Uterine fibroid

Uterine fibroids

Uterine Fibroids
Classification and external resources
ICD-10 D25
ICD-9 218.9
OMIM 150699
DiseasesDB 4806
MedlinePlus 000914
eMedicine radio/777
Patient UK Uterine fibroid
MeSH D007889

A uterine fibroid (also known as uterine leiomyoma,[1] myoma, fibromyoma, fibroleiomyoma) is a leiomyoma (benign tumor from smooth muscle tissue) that originates from the smooth muscle layer (myometrium) of the uterus. Fibroids are often multiple and if the uterus contains too many leiomyomata to count, it is referred to as diffuse uterine leiomyomatosis. The cancerous version of a fibroid is extremely uncommon and termed a leiomyosarcoma.

Fibroids are the most common benign tumors in females and typically found during the middle and later reproductive years. While most fibroids are asymptomatic, they can grow and cause heavy and painful menstruation, painful sexual intercourse, urinary frequency and urgency. Some fibroids may interfere with pregnancy although this appears to be uncommon.[2]

In the United States, symptoms caused by uterine fibroids are a very frequent indication for surgical removal of the uterus.[3]

Signs and symptoms

Fibroids, particularly when small, may be entirely asymptomatic. Symptoms depend on the location of the lesion and its size. Important symptoms include abnormal uterine bleeding, heavy or painful periods, abdominal discomfort or bloating, painful defecation, back ache, urinary frequency or retention, and in some cases, infertility.[4] There may also be pain during intercourse, depending on the location of the fibroid. During pregnancy they may also be the cause of miscarriage, bleeding, premature labor, or interference with the position of the fetus.

While fibroids are common, they are not a typical cause for infertility accounting for about 3% of reasons why a woman may not be able to have a child.[5] The majority of women with uterine fibroids will have normal pregnancy outcomes.[6][7] In cases of intercurrent uterine fibroids in infertility, a fibroid is typically located in a submucosal position and it is thought that this location may interfere with the function of the lining and the ability of the embryo to implant.[5] Also larger fibroids may distort or block the fallopian tubes.

Cause

Genetics

An association with fatty acid synthase has been reported.[8]

Familial leiomyomata

A syndrome (Reed's syndrome) that causes uterine leiomyomata along with cutaneous leiomyomata and renal cell cancer has been reported.[9][10][11] This is associated with a mutation in the gene that produces the enzyme fumarate hydratase, located on the long arm of chromosome 1 (1q42.3-43). Inheritance is autosomal dominant.

Pathophysiology

An enucleated uterine leiomyoma – external surface on left, cut surface on right.

Leiomyomata grossly appear as round, well circumscribed (but not encapsulated), solid nodules that are white or tan, and show whorled appearance on histological section. The size varies, from microscopic to lesions of considerable size. Typically lesions the size of a grapefruit or bigger are felt by the patient herself through the abdominal wall.

Micrograph of a lipoleiomyoma, a type of leiomyoma. H&E stain.

Microscopically, tumor cells resemble normal cells (elongated, spindle-shaped, with a cigar-shaped nucleus) and form bundles with different directions (whorled). These cells are uniform in size and shape, with scarce mitoses. There are three benign variants: bizarre (atypical); cellular; and mitotically active.

The appearance of prominent nucleoli with perinucleolar halos should alert the pathologist to investigate the possibility of the extremely rare hereditary leiomyomatosis and renal cell cancer (Reed) syndrome.[12]

Location and classification

Schematic drawing of various types of uterine fibroids: a=subserosal fibroids, b=intramural fibroids, c=submucosal fibroid, d=pedunculated submucosal fibroid, e=fibroid in statu nascendi, f=fibroid of the broad ligament

Growth and location are the main factors that determine if a fibroid leads to symptoms and problems.[3] A small lesion can be symptomatic if located within the uterine cavity while a large lesion on the outside of the uterus may go unnoticed. Different locations are classified as follows:

Fibroids may be single or multiple. Most fibroids start in the muscular wall of the uterus. With further growth, some lesions may develop towards the outside of the uterus or towards the internal cavity. Secondary changes that may develop within fibroids are hemorrhage, necrosis, calcification, and cystic changes.

Extrauterine fibroids of uterine origin, metastatic fibroids

Fibroids of uterine origin located in other parts of the body, sometimes also called parasitic myomas have been historically extremely rare, but are now diagnosed with increasing frequency. They may be related or identical to metastasizing leiomyoma.

They are in most cases still hormone dependent but may cause life-threatening complications when they appear in distant organs. Some sources suggest that a substantial share of the cases may be late complications of surgeries such as myomectomy or hysterectomy. Particularly laparoscopic myomectomy using a morcellator has been associated with a substantially increased risk of this complication.[13][14][15][16][17]

There are a number of rare conditions in which fibroids metastasize. They still grow in a benign fashion, but can be dangerous depending on their location.[18]

Pathogenesis

large subserosal fibroid

Fibroids are monoclonal tumors and approximately 40 to 50% show karyotypically detectable chromosomal abnormalities. When multiple fibroids are present they frequently have unrelated genetic defects. Specific mutations of the MED12 protein have been noted in 70 percent of fibroids.[19]

The exact cause of fibroids is not clearly understood, but the current working hypothesis is that genetic predispositions, prenatal hormone exposure and the effects of hormones, growth factors and xenoestrogens cause fibroid growth. Known risk factors are African descent, obesity, polycystic ovary syndrome, diabetes, hypertension, and never having given birth.[20]

Fibroid growth is strongly dependent on estrogen and progesterone. Although both estrogen and progesterone are usually regarded as growth-promoting they will also cause growth restriction in some circumstances. Paradoxically, fibroids rarely grow during pregnancy despite very high steroid hormone levels and pregnancy appears to exert a certain protective effect.[2] This protective effect might be partially mediated by an interaction between estrogen and the oxytocin receptor.[21]

It is believed that estrogen and progesterone have a mitogenic effect on leiomyoma cells and also act by influencing (directly and indirectly) a large number of growth factors, cytokines and apoptotic factors as well as other hormones. Furthermore, the actions of estrogen and progesterone are modulated by the cross-talk between estrogen, progesterone and prolactin signalling which controls the expression of the respective nuclear receptors. It is believed that estrogen promotes growth by up-regulating IGF-1, EGFR, TGF-beta1, TGF-beta3 and PDGF, and promotes aberrant survival of leiomyoma cells by down-regulating p53, increasing expression of the anti-apoptotic factor PCP4 and antagonizing PPAR-gamma signalling. Progesterone is thought to promote the growth of leiomyoma through up-regulating EGF, TGF-beta1 and TGF-beta3, and promotes survival through up-regulating Bcl-2 expression and down-regulating TNF-alpha. Progesterone is believed to counteract growth by downregulating IGF-1.[22][23][24] Expression of transforming growth interacting factor (TGIF) is increased in leiomyoma compared with myometrium.[25] TGIF is a potential repressor of TGF-β pathways in myometrial cells.[25]

Whereas in premenopausal fibroids the ER-beta, ER-alpha and progesterone receptors are found overexpressed, in the rare postmenopausal fibroids only ER-beta was found significantly overexpressed.[26] Most studies found that polymorphisms in ER and PR gene encodings are not correlated with incidence of fibroids in Caucasian populations[27][28] however a special ER-alpha genotype was found correlated with incidence and size of fibroids. The higher prevalence of this genotype in black women may also explain the high incidence of fibroids in this group.[29]

Uterine leiomyoma was more sensitive than normal myometrium to PPAR-gamma receptor activation resulting in reduced survival and apoptosis of leiomyoma cells. The mechanism is thought to involve negative cross-talk between ER and PPAR signaling pathways. Several PPAR-gamma ligands were considered as potential treatment.[30] PPAR-gamma agonists may also counteract leiomyoma growth by several other mechanisms of action such as TGF-beta3 expression inhibition.[31]

Aromatase and 17beta-hydroxysteroid dehydrogenase are aberrantly expressed in fibroids, indicating that fibroids can convert circulating androstenedione into estradiol.[32] Similar mechanism of action has been elucidated in endometriosis and other endometrial diseases.[33] Aromatase inhibotors are currently considered for treatment, at certain doses they would completely inhibit estrogen production in the fibroid while not largely affecting ovarian production of estrogen (and thus systemic levels of it). Aromatase overexpression is particularly pronounced in Afro-American women.[34]

Genetic and hereditary causes are being considered and several epidemiologic findings indicate considerable genetic influence especially for early onset cases. First degree relatives have a 2.5-fold risk, and nearly 6-fold risk when considering early onset cases. Monozygotic twins have double concordance rate for hysterectomy compared to dizygotic twins.[35]

Expansion of uterine fibroids is by a slow rate of cell proliferation combined with the production of copious amounts of extracellular matrix.[36] Recent studies suggest that this production may represent an abnormal response to ischemic and mechanical tissue stress.[37] Several factors indicate significant involvement of extracellular signaling pathways such as ERK1 and ERK2, which in fibroids are prominently influenced by hormones.[38] Paradoxically and unlike most other conditions involving significant fibrosis the CYR61 gene has been found downregulated in fibroids.[39]

Cyr61 is also known for its role as tumor suppressing factor and in angiogenesis. Hence fibroids are one of the very few tumors with reduced vascular density.[39]

A small population of the cells in an uterine fibroid have properties of stem cells or progenitor cells, and contribute significantly to ovarian steroid-dependent growth of fibroids. These stem-progenitor cells are deficient in estrogen receptor α and progesterone receptor and instead rely on substantially higher levels of these receptors in surrounding differentiated cells to mediate estrogen and progesterone actions via paracrine signalling.[36]

Diagnosis

While a bimanual examination typically can identify the presence of larger fibroids, gynecologic ultrasonography (ultrasound) has evolved as the standard tool to evaluate the uterus for fibroids. Sonography will depict the fibroids as focal masses with a heterogeneous texture, which usually cause shadowing of the ultrasound beam. The location can be determined and dimensions of the lesion measured. Also magnetic resonance imaging (MRI) can be used to define the depiction of the size and location of the fibroids within the uterus.

Imaging modalities cannot clearly distinguish between the benign uterine leiomyoma and the malignant uterine leiomyosarcoma, however, the latter is quite rare. Fast growth or unexpected growth, such as enlargement of a lesion after menopause, raise the level of suspicion that the lesion might be a sarcoma. Also, with advanced malignant lesions there may be evidence of local invasion. A more recent study has suggested that diagnostic capabilities using MRI have improved the ability to detect sarcomatous lesions.[40] Biopsy is rarely performed and if performed, is rarely diagnostic. Should there be an uncertain diagnosis after ultrasounds and MRI imaging, surgery is generally indicated.

Other imaging techniques that may be helpful specifically in the evaluation of lesions that affect the uterine cavity are hysterosalpingography or sonohysterography.

Coexisting disorders

Fibroids that lead to heavy vaginal bleeding lead to anemia and iron deficiency. Due to pressure effects gastrointestinal problems such as constipation and bloatedness are possible. Compression of the ureter may lead to hydronephrosis. Fibroids may also present alongside endometriosis, which itself may cause infertility. Adenomyosis may be mistaken for or coexist with fibroids.

In very rare cases, malignant (cancerous) growths, leiomyosarcoma, of the myometrium can develop.[41] In extremely rare cases uterine fibroids may present as part or early symptom of the hereditary leiomyomatosis and renal cell cancer syndrome.

Treatment

Most fibroids do not require treatment unless they are causing symptoms. After menopause fibroids shrink and it is unusual for them to cause problems. In those who have symptoms uterine artery embolization and surgical options have similar outcomes with respect to satisfaction.[42]

Symptomatic uterine fibroids can be treated by:

Medication

A number of medications may be used to control symptoms. NSAIDs can be used to reduce painful menses. Oral contraceptive pills are prescribed to reduce uterine bleeding and cramps.[5] Anemia may have to be treated with iron supplementation. Vitamin D3 supplementation can be tried.[43][44][45]

Levonorgestrel intrauterine devices are highly effective in limiting menstrual blood flow and improving other symptoms. Side effects are typically very moderate because the levonorgestrel (a progestin) is released in low concentration locally. There is now substantial evidence that Levongestrel-IUDs provide good symptomatic relief for women with fibroids.[46] While most Levongestrel-IUD studies concentrated on treatment of women without fibroids a few reported very good results specifically for women with fibroids including a substantial regression of fibroids.[47][48][49]

Dostinex in a moderate and well tolerated dosis has been shown in 2 studies to shrink fibroids effectively. Mechanism of action is unclear.[48][50]

Ulipristal acetate is a synthetic selective progesterone receptor modulator which has been tested in several randomized trials with good results for the treatment of fibroids.[51][52] Similar to other selective progesterone receptor modulators and antagonists benign histologic endometrial changes were reported and long term safety outside of clinical studies has not been established yet.[51][53][54]

Danazol is an effective treatment to shrink fibroids and control symptoms. Its use is limited by unpleasant side effects. Mechanism of action is thought to be antiestrogenic effects. Recent experience indicates that safety and side effect profile can be improved by more cautious dosing.[48]

Gonadotropin-releasing hormone analogs cause temporary regression of fibroids by decreasing estrogen levels. Because of the limitations and side effects of this medication it is rarely recommended other than for preoperative use to shrink the size of the fibroids and uterus before surgery. It is typically used for a maximum of 6 months or less because after longer use they could cause osteoporosis and other typically postmenopausal complications. The main side effects are transient postmenopausal symptoms. In many cases the fibroids will regrow after cessation of treatment, however significant benefits may persist for much longer in some cases. Several variations are possible, such as GnRH agonists with add-back regimens intended to decrease the adverse effects of estrogen deficiency. Several add-back regimes are possible, tibolone, raloxifene, progestogens alone, estrogen alone, and combined estrogens and progestogens.[48]

Progesterone antagonists such as Mifepristone have been tested, there is evidence that it relieves some symptoms and improves quality of life but because of adverse histological changes that have been observed in several trials it can not be currently recommended outside of research setting.[55][56][57] Fibroid growth has recurred after antiprogestin treatment was stopped.[36] Selective progesterone receptor modulators, such as Progenta, have been under investigation.

The selective progesterone receptor modulator Asoprisnil is currently tested with very promising results as a possible use as a treatment for fibroids - the hope is that it will provide the advantages of progesterone antangonitst without their adverse effects.[48]

The long term safety of progesterone antagonists as well as selective progesterone receptor modulators has yet to be established.[58]

Aromatase inhibitors have been used experimentally to reduce fibroids. The effect is believed to be due partially by lowering systemic estrogen levels and partially by inhibiting locally overexpressed aromatase in fibroids.[48] However, fibroid growth has recurred after treatment was stopped.[36] Experience from experimental aromatase inhibitor treatment of endometriosis indicates that aromatase inhibitors might be particularly useful in combination with a progestogenic ovulation inhibitor.

Uterine artery embolization

Uterine artery embolization (UAE): is a noninvasive, endovascular procedure effectively treating symptomatic fibroids. Using interventional radiology techniques, the interventional radiologist occludes both uterine arteries, thus reducing blood supply to the fibroid.[59] This intervention is not usually recommended when fertility should be preserved although subsequent pregnancies are usually possible. A small catheter (1 mm in diameter) is inserted into the femoral artery at the level of the groin under local anesthesia. Under imaging guidance, the interventional radiologist will enter selectively into both uterine arteries and inject small (500 µm) particles that will block the blood supply to the fibroids. A patient will usually recover from the procedure within a few days. The UAE procedure should result in limited blood supply to the fibroids which should prevent them from further growth, heavy bleeding and possibly shrink them.

In 1994, Dr. Bruce McLucas pioneered the first successful Uterine Artery Embolization (UAE) procedure in the United States. Since then, he has successfully performed UAE on thousands of patients worldwide. He is one of the few gynecologists in the world with the expertise to perform UAE. Dr. McLucas also trains physicians throughout the world to successfully perform UAE.

Uterine artery ligation

Uterine artery ligation, sometimes also laparoscopic occlusion of uterine arteries are minimally invasive methods to limit blood supply of the uterus by a small surgery that can be performed transvaginally or laparoscopically. The principal mechanism of action may be similar like in UAE but is easier to perform and fewer side effects are expected.[60][61][62] UAE currently appears much more effective than this method in direct comparison.[63]

Radio frequency ablation

Radiofrequency ablation is a minimally invasive treatments for fibroids.[64] In this technique the fibroid is shrunk by inserting a needle-like device into the fibroid through the abdomen and heating it with radio-frequency (RF) electrical energy to cause necrosis of cells. The treatment is a potential option for women who have fibroids, have completed child-bearing and want to avoid a hysterectomy.

Myomectomy

submucosal fibroid in hysteroscopy
Treatment of an intramural fibroid by laparoscopic surgery
After treatment of an intramural fibroid by laparoscopic surgery

Myomectomy is a surgery to remove one or more fibroids. It is usually recommended when more conservative treatment options fail for women who want fertility preserving surgery or who want to retain the uterus.[65]

There are three types of myomectomy:

Laparoscopic myomectomy has less pain and shower time in hospital than open surgery.[67]

Hysterectomy

Hysterectomy was the classical method of treating fibroids. Although it is now recommended only as last option, fibroids are still the leading cause of hysterectomies in the US.

Endometrial ablation

Endometrial ablation can be used if the fibroids are only within the uterus and not intramural and relatively small. High failure and recurrence rates are expected in the presence of larger or intramural fibroids.

Magnetic resonance guided focused ultrasound

Magnetic resonance guided focused ultrasound, is a non-invasive intervention (requiring no incision) that uses high intensity focused ultrasound waves to destroy tissue in combination with magnetic resonance imaging (MRI), which guides and monitors the treatment. During the procedure, delivery of focused ultrasound energy is guided and controlled using MR thermal imaging.[68] Patients who have symptomatic fibroids, who desire a non-invasive treatment option and who do not have contraindictions for MRI are candidates for MRgFUS. About 60% of patients qualify. It is an outpatient procedure and takes one to three hours depending on the size of the fibroids. It is safe and about 75% effective.[69] Symptomatic improvement is sustained for two plus years.[70] Need for additional treatment varies from 16-20% and is largely dependent on the amount of fibroid that can be safely ablated; the higher the ablated volume, the lower the re-treatment rate.[71] In comparison to available treatment options, the cost effectiveness of MRgFUS in the U.S. and U.K. has been found to be reasonable and comparable to alternative treatments (hysterectomy, pharmacotherapy, uterine artery embolization).[72][73] There are currently no randomized trial between MRgFUS and UAE. A multi-center trial is underway to investigate the efficacy of MRgFUS vs. UAE.

Prognosis

About 1 out of 1000 lesions[5] are or become malignant, typically as a leiomyosarcoma on histology. A sign that a lesion may be malignant is growth after menopause.[5] There is no consensus among pathologists regarding the transformation of leiomyoma into a sarcoma.

Metastasis

There are a number of rare conditions in which fibroids metastasize. They still grow in a benign fashion, but can be dangerous depending on their location.[18]

See extrauterine fibroids.


Epidemiology

Globally approximately 235 million people are affected with uterine fibroids as of 2010 (6.6% of females).[74] About 20–40% of women will be diagnosed with leiomyoma at some point in their life but only a fraction of those will cause problems or require treatment.[3]

Leiomyomata are more common in obese women.[75] Fibroids are dependent on estrogen and progesterone to grow and therefore relevant only during the reproductive years, they are expected to shrink after menopause.

United States

Eighty percent of African American women will develop benign uterine fibroid tumors by their late 40s, according to the National Institute of Environmental Health Sciences.[76] African American women are two to three times more likely to get fibroids than Caucasian women.[75][77][78] In African-American women fibroids seem to occur at a younger age, grow more quickly, and are more likely to cause symptoms.[79] This leads to higher rates of surgery for African Americans, both myomectomy and hysterectomy.[80] Increased risk of fibroids in African- Americans causes them to fare worse in in-vitro fertility treatments and raises their risk of premature births and delivery by Cesarean section.[80]

It is unclear why fibroids are more common in African American women. Some studies suggest that black women who are obese and who have high blood pressure are more likely to have fibroids.[80] Black women consume fewer servings of dairy than white women and have lower intake of calcium, magnesium and phosphorus, while some data suggest that increased dairy intake in African American women is associated with lower risk of fibroids.[81] A relation between the use of hair relaxers and risk of developing fibroids has been found, high prevalence of the use of hair relaxer among African American women may explain some of the risk.[82]

Society and culture

United States law

The 2005 S.1289 bill was read twice and referred to the committee on Health, Labor and Pensions but never passed for a Senate or House vote. The proposed Uterine Fibroid Research and Education Act of 2005 mentioned that $5 billion is spent annually on hysterectomy surgeries each year, which affect 22% of African Americans and 7% of Caucasian women. The bill also called for more funding for research and educational purposes. It also states that of the $28 billion issued to NIH,[83] $5 million was allocated for uterine fibroids in 2004.

Other animals

Uterine fibroids are rare in other mammals, although they have been observed in certain dogs and Baltic grey seals.[84]

References

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