Uterine fibroids and their treatment
Uterine Fibroids (UFs)
(Uterine leiomyoma, myoma,
What are Uterine Fibroids (UFs)?
usually multiple TUMORS originate from and
are composed of SMOOTH MUSCLE cells
(myocytes) of the
uterine wall’s muscle layer
(myometrium, the middle layer of the uterine wall used for
contracting the uterus)
its accompanying connective tissue;
It is rare for uterine
leiomyomas to progress to leiomyosarcomas
(1.7 women per 100,000 women are diagnosed annually with
uterine sarcoma, which includes leiomyosarcoma)
National Cancer Institute
Vary in size - from microscopic to very large (can weigh several pounds).
Fibroids are often described by their location in
Myometrial - in
the muscle wall of the uterus
just under the surface of the uterine lining
- just under the outside covering of the uterus
occurring on a long stalk on the outside of the uterus or inside the cavity of
Called DIFFUSE uterine leiomyomatosis -
when there are too
many fibroids to count.
Diagnosis can be wrong - pelvic
examination may show an irregularly shaped, lumpy, or enlarged uterus, but in
obese women it is difficult to diagnose fibroids, which may be mistaken for:
Inflammation of the fallopian tubes
Uterine adenomyosis (a
condition in which the uterine lining grows into the muscle wall of the uterus)
Fibroids can be confirmed -
by a transvaginal ultrasound, ar pelvic
ultrasound or a pelvic MRI .
Who gets Uterine Fibroids (UFs)?
UFs are the most common pelvic tumor in females,
typically found during the mid- to late-reproductive years
Uterine fibroid incidence
rate is 70% by age 50 in U.S. white women and 80% in African-American women -
with a staggering half of reproductive age U.S. women having fibroids. Typically affects women over 30, but not under 20;
Baird DD, Dunson DB, Hill MC, et al. High cumulative incidence of uterine
leiomyoma in balack and white women: ultrasound evidence. Am J Obstet Gynecol
2003; 188: 100-107
More common in
African-American women than Caucasian
women - ~25% of white women and 50% of black women have
symptomatic uterine fibroids.
Palmer, J., Bernard, H., Stewart, E., Rosenberg, L., (2005) Age-Specific
Incidence rates for Self-Reported Uterine Leiomyomata in the Black Women’s
Health Study Obstet Gynecol 105(3): 563-568
More common in overweight
because of increased
from adipose aromatase enzyme
activity that converts the androgens
ANDROSTENEDIONE and TESTOSTERONE to
UFs often have a
growth spurt before menopause – and then become
Higher UF incidence in women who have not given
birth or had early menarche or have a UF history in first degree relatives
Smokers have LESS
risk of UFs
seems to protect against having UFs
Flake GP, Andersen J, Dixon D.
Review Etiology and pathogenesis of uterine leiomyomas: a review. Environ Health
Perspect. Environ Health Perspect. 2003 Jun; 111(8):1037-54.
Baird DD, et al. (2007)
Association of physical activity with
development of uterine leiomyoma.
Am. J. Epidemiol.
Properties /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
described as hyaline, myxomatous, calcific, cystic, fatty, red
(usually only during pregnancy), or necrotic.
Fibroid growth seems to depend on both
maintain that serum
PROGESTERONE levels are unchanged by
UFs - however, these serum levels are only
meaningful if their free levels
have been measured, which is not usually the case.
Fibroid cells can
make their own
and have more estrogen
receptors (to respond to these hormones) than normal uterine muscle cells
seems to have a dominant role by INCREASING mitotic rates in fibroids in the
secretory phase of the menstrual cycyle - The PROGESTERONE
antagonist mifepristone INHIBITS fibroid growth lending support to the
dominant role of PROGESTERONE . 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. 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 fall of PROGESTERONE
higher levels of
– the enzyme which
catalyzes conversion of
Walker CL, Stewart EA Uterine fibroids: the elephant in the room. Science. June
10, 2005; 308.
LEPTIN (the “appetite suppressor” hormone) has also been shown to
Estrogen Dominance -
a dominance of
estrogen over other hormones
is a recognized problem of today, due to dietary and environmental changes.
receptors, fibroids tend to enlarge during the
reproductive years and shrink after menopause
excessive production of disorganized but very stable extracellular matrix
(ECM) / Altered collagen fibrils –
collagen fibers are short,
widely dispersed and lying non-parallel in fibroids, compared to well-packed and
lying parallel in the myometrium. 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.
The stability of this allbeit disorganized ECM
requires therapeutic interventions that address ECM dissolution in addition to
inhibiting cell proliferation
UFs involve growth factors:
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
factors acting on myometrial cells
– epidermal growth factor (EGF), Insulin-Like Growth
Factor (IGF), platelet-dericed growth factor (PDGF), vascular endothelial growth
Increased profibrotic cytokines
(E.g. IL-1, IL-6, interferon, Tumor Necrosis Factor-α (TNF- α )) - Cytokines
involved with inflammatory response are changed in UFs, 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
Integrins are changed in UFs
>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.
Organochlorine pesticides stimulate
leiomyomata cell proliferation in animals –
in the body
Hodges LC, Bergerson JS, Hunter DS, Walker CL. Estrogenic effects of
organochlorine pesticides on uterine leiomyoma cells in vitro.
Toxicol Sci. 2000 Apr;54(2):355–364.
Symptomatic Uterine Fibroids
When fibroids are symptomatic, they can grow and
Heavy and painful menstruation; bleeding
between periods; longer-lasing periods
Painful sexual intercourse
Urinary frequency and urgency
Pelvic pain / pressure;
Abdominal fullness, gas, constipation
Pregnancy complications (rare) –
increased blood flow and ESTROGEN levels during pregnancy may cause UFs to grow,
but return to normal size after delivery. Insufficient room in uterus may
require early delivery; C-section may be needed if UFs block birth canal or
cause wrong positioning of baby; may cause heavy bleeding immediately after
Other complications of fibroids include:
A pedunculated fibroid can become twisted and
cause a kink in the blood vessels feeding the tumor - may need surgery;
Anemia - may be
severe with heavy bleeding
Urinary tract infections -
pressure from the fibroid can prevent bladder emptying fully;
(extremely uncommon) – called a leiomyosarcoma.
Generally accepted effects of Estrogen
Mitogenic effect on
leiomyoma cells –
Act by influencing (directly and indirectly) a large
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).
It is believed that:
growth-promoting by up-regulating
thought to promote the growth
of leiomyoma via up-regulation of
TGF-β1 and TGF-β3
thought to promote the survival
of leiomyoma via up-regulation of
expression and down-regulating
is thought to counteract growth
of leiomyoma by downregulating IGF-1.
interacting factor (TGIF)
is increased in
leiomyoma compared with myometrium
TGIF is a potential
repressor of anti-proliferative
TGF-β pathways in myometrial
Cytokines – signaling molecules secreted by nervous system glial cells and
many immune system cells for intercellular communication.
expression of the anti-apoptotic factor
Apoptotic factors -
PDGF, promotes aberrant survival of leiomyoma cells by down-regulating
the tumor-suppressor protein
modulated by the “cross-talk” between themselves and
which controls the expression of their
respective nuclear receptors.
In PREmenopausal fibroids the
PROGESTERONE receptors are found
compared to only
in POSTmenopausal fibroids (which are rare)
Strissel, P.; Swiatek, J.; Oppelt, P.; Renner, S.; Beckmann, M.; Strick, R.
(2007). "Transcriptional analysis of steroid hormone receptors in smooth muscle
uterine leiomyoma tumors of postmenopausal patients". The Journal of Steroid
Biochemistry and Molecular Biology
107 (1-2): 42–47. .
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, A.; Salama, S.
(2006). "Ethnic distribution of ESTROGEN receptor-α polymorphism is associated
with a higher prevalence of uterine leiomyomas in black Americans". Fertility
and Sterility 86 (3): 686
17ß-hydroxysteroid dehydrogenase are aberrantly expressed in fibroids -
indicating that fibroids
can convert circulating
androstenedione into ESTRADIOL
M.; Murakami, K.; Inoue, M. (2004). "Aromatase and Leiomyoma of the Uterus".
Seminars in Reproductive Medicine 22 (1): 51.
Aromatase over-expression in uterine leiomyoma
tissue is particularly pronounced in African-American women
Ishikawa, H.; Reierstad,
S.; Demura, M.; Rademaker, A. W.; Kasai, T.; Inoue, M.; Usui, H.; Shozu, M. et
al. (2009). "High Aromatase Expression in Uterine Leiomyoma Tissues of
African-American Women". Journal of Clinical Endocrinology & Metabolism 94 (5):
Rarely, leiomyomas progress to leiomyosarcomas
and evolve to a hormone-non-responsive state - since
many sarcomas have markedly reduced or
no steroid hormone receptors