Uterine fibroids are common, benign tumors that cause considerable morbidity. Insights into the biologic and genetic mechanisms underlying these tumors at the cellular level are pointing the way to novel treatment approaches. The latest review in our Mechanisms of Disease series is on this topic.
Uterine fibroids (leiomyomas) represent the most common tumor in women. These lesions disrupt the functions of the uterus and cause excessive uterine bleeding, anemia, defective implantation of an embryo, recurrent pregnancy loss, preterm labor, obstruction of labor, pelvic discomfort, and urinary incontinence and may mimic or mask malignant tumors.
• How common are uterine fibroids, and how does presentation differ between black and white women?
By the time they reach 50 years of age, nearly 70% of white women and more than 80% of black women will have had at least one fibroid; severe symptoms develop in 15 to 30% of these women. Uterine fibroids in black women are significantly larger at diagnosis than those in white women, are diagnosed at an earlier age, and are characterized by more severe symptoms and a longer period of sustained growth.
• How does fibroid location impact clinical manifestations?
The location and size of the fibroid in the uterus are critical determinants of its clinical manifestations. As compared with other fibroids, submucous fibroids that extend into the uterine cavity are the most disruptive to endometrial integrity, implantation, and the capacity of the myometrium to contract and stop menstrual bleeding from the endometrial blood vessels; thus, even small submucous fibroids are associated with excessive or irregular bleeding, infertility, and recurrent pregnancy loss. In contrast, subserous fibroids that grow out into the peritoneal cavity can cause “bulk symptoms” only if they reach a certain size.
Morning Report Questions
Q: What are examples of genetic defects that are associated with uterine fibroids?
A: A limited number of genetic defects transmitted by germ cells have been associated with familial uterine fibroid syndromes. Most notable are germline mutations causing fumarate hydratase deficiency, which predisposes women to the development of multiple uterine fibroids. In addition, a variety of somatic chromosomal rearrangements have been described in up to 40% of uterine fibroids. Recently, a somatic single-gene defect was found in a majority of uterine fibroid tumors; this group of mutations affects the gene encoding mediator complex subunit 12 (MED12).
Q: What are the roles of estrogen and progesterone in the growth of uterine fibroids?
A: A large body of experimental data and circumstantial evidence suggests that estrogen stimulates the growth of uterine fibroids through estrogen receptor (alpha). The primary roles of estrogen and estrogen receptor (alpha) in fibroid growth are permissive in that they enable tissue to respond to progesterone by inducing the expression of progesterone receptor. Fibroid tissue is exposed to ovarian estrogen and to estrogen produced locally through the aromatase activity in fibroid cells. An in vivo model has revealed that progesterone and its receptor were essential and sufficient for tumor growth, as indicated by the stimulation of cell proliferation, the accumulation of extracellular matrix, and cellular hypertrophy. A number of clinical observations also support these findings. The use of progestins in hormone-replacement regimens stimulates the growth of fibroids in postmenopausal women in a dose-dependent manner, and the addition of progestins to GnRH agonists diminishes the inhibitory effects of these agonists on leiomyoma size.