Overview of treatment of uterine leiomyomas Author Elizabeth A Stewart, MD Section Editor Robert L Barbieri, MD Deputy Editor Sandy J Falk, MD
Last literature review version 17.1: January 2009|This topic last updated: November 25, 2008(More)
INTRODUCTIONUterine leiomyomas are benign tumors. Since histological confirmation of the clinical diagnosis is not necessary in most cases, asymptomatic uterine leiomyomas can usually be followed without intervention  . Women with leiomyomas whose physicians prescribed "watchful waiting" experienced no significant change in symptoms or decline in quality of life, thereby providing some reassurance to women who are asymptomatic or have mild symptoms and choose to avoid intervention  .
Prophylactic therapy to avoid potential future complications from myomas or their treatment is not recommended  . Possible exceptions include women with significant submucosal leiomyomas who are contemplating pregnancy and women with ureteral compression leading to moderate or severe hydronephrosis. In these women, prophylactic myomectomy may prevent miscarriage or urinary tract obstruction.
Relief of symptoms (eg, abnormal uterine bleeding, pain, pressure) is the major goal in management of women with significant symptoms  . The type and timing of any intervention should be individualized, based upon factors such as  : Size of the myoma(s) Location of the myoma(s) Severity of symptoms Patient age Reproductive plans and obstetrical history
An overview of the treatment of uterine leiomyomas will be presented here. The clinical manifestations, diagnosis, and natural history of these tumors are reviewed elsewhere. (See "Epidemiology, clinical manifestations, diagnosis, and natural history of uterine leiomyomas").
EXPECTANT MANAGEMENTThere is no high quality data regarding follow-up of fibroids in patients who are asymptomatic or who decline medical or surgical treatment. We order an initial imaging study (usually an ultrasound) to confirm that a pelvic mass is a fibroid and not an ovarian mass. After an initial evaluation, we perform annual pelvic exams and, in patients with anemia or menorrhagia, check a complete blood count. If symptoms or uterine size are increasing, we proceed with further evaluation and patient counseling regarding treatment options. We also screen women with menorrhagia for hypothyroidism, a disease that is common in reproductive age women.
MEDICAL THERAPYA comprehensive evidence-based report noted "a remarkable lack of randomized trial data demonstrating the effectiveness of medical therapies in the management of women with symptomatic fibroids"  . Given the high prevalence of both leiomyomas and the use of gonadal steroid preparations (eg, contraception, management of menstrual cycle abnormalities), it is difficult to isolate the effect of these drugs on mild leiomyoma-related symptoms.
Anecdotal data suggest medical therapy provides adequate symptom relief in some women, primarily in situations where bleeding is the dominant or only symptom. In general, 75 percent of women get some improvement over one year of therapy, but long-term failure rates are high  . A systematic review observed that in trials where women were randomly assigned to oral medical therapy, almost 60 percent had undergone surgery by two years  .
A trial of medical therapy in women with mild symptoms and/or mildly enlarged uteri can also be useful for helping to distinguish symptoms primarily related to leiomyomas from those primarily due to a concurrent problem. This is especially true in patients in whom concomitant issues, such as oligoovulation, may be contributing to abnormal uterine bleeding or infertility. However, caution should be exercised when raising the level of steroid hormones from the physiologic baseline, as there is indirect evidence from postmenopausal women taking hormone replacement therapy that leiomyomas grow in this setting [9-12] .
Hormonal therapiesCombined hormonal contraceptives and progestational agents are commonly prescribed to regulate abnormal uterine bleeding, but appear to have limited efficacy in the treatment of uterine leiomyomas [13,14] . These drugs can be useful in some women, particularly those with coexisting problems (eg, dysmenorrhea or oligoovulation); but they do not appear to be effective in decreasing bulk symptoms. There is also evidence that, in some women, contraceptive steroids may be associated with a decreased risk of uterine fibroids; however, it is not clear that these agents are useful for either primary or secondary prevention  .
Steroid hormones influence the pathogenesis of leiomyomas, but the relationship is complex. As an example, although there are high levels of both estrogen and progesterone during pregnancy and with oral contraceptive use, both decrease the risk of developing new leiomyomas but may lead to leiomyoma growth. The specific hormonal compound, the timing and duration of exposure, the delivery method (endogenous, oral, transdermal, depot, local) and other factors may all be important.
Oral contraceptive pills (OCP)Many texts continue to suggest that oral contraceptive pills are contraindicated in women with uterine leiomyomas. However, clinical experience suggests some women with heavy menstrual bleeding associated with leiomyomas respond to OCP therapy. This, plus data that OCPs decrease the risk of forming new leiomyomas and reduce symptoms from other concurrent gynecologic conditions, suggests that a therapeutic trial may be appropriate before proceeding to more invasive therapies. The purported mechanism of action is via endometrial atrophy.
This approach should be reassessed if a woman has exacerbation of bulk-related symptoms on OCPs. Since most pill formulations appear to work similarly, switching to other formulations does not appear to be effective in the woman who does not respond to a short trial of one formulation.
Data are not available regarding treatment using other methods of contraceptive steroid delivery (eg, ring, patch). However, with vaginal administration (Nuva Ring), the uterus is likely to receive a higher dose of medication than other systemic tissues, which could affect how leiomyomas respond to hormone therapy.
Levonorgestrel-releasing intrauterine systemThere are no randomized trials evaluating the use of levonorgestrel-releasing intrauterine system (IUS) for the treatment of menorrhagia related to uterine leiomyomas. Observational studies and a systematic review have shown a reduction in uterine volume and bleeding, and an increase in hematocrit after placement of this IUS [8,16-18] . The device is widely used for control of heavy menstrual bleeding and is endorsed for this indication by many experts. The presence of intracavitary leiomyomas amenable to hysteroscopic resection is a contraindication to use. A second advantage of this treatment is that it provides contraception for women who do not desire pregnancy. (See "Approach to intrauterine contraception").
Progestin implants, injections, and pillsAs with OCPs, it is difficult to discern the effectiveness of progestin-only contraceptive steroids specifically for treatment of leiomyomas. As with the breast, progesterone is a growth factor for myomas and may even be more critical than estrogen. That being said, progestin-only contraceptives cause endometrial atrophy and thus provide relief of menstrual bleeding-related symptoms. They can be considered for treatment of mild symptoms, especially for women who need contraception. There is also evidence from a large cohort study that these agents may decrease the risk of leiomyoma formation in black women  .
In contrast to gonadotropin-releasing agonists and antagonists, most of these "contraceptives" provide continuous exposure to low doses of hormones, which should minimize deleterious effects (see "Gonadotropin-releasing hormone agonists" below and see "Gonadotropin-releasing hormone antagonists" below).
Gonadotropin-releasing hormone agonistsGonadotropin-releasing hormone (GnRH) agonists are the most effective medical therapy for uterine myomas. These drugs work by initially increasing the release of gonadotropins, followed by desensitization and downregulation to a hypogonadotropic, hypogonadal state that clinically resembles menopause. Most women will develop amenorrhea, improvement in anemia (if present), and a significant reduction (35 to 60 percent) in uterine size within three months of initiating this therapy, thus achieving improvement in both categories of myoma symptomatology [13,14,20] .
However, there is rapid resumption of menses and pretreatment uterine volume after discontinuation of GnRH agonists. In addition, significant symptoms can result from the severe hypoestrogenism that accompanies such therapy, including hot flashes, sleep disturbance, vaginal dryness, myalgias and arthralgias, and possible impairment of mood and cognition  . Bone loss leading to osteoporosis after long-term (12+ months) use is the most serious complication and most often limits therapy. A rule of thumb for women with endometriosis is that approximately 6 percent of bone is lost over 12 months of therapy and 3 percent is regained following the cessation of therapy  . However, women with leiomyomas tend to be older and heavier than women with endometriosis, thus they may have less bone loss.
Because of the rapid rebound in symptoms and side effects, GnRH agonists are primarily used as preoperative therapy. GnRH agonists are approved for administration for three to six months prior to leiomyoma-related surgery to facilitate the procedure and enable correction of anemia  . Reduction in uterine size can facilitate subsequent surgery by reducing intraoperative blood loss and by increasing the number