Leiomyomas, also called fibroids, are the most common benign gynecological tumor in premenopausal women . The economic impact of fibroids is profound, affecting an estimated 11 million women  and costing approximately 34 billion dollars in the United States annually . This article presents the general approach to diagnosis, pathophysiology, histology, and treatment of leiomyomas.
Leiomyomas are comprised of monoclonal cells arising from the myometrium . Continued research to determine the etiology of leiomyomas is ongoing. Several studies have identified specific gene mutations associated with fibroids . Some mutations have been linked to defects in cell transformation involving the RNA polymerase II transcriptional mediator subunit, MED12 .
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 . 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 .
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 . 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 .
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 . Important determinants of symptoms are the location, size, and the number of leiomyomas . Physical examination usually confirms an enlarged, irregularly-shaped uterus .
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 .
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 .
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.
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 .
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 .
The economic impact on the United States by the cost of care for symptomatic leiomyomas is excessive . 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 .
The patient’s age and reproductive goals direct the modality and goals of treatment. Treatment options include both medical and surgical intervention . Treatment goals should fulfill three objectives:
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 .
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 . 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 . 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 . 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 .
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 . There are few side effects associated with tranexamic acid. The most common is gastrointestinal upset, while the most feared is venous thromboembolism . Clinical studies have found no significant evidence for the theoretical increased risk of venous thromboembolism from use of tranexamic acid . However, due to potential increased thrombotic risk with hormonal therapy, tranexamic acid is usually prescribed as a single agent therapy .
NSAIDs have been useful for reducing menstrual blood loss . NSAIDs decrease the endometrial prostaglandins, which subsequently inhibit aberrant vascularization and neovascularization . While NSAIDs are effective for decreasing menstrual flow, they are inferior to tranexamic acid and levonorgestrel-releasing IUDs  .
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 . 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 .
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 . While these cancers are rare causes of symptoms consistent with leiomyomas, the clinician must maintain a high index of suspicion during evaluation.
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.
Considering the high prevalence and incidence of uterine leiomyomas, the need for full integration of care among health care professionals is essential. To expand our knowledge of leiomyomas, we need further research to identify predisposing genetic factors for potential use to better target preventive care. Current randomized trials have shown progress in the treatment of symptoms to improve quality of life. One of the most recent phase three trials found the use of ulipristal acetate, an oral progesterone receptor modulator significantly improves bleeding among women with symptomatic leiomyomas . While this is a step in the right direction, the need for further understanding of the pathophysiology of leiomyomas is essential for optimal care of this large population of patients.
|||Role of Medical Management for Uterine Leiomyomas., Kashani BN,Centini G,Morelli SS,Weiss G,Petraglia F,, Best practice & research. Clinical obstetrics & gynaecology, 2015 Nov 25 [PubMed PMID: 26796059]|
|||Stewart EA,Laughlin-Tommaso SK,Catherino WH,Lalitkumar S,Gupta D,Vollenhoven B, Uterine fibroids. Nature reviews. Disease primers. 2016 Jun 23; [PubMed PMID: 27335259]|
|||Marsh EE,Al-Hendy A,Kappus D,Galitsky A,Stewart EA,Kerolous M, Burden, Prevalence, and Treatment of Uterine Fibroids: A Survey of U.S. Women. Journal of women's health (2002). 2018 Nov; [PubMed PMID: 30230950]|
|||Cardozo ER,Clark AD,Banks NK,Henne MB,Stegmann BJ,Segars JH, The estimated annual cost of uterine leiomyomata in the United States. American journal of obstetrics and gynecology. 2012 Mar [PubMed PMID: 22244472]|
|||Li Z,Maeda D,Kudo-Asabe Y,Tamura D,Nanjo H,Hayashi A,Ikemura M,Fukayama M,Goto A, MED12 is frequently mutated in ovarian and other adnexal leiomyomas. Human pathology. 2018 Nov; [PubMed PMID: 29944972]|
|||Doherty L,Mutlu L,Sinclair D,Taylor H, Uterine fibroids: clinical manifestations and contemporary management. Reproductive sciences (Thousand Oaks, Calif.). 2014 Sep; [PubMed PMID: 24819877]|
|||Ghosh S,Naftalin J,Imrie R,Hoo WL, Natural History of Uterine Fibroids: A Radiological Perspective. Current obstetrics and gynecology reports. 2018; [PubMed PMID: 30101039]|
|||Holdsworth-Carson SJ,Zaitseva M,Vollenhoven BJ,Rogers PA, Clonality of smooth muscle and fibroblast cell populations isolated from human fibroid and myometrial tissues. Molecular human reproduction. 2014 Mar; [PubMed PMID: 24243625]|
|||Munro MG,Critchley HO,Fraser IS, The FIGO classification of causes of abnormal uterine bleeding in the reproductive years. Fertility and sterility. 2011 Jun; [PubMed PMID: 21496802]|
|||Lethaby A,Duckitt K,Farquhar C, Non-steroidal anti-inflammatory drugs for heavy menstrual bleeding. The Cochrane database of systematic reviews. 2013 Jan 31; [PubMed PMID: 23440779]|
|||Fleischer AC,James AE Jr,Millis JB,Julian C, Differential diagnosis of pelvic masses by gray scale sonography. AJR. American journal of roentgenology. 1978 Sep; [PubMed PMID: 98992]|
|||Simon JA,Catherino W,Segars JH,Blakesley RE,Chan A,Sniukiene V,Al-Hendy A, Ulipristal Acetate for Treatment of Symptomatic Uterine Leiomyomas: A Randomized Controlled Trial. Obstetrics and gynecology. 2018 Mar [PubMed PMID: 29420395]|