Treatment

PHARMACOLOGICAL THERAPY

  • Short-term objectives in treating endometriosis are decreasing pain & enhancing fertility; long-term goal is to prevent progression or recurrence
    • Medical management of infertile patients w/ minimal & mild endometriosis should not be offered since it does not improve fertility
  • No studies have shown benefit of one medical therapy over another when treating pain due to endometriosis
  • 80-90% of patients will have some improvement in symptoms w/ medical therapy
    • W/ recurrence rate of 5-15% in the 1st year & 40-50% in the 5th year
  • Patients w/ persistent symptoms after medical therapy should be referred for laparoscopy

1 First-line Therapeutic Options


1.1 Oral Contraceptives (OC)1

  • Combined estrogen & progestin oral contraceptive is considered the 1st-line treatment for pelvic pain secondary to endometriosis
    • Decreases dysmenorrhea, non-menstrual pain, endometriosis-related dyspareunia
  • Induce decidualization & subsequent atrophy of endometrial tissue by suppression of ovarian function
    • Low-estrogen combination pill w/ relatively high progestin is given to induce amenorrhea & “pseudopregnancy”
  • A good choice for women w/ minimal or mild symptoms
  • May be administered cyclically w/ 7 days placebo pills between cycles or may be taken continuously
    • Better pain relief may be achieved w/ continuous therapy since menses, withdrawal bleeding & associated pain are prevented
      • Withdrawal of pills every month that causes cyclic menstrual bleeding may be associated w/ some retrograde spill of blood that contains cytokines & other inflammatory chemicals
    • May decrease 80% of symptoms of patients during therapy
  • Provide contraception & have a low rate of side effects (eg weight gain, breast tenderness)
  • No OC combination has been shown to be more effective than another


1.2 Progestins
  • Used for treating chronic pain in patients w/ endometriosis
  • Inhibit endometriotic tissue growth by directly causing initial decidualization & eventual atrophy
    • Also inhibit pituitary gonadotropin secretion & ovarian hormone production
  • First choice for the treatment of endometriosis due to its effective reduction in AFS scores & pain, w/ lower cost & side effects as compared to GnRH analogues & Danazol
  • >80% of patients have partial or complete relief
  • Adverse Reactions
    • GI effects (GI disturbances, change in wt/ appetite); Breast changes (enlargement, secretion, discomfort); Androgenic effects (acne, mental depression, changes in libido, hair loss, hirsutism, irregular menstrual bleeding); Dermatologic effects (allergic rash, pruritus, erythema multiforme, erythema nodosum, urticaria); Other effects (asthenia, malaise, headache, migraine, change in vag secretions, fluid retention, edema, fatigue, alterations in lipid profile)
      • Androgenic effects & lipid changes are more likely w/ Norethisterone?
  • Special Instructions
    • Avoid use in patients w/ unexplained vag bleeding, history or current high risk of arterial disease, severe hepatic impairment, breast or genital tract carcinoma unless progestogen is part of the management
    • Use w/ caution in women w/ hypertension, cardiac or renal impairment, asthma, epilepsy, migraine, or other conditions aggravated by fluid retention, in patients w/ history of depression
      • High doses should be used w/ caution in patients at risk for thromboembolism
  • Dienogest
    • A progestin w/ selective 19-nortestosterone & progesterone activity
    • Same effectivity as GnRH agonist therapy in relieving endometriosis-associated pelvic pain as shown in clinical trials
      • May be an effective option in long-term treatment of endometriosis
  • Depot Medroxyprogesterone acetate
    • May alleviate pelvic pain w/ low treatment cost
    • Not an option for women who desire pregnancy in the near future as it delays resumption of ovulation
    • May be best indicated for patients w/ no issues regarding future conception & irregular uterine bleeding & has remaining endometriosis after hysterectomy w/ or w/o bilateral salpingo-oophorectomy
    • Not recommended for long-term use as it may have negative effect on bone mineral density (BMD)
  • Norethindrone Acetate
    • Approved for continuous use in treating endometriosis
      • Relieves dysmenorrhea & chronic pelvic pain
    • May cause breakthrough bleeding in some patients but likely to have a positive effect on calcium metabolism maintaining a good BMD

 

Dosage Guidelines1:

  

a. Dienogest

  • 2 mg PO 24 hrly taken at the same time each day w/o interruption
  • May be started on any day of the menstrual cycle

  • b. Dydrogesterone
    • 10 mg PO 8-12 hrly from day 5-25 of cycle or administer continuously
    • Duration: 3 mth

    c. Lynestrenol
    • 5 mg PO 24 hrly
    • Duration: At least 6 mth

    d. Medroxyprogesterone
    • 10 mg PO 8 hrly on consecutive days beginning on day 1 of cycle
    • Duration: 3 mth
    • 50 mg IM wkly or 100 mg IM every 2 wk
    • Duration: At least 6 mth

    e. Nomegestrol
    • 5 mg PO 24 hrly from 16th-25th day of menstrual cycle

    f. Norethisterone (Norethindrone)
    • 5 mg PO 24 hrly on days 5-25 of cycle
    • Duration: 6 mth

    or

    • 2.5 mg PO 24 hrly continuously starting on day 5 of cycle then increase the dose by 2.5 mg every 2-3 wk as required to avoid breakthrough bleeding
    • Duration: 4-6 mth
    or
    • 5 mg PO 12 hrly starting on day 5 of cycle
    • May increase to 10 mg PO 12 hrly if spotting occurs
    • Resume initial dose when spotting ceases
    • Duration: 4-6 mth
    • Usual Dose: 5-25 mg/day continuously for 4-9 mth


    1Various combinations of Estrogen & Progestogen are available. Please see the latest MIMS for specific formulations.


    2 Second-line Therapeutic Options

    2.1 Danazol
    • Effective in resolving implants when treating mild or moderate stages of disease
    • A synthetic isoxazole derivative of ethisterone
    • Inhibits pituitary gonadotropin secretion, endometriotic implant growth & ovarian enzymes responsible for estrogen production
      • Has immunologic effects like decreasing serum immunoglobulins, auto-antibodies, & CA-125 levels, increasing serum C4, & inhibiting IL-1 & TNF production
    • Causes high androgen & low estrogen levels, amenorrhea, & prevents new seeding of implants from the uterus into the peritoneal cavity
    • >80% of patients experience relief or improvement of pain symptoms w/in 2 mth of treatment w/ beneficial effects lasting up to 6 mth after stopping it
    • Large endometriotic cysts & adhesions do not respond well to Danazol
    • Use is limited by the occurrence of androgenic side effects (eg weight gain, acne, hirsutism)
      • Should be used if other medical therapies are unavailable
      • A small study showed increased risk for ovarian cancer in endometriosis patients treated w/ Danazol
    • Adverse Reactions
      • Effects due to inhibition of pituitary-ovarian axis (menstrual disturbances, amenorrhea, sweating, hot flushes, libido changes, vag dryness & irritation, decreased breast size, nervousness); Androgenic effects (increased hair growth, acne, oily skin, mood changes, deepening of voice, wt gain, effects on serum lipids [ie decreased HDL & TG, increased LDL] & rarely liver damage); Other effects (GI disturbances, headache, dizziness, fatigue, muscle spasm, tachycardia & hypertension)
    • Special Instructions
      • Contraindicated in patients w/ severe hepatic, renal or cardiac dysfunction, porphyria, thromboembolic disease, w/ undiagnosed genital bleeding, & androgen-dependent tumors
      • Use w/ caution in conditions that may worsen fluid retention (eg CV, hepatic & renal disorders); Use w/ caution in patients w/ migraine, epilepsy, DM or polycythemia
      • Liver function should be monitored regularly during therapy

     

    Dosage Guidelines:


    a. Danazol

    • Initial dose: 200-800 mg/day PO divided 6-12 hrly should be started at menstrual onset
    • Individualize dose depending on severity of endometriosis
    • Maintenance dose: 800 mg/day PO divided 12 hrly
    • Duration: 3-6 mth; May extend to 9 mth


    b. Gestrinone

    • 2.5 mg PO on day 1 of menstrual cycle, 2.5 mg PO on day 4 of menstrual cycle, then 2.5 mg PO 2x/wk on succeeding wk
    • May increase dose to 3x/wk
    • Doses are preferably taken at consistent twice-wkly schedule
    • Duration: 6 mth

    2.2 Gonadotropin-releasing Hormone (GnRH) Agonists

    • Very effective in alleviating endometriosis-associated pelvic pain but not superior than other therapeutic options
    • Recommended for patients who failed to respond w/ combined OCs or progestins, or who have symptom recurrence after initial improvement
    • May induce hypoestrogenism that inactivates pelvic lesions & resolves pelvic pain
    • Monotherapy w/ GnRH agonist may result in symptoms secondary to estrogen deficiency (eg hot flushes, insomnia, vaginal dryness, loss of BMD)
      • Hence, GnRH agonist should always be given w/ addback therapy which can be started immediately
      • In estrogen & progestin addback therapy, the concentration of serum estrogen is low enough to cause endometriosis but high enough to prevent hypoestrogenic symptoms
      • Addition of addback therapy lessens or eliminates GnRH agonist-induced bone mineral loss & is also useful in relieving symptoms w/o affecting efficacy of GnRH agonist
      • Addback regimens (eg sex steroid hormones or other specific bone-sparing agents) are recommended in women who will undergo >6 mth of GnRH agonist therapy
    • Should be given w/ caution in young women & adolescents since they may not have reached their maximum bone density
    • Daily calcium supplementation (1,000 mg) is advised in patients using GnRH agonists w/ addback therapy
    • Adverse Reactions
      • Hypoestrogenism that manifests as transient vag bleeding, hot flushes, vag dryness, decreased libido, breast tenderness, insomnia, depression, irritability & fatigue, decreased elasticity of the skin, headache, after several wk of treatment: increased bone pain, osteoporosis; GI effects (nausea, abdominal discomfort); Other effects (reduction in glucose tolerance, changes in serum lipids, hepatic effects & hypersensitivity reactions, skin rashes, hair loss, increased sweating)
    • Special Instructions
      • Addback strategy w/ Estrogen/ Progesterone or Tibolone can eliminate most of the side effects
      • OCs should be discontinued prior to therapy & other non-hormonal methods of birth control should be used
        • In later stages of treatment, pregnancy is unlikely as long as recommended doses are administered
      • Avoid in patients w/ metabolic bone disease, urinary tract obstruction or metastatic vertebral lesions
      • Monitor bone density during long-term treatment

     

    Dosage Guidelines2:

     

    a. Buserelin

    • 1 spray (0.15 mg) into each nostril 8 hrly
    • Duration: 6 mth

    b. Goserelin    
    • 3.6 mg depot inj SC into the anterior abdominal wall every 28 days
    • Duration: 6 mth

    c. Leuprorelin/Leuprolide
    • 3.75 mg depot inj SC/IM once mthly or 11.25 mg depot inj SC/IM as a single dose every 3 mth
    • Start therapy during the 1st 5 days of the menstrual cycle
    • Duration: 6 mth

    d. Nafarelin
    • 1 spray (200 mcg) in 1 nostril each morning & another spray in other nostril each evening on days 2-4 of menstrual cycle
    • May be increased to 2 sprays (400 mcg/nostril) if amenorrhea is not achieved after 2 mth
    • Duration: 6 mth

    e. Triptorelin
    • 3.75 mg depot inj SC/IM once mthly or 11.25 mg depot inj SC/IM as a single dose every 3 mth
    • Start therapy during the 1st 5 days of the menstrual cycle
    • Duration: 6 mth


    2Recommended to be given w/ addback therapy. Please see the latest MIMS for specific formulations.


    2.3 Levonorgestrel Intrauterine System

    • A 19-nortestosterone-derived progestin that has effective anti-estrogenic effects on the endometrium
      • Causes atrophic endometrium & amenorrhea in up to 60% of patients w/o affecting ovulation
    • Provides continuous therapy for 5 yr & has lesser systemic side effects
    • May be a good option for rectovaginal endometriosis
      • Reduces dysmenorrhea, non-menstrual pelvic pain, deep dyspareunia & dyschezia
    • May have 5% expulsion rate, 1.5 % risk for pelvic infection & increased risk for ovarian endometrioma

    2.4 Aromatase Inhibitors

    • Can reduce pain from rectovaginal endometriosis when combined w/ oral contraceptives, progestogens or GnRH analogs
    • Should only be given to women refractory to medical or surgical treatment due to severe side effects (hot flushes, vaginal dryness, decreased bone mineral density)
    • Studies show lack of evidence on long-term effects

    Supportive Therapy


    Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

    • Central inhibition of prostaglandin synthesis, local anti-nociceptive effects, & anti-inflammatory effect
    • Frequently given as initial treatment to women w/ pelvic pain where diagnosis of endometriosis is still uncertain
    • May be given to patients to provide analgesia until primary medical management becomes effective

     

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    SURGERY

    • Recommended in some circumstances to confirm the diagnosis & provide treatment to achieve pain relief or improved fertility ie “see & treat”
    • May be performed by laparoscopy or laparotomy
    • After surgery, the median time for pain recurrence is 20 mth
    • May improve fertility
      • Patient benefits from the mechanical clearance of adhesions & obstructive lesions
      • Please see Infertility Management Chart for more details
    • Surgery should only be done in women w/ endometriosis-related pain after medical treatment has failed
    • Indications:
      • Symptoms are severe, incapacitating or acute
      • Symptoms have failed to resolve or have worsened under medical management
      • W/ advanced disease
      • Anatomic distortion of the pelvic organs, endometriotic cysts or obstruction of the bowel or urinary tract
    • May be classified as “conservative” or “definitive”


    Conservative Surgery
    • Preserves the uterus & as much ovarian tissue as possible
    • Includes removal of macroscopic endometrial tissue, lysis of adhesions, & repair of normal anatomy
      • High recurrence rate (80-100%) is noted after 6 mth of drainage of endometriomas
      • Excision of endometriomas provides better pain relief, decreased recurrence rate, a histopathological diagnosis, & improves chances of pregnancy
        • Women w/ >3 cm ovarian endometriomas & w/ pelvic pain should be advised to undergo excision of endometrioma
      • Surgical ablation or resection of endometriosis plus laparoscopic adhesiolysis should be offered to patients w/ minimal or mild endometriosis who will undergo laparoscopy to improve chances of pregnancy
    • Presacral neurectomy
      • Though rarely indicated, it may be helpful in decreasing midline pain (eg dysmenorrhea, dyspareunia) but not in other pelvic areas
      • May be considered adjunct to surgical management of endometriosis-related pelvic pain
    • Laser uterosacral nerve ablation (LUNA)
      • Reduces pain in minimal-moderate endometriosis
      • Disrupts the efferent nerve to reduce uterine pain
      • Not performed as an additional procedure to conservative surgery for pain reduction as RCTs showed no additional benefit
    • Tubal Flushing
      • Studies have shown that flushing of fallopian tubes using oil-soluble media may increase chances of pregnancy


    Definitive Surgery
    • Hysterectomy, w/ or w/o removal of the fallopian tubes & ovaries
      • Case series studies have shown that 80-90% of women who failed w/ medical or surgical management experienced pain relief after hysterectomy w/ bilateral salpingo-oophorectomy; however, recurrence of pain was noted w/in 1-2 yr in 10% of women
    • May be an option for patients w/ intractable pain, if childbearing is no longer desired
    • In young women who underwent TAHBSO, hormonal replacement therapy (HRT) is recommended
    • In women w/ ovarian endometrioma, cystectomy rather than drainage & coagulation or CO2 laser vaporization should be performed

     

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    COMBINED MEDICAL & SURGICAL THERAPY

    • Combination therapy wherein medical therapy is given before &/or after surgery
      • Hormonal suppression may be given prior to surgery in hopes of decreasing the size of endometriotic implants, thereby reducing the extent of surgery required
      • In cases where complete removal of implants is not possible or advisable, post-op medical therapy may be used to treat residual disease & delay recurrence
        • Levonorgestrel intrauterine system (LNG-IUS) implanted after surgery, showed major decrease in recurrence (10%) of moderate-severe dysmenorrhea after 1 yr
      • Progestin, Danazol, or GnRH analogs may be used in conjunction w/ laparotomy or laparoscopic conservative or definitive surgical treatment
    • It is not recommended to prescribe preoperative or adjunctive hormonal therapy after surgery for treatment of pain as it does not improve surgery’s outcome for pain

     

    All dosage recommendations are for non-elderly adults w/ normal renal & hepatic function unless otherwise stated.


    Not all products are available or approved for above use in all countries.


    Products listed above may not be mentioned in the disease management chart but have been placed here based on indications listed in regional manufacturers’ product information. 

     

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