Aetiology and pathogenesis

Fibroids are monoclonal tumors, approximately 40 to 50% show karyotypically detectable chromosomal

abnormalities. When multiple fibroids are present they will usually have mostly unrelated genetic defects. Exact

aetiology is not nearly understood, 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-American descent, nulliparity, obesity, polycystic ovary syndrome, diabetes and hypertension.[7]

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 will 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 estrogen and

theoxytocin receptor.[8]

It is believed that estrogen and progesterone have both 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 is growth promoting by up-regulating IGF-1, EGFR, TGF-beta1, TGF-beta3 and PDGF, 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 the survival through up-regulating Bcl-2 expression and

down-regulating TNF-alpha. Progesterone is believed to counteract growth by downregulating IGF-1.[9][10]

[11]
 Expression of transforming growth interacting factor (TGIF) is increased in leiomyoma compared with myometrium.
[12]
 TGIF is a potential repressor of TGF-β pathways in myometrial cells.[12]

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.[13] Most studies found that

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

populations [14][15] 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.[16]

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.[17] PPAR-

gamma agonists may also counteract leiomyoma growth by several other mechanisms of action such as TGF-beta3

expression inhibition.[18]
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.[19][20]

Aromatase and 17beta-hydroxysteroid dehydrogenase are aberrantly expressed in fibroids, indicating that fibroids

can convert circulating androstenedione into estradiol. [21] Similar mechanism of action has been elucidated

in endometriosis and other endometrial diseases. [22] 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 [23]

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.[24]

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.[25] Several factors indicate significant

involvement of extracellular signaling pathways such as ERK1 and ERK2, which in fibroids are prominently influenced

by hormones.[26] Paradoxically and unlike most other conditions involving significant fibrosis the Cyr61 gene has been

found downregulated in fibroids.[27]

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. [27]

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. However fast growth or unexpected growth such as enlargement of

a lesion after the 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.[31] 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.

They are of two types.

 The leiomyoma occurs in the skin or gut but the common form is the uterine fibroid.

 Rhabdomyomas are rare tumors of muscles, they occur in childhood and often become malignant.