Endometriosis

Description

Alternative Names

Medications

The basic approach in hormonal treatments for endometriosis is to block production of female hormones (estrogen and progesterone) or to prevent ovulation with other hormonal effects. Hormonal agents are used for pain relief only. None improve fertility rates and in some cases may delay conception. Specific hormonal agents may have different effects for women with endometriosis.

• Inducing Pseudopregnancy: Agents that. 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.
• Inducing Pseudomenopause: Gonadotropin-releasing hormone (GnRH) agonists or gestrinone, an anti-progesterone that mimic menopause. They reduce estrogen and progesterone to their lowest level.
• Inducing On-going Blockage of Ovulation. Danazol, a derivative of male hormones, is a powerful ovulation blocker.

At this time, studies report that between 80% and 85% of women achieve pain relief after taking these agents. To date, comparison studies have found few differences in effectiveness among the major hormonal treatments. Differences occur mostly in their side effects. It should be noted that research on hormonal treatments for endometriosis is very scanty, and even physicians may not have the best data needed to make optimal decisions for their patients. Women should discuss the effects of particular medications with their physicians 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 progestogen). 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% to 50% and of endometrial cancer by 50%, which is a potentially important benefit in women with endometriosis. (Patch contraceptives are available, but they may increase the risk for menstrual cramping.)

Click the icon to see an illustrated series detailing the birth control pill.

When used throughout a menstrual cycle, they suppress the actions of other reproductive hormones (luteinizing hormone, or LH, and follicle stimulating hormone, or FSH) and prevents 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 physician.

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 attacks or strokes in rare cases. It should be noted that a long-term study of 46,000 British women found no difference in mortality rates between women who took OCs and those who did not. 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. A reassuring 2002 study supported an earlier major study, with both finding no evidence that OC use increases the risk for breast cancer, even in women who have taken them for 15 years of more or had taken them at young ages. Still, more research is needed to verify these findings, given previous reports of a slightly higher 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:

• They luteinizing hormone (LH), one of the reproductive hormones important in ovulation.
• They change the lining of the uterus and eventually cause it to atrophy.
• One study reported that progestins provide temporary pain relief equivalent to the more powerful hormone drugs, such as danazol or a GnRH agonist. Some experts recommend them as the first choice for women with endometriosis who do not want to become pregnant. Progestins given during the luteal phase do not appear to be beneficial. (This is the premenstrual phase, which is 14 days before a period.)

Specific Progestins. Medroxyprogesterone (Depo-Provera), which is administered by injection typically every three months, are the standard progestins used.

Other progestins that are showing benefits include norethisterone (Micronor, Noriday, Noristerat), dienogest, and lynestrenol. Some of these progestins, such as dienogest, are proving to be as effective as some GnRH agonists -- the other standard hormonal therapy for endometriosis. They also may have fewer side effects than Depo-Provera. For example, in one study 94% of patients achieved some pain relief from norethindrone (Aygestin, Norlutate); only 7% dropped out because of side effects.

Progestin-releasing intrauterine devices 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 are suggesting that the LNG-IUS reduces endometrial cell proliferation and increases cell self-destruction. Progestin released by the IUD mainly effects the uterus and cervix and so it causes fewer widespread side effects than the other forms of progestins do.

Click the icon to see an image of an IUD.

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 the following:

• Changes in uterine bleeding. Such as higher amounts during periods, spotting and bleeding between periods (called break-through bleeding), or absence of periods. Be sure to check with the physician if any of these occur.
• Unexpected flow of breast milk. (Check with the physician if this occurs to be sure other abnormalities are not causing it.)
• Abdominal pain or cramps.
• Diarrhea.
• Fatigue, unusual tiredness, weakness.
• Hot flashes.
• Decreased sex drive.
• Nausea.
• Trouble sleeping.
• Acne or skin rash. (Low-dose OCs actually improve acne. Only Ortho Tri-Cyclen is approved for this.)
• Depression, irritability, or other mood changes.
• Swelling in the face, ankles, or feet.
• 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 physician. 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.

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 them for more than six months. Certain approaches may preserve enough estrogen to protect bones and still effectively relieve endometriosis symptoms:

• 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.
• Intermittent leuprolide uses repeated six-month courses of GnRH agonists followed by an average of nine months of symptom control only.
• Taking GnRH agonists in very low doses is an alternate approach, but is still largely untested.
• Adding a bone-protective agents may be helpful. The standard ones are bisphosphonates and include alendronate (Fosamax), risedronate (Actonel), and etidronate (Didronel). Other agents 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 substance that resembles a male hormone. 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 help reduce side effects. As with GnRH agents, pregnant women or those trying to become pregnant should not take this drug because it may cause birth defects.

Antiprogestins

Antiprogestins are promising agents for endometriosis because they reduce both estrogen and progesterone receptors.

Gestrinone. Gestrinone is the most studied antiprogestin and may be comparable to GnRH agonists in reducing pain and have 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 is effective for treating endometriosis. In one six-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.

Investigative Hormones

GnRH Antagonists. GnRH antagonists include ganirelix (Antagon) and cetrorelix (Cetrotide). These are newer agents 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. The actions of some other SERMs, however, such as raloxifene (Evista) or tibolone (only available in Europe at present), may be beneficial and warrant more research.

Fulvetrant. Fulvetrant (Faslodex) blocks estrogen and has been studied for uterine fibroids and endometriosis, although development in these areas has stalled in favor of research for its use in breast cancer.