Uterine Fibroids and Hysterectomy

Description

Alternative Names

Medications

Because fibroid growth tends to stop and regress after menopause, the important reproductive hormones--estrogen, progesterone, or both--most likely play a critical role in their survival. Some agents that block either of these hormones are used to treat severe fibroids with some success.

Contraceptives

Because fibroids are sensitive to estrogen and possibly progesterone, oral contraceptives, which contain these hormones, are not generally used to treat uterine fibroids. Early reports, in fact, suggested they might be a risk factor. Some studies conducted more recently on the newer low-dose OC combinations suggest they may be protective and may even reduce the risk of fibroids. It is not clear, however, how or if they should be used in women with fibroids. For example, a new form of IUD called the Levonorgestrel Intrauterine System (LNG IUS) is an excellent contraceptive that helps reduce uterine bleeding, even in women with fibroids, although it seems to have minimal effects on fibroids themselves.

Progestins (either natural progesterone or synthetic progestogen) are useful for women who clearly have heavy uterine bleeding caused by unopposed production of estrogen. Some may be useful for women with bleeding due to fibroids, although it is not yet clear which ones will be beneficial.

GnRH Agonists

Gonadotropin releasing hormone (GnRH) blocks 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. GnRH agonists include goserelin (Zoladex), buserelin, a monthly injection of leuprolide (depot Lupron), and nafarelin (Synarel), a nasal spray. Such agents may be used to alone or in preparation for procedures used to destroy the uterine lining.

These agents may be used in the following situations:

• As preoperative treatment three to four months before uterine surgery. In a major analysis, the use of GnRH agonists in such cases reduced fibroid size and uterus volume, helped correct any existing anemia due to blood loss, reduced blood loss during surgery, and reduced the duration of hospital stay. (Some experts question, however, whether the benefits outweigh the costs.)
• For women with fibroids nearing menopause. (Such women only need them for a short period.)
• Possibly helpful in improving subsequent fertility. (It is important to note, however, that women should not try to become pregnant while taking these drugs. They pose a risk for birth defects.)

While GnRH agonists can reduce fibroids by between 30% and 90% of original size, they have certain limitations:

• They are not permanent cures and fibroids regrow after the drugs are discontinued.
• They cant be taken orally.
• They are expensive.
• Long-term use of GnRh agonists has an adverse effect on bone density.

Before using these drugs, the physician should be certain that no other complicating conditions are present, particularly leiomyosarcoma (cancer). The use of these drugs can delay treatment of the malignancy and cause severe complications.

Commonly reported side effects (which can be severe in some women) include menopausal-like symptoms that include hot flashes, night sweats, 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, which 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.
• Intermittent leuprolide, which 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 agent 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.

Androgens

Danazol (Danocrine) resembles a male hormone. It suppresses estrogen and is effective for heavy menstrual bleeding caused by fibroids. In some women it produces male characteristics, such as facial hair and voice change. Exercise may help reduce the male-related side effects. Other side effects include weight gain, acne, and dandruff. It may increase the risk for unhealthy cholesterol levels. A few cases of blood clots and strokes have been reported. At present there is no long-term experience using danazol for fibroids.

Antiprogestins

Gestrinone. Antiprogestins are promising agents for fibroids. Gestrinone has been shown to reduce uterine volume and stop bleeding. In addition, benefits appear to persist. In one study, 89% of the women maintained a smaller uterine for at least 18 months after stopping the treatment. In another 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. Adverse effects of gestrinone include male hormone symptoms, such as acne, and possibly the development of unhealthy cholesterol levels.

Mifepristone. Mifepristone (Mifeprex) is used for emergency contraception, but is controversial because of its name: the abortion pill. This agent is an anti-progestin that has reduced fibroid size in some studies. In one study, it reduced fibroids as significantly as GnRH agonists and the fibroids were less likely to recur.

Asoprisnil. A promising new antiprogestin called Asoprisnil has been shown to reduce fibroids. The drug is in the final stages of evaluation by the FDA and is expected to be approved in 2004.

Investigative Agents

A number of agents are under investigation for treating fibroids.

• Selective estrogen-receptor modulators (SERMs) are agents that have some of the effects of estrogen but do not produce some of its complications, such as a higher risk for uterine cancer. They are being studies for fibroids. Raloxifene (Evista) is the most studied of these agents. It is proving to be helpful in preventing bone loss in patients taking GnRH agonists for uterine fibroids, but it does not appear to have any effect on fibroids themselves. (The other well-studied SERM, tamoxifen, also does not appear to have any benefit for reducing fibroids.)
• Agents that block growth factors believed to play a role in fibroids are also under investigation. Pirfenidone is one such agent, which blocks fibroid cell reproduction. Another is interferon alpha, substance that inhibits angiogenesis (the growth of new blood vessels).
• Agents derived from retinoids (vitamin A compounds) may inhibit cell proliferation in fibroid tissue. One such agent LGD1069 (Targretin) is showing promise in animal studies.
• Fulvetrant (Faslodex) blocks estrogen and has been studied for uterine fibroids and endometriosis, although progress in these areas has stalled in favor of research for its use in breast cancer.