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Uterine Myomata (Fibroid Tumors) -
Myoma
Leiomyomata uteri are benign tumors of the muscular layers of the
uterus. They are a frequent cause of abnormal uterine bleeding and the leading indication given for
hysterectomy. Since they are estrogen dependent, they affect women of reproductive age
for the most part. There appears to be a genetic component, but the cause is unknown. The
relationship between myoma and infertility is not well defined, but there appears to be an
association with early fetal wastage. In addition to bleeding and infertility, myomata can
cause pelvic pain.
The estrogen dependence of leiomyomata has led to empirical treatment
with many of the same therapies as were mentioned above under endometriosis, including
progestins, danazol, and GnRH analogs to prevent or oppose the action of estrogen. However, the
long-term safety and efficacy of analogs have not been determined, the long-term
hypoestrogenic state raises the risk of osteoporosis, and the tumors regrow promptly upon
the cessation of treatment. For this reason, they are often used as an adjunct to facilitate
surgery, rather than as definitive therapy.
There is a great need for more knowledge about the process of myoma initiation and
growth. If safe, long-term medical therapies were developed based on solid scientific
rationales, thousands of women annually might be spared surgery, with resulting reduced
morbidity and preservation of fertility.
Fibroid tumor cells frequently have chromosomal abnormalities,
particularly chromosomal rearrangements in bands 12q13-15. Recently,
rearrangements disrupting a member of the high mobility group family of
proteins that are believed to play a role in controlling gene transcription were shown to be associated with mesenchymal tumors,
providing a potential molecular handle for studying the growth
abnormality in these cells. This interesting observation does not,
however, elucidate the proximate cause of the abnormal growth process
(1, 2). Deletions of the tandem 5(IV) and 6(IV) type IV collagen gene
located on the X chromosome were recently found to cause familial
systemic fibroid tumors, indicating that the matrix surrounding smooth
muscle cells can influence their proliferation (3). In addition,
abnormalities in programmed cell death have been described in fibroid
tumors. The observations provide a new framework through which abnormal
myometrial cell growth can be explored.
The growth of fibroid tumors has long been known to be under the
regulation of ovarian steroid hormones; tumor growth stops and tumors
regress after the menopause. Tumor size can be reduced by suppression of
pituitary gonadotropin secretion and hence ovarian function, but tumors
reappear after therapy is discontinued. The basis of the rapid recurrence of these tumors is not understood. Growth factors,
particularly the insulin-like growth factors (IGFs), have been
implicated in estrogen's action on fibroid growth, but the exact
interaction between estrogen and IGFs, as well as factors that modify
IGF action, and other growth factors remains to be clarified. Recently,
progestins and antiprogestins have been suggested to have therapeutic
effects. The appearance of fibroid tumors can be suppressed or delayed
by the intrauterine administration of a low dose of the progestin,
levonorgestrel, from a drug delivery system mounted on an intrauterine
device. The unexpected antimyoma effect is likely due to a direct local
effect of the progestin since cyclic ovarian function with continued
secretion of estradiol and progesterone occurs at the appropriate times
in each cycle in women using this device. This IUD is not only an excellent contraceptive but also provides the health benefits of reduced
formation of myomata and hypomenorrhea. These observations demonstrate
that increased knowledge of the mechanism of action of steroid hormones,
which are now appreciated to have tissue-specific effects, may open up
new avenues to medically treat fibroid tumors.
In order to provide a
basis for improved clinical treatments supporting the preservation of
fertility potential, the Reproductive Sciences Branch of the NICHD has
supported research to explore the fundamental biology of uterine myoma
both in vivo and in vitro. A transgenic animal in which myometrial tumor development is
regulated by estrogen was recently developed. The model was based on
targeting expression of an oncogenic protein to smooth muscle with a
gene promoter harboring an estrogen response element. This novel animal
may be useful in screening for candidate therapeutic agents to suppress
smooth muscle cell proliferation. These results add key knowledge to
that collected from the Ecker rat model, in which reproductive tract
fibroid tumors arise spontaneously in about 30% of animals greater than
1 year of age.
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