Treatment

  Treatment Guidelines / Endometriosis Overview / Treatment

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

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


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    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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