarche, late menopause) ^r2^c32^c33^c34
- Endocrine-disrupting chemical exposure ^r2
  - 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 ^c35^c36^c37^c38^c39
- Short menstrual cycles ^r2^c40
- Trans fats and red meat consumption ^r2^c41^c42
- Low BMI ^r13^c43
  - Average BMI of females with endometriosis: 21.3 ± 0.6 kg/m² ^r18
  - For each unit (kg/m²) increase in BMI, there is approximately 12% to 14% decrease in the likelihood of endometriosis diagnosis ^r18
Risk of endometriosis is less in females who have had multiple pregnancies or with prolonged lifetime duration of lactation (more than 23 months) ^r19
Decreased risk of developing endometriosis is associated with diet containing fruits, green vegetables, and ω-3 long-chain fatty acids (found in fatty fish) ^r20^c44^c45

Diagnostic Procedures

Primary diagnostic tools

Presumptive diagnosis of endometriosis is based on combination of symptoms, signs, and imaging findings ^c46
- Perform pelvic and abdominal examination in all patients in whom endometriosis is suspected on the basis of history ^r6^r21^c47
- Abnormal pelvic examination findings (eg, tenderness, focal pain, palpable mass) correlate with laparoscopic endometriosis diagnosis in 70% to 90% of cases ^r6
  - However, more than 50% of females surgically diagnosed with endometriosis have normal pelvic examination findings ^r6
- Obtain imaging (ultrasonography or MRI) in patients with suspected endometriosis; however, negative imaging finding does not exclude endometriosis, particularly superficial peritoneal disease ^r6
  - Ultrasonography is indicated in all patients in whom endometriosis is suspected; may include the following types: ^r6^r21
    - Transabdominal and transvaginal scans (typically performed) ^r22
    - 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 ^r6^r21
    - Especially useful for evaluation of endometrial ovarian cyst and tubal endometriosis ^r23
    - Used less frequently than ultrasonography owing to higher cost
Laparoscopy is indicated only for patients with clinical diagnosis of symptomatic endometriosis and negative imaging results and/or unsuccessful empirical treatment ^r4^r6^r21
- Detection of ectopic endometrial tissue defines the diagnosis, with surgeons mainly relying on the visual appearance of endometrial implants ^r6
  - Biopsy of presumed endometrial implants is left to discretion of surgeon; histological confirmation of endometriotic lesions is recommended. However, negative histology does not entirely exclude endometriosis ^r4^c48
- No longer considered the gold standard for diagnosing endometriosis ^r4
- Not routinely used for diagnosis, owing to invasiveness and risk of complications; typically performed to treat surgically ^r6^r22
Measurement of biomarkers in endometrial tissue, blood, menstrual or uterine fluids has no role in diagnosis of endometriosis ^r4

Imaging

Ultrasonography ^c49^c50^c51^c52
- Obtain transabdominal and transvaginal ultrasonography in all patients with symptoms of endometriosis ^r4
  - Transvaginal mode is more sensitive than transabdominal mode for the detection of endometriomas; small pelvic implants may not be detected by transvaginal scan ^r24
    - 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) ^r24
      - Observed in up to 95% of patients with endometriomas ^r24
      - Color Doppler scan may assist in identification, given the poor vascularity ^r23
  - Endometrioma also may appear as a simple cyst (5.5% of endometriomas) or a solid mass (4.9% of endometriomas) ^r24
- Other endometriosis
  - Transvaginal ultrasonography along with transabdominal ultrasonography can detect lesions within pelvic cavity: in peritoneum, in any pelvic organs, and in rectouterine pouch ^r6
  - Transvaginal ultrasonography also evaluates deeply infiltrating endometriosis ^r23
    - 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 ^r24
- 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 ^r25
MRI ^c53^c54
- Indicated when ectopic endometrial tissue was not clearly detected via ultrasonography and clinical suspicion remains high ^r21
  - 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) ^r1^r23
    - 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 ^r6

Indication

May be indicated when endometriosis is suspected based on clinical signs but has not been demonstrated in preoperative investigations ^r21
Females with clinically diagnosed endometriosis who: ^r6
- Do not respond to empiric therapy
- Want to become pregnant

Contraindications

Abdominal wall infection ^r6
Uncorrected coagulopathy ^r6
Tense, distended abdomen ^r6

Complications

Injury to pelvic organs (2% risk) ^r6
Major blood vessel damage (1% risk) ^r26

Interpretation of results

Primary types of endometriosis
- Pelvic endometriosis ^r6
  - Endometrial tissue within pelvic cavity, including within peritoneum, any pelvic organ, and rectouterine pouch
- Ovarian endometriosis ^r6
  - Diagnosed if adnexal endometrioma is detected
- Deeply infiltrating endometriosis ^r6
  - Diagnosed if deep endometriotic lesions are detected and extend more than 5 mm below peritoneum in pelvic/abdominal cavity
Rare types of endometriosis ^r6
- Bladder endometriosis
- Ureteral endometriosis
- Extrapelvic/atypical endometriosis
Histologic evaluation of ectopic endometrial tissue can be performed to confirm diagnosis ^r4
- Endometriosis diagnosis is confirmed if ectopic tissue is verified to be endometrial
- Improves accuracy of diagnosis by 20% ^r27

Differential Diagnosis

Most common

Dysmenorrhea ^c56^d1
- Painful menstrual cramps, originating from the uterus
- Usually pain 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 ^r28
- Differentiated by lack of ultrasonographic or other imaging findings suggesting endometriosis
Adenomyosis ^r29^c57
- 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; asymmetric 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 ^r29
- Findings on MRI include a focal or diffuse thickened junctional zone due to uncoordinated proliferation of the inner myometrial cells causing junctional zone hyperplasia ^r29
- 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 ^r30
- Differentiated from endometriosis by ultrasonography; if differentiation is not clear, obtain MRI scan
Cystadenoma ^r24^c59
- Type of benign serous or mucinous epithelial tumor of ovary
- As in endometriosis, symptoms may include cyclic pelvic pain and dyspareunia
- On ultrasound, 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 ^r24^c60
- 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 ^r24^c61^d2
- 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 ^r31^c62^d3
- 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 ^c63^d4
- Infection of fallopian tube commonly caused by Neisseria gonorrhoeae or Chlamydia trachomatis and resulting in a spectrum of clinical disease ^r32
- As in endometriosis, symptoms may include noncyclic pelvic pain and dyspareunia, and pelvic examination may find uterine and adnexal tenderness
- However, acute pelvic inflammatory disease is typically also accompanied by fever and chills, abnormal uterine bleeding, and abnormal vaginal discharge ^r32
- 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 ^r32
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

Manage pain ^r2
Preserve fertility ^r2

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 ^r22
- Those for whom diagnosis cannot be established

Treatment Options

No cure for endometriosis yet exists; primary treatment is directed toward relief of pain ^r6

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

Initial therapy of NSAIDs is used for all patients who present with pelvic pain that is likely to be due to endometriosis, especially dysmenorrhea ^r2^r4

If response to NSAIDs is inadequate and pregnancy is not desired, additional medical therapy includes the following: ^r4^r11

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 of endometriosis; however, combined hormonal options may be less effective than progestin-dominant therapy ^r22
Progestogens, including medroxy progesterone 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 ^r22
GnRH (gonadotropin-releasing hormone) agonists (eg, leuprolide, goserelin) or GnRH antagonists (eg, Elagolix) may be prescribed as second line options if hormonal contraceptives or progestogens have been ineffective ^r33^r34
- To prevent bone loss and hypoestrogenic complications with these agents, administer hormonal add-back therapy using estrogen and progestogen combination ^r4
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 recommended as a medical treatment of endometriosis-associated pain due to its severe adverse effects ^r4
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 ^r4
- 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/vaporisation ^r4^r35
- In patients with ovarian endometrioma, ovarian cystectomy is preferred rather than drainage and coagulation ^r4^r35
  - 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 ^r4
- Laparoscopic uterosacral nerve ablation offers no additional benefit over conventional laparoscopic surgery for endometriosis ^r4
- 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 ^r4
- 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 ^r4
Hysterectomy ^r4
- 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 ^r2
- 10% of patients experience pain recurrence within 1 to 2 years after surgery ^r2
- Combined estrogen/progestogen is recommended for patients with endometriosis after surgical menopause until the age of natural menopause ^r4

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 ^r4
Hormone treatment for secondary prevention of recurrence ^r4
- 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
- In 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 ^r2

Laparoscopic excision or ablation of endometriotic lesions and adhesions generally improves chances of natural pregnancy ^r4
Endometriosis Fertility Index can be used to identify patients that may benefit from assisted reproductive technologies after surgery
No specific protocol is recommended ^r4

Drug therapy

NSAIDs ^r4^c65
- 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 in females who have difficulties conceiving or who are undergoing infertility evaluation ^r36
  - Celecoxib Oral capsule; Adults: 400 mg PO initially, then followed by an additional 200 mg PO on the first day, if needed. On subsequent days, 200 mg PO twice daily, as needed. Consider starting celecoxib at half the lowest recommended dose in patients who are poor CYP2C9 metabolizers.
Cyclic oral contraceptives ^r2^c70
- 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 ^r2^c75
- 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) ^r4^c78
- 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 ^r4^c81
- Females at high risk for osteoporosis are not good candidates for the use of gonadotropin-releasing hormone agonists
- Leuprolide ^c82
  - Leuprolide Acetate Suspension for injection; Adult females: 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.
Gonadotropin-releasing hormone antagonists
- Elagolix ^r33^r37^r38^c83
  - 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.
Aromatase inhibitors ^r2^c84
- Letrozole ^c85
  - Letrozole Oral tablet; Adults: 2.5 mg PO once daily for up to 6 months, with or without other hormonal therapies, has been studied; guidelines recommend letrozole in combination with oral contraceptive pills, progestogens, or gonadotropin-releasing hormone analogs for endometrioses-associated pain refractory to other medical or surgical treatment.

Nondrug and supportive care

Procedures

Laparoscopic treatment of endometriosis ^c86

General explanation

Minimally invasive abdominal surgery to remove ectopic endometrial tissue ^r2^r4
Highly effective at reducing pain and improving fertility, but the recurrence rate is 40% to 50% at 5 years after surgery ^r6
Any of 3 methods of endometrial tissue removal may be chosen based on symptoms and disease severity ^r2
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 (preferred^r39) or drainage and ablation of ectopic endometrial tissue ^r2
- 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 ^r2
- 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 ^r2
- 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: ^r27
- 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: ^r2
- Infection
- Internal organ damage
- Hemorrhage
- New adhesion formation
Complications associated with laparoscopic presacral neurectomy include: ^r2
- Hemorrhage of adjacent venous plexus
- No pain during first-stage labor
- Constipation
- Urinary urgency

Hysterectomy with or without bilateral salpingo-oophorectomy ^r4^c87

General explanation

Surgical removal of uterus, fallopian tubes, and both ovaries ^r2

Indication

Fourth line therapy for noncyclic chronic pelvic pain resistant to all other therapies ^r2

Contraindications

Desire to maintain fertility ^r4

Complications

Persistent or recurrent pain ^r2
Bowel injury or bladder injury
Infection (greatest risk with vaginal hysterectomy) ^r40

Comorbidities

Patients may have coexistent polycystic ovary syndrome, which can cause irregular cycles, as well as manifestations encountered in patients with endometriosis, such as menorrhagia and infertility ^c88^c89^c90^d5
- In addition to oral contraceptives, these patients may require statins to control high cholesterol, hormones to increase fertility, and metformin to prevent diabetes ^r41

Special populations

Females who may be pregnant or are breastfeeding
- Do not administer combined oral contraceptives ^r42
- Do not start or continue progestin therapy
- Stop administering gonadotropin-releasing hormone agonists

Complications and Prognosis

Complications

Infertility is the 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) ^r43
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 ^r13^c92
- Antepartum bleeding or placental complications ^r13^c93
- Cesarean delivery ^r13^c94

Prognosis

After 1 year of laparoscopically diagnosed endometriosis: ^r2
- 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 ^r3
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) ^r3
0.6% to 1% of females with ovarian endometriosis develop ovarian cancer ^r31

Screening and Prevention

Screening ^c95

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Endometriosis

Synopsis

Key Points

Pitfalls

Terminology

Clinical Clarification

Classification

Diagnosis

Clinical Presentation

History

Physical examination

Causes and Risk Factors

Causes

Risk factors and/or associations

Age

Genetics

Other risk factors/associations

Diagnostic Procedures

Primary diagnostic tools

Imaging

Procedures

Laparoscopy c55

General explanation

Indication

Contraindications

Complications

Interpretation of results

Differential Diagnosis

Most common

Treatment

Goals

Disposition

Recommendations for specialist referral

Treatment Options

Drug therapy

Nondrug and supportive care

Procedures

Laparoscopic treatment of endometriosis c86

Hysterectomy with or without bilateral salpingo-oophorectomy r4c87

Comorbidities

Special populations

Complications and Prognosis

Complications

Prognosis

Screening and Prevention

Screening c95

Laparoscopy ^c55

Laparoscopic treatment of endometriosis ^c86

Hysterectomy with or without bilateral salpingo-oophorectomy ^r4^c87

Screening ^c95