Uterine leiomyomas, or fibroids, are the most common pelvic tumors in women. These smooth muscle cell tumors are associated with symptoms that include pelvic pain or pressure, excessive menstrual bleeding, infertility and spontaneous abortion. Leiomyomas appear to be estrogen/progesterone dependent but it is not clear how these ovarian steroids regulate their growth. Despite the fact that these tumors can grow quite rapidly, they display very low rates of mitotic activity. Fibroids are characterized by excessive amounts of extra-cellular matrix. The proposed research focuses on the regulation of extra-cellular matrix production in leiomyomas and normal myometrium by the ovarian steroids and the autocrine growth regulators, transforming growth factor-beta and parathyroid hormone-related peptide.
The specific aims of this proposal are: 1. To compare human uterine leiomyoma and myometrial expression of a) the extra-cellular matrix proteins collagen Type I, collagen Type III and fibronectin, and b) the matrix-degrading enzymes stromelysin and collagenase. 2. To determine whether expression of these extra-cellular matrix proteins and matrix-degrading enzymes in leiomyomas and myometrium is regulated by estrogen and/or progesterone. 3. To determine a) whether leiomyomas produce higher amounts of PTHrP and TGF-B than normal myometrium, and b) whether PTHrP and TGF-B regulate the production of extra-cellular matrix proteins or matrix-degrading enzymes. These studies should provide new information on the regulation of extra-cellular matrix production in both normal myometrium and leiomyomas. Overproduction or decreased degradation of certain extra-cellular matrix proteins by fibroids may account for much of their increase in size or """"""""growth"""""""". Overexpression of one or more of these matrix proteins by leiomyomas, enhanced responsiveness to the effects of estrogen/progesterone, or increased production of autocrine regulators such as PTHrP or TGF-B may be some of the mechanisms responsible for this excessive accumulation of matrix. The findings may facilitate developments in the clinical management of these common tumors.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD030496-03
Application #
2202823
Study Section
Biochemical Endocrinology Study Section (BCE)
Project Start
1992-09-30
Project End
1995-08-31
Budget Start
1993-09-01
Budget End
1995-08-31
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
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Stewart, E A; Rhoades, A R; Nowak, R A (1998) Leuprolide acetate-treated leiomyomas retain their relative overexpression of collagen type I and collagen type III messenger ribonucleic acid. J Soc Gynecol Investig 5:44-7
Anania, C A; Stewart, E A; Quade, B J et al. (1997) Expression of the fibroblast growth factor receptor in women with leiomyomas and abnormal uterine bleeding. Mol Hum Reprod 3:685-91

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