Endometriosis
Description
An in-depth report on the causes, diagnosis, treatment, and prevention of endometriosis
Alternative Names
Hysterectomy and endometriosis
Medications
The basic approach in hormonal treatments for endometriosis is to block production of female hormones (estrogen and progesterone) or to prevent ovulation. Hormonal drugs are used for pain relief only. None have been proven to improve fertility rates and in some cases may delay conception. Specific hormonal drugs may have different effects for women with endometriosis.
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Inducing Pseudopregnancy: Oral contraceptives that contain estrogen and progestins mimic a pregnant state and block ovulation. (Progestins are natural or synthetic forms of progesterone). Progestins may also be used alone, since they have specific effects that can cause the endometrial tissue itself to atrophy.
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Inducing Pseudomenopause: Gonadotropin-releasing hormone (GnRH) agonists or gestrinone, an anti-progesterone that mimic menopause. They reduce estrogen and progesterone to their lowest level.
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Inducing On-going Blockage of Ovulation. Danazol, a derivative of male hormones, is a powerful ovulation blocker.
Studies report that around 80% of women achieve pain relief after taking these drugs. To date, comparison studies have found few differences in effectiveness among the major hormonal treatments. Differences occur mostly in their side effects. Women should discuss the effects of particular medications with their doctors to determine the best choice.
Oral Contraceptives
Oral contraceptives (OCs), commonly known collectively as "the Pill," contain combinations of an estrogen and a progestin (either a natural progesterone or the synthetic form called progestin). They are most often used for treating endometriosis and are as effective for most women in treating pain from endometriosis as the more potent gonadotropin releasing hormone agonists. OCs may reduce the risk of ovarian cancer by 30 - 50% and of endometrial cancer by 50%, a potentially important benefit in women with endometriosis. Patch contraceptives are available, but they may increase the risk for menstrual cramping.
When used throughout a menstrual cycle, OCs suppress the actions of other reproductive hormones (luteinizing hormone, or LH, and follicle stimulating hormone, or FSH) and prevent ovulation. There are many brands available. The estrogen compound used in most oral contraceptives is
estradiol
. Many different progestins are used, and there are many brands. None to date have proven to be superior over others. Women should discuss the best options for their individual situations with their doctor.
Estrogen and progestin each cause different side effects. The most serious side effects are due to the estrogen in the combined pill. Uncommon but more dangerous complications of OCs include high blood pressure and deep-vein blood clots (thrombosis), which may contribute to heart attack or stroke. Studies have been conflicting about whether estrogen in oral contraception increases the chances for breast cancer, and if it does, which women are at risk.
Progestins
Progestins alone may be helpful and are the oldest drugs used for endometriosis. Progestins can prevent ovulation and reduce the risk for endometriosis in the following ways:
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They block luteinizing hormone (LH), one of the reproductive hormones important in ovulation.
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They change the lining of the uterus and eventually cause it to atrophy.
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They may provide pain relief equivalent to the more powerful hormone drugs. Some experts recommend them as the first choice for women with endometriosis who do not want to become pregnant.
Specific Progestins.
Progestins are available in pill or injectable form, or as a progestin-releasing intrauterine device (IUD). Medroxyprogesterone (Depo-Provera), which is administered by injection every 3 months, is one of the standard progestins used. A new low-dose formulation, Depo-subQ Provera 104, was approved in 2005. Oral progestins include norethindrone (Micronor, Aygestin, Norlutate). Norethindrone is also known as norethisterone.
A 2006 study compared low-dose depot medroxyprogesterone with the gonadotropin releasing hormone (GnRH) agonist leuprolide (Lupron). The two drugs worked equally well in controlling endometriosis pain. However, leuprolide caused more loss of bone mineral density, a condition associated with osteoporosis. Patients who received medroxyprogesterone injections had fewer hot flashes than those who received leuprolide, but they had more episodes of bleeding and spotting.
Progestin-releasing IUDs can be very helpful for many women with endometriosis, particularly an advanced version called the levonorgestrel-releasing intrauterine system, or LNG-IUS (Mirena). Studies suggest that the LNG-IUS reduces endometrial cell proliferation and increases cell self-destruction. Progestin released by the IUD mainly affects the uterus and cervix and causes fewer widespread side effects than other forms of progestins.
The LNG-IUS has proved effective for heavy bleeding (menorrhagia) and studies indicate that it helps control the symptoms of minimal to moderate endometriosis. Studies indicate that the LNG-IUS works as well as GnRH agonists in managing endometriosis pain, and causes less loss of estrogen. Some experts think that the LNG-IUS could become the treatment of choice for women with endometriosis pelvic pain who do not wish to become pregnant.
Side Effects of Progestins.
Side effects of progestin occur in both the combination oral contraceptives and any contraceptive that only uses progestin, although they may be less or more severe depending on the form and dosage of the contraceptive. Side effects may include:
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Changes in uterine bleeding such as higher amounts during periods, spotting and bleeding between periods (called break-through bleeding), or absence of periods
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Unexpected flow of breast milk
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Abdominal pain or cramps
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Diarrhea
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Fatigue, unusual tiredness, weakness
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Hot flashes
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Decreased sex drive
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Nausea
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Trouble sleeping.
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Acne or skin rash (although low-dose OCs actually improve acne)
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Depression, irritability, or other mood changes
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Swelling in the face, ankles, or feet
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Weight gain
Newer formulations of combination pills that use low-dose estrogen and newer progestins may reduce and even avoid many of these side effects. Progestins used in non-oral contraceptives, such as the LNG-IUS IUD, also may not pose as high a risk for these side effects. If side effects persist or are severe, a woman should always talk to her doctor. Many women do not experience these side effects, or if they do, their bodies eventually adjust.
GnRH Agonists
Gonadotropin releasing hormone (GnRH) agonists are effective hormone treatments for endometriosis. They are able to block the release of the reproductive hormones LH (luteinizing hormone) and FSH (follicular-stimulating hormone). As a result, the ovaries stop ovulating and no longer produce estrogen. Ovulation and menstruation resume around 4 to 10 weeks after stopping the drug. The specific length of time depends on the type of GnRH agonist used.
Women with endometriosis often have a difficult time getting pregnant. A 2006 review suggested that GnRH agonists may help women with endometriosis become pregnant when the drug is given along with in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). (IVF and ICSI are standard infertility treatments.) The review found that 3 to 6 months of GnRH therapy in combination with infertility treatment quadrupled the pregnancy rate. However, the study did not supply data on how many women actually gave birth. In addition, there is not enough information on whether these drugs may adversely affect a woman or her fetus.
Specific GnRH Agonists.
GnRH agonists include goserelin (Zoladex), buserelin, a monthly injection of leuprolide (depot Lupron), and a nasal spray, Nafarelin (Synarel). Studies have reported that nafarelin shrank all implants and significantly relieved symptoms in 85% of patients, delayed recurrence of endometriosis after surgery, and in comparison with leuprolide, was less expensive, had fewer side effects, and a provided better quality of life.
Side Effects and Complications.
Commonly reported side effects (which can be severe in some women) include menopause-like symptoms that include hot flashes, night sweat, and changes in the vagina, weight change, and depression. The side effects vary in intensity depending on the GnRH agonist. They may be more intense with leuprolide and persist after the drug has been stopped.
The most important concern is possible osteoporosis from estrogen loss. Women ordinarily should not take GnRH agonists for more than 6 months. Certain approaches may preserve enough estrogen to protect bones and still effectively relieve endometriosis symptoms:
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Add-back therapy provides doses of estrogen and progestin that are high enough to maintain bone density, but are too low to offset the beneficial effects of the GnRH agonist. Studies suggest this is safe and effective for protecting bone.
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Intermittent leuprolide uses repeated 6-month courses of GnRH agonists followed by an average of 9 months of symptom control only.
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Taking GnRH agonists in very low doses is an alternate approach, but is still largely untested.
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Adding bone-protective drugs may be helpful. The standard ones are bisphosphonates and include alendronate (Fosamax), risedronate (Actonel), and etidronate (Didronel). Other drugs are being tested in combination with a GnRH agonist to preserve bone. They include the parathyroid hormone teriparatide (Forteo) and selective estrogen-receptor modulators (SERMs), such as raloxifene (Evista).
GnRH treatments used alone do not prevent pregnancy. Furthermore, if a woman becomes pregnant during their use, there is some risk for birth defects. Women who are taking GnRH agonists should use non-hormonal birth control methods, such as the diaphragm, cervical cap, or condoms while on the treatments.
Danazol
Danazol (Danocrine) is a synthetic drug that resembles a male hormone (androgen). It suppresses the pathway leading to ovulation. Studies have shown symptomatic improvement in 90% of women, although in one study, only about 58% of women expressed satisfaction with this therapy. A high drop-out rate occurs, most often because of adverse side effects, particularly male characteristics, such as growth of facial hair, acne, weight gain, dandruff and deepening of the voice.
Danazol may increase the risk for unhealthy cholesterol levels. A few cases of blood clots and strokes have also been reported, as well as rare cases of liver damage. One study reported that taking a low dose may relieve endometrial symptoms and reduce the risk for these side effects. Exercise may also help reduce side effects. As with GnRH drugs, pregnant women or those trying to become pregnant should not take this drug because it may cause birth defects.
Antiprogestins
Antiprogestins are promising drugs for endometriosis because they reduce both estrogen and progesterone receptors.
Gestrinone.
Gestrinone is the most studied antiprogestin and appears comparable to GnRH agonists in reducing pain and while causing fewer menopausal symptoms. In one study, bone density even increased slightly. Adverse effects of gestrinone include male hormone symptoms, such as acne, and possibly the development of unhealthy cholesterol levels.
Mifepristone.
Mifepristone (Mifeprex) is another antiprogestin that may be helpful for treating endometriosis. In one 6-month study, mifepristone improved symptoms and reduced endometrial implants without causing menopausal side effects. Long-term use, however, may cause changes in the uterine tissue and cell proliferation.
Pain Medication
Nonsteroidal Anti-inflammatory Drugs (NSAIDs).
Over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs) may be sufficient for about 75% of women with endometrial pain. NSAIDs block prostaglandins (the substances that increase uterine contractions). They are effective painkillers and also have other properties that act against inflammatory factors. Aspirin is the most common NSAID, but there are dozens of others available over the counter or by prescription. Among the most effective NSAIDs for menstrual disorders are ibuprofen (Advil, Motrin, Midol PMS), naproxen (Aleve, Naprosyn, Naprelan, Anaprox), and mefenamic acid (Ponstel). For maximum benefit, they should be taken 7 to 10 days before a period is expected. However, long-term use of NSAIDs can increase the risk for
gastrointestinal
bleeding and ulcers. One study of women with iron deficiency anemia reported that overuse of NSAIDs for menstrual disorders contributes to anemia.
Acetaminophen.
Acetaminophen (Tylenol) reduces levels of female hormones (gonadotropins and estradiol, an estrogen), which may have some beneficial effect on menstrual disorders. A combination of acetaminophen and pamabrom (Women's Tylenol Menstrual Relief) is specifically aimed at treating menstrual pain and bloating. (Pamabrom is a diuretic, a drug used to reduce fluid build-up and bloating.)
Opioids.
Drugs containing codeine should not generally be used for endometriosis pain management. They can cause pelvic congestion and constipation, which can worsen symptoms in patients with gastrointestinal distress.
Investigative Drugs
GnRH Antagonists.
GnRH antagonists include ganirelix (Antagon) and cetrorelix (Cetrotide). These newer drugs differ from GnRH agonists in that they have a direct effect on the pituitary gland. The result is quicker action. They also pose a lower risk for complications and side effects.
Aromatase Inhibitors.
Drugs that inhibit aromatase, an enzyme that is a major source of estrogen, are being studied for effects against endometriosis. Such drugs include anastrozole, letrozole, exemestane, and vorozole. Aromatase levels may be abnormal in women with endometriosis. A 2004 pilot study of letrozole combined with a progestin showed reduction of endometriosis as well as decrease in pelvic pain, suggesting that this treatment holds promise.
Selective Estrogen-Receptor Modulators (SERMs).
Drugs known as selective estrogen-receptor modulators (SERMs) are thought to act like estrogen in some tissues but behave like estrogen blockers (antiestrogens) in others. They have not been widely studied for endometriosis since tamoxifen (Nolvadex), the most commonly used SERM, may worsen endometriosis. However, the actions of other SERMs such as raloxifene (Evista) or tibolone (only available in Europe), may be beneficial and warrant more research.
Selective Progesterone Receptor Modulators (SPRMs)
. SPRMs, also called mesoprogestins, have both agonist and antagonist properties. This new class of drugs may be effective for suppressing endometrial growth.
Other investigative drugs for treatment of endometriosis include tumor necrosis factor alpha (TNF-alpha) inhibitors, angiogenesis inhibitors, and various immune modulators.
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Review Date: 6/13/2006
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Reviewed By: Harvey Simon, M.D., Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital
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