Endometriosis Management

Principles of Therapy

The short-term objectives in treating endometriosis are decreasing pain and enhancing fertility. The 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 the benefits of one medical therapy over another when treating pain due to endometriosis.

Eighty to ninety percent of patients will have some improvement in symptoms with medical therapy; however, there is a recurrence rate of 5-15% in the first year and 40-50% in the fifth 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 a laparoscopy. The severity of symptoms does not match with the degree of endometriosis. 

Pharmacological therapy

First-line Therapeutic Options

Combined Oral Contraceptives (COCs)¹  

Combined estrogen and progestin oral contraceptives are considered the first-line treatment for pelvic pain secondary to endometriosis. It decreases dysmenorrhea, non-menstrual pain, and endometriosis-related dyspareunia and is considered a good choice for women with minimal or mild symptoms.

It induces 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”.

It may be administered cyclically with 7 days of 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. This administration may decrease 80% of the symptoms of patients during therapy.

It provides contraception and has a low rate of side effects (eg weight gain, breast tenderness). No oral contraceptive combination has been shown to be more effective than another.

¹Various combinations of estrogens and progestogens are available. Please see the latest MIMS for specific formulations.  

Progestins  

Progestins are used for treating chronic pain in patients with endometriosis. It inhibits endometriotic tissue growth by directly causing initial decidualization and eventual atrophy. It also inhibits pituitary gonadotropin secretion and ovarian hormone production. It is considered the first choice for the treatment of endometriosis due to its effective reduction in ASRM scores and pain, with lower cost and less side effects as compared to gonadotropin-releasing hormone (GnRH) analogs and Danazol. More than 80% of patients have partial or complete relief with progestin use. 

Depot Medroxyprogesterone acetate may alleviate pelvic pain with low treatment cost. It may be best indicated for patients with no issues regarding future conception and irregular uterine bleeding and have remaining endometriosis after hysterectomy with or without bilateral salpingo-oophorectomy. It is not an option for women who desire pregnancy in the near future as it delays the resumption of ovulation and not for long-term use as it may have negative effects on bone mineral density (BMD).

Dienogest is a progestin with selective 19-nortestosterone and progesterone activity. It is recommended as a first-line treatment for all types of endometriosis including ovarian endometriosis, adenomyosis, and deep infiltrating endometriosis. It has the same effectivity as GnRH agonist therapy in relieving endometriosis-associated pelvic pain as shown in clinical trials. It may be an effective option in long-term treatment of endometriosis. 

Etonogestrel is administered as a progestin subdermal implant for long-term contraception. It decreases menstrual bleeding and has been used to treat endometriosis-related pain, but data is limited.  

Levonorgestrel intrauterine system (LNG-IUS) is a 19-nortestosterone-derived progestin that has effective anti-estrogenic effects on the endometrium. It causes atrophic endometrium and amenorrhea in up to 60% of patients without affecting ovulation. It provides continuous therapy for 5 years and has lesser systemic side effects. It may be a good option for rectovaginal endometriosis, and it reduces dysmenorrhea, non-menstrual pelvic pain, deep dyspareunia, and dyschezia. It may have a 5% expulsion rate, a 1.5% risk for pelvic infection, and an increased risk for ovarian endometrioma.  

Norethindrone acetate is approved for continuous use in treating endometriosis. It relieves dysmenorrhea and chronic pelvic pain. It may cause breakthrough bleeding in some patients but is likely to have a positive effect on calcium metabolism maintaining a good BMD. 

Second-line Therapeutic Options

Gonadotropin-Releasing Hormone (GnRH) Agonists

Example drugs: Buserelin, Goserelin, Leuprorelin, Nafarelin, Triptorelin

GnRH agonists are recommended for patients who failed to respond to combined oral contraceptives or progestins or who have symptom recurrence after initial improvement. It is very effective in alleviating endometriosis-associated pelvic pain but is not superior to other therapeutic options. It 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 first month of therapy, irritability, fatigue, and skin problems). Hence, GnRH agonists may be given add-back therapy which can be started immediately.

In estrogen and progestin add-back therapy, the concentration of serum estrogen is low enough to cause endometriosis but high enough to prevent hypoestrogenic symptoms. The addition of add-back therapy lessens or eliminates GnRH agonist-induced bone mineral loss and is also useful in relieving symptoms without affecting the efficacy of GnRH agonist. Add-back regimens (eg sex steroid hormones or other specific bone-sparing agents) are recommended in women who will undergo >6 months of GnRH agonist therapy.

GnRH agonists 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 add-back therapy.

GnRH Receptor Antagonists

Example drug: Elagolix  

GnRH receptor antagonists are indicated in patients with moderate to severe pain associated with endometriosis. It is an oral, non-peptide, small molecule GnRH receptor antagonist that can dose-dependently suppress luteinizing hormone (LH), follicle-stimulating hormone FSH, estradiol and progesterone secretion.

In comparison to GnRH agonists, its dose can be titrated to obtain a nearly full or partial hormonal suppression. It causes a dose- and duration-dependent reduction in BMD. It is therefore vital to assess the patient’s BMD if the patient has risk factors for bone loss and limit treatment duration to decrease bone loss. Patients are advised to take adequate amounts of calcium and vitamin D. 

Relugolix/estradiol/norethisterone is an option for treating endometriosis symptoms (eg moderate to severe pain) in women of reproductive age who had medical or surgical treatment for endometriosis. It may be used as an alternative to GnRH agonists or surgery, as a bridge to surgery in the short term as part of combination treatment for symptom relief, for a longer period if there is a delay in surgery, or after surgery to help manage ongoing pain. 
 
Aromatase Inhibitors

Example drugs: Letrozole, Anastrozole

Aromatase inhibitors work by decreasing the local estradiol production thus lessening lesion growth. It can reduce pain from rectovaginal endometriosis when combined with oral contraceptives, progestogens, or GnRH analogs.

It should only be given to women refractory to medical or surgical treatment due to severe side effects (eg hot flushes, vaginal dryness, decreased BMD, arthralgia). Studies show a lack of evidence on long-term effects.

Danazol  

Danazol is a synthetic isoxazole derivative of ethisterone which inhibits pituitary gonadotropin secretion, endometriotic implant growth, and ovarian enzymes responsible for estrogen production. It has immunologic effects like decreasing serum immunoglobulins, auto-antibodies, and CA-125 levels, increasing serum C4, and inhibiting interleukin-1 (IL-1) and tumor necrosis factor (TNF) production. It is effective in resolving implants when treating mild or moderate stages of disease. However, large endometriotic cysts and adhesions do not respond well to Danazol. More than 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. Though it is effective at treating endometriosis-related pain, it is not commonly used due to its androgenic side effects (eg weight gain, acne, hirsutism, breast atrophy, and rarely virilization) and adverse effects on blood lipid levels. It should be used if other medical therapies are unavailable and should be given in low doses or via the vaginal route. It should not be used long term. 

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Surgery

Surgery is recommended when medical treatment is not tolerated or has failed and when drug therapies are contraindicated (ie patients trying to conceive). It is also recommended in some circumstances to confirm the diagnosis and provide treatment to achieve pain relief or improve fertility (ie “see and treat”). 

It may improve fertility as the patient benefits from the mechanical clearance of adhesions and obstructive lesions. 

Please see Infertility disease management chart for further information.

The following are indications of surgical management:

• Symptoms are severe, incapacitating, or acute (eg acute adnexal torsion or rupture of ovarian cyst)
• Symptoms have failed to resolve or have worsened under medical management
• Advanced disease or invasive disease affecting the bowel, ureters, bladder, or pelvic nerves
• Anatomic distortion of the pelvic organs, endometriotic cysts, or obstruction of the bowel or urinary tract
• Patient declines or has contraindications to medical treatment
• Endometriosis-related infertility, pain, or pelvic mass
• Treatment for postmenopausal endometriosis

It may be performed by laparoscopy or laparotomy, although laparoscopy is preferred over laparotomy for the treatment of endometriosis-related infertility. After surgery, the median time for pain recurrence is 20 months. Surgical management may be classified as “conservative” or “definitive” surgery.

Surgical management may be classified as “conservative” or “definitive” surgery. 

Conservative Surgery

Conservative surgery preserves the uterus and as much ovarian tissue as possible. It is performed in women of reproductive age, those who wish to get pregnant, or those who wish to avoid menopausal induction at an early age.

It includes removal of macroscopic endometrial tissue, lysis of adhesions, and repair of normal anatomy. A high recurrence rate (80-100%) is noted after 6 months of drainage of endometriomas.

The excision of endometriomas provides better pain relief, decreased recurrence rate, a histopathological diagnosis, and improves the chances of pregnancy. Women with >3 cm ovarian endometriomas and with pelvic pain should be advised to undergo excision of endometrioma.

Surgical ablation or resection of endometriosis plus laparoscopic adhesiolysis should be offered to patients with minimal or mild endometriosis who will undergo laparoscopy to improve the chances of pregnancy. Operative laparoscopy in patients with severe endometriosis increases spontaneous pregnancy rates.

Laser Uterosacral Nerve Ablation (LUNA)  

LUNA reduces the pain of minimal to moderate endometriosis. It works by disrupting the efferent nerve to reduce uterine pain. It is not performed as an additional procedure to conservative surgery for pain reduction as randomized controlled trials (RCTs) showed no additional benefit.

Presacral Neurectomy

Although rarely indicated, presacral neurectomy may be helpful in decreasing midline pain (eg dysmenorrhea, dyspareunia) but not in other pelvic areas. It may be considered as an adjunct to surgical management of endometriosis-related pelvic pain.

Tubal Flushing

Studies have shown that flushing of fallopian tubes using oil-soluble media may increase the chances of pregnancy.

Definitive Surgery

Cystectomy

In women with ovarian endometrioma, cystectomy rather than drainage and coagulation or carbon dioxide (CO₂) laser vaporization should be performed.

Hysterectomy

Hysterectomy with or without removal of the fallopian tubes and ovaries may be done on patients with endometriosis. Case series studies have shown that 80-90% of women who failed with medical or surgical management experienced pain relief after hysterectomy with bilateral salpingo-oophorectomy; however, recurrence of pain was noted within one to two years in 10% of women.

It may be an option for patients with intractable pain despite conservative treatment, severe disease, adenomyosis or severe menstrual bleeding, and if childbearing is no longer desired.  

In young women who underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAHBSO), hormonal replacement therapy (HRT) is recommended. Combined hormone therapy (estrogen and progestin) or Tibolone may be given.

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