The future of fibroid therapy
By Elizabeth A. Stewart, MD, and Adriana Faur, MD
While medical and surgical treatment are the mainstays
of therapy today, advances in molecular biology and genetics promise to
dramatically change the ob/gyn's approach to these common tumors.
Uterine leiomyomas, also known as myomas or fibroids, are an important
part of every gynecologist's practice. Traditionally fibroids are viewed
as a surgical disease and thus, hysterectomies, myomectomies, and an ever-increasing
array of minimally invasive techniques are used to relieve the symptoms
caused by myomas.
Research regarding the effects of the steroid hormones estrogen and progesterone
led to a new view of leiomyomas: that of steroid-hormone responsive neoplasms
(Figure 1). This work opened the way for medical treatments based on the
manipulation of steroid hormones, such as the use of GnRH agonist. Newer
drugs may make treatment of fibroids based on hormonal manipulation safer
and more effective.
Current research on the basic biology of leiomyoma cells (Figure 2),
as well as the normal myometrium from which it arises, will also lead to
new treatments. These future treatments may improve hormonal therapy or
provide entirely new ways of treating myomas. Viewing fibroids as tumors
with abnormal blood vessels, or as a genetic disease, may lead to radically
different approaches to these tumors in the future.
The present: fibroids and surgery
Uterine leiomyomas are the most common pelvic tumors in women, with a
clinical incidence of 20% to 25%. They are benign smooth-muscle tumors of
the uterus and cause a variety of symptoms for women, which lead them to
seek surgical therapy including hysterectomy, and alternatives to hysterectomy
including myomectomy. As alternatives to hysterectomy become more popular,
the limitation of conservative surgical therapy becomes evident: Although
surgical therapy is very successful in treating the symptoms caused by the
leiomyomas present at that time, it does not affect the underlying disease
process. New myomas continue to form and may cause additional symptoms and
even the need for additional surgery. Studies have indicated that up to
51% of women will have fibroids visible on transvaginal ultrasound 5 years
after an abdominal myomectomy, and that the risk of having a second surgery
appears to be between 15% and 26%.1,2 Thus, although surgical
therapy is effective in the short term, the long-term results are less satisfactory.
The present: medical treatment
Medical treatment for leiomyomas is also currently an option. All current
medical treatment for leiomyomas is based on the understanding that these
are steroid-responsive tumors. This concept grew out of a body of research
that demonstrated that leiomyomas were affected by the steroid hormones
estrogen and progesterone and that there were differences in their behavior
compared to normal myometrium. For example, the concentration of estradiol
was found to be significantly higher in myomas than in normal myometrium,
and the conversion of the more potent estradiol to the weaker estrone significantly
lower in myomas.3,4 Similar biochemical, pathologic, and clinical
evidence supports the role of progestins in leiomyoma growth.5 Thus,
since the gonadal steroid hormones estrogen and progesterone differentially
affect leiomyomas, medications that manipulate the levels of steroid hormones
are treatment options for leiomyomas.
GnRH agonists are widely used to treat uterine fibroids. GnRH agonists
create a hypogonadotropic hypogonadal environment, termed a "medical
menopause" because of the extreme suppression of both estrogen and
progesterone. This withdrawal of steroid hormones results in two major endpoints
that are useful in the treatment of myomas: induction of amenorrhea, which
thereby controls bleeding and secondly a significant reduction in uterine
size in most women, which in turn controls bulk-related symptoms. These
two benefits have been demonstrated in a number of studies.6
Although it is effective, GnRH-agonist therapy has three important limitations.6
First and most important, this therapy affects all estrogen-dependent tissues
and thus causes significant hypoestrogenic symptoms. Although symptoms such
as hot flashes and sleep disturbance can significantly limit patient acceptance
of the therapy, it is the effect on bone, that limits the duration of its
use and can lead to osteoporosis. Second, upon discontinuation of therapy,
there is rapid regrowth of the uterus, often to a size above pretreatment
levels. Finally, in a small proportion of women, vaginal hemorrhage can
be precipitated by this therapy.
Since leiomyomas are chronic or recurrent in nature, it would be advantageous
to modify therapy to allow more prolonged treatment or retreatment. Several
groups have addressed this problem by adding hormone replacement therapy
(HRT) or "add-back" regimens to GnRH-agonist therapy to make it
more acceptable in terms of bone loss and other adverse effects. The ideal
HRT regimen would prevent symptomatic side effects, prevent bone loss, cause
no significant adverse effects of its own, and not affect the clinical efficacy
of the GnRH agonist.
Some of the earliest attempts at add-back therapy used medroxyprogesterone
acetate on the hypothesis that estrogen was the important hormone governing
leiomyoma growth. Both studies showed that progestin started simultaneous
to the GnRH therapy inhibited the decrease in uterine and leiomyoma volume
seen with GnRH-agonist therapy alone.7,8
Further studies using a GnRH agonist with low-dose add-back estrogen
and progestin (equivalent to levels used for menopausal replacement) have
demonstrated that this approach retards bone resorption and decreases hypoestrogenic
symptoms without causing myoma growth. Studies have documented the efficacy
of this treatment for up to 2 years.9 Thus GnRH agonist with
add-back estrogen and progesterone therapy is one of the most frequently
studied medical therapies.
The future: innovative add-back
GnRH agonist with tibolone add-back is a newer alternative for medical
treatment. A synthetic steroid that exhibits estrogenic, progestational,
and androgenic activity, tibolone has been widely used outside the United
States for the treatment of menopausal symptoms. It appears to prevent postmenopausal
bone loss and reduce vasomotor symptoms without causing significant endometrial
or breast stimulation. Tibolone appears to provide the advantage of a decreased
incidence of bleeding at the start of therapy.10
Among postmenopausal women with myomas, those receiving tibolone were
more likely to become amenorrheic with the drug than with more conventional
HRT.11 A study of premenopausal women receiving tibolone with
GnRH agonist for the treatment of symptomatic fibroids did show that there
was no inhibition of uterine shrinkage with preservation of bone density,
symptomatic improvement, and improvement in lipid profiles compared to GnRH
agonist with placebo treatment.12 This might make long-term GnRH-agonist
therapy more acceptable to women with myomas.
The future: antagonists and receptor blockers
There are several new therapies based on the manipulation of steroid
hormone levels that may be useful in the future for treating leiomyomas.
First, GnRH antagonists have been shown in small studies to produce equivalent
levels of amenorrhea and uterine shrinkage to that seen with GnRH agonist.13,14
There are two clear advantages to GnRH-antagonist therapy compared to GnRH
agonist. First, the initial increase in estrogen seen with agonist therapy
is eliminated, and thus women are less likely to get an estrogen-withdrawal
bleed early in treatment. Secondly, the rapid shrinkage, seen over approximately
2 weeks, is a major advantage, especially when preoperative therapy is needed.
In addition to decreasing peripheral hormone levels through a central
action on GnRH, estrogen or progesterone antagonists may provide a different
route to block hormone action peripherally. Mifepristone, also know as RU-486,
is a steroidogenic molecule that acts in most circumstances as a progesterone
antagonist. In pilot studies, RU-486 has been shown to be effective in causing
equivalent uterine shrinkage and rates of amenorrhea to that seen with GnRH-agonist
therapy.15,16 The advantage of mifepristone is that normal levels
of estradiol are maintained and thus the symptoms of therapy are less and
the impact on bone is minimized.15 Estrogen antagonists may also
be useful, although there is currently no available data in this area.
The future: growth factor therapy
Many scientific studies have suggested that the effects of steroid hormones
are mediated through the local production of growth factors, small peptide
hormones that act locally on many cellular processes. Therefore, by looking
for differences in growth factor expression between leiomyomas and normal
myometrium, we may better understand the process by which leiomyomas grow
and cause symptoms. Although a number of growth factors are expressed differentially
in leiomyomas and normal myometrium, one factor appears central to the pathogenesis
of uterine leiomyomas: basic fibroblastic growth factor (bFGF). bFGF is
a factor important in the formation of new blood vessels, termed angiogenesis,
and thus provides a new way of thinking about fibroid treatment.
In most organs, angiogenesis is a pathologic process; it is important,
for example, in the pathogenesis of diabetic retinopathy and the growth
of malignant tumors. In the uterus, however, angiogenesis is crucial to
a nonpathologic process: menstruation. After every menstrual flow, new blood
vessels must be formed.
The concept that the arteries and veins are important in the pathogenesis
of leiomyomas and leiomyoma-related menorrhagia dates back almost 100 years.17
Injection of the blood vessels in the fibroid uterus showed an increase
in the number of blood vessels and a dilation of the veins.17
It is a recent idea, however, that molecules produced in or around fibroids
could be having an effect on blood vessel structure and function.18
bFGF is a protein that can play that role: It promotes angiogenesis or the
formation of new blood vessels through a number of mechanisms. It is also
a potential candidate for a role in the pathogenesis of these smooth-muscle-cell
tumors since it causes smooth-muscle-cell growth.
Laboratory studies have shown that bFGF appears to be overproduced and
stored in leiomyoma tissue.19 Additionally, a receptor for this
molecule is expressed at different times in the menstrual cycle in women
who have fibroid-related bleeding compared with normal women.20
Thus, for women with leiomyoma-related bleeding, this factor or its receptor
may be useful in targeting treatment.
One such treatment might be interferon- or interferon-ß. These
two classes of agents have been shown in a number of systems to oppose the
actions of bFGF. Studies specifically in leiomyoma cells in culture have
shown interferon- to decrease cellular proliferation.21 Although
trials in women have not been conducted, there is a case report of a woman
who received interferon for the treatment of hepatitis C and simultaneously
had dramatic shrinkage of a uterine leiomyoma.22 Most interesting,
however, was the fact that in this report the shrinkage was sustained for
up to 17 months after treatment, raising the possibility that treatment
effects might be maintained after therapy is discontinued.22
The future will bring us an understanding of the leiomyoma at the genetic
level. At least one gene has been identified that plays a role in myomas,
and through in vitro work in mice, we are beginning to understand the proper
vectors needed to deliver gene therapy to these tumors.23,24
Understanding the genetic contribution to these tumors may also identify
new target molecules for therapy.
New research inevitably leads to new potential treatments. Molecular
biology and molecular genetics particular to uterine leiomyomas are beginning
to uncover new potential targets for therapies. Newer therapies may dramatically
change our approach to these common tumors in the future.
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16. Murphy AA, Morales AJ,
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18. Stewart EA, Nowak RA. Leiomyoma-related
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M, et al. Isolation and characterization of heparin-binding growth factors
in human leiomyomas and normal myometrium. Biol Reprod. 1995;53:636-646.
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Quade BJ, et al. Expression of the fibroblast growth factor receptor in
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21. Lee BS, Stewart EA, Sahakian
M, et al. Interferon-alpha is a potent inhibitor of basic fibroblast growth
factor-stimulated cell proliferation in human uterine cells. Am J Reprod
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Tsujimura A, et al. Remarkable and persistent shrinkage of uterine leiomyoma
associated with interferon alfa treatment for hepatitis. Lancet.
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in uterine leiomyomata suggest dysregulation of this gene by a mechanism
different from that in lipomas. Genes Chromosomes Cancer. 1996;17:1-6.
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Dr. Stewart is Clinical Director, Center for Uterine Fibroids, Department
of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, Mass.,
and Assistant Professor of Obstetrics, Gynecology, and Reproductive Biology
at Harvard Medical School. Dr. Faur is formerly the research coordinator
at the Center for Uterine Fibroids and is currently a resident in Obstetrics
and Gynecology at Henry Ford Hospital, Detroit, Mich.
Dr. Stewart serves as a consultant to TAP pharmaceuticals.
Elizabeth Stewart, Adriana Faur. Cover Story: The future of fibroid therapy. Contemporary Ob/Gyn 2000;7:26-38.