REVIEW / SYNTH~SE

Pathophysiology of uterine leiomyomas

Laval University Hospital Research Center and Department of Obstetrics and Gynecology, Laval University,
2705 Blvd. Laurier, Ste. Foy, Quk., Canada Gl V 4G2
Received September 20, 1991
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KOUTSILIERIS,
M. 1992. Pathophysiology of uterine leiomyomas. Biochem. Cell Biol. 70: 273-278.
Uterine leiomyomas is the most common benign neoplasia in women, one of the most frequent causes of infertility
in reproductive years, and the leading cause for hysterectomy. The pathophysiology of uterine leiomyomas is uncertain.
Therefore, therapeutic approaches have been primarily empirical. It is now well documented that growth factors control
the functional and possibly the histological integrity of several tissues. Recently the presence of growth substances in
uterine tissues suggested that the role of sex steroid hormones in the pathophysiology of leiomyomas may be mediated
by substances influencing the proliferation of smooth muscle cells and fibroblasts. This report summarizes the data
related to the pathophysiology of leiomyomas, which indicate a possible role of growth factors in uterine leiomyomas.
Key words: leiomyomas, growth factors, uterus, smooth muscle cells, fibroblasts.
KOUTSILIERIS,
M. 1992. Pathophysiology of uterine leiomyomas. Biochem. Cell Biol. 70 : 273-278.
Le ltiomyome uttrin est la ntoplasie bknigne la plus commune chez les femmes, l'une des causes les plus frtquentes
d'infertilitt au cours des anntes de reproduction et la principale cause d'hysttrectomie. La pathophysiologie des
ltiomyomes uttrins est ma1 connue. Les premitres approches thtrapeutiques ont donc t t t empiriques. Nous savons
bien maintenant que des facteurs de croissance contr6lent I'integritt fonctionnelle et probablement histologique de
plusieurs tissus. Rhmment, la presence de facteurs de croissance dans les tissus utkrins a suggbt que le r6le des hormones
sexuelles sttroi'diennes dans la pathophysiologie des ltiomyomes pourrait s'exercer par l'intermkdiaire de substances
For personal use only.

influen~antla proliftration des cellules musculaires lisses et des fibroblastes. Nous rksumons ici des donntes relatives
5 la pathophysiologie des ltiomyomes qui montrent le r6le possible de facteurs de croissance dans les lkiomyomes uttrins.
Mots elks : lleomyomes, facteurs de croissance, utbus, cellules musculaires lisses, fibroblastes.
[Traduit par la rtdaction]

Introduction years where first pregnancies are delayed beyond age 30

Leiomyomas are common, benign tumors which may
occur at any anatomical location containing smooth muscle
cells (Marshall et al. 1960). Most of these tumors originate
in the female genital tract, and in particular, in the uterus
(Marshall et al. 1960; Farman 1975). Approximately 28 cases
of leiomyomas of the female urethra (Fry et al. 1988) and
200 cases of leiomyomas of the bladder (Kabalin et al. 1990)
have been reported in the world literature. Although uterine
leiomyoma is the most common solid tumor in women, very
little is known regarding its etiology. It is estimated that 20%
of all women over the age 35 have leiomyomas (Novak and
Woodruff 1979). Other studies suggested that uterine
leiomyomas are more common among black and nulliparous
women (Novak and Woodruff 1979). A recent study analys-
ing data from gross serial sectioning at 2-mm intervals in
100 consecutive hysterectomies adjuncted to routine pathol-
ogy concluded that epidemiological studies may not be valid,
if they are based only on clinical diagnosis or routine
pathology reports (Cramer and Pate1 1990). Therefore, the
real incidence of uterine leiomyomas remains unknown.
Despite this, leiomyomas arise most often during the third
and fourth decades of life and have an important impact
upon reproductive performance. The social trend in recent
ABBREVIATIONS:G-6-PD, glucose-6-~hos~hate dehydrogenase;
17b-HSD9 17b-h~dr0x~ster0iddeh~drOgenase; GnRH-A,
gonadotropin-releasing hormone analogs; LH, luteinizing
hormone; kDa, kilodalton(s); EGF, epidermal growth factor; IGF.
insulin-like growth factor; IGFBP-I, IGF-binding protein-l;
PDGF-A, plateletderived growth factor A; bFGF, basic fibroblast
growth factor.
Printed in Canada / Imprime au Canada
could increase the relative frequency of leiomyomas
(Buttram 1986).
Leiomyomas themselves are relatively avascular and
tightly compacted tumors of smooth muscle cells and
fibroblasts. Usually they are surrounded by a pseudocapsule
of alveolar tissue and have two large vessels to nourish the
tumor (Buttram 1986). In certain cases, extensive
extramedullary haemopoietic sites in degenerating
leiomyomas (Schmid et al. 1990) and histiocytes in
leiomyomas in densities higher than in adjacent normal
myometrium (Adany et al. 1990) were described. The poten-
tial significance of these observations for the pathophys-
iology of the disease is at the present time unclear.
Leiomyomas tend to be multiple and slow growing (Buttram
1986). Most patients who have small leiomyomas are asyrnp-
tomatic, but the leiomyomas range in size and can extend
to giant tumor masses that fill the pelvic and abdominal
cavities. The intramucosal location and submucosal varieties
are associated with the greatest influence upon reproduc-
tive capabilities. Since all leiomyoma cells are of identical
G-6-PD electrophoretic type, the tumor is considered of
unicellular origin, although the (3-6-PD type may vary from
one tumor to another within the same uterus (Townsend
et al. 1970).
~ecentl;leiomyomas have been reported to bear tumor-
specific chromosome aberations, although the majority of
them (50-80%) are of normal karyotype (Nibert and Heim
1990). There have been four cfiogenetically
subgroups identified as rearrangements of 6p, del(7) (q21.2
q31.2), + 12, and t(12;14) (q14-15; q23-24). Few cfiogenetic
similarities so far have been detected between leiomyomas
 274 BIOCHEM. CELL
and malignant smooth muscle tumors (leiomyomas and
rhabdomyosarcomas), but the leiomyoma cytogenic profile
has been strikingly similar to lipoma. Similarities existing
between leiomyomas and pleomorphic adenomas of the
salivary gland and with myxoid liposarcomas have been
reported (Nibert and Heim 1990). Leiomyoma is rarely
associated with benign-appearing smooth muscle tumors in
sites such as lungs and lymph nodes. In the gynecologic lit-
erature this was referred to as benign metastasizing
leiomyomas (Hartz and Hugenholtz 1942; Clark and Weed
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1977). It was suggested that either the primary lesion is a
low-grade sarcoma with malignant potential or this is the
"end-stage" of intravenous leiomyomatosis (Spiro and
McPeak 1966; Wolff et al. 1979). The multifocal origin of
these tumors was proposed also (Cho et al. 1989). In pathol-
ogy, mitotic indices have proven to be highly effective in
predicting the courses of smooth muscle tumors of the
uterus, but metastasizing smooth muscle tumors with low
mitotic indices and histologic appearance of ordinary
leiomyomas were reported (Hartz and Hugenholtz 1942).
In addition, mitotic activity of leiomyomas was reported to
be significantly influenced by the hormonal milieu suggesting
that (i) the growth of leiomyomas is affected by sex steroid
hormones, and (ii) mitotic indices must be evaluated within
the context of the phase of the menstrual cycle before it can
be determined whether a smooth muscle cell tumor is malig-
For personal use only.
nant (Kawaguchi et al. 1989).
Pathogenesis of uterine leiomyomas
Enzymatic implications
Cytochrome P-450 serves a vital role as the terminal
oxidase in the microsomal monooxygenase hydroxylation
reaction of a wide variety of xenobiotics including drugs and
carcinogens, as well as endogenous substrates such as steroid
hormones. Recently sensitive spectrophotometric assays
have detected significantly higher cytochrome P-450 activity
in leiomyoma than adjacent myometrium. This was pro-
posed to be part of the pathogenetic mechanisms involved
in the pathophysiology of leiomyomas (Senler et al. 1985a,
19856).
In addition, the 170-HSD activity in leiomyomas did not
follow the significant increase of enzymatic activity detected
after ovulation as normal myometrium of the same uterus
(Eiletz et al. 1980). The moderate increase of the 170-HSD
levels after ovulation and the low progesterone receptor
binding sites detected in leiomyomas was suggestive for a
possible multiple defect of sex steroid hormone metabolism
which, in turn, may be causatively linked to the pathogenesis
of the disease.
Other studies (Herrmann et al. 1987) reported that the
specific activity (activity per unit tissue mass) of enzymes
involved in the carbohydrate metabolism (hexokinase,
phosphofructokinase, lactase dehydrogenase, and glucogen
phosphorylase) is not different in leiomyoma tissues when
compared with normal adjacent myometrium. The same was
true for the specific activity of enzymes involved in tricar-
boxylic acid cycle (succinate dehydrogenase), but significant
differences were detected in the specific activity of enzymes
involved in fatty acid oxidation (hydroxyacetyl-CoA dehy-
drogenase). The latter observation suggested that increased
fatty acid utilisation by leiomyomas may be related to
increase growth potential of this tissue (Herrmann et al.
1987).
BIOL. VOL. 70, 1992
TABLE1. Pathophysiology of leiomyomas
Enzymatic involvement
Higher cytochrome P-450 activity (Senler et al. 1 9 8 5 ~ 19856)
.
Lower tissue levels of glutathionine (Basu et al. 1988)
Lower levels of p-carotene (Palan et al. 1988)
Lower tissue aromatase activity (Folkerd et al. 1984)
Higher levels of hydroxyacyl-COA dehydrogenase (Herrmann
et al. 1987)
Also decreased tissue levels of reduced glutathione (Basu
et al. 1988) and 0-carotene (Palan et al. 1988), as well as
decreased aromatase activity (Folkerd et al. 1984), was
reported in leiomyoma tissue. These findings were compati-
ble with a direct or indirect enzymatic involvement with the
metabolic defects underlining the presence of leiomyomas
(Table 1). The question is whether these findings are
causatively linked with leiomyomas or are the direct result
of such pathology.
Hormonal implications
Cell division, differentiation, and growth of uterine tissues
are based on the well-orchestrated secretion of sex steroid
hormones by the ovaries. The biological activity of these
hormones depends on their specific interaction with specific
binding proteins inside the cell. These proteins are referred
to as receptors. The tendency of uterine leiomyomas to grow
during the reproductive years and to regress post-
menopausally suggested that sex steroid hormones may be
implicated in the pathophysiology of the disease. This obser-
vation led to the initial hypothesis that women bearing such
tumors would either have altered serum sex steroid hormone
levels or increased sex steroid hormone activity in the tumor.
However, serum levels of sex steroid hormones in women
with leiomyomas were similar to those of normal women
(Buttram 1986).
The concentration of tissue levels of estradiol, estrone,
and progesterone in normal myometrium was studied during
menstrual cycle and was found to be similar to serum con-
centrations, except for higher levels of tissue estrone in the
luteal phase and of 170-HSD activity during the early
secretory phase (Eiletz et al. 1980). Other studies detected
an increase in intramyoma estrogen concentration (estradiol
levels), resulting presumably from inadequate conversion of
estradiol to estrone (Pollow et al. 1978). This was explained
by a moderate increase of the 170-HSD activity in
leiomyoma tissues, as compared with normal myometrium,
which was also compatible with the lower levels of estrone
reported in leiomyoma tissues (Eiletz et al. 1980). The assess-
ment of estrogen receptor content in leiomyomas with
respect to normal myometrium revealed conflicting data,
such as (i) altered but not significantly higher content
(Otsuka et al. 1989), (ii) not different in content (Sadan et al.
1988), (iii) not different in content and moreover similar
regulation of the estrogen receptor by cyclic changes during
the menstrual cycle (Soules and McCarty 1982), and (iv) sig-
nificantly higher content (Tamaya et al. 1985). At this point
the progesterone receptor (which is induced by estrogens in
uterine tissues) was implicated in the pathogenesis of the
disease. Again the number and (or) the regulation of pro-
gesterone receptor content throughout the menstrual cycle
in leiomyomas, as compared with normal myometrium,
revealed conflicting data; i.e., (i) normal (Buchi and Keller
 TABLE2. The effect of GnRH-analogs on leiomyomas

Uterine leiomyomas shrink up to 50% of their initial volume within 3-4 months
of commencing therapy (Healy 1991)
Tumors re-enlarge back to their original size 6-12 months after commencement
of therapy (Healy 1991)
There is a significant reduction in cellularity but there are no significant changes
in fibrosis, edema, and mitotic activity (Upadhyaya et al. 1990)
Estrogen deprivation is causing hypoplasia but not cell death of smooth muscle
cell (Healy 1991)
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Estradiol, estrone, and estradiol plus estrone sulfate tissue levels are decreased
(Pasqualini et al. 1990)
Progesterone receptor content is decreased (Pasqualini et al. 1990)
Short-term recurrence of leiomyomas is increased in women receiving GnRH-A
therapy before myomectomy (Fedele et al. 1990)

TABLE3. The possible role of growth factors and growth factor receptors in the
physiology and pathophysiology of uterus

Animal tissues
Estromedins (Sirbasku 1978; Biro 1986)
Metastatic-stimulating activity from mouse uterus (Pantazis and Howard 1987;
Maharajan et al. 1988)
Rat-, rabbit-, bovine-, and porcine-derived growth factors (Simmen et al. 1988;
Beck and Garner 1989; Milner et al. 1989)
Estrogen-induced EGF in rat uterus (Gonzalez et al. 1984)
Human tissues
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EGF receptors in human leiomyomas (Lumsden et al. 1988)

Increased expression of mRNA for the PDGF-A chain in human myometrium
during pregnancy (Mendoza et al. 1990)
Human myometrium-derived (MDGE) and leiomyoma-derived growth factors
(LDGF) (Koutsilieris 1989, 1990)

1983; Soules and McCarty 1982; Sadan et al. 1990),
(ii) higher (Tamaya et al. 1985; Chrapusta et al. 1990; Vij
et al. 1990; Pasqualini et al. 1990; Benagiano et al. 1990),
and (iii) lower and not changing during the menstrual cycle
(Eiletz et al. 1980; Folkerd et al. 1984). Estrogen and pro-
gesterone receptor content was higher in Caucasian than in
Negroid patients (Sadan et al. 1988). This was suggestive
of a genetic predisposition and the fact that the estrogen and
progesterone receptor content could participate in the
pathophysiology of the disease (Sadan et al. 1990).
In addition, prostaglandin receptor content (E and F2a)
was reported to be lower in leiomyomas than in normal
myometrium (Hoffmann et al. 1984), suggesting relative
insensitivity to the biological actions of prostaglandins. The
prostaglandin insensitivity and estrogen hyperreactivity were
proposed to be possible causes for the pathogenesis of the
disease (Hoffmann et al. 1984).
Recently specific binding sites for GnRH-A were
documented in leiomyomas, suggestive of a possible direct
effect of GnRH-A on tumor growth (Wiznitzer et al. 1988).
GnRH-As have effected regression of uterine leiomyomas
through a mechanism thought to be mediated by the inhibi-
tion of LH release and steroid synthesis (Maheux and Lemay
1988). Histopathologically, treatment with GnRH-A cor-
related with a significant reduction in cellularity of
leiomyomas, although no significant changes in fibrosis,
edema, or mitotic activity were reported (Upadhyaya et al.
1990). There is now agreement that uterine leiomyomas will
shrink to 50% of their initial volume within 3-4 months of
commencing treatment and that tumor will then re-enlarge
back to their original size anywhere from 6 to 12 months
after commencement of therapy (Table 2). The shrinkage
of the tumor appears to be estrogen mediated, causing
hypoplasia of smooth muscle, but not cell death (Healy
1991). GnRH-A treatment provoked a significant decrease
in tissue estradiol and in particular, estrone-S and estradiol-S
levels. Progesterone receptor content of leiomyomas was
decreased significantly after 3-4 months of GnRH-A treat-
ment (Pasqualini et al. 1990). The mean leiomyoma estrogen
content in women treated with GnRH-A was significantly
higher than in women receiving placebo. Clinically, the
significant increase in leiomyoma estrogen receptor may
account for the rapid regrowth of leiomyomas observed after
the cessation of GnRH-A therapy (Rein et al. 1990b). This
may also explain recent findings showing higher short-term
recurrence of uterine leiomyomas in women receiving
GnRH-A before myomectomy, thus limiting the efficacy of
surgery (Fedele et al. 1990). Therefore, the initial enthusiasm
for the potential use of GnRH-As in the therapy of
leiomyomas has subsided. Despite this, GnRH-As have
nevertheless provided further evidence for the implication
of sex steroids in uterine pathophysiology.
Although the influence of sex steroid hormones on the
growth of uterine leiomyomas is accepted, a good molecular
basis for the pathogenesis of the disease is lacking. It is also
unclear whether the preceding evidence of a steroid hormone
component in the pathophysiology of the disease is related
with the initiation of this pathology or would only promote
the growth of leiomyomas, which may have been initiated
by another mechanism.
Growth factor implications
The remarkable increase of tissue by in vivo treatment
with estrogens is a well-known response of estrogen-target
 BIOCHEM. CELL BIOL. VOL. 70, 1992

TABLE
4. IGF-1, IGF-11, IGFS receptors, and IGFBPs in uterine physiology and
pathophysiology
Estrogen-induced IGF-I and -11 mRNA is expressed in rat uterus (Murphy and
Friesen 1988; Murphy et al. 1988; Murphy and Ghahary 1990)
Estrogen-induced IGF-I and -11 mRNA is expressed in pig uterus (Simmen et al.
1990; Ogasawara et al. 1989)
Type I IGF receptor is expressed in rat uterus (Ghahary and Murphy 1989)
Diminishing volumes of leiomyomas in women treated with GnRH-As correlated
well with decreasing IGF-I and -11 levels in explant cultures of these tissues
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(Rein et al. 1990a)

IGFBP mRNAs are expressed in uterine tissues (Croze et al. 1990)

organs. A 5- to 10-fold increase of pituitary gland and a
2- to 5-fold enlargement of mammary and uterus tissues are
normal consequences of estrogen treatment. Depending on
the dose and duration of estrogen administration, uterine
mass may be increased by hypertrophy (increase in cell
mass), hyperplasia (increase in cell number), or both.
Estrogens stimulate protein synthesis in vivo and in vitro,
but a clear demonstration of their effects in vitro is very
limited compared with their in vivo mitogenic effects (Biro
1986). Therefore, it is conceivable local regulators could
indirectly mediate steroid hormone actions to be implicated
(Pollard 1990). Estromedins are the best example of this
concept (Sirbasku 1978; Biro 1986), and have been proposed
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of this binding protein either to increase or to inhibit the
action of IGF-I in various bioassay systems suggested that
IGFs and IGFBPs could be implicated in various patho-
physiological processes in the uterus (Murphy and Ghahary
1990).
The possible involvement of growth factors in the
pathophysiology of uterus was further advanced by studies
reporting increased expression of mRNA for the PDGF-A
chain gene. This was detected in smooth muscle cells of
human uterus during physiologic hypertrophy, which occurs
in the course of pregnancy (Mendoza et al. 1990; Boehm
et al. 1990). In addition, the presence of EGF receptor was
detected in mouse uteri (Brown et al. 1989) and human

as (i) mediators of estrogen action on target organs and
(ii) specific stimulators of estrogen-dependent cells or tissues
in an endocrine, paracrine, or autocrine manner. This con-
cept gave rise to the identification of several biologically
active peptides from uterine tissues (Table 3) such as
(i) metastasis-stimulating factors from mouse uterus
(Pantazis and Howard 1987; Maharajan et al. 1988); (ii) rat,
rabbit, and bovine uterus-derived growth factors that were
acid stable, heat labile, reduced by trypsin, and eluted at
molecular mass of 10-30 kDa by gel filtration (Beck and
Garner 1989); (iii) a 17-kDa heparin-binding growth factor
(HBGF-8) purified from bovine uterus similar to bFGF
(Milner et al. 1989); (iv) mitogens distinct from EGF, derived
from porcine uterus (Simmen et al. 1988); and (v) heparin-
binding growth factors derived from porcine uterus
(Bridstock et al. 1990).
Of special interest, in this context, is the group of IGFs
(Table 4). The inductive effect of estrogens on uterine IGF-I
mRNA in rat uterus was reported (Murphy et al. 1988;
Murphy and Friesen 1988; Norstedt et al. 1989) and was
related to authentic type I IGF receptor which was localized
in rat myometrial smooth muscle cells. The expression of
mRNA for type I receptor was also regulated by estrogens
(Ghahary and Murphy 1989), although similar effects of
steroid hormones on uterine IGF-I receptor expression in
the pig were not observed (Hofig et al. 1991). The expression
and the regulation of the IGF-I gene by estrogens and
progesterone were reported also in pig uterus (Simrnen et al.
1990), as well a truncated form of IGF-I was purified from
porcine uterus (Ogasawara et al. 1989). This truncated IGF-I
form was of high biologic activity for mesenchymal cell
types. In addition, decreasing levels of IGF-I and IGF-I1
were detected in explant cultures of leiomyoma and
myometrial tissues that were associated with diminishing
leiomyoma tumor volumes after treatment by GnRH-A
(Rein et al. 1990a). Interestingly, the expression of IGFBP-1
was detected in rat uterus (Croze et al. 1990). The capacity
uterine leiomyoma cells (Fayed et al. 1989). Furthermore,
estradiol-induced EGF in immature mice uteri (Gonzalez
et al. 1984) and binding sites of EGF were detected in the
human uterus (Lumsden et al. 1988). Leiomyoma receptors
for EGF in leiomyomas treated with GnRH-A were decreased
significantly compared with those in leiomyomas of non-
treated women (Lumsden et al. 1988). Human uterine
extracts were also documented to contain mitogens and
inhibitors of skin fibroblast growth (Koutsilieris 1989);
normal rat osteoblasts and osteoblast-derived osteosarcoma
cells (Koutsilieris 1989; Koutsilieris and Michaud 1990); and
myoblasts and smooth muscle cells (Koutsilieris 1990;
Koutsilieris et al. 1990). Preferential growth factors for
fibroblasts and smooth muscle were also detected in
leiomyoma extracts. These mitogen(s) were undetectable in
myometrial and endometrial extracts treated and processed
identically (Koutsilieris et al. 1990). These data provided
additional evidence for the validity of the concept involv-
ing locally acting growth factors in the regulation of human
myometrium and have supported the argument that locally
acting growth substances may be involved in human uterine
pathophysiology.
Finally, it appears that it will be important to assess the
role of certain members of the cell-cycle regulating genes
(cyclin family), one of which (PRADI cyclin-like gene) was
documented to be overexpressed in a benign parathyroid
tumor. This was the result of a chromosome rearrangement
that had placed cyclin gene under the control of a new pro-
moter (Motokura et al. 1991). Certainly this type of
approach could provide new insights in the pathophysiology
of benign tumors, suggesting new avenues of research.
Conclusions and future directions
It is now apparent that the uterus is a rich source of
growth factors involved in complex autocrine-paracrine
regulatory circuits, which in turn interact with sex steroid
hormones. Detailed studies of the appearance of these
 REVIEW /
growth factors and their receptors in leiomyomas and
myometrium during pregnancy and under different hor-
monal regimens have yet to be performed. It is presently
unclear whether estrogens or growth factors would initiate
the growth of leiomyomas, or would promote the growth
of these lesions initiated by another mechanism. Although
no causative role has been yet directly established for any
of the growth factors in uterine biology and patho-
physiology, current data provide strong evidence to support
such a pathophysiologically important function. Therefore,
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the study of the growth factor expression in leiomyoma
tissues and of their estrogen responsiveness is of fundamen-
tal importance in advancing our current knowledge for the
pathophysiology of uterine leiomyomas.
Acknowledgements
The author thanks his colleagues of the Department of
Obstetrics and Gynecology for their support in this project
and Mrs. L. Turcotte for excellent secretarial assistance.
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