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Department of Obstetrics and Gynecology, Kanazawa University School of Medicine, 13–1 Takaramachi, Kanazawa 920-0934, Japan
Address all correspondence and requests for reprints to: Makio Shozu, M.D., Ph.D., Department of Obstetrics and Gynecology, Kanazawa University School of Medicine, 13–1 Takaramachi, Kanazawa 920-0934, Japan. E-mail: shozu{at}med.kanazawa-u.ac.jp
In the present study we characterized in detail the expression of
aromatase P450 in leiomyomas to determine the role of in
situ estrogen in the growth advantage of leiomyomas. The levels
of aromatase P450 transcripts were determined by quantitative RT-PCR to
be significantly higher in leiomyomas than in corresponding myometrium.
The overexpression of aromatase P450 in leiomyomas was also confirmed
by Western blot analysis. The estimated size of immunoreactive
aromatase was 58 kDa, similar to that in placenta. To identify a cell
type that express aromatase P450 in leiomyomas, histological specimens
were stained for aromatase P450 using a polyclonal antibody. Strong
immunoreactivity was detected in the cytoplasm of leiomyoma cells,
whereas surrounding normal myometrium displayed weak or negative
staining. Smooth muscle-like cells in culture obtained from leiomyomas,
positive for actin D fiber, possessed immunoreactive granules of
aromatase in the cytoplasm. Conversion of androgen to estrogen was
effectively stimulated by phorbol myristate acetate and dexamethasone
plus interleukin-1ß and was completely abolished by selective
inhibitors of aromatase P450 (fadrozole and TZA-2209), but not by
inhibitors of 5
-reductase (finasteride and flutamide).
The apparent Km of androstenedione was 3 nM in
the presence of dexamethasone and interleukin-1ß, corresponding to
the plasma concentration of androstenedione in women of reproductive
age. To determine whether endogenous aromatase P450 plays a role in the
growth promotion of leiomyoma cells, we evaluated the cell growth of
smooth muscle-like cells treated with various concentrations of
estrogen and androgen using a WST-1 assay. Treatment with testosterone
(10-8 and 10-7 M) and
androstenedione (10-8 and 10-7 M)
stimulated the growth of smooth muscle-like cells obtained from
leiomyomas to the same extent as estradiol
(10-10–10-7 M), whereas
dihydrotestosterone (10-11–10-8
M) did not. The stimulatory effect of testosterone on cell
growth was again abolished by cotreatment with fadrozole. The level of
estradiol in the medium of testosterone (10-8
M)-treated smooth muscle-like cells was 10-11
M, which was 1 order lower than the minimum concentration
of estradiol necessary to promote cell growth (10-10
M). This indicates that estradiol synthesized in leiomyomas
promotes their growth via an autocrine/intracrine mechanism. We
conclude that myometrial cells of leiomyomas overexpress aromatase P450
and are able to synthesize sufficient estrogen to accelerate their own
cell growth. Overexpression of aromatase P450 may play a role in the
growth advantage of leiomyoma tissue over surrounding myometrium via an
autocrine/intracrine mechanism.
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