Leiomyoma

Etiology

Leiomyomas are comprised of monoclonal cells arising from the myometrium [5]. Continued research to determine the etiology of leiomyomas is ongoing. Several studies have identified specific gene mutations associated with fibroids [2]. Some mutations have been linked to defects in cell transformation involving the RNA polymerase II transcriptional mediator subunit, MED12 [5].

Epidemiology

Leiomyomas are diagnosed in close to 70% of white women and more than 80% of black women by age 50, but the incidence of clinical symptoms in blacks is double that found in whites [2].  In addition to African descent, several factors are commonly associated with a higher risk of developing fibroids: early menarche, use of oral contraception before the age of 16 and an increase in body mass index. Conversely, the use of progestin-only contraceptives as well as multiparity decrease this risk [2].

Pathophysiology

Clinically, it is well established that leiomyomas are highly sensitive to the effects of steroid hormones. Leiomyomas have an increased expression of both estrogen and progesterone receptors when compared to normal myometrium [6]. Studies indicate that ovarian steroids, estradiol, and progesterone, promote the growth of leiomyomas; and that the size of fibroids often decline after menopause when levels of those hormones fall [7].

Histopathology

Leiomyomas are benign tumors of monoclonal origin which arise from the smooth muscle of the uterus[2][8]. Leiomyomas are primarily composed of extracellular matrix and cells with a low mitotic index [7][8]. They are encapsulated with a pseudocapsule composed of areolar tissue [8].

History and Physical

The clinical presentation of fibroids is variable, ranging from asymptomatic patients to those with recurrent, progressive symptoms that adversely affect a woman’s daily activities. The most common presenting symptoms are pain, pressure, and abnormal vaginal bleeding [7]. Important determinants of symptoms are the location, size, and the number of leiomyomas [1]. Physical examination usually confirms an enlarged, irregularly-shaped uterus [2].

Evaluation

Diagnosis of uterine leiomyomas is generally made by comprehensive physical examination and clinical history. On physical exam, the most common finding is an enlarged uterus that is often irregular in shape. Confirmation of clinical diagnosis is most easily accomplished with ultrasonography. A pelvic sonogram is a cost-effective method that allows for rapid diagnosis [2].

Further imaging, such as magnetic resonance imaging (MRI), can be useful for determining the extent of vascularization or degeneration of the leiomyomas. MRI can also better define the relationship of the leiomyomas to the serosal and mucosal surfaces. The proximity to these surfaces often dictates the type of intervention recommended [2].

The International Federation of Gynecology and Obstetrics (FIGO) has developed a classification system that allows for the determination of the extent of invasion into the endometrial cavity. The FIGO scale ranges from 0 to 8, with the lower number indicating closer proximity to the endometrium[2][9].

If bleeding is the predominant symptom and there is a concern for anemia or other sequelae of recurrent blood loss, a complete blood count (CBC) is indicated. Further evaluation of blood work should include a thyroid-stimulating hormone level to rule out thyroid disease as the cause of abnormal bleeding if the index of suspicion is low for leiomyomata as the etiology [2].

At this time, there is no recommendation for surveillance imaging. While the growth of the leiomyoma can be surveyed, there is no current basis for a set time interval or current guidelines on how the growth should be monitored. Interval reassessment is usually based on a change in clinical symptoms [2].

Treatment / Management

The economic impact on the United States by the cost of care for symptomatic leiomyomas is excessive [1]. Effective treatment is necessary to not only reduce the detrimental effects they pose on a women’s daily function, but also to mitigate the economic burden on healthcare [2].

The patient’s age and reproductive goals direct the modality and goals of treatment. Treatment options include both medical and surgical intervention [1]. Treatment goals should fulfill three objectives: 

• Relieve bothersome signs and symptoms
• Reduce the leiomyoma size 
• Maintain or improve a woman’s fertility if desired [1].

Medical management is often the initial intervention for symptomatic fibroids and includes hormonal therapy, nonsteroidal anti-inflammatory drugs (NSAIDs) and/or modulation of the hypothalamic-pituitary axis. The major drawback of medical management is the limited duration of use. Many of the medical management options are only able to be used for a short duration, and after the cessation of treatment, symptoms reoccur, and the fibroids often continue to grow [1].

Hormonal options for treatment include combination oral contraceptives, single agent progesterone suppression or GnRH agonists. Systemic hormonal therapy is primarily used to control menorrhagia caused by fibroids, rarely impacts the size of fibroids and does not improve fertility.  Additionally, increased complications are associated with long-term treatment using exogenous hormones; therefore, they are generally only used for short durations [1]. Gonadotropin-releasing hormone (GnRH) agonists inhibit production of endogenous progesterone and estrogen.  The overall effects are similar to those of menopause, thus resulting in amenorrhea and subsequent decrease in uterine volume [1][2].  However, these effects are limited to the duration of use.

Intrauterine devices that release levonorgestrel act locally to achieve results similar to systemic progesterone suppression, resulting in decreased menstrual bleeding and improved quality of life [2]. While they provide symptomatic relief, they do not have any long-term effect on decreasing the overall size of the uterine fibroids; thus providing little help with bulk symptoms [2].

Non-hormonal options involve NSAIDs and tranexamic acid. Tranexamic acid is a derivative of the amino acid, lysine.  This medication is a reversible inhibitor of lysine receptor sites on plasminogen that, when bound, prevent fibrin degradation and functionally stabilize clot formation [1]. There are few side effects associated with tranexamic acid. The most common is gastrointestinal upset, while the most feared is venous thromboembolism[1] [2]. Clinical studies have found no significant evidence for the theoretical increased risk of venous thromboembolism from use of tranexamic acid [1]. However, due to potential increased thrombotic risk with hormonal therapy, tranexamic acid is usually prescribed as a single agent therapy [2].

NSAIDs have been useful for reducing menstrual blood loss [1]. NSAIDs decrease the endometrial prostaglandins, which subsequently inhibit aberrant vascularization and neovascularization [1][2]. While NSAIDs are effective for decreasing menstrual flow, they are inferior to tranexamic acid and levonorgestrel-releasing IUDs [2] [10].(A1)

Surgical intervention remains the most successful treatment for leiomyomas. Endometrial ablation is hysteroscopic destruction of the full-thickness endometrium, but this treatment precludes future endometrial assessment and requires permanent contraception.  Uterine artery embolization reduces blood flow to individual fibroids to reduce growth and mitigate symptoms.  Successful myomectomy (surgical removal of fibroids only) enables future fertility while reducing size and symptoms from fibroids; however, many women will require additional subsequent procedures for recurrent symptomatic fibroids.  Hysterectomy is the only treatment that provides definitive therapy [2]. There are various methods of performing a hysterectomy, the choice of which is highly dependent on the patients’ history, physical findings and the individual surgeon's training and experience [2].

Differential Diagnosis

The differential diagnosis for uterine leiomyomas includes both benign and malignant diseases that cause uterine enlargement, bleeding or pelvic pain. The most common diagnoses to consider are adenomyosis, endometriosis, pregnancy, leiomyosarcoma, endometrial carcinoma and uterine carcinosarcoma [11]. While these cancers are rare causes of symptoms consistent with leiomyomas, the clinician must maintain a high index of suspicion during evaluation.

Prognosis

The prognosis of uterine fibroids varies extensively for individual patients. Many patients have an excellent prognosis and remain asymptomatic for many years or indefinitely. Whereas, others will fail medical management and depending on their desire for future fertility, may experience recurrent fibroids requiring multiple surgeries. 

Complications

• Chronic pelvic pain
• Heavy menstrual bleeding, which can lead to anemia
• Poor pregnancy outcomes 
• Infertility 
• Constipation 
• Urinary tract infections or urinary incontinence
• Torsion of a pedunculated fibroid 
• Degeneration with or without infection