GSE
Uterine fibroids and their treatment
Estrogen
and
Progesterone generally promote uterine
fibroid growth
It's the "free" hormone levels that count
Some researchers
maintain that serum
estrogen
and
Progesterone levels are unchanged by
UFs - however, these serum levels are only
meaningful if their free
Overall effects of
Estrogen and
Progesterone :
i) Mitogenic effect on
leiomyoma cells. Encourages
cell division/mitosis;
ii) Act by influencing (directly and indirectly)
a large
number of growth factors. Usually a protein or steroid hormone capable of stimulating
cellular growth, proliferation and cellular differentiation (less specialized
cell becomes a more specialized cell type).
Estrogen
Dominance.
A dominance of
estrogen over other hormones
is a recognized problem of today, due to dietary and environmental changes.
ESTROGEN
Dominance
Effects of
estrogen on uterine fibroid growth
Fibroids make a lot of
estrogen
Fibroid cells can
make their own
ESTRADIOL and the conversion enzymes to make it
are over-expressed in fibroids -
Fibroids express
higher levels of
aromatase
and
can convert circulating
androstenedione into
ESTRADIOL
via the enzymes
Aromatase and
17ß-hydroxysteroid dehydrogenase
(Walker
& Stewart, 2005;
Shozu, 2004 )
Aromatase over-expression in uterine leiomyoma
tissue is particularly pronounced in African-American women
(Ishikawa et al, 2009) LEPTIN (the "appetite suppressor" hormone) has also been shown to
increase
aromatase expression
Fibroids have a lot of
Estrogen receptors
Fibroid cells have more estrogen
receptors (to
respond to estrogen)
than normal uterine muscle cells
Having
estrogen receptors, fibroids tend to enlarge during the
reproductive years and shrink after menopause
- In PREmenopausal fibroids the
ER-ß,
ER-α (and
Progesterone) receptors are found
over-expressed -
compared to only
ER-ß in POSTmenopausal fibroids (which are rare)
(Strissel et al, 2007)
A special
ER-α
genotype was found correlated with incidence and
size of fibroids -
Higher prevalence of this genotype in black women may also explain higher
incidence of fibroids in Afro-American women. Most studies found that other
different phenotypes in
ER and
Pr gene encodings are not correlated with
incidence of fibroids in Caucasian populations
(Alhendy, 2006)
Believed that
Estrogen is
growth-promoting by up-regulating:
IGF-1 ,
EGFR ,
TGF-β1 - Expression of transforming growth
interacting factor (TGIF) is increased in
leiomyoma compared with myometrium (In myometrial cells,TGIF is a potential
repressor of anti-proliferative TGF-β pathways).Cytokines - signaling molecules secreted by nervous system glial cells and
many immune system cells for intercellular communication. Apoptotic factors -
TGF-ß3 and
PDGF, promotes aberrant survival of leiomyoma cells by down-regulating the
tumor-suppressor protein p53.
Other hormones
Effects of Progesterone
on uterine fibroid growth
Uterine fibroids have more Progesterone receptors (to respond to
Progesterone) than normal uterine muscle cells.
Progesterone is thought to
promote the growth
EGF ,
TGF-β1 and TGF-β3Progesterone is
thought to promote the survival
of leiomyoma via up-regulation of
Bcl-2
expression and down-regulating
TNF-α .Progesterone is thought to counteract growth
of leiomyoma by downregulating IGF-1.
A recent study emphasized the anomaly whereby
>72% of women who were pregnant (or recently postpartum) have > 50% regression
of pre-existing fibroids - One explanation points to the postpartum fall
of Progesterone .
Progesterone
seems to have a dominant role by
INCREASING mitotic rates in fibroids in the
luteal phase of the menstrual cycyle (2nd
half of cycle when corpus luteum secretes a lot of Progesterone) -
the drug mifepristone, a
Progesterone antagonist,
INHIBITS fibroid growth lending support to Progesterone's dominant role. One theory is
that Progesterone upregulates EGF and TGF-β expression. However,
Progesterone also REDUCES the growth
factor IGF-1 in vitro and INHIBITS MMPs, which activate growth factors and
degrade extra cellular matrix (ECM), affecting ECM assembly and deposition, and
so counters UF enlargement .
Other notes
Actions of
estrogen
and
Progesterone are
modulated by the "cross-talk" between themselves and
PROLACTIN - which controls the expression of their
respective nuclear receptors.
Rarely, leiomyomas progress to leiomyosarcomas
and evolve to a hormone-non-responsive state - since
many sarcomas have markedly reduced or
no steroid hormone receptors
References
Alhendy, A.; Salama, S.
(2006). "Ethnic distribution of ESTROGEN receptor-αpolymorphism is associated
with a higher prevalence of uterine leiomyomas in black Americans". Fertility
and Sterility 86 (3): 686
PubMed
Shozu,
M.; Murakami, K.; Inoue, M. (2004). "Aromatase and Leiomyoma of the Uterus".
Seminars in Reproductive Medicine 22 (1): 51.
PubMed
Strissel, P.; Swiatek, J.; Oppelt, P.; Renner, S.; Beckmann, M.; Strick, R.
(2007). "Transcriptional analysis of steroid hormone re ceptors in smooth muscle
uterine leiomyoma tumors of postmenopausal patients". The Journal of Steroid
Biochemistry and Molecular Biology 107(1-2): 42-47. .
PubMed
