Copyright © 2013 Massachusetts Medical Society Uterine fibroids (leiomyomas) represent the most common tumor in women. These lesions disrupt the functions of the uterus and cause excessive uterine bleeding, anemia, defective implantation of an embryo, recurrent pregnancy loss, preterm labor, obstruction of labor, pelvic discomfort, and urinary incontinence and may mimic or mask malignant tumors. By the time they reach 50 years of age, nearly 70% of white women and more than 80% of black women will have had at least one fibroid; severe symptoms develop in 15 to 30% of these women.1,2 Uterine fibroids in black women are significantly larger at diagnosis than those in white women, are diagnosed at an earlier age, and are characterized by more severe symptoms and a longer period of sustained growth.3-5 Approximately 200,000 hysterectomies, 30,000 myomectomies, and thousands of selective uterineartery embolizations and high-intensity focused ultrasound procedures are performed annually in the United States to remove or destroy uterine fibroids. The annual economic burden of these tumors is estimated to be between $5.9 billion and $34.4 billion.6 There may be one predominant uterine fibroid or a cluster of many fibroids (Fig. 1). Very large fibroids can cause the uterus to expand to the size reached at 6 or 7 months of pregnancy. The location and size of the fibroid in the uterus are critical determinants of its clinical manifestations. As compared with other fibroids, submucous fibroids that extend into the uterine cavity are the most disruptive to endometrial integrity, implantation, and the capacity of the myometrium to contract and stop menstrual bleeding from the endometrial blood vessels; thus, even small submucous fibroids are associated with excessive or irregular bleeding, infertility, and recurrent pregnancy loss. In contrast, subserous fibroids that grow out into the peritoneal cavity can exert pressure that is sensed by the patient as pelvic discomfort only if they reach a certain size. Intramural fibroids that reside in the myometrial wall represent an intermediary group. Regardless of their size or location, fibroids may have paracrine molecular effects on the adjacent endometrium that are extensive enough to cause excessive uterine bleeding or defective implantation.7 Uterine fibroids are monoclonal tumors that arise from the uterine smoothmuscle tissue (i.e., the myometrium).8 Histologically, fibroids are benign neoplasms composed of disordered smooth-muscle cells buried in abundant quantities of extracellular matrix (Fig. 1). The cells proliferate in vivo at a modest rate. Formation of the extracellular matrix also accounts for a substantial portion of tumor expansion. Uterine fibroids are almost always benign.9 A striking feature of uterine fibroids is their dependency on the ovarian steroids estrogen and progesterone.10 Ovarian activity is essential for fibroid growth, and most fibroids shrink after menopause. The sharp elevations and declines in the production of estrogen and progesterone that are associated with very early pregnancy and the postpartum period have a dramatic effect on fibroid growth.11-13 Gonadotropin-releasing-hormone (GnRH) analogues, which suppress ovarian activity and reduce circulating levels of estrogen and progesterone, shrink fibroids and reduce associated uterine bleeding.14

Mechanisms of disease: Uterine fibroids

Uterine fibroids (also known as leiomyomas or myomas) are the most common form of benign uterine tumors. Clinical presentations include abnormal bleeding, pelvic masses, pelvic pain, infertility, bulk symptoms and obstetric complications.Almost a third of women with leiomyomas will request treatment due to symptoms. Current management strategies mainly involve surgical interventions, but the choice of treatment is guided by patient's age and desire to preserve fertility or avoid 'radical' surgery such as hysterectomy. The management of uterine fibroids also depends on the number, size and location of the fibroids. Other surgical and non-surgical approaches include myomectomy by hysteroscopy, myomectomy by laparotomy or laparoscopy, uterine artery embolization and interventions performed under radiologic or ultrasound guidance to induce thermal ablation of the uterine fibroids.There are only a few randomized trials comparing various therapies for fibroids. Further investigations are required as there is a lack of concrete evidence of effectiveness and areas of uncertainty surrounding correct management according to symptoms. The economic impact of uterine fibroid management is significant and it is imperative that new treatments be developed to provide alternatives to surgical intervention.There is growing evidence of the crucial role of progesterone pathways in the pathophysiology of uterine fibroids due to the use of selective progesterone receptor modulators (SPRMs) such as ulipristal acetate (UPA). The efficacy of long-term intermittent use of UPA was recently demonstrated by randomized controlled studies.The need for alternatives to surgical intervention is very real, especially for women seeking to preserve their fertility. These options now exist, with SPRMs which are proven to treat fibroid symptoms effectively. Gynecologists now have new tools in their armamentarium, opening up novel strategies for the management of uterine fibroids.

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Uterine fibroid management: from the present to the future

A 47-year-old black woman has heavy menstrual bleeding and iron-deficiency anemia.She reports nocturia and urinary frequency. A colonoscopy is negative. Ultrasonography shows a modestly enlarged uterus with three uterine fibroids. She is not planning to become pregnant. How should this case be evaluated and managed?

Clinical practice. Uterine fibroids.

BACKGROUND
Uterine leiomyomas (fibroids) are highly prevalent benign smooth muscle tumors of the uterus. In the USA, the lifetime risk for women developing uterine leiomyomas is estimated as up to 75%. Except for hysterectomy, most therapies or treatments often provide only partial or temporary relief and are not successful in every patient. There is a clear racial disparity in the disease; African-American women are estimated to be three times more likely to develop uterine leiomyomas and generally develop more severe symptoms. There is also familial clustering between first-degree relatives and twins, and multiple inherited syndromes in which fibroid development occurs. Leiomyomas have been described as clonal and hormonally regulated, but despite the healthcare burden imposed by the disease, the etiology of uterine leiomyomas remains largely unknown. The mechanisms involved in their growth are also essentially unknown, which has contributed to the slow progress in development of effective treatment options.

Epidemiological and genetic clues for molecular mechanisms involved in uterine leiomyoma development and growth

Uterine fibroids are common benign neoplasms, with a higher prevalence in older women and in those of African descent. Many are discovered incidentally on clinical examination or imaging in asymptomatic women. Fibroids can cause abnormal uterine bleeding, pelvic pressure, bowel dysfunction, urinary frequency and urgency, urinary retention, low back pain, constipation, and dyspareunia. Ultrasonography is the preferred initial imaging modality. Expectant management is recommended for asymptomatic patients because most fibroids decrease in size during menopause. Management should be tailored to the size and location of fibroids; the patient's age, symptoms, desire to maintain fertility, and access to treatment; and the experience of the physician. Medical therapy to reduce heavy menstrual bleeding includes hormonal contraceptives, tranexamic acid, and nonsteroidal anti-inflammatory drugs. Gonadotropin-releasing hormone agonists or selective progesterone receptor modulators are an option for patients who need symptom relief preoperatively or who are approaching menopause. Surgical treatment includes hysterectomy, myomectomy, uterine artery embolization, and magnetic resonance-guided focused ultrasound surgery.

Uterine Fibroids: Diagnosis and Treatment.

Background
Uterine fibroids are the most common benign uterine tumours present in women of reproductive age. Mifepristone (RU-486) competitively binds and inhibits progesterone receptors. Studies have suggested that fibroid growth depends on the sexual steroids. Mifepristone has been shown to decrease fibroid size. This review summarises the effects of mifepristone treatment on fibroids and the associated adverse effects as described in randomised controlled trials.

Objectives
To determine the efficacy and safety of mifepristone for the management of uterine fibroids in pre-menopausal women.

Search methods
We searched the specialised register of the Cochrane Menstrual Disorders and Subfertility (Cochrane Menstrual Disorders and subfertility Review Group), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 4), MEDLINE, EMBASE, PsycINFO, and CINAHL (to November 2011). We handsearched a number of journals, and searched reference lists, databases of ongoing trials and the Internet. There were no language restrictions.

Selection criteria
Only truly randomised controlled trials of mifepristone versus other forms of medical therapy or placebo in pre-menopausal women with confirmed uterine fibroids were included.

Data collection and analysis
Four authors independently extracted data and assessed trial quality. Data were analysed using the Peto odds ratios (OR) for dichotomous data and the weighted mean differences for continuous data, with 95% confidence intervals (CI). Meta-analyses were performed using the fixed-effect model.

Main results
Three studies involving 112 participants were included. Comparison interventions included different dosages of mifepristone, placebo and vitamin B tablets. There is evidence that treatment with mifepristone relieves heavy menstrual bleeding compared with placebo (Peto OR 17.84; 95% CI 6.72 to 47.38; 2 RCTs, 77 women, I2 = 0%). Three studies (Bagaria 2009; Engman 2009; Fiscella 2006) were included in the meta-analysis of this comparison. There was no evidence of an effect of mifepristone on the fibroid volume (standardised mean difference (SMD) -0.02; 95% CI -0.38 to 0.41; 99 women). Two studies (Bagaria 2009; Fiscella 2006) were included in the meta-analysis of this comparison. There was no evidence of an effect of mifepristone on uterine volume (mean difference (MD) -77.24; 95% CI -240.62 to 86.14; 72 women). The pooled data suggest an increased adverse event (abnormal endometrial histology) in the mifepristone group compared to placebo (OR 31.65; 95% CI 4.83 to 207.35; 2 RCTs; 54 women; I2 = 0%). Only one study (Bagaria 2009) reported endometrial hyperplasia at the end of the therapy (12/19 women in the mifepristone group versus 0/16 in the placebo group; OR 55.0; 95% CI 2.86 to 105.67). Engman 2009 found a significantly higher rate of cystic glandular dilatation in women in the mifepristone group (5/8 women biopsied) compared with the placebo group (1/11 women biopsied) (OR 16.67; 95% CI 1.36 to 204.03). One study (Fiscella 2006) suggested significant improvements (P < 0.001) for specific quality of life outcomes.

Authors' conclusions
Mifepristone reduced heavy menstrual bleeding and improved fibroid-specific quality of life. However, it was not found to reduce fibroid volume. Further well-designed, adequately powered RCTs are needed before a recommendation can be made on the use of mifepristone for the treatment of uterine fibroids.

Antonia Steed

Papers

Mifepristone for uterine fibroids