A uterine fibroid is a leiomyoma (benign (non-cancerous) 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 malignant version of a

fibroid is extremely uncommon and termed a leiomyosarcoma. 

Other common names are uterine leiomyoma,[1] myoma, fibromyoma,

fibroleiomyoma.

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, and

urinary frequency and urgency. Some fibroids may interfere with pregnancy

although this appears to be very rare.[2]

Signs and symptoms[edit] 

Fibroids, particularly when small, may be entirely asymptomatic. Symptoms depend

on the location of the lesion and its size. Important symptoms include abnormal

gynecologic hemorrhage,  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 have a child.[5] Typically in such cases a

fibroid is 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.

Pathophysiology[edit] 

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 syndrome.[6]

Location and classification[edit] 

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:

•  Intramural fibroids are located within the wall of the uterus and are the most

common type; unless large, they may be asymptomatic. Intramural fibroids

begin as small nodules in the muscular wall of the uterus. With time,

intramural fibroids may expand inwards, causing distortion and elongation of

 

the uterine cavity.

•  Subserosal fibroids are located underneath the mucosal (peritoneal) surface of the

uterus and can become very large. They can also grow out in a papillary

manner to become pedunculated fibroids. These pedunculated growths can

actually detach from the uterus to become a parasitic leiomyoma.

•  Submucosal fibroids are located in the muscle beneath the endometrium of the

uterus and distort the uterine cavity; even small lesions in this location may

lead to bleeding and infertility.  A pedunculated lesion within the cavity is

termed an intracavitary fibroid and can be passed through the cervix.

•  Cervical fibroids are located in the wall of the cervix (neck of the uterus). Rarely

fibroids are found in the supporting structures (round ligament,  broad

ligament,  or uterosacral ligament)  of the uterus that also contain smooth

muscle tissue.

Fibroids may be single or multiple. Most fibroids start in an intramural location, that

is the layer of the muscle 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[edit] 

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.[7][8][9][10][11]

Pathogenesis[edit] 

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.[12]

Exact aetiology 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, nulliparity,  obesity,  polycystic ovary syndrome,  diabetes and

hypertension.[13]

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.[14]

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.[15][16][17] Expression of transforming growth interacting

factor (TGIF) is increased in leiomyoma compared with myometrium.[18] TGIF is a

potential repressor of  TGF-β pathways in myometrial cells.[18]

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.[19] Most studies found that

polymorphisms in ER and PR gene encodings are not correlated with incidence of

fibroids in Caucasian populations[20][21] 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.[22]

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.[23] PPAR-gamma agonists may also counteract leiomyoma growth by

several other mechanisms of action such as TGF-beta3 expression inhibition.[24]

Hypertension is significantly correlated with fibroids. Although a causal relationships

is not at all clear the hypothesis has been formulated that atherosclerotic injury to

uterine blood vessels and the resulting inflammatory state may play a role.

Furthermore endocrine factors related to blood pressure such as angiotensin II are

suspected to cause fibroid proliferation via angiotensin II type 1 receptor.[25][26]

Aromatase and 17beta-hydroxysteroid dehydrogenase are aberrantly expressed in

fibroids, indicating that fibroids can convert circulating androstenedione into

estradiol.[27] Similar mechanism of action has been elucidated in endometriosis and

other endometrial diseases.[28] 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[29]

 

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.[30]

Like keloids,  fibroids have disregulated production of extracellular matrix.  Recent

studies suggest that this production may represent an abnormal response to

ischemic and mechanical tissue stress.[31] Several factors indicate significant

involvement of extracellular signaling pathways such as ERK1 and ERK2,  which in

fibroids are prominently influenced by hormones.[32] Paradoxically and unlike most

other conditions involving significant fibrosis the Cyr61 gene has been found

downregulated in fibroids.[33]

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.[33]

Diagnosis[edit] 

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.[34] 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. 

• 

•  A very large (9 cm) fibroid of the uterus which is causing pelvic congestion

 

syndrome as seen on CT 

•  A very large (9 cm) fibroid of the uterus which is causing pelvic congestion

syndrome as seen on ultrasound 

•  A relatively large submucosal leiomyoma; it fills out the major part of the

endometrial cavity 

•  A small uterine fibroid seen within the wall of the myometrium on a cross

sectional ultrasound view 

•  Two calcified fibroids (in the uterus) 

Coexisting disorders[edit] 

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.[35]

In extremely rare cases uterine fibroids may present as part or early symptom of the

hereditary leiomyomatosis and renal cell cancer syndrome.

Treatment[edit] 

 

Most fibroids do not require treatment unless they are causing symptoms. After

menopause fibroids shrink and it is unusual for fibroids to cause problems.

Symptomatic uterine fibroids can be treated by:

•  medication to control symptoms

•  medication aimed at shrinking tumours

•  ultrasound fibroid destruction

•  myomectomy or radio frequency ablation

•  hysterectomy

•  uterine artery embolization

Medication[edit] 

A number of medications are in use to control symptoms caused by fibroids. 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.

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.[36] 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.[37][38][39]

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.[38]

Dostinex in a moderate and well tolerated dosis has been shown in 2 studies to

shrink fibroids effectively. Mechanism of action is unclear.[38][40]

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.[38]

Ulipristal acetate is a synthetic selective progesterone receptor modulator which has

been tested in small radomized trials with good results for the treatment of

fibroids.[41] 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.[41][42][43]

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.[44][45][46]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.[38]

The long term safety of progesterone antagonists as well as selective progesterone

receptor modulators has yet to be established.[47][48]

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.[38] 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[edit] 

Uterine artery embolization (UAE): Using interventional radiology techniques, the

interventional radiologist occludes both uterine arteries, thus reducing blood supply

to the fibroid.[49] 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.

A retrospective cohort study showed that UAE has much fewer serious adverse

effects than hysterectomy (odds ratio 0.25) and similar rates of satisfaction. In this

study, 86% of women treated with UAE would recommend the treatment to a friend

compared to 70% of those treated by hysterectomy.[50]

Uterine artery ligation[edit] 

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.[51][52][53] UAE currently appears much more effective than this method

in direct comparison.[54]

Radio frequency ablation[edit] 

 

Radiofrequency ablation is one of the newest minimally invasive treatments for

fibroids.[55] 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[edit] 

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.[56]

There are three types of myomectomy:

•  In a hysteroscopic  myomectomy (also called transcervical resection), the fibroid

can be removed by either the use of a resectoscope, an endoscopic

instrument inserted through the vagina and cervix that can use high-

frequency electrical energy to cut tissue, or a similar device.

•  A  laparoscopic myomectomy is done through a small incision near the navel. The

physician uses a laparoscope and surgical instruments to remove the fibroids.

Studies have suggested that laparoscopic myomectomy leads to lower

morbidity rates and faster recovery than does laparotomic myomectomy.[57]

•  A  laparotomic myomectomy (also known as an open or abdominal  myomectomy)

is the most invasive surgical procedure to remove fibroids. The physician

makes an incision in the abdominal wall and removes the fibroids from the

uterus.

Hysterectomy[edit] 

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[edit] 

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[edit] 

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.[58] 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.[59] Symptomatic

 

improvement is sustained for two plus years.[60] 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.[61]

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).[62][63]

There are currently no randomized trial between MRgFUS and UAE. A multi-center

trial is underway to investigate the efficacy of MRgFUS vs. UAE.

Genetic associations[edit] 

An association with fatty acid synthase has been reported.[66]

Familial leiomyomata[edit] 

A syndrome (Reed’s syndrome) of cutaneous and uterine leiomyomata and renal cell

cancer has been reported.[67][68][69] This is associated with a mutation in the

fumarate hydratase which is located on the long arm of  chromosome 1 (1q42.3-43).

Inheritance is autosomal dominant.

This syndrome is described in greater detail on the page  Hereditary leiomyomatosis

and renal cell cancer. 

Prognosis[edit] 

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. Most pathologists believe that a

Leiomyosarcoma is a de novo disease[citation needed 

].

Metastasis[edit] 

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.[77]

•  In leiomyoma with vascular invasion, an ordinary-appearing fibroid invades into a

vessel but there is no risk of recurrence.

•  In Intravenous leiomyomatosis, leiomyomata grow in veins with uterine fibroids as

their source. Cardiac involvement can be fatal.

•  In benign metastasizing leiomyoma, leiomyomata grow in more distant sites such

as the lungs and lymph nodes. The source is not entirely clear. Pulmonary

involvement can be fatal.

In disseminated intraperitoneal leiomyomatosis, leiomyomata grow diffusely on the

peritoneal and omental surfaces, with uterine fibroids as their source. This can

simulate a malignant tumor but behaves benignly.