Endometriosis: A Healthcare Professional's Guide
Medically reviewed on Feb 27, 2018 by L. Anderson, PharmD.
What is Endometriosis?
Endometriosis is a gynecological disorder occurring in about 6% to 10% of women of reproductive age and is distinguished by the presence of endometrial tissue lying outside the uterine cavity.
The exact prevalence of endometriosis is not known, as some women are asymptomatic or have mild symptoms and may go undiagnosed.
Endometriosis can be painful, inconvenient due to excessive bleeding, and can affect fertility in women in their childbearing years. According to the American Society for Reproductive Medicine, endometriosis can be found in one-quarter to one-half of women who experience infertility.
Estrogen is generally thought to aggravate and be linked with endometriosis, as symptoms drastically improve in the menopausal years and after hysterectomy.
Because endometriosis is hormone-dependent and progressive, it is often diagnosed during the reproductive years in women from 25 to 35 years of age. Pain is thought to be due to misplaced tissue from the endometrium that relocates in the pelvis or elsewhere in the body.
Within the pelvis, common sites for displaced tissue include the ovaries, fallopian tubes, uterine ligaments, areas between vagina and rectum, and the outer surfaces of uterus.
Outside of the pelvic cavity, misplaced endometrial tissue can be found in the bladder, rectum, bowel, vagina, cervix, vulva, and within internal surgical scars. The misplaced tissue responds to monthly hormones and can cause swelling, pain and scar tissue.
What Puts Someone at Risk for Endometriosis?
Factors that increase the risk of a woman developing endometriosis include:
- Nulliparity (no naturally-born children) or having children after age 30
- Having a first-degree relative with the disease (mother, daughter, sister)
- Caucasian race
- Early menarche/late menopause
- Short or prolonged menstrual cycles
- Environmental toxins like certain pesticides
- Multiple births
- Extended intervals of lactation
- Late menarche (after age 14 years)
- Use of hormonal contraceptives
What Causes Endometriosis? Pathology and Symptoms
Biologic factors that are hypothesized to lead to endometriosis include:
- Retrograde menstruation - tissue backs up from fallopian tubes to abdomen
- Changes in the immune system
- Genetics and family history
Symptoms often associated with endometriosis include: painful menstrual cramps (dysmenorrhea), painful urination or bowel movements during menstruation, pain during intercourse (dyspareunia), heavy menstrual bleeding, and temporary or permanent infertility.
How is Endometriosis Diagnosed?
After ruling out other causes, treatment can be started for endometriosis with clinical suspicion only. A transvaginal ultrasound (TVUS) may be performed; however, to definitively diagnose endometriosis, a laparoscopy must be performed.
A laparoscopy is an outpatient surgery in which a thin laparoscope is inserted through a small incision in the abdominal wall (often around the belly button area) to view the pelvic area. This allows the surgeon to see the misplaced endometrial tissue and allows staging of the disease (location, extent, depth of tissue growths). Abnormal tissue may be removed for biopsy during the procedure.
Other procedures for diagnosis may include computed tomography (CT) scan or Magnetic resonance imaging (MRI).
Endometriosis is staged levels I-IV, (minimal to severe), but this does not necessarily predict the pain severity. Pain can be minimal or severe in any stage.
Ruling Out Other Complications
Other suspected complications that may be considered in the differential include:
- pelvic inflammatory disease (PID)
- ovarian cysts
- irritable bowel syndrome
- fibroids (leiomyomas)
- interstitial cystitis.
Laboratory tests such as a complete blood count (CBC) with differential, erythrocyte sedimentation rate, urinalysis, and testing for STDs may be obtained to rule out an infectious or inflammatory process. An ultrasound may be used to visualize the pelvic organs to look for a mass.
Medication Treatments for Endometriosis
The primary goals of treatment for endometriosis include:
- pain relief
- reduction or clearance of endometrial tissue
- slowing of disease progression
- return to normal anatomy
Options for treatment include drug therapy or surgery, and the healthcare provider should take into consideration whether or not a woman desires pregnancy. Medication is typically preferred before choosing surgery as an option.
For pain control and to help slow disease progession, a number of treatments are available:
- Hormonal contraceptives (cyclic or continuous, usually oral, such as birth control pills; also patches and vaginal rings)
- NSAIDs like ibuprofen (Motrin, Advil) or naproxen (Aleve) for pain, which can be used with contraceptives for more moderate pain
- Gonadotropin releasing hormone (Gn-RH) analogues
- Progestins, like medroxyprogesterone (Depo-Provera), norethindrone (i.e., Aygestin, Camila, Errin, others)
- danazol (not commonly used)
NSAIDs, with or without hormonal contraceptives (based on pregnancy desire), are typically used first-line.
NSAIDs for Endometriosis Pain
Oral NSAIDs are often used empirically for acute, mild pelvic or abdominal pain in suspected endometriosis.
NSAIDs (ibuprofen [Advil, Motrin IB], naproxen [Aleve], others) inhibit prostaglandins and lower inflammation and pain theorized to be involved in endometrial growths. In addition, NSAIDs can be easily combined with hormonal contraceptives and other therapies as needed for breakthrough pain, or used regularly during the first few days of each menstruation to prevent monthly pain.
Some experts suggest avoiding selective COX-2 inhibitors such as celecoxib as some studies indicate these drugs can prevent or delay ovulation.
No individual NSAID has been shown to be superior in endometriosis; selection should be based on preferences for dosing frequency, possible side effects and costs.
NSAIDs and/or contraceptives may be all that is needed for mild pain in endometriosis. However, for long-term use be sure to review gastrointestinal, heart and kidney warnings for use of all NSAIDs with your patients.
Treatment: Hormonal Contraceptives
Oral hormonal contraceptives are considered first-line therapy for endometriosis and pain control. Oral contraceptives inhibit production of estrogen via negative feedback and lessen endometrial tissue build-up. Low-dose, continuous oral contraceptives can steadily inhibit ovarian hormones and suppress endometrium growth, although breakthrough bleeding may occur in the first few months.
Limitations to hormonal contraceptive use may be side effects related to thromboembolic disease in women, especially in smokers over age 35 years, and the possible return of endometriosis upon discontinuation.
- Birth Control Pills - Use a continuous cycle oral contraceptive; take one active pill every day at the same time.
- Vaginal Contraceptive Ring (NuvaRing [ethinyl estradiol and etonogestrel]) - Insert a new vaginal ring every 3-4 weeks
- Contraceptive Patch (Ortho Evra, Xulane [ethinyl estradiol and norelgestromin transdermal]) - Change patch weekly
If symptoms do not improve with NSAID treatment, consider an alternate hormonal combination (for example, a different combined contraceptive or norethindrone acetate). All hormonal treatments for endometriosis seem most effective when used in a daily, continuous fashion.
Progestins are effective as monotherapy in the treatment of pain due to endometriosis; however some women may not tolerate treatment due to side effects such as weight gain, bleeding, spotting, breast tenderness, or mood changes/depression.
Progestin options include:
- Oral norethindrone acetate (Aygestin)
- Progestin only birth control pills (Camila, Nor-QD)
- Oral medroxyprogesterone (Provera)
- Depot medroxyprogesterone (Depo-Provera)
- Levonorgestrel intrauterine device, IUD (Kyleena, Liletta, Mirena, Skyla)
Progestins are effective in roughly 75 percent of women with endometriosis. The levonorgestrel IUD may be especially effective in women with more severe disease and does not have to be replaced for 5 years.
Side Effects: Progestins
A lowering of bone density is a serious concern with long-term use of high-dose oral medroxyprogesterone or the depot form, although bone density may improve if treatment is stopped.
Higher dose norethindrone can negatively affect lipids by increasing LDL/HDL ratio and triglycerides. Laboratory monitoring for lipids and bone mineral density may be needed for long-term treatment.
Other common side effects include weight gain, bloating, spotting, mood changes, and depression. The levonorgestrel IUD may be preferable if bone density or lipids are a concern.
"Breakthrough” bleeding may occur at the outset but lessens over time.
Treatment: Gn-RH Agonists
If pain is moderate-to-severe and is not controlled with NSAIDs and/or hormonal contraceptives, a gonadotropin-releasing hormone (Gn-RH) agonist may be used. In addition, Gn-RH agonists have been shown to lessen the size of ectopic implants, although they will not effect fertility. Gn-RH agonists can be used empirically or after laparoscopy. Gn-RH agonists stop ovarian hormonal production, creating a drug-induced 'menopause' and amenorrhea.
Gn-RH agonists include:
- Leuprolide (Lupron, Lupron Depot) - IM injection given every month or every 3 months; generic available
- Goserelin (Zoladex) - subcutaneous implant given every 28 days.
- Nafarelin (Synarel) - intranasal spray given each day.
- Triptorelin (Trelstar, Triptodur) - off label use
Common treatment regimen options for endometriosis include:
- leuprolide (Lupron) 3.75 mg intramuscular (IM) injection given once a month for up to 6 months
- leuprolide (Lupron) 11.25 mg IM injection given every three months for up to 6 months
- nafarelin 200 mcg given intranasally twice daily
The doses of GnRH agonists in endometriosis are lower than those used to treat prostate cancer.
In women receiving Gn-RH agonists for endometriosis, hormone replacement therapy (i.e., oral norethindrone 5 mg daily) is recommended to reduce bone mineral density loss and vasomotor symptoms due to hypoestrogenic side effects.
Side Effects: Gn-RH
Gn-RH agonist treatment is limited to six months due to side effects such as vasomotor symptoms (flushing, vaginal dryness or itching, vaginitis), sleep disturbances, headache and early bone loss which boost risk of fracture. However, treatment can be lengthened when a Gn-RH agonist is used with a daily oral 'add-back' therapy (such as norethindrone 5 mg; or conjugated estrogen 0.625 mg plus medroxyprogesterone 5 mg).
Gn-RH treatment can be expensive and may be a limiting factor for some women. Also, when early bone loss is a concern, progestins may be a preferred option. A discussion of insurance and cost concerns with your patient should be a priority.
Lupaneta Pack is a combination package of leuprolide depot and norethindrone tablets, but it is very costly. It is more affordable to combine these separately using generic options. Use of Lupaneta Pack for longer than a total of 12 months is not recommended.
Due to a bothersome side effect profile, androgen therapy like danazol is not commonly used for endometriosis. Hormonal contraceptives, progestin therapy, and Gn-RH analogues are prefered.
The danazol mechanism is via suppression of the hypothalamic-pituitary-ovarian axis which leads to amenorrhea and subsequent clinical effect. An increase in free testosterone levels occurs.
Androgen side effects may occur with danazol use, such as:
- hirsutism (facial hair growth)
- acne/oily skin, oily hair
- decreased breast size
- weight gain
- mood changes
- male-pattern hair loss
Effects are usually reversible but may take 6 to 8 months after treatment discontinuation. In addition, clinical reports have linked danazol with the occurrence of ovarian cancer.
Treatment: Investigational Use of Aromatase Inhibitors
"Off-label" use of aromatase inhibitors in endometriosis may be an option for women who are refractory to all other treatments, or cannot tolerate side effects. No aromatase inhibitor is currently FDA-approved for the treatment of endometriosis. Some studies suggest this may be an effective alternative. According to the American College of Obstetrics and Gynecology (June 2016) "Aromatase inhibitors are a promising therapeutic option that may help manage endometriosis-associated pain in combination therapy with progestins."
How do they work? The enzyme aromatase converts androgens into estrogen in the body. Endometriosis is an estrogen driven disease. Studies have shown that aromatase is found in the ectopic endometrial tissue of women with endometriosis and can lead to the growth of endometrial tissue. By inhibiting the aromatase enzyme, the endometrial tissue growth slows and the pelvic pain of endometriosis subsides.
Typical treatments include:
Disadvantages to the use of aromatase inhibitors include bone loss and ovarian follicular cyst development; therefore they are used in combination with other endometriosis treatments such as progestins, combined oral contraceptives, or GnRH agonists. According to ACOG, aromatase inhibitors with add-back progestin or oral contraceptives does not appear to be associated with significant bone loss after 6 months of treatment and, based on the available data, may be suitable for long-term (greater than 6 months) use.
Treatment: Investigational Elagolix
Elagolix, in development from AbbVie, is an investigational, orally administered gonadotropin-releasing hormone (GnRH) antagonist under study for the management of endometriosis and associated pain. Phase 3 pivotal and extension studies are either in process or completed.
On September 6, 2017 AbbVie submitted a new drug application (NDA) to the FDA for approval of elagolix. According to the sponsor, in two Phase 3 clinical studies of nearly 1,700 women with moderate-to-severe endometriosis-associated pain, elagolix demonstrated superiority compared to placebo in reducing three types of endometriosis-associated pain – daily menstrual pelvic pain, non-menstrual pelvic pain and painful intercourse.
- After 3 and 6 months when compared to placebo, elagolix doses (150 mg once daily and 200 mg twice daily) resulted in significant improvement in menstrual and non-menstrual pelvic pain (dysmenorrhea) as measured by the Daily Endometriosis Pain Impact scale.
- Significant improvements compared to placebo were also observed at month three for the 200 mg twice daily dose in scores for painful intercourse (dyspareunia).
- A reduction in the use of rescue pain medications (NSAIDs, opioids) was also seen with the higher 200 mg twice daily dose.
- Elagolix treatment decreased endometrial proliferation in a dose-dependent manner after six months of treatment with no adverse endometrial findings.
Reported side effects included hot flushes and headache. The FDA is expected to complete its review on Elagolix by the 2nd quarter of 2018.
Treatment: How to Choose
There are no definitive clinical trials that prove that one medical therapy is superior to another for pain control or maintenance of fertility in endometriosis.
Therefore, treatment should be a shared decision between doctor and patient, taking into account the age of the patient, severity of pain, extent of disease, whether a woman desires contraception or pregnancy, drug preferences, side effect profiles, and cost concerns.
In women who have severe acute, disease or anatomical abnormalities, surgery may be the preferred treatment.
Endometriosis: Costs of Treatment
Healthcare providers should discuss insurance coverage and cost concerns with patients prior to prescribing medications for endometriosis.
Birth control, NSAIDs, and generic progestins can be more affordable for many patients. However, brand name products and newer treatments without generics can be very expensive if paying cash, often in the thousands of dollars.
In addition, some products are only available via a specialty pharmacy. A levonorgestrel IUD, while expensive initially, may be fully covered by insurance and only needs replacement every 5 years. Some pharmaceutical companies may offer a patient assistance program to those who qualify.
Join Other Women in the Fight
While treatments are available for endometriosis, for many women it is a chronic condition that requires ongoing control.
Seeking out others with similar challenges can add strength to your patient's ongoing medical care. However, it's important to remind your patient to:
- be wary of unproven remedies
- alternative and herbal treatments without sound clinical evidence
- to always check with their health care provider before starting or stopping any treatments
Finished: Endometriosis: A Healthcare Professional's Guide
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