endometriosis
ENDOMETRIOSIS

Endometriosis is having extrauterine endometrial tissue that causes chronic inflammatory response.

The patient experiences chronic pelvic pain, pain during intercourse and/or menstruation and infertility.

Diagnosis is attained by pathologic examination of the tissue obtained from laparoscopy or laparotomy.

Goals of treatment are decreasing pain, enhancing fertility, and preventing progression or recurrence. 

 

Principles of Therapy

  • Short-term objectives in treating endometriosis are decreasing pain and enhancing fertility; long-term goal is to prevent progression or recurrence
    • Medical management of infertile patients with minimal and 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
  • Severity of symptoms does not match with the degree of endometriosis
  • 80-90% of patients will have some improvement in symptoms with medical therapy
    • With recurrence rate of 5-15% in the 1st year and 40-50% in the 5th year
  • Due to the chronic nature of the condition, medical therapy should be safe and effective to use until pregnancy is desired or until menopause  
  • Patients with persistent symptoms after medical therapy should be referred for laparoscopy

Pharmacotherapy

First-line Therapeutic Options
Oral Contraceptives (OC)
  • Combined estrogen and 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 and subsequent atrophy of endometrial tissue by suppression of ovarian function
    • Low-estrogen combination pill with relatively high progestin is given to induce amenorrhea and "pseudopregnancy"
  • A good choice for women with minimal or mild symptoms
  • May be administered cyclically with 7 days placebo pills between cycles or may be taken continuously
    • Better pain relief may be achieved with continuous therapy since menses, withdrawal bleeding and associated pain are prevented
      • Withdrawal of pills every month that causes cyclic menstrual bleeding may be associated with some retrograde spill of blood that contains cytokines and other inflammatory chemicals
    • May decrease 80% of symptoms of patients during therapy
  • Provide contraception and have a low rate of side effects (eg weight gain, breast tenderness)
  • No OC combination has been shown to be more effective than another
Progestins
  • Used for treating chronic pain in patients with endometriosis
  • Inhibit endometriotic tissue growth by directly causing initial decidualization and eventual atrophy
    • Also inhibit pituitary gonadotropin secretion and ovarian hormone production
  • First choice for the treatment of endometriosis due to its effective reduction in ASRM scores and pain, with lower cost and side effects as compared to GnRH analogues and Danazol
  • >80% of patients have partial or complete relief
  • Dienogest
    • A progestin with selective 19-nortestosterone and 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 with 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 with no issues regarding future conception and irregular uterine bleeding and has remaining endometriosis after hysterectomy with or without 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 and chronic pelvic pain
    • May cause breakthrough bleeding in some patients but likely to have a positive effect on calcium metabolism maintaining a good BMD
  • Various combinations of Estrogen and Progestogens are available. Please see the latest MIMS for specific formulations
Second-line Therapeutic Options
Gonadotropin Releasing Hormone (GnRH) Agonists
  • Recommended for patients who failed to respond with combined OCs or progestins, or who have symptom recurrence after initial improvement
  • Very effective in alleviating endometriosis-associated pelvic pain but not superior than other therapeutic options
  • May induce hypoestrogenism that inactivates pelvic lesions and resolves pelvic pain
  • Monotherapy with GnRH agonist may result in symptoms secondary to estrogen deficiency (eg hot flushes, insomnia, vaginal dryness, loss of BMD, breakthrough bleeding in the 1st month of therapy, irritability, fatigue, skin problems)  
    • Hence, GnRH agonist may be given with addback therapy which can be started immediately
    • In estrogen and 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 and is also useful in relieving symptoms without 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 months of GnRH agonist therapy)
  • Should be given with caution in young women and adolescents since they may not have reached their maximum bone density
  • Daily calcium supplementation (1,000 mg) is advised in patients using GnRH agonists with addback therapy
Levonorgestrel Intrauterine System 
  • A 19-nortestosterone-derived progestin that has effective anti-estrogenic effects on the endometrium
    • Causes atrophic endometrium and amenorrhea in up to 60% of patients without affecting ovulation
  • Provides continuous therapy for 5 years and has lesser systemic side effects
  • May be a good option for rectovaginal endometriosis
    • Reduces dysmenorrhea, non-menstrual pelvic pain, deep dyspareunia and dyschezia
  • May have 5% expulsion rate, 1.5 % risk for pelvic infection and increased risk for ovarian endometrioma
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 and ovarian enzymes responsible for estrogen production
    • Has immunologic effects like decreasing serum immunoglobulins, auto-antibodies, and CA-125 levels, increasing serum C4, and inhibiting IL-1 and TNF production
  • Causes high androgen and low estrogen levels, amenorrhea, and prevents new seeding of implants from the uterus into the peritoneal cavity
  • >80% of patients experience relief or improvement of pain symptoms within 2 months of treatment with beneficial effects lasting up to 6 months after stopping it
  • Large endometriotic cysts and adhesions do not respond well to Danazol
  • Use is limited by the occurrence of androgenic side effects (eg weight gain, acne, hirsutism, breast atrophy, rarely virilization) and adeverse effect on blood lipid levels
    • Should be used if other medical therapies are unavailable and given in low doses or via vaginal route
    • Not to be used long term
    • A small study showed increased risk for ovarian cancer in endometriosis patients treated with Danazol
Aromatase Inhibitors
  • Can reduce pain from rectovaginal endometriosis when combined with 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, arthralgia)
  • 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, and anti-inflammatory effect
  • Frequently given as initial treatment to women with pelvic pain where diagnosis of endometriosis is still uncertain
  • May be given to patients to provide analgesia until primary medical management becomes effective

Combined Medical/Surgical Therapy

  • Combination therapy wherein medical therapy is given before and/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 and delay recurrence
      • Levonorgestrel intrauterine system (LNG-IUS) implanted after surgery, showed major decrease in recurrence (10%) of moderate-severe dysmenorrhea after 1 year
    • Progestin, Danazol, or GnRH analogs may be used in conjunction with 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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