GSE
Uterine fibroids and their treatment
Causes of
Uterine Fibroids (UFs)
During a woman's menstruating years, UFs
typically continue to grow slowly
Large fibroids may outgrow their blood supply and
degenerate - described as hyaline, myxomatous, calcific, cystic, fatty, necrotic or red
(usually only during pregnancy).
Fibroid growth seems to depend on both
estrogen
and
Progesterone
hormones
Effects of Estrogen
and Progesterone in Uterine FIbroids
UFs have altered collagen fibers
UFs have
excessive production of a disorganized but stable extracellular matrix
(ECM) and
altered collagen fibrils
in the ECM - fibroid collagen fibers (bunches of fibrils) are short,
widely dispersed and lying non-parallel, compared to well-packed and
lying parallel in the myometrium (smooth muscle tissue of the uterus).
It is the abnormal and overproduced ECM that causes UF expansion ,
and not the slowly proliferating fibroid cells - UF tumors contain decreased/disrupted matrix metalloproteinases (MMPs)
and more proteins in their ECM, such as collagen subtypes, proteoglycans,
fibronectin, matrix glycoproteins and matricellular proteins (in particular
thrombospondin-1 (TSP-1), which activates
TGF- β and has a role
in angiogenesis). The ECM binds cytokines and growth factors ready for action in
the vicinity of the UF. Integrins are changed in UFs
- The stability of this allbeit disorganized ECM
requires therapeutic interventions that address ECM dissolution in addition to
inhibiting cell proliferation
UFs involve growth factors:
- Transforming Growth
Factors-β1 and β3 (TGF- β1,TGF- β3) - have a central role in UF enlargement, in that they stimulate
production/deposition of ECM and are acknowledged as important growth factors in
fibrotic disease. E.g. Fibroids have more concentrated TGF-β receptors.
Conversely, reduced TGF-β expression
yields reduced ECM production and fibroid shrinkage
- Other growth
factors acting on myometrial (uterine smooth
muscle) cells
- epidermal growth factor (EGF), Insulin-Like Growth
Factor (IGF), platelet-derived growth factor (PDGF), vascular endothelial growth
factor (VEGF)
Increased profibrotic cytokines
(E.g. IL-1, IL-6, interferon, TNF- α)
in UFs
-
involved with inflammatory response, cytokines are produced when growth
factors act on target tissue.
UFs grow at different rates (even in the same
woman) - and with different growth-rate patterns in white and African-American
women
>50% of UFs are asymptomatic
(i.e. have no symptoms) -
~70% of women by age 45 will be diagnosed
with UFs, but only a fraction of those
will cause problems or require treatment. ( Merck Manual)
Organochlorine pesticides stimulate
leiomyomata cell proliferation in animals - organochlorines are
xenoestrogens
(i.e. mimic
estrogen
in the body). (Hodges et al, 2000)
References
Hodges LC, Bergerson JS, Hunter DS, Walker CL. (2000 Apr) Estrogenic effects of
organochlorine pesticides on uterine leiomyoma cells in vitro. Toxicol Sci. ;54(2):355-364.
PubMed
Walker CL, Stewart EA (June 10, 2005) Uterine fibroids: the elephant in the room. Science. ; 308.
