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.
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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.